Current Good Manufacturing Practice in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements, 34752-34958 [07-3039]
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34752
Federal Register / Vol. 72, No. 121 / Monday, June 25, 2007 / Rules and Regulations
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
21 CFR Part 111
[Docket No. 1996N–0417] (formerly Docket
No. 96N–0417)
RIN 0910–AB88
Current Good Manufacturing Practice
in Manufacturing, Packaging, Labeling,
or Holding Operations for Dietary
Supplements
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Final rule.
SUMMARY: The Food and Drug
Administration (FDA) is issuing a final
rule regarding current good
manufacturing practice (CGMP) for
dietary supplements. The final rule
establishes the minimum CGMPs
necessary for activities related to
manufacturing, packaging, labeling, or
holding dietary supplements to ensure
the quality of the dietary supplement.
The final rule is one of many actions
related to dietary supplements that we
are taking to promote and protect the
public health.
DATES: This rule is effective August 24,
2007.
Compliance Dates: The compliance
date is June 25, 2008; except that for
businesses employing fewer than 500,
but 20 or more full-time equivalent
employees, the compliance date is June
25, 2009; and except that for businesses
that employ fewer than 20 full-time
equivalent employees, the compliance
date is June 25, 2010.
FOR FURTHER INFORMATION CONTACT:
Vasilios H. Frankos, Center for Food
Safety and Applied Nutrition (HFS–
810), Food and Drug Administration,
5100 Paint Branch Pkwy., College Park,
MD 20740, 301–436–1696.
SUPPLEMENTARY INFORMATION:
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Table of Contents
I. Background and Related Information
II. How is the Final Rule Organized?
III. What Does the Final Rule Do?
A. Overview of CGMP
B. Highlights of the Final Rule
IV. What General Comments Did We
Receive?
A. What Comments Did We Receive
on the Structure and Organization
of the Rule?
B. What Comments Did We Receive
on the Need for Dietary Supplement
CGMP Requirements?
C. What Comments Did We Receive
on Written Procedures?
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1. Overview
2. Written Procedures That Are
Required by This Final Rule
3. Written Procedures That Are Not
Required by This Final Rule
D. Other Comments on Written
Procedures
E. What Other General Comments Did
We Receive?
V. What Legal Authority Comments Did
We Receive?
A. Modeled After CGMP for Food
B. Records Authority
C. Public Health Service Act
Authority
1. The Communicable Disease Risk
Posed by Dietary Supplements
2. Activities For Which We Are
Asserting Legal Authority Under
the PHS Act
D. The Interstate Commerce Nexus for
the Final Rule
1. The PHS Act
2. The Act
3. Commerce Clause
E. Fifth Amendment
F. Miscellaneous
VI. What Comments Did We Receive on
the General Provisions? (Subpart A)
A. Organization of Final Subpart A
B. Who Is Subject to This Part? (Final
§ 111.1)
C. What Definitions Apply to This
Part? (Final § 111.3)
1. Actual Yield
2. Batch
3. Batch Number, Lot Number, or
Control Number
4. Component
5. Contact Surface
6. Ingredient
7. In-Process Material
8. Lot
9. Microorganisms
10. Must
11. Pest
12. Physical Plant
13. Product Complaint
14. Quality
15. Quality Control
16. Quality Control Personnel
17. Representative Sample
18. Reprocessing
19. Reserve Sample
20. Sanitize
21. Theoretical Yield
22. Water Activity
23. We
24. You
25. What Other Terms Did the
Comments Want Defined?
26. What Definitions Did the
Comments Want Us to Delete?
D. Do Other Statutory Provisions and
Regulations Apply? (Final § 111.5)
E. What Sections Did We Remove
From the Rule, and Why?
1. ‘‘What Are These Regulations
Intended to Accomplish?’’
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(Proposed § 111.2)
2. ‘‘Exclusions’’ (Proposed § 111.6)
VII. Comments on Personnel (Final
Subpart B)
A. Organization of Final Subpart B
B. Highlights of Changes to the
Proposed Requirements for
Personnel
1. Revisions
2. Changes After Considering
Comments
C. General Comments on Proposed
Subpart B
D. What Are the Requirements Under
This Subpart for Written
Procedures? (Final § 111.8)
E. What Requirements Apply for
Preventing Microbial
Contamination From Sick or
Infected Personnel and for Hygienic
Practices? (Final § 111.10)
1. Final § 111.10(a)
2. Final § 111.10(b)
F. What Personnel Qualification
Requirements Apply? (Final
§ 111.12)
G. What Supervisor Requirements
Apply? (Final § 111.13)
H. Under This Subpart, What Records
Must You Make and Keep? (Final
§ 111.14)
VIII. Comments on Physical Plant and
Grounds (Final Subpart C)
A. Organization of Final Subpart C
B. Highlights of Changes to the
Proposed Requirements for Physical
Plant and Grounds
1. Revisions
2. Changes After Considering
Comments
C. General Comments on Proposed
Subpart C
D. What Sanitation Requirements
Apply to Your Physical Plant and
Grounds? (Final § 111.15)
1. Final § 111.15(a)
2. Final § 111.15(b)(1)
3. Final § 111.15(c)
4. Final § 111.15(d)
5. Final § 111.15(e)
6. Final § 111.15(f)
7. Final § 111.15(g)
8. Final § 111.15(h)
9. Final § 111.15(i)
10. Final § 111.15(j)
11. Final § 111.15(k)
E. What Are the Requirements Under
This Subpart for Written
Procedures? (Final § 111.16)
F. What Design and Construction
Requirements Apply to Your
Physical Plant? (Final § 111.20)
1. Final § 111.20(a) and (b)
2. Final § 111.20(c)
3. Final § 111.20(d)
4. Final § 111.20(e)
5. Final § 111.20(f)
6. Final § 111.20(g)
7. Final § 111.20(h)
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G. Under This Subpart, What Records
Must You Make and Keep? (Final
§ 111.23)
IX. Comments on Requirements Related
to Equipment and Utensils (Subpart D)
A. Organization of Final Subpart D
B. Highlights of Changes to the
Proposed Requirements for
Equipment and Utensils
1. Revisions
2. Revisions Associated With the
Reorganization
3. Changes After Considering
Comments
C. General Comments on Proposed
Subpart D
D. What Are the Requirements Under
This Subpart for Written
Procedures? (Final § 111.25)
E. What Requirements Apply to the
Equipment and Utensils That You
Use? (Final § 111.27)
1. Final 111.27(a)
2. Final § 111.27(b)
3. Final § 111.27(c)
4. Final § 111.27(d)
F. Reorganization of Certain
Paragraphs in Proposed § 111.25
G. What Requirements Apply to
Automated, Mechanical, or
Electronic Equipment? (Final
§ 111.30)
1. Comments on the Organization and
Framework of Proposed § 111.30
2. Comments Specific to Proposed
§ 111.30
3. Reorganization of Certain
Paragraphs in Proposed § 111.30
H. Under This Subpart, What Records
Must You Make and Keep? (Final
§ 111.35)
1. Final § 111.35(a)
2. Final § 111.35(b)(1) and (b)(2)
3. Final § 111.35(b)(3)
4. Final § 111.35(b)(4)
5. Final § 111.35(b)(5)
6. Final § 111.35(b)(6)
X. Comments on Requirement to
Establish a Production and Process
Control System (Final Subpart E)
A. Reorganization of Proposed
§ 111.35 Into Final Subpart E
B. General Comments on Proposed
§ 111.35
C. Final Subpart E and Highlights of
Changes to the Proposed
Regulations
D. What Are the Requirements to
Implement a Production and
Process Control System? (Final
§ 111.55)
E. What Are the Design Requirements
for the Production and Process
Control System? (Final § 111.60)
F. What Are the Requirements for
Quality Control Operations? (Final
§ 111.65)
G. What Specifications Must You
Establish? (Final § 111.70)
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1. Final § 111.70(a)
2. Final § 111.70(b)
3. Final § 111.70(c)
4. Final § 111.70(d)
5. Final § 111.70(e)
6. Final § 111.70(f)
7. Final § 111.70(g)
H. What is Your Responsibility for
Determining Whether Established
Specifications Are Met? (Final
§ 111.73)
I. What Must You Do to Determine
Whether Specifications Are Met?
(Final § 111.75)
1. Final § 111.75(a)
2. Final § 111.75(b)
3. Final § 111.75(c) and (d)
4. Final § 111.75(e)
5. Final § 111.75(f)
6. Final § 111.75(g)
7. Final § 111.75(h)
8. Final § 111.75(i)
J. What Must You Do if Established
Specifications Are Not Met? (Final
§ 111.77)
1. Final § 111.77
2. Final § 111.77(a)
3. Final § 111.77(b)
4. Final § 111.77(c)
K. Comments on Shelf Life
L. What Representative Samples Must
You Collect? (Final § 111.80)
1. Final § 111.80(a)
2. Final § 111.80(b)
3. Final § 111.80(c)
4. Final § 111.80(d)
5. Final § 111.80(e)
M. What Are the Requirements for
Reserve Samples? (Final § 111.83)
1. Final § 111.83(a)
2. Final § 111.83(b)(1)
3. Final § 111.83(b)(2)
4. Final § 111.83(b)(3)
5. Final § 111.83(b)(4)
N. Who Conducts a Material Review
and Makes a Disposition Decision?
(Final § 111.87)
O. What Requirements Apply to
Treatments, In-Process
Adjustments, and Reprocessing
When There is a Deviation or
Unanticipated Occurrence or When
a Specification Established in
Accordance With § 111.70 Is Not
Met? (Final § 111.90)
1. Final § 111.90
2. Final § 111.90(a)
3. Final § 111.90(b)
4. Final § 111.90(c)
P. Under This Subpart, What Records
Must You Make and Keep? (Final
§ 111.95)
1. Final § 111.95(a)
2. Final § 111.95(b)
XI. Comments on Requirements for
Quality Control (Final Subpart F)
A. Organization of Final Subpart F
B. Highlights of Changes to the
Proposed Requirements for Quality
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Control Operations
1. Revisions
2. Changes Associated With the
Reorganization
3. Changes After Considering
Comments
C. General Comments on Proposed
§ 111.37 (Final Subpart F)
D. What Are the Requirements Under
This Subpart for Written
Procedures? (Final § 111.103)
E. What Must Quality Control
Personnel Do? (Final § 111.105)
1. Final § 111.105(a)
2. Final § 111.105(b), (c), (d), and (e)
3. Final § 111.105(f)
4. Final § 111.105(g)
5. Final § 111.105(h)
6. Final § 111.105(i)
F. What Quality Control Operations
Are Required for Laboratory
Operations Associated With the
Production and Process Control
System? (Final § 111.110)
1. Final § 111.110(a)
2. Final § 111.110(b)
3. Final § 111.110(c)
G. What Quality Control Operations
Are Required for a Material Review
and Disposition Decision? (Final
§ 111.113)
1. Final § 111.113(a)
2. Final § 111.113(b)
3. Final § 111.113(c)
H. What Quality Control Operations
Are Required for Equipment,
Instruments, and Controls? (Final
§ 111.117)
1. Final § 111.117(a) through (c)
2. Final § 111.117(d)
I. What Quality Control Operations
Are Required for Components,
Packaging, and Labels Before Use in
the Manufacture of a Dietary
Supplement? (Final § 111.120)
1. Final § 111.120(a)
2. Final § 111.120(b)
3. Final § 111.120(c)
4. Final § 111.120(d)
5. Final § 111.120(e)
J. What Quality Control Operations
Are Required for the Master
Manufacturing Record, the Batch
Production Record, and
Manufacturing Operations? (Final
§ 111.123)
1. Final § 111.123(a)(1)
2. Final § 111.123(a)(2)
3. Final § 111.123(a)(3)
4. Final § 111.123(a)(4)
5. Final § 111.123(a)(5)
6. Final § 111.123(a)(6)
7. Final § 111.123(a)(7)
8. Final § 111.123(a)(8)
9. Final § 111.123(b)
K. What Quality Control Operations
Are Required for Packaging and
Labeling Operations? (Final
§ 111.127)
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1. Final § 111.127(a) and (b)
2. Final § 111.127(c)
3. Final § 111.127(d)
4. Final § 111.127(e)
5. Final § 111.127(f) and (g)
6. Final § 111.127(h)
L. What Quality Control Operations
Are Required for Returned Dietary
Supplements? (Final § 111.130)
1. Final § 111.130(a)
2. Final § 111.130(a)(1) and (a)(2)
3. Final § 111.130(b)
4. Final § 111.130(c)
5. Final § 111.130(d)
M. What Quality Control Operations
Are Required for Product
Complaints? (Final § 111.135)
N. What Records Must You Make and
Keep? (Final § 111.140)
1. Final § 111.140(a)
2. Final § 111.140(b)(1)
3. Final § 111.140(b)(2)
4. Final § 111.140(b)(3)
XII. Comments on the Production and
Process Control System: Requirements
for Components, Packaging, and Labels,
and for Product That You Receive for
Packaging or Labeling as a Dietary
Supplement (Final Subpart G)
A. Organization of Final Subpart G
B. Highlights of Changes to the
Proposed Requirements for
Components, Packaging, and
Labels, and Product That You
Receive for Packaging or Labeling as
a Dietary Supplement
1. Revisions
2. Changes After Considering
Comments
C. General Comments on Proposed
§ 111.40 (Final Subpart G)
D. What Are the Requirements Under
This Subpart for Written
Procedures? (Final § 111.153)
E. What Requirements Apply to
Components of Dietary
Supplements? (Final § 111.155)
1. Proposed § 111.35(d)
2. Final § 111.155(a)
3. Final § 111.155(b)
4. Final § 111.155(c)
5. Final § 111.155(d)
6. Final § 111.155(e)
F. What Requirements Apply to
Packaging and Labels Received?
(Final § 111.160)
1. Final § 111.160(a)
2. Final § 111.160(b)
3. Final § 111.160(c)
4. Final § 111.160(d)
5. Final § 111.160(e)
G. What Requirements Apply to a
Product Received for Packaging or
Labeling as a Dietary Supplement
(and for distribution rather than for
return to the supplier)? (Final
§ 111.165)
1. Final § 111.165(a)
2. Final § 111.165(b)
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3. Final § 111.165(c)
4. Final § 111.165(d)
5. Final § 111.165(e)
H. What Requirements Apply to
Rejected Components, Packaging,
and Labels, and to Rejected
Products That Are Received for
Packaging or Labeling as a Dietary
Supplement? (Final § 111.170)
I. Under This Subpart, What Records
Must You Make and Keep? (Final
§ 111.180)
1. Final § 111.180(a)
2. Final § 111.180(b)(1)
3. Final § 111.180(b)(2)
4. Final § 111.180(b)(3)
XIII. Comments on the Production and
Process Control System: Requirements
for the Master Manufacturing Record
(Final Subpart H)
A. Organization of Final Subpart H
B. Highlights of Changes to the
Proposed Requirements for the
Master Manufacturing Record
1. Revisions
2. Changes Associated With the
Reorganization
3. Changes After Considering
Comments
C. General Comments on Proposed
§ 111.45 (Final Subpart H)
1. Comments on Written Procedures
2. Comments That Support Proposed
§ 111.45
D. What Is the Requirement to
Establish a Master Manufacturing
Record? (Final § 111.205)
1. Final § 111.205(a)
2. Final § 111.205(b)(1)
3. Final § 111.205(b)(2)
4. Final § 111.205(c)
E. What Must the Master
Manufacturing Record Include?
(Final § 111.210)
1. Final § 111.210(a)
2. Final § 111.210(b)
3. Final § 111.210(c)
4. Final § 111.210(d)
5. Final § 111.210(e)
6. Final § 111.210(f)
7. Final § 111.210(g)
8. Final § 111.210(h)(1)
9. Final § 111.210(h)(2)
10. Final § 111.210(h)(3)
11. Final § 111.210(h)(4)
12. Final § 111.210(h)(5)
F. Quality Control Responsibility
(Proposed § 111.45(c))
XIV. Comments on the Production and
Process Control System: Requirements
for the Batch Production Record (Final
Subpart I)
A. Organization of Final Subpart I
B. Highlights of Changes to the
Proposed Requirements for the
Batch Production Record
1. Revisions
2. Changes Associated With the
Reorganization
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3. Changes After Considering
Comments
C. What Is the Requirement to
Establish a Batch Production
Record? (Final § 111.255)
D. What Must the Batch Record
Include? (Final § 111.260)
1. Final § 111.260(a)
2. Final § 111.260(b)
3. Final § 111.260(c)
4. Final § 111.260(d)
5. Final § 111.260(e) and (f)
6. Final § 111.260(g)
7. Final § 111.260(h)
8. Final § 111.260(i)
9. Final § 111.260(j)
10. Final § 111.260(k)
11. Final § 111.260(l)
12. Final § 111.260(m)
13. Final § 111.260(n)
E. Review of Batch Production Record
Deviations (Proposed § 111.50(d)(1),
(e)(2), (e)(3), and (e)(4))
XV. Comments on Production and
Process Control System: Requirements
for Laboratory Operations (Final
Subpart J)
A. Organization of Final Subpart J
B. Highlights of the Changes to the
Proposed Requirements for
Laboratory Operations
1. Revisions
2. Changes Associated With the
Reorganization
3. Changes After Considering
Comments
C. What Are the Requirements Under
This Subpart for Written
Procedures? (Final § 111.303)
D. What Are the Requirements for the
Laboratory Facilities That You Use?
(Final § 111.310)
E. What Are the Requirements for
Laboratory Control Processes?
(Final § 111.315)
1. Final § 111.315(a)
2. Final § 111.315(b)
3. Final § 111.315(c)
4. Final § 111.315(d)
5. Final § 111.315(e)
F. What Requirements Apply to
Laboratory Methods for Testing and
Examination? (Final § 111.320)
1. Final § 111.320(a)
2. Final § 111.320(b)
G. Appropriate Test Method
Validation (Proposed
§ 111.60(b)(1)(v))
H. Under This Subpart, What Records
Must You Make and Keep? (Final
§ 111.325)
1. Final § 111.325(a)
2. Final § 111.325(b)(1)
3. Final § 111.325(b)(2)
XVI. Comments on the Production and
Process Control System: Requirements
for Manufacturing Operations (Final
Subpart K)
A. Organization of Final Subpart K
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B. Highlights of Changes to the
Proposed Requirements for
Manufacturing Operations
1. Revisions
2. Changes Made After Considering
Comments
3. Revisions Associated With the
Reorganization
C. General Comments on
Manufacturing Operations
D. What Are the Requirements Under
This Subpart for Written
Procedures? (Final § 111.353)
E. What Are the Design Requirements
for Manufacturing Operations?
(Final § 111.355)
F. What Are the Requirements for
Sanitation? (Final § 111.360)
G. What Precautions Must You Take
to Prevent Contamination? (Final
§ 111.365)
1. Final § 111.365(a)
2. Final § 111.365(b)
3. Final § 111.365(c)
4. Final § 111.365(d)
5. Final § 111.365(e)
6. Final § 111.365(f)
7. Final § 111.365(g)
8. Final § 111.365(h)
9. Final § 111.365(i)
10. Final § 111.365(j)
11. Final § 111.365(k)
H. What Requirements Apply to
Rejected Dietary Supplements?
(Final § 111.370)
I. Under This Subpart, What Records
Must You Make and Keep? (Final
§ 111.375)
XVII. Comments on the Production and
Process Control System: Requirements
for Packaging and Labeling Operations
(Final Subpart L)
A. Organization of Final Subpart L
B. Highlights of Changes to the
Proposed Requirements for
Packaging and Labeling Operations
1. Revisions
2. Changes Associated With the
Reorganization
3. Changes After Considering
Comments
C. General Comments on Proposed
Requirements for Packaging and
Labeling Operations
D. General Comments on
Requirements for What Must Be on
the Product Label Rather Than for
Labeling Operations
E. What Are the Requirements Under
This Subpart for Written
Procedures? (Final § 111.403)
F. What Requirements Apply to
Packaging and Labels? (Final
§ 111.410)
1. Final § 111.410(a)
2. Final § 111.410(b)
3. Final § 111.410(c)
4. Final § 111.410(d)
G. What Requirements Apply to
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Filling, Assembling, Packaging,
Labeling, and Related Operations?
(Final § 111.415)
H. What Requirements Apply to
Repackaging and Relabeling? (Final
§ 111.420)
1. Final § 111.420(a)
2. Final § 111.420(b) and (c)
I. What Requirements Apply to a
Packaged and Labeled Dietary
Supplement That Is Rejected for
Distribution? (Final § 111.425)
J. Under this Subpart, What Records
Must You Make and Keep? (Final
§ 111.430)
1. Final § 111.430(a)
2. Final § 111.430(b)
XVIII. Comments on Holding and
Distributing (Final Subpart M)
A. Organization of Final Subpart M
B. Highlights of Changes to the
Proposed Requirements for Holding
and Distributing
1. Revisions
2. Changes Associated With the
Reorganization
3. Changes After Considering
Comments
C. General Comments on Proposed
§§ 111.80, 111.82, 111.83, and
111.85
D. What Are the Requirements Under
This Subpart for Written
Procedures? (Final § 111.453)
E. What Requirements Apply to
Holding Components, Dietary
Supplements, Packaging, and
Labels? (Final § 111.455)
1. Final § 111.455(a)
2. Final § 111.455(b)
3. Final § 111.455(c)
F. What Requirements Apply to
Holding In-Process Material? (Final
§ 111.460)
1. Final § 111.460(a)
2. Final § 111.460(b)
G. Proposed Requirement for Holding
Reserve Samples of Components
(Proposed § 111.83(a))
H. What Requirements Apply to
Holding Reserve Samples of Dietary
Supplements? (Final § 111.465)
1. Final § 111.465(a)
2. Final § 111.465(b)
I. What Requirements Apply to
Distributing Dietary Supplements?
(Final § 111.470)
J. Under This Subpart, What Records
Must You Make and Keep? (Final
§ 111.475)
XIX. Comments on Returned Dietary
Supplements (Final Subpart N)
A. Organization of Final Subpart N
B. Highlights of Changes to the
Proposed Requirements for
Returned Dietary Supplements
1. Revisions
2. Changes After Considering
Comments
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C. General Comments on Proposed
§ 111.85
D. What Are the Requirements Under
This Subpart for Written
Procedures? (Final § 111.503)
E. What Requirements Apply When a
Returned Dietary Supplement is
Received? (Final § 111.510)
F. When Must a Returned Dietary
Supplement be Destroyed, or
Otherwise Suitably Disposed Of?
(Final § 111.515)
G. When May a Returned Dietary
Supplement Be Salvaged? (Final
§ 111.520)
H. What Requirements Apply to a
Returned Dietary Supplement That
Quality Control Personnel Approve
for Reprocessing? (Final § 111.525)
I. When Must an Investigation Be
Conducted of Your Manufacturing
Processes and Other Batches? (Final
§ 111.530)
J. Under This Subpart, What Records
Must You Make and Keep? (Final
§ 111.535)
1. Final § 111.535(a)
2. Final § 111.535(b)(1)
3. Final § 111.535(b)(2)
4. Final § 111.535(b)(3)
5. Final § 111.535(b)(4)
XX. Comments on Product Complaints
(Final Subpart O)
A. Organization of Final Subpart O
B. Highlights of Changes to the
Proposed Requirements for Product
Complaints
1. Revisions
2. Changes After Considering
Comments
C. General Comments on Proposed
§ 111.95 (Final Subpart O)
D. What Are the Requirements Under
This Subpart for Written
Procedures? (Final § 111.553)
E. What Requirements Apply to the
Review and Investigation of a
Product Complaint? (Final
§ 111.560)
1. Final § 111.560(a)(1)
2. Final § 111.560(a)(2), (b), and (c)
F. Under This Subpart, What Records
Must You Make and Keep? (Final
§ 111.570)
1. Final § 111.570(a)
2. Final § 111.570(b)(1)
3. Final § 111.570(b)(2)
4. Final § 111.570(b)(2)(i)
5. Final § 111.570(b)(2)(ii)
XXI. Comments on Records and
Recordkeeping (Final Subpart P)
A. Organization of Final Subpart P
B. Highlights of Changes to the
Proposed Requirements for Records
and Recordkeeping
1. Revisions
2. Changes After Considering
Comments
C. General Comments on Proposed
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§ 111.125
D. What Requirements Apply to the
Records That You Make and Keep?
(Final § 111.605)
1. Final § 111.605(a)
2. Final § 111.605(b)
3. Final § 111.605(c)
E. What Records Must Be Made
Available to FDA? (Final § 111.610)
1. Final § 111.610(a)
2. Final § 111.610(b)
XXII. Other Comments and
Miscellaneous
A. Comments on Guidance
Documents To Be Used With the
Final Rule
B. Comments on Consideration for
Other CGMP Programs
C. Comments on Public Involvement
D. Comments on Implementation and
Enforcement
E. Removal of References to Part 112
XXIII. Paperwork Reduction Act of 1995
XXIV. Analysis of Impacts
A. Introduction
1. Summary of the Economic Analysis
2. Summary of Comments on the
Economic Analysis
B. Final Regulatory Impact Analysis
1. The Need for the Final Current
Good Manufacturing Practice Rule
2. Regulatory Options
3. Coverage of the Final Rule
4. Baseline Practices
5. Baseline Risk
6. Benefits
7. Costs
8. Summary of Benefits and Costs
9. Benefits and Costs of Regulatory
Options
10. Cost Effectiveness Analysis
11. Uncertainties in the Analysis
C. Final Regulatory Flexibility
Analysis
1. Introduction
2. Economic Effects on Small Entities
3. Regulatory Options
4. Description of Recordkeeping and
Reporting
5. Summary
D. Unfunded Mandates
XXV. Analysis of Environmental Impact
XXVI. Federalism
XXVII. References
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I. Background and Related Information
On October 25, 1994, the Dietary
Supplement Health and Education Act
(DSHEA) (Public Law 103–417) was
signed into law. DSHEA, among other
things, amended the Federal Food,
Drug, and Cosmetic Act (the act) by
adding section 402(g) of the act (21
U.S.C. 342(g)). Section 402(g)(2) of the
act provides, in part, that the Secretary
of Health and Human Services (the
Secretary) may, by regulation, prescribe
good manufacturing practices for dietary
supplements. Section 402(g) of the act
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also stipulates that such regulations
shall be modeled after CGMP
regulations for food and may not impose
standards for which there are no current
and generally available analytical
methodology. The final rule establishes,
in part 111 (21 CFR part 111), the
minimum CGMPs necessary for
activities related to manufacturing,
packaging, labeling, or holding dietary
supplements to ensure the quality of the
dietary supplement. The final rule is
one of many actions related to dietary
supplements that we are taking to
promote and protect the public health.
In response to DSHEA, we issued an
Advance Notice of Proposed
Rulemaking (the 1997 ANPRM) in the
Federal Register of February 6, 1997 (62
FR 5700). The 1997 ANPRM contained
a CGMP outline submitted to us on
November 20, 1995, by representatives
of the dietary supplement industry. The
1997 ANPRM also asked nine questions
that addressed issues that the industry
outline did not. For example, we asked
if there is a need to develop specific
defect action levels (DALs) for dietary
ingredients. We also asked whether a
CGMP rule should require
manufacturers to establish procedures to
document, on a continuing or daily
basis, that they followed pre-established
procedures for making dietary
supplements.
We received more than 100 comments
in response to the 1997 ANPRM. We
evaluated these comments before we
drafted and ultimately issued a
proposed rule on CGMPs for dietary
ingredients and dietary supplements
(which we discuss later in this section
of this document).
Additionally, during 1999, we
conducted a number of outreach
activities related to dietary
supplements. We held several public
meetings to develop our overall strategy
for achieving effective regulation of
dietary supplements, which could
include establishing CGMP regulations.
We also held public meetings focused
specifically on CGMPs and the
economic impact that any CGMP rule
for dietary ingredients and dietary
supplements might have on small
businesses. Further, we toured several
dietary supplement manufacturing
facilities to better understand the
manufacturing processes and practices
that potentially would be subject to
CGMP requirements for dietary
ingredients and dietary supplements
(Refs. 1 through 6). These activities
contributed to our knowledge about the
industry.
In the Federal Register of March 13,
2003 (68 FR 12157), we published a
proposed rule to establish CGMP
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requirements for dietary ingredients and
dietary supplements (the 2003 CGMP
Proposal). The preamble to the 2003
CGMP Proposal addressed the
comments we had received regarding
the nine questions in the 1997 ANPRM,
discussed our legal authority to issue a
CGMP rule, and described the basis for
each proposed requirement.
The 2003 CGMP Proposal specifically
requested comment on a variety of
areas, including the need for written
procedures and recordkeeping
requirements. Although the proposed
rule’s comment period was scheduled to
end on June 11, 2003, in the Federal
Register of May 19, 2003 (68 FR 27008),
we extended the comment period to
August 11, 2003.
After we published the proposed rule,
we conducted and/or participated in
outreach activities related to dietary
supplements and dietary ingredients.
We held public stakeholder meetings on
April 29, 2003, in College Park, MD, and
on May 6, 2003, in Oakland, CA. We
also held a public meeting, via satellite
downlink, on May 9, 2003, with viewing
sites at our district and regional offices
throughout the country. These public
meetings gave an overview of the
proposed rule, and clarified specific
points in the proposed rule. Since the
public stakeholder meetings held as part
of our outreach efforts, we also have
participated in several meetings with
industry and other interested parties
which are reflected in the public docket.
We received approximately 400
comments in response to the proposal.
The comments came from trade
associations, government organizations
and officials, manufacturers of dietary
supplements and dietary ingredients,
health care practitioners, consumer
groups, and individuals. In general, the
comments supported the idea of
CGMPs, although many comments
disagreed with specific aspects of the
proposal.
Published elsewhere in this issue of
the Federal Register we are also issuing
an interim final rule that sets forth a
procedure for requesting an exception to
a CGMP requirement in this final rule.
The interim final rule allows for
submission to, and review by, FDA of an
alternative to the required 100-percent
identity testing of components that are
dietary ingredients (as discussed in
section X of this document (subpart E)),
provided certain conditions are met.
The interim final rule also includes a
requirement for retention of records
related to the FDA grant of an exception
request.
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II. How is the Final Rule Organized?
The 2003 CGMP Proposal was divided
into eight subparts, with each subpart
devoted to a particular topic. For
example, proposed subpart A was titled
‘‘General Provisions’’ and contained
sections describing the rule’s scope,
purpose, definitions, applicability of
other statutory and regulatory
provisions, and exclusions. As another
example, proposed subpart B was titled
‘‘Personnel’’ and described microbial
contamination and hygiene
requirements, personnel qualification
requirements, and supervisor
requirements.
In response to comments seeking a
simpler, more ‘‘user-friendly’’ final rule
or seeking clarification of the rule’s
applicability to certain persons, items,
or activities, and to reduce redundant
provisions or combine similar
provisions, we have reorganized the
final rule into 16 subparts, with new
subparts focusing on specific aspects of
the manufacturing process or addressing
specific issues. For example, the
proposed rule placed all production and
34757
process control requirements for
manufacturing, packaging, labeling, and
laboratory operations in a single subpart
(proposed subpart E). The final rule
creates separate subparts for the specific
operations to make it easier to find the
relevant production and process control
requirements for a particular activity.
Table 1 of this document summarizes
how we reorganized the rule. We are
providing this information to help
readers understand the structural
changes we made between the proposed
and final rules.
TABLE 1.—REORGANIZATION AND REVISIONS: 2003 CGMP PROPOSAL AND FINAL RULE
Proposed Sections
in the Subpart
Proposed Subpart and Title
A—General Provisions
Final Subpart
and Title
111.1
111.2
111.3
111.5
111.6
Final Sections
in the Subpart
A—General Provisions
111.1
111.3
111.5
111.10
111.12
111.13
B—Personnel
111.8 (new)
111.10
111.12
111.13
111.14 (new)
C—Physical Plant
111.15
111.20
C—Physical Plant and
Grounds
111.15
111.16 (new)
111.20
111.23 (formerly proposed
§ 111.15(d)(3) and (e)(2))
D—Equipment and Utensils
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B—Personnel
111.25
111.30
D—Equipment and Utensils
111.25 (formerly proposed
§ 111.25(c)(1) and (e)(1))
111.27 (formerly proposed
§ 111.25 (a), (b), (d)1, and (e))
111.30
111.35 (formerly proposed
§§ 111.25 (c)(1), (c)(2), (d), (f),
111.30(b)(2), (b)(5), and (c),
111.50(c)(4))
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TABLE 1.—REORGANIZATION AND REVISIONS: 2003 CGMP PROPOSAL AND FINAL RULE—Continued
Proposed Sections
in the Subpart
Proposed Subpart and Title
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E—Production and Process Controls
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Final Subpart
and Title
111.35
111.37
111.40
111.45
111.50
111.60
111.65
111.70
111.74
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Final Sections
in the Subpart
E—Requirement to Establish
a Production and Process
Control System
111.55 (formerly proposed
§ 111.35(a))
111.60 (formerly proposed
§ 111.35(b))
111.65 (formerly proposed
§ 111.35(c))
111.70 (formerly proposed
§ 111.35(e), (f), (g), and (k))
111.73 (formerly proposed
§ 111.35(f), (g), and (h)
111.75 (formerly proposed
§ 111.35(e) through (i), (k), and
(l)), § 111.37(b)(11(iv), and
§ 111.40(a)(2)
111.77 (new)
111.80 (formerly proposed
§ 111.37(b)(11))
111.83 (formerly proposed
§§ 111.37(b)(12), 111.50(h), and
111.83(b)(2))
111.87 (formerly proposed
§§ 111.35(i) and (n), 111.37(b)(5)
and (b)(14), 111.40(a)(3),
111.50(d)(1), and 111.85(a) and
(c))
111.90 (formerly proposed
§§ 111.35(i)(4), 111.50(d)(1), (f),
and (g), and 111.65(d))
111.95 (formerly proposed
§ 111.35(o))
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TABLE 1.—REORGANIZATION AND REVISIONS: 2003 CGMP PROPOSAL AND FINAL RULE—Continued
Proposed Sections
in the Subpart
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111.103 (new)
111.105 (formerly proposed
§ 111.37(a), (b)(1), (b)(11), and
(b)(12))
111.110 (formerly proposed
§ 111.37(b)(9) and (b)(13))
111.113 (formerly proposed
§§ 111.35(i)(2), (i)(3), (i)(4)(i),
(i)(4)(ii), (j), and (n), 111.37(b)(3)
and (c), 111.40(a)(3) and (b)(2),
111.50(d)(1), 111.65(d), and
111.70(c))
111.117 (formerly proposed
§§ 111.30(b)(4) and 111.37(b)(6)
through (b)(8))
111.120 (formerly proposed
§§ 111.35(i)(4)(i) and (i)(4)(ii),
111.37(b)(2) and (b)(10),
111.40(a)(3) and (b)(2), and
111.50(e)(1))
111.123 (formerly proposed
§§ 111.35(e)(2), (f), (i)(2), and
(o)(2) 111.37(a), (b)(2), (b)(4),
(b)(5), and (b)(11), 111.45(c),
and 111.50(d)(1), (d)(2), and (g))
111.127 (formerly proposed
§§ 111.37(b)(2), (b)(10), and
(b)(11), 111.40(a)(2) and (a)(3),
and 111.70(c), (d) and (e))
111.130 (formerly proposed
§§ 111.37(b)(2) and (b)(15), and
111.85(a))
111.135 (new)
111.140 (formerly proposed
§§ 111.35(j) and 111.37(c) and
(d)
111.153 (new)
111.155 (formerly proposed
§§ 111.35(d)(1) through (d)(5)
and 111.40(a)(1) through (a)(5))
111.160 (formerly proposed
§§ 111.35(e)(4), and 111.40(a)(2)
and (b)(1) through (b)(4))
111.165 (formerly proposed
§ 111.40(a)(1) through (a)(5))
111.170 (formerly proposed
§ 111.74)
111.180 (formerly proposed
§§ 111.35(d)(4), and
111.40(c)(1)(i) through (c)(1)(iv)
and (c)(2))
H—Production and Process
Control System: Requirements for the Master Manufacturing Record
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Final Sections
in the Subpart
G—Production and Process
Control System: Requirements for Components,
Packaging, and Labels and
for Product That You Receive for Packaging or Labeling a Dietary Supplement
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Final Subpart
and Title
F—Production and Process
Control System: Requirements for Quality Control
Proposed Subpart and Title
111.205 (formerly proposed
§ 111.45(a)(1), (a)(2), and (d))
111.210 (formerly proposed
§ 111.45(b))
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TABLE 1.—REORGANIZATION AND REVISIONS: 2003 CGMP PROPOSAL AND FINAL RULE—Continued
Proposed Sections
in the Subpart
Final Subpart
and Title
Final Sections
in the Subpart
I—Production and Process
Control System: Requirements for the Batch Production Record
111.255 (formerly proposed
§ 111.50(a), (b), and (i))
111.260 (formerly proposed
§§ 111.35(i)(2), (j), (m), and
(o)(2), 111.37(b)(3), (b)(5), (b)(9)
and 111.50(c)(1) through (c)(11),
(c)(13), (c)(14), (d)(2), (e), and
(g), and 111.70(b)(6) and (g))
J—Production and Process
Control System: Requirements for Laboratory Operations
111.303 (new)
111.310 (formerly proposed
§ 111.60(a))
111.315 (formerly proposed
§ 111.60(b)(1))
111.320 (formerly proposed
§ 111.60(c) and (d))
111.325 (formerly proposed
§ 111.60(b)(2) and (b)(3))
K—Production and Process
Control System: Requirements for Manufacturing Operations
Proposed Subpart and Title
111.353 (new)
111.355 (formerly
§ 111.65(a))
111.360 (formerly
§ 111.65(b))
111.365 (formerly
§ 111.65(c))
111.370 (formerly
§ 111.74)
111.375 (new)
proposed
proposed
proposed
proposed
L—Production and Process
Control System: Requirements for Packaging and
Labeling Operations
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F—Holding and Distributing
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111.80
111.82
111.83
111.85
111.90
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111.403 (new)
111.410 (formerly proposed
§ 111.70(a), (b)(6), and (f))
111.415 (formerly proposed
§ 111.70(b))
111.420 (formerly proposed
§ 111.70(d) and (e))
111.425 (formerly proposed
§ 111.74)
111.430 (formerly proposed
§ 111.70(g) and (h))
M—Holding and Distributing
111.453 (new)
111.455 (formerly proposed
§ 111.80)
111.460 (formerly proposed
§ 111.82)
111.465 (formerly proposed
§ 111.83(b)(1) and (b)(2))
111.470 (formerly proposed
§ 111.90)
111.475 (new)
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34761
TABLE 1.—REORGANIZATION AND REVISIONS: 2003 CGMP PROPOSAL AND FINAL RULE—Continued
Proposed Sections
in the Subpart
Proposed Subpart and Title
Final Subpart
and Title
Final Sections
in the Subpart
N—Returned Dietary Supplements
111.95
H—Records and Recordkeeping
1The
111.553 (new)
111.560 (formerly proposed
§ 111.95(a) through (d))
111.570 (formerly proposed
§ 111.95(e) and (f))
P—Records and Recordkeeping
111.605 (formerly proposed
§ 111.125((a) and (b))
111.610 (formerly proposed
§ 111.125(b) and (c))
reference to (d) is the second (d) in the proposed rule in this section due to a misnumbering in the proposed rule.
We discuss all subparts and sections,
and our reasons for amending or
creating subparts and sections, in our
discussion of the comments to the
proposal.
III. What Does the Final Rule Do?
A. Overview of CGMP
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O—Product Complaints
111.125
G—Consumer Complaints
111.503 (new)
111.510 (formerly proposed
§ 111.85(a))
111.515 (formerly proposed
§ 111.85(b) and (c))
111.520 (formerly proposed
§ 111.37(b)(15))
111.525 (formerly proposed
§ 111.50(g))
111.530 (formerly proposed
§ 111.85(d))
111.535 (formerly proposed
§§ 111.50(g) and 111.85(e) and
(f))
In considering the specific
requirements necessary for dietary
supplement CGMPs, we considered
information from a variety of sources.
We considered information from our
outreach activities, as described in
section I of this document; comments to
the 2003 CGMP Proposal; our own
knowledge and expertise about CGMP
for foods, including dietary
supplements; and characteristics of
CGMP that apply to manufacturing,
labeling, packaging, and holding
operations.
The general food CGMPs in part 110
(21 CFR part 110) largely address
practices designed to ensure that food is
manufactured, processed, packed, and
held under sanitary conditions and that
the food is safe, clean, and wholesome.
Although the general food CGMPs in
part 110 apply to a variety of food
products, including dietary
supplements, they do not address the
unique characteristics of certain specific
types of food products. The agency has
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implemented separate, and more
specific, CGMPs for various types of
food products to provide for process
controls in manufacturing that are not
captured by the more general part 110
food CGMPs. (See discussion in section
V of this document (‘‘Legal Authority’’)
on product specific CGMP
requirements). At the time DSHEA was
enacted, there were four such
additional, specific food CGMP
regulations: Those for infant formula
(part 106 (21 CFR part 106)), thermally
processed low-acid canned food (part
113 (21 CFR part 113)), acidified food
(part 114 (21 CFR part 114)), and bottled
water (part 129 (21 CFR part 129)).
Dietary supplements are a type of
food product for which specific food
CGMPs also are needed. Manufacturing
process controls are needed to ensure
that a dietary supplement contains what
the manufacturer intends. Unlike most
foods, the majority of dietary
supplements are packaged into tablets,
gelcaps, and capsules. Some dietary
supplements may contain bioactive
ingredients for which certain, controlled
amounts are intended to be in each
tablet or capsule. The process controls
that must be in place to ensure the tablet
or capsule contains what it purports to
contain are different than those that
must be in place to ensure a food is
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manufactured, processed, packed, and
held under sanitary conditions. Process
controls for dietary supplement
manufacture include establishing and
meeting specifications to ensure the
finished dietary supplement contains
the correct ingredient, purity, strength,
and composition intended.
Vitamins can present a concentrated
source of biologically active
components. A vitamin, for example,
that contains too high a concentration,
such as vitamin D at levels that are
many times greater than intended, can
lead to illness and hospitalization (Refs.
7 and 8). A manufacturer must establish
a process for manufacturing a dietary
supplement product in order to produce
the product consistently and reliably
each time. In order to achieve
consistency and reliability, there must
be process controls in place to ensure,
for example, that appropriate tests and
examinations are conducted, a master
manufacturing record is prepared, each
batch production follows the master
manufacturing record, and the finished
tablet or capsule is placed in the
intended package with the intended
label.
These same types of controls are
needed for herbal and botanical dietary
supplements. Botanicals are often
complex mixtures that can vary in
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Federal Register / Vol. 72, No. 121 / Monday, June 25, 2007 / Rules and Regulations
composition depending on factors such
as the part of the plant used, the
location of harvesting and growing
conditions that can vary from year to
year even in the same location. It can be
difficult to distinguish between closely
related species of botanicals, and the
biological activity of components of an
incorrectly identified species can lead to
adverse consequences. In addition,
different species may be present in
different ratios or blends in a particular
product. Various products might
contain different parts of the plant—
flower, leaf, root, stem, extract—and the
test methods for each can vary in the
nature, sensitivity, and specificity of the
test.
Well-established principles of CGMP
require process controls at each step of
the manufacturing process as early in
the production process as possible.
Quality cannot be tested into the
product only at the end (Ref. 9). Instead,
the quality of the dietary supplement
must be built into the product
throughout the manufacturing process;
quality begins with the starting material
and continues with the product being
manufactured in a reproducible manner
according to established specifications.
It is not sufficient, nor effective, to rely
solely on end product testing to assure
the quality of the individual dietary
supplement product sold to the
consumer.
CGMPs are intended to establish a
comprehensive system of process
controls, including documentation of
each stage of the manufacturing process,
that can minimize the likelihood of, or
detect, problems and variances in
manufacturing as they occur and before
the product is in its finished form.
These process controls that are a part of
CGMPs are essential to ensure that the
dietary supplement is manufactured,
packaged, held, and labeled in a
consistent and reproducible manner.
Manufacturing according to CGMP
means that the manufacturing process
incorporates a set of controls in the
design and production processes to
assure a quality finished product.
CGMPs specific to dietary supplements
are necessary to help ensure that these
products have the identity, purity,
strength, and composition that meet
specifications established in the master
manufacturing record and that they are
not adulterated.
Many comments stressed that the
most critical aspect of a successful
CGMP system is effective process
control. Comments asserted that, with
effective process control, quality is built
into a product throughout the entire
production process. The term ‘‘quality’’
came up repeatedly in comments as the
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desired outcome of the dietary
supplement manufacturing process.1 In
fact, several comments asked us to
define ‘‘quality’’ and suggested various
definitions, each of which related to a
dietary supplement having the identity,
purity, strength, and composition
intended (see comment 49 in section VI
of this document). Some comments
distinguished the concept of quality
from that of preventing adulteration.
These comments objected to our
statement that dietary supplement
CGMP requirements are needed to
prevent adulteration and stated that
CGMP is focused on assuring that
finished products are manufactured
using quality procedures, but are not
related to preventing adulteration. Other
comments asked us to define
‘‘adulteration.’’
We agree that a critical aspect of
CGMP is achieving control over
manufacturing processes. Controls are
necessary to ensure that you
manufacture what you intend so that the
characteristics and/or attributes desired
in a final product will be consistently
and reliably achieved. We disagree with
the comments to the extent that they
were suggesting that quality is not
related to preventing contamination in
the manufacturing process that may
adulterate the finished product.
However, we have reconsidered, as
discussed in this section, what types of
adulteration and misbranding are
necessary to control for in this dietary
supplement CGMP rule.
To clarify what dietary supplement
CGMP requirements are intended to
achieve, we have added a definition of
quality in the final rule. As defined,
quality means ‘‘that the dietary
supplement consistently meets the
established specifications for identity,
purity, strength, and composition and
has been manufactured, packaged,
labeled, and held under conditions to
prevent adulteration under section
402(a)(1), (a)(2), (a)(3), and (a)(4) of the
Federal Food, Drug, and Cosmetic Act.’’
Ensuring the quality of the dietary
supplement means that you consistently
and reliably manufacture what you
intend and that you establish
1 Throughout this final rule, we refer to the
‘‘manufacture’’ or ‘‘manufacturing process’’ of
dietary supplements. We use these terms in the
broad sense, i.e., the terms refer to those activities
that may be done from receipt of raw ingredients
through the distribution of a finished dietary
supplement, including labeling, packaging, and
holding activities. We discuss the various roles and
responsibilities of those who ‘‘manufacture’’ dietary
supplements in the context of final § 111.1 ‘‘Who
is subject to this part?’’ We also sometimes use the
terms to apply to only part of the process, i.e., those
operations other than labeling, packaging, and
holding.
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manufacturing controls to prevent the
dietary supplement from being
adulterated under section 402(a)(1) of
the act due to the presence of
contaminants, under section 402(a)(2) of
the act, for example, if it bears or
contains any unintentionally added
poisonous or deleterious substance,
under section 402(a)(3) of the act if the
dietary supplement consists in whole or
in part of any filthy, putrid, or
decomposed substance, or if it is
otherwise unfit for food, or under
section 402(a)(4) of the act if the dietary
supplement has been prepared, packed,
or held under insanitary conditions
whereby it may have become
contaminated with filth, or whereby it
may have been rendered injurious to
health. The definition of quality limits
to section 402(a)(1), (a)(2), (a)(3), and
(a)(4) of the act the types of adulteration
that you must control for in this CGMP
final rule. The definition applies to the
controls that are designed to prevent
contamination of the product that you
intend to manufacture.
In the 2003 CGMP Proposal, we said
that our purpose was to present a broad
enough scope to the proposed rule so
that we could receive the depth and
breadth of comment needed to develop
a final rule that would provide the
proper balance of regulation (68 FR
12157 at 12161). We asked for comment
on whether each of the provisions
proposed was necessary to ensure the
safety and quality of the dietary
supplement and was adequate to protect
the public health (id.). We stated that
the proposed rule ‘‘would establish the
minimum CGMPs necessary to ensure
that, if you engage in activities related
to manufacturing, packaging, or holding
dietary ingredients or dietary
supplements, you do so in a manner
that will not adulterate and misbrand
such dietary ingredients or dietary
supplements’’ (68 FR 12157 at 12158).
For example, we stated that the
proposed rule would require the
manufacturer to test for toxic
compounds in botanicals that may
likely be present to ensure that no such
compounds are present that may
adulterate the dietary supplement (68
12157 FR at 12162). Further, we
included a requirement that the
ingredients, other than dietary
ingredients under section 201(ff) of the
act, be lawful under the applicable food
additive regulations or be generally
recognized as safe (GRAS) (proposed
§ 111.35(d).
The approach that we set forth in the
2003 CGMP Proposal was designed to
prevent a manufacturer, under CGMP
regulations, from using an ingredient,
whether a dietary ingredient or another
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component, in the manufacture of a
dietary supplement that would
adulterate the product under relevant
provisions of the act, such as section
402(a)(1) or (a)(2)(C). The manufacturer
would have been required to establish
specifications at any point, step, or stage
in the manufacturing process where
control is necessary to prevent
adulteration (proposed § 111.35(e)).
Thus, the manufacturer would not have
been able to establish a specification,
consistent with proposed § 111.35(e), for
the use of an unlawful ingredient
because such use would not prevent
adulteration. In addition, the
manufacturer would have to establish
specifications for contaminants that may
adulterate or that could lead to
adulteration of the dietary supplement.
The manufacturer would have to take
necessary precautions to prevent the
presence or level of contaminants, that
would otherwise adulterate the dietary
supplement under another provision of
the act, from being present in the dietary
supplement. The specifications were
intended to ensure that adulterated and
misbranded dietary supplements would
not reach the marketplace (68 FR 12157
at 12197).
In addition to the general
specifications established under
proposed § 111.35(e), the proposed rule
would have required the manufacturer
to establish specifications for the
identity, purity, quality, strength, and
composition of the components received
(proposed § 111.35(e)(1)) and for the
finished batch of dietary supplement
(proposed § 111.35(e)(3)). Although we
stated that the proposed rule did not
address questions related to the safety of
dietary ingredients used (68 FR 12157 at
12172), if a dietary ingredient was
deemed to be unsafe under the act—
under section 402(a)(1) or another
provision—a specification could not
have been established for that dietary
ingredient, consistent with proposed
§ 111.35(e). Thus, a manufacturer would
not be able to use, under dietary
supplement CGMP, a dietary ingredient,
or other component, that would
otherwise adulterate the product under
another provision of the act.
Further, the proposed rule was
designed to ensure that the correct label
was applied during manufacture so that
the dietary supplement label would
accurately identify the dietary
supplement (proposed §§ 111.45(b)(7),
111.50(c)(12), and 111.70(b)(7)). The
proposed rule also would have required
the master manufacturing record to
contain the identity of each ingredient
that is required to be declared on the
ingredient list in section 403 of the act
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(21 U.S.C. 343) (proposed
§ 111.45(b)(4)).
Several comments seemed to question
why the dietary supplement CGMP rule
would require that a manufacturer use
lawful ingredients when other
provisions of the act would require such
use. In fact, some comments objected to
the proposed requirement in the rule
that required that a component, other
than a dietary ingredient, be approved
for use as a food additive or be GRAS.
The comments stressed that such a
provision was not necessary because the
statute already requires that such an
ingredient be approved as a food
additive or be GRAS. In light of these
comments, we reconsidered our
interpretation of the scope of ‘‘prevent
adulteration’’ in the proposed rule and
whether that interpretation should be
narrowed. We also considered whether
to require, as part of a CGMP
requirement, that the label that
accurately reflects the ingredients in the
product be applied or whether such a
requirement was not necessary, given
our existing authority in section 403 of
the act.
We determined that ensuring quality
in dietary supplement CGMP, in part,
means that you produce what you
intend to produce. As stated in section
V of this document, manufacturers must
plan what they intend to produce,
institute adequate controls to achieve
the desired outcome, and ensure that
the controls work so that the desired
outcome is consistently achieved. Thus,
for example, the manufacturer decides
on the identity, purity, strength, and
composition of the dietary supplement
it manufactures. The focus of CGMP is
on process controls to ensure that the
desired outcome is consistently
achieved, and not on the inherent safety
of the ingredients used (which is
addressed by other statutory
prohibitions).
We agree with the comments that the
safety of a particular ingredient is
governed by other provisions of the act.
If you manufacture a dietary
supplement, you have a responsibility
as a manufacturer to evaluate the safety
of the ingredients under, for example,
section 402(f) of the act.2 Dietary
supplement CGMP would require you to
establish the identity, purity, strength,
and composition specifications for the
product and ensure that such
specifications are met in the finished
2Under section 402(f) of the act, a dietary
supplement is deemed to be adulterated if it is or
contains a dietary ingredient that presents a
significant or unreasonable risk of illness or injury
under conditions of use recommended or suggested
in labeling or, if no such conditions, under ordinary
conditions of use.
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batch of dietary supplement. Nothing in
the dietary supplement CGMPs relieves
manufacturers from complying with any
other substantive provisions of the act
relating to the safety of ingredients and
other components.
Quality not only means that you
produce what you intend, but that you
prevent contamination in your
manufacturing process that could
adulterate your product. Food CGMP
regulations, after which the dietary
supplement CGMP rule is modeled,
require that the manufacturer take
precautions to ensure that the
manufacturer does not adulterate the
product under section 402(a)(1), (a)(2),
(a)(3), and (a)(4) of the act. For example,
under § 110.5 (food CGMP), the criteria
and definitions apply in determining
whether a food is adulterated under
section 402(a)(3) and (a)(4) of the act.
Specifically, § 110.80(a)(2) states that
raw materials shall not contain levels of
microorganisms that may produce food
poisoning or other disease in humans,
unless otherwise treated during
manufacturing operations so that they
no longer contain levels that would
adulterate the product within the
meaning of the act. In addition,
§ 110.80(a)(3) states that raw materials
and other ingredients susceptible to
contamination with natural toxins must
comply with current FDA regulations
and action levels for poisonous or
deleterious substances before such
materials are incorporated into finished
food. Under dietary supplement CGMP,
we believe it is appropriate to require
you to establish specifications that are
designed to prevent adulteration under
section 402(a)(1), (a)(2), (a)(3), and (a)(4)
of the act from contamination during the
manufacturing, packaging, labeling, and
holding operations. For example, if you
are manufacturing a dietary supplement
that you know is likely to contain a
contaminant, you would need to
establish limits on the contaminant in
your supplement, and you must design
these limits to prevent the dietary
supplement from being adulterated
under section 402(a)(1), (a)(2), (a)(3),
and (a)(4) of the act.
Quality, as the term is used for the
purposes of this final rule, relates both
to producing what is intended (i.e.,
establishing and ensuring that
specifications for the identity, purity,
strength, and composition are met) and
to ensuring that the dietary supplement
that you intend to produce has been
manufactured, packaged, labeled, and
held under conditions to prevent
adulteration within the meaning of
section 402(a)(1), (a)(2), (a)(3), and (a)(4)
of the act. Thus, this final rule is not
designed to specifically prevent all
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types of adulteration that may occur
under the act. Rather, this final rule is
designed to prevent adulteration from
those types of contamination that are
commonly controlled in other food
CGMP regulations. We do expect,
however, that compliance with CGMP
requirements in the final rule will help
to avoid other types of adulteration.
Also, nothing in this rule exempts a
manufacturer from compliance with
other relevant adulteration provisions of
the act.
We are replacing the phrase ‘‘prevent
adulteration’’ in the codified with words
that relate to ensuring the quality of the
dietary supplement. Thus, for example,
we have modified proposed § 111.35(e)
(now final § 111.70(a)) to read, ‘‘You
must establish a specification for any
point, step, or stage in the
manufacturing process where control is
necessary to ensure the quality of the
finished dietary supplement and that
the dietary supplement is packaged and
labeled as specified in the master
manufacturing record’’ instead of
‘‘* * * necessary to prevent
adulteration.’’ This phrase is replaced in
several codified provisions and an
explanation of this change is not
provided in the preamble of this
document each time it is made.
Moreover, you have a responsibility
under CGMP to ensure that the label
you specify in the master manufacturing
record is applied to the product. Under
section 403 of the act, you are required
to ensure that your label accurately
reflects the ingredients in the product.
Because section 403 of the act provides
that food, including dietary
supplements, is misbranded if a label
that does not contain accurate
statements is applied, we do not need to
impose the same requirement in this
final rule. Thus, if the representative
label in the master manufacturing
record for the product does not identify
the correct dietary ingredients and the
label that lists inaccurate information is
applied, that dietary supplement would
be misbranded under section 403 of the
act. Such labeling would not be a
violation of dietary supplement CGMP
unless there is a mixup in your process
control and you do not put the
representative label specified in the
master manufacturing record on the
product. Such a mixup would be a
violation of dietary supplement CGMP
requirements (see e.g., final
§§ 111.127(d), 111.160(e), 111.410(c),
111.415).
Thus, in addition to stating ‘‘ensure
the quality of the dietary supplement,’’
in the codified instead of ‘‘prevent
adulteration,’’ we are adding the
language ‘‘and that the dietary
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supplement is packaged and labeled as
specified in the master manufacturing
record.’’ Such change is intended to
clarify that the use of the packaging and
labeling that is stated in the master
manufacturing record is what is
required in this final rule.
A failure to follow the requirements
in this final rule, including a failure to
establish required specifications, could
result in an enforcement action by the
agency under section 402(g) of the act
because the dietary supplement is
adulterated in that it was prepared,
packed, labeled, or held under
conditions that do not meet CGMPs for
dietary supplements. The act establishes
certain prohibited acts and enforcement
mechanisms to remove adulterated
product from the market and prevent
manufacturers from continuing to
manufacture adulterated product.
Enforcement mechanisms currently
available to us under the act are not
affected by this final rule.
Finally, we have included in this final
rule the existing requirements in part
110 that we believe are common to
dietary supplement manufacturing. For
example, the requirements in subpart C,
Physical Plant and Grounds, are similar
to those in § 110.20. We recognize that
there may be operations related to the
manufacturing of dietary supplements
for which certain provisions in part 110
apply, but that we did not determine to
be common to most dietary supplement
manufacturing operations. For example,
there may be some dietary supplements
that are dehydrated and rely on the
control of moisture consistent with
§ 110.80(b)(14). A manufacturer would
be expected to comply with the
regulations in part 110 in addition to the
regulations in part 111, unless the
regulations conflict. To the extent that
the regulations conflict, the dietary
supplement manufacturer must comply
with the regulation in part 111.
B. Highlights of the Final Rule
The final rule:
• Applies to persons who
manufacture, package, label, or hold
dietary supplements unless subject to an
exclusion in § 111.1;
• Establishes minimum requirements
for personnel, physical plant and
grounds, and equipment and utensils;
• Requires the establishment and use
of written procedures for certain
operations, including those related to
equipment, physical plant sanitation,
certain manufacturing operations,
quality control, laboratory testing,
packaging and labeling, and product
complaints;
• Requires the establishment of
specifications in the production and
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process control system that will ensure
dietary supplements meet the identity,
purity, strength, and composition
established in specifications and are
properly packaged and labeled as
specified in the master manufacturing
record;
• Provides for the option to use a
certificate of analysis (for specifications
other than the identity of a dietary
ingredient) from a component supplier
instead of having manufacturers
conduct tests or examinations on the
components they receive;
• Requires testing of a subset of
finished batches of dietary supplements
based on a sound statistical sampling or,
alternatively, testing all finished
batches;
• Requires implementation of quality
control operations to ensure the quality
of a dietary supplement;
• Requires the preparation and use of
a written master manufacturing record
for each unique formulation of
manufactured dietary supplement, and
for each batch size, to ensure your
manufacturing process is performed
consistently and to ensure uniformity in
the finished batch from batch to batch;
• Requires the preparation of a batch
production record every time a dietary
supplement batch is made. The batch
production record must accurately
follow the appropriate master
manufacturing record;
• Requires the establishment and use
of laboratory control processes related to
establishing specifications and to the
selection and use of testing and
examination methods;
• Requires reserve samples of dietary
supplements to be held in a manner that
protects against contamination and
deterioration;
• Requires identification and
quarantine of returned dietary
supplements until quality control
personnel conduct a material review
and make a disposition decision;
• Requires quality control personnel
to conduct a material review and make
a disposition decision under certain
circumstances;
• Requires a qualified person to
investigate any ‘‘product complaint’’
that involves a possible failure of a
dietary supplement to meet any CGMP
requirement, with oversight by quality
control personnel; and
• Requires records associated with
the manufacture, packaging, labeling, or
holding of a dietary supplement to be
kept for 1 year beyond the shelf life
dating (when such dating is used, such
as expiration dating, shelf life dating, or
‘‘best if used by’’ dating), or if shelf life
dating is not used, for 2 years beyond
the date of distribution of the last batch
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those records.
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IV. What General Comments Did We
Receive?
We received approximately 400
comments on the proposed rule.
Although most comments support
CGMP requirements for dietary
supplements and dietary ingredients,
others question the need for a regulation
and many sought changes to the rule.
We describe, in this section, comments
on general aspects of the final rule. We
include comments related to the
structure and organization of the final
rule, comments we received on why
CGMP requirements are needed, and
comments on written procedures. In
addition, we describe some general
comments we received on multiple
sections of the proposed rule that we
believe are better addressed in one
response.
To make it easier to identify
comments and our responses, the word
‘‘comment,’’ in parentheses, will appear
before each comment, and the word
‘‘response’’ will appear before each
response. We also have numbered the
comments to make it easier to
distinguish between comments; the
numbers are for organizational purposes
only and do not reflect the order in
which we received the comments or any
value associated with the comment.
A. What Comments Did We Receive on
the Structure and Organization of the
Rule?
(Comment 1) Several comments seek
to restructure or reorganize the rule. For
example, one comment states we should
simplify the entire section on
production and process controls. The
comment asserts it would be more
logical to list contaminants that may
adulterate a dietary supplement or lead
to adulteration as part of the
requirements for specifications
(proposed § 111.35(e)) than to list such
contaminants as part of the testing
requirements (proposed § 111.35(k)).
Other comments say it would be more
logical to list the tests that are
considered appropriate as part of
proposed § 111.35(h) (concerning
appropriate tests or examinations to
determine whether specifications are
met) than to have a separate
requirement for appropriate tests in
proposed § 111.35(l) (which listed the
types of analyses that should be part of
a test).
Another comment claims the rule is
too complex, asserting it would create
chaos. Other comments say that the
proposal’s degree of detail required is
unrealistic for small dietary supplement
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firms, and we should rewrite the rule to
be more user friendly.
Yet another comment says that any
final rule we issue must clearly set forth
CGMP requirements. This comment
seems to suggest the requirements need
to be more detailed in describing what
is required. The comment asserts that
ambiguities in interpretation could
result in economic disadvantage for
small businesses because they typically
do not have in-house legal counsel and,
thus, must be more conservative in
interpreting ambiguous regulatory
provisions.
(Response) In response to these
comments, as well as comments on
specific subparts and provisions, we
have reorganized the final rule and have
re-phrased or introduced concepts in a
‘‘user-friendly’’ or plain language
format. We also have eliminated certain
redundant regulatory requirements and
combined similar requirements. For
example, rather than put all production
and process control system
requirements in a single subpart, we
have reorganized the final rule to create
a series of subparts that first describe
the requirements for the overall design
and implementation of the production
and process control system and then
describe the requirements of the
individual operations associated with
that system. We also present each
requirement as a question rather than as
a paragraph within a section. This
question format will help readers focus
on the subparts or sections that apply to
specific operations.
As another example, we reduced the
redundancy associated with the
interrelated nature of the proposed rule
by combining most similar
requirements. Both proposed
§§ 111.35(m) and 111.60(b)(2) would
require you to keep testing and
examination results. The final rule
places this requirement in a single
section (§ 111.325(b)(2)(ii)).
The final rule also shortens the
construction ‘‘includes, but is not
limited to’’ to ‘‘includes.’’ We did this
because the use of the word ‘‘includes’’
indicates that the specified list that
follows is not exclusive. The phrase
‘‘but is not limited to’’ is unnecessary.
Finally, some changes we have made
to one specific section have an impact
on other sections. For example, after
considering the comments, we revised
subpart B to require you to establish and
follow written procedures to fulfill the
requirements of subpart B. Those
written procedures are records you must
make and keep in accordance with the
recordkeeping requirements of subpart
P, thus we made changes to include that
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requirement of making and keeping
records.
B. What Comments Did We Receive on
the Need for Dietary Supplement CGMP
Requirements?
(Comment 2) Some comments state
that dietary supplement CGMP
requirements will protect consumers
from supplements that contain
inherently unsafe dietary ingredients.
Other comments request that we take
additional action to ensure the safety of
dietary ingredients.
(Response) This final rule focuses on
the manufacturing practices of dietary
supplements and not on whether certain
dietary ingredients are or are not safe.
Therefore, comments related to whether
certain dietary ingredients are
inherently unsafe and any request to
take actions related to the inherent
safety of dietary ingredients are outside
the scope of this rule.
(Comment 3) Some comments support
the rule, explaining that it will address
current problems with superpotent and
subpotent dietary supplements,
undeclared ingredients, and varying
levels of ingredients. Others indicate the
rule will better protect consumers and
increase consumer confidence. One
comment states that CGMP
requirements for dietary supplements
are not needed for responsible
manufacturers because they already
manufacture safe dietary supplements.
Some comments state that dietary
supplement CGMP requirements are not
needed because the dietary supplements
have a track record of safety. Other
comments say there were more adverse
events reported from drug use than from
dietary supplement use and that a large
number of Americans take dietary
supplements, and on that basis
suggested that dietary supplements are
safer than foods or drugs.
(Response) We agree the final rule
will better protect consumers and help
address the types of manufacturing
problems identified in the preamble to
the 2003 CGMP Proposal (see 68 FR
12157 at 12162 through 12163) through
consistent use of established production
processes and controls.
However, we disagree with the
comments asserting dietary
supplements have a track record of
safety such that dietary supplement
CGMP requirements are unnecessary.
Section 402(g) of the act does not
require us to establish a ‘‘bad’’ track
record of safety in the manufacture of
dietary supplements before we may
issue a dietary supplement CGMP rule.
Furthermore, we disagree with the
comments comparing dietary
supplement safety to drug safety; there
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are different statutory requirements,
different regulatory requirements, and
different safety evaluations for dietary
supplements and drugs.
We also disagree that the final rule
should apply only to manufacturers
who cannot manufacture dietary
supplements responsibly. Establishing
who is or is not a responsible
manufacturer is not a threshold
requirement in section 402(g) of the act,
and it would be impractical to regulate
dietary supplement CGMP in such a
manner, because parties may differ as to
whether a particular manufacturer acted
‘‘responsibly’’ in a particular situation.
All dietary supplement manufacturers
are subject to this final rule, just as all
dietary supplement manufacturers are
subject to section 402(g) of the act. We
therefore are not persuaded that dietary
supplement CGMP requirements are not
needed, or should only be applied to
manufacturers who have not acted
‘‘responsibly.’’
(Comment 4) Some comments state
that our authority under the current
food CGMP regulation in part 110 and
our authority to take actions against
adulterated and misbranded products
generally are sufficient. Other comments
state that DSHEA gives us the necessary
legal authority to protect the public
health and that additional regulatory
requirements are unnecessary. Several
comments object to our statement that
dietary supplement CGMP requirements
are needed to prevent adulteration.
These comments suggest dietary
supplement CGMP is focused on
ensuring finished products are
manufactured using quality procedures,
but are not related to preventing
adulteration. Other comments state we
should enforce current food CGMP
regulations rather than adopt new
regulations.
(Response) We disagree that dietary
supplement CGMP requirements are not
related to preventing adulteration. In
fact, under the statutory scheme a
dietary supplement is deemed to be
adulterated under section 402(g)(1) of
the act if it fails to meet CGMP
requirements we promulgate by
regulation. As we discussed in section
III of this document, dietary supplement
CGMP requirements are necessary to
ensure the quality of the dietary
supplement; ensuring quality includes
ensuring that the dietary supplement
has been manufactured, packaged,
labeled, and held under conditions to
prevent adulteration under section
402(a)(1), (a)(2), (a)(3), and (a)(4) of the
act.
We also disagree with those
comments stating that the requirements
in part 110 are adequate and that no
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additional requirements are necessary.
The comments do not explain why the
specific requirements set forth in the
proposed rule that are not also in part
110 are unnecessary. As discussed in
greater detail in response to comments
on our legal authority in section V of
this document, the particular
characteristics and hazards of dietary
supplements call for CGMP
requirements tailored to dietary
supplements. Congress specifically
provided independent authority under
section 402(g) of the act for us to
promulgate CGMP requirements for
dietary supplements. That authority
would have been unnecessary if
Congress had concluded that part 110
was adequate.
We also disagree that enforcement of
part 110 would eliminate a need for
dietary supplement CGMP
requirements. The dietary supplement
CGMP requirements include practices
specifically tailored to the
characteristics and hazards of dietary
supplements and their manufacturers.
The comments asserting that current
food CGMP requirements in part 110 are
sufficient provided no persuasive or
compelling reasons for that assertion, or
for why we should not implement
dietary supplement CGMP requirements
under section 402(g) of the act. For these
reasons, we are not persuaded by the
comments that these dietary supplement
CGMP requirements are not needed.
(Comment 5) Some comments object
to the examples of manufacturing
problems that we used to support the
need for CGMP requirements.
Specifically, some comments object to
the Prevention magazine citation and
also object to the nine examples we
presented in the preamble to the 2003
CGMP Proposal (see 68 FR 12157 at
12161 through 12163). We cited the
Prevention magazine survey on
consumer use of dietary supplements to
show that only 41 percent of surveyed
consumers who use vitamins and
minerals think those products are very
safe, and only 50 percent think the
products are somewhat safe; among
those using herbal products, only 24
percent thought the products were very
safe, and only 53 percent thought the
products were somewhat safe. We noted
that 74 percent supported increased
government regulation of dietary
supplements (see, id.). As one example
of adulterated dietary supplements
caused by manufacturing practices, the
preamble to the 2003 CGMP Proposal
mentioned an instance where a young
woman suffered a life-threatening
abnormal heart function that was traced
to a mislabeled or contaminated dietary
ingredient (68 FR 12157 at 12162).
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Another example involved recalls of
super- and subpotent dietary
supplements (id.).
Comments objecting to the Prevention
survey said it provided no rationale for
why CGMP requirements are needed.
Other comments said the nine examples
we provided represent a failure to
conform to an existing regulation and do
not demonstrate a need for a new CGMP
regulation for dietary supplements. One
comment disagrees that the CGMP
requirements would prevent adverse
reactions, as one example suggested in
the preamble to the 2003 CGMP
Proposal (see 68 FR 12157 at 12162)
because, the comment claims, most
adverse reactions are not the result of
manufacturing problems. Another
comment states the example involving
plantain (68 FR 12157 at 12162), where
a raw material was labeled as ‘‘plantain’’
when it was, in fact, Digitalis lanata (a
plant that can cause life-threatening
heart reactions), shows that, had there
been a system in place to test finished
product for purity and identity or to
perform identity testing upon receipt,
the manufacturer could have prevented
that adulterated product from entering
the market place. The comment states
identity testing is necessary in the final
rule.
Another comment objects to the
example of ‘‘non-food grade chemicals’’
(id.) because the reference supporting
the example involved GammaButyrolactone, a substance we have
stated is an unapproved new drug and
not a dietary supplement. Some
comments say the risks cited in the
justification for these regulations are
hypothetical or theoretical and current
statutory or regulatory authority is
adequate.
(Response) We disagree, in most part,
with the comments. We cited the
Prevention survey to illustrate consumer
perception and support for increased
government involvement in dietary
supplement regulation. We did not
describe the survey as illustrating CGMP
problems associated with dietary
supplements.
We also disagree that the risks cited
in the preamble to the 2003 CGMP
Proposal are merely hypothetical or
theoretical. We provided actual
examples of failures in the
manufacturing of products marketed as
dietary supplements. The comments
may have misunderstood what the
CGMP requirements for dietary
supplements are intended to
accomplish. A principal goal of the
CGMP requirements is to have those
who manufacture, package, label, or
hold dietary supplements do so in a
manner that ensures the quality of the
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dietary supplement and that the dietary
supplement is packaged and labeled as
specified in the master manufacturing
record. It is the manufacturer who needs
to establish procedures for its
manufacturing operations to ensure, for
example, the final product is produced
according to its specifications in the
master manufacturing record, meets
limits on contaminants, and is a quality
dietary supplement. If a product does
not meet its specifications, a
manufacturer who observes the CGMP
requirements should know that and be
able to take corrective action before the
dietary supplement enters the
marketplace. The onus is on the
manufacturer, and not simply on us, to
take action to prevent the adulterated
product from entering the market or, if
the product has already been released,
to remove the product from the market.
The umbrella food CGMP requirements
in part 110 do not contain specific
provisions establishing specifications,
requiring identity testing, or requiring
in-process and/or finished product
testing. Through this final rule, we are
establishing a new CFR part regarding
CGMP requirements specifically for
dietary supplements.
The examples we used in the
preamble to the 2003 CGMP Proposal
included adverse event reports
associated with contamination with
Digitalis lanata, the possible
contamination of botanical ingredients
with toxic compounds, the use of nonfood grade chemicals, the manufacture
of super- and subpotent dietary
supplements, the presence of
undeclared ingredients, and the
variability of ingredients from what is
declared on the label (Refs. 7, 8, and 10;
see, also, 68 FR 12157 at 12162 through
12163). These were all examples where
products were manufactured, labeled,
and sold to the consumer as dietary
supplements. We disagree with the
comments’ assertions that all these
problems can be adequately dealt with
by the food CGMP requirements in part
110, but agree with the comment that,
had there been a system in place ‘‘to
perform identity testing upon receipt,
the manufacturer could have prevented
that adulterated product from entering
the market place.’’ Most of these
examples present situations in which
the manufacturer could have identified
these problems through the dietary
supplement CGMP requirements for
specifications and testing or
examination, such as identity
verification, and could have prevented
such products from entering the market
or at least provided a greater assurance
that such products would not make it
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into the marketplace. The dietary
supplement CGMP requirements ensure
adequate controls are in place to
identify many of these types of
manufacturing errors before the product
is in the marketplace and not through
postmarketing adverse event reports or
consumers’ illnesses.3
The dietary supplement industry is
diverse, as are the number and types of
products marketed as dietary
supplements. As we stated in the
preamble to the 2003 CGMP Proposal
(68 FR 12157 at 12163), given the wide
range of public health concerns
presented by the manufacturing
practices for dietary supplements, a
comprehensive system of controls is
necessary. This final rule will set the
standards for CGMP for dietary
supplements that, if followed, will help
ensure the quality of the dietary
supplement and that the dietary
supplement is packaged and labeled as
specified in the master manufacturing
record. The establishment of production
and process controls and adherence to
these and other CGMP requirements of
this final rule will help to prevent the
types of events (and others) we
described in the nine examples
presented in the preamble to the 2003
CGMP Proposal.
(Comment 6) Several comments
suggest that dietary supplements are no
different in safety or physiologic effect
and require no different requirements
than conventional food with respect to
CGMP. One comment disagrees with us
that dietary supplements require
different requirements than
conventional food because dietary
supplements are ground up or in
powder form and may not be easily
recognized or differentiated; the
comment says the same is true of many
food ingredients as well.
(Response) We disagree with the
suggestions by these comments that
dietary supplement CGMP requirements
need not differ from those for
conventional foods. By definition, a
dietary supplement is in a category of
food separate and distinct from the
category of conventional food. The
definition of dietary supplement in
section 201(ff) of the act, in part,
essentially describes a dietary
supplement as a type of food that differs
from conventional food. The definition
refers to section 411(c)(1)(B)(i) and
(c)(1)(B)(ii) of the act (21 U.S.C.
350(c)(1)(B)(i) and (c)(1)(B)(ii)), which
3Mandatory reporting to FDA of serious adverse
events is now required as a result of the enactment
of the ‘‘Dietary Supplement and Non-Prescription
Drug Consumer Protection Act’’ (Public Law 109–
462) signed into law on December 22, 2006 (see
discussion in section XX of this document).
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describes the forms that dietary
supplements intended to be ingested
may take, i.e., tablet, capsule, powder,
softgel, gelcap, or liquid form, and if not
in such a form, limitations on how
dietary supplements can be represented,
i.e., not as conventional food or as a sole
item of a meal or the diet.
Congress included separate additional
provisions under section 402 of the act
(see section 402(f) and (g) of the act) for
when a dietary supplement may be
adulterated. Congress considered that
dietary supplements may warrant CGMP
requirements that are different than
those for conventional food. Although
dietary supplements may include
substances that are used as ingredients
in conventional foods, the amounts
consumed as a dietary supplement and
as a conventional food product may not
be the same and, in fact, may be more
concentrated, and in higher amounts,
when taken as a dietary supplement.
The forms in which dietary
supplements are consumed differ (e.g.,
capsule, tablet), as may the frequency,
when compared to conventional foods.
The uses of dietary supplements also
differ from use as conventional food.
Consequently certain manufacturing
practices considered to be a part of
CGMP for dietary supplement
manufacturing may not be necessary for
all types of food.
C. What Comments Did We Receive on
Written Procedures?
1. Overview
In the 2003 CGMP Proposal (68 FR
12157 at 12165), we stated that written
procedures were included in the dietary
supplement CGMP outline submitted to
us by industry, namely, the National
Nutritional Foods Association standards
(NNFA), the NSF International draft
standards, and the United States
Pharmacopoeia (USP) draft
manufacturing practices. We also stated
that, to limit the burden to
manufacturers, we were not proposing
to require written procedures for all the
requirements. We invited comment on
whether we should require written
procedures for a variety of operations;
specifically, for complying with the
CGMP requirements, under proposed
§ 111.10 for personnel hygiene and for
preventing microbial contamination due
to personnel (68 FR 12157 at 12182);
maintenance, cleaning, and sanitation
for the physical plant under proposed
§ 111.15 (68 FR 12157 at 12187);
calibrating instruments and controls
under proposed § 111.25(b), (c), and (d)
(68 FR 12157 at 12191); maintaining,
cleaning, and sanitizing equipment and
utensils under proposed § 111.25(e) (68
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FR 12157 at 12192); calibrating,
inspecting, and checking automatic
equipment under proposed § 111.30 (68
FR 12157 at 12193); the duties of the
quality control unit under proposed
§ 111.37 (68 FR 12157 at 12201);
implementing the proposed
requirements for receipt of components,
dietary supplements, packaging, and
labels under proposed § 111.40(a) and
(b) (68 12157 at FR 12203); preparing
the master manufacturing record under
proposed § 111.45 (68 FR 12157 at
12205); laboratory operations under
proposed § 111.60 (68 FR 12157 at
12209); manufacturing operations under
proposed § 111.65 (68 FR 12157 at
12211); packaging and labeling
operations under proposed § 111.70 (68
FR 12157 at 12213); holding
components, dietary supplements,
packaging, labels, and in-process
materials under proposed §§ 111.80 and
111.82 (68 FR 12157 at 12214);
identifying, quarantining, and salvaging
returned dietary supplements under
proposed § 111.85 (68 FR 12157 at
12216); and receiving, reviewing, and
investigating consumer complaints
under proposed § 111.95 (68 FR 12157
at 12217).
We stated that if comments assert that
written procedures are necessary,
comments should include an
explanation of why the requirement is
necessary to prevent adulteration
including how such a requirement
would ensure the identity, purity,
quality, strength, and composition of the
dietary supplement. Conversely, if
comments assert that written procedures
are not necessary, we asked for an
explanation of why and how, in the
absence of the requirement, one can
prevent adulteration and ensure the
identity, purity, quality, strength, and
composition of the dietary supplement.
(Comment 7) Many comments stress
the most critical aspect of a successful
CGMP system is effective process
control, which requires conducting key
operations using written procedures.
Several comments assert that written
procedures are an important part of
manufacturing operations to ensure
uniform practices in production
operations, from receiving through final
operations. Several comments assert
written procedures provide a sound
basis for employee training and
supervision. Several comments state
that without a written training program,
it is very likely that some employees
may not receive sufficient training, or in
some cases, any CGMP training at all.
One comment specifically suggests that
companies develop written procedures
for the minimum CGMP training
common to all departments.
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One comment points out that all wellrecognized quality systems require
establishment of written procedures to
ensure consistent process control, and
cites examples such as the International
Organization for Standardization, the
American National Standards Institute
(ANSI), and the Malcolm Baldridge
National Quality Award criteria. Other
comments state that written procedures
are necessary for the definition,
operation, and documentation of a
process control system, and that without
such procedures it would be virtually
impossible for any company, regardless
of size, to consistently manufacture
products that meet established
requirements for identity, purity,
quality, strength, and composition. The
comments note that written procedures
contain the necessary instructions for all
employees to successfully execute their
respective functions. Another comment
supports a requirement for conducting
key operations using written procedures
and states that records document that
operations were performed, but that
written procedures show how the task is
to be performed and at what frequency
it should be performed. One comment
states effective communication is
essential to build quality into a process,
and written procedures provide that
throughout all levels of an organization.
Another comment states it is difficult to
imagine how the quality control unit
could carry out its obligations under
proposed § 111.37(b)(1) to ‘‘approve or
reject all processes, specifications,
controls, tests, and examinations, and
deviations from or modifications to
them * * *’’ if these are not subject to
written procedures.
Many comments which present one or
more of these general reasons for
requiring written procedures also list
operations that they believe should be
conducted using written procedures.
The operations that one or more
comments list as key operations are:
• Employee training;
• Cleaning the physical plant,
including pest control;
• Maintenance, cleaning, and
sanitizing of equipment and utensils;
• Calibration of equipment used in
manufacturing or testing;
• All aspects of the production
process, including a general procedure
to document the minimum
investigation, review, and approval
requirements for failures in
manufacturing or packaging operations;
• All quality control operations;
• Reprocessing of batches or start-up
materials that do not conform to
specifications;
• Receipt, identification,
examination, handling, sampling,
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testing, and approval or rejection of
components, packaging, and labels;
• Laboratory operations, including
the establishment of specifications and
descriptions of laboratory test methods
used to ensure that components, inprocess materials, and finished product
meet established specifications;
• Packaging and labeling operations,
including issuance and use of
appropriate labels, labeling, and
packaging materials;
• Holding and distribution
procedures, including procedures for
quarantine and parameters for storage;
• Return and salvage operations;
• Handling of consumer complaints;
and
• Procedures for product recall.
Many comments assert an effective
process control system that includes
extensive written procedures would
justify a decreased testing burden with
respect to the finished product. One
comment suggests we exempt
manufacturers from the requirement to
test each finished batch of product if
they have a qualified manufacturing
process that meets certain basic criteria,
including a requirement for written
procedures for each stage of the process.
One comment notes it would be clearer
to all parties if specific written
procedures were listed as required and
stresses the importance of having all
companies know exactly what is
procedurally expected of them.
In addition to these general reasons
for requiring that key operations be
conducted using written procedures,
several comments provide specific
reasons for requiring that specific
operations be conducted using written
procedures. In response to our request
for comment on whether written
procedures should be required for
complying with proposed § 111.10
(personnel hygiene and for preventing
microbial contamination due to
personnel), one comment states that
written procedures help to ensure
compliance with the proposed hygiene
requirements by clearly listing the
requirements and requiring the
employees to follow them on a
consistent basis.
In response to our request for
comment on whether written
procedures should be required for
complying with the proposed
requirements for maintenance, cleaning,
and sanitation for the physical plant
under proposed § 111.15, one comment
states that having written procedures in
place to clean the physical plant will
ensure that there is no crosscontamination. Another comment states
utility areas such as effluent treatment,
boilers, cooling towers, and water
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treatment plants also should have
documented procedures for cleaning in
order to create a general awareness of
cleanliness throughout the plant. Other
comments state that such written
procedures should not be required
because they would not directly prevent
contamination or ensure the identity,
purity, quality, strength, and
composition of the dietary supplement
if, as the ‘‘bottom line,’’ a manufacturer
maintains the physical plant in a clean
and sanitary condition.
Responding to our request for
comment on whether written
procedures should be required for
complying with the proposed
requirements for calibrating instruments
and controls under proposed
§ 111.25(b), (c), and (d), several
comments assert we should require
manufacturers to establish and follow
written procedures for calibrating
equipment and controls. According to
these comments, such procedures
would provide us with a written record
that is sufficient to evaluate the
adequacy of the company’s calibration
procedures and would provide the
necessary controls to meet the
underlying intent of the rule. These
comments assert that written procedures
will lessen the risk that adulterated
products will be produced.
In response to our request for
comment on whether written
procedures should be required for
complying with the proposed
requirements for maintaining, cleaning,
and sanitizing equipment and utensils
under proposed § 111.25(e), several
comments assert such written
procedures are crucial. These comments
claim that written procedures promote
consistency, clearly lay out expectations
for employees, facilitate training, and
provide a reference for individuals in
performing their job functions. One
comment states that written procedures
for maintaining, cleaning, and sanitizing
equipment are an industry standard.
In response to our request for
comment on whether written
procedures should be required for
complying with the proposed
requirements for preparing the master
manufacturing record under proposed
§ 111.45, one comment states that
written procedures for in-process
control and quality checks should
ensure the addition of the proper
ingredients in the proper amount, and
proper blending and control of other
critical points. Another comment states
written procedures are a critical element
for ensuring consistent implementation
of proper corrective action. Other
comments state they do not support a
requirement for written procedures for
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preparing the master manufacturing
record; and one comment suggests such
a written procedure is not necessary
because the proposed regulations for
preparing the master manufacturing
record already delineate the
requirements for what information must
be included in the master
manufacturing record.
In response to our request for
comment on whether written
procedures should be required for
complying with the proposed
requirements for laboratory operations
under proposed § 111.60, some
comments specifically note the need for
written procedures for the laboratory
test methods used to ensure that
components, in-process materials, and
finished product meet established
specifications. Some comments
emphasize written procedures would
create a standard for testing of products
or groups of products and establishing
parameters for passing or failing
products.
In response to our request for
comment on whether written
procedures should be required for
complying with the proposed
requirements for manufacturing
operations under proposed § 111.65, one
comment asserts this is an effective way
to train personnel and a means to hold
operators accountable to a quality
standard. Another comment states
written procedures can improve quality
and consistency in a manufacturing
operation.
In response to our request for
comment on whether written
procedures should be required for
complying with the proposed
requirements for packaging and labeling
operations under proposed § 111.70, one
comment asserts this is an effective way
to train personnel and a means to hold
operators accountable to a quality
standard.
Responding to our request for
comment on whether written
procedures should be required for
complying with the proposed
requirements for holding components,
dietary supplements, packaging, labels,
and in-process materials under
proposed §§ 111.80 and 111.82, one
comment asserts this is an effective way
to train personnel and a means to hold
operators accountable to a quality
standard. Another comment states a
company cannot be considered to be a
CGMP operation without having written
procedures for every product
manufacturing activity, including
holding and distributing. This comment
states mixups and adulterations will be
more likely to occur if there are no
written procedures for control of storage
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locations, manner of storage, and
container and storage location
identification codes.
In response to our request for
comment on whether written
procedures should be required for
complying with the proposed
requirements for returned dietary
supplements, one comment states
written procedures should govern all
return and salvage operations to create
a standard for quarantine and salvage
and to establish parameters for proper
salvage conditions.
Responding to our request for
comment on whether written
procedures should be required for
complying with the proposed
requirements for handling consumer
complaints, some comments state
written procedures will encourage
companies to handle consumer
complaints in a uniform manner. One
comment asserts written procedures
should be required for handling
consumer complaints because some
complaints could relate to serious
illness or injury. The comment states
that written procedures would set out
exactly what steps need to be taken
when complaints are reviewed, and are
the best way to ensure the essential
information is captured.
(Response) We agree with the
comments that effective process control,
using written procedures, is an
important aspect of a successful CGMP
program. We also agree requiring
written procedures will help to ensure
consistent practices in operations i.e.,
help to ensure the operation is
conducted in the same manner
regardless of who conducts the
operation or when the operation is
conducted. We also agree that written
procedures provide a sound basis for
employee training and supervision, are
an effective communication tool, and
enable quality control personnel to carry
out the responsibility to approve or
reject all processes, specifications,
controls, tests, and examinations, and
deviations from or modifications to
them. In addition, written procedures
establish expectations for each covered
operation so the operation does not
proceed in an ad-hoc manner. Written
procedures provide specific guidance if
there is an unanticipated occurrence
and, thus, can play a key role in
ensuring a quality product, because
actions to correct the unanticipated
occurrence can take place swiftly and
with confidence in the outcome.
This final rule establishes the
minimum CGMPs necessary for
activities related to manufacturing,
packaging, labeling, and holding dietary
supplements to ensure a quality
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product. The operations required by this
final rule must be conducted in a
consistent manner, regardless of who is
conducting an operation or when the
operation is conducted. As discussed in
the following paragraphs, with a few
exceptions, we are requiring that you
establish and follow written procedures
to fulfill the requirements for the
operations covered by this final rule.
The exceptions include final subpart A,
which addresses the scope of the rule,
rather than operations covered by the
rule; final subparts E, H, and I, in which
we conclude that a requirement for
written procedures would be redundant
to other requirements; and final subpart
P, which establishes requirements for
making and keeping records, rather than
for conducting operations.
We believe requiring you to establish
and follow written procedures to fulfill
the requirements of subparts B through
D, F, G, and J through O, when
combined with other requirements of
this final rule, justifies reduced
requirements for testing finished
batches of product compared to the
proposed requirements for such testing
as found in proposed § 111.35. By
establishing and following written
procedures, you will focus your
production and process control system
on ensuring the quality of the finished
product at each stage in the production
process, rather than relying entirely on
testing at the end of the process.
2. Written Procedures That Are
Required by This Final Rule
a. Written procedures for personnel
(final subpart B). We believe that
successful programs for process control
are directly connected to appropriate
training programs. Employee training
must be conducted in a consistent
manner, regardless of who conducts the
training or when it is conducted. Failure
to conduct employee training in a
consistent manner could lead to a
failure in ensuring product quality. For
example, an employee who has not
received appropriate training on how to
conduct a specific physical examination
to verify the identity of a dietary
ingredient may erroneously report that
the correct ingredient was received
when, in fact, the received dietary
ingredient is related to, but different
from, the ingredient that is specified in
the master manufacturing record.
We also believe the requirements that
apply to preventing microbial
contamination due to sick or infected
personnel and that apply to proper
hygienic practices must be conducted in
a consistent manner. For example, it is
well known that foodborne illness can
be transmitted by workers who are sick.
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For example, volunteer food workers at
an outdoor music festival were found to
be the source of contamination for an
outbreak of Shigellosis (Ref. 11).
We include in final subpart B a
requirement (final § 111.8) that you
establish and follow written procedures
for fulfilling the requirements of subpart
B.
b. Written procedures for cleaning the
physical plant, including pest control
(final subpart C). We agree with the
comments that written procedures for
cleaning the physical plant would
reduce the potential for crosscontamination and that such written
procedures must include written
procedures for pest control. Cleaning
operations and pest control must be
conducted in a consistent manner,
regardless of who conducts the
operation or when it is conducted.
Failure to conduct cleaning operations
and pest control in a consistent manner
could lead to failure in ensuring product
quality. For example, application of a
chemical such as a fumigating agent or
rodenticide in a production area must
be performed correctly to avoid
contaminating dietary supplements.
Therefore, we disagree that written
procedures would not directly prevent
contamination or ensure the identity,
purity, strength, and composition of the
dietary supplement even if a
manufacturer maintains the physical
plant in a clean and sanitary condition.
We include in final subpart C a
requirement that you establish and
follow written procedures for cleaning
the physical plant and for pest control
(final § 111.16).
c. Written procedures for calibrating
instruments and controls and for
calibrating, inspecting, and checking
automated, mechanical, or electronic
equipment (final subpart D). Calibrating
instruments and controls, and
calibrating, inspecting, and checking
automated, mechanical, or electronic
equipment must be conducted in a
consistent manner, regardless of who
conducts the operation or when it is
conducted. Without a consistent
approach, the performance of these
operations could lead to equipment that
produces inaccurate results. For
example, if a scale is out of calibration,
the wrong amounts of components
could be added to a mixer. We include
in final subpart D a requirement that
you establish and follow written
procedures for calibrating instruments
and controls that you use in
manufacturing or testing a component
or dietary supplement (final § 111.25(a))
and for calibrating, inspecting, and
checking automated, mechanical, and
electronic equipment (final § 111.25(b)).
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We note that the manufacturers of
equipment often provide written
procedures for calibrating equipment.
Depending on your circumstances and
applications, you may be able to rely on
written procedures provided by the
manufacturer of the equipment with
little or no modification.
Final § 111.25(a), pertaining to
establishing and following written
procedures for calibrating instruments
and controls used in manufacturing or
testing components or dietary
supplements, is similar to proposed
§ 111.25(c)(1) which would provide an
option, in relevant part, that you
establish written procedures for
calibrating such instruments and
controls in addition to requiring you to
document that the procedure was
followed each time a calibration is
performed.
d. Written procedures for
maintaining, cleaning, and sanitizing
equipment and utensils (final subpart
D). Maintaining, cleaning, and
sanitizing equipment and utensils must
be conducted in a consistent and
appropriate manner, regardless of who
conducts the operation or when it is
conducted. Failure to clean and sanitize
equipment and utensils in a consistent
and appropriate manner could lead to a
product that is adulterated because, for
example, equipment and utensils that
are not properly cleaned and sanitized
could be a source of microorganisms, or
could lead to cross-contamination of
products. In addition, failure to
maintain equipment in a consistent
manner could lead to the failure to
ensure product quality. For example,
equipment that is properly maintained
is less likely to malfunction than
equipment that is not maintained, and
using equipment that malfunctions
could lead to errors in production, such
as dispensing an incorrect amount of
each ingredient.
We include in final subpart D a
requirement that you establish and
follow written procedures for
maintaining, cleaning, and sanitizing
equipment and utensils (final
§ 111.25(c)). Final § 111.25(c) applies to
equipment, utensils, and any other
contact surfaces used in labeling
operations as well as in manufacturing,
packaging, and holding operations.
Although the factors you must consider
for maintaining, cleaning, and sanitizing
equipment used for labeling operations
likely are different from those for
equipment used in manufacturing or
packaging operations, you nevertheless
must determine the appropriate steps to
take to ensure that labeling equipment
is appropriately maintained and does
not become a source of contamination
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for dietary supplements. For example,
equipment used for labeling operations
has a greater potential to contaminate a
dietary supplement when labeling
operations are carried out in concert
with packaging operations, because the
dietary supplement could be exposed to
one or more contact surfaces during the
packaging operations.
Final § 111.25(c) requires you to
establish and follow written procedures
for maintaining, cleaning, and
sanitizing, as necessary, all equipment,
utensils, and any other contact surfaces
used to manufacture, package, label, or
hold components or dietary
supplements. Final § 111.25(c) relates to
proposed § 111.25(e)(1) which would, in
relevant part, require you to maintain,
clean, and sanitize as necessary, all
equipment, utensils, and contact
surfaces used to manufacture, package,
label, or hold components, dietary
ingredients, or dietary supplements.
(Comment 8) Some comments suggest
that written procedures for maintaining,
cleaning, and sanitizing equipment
require visual inspection of equipment
when more than one product is
manufactured using the same
equipment, and that the presence of
residual components from one product
in a different product could be harmful.
The comments also suggest the written
procedures include residual limits of
components from different product lines
to guarantee the safety of the dietary
supplement.
(Response) The final rule gives you
flexibility to develop written procedures
appropriate to your products and
equipment. Consequently, final
§ 111.25(c) neither requires nor
prohibits any specific procedure, such
as the visual inspection suggested by the
comment.
As for the residual limits, the
comment provides no data or other
information that would provide a basis
for setting residual limits for any
particular components. However, as we
discuss more fully in the discussion of
final § 111.70(e) in section X of this
document, the final rule requires you to
establish and meet specifications for the
identity, purity, strength, and
composition of dietary supplements and
for limits on contamination for dietary
supplements that you manufacture.
When considering the specifications
you must establish to ensure the quality
of the dietary supplements, you must
take into account the need to ensure that
components or dietary supplements are
not contaminated as a result of using the
same equipment. Such equipment could
be a source of contamination if more
than one product is manufactured using
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the equipment and it is not properly
cleaned and/or sanitized.
e. Written procedures for quality
control operations, including written
procedures for conducting a material
review and making a disposition
decision and written procedures for
approving or rejecting reprocessing
(final subpart F). Quality control
operations must be conducted in a
consistent manner. Failure to carry out
quality control operations in a
consistent and appropriate way could
lead to failure to ensure product quality
and to ensure the dietary supplement is
packaged and labeled as specified in the
master manufacturing record. For
example, you could use a component
that should not have been released for
use in manufacturing, or you could
distribute a packaged and labeled
dietary supplement that should not have
been released for distribution.
We include in final subpart F a
requirement that you establish and
follow written procedures for quality
control operations (final § 111.103). We
agree with the comments that there
should be written procedures for
investigating failures in manufacturing
operations. In the 2003 CGMP Proposal,
we referred to the process of
investigating such failures as a ‘‘material
review’’ and proposed a series of
requirements related to a material
review and the disposition decision that
follows a material review. The review
must be conducted in a consistent
manner, and the criteria for making a
disposition decision must be consistent,
regardless of who is conducting the
material review or when it is conducted,
and regardless of who makes the
disposition decision and when the
decision is made. For example, if you do
not have written criteria for determining
whether a deviation from specifications
has resulted in, or could lead to,
adulteration, different individuals who
conduct a material review could reach
different decisions regarding the
appropriate disposition of the affected
dietary supplement, including decisions
that incorrectly result in the release of
an adulterated product. As discussed
more fully in sections X and XI of this
document, the final rule requires that
quality control personnel conduct all
required material reviews and make all
required disposition decisions.
Therefore, we are requiring that the
written procedures for quality control
operations include written procedures
for conducting a material review and
making a disposition decision (final
§ 111.103).
We considered the comments that
suggest that there should be a
requirement for you to establish and
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follow written procedures for
reprocessing from two perspectives: (1)
Determining whether reprocessing
should be approved or rejected and (2)
performing the reprocessing. In general,
reprocessing is performed when there is
a problem with the manufacturing
process, such as when a specification is
not met or any step in the master
manufacturing record is omitted.
Depending on the nature of the dietary
supplement, the manufacturing process,
and the problem, reprocessing may or
may not be able to correct the problem.
From the perspective of determining
whether reprocessing should be
approved or rejected, under the final
rule it is quality control personnel who
must approve or reject any reprocessing
(see final §§ 111.90, 111.113, 111.120,
111.123, and 111.130). The decision to
approve reprocessing must be made in
a consistent manner, regardless of who
conducts the operation or when it is
conducted. For example, if it is not
possible to test the product at the
finished batch stage to determine
whether the reprocessing corrected the
problem (because, for example, there is
no scientifically valid method available
to test for a specification that is directly
related to the reason for reprocessing),
you must have a clear basis to decide
that reprocessing will actually correct
the problem or you will not know if all
required specifications can be met.
Without written procedures for
approving reprocessing, different
individuals who approve or reject any
reprocessing could make very different
decisions on when reprocessing can
correct a problem and when it cannot.
Therefore, we are specifically requiring
that the written procedures for quality
control operations include written
procedures for approving or rejecting
any reprocessing.
From the perspective of performing
the reprocessing, we agree that any
procedure for reprocessing must be
written because, for example, quality
control personnel may need to rely on
the procedure that you followed to
determine whether all specifications are
met for the reprocessed material.
However, the final rule requires you to
document any reprocessing in the batch
record (final § 111.260(n)) rather than
establishing and following written
procedures to conduct reprocessing,
because the actual procedure you follow
to reprocess a dietary supplement likely
will be different depending on the
circumstances.
f. Written procedures for components,
packaging, labels, and product that is
received for packaging and labeling as
a dietary supplement (final subpart G).
We agree with the comments that the
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receipt, examination, quarantine, and
release from quarantine of components,
packaging, labels, and product that are
received for packaging and labeling as
dietary supplements must be conducted
in a consistent manner, regardless of
who conducts the operation or when it
is conducted. Failure to carry out these
operations in a consistent way could
lead to failure to ensure product quality
if, for example, you use a component
that should not have been released for
use in manufacturing.
We include in final subpart G a
requirement that you establish and
follow written procedures for fulfilling
the requirements of subpart G (final
§ 111.153).
g. Written procedures for laboratory
operations (final subpart J). Testing and
examination of components, packaging,
labels, and product that are received for
packaging or labeling as a dietary
supplement, or packaged and labeled
dietary supplements, must be conducted
in a consistent manner, regardless of
who conducts the operation or when it
is conducted. The reason a firm
conducts these tests and examinations is
to ensure that a dietary supplement
meets established specifications. Failure
to conduct tests and examinations in a
consistent manner could lead to failure
in ensuring the quality of the dietary
supplement. For example, a test
designed to determine the concentration
of a product before it is diluted to the
appropriate concentration could provide
different results if it is conducted in a
different manner by different
individuals.
In addition, laboratory operations
such as use of criteria for establishing
appropriate specifications and use of
sampling plans for obtaining
representative samples must be
conducted in a consistent manner,
regardless of who conducts the
operation or when it is conducted. For
example, failure to consider that
specifications are needed to ensure that
a dietary supplement derived from a
botanical source does not contain
contaminants, such as an unlawful
pesticide, could result in a dietary
supplement that contains unsafe levels
of a contaminant.
We include in final subpart J a
requirement that you establish and
follow written procedures for laboratory
operations, including written
procedures for the tests and
examinations that you conduct to
determine whether specifications are
met (final § 111.303).
h. Written procedures for
manufacturing operations (final subpart
K). We agree with the comments that
written procedures for manufacturing
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operations would be an effective way to
train personnel, provide a means to hold
operators accountable to a quality
standard, and improve quality and
consistency in a manufacturing
operation. The final provisions for
manufacturing operations require you to
design or select manufacturing
processes to ensure that dietary
supplement specifications are
consistently achieved, conduct all
manufacturing operations in accordance
with adequate sanitation principles, and
take all necessary precautions to prevent
contamination of components and
dietary supplements. These
manufacturing operations must be
conducted in a consistent manner,
regardless of who conducts the
operation or when it is conducted.
Failure to perform these operations in a
consistent way could lead to failure to
ensure the quality of the dietary
supplement. For example, surfaces that
come in contact with a dietary
supplement are potential sources of
microbial contamination if consistent
procedures are not in place to ensure
good sanitary practices. We are
including in final subpart K a
requirement that you establish and
follow written procedures for
manufacturing operations (final
§ 111.353).
i. Written procedures for packaging
and labeling operations (final subpart
L). We agree with the comments that
written procedures for packaging and
labeling operations are an effective
means to hold operators accountable to
ensure the quality of the dietary
supplement and that the dietary
supplement is packaged and labeled as
specified in the master manufacturing
record. The final provisions for
packaging and labeling operations
require that you fill, assemble, package,
label, and perform other related
operations in a way that ensures the
quality of the finished product,
including practices such as cleaning and
sanitizing all filling and packaging
equipment, utensils, and containers;
protecting manufactured dietary
supplements against airborne
contamination, using sanitary handling
procedures; taking actions to prevent
mixups; and suitably disposing of
obsolete packaging and labels. These
packaging and labeling operations must
be conducted in a consistent manner,
regardless of who conducts the
operation or when it is conducted.
Failure to perform these operations in a
consistent way could lead to a failure to
ensure the quality of the dietary
supplement and that the dietary
supplement is labeled and packaged as
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specified in the master manufacturing
record. For example, if you do not have
procedures for identifying filled, but
unlabeled, containers of dietary
supplements, mixups could occur
before the labels are applied. The final
product could contain ingredients other
than those identified on the label
specified in the master manufacturing
record. Therefore, we include in final
subpart L a requirement that you
establish and follow written procedures
for packaging and labeling operations
(final § 111.403).
j. Written procedures for holding and
distributing operations (final subpart
M). We agree with the comments that
written procedures for holding and
distributing operations are an effective
means to hold operators accountable to
CGMP standards, and that mixups and
other problems that affect the final
product will be more likely to occur if
there are no written procedures for
operations such as control of storage
locations, manner of storage, and
container and storage location
identification codes. The final
provisions for holding and distributing
operations require, among other things,
that you hold components and dietary
supplements under appropriate
conditions of temperature, humidity,
and light so that the identity, purity,
strength, and composition of the
components and dietary supplements
are not affected; that you hold
components, dietary supplements, and
in-process materials under conditions
that do not lead to the mixup,
contamination, or deterioration of
components or dietary supplements;
and that you distribute dietary
supplements under conditions that will
protect them against contamination and
deterioration.
These holding and distributing
operations must be conducted in a
consistent manner, regardless of who
conducts the operation or when it is
conducted. Failure to follow these
requirements for holding and
distributing in a consistent manner
could lead to a failure to ensure the
quality of the dietary supplement
product. For example, if employees do
not know how to store an in-process
batch of a botanical dietary supplement
to control humidity, the growth of mold
could be promoted. Furthermore, if a
distributor does not refrigerate a dietary
supplement that requires refrigeration to
ensure its strength, the dietary
supplement may not meet its
specification for strength. Therefore, we
include in final subpart M a
requirement that you establish and
follow written procedures for holding
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and distributing operations (final
§ 111.453).
k. Written procedures for returned
dietary supplements (final subpart N).
We agree with the comments that
written procedures for returned dietary
supplements would help to ensure
appropriate handling of such
supplements prior to a disposition
decision. The final rule requires you,
among other things, to identify and
quarantine returned dietary
supplements until quality control
personnel conduct a material review
and make a disposition decision. You
must destroy, or otherwise suitably
dispose of, any returned dietary
supplement that quality control
personnel do not approve for salvage or
reprocessing. These operations for
returned dietary supplements must be
conducted in a consistent manner,
regardless of who conducts the
operation or when it is conducted.
Failure to comply with these
requirements for quarantine, salvage,
and disposition in a consistent way
could lead to a failure to ensure the
quality of the dietary supplement. For
example, if an investigation leads to a
conclusion that a dietary supplement
requiring refrigeration to ensure its
strength was not refrigerated while held
at a customer’s warehouse, and this
dietary supplement was not quarantined
while quality control personnel
conducted a material review, the dietary
supplement could be inadvertently comixed with other containers of that
same lot of product and then
inadvertently redistributed. Therefore,
we are including in final subpart N a
requirement that you establish and
follow written procedures to fulfill the
requirements of subpart N (final
§ 111.503).
l. Written procedures for product
complaints (final subpart O). We agree
with the comments that written
procedures for handling consumer
complaints (now called product
complaints) will encourage companies
to handle product complaints in a
consistent manner and help ensure the
essential information is captured during
investigation of a product complaint.
The final rule requires you, among other
things, to review all product complaints
to determine whether the product
complaint involves a possible failure of
a dietary supplement to meet any of its
specifications; investigate any product
complaint that involves a possible
failure of a dietary supplement to meet
any of its specifications; and extend the
review and investigation of the product
complaint to all relevant batches and
records. These operations must be
conducted in a consistent manner,
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regardless of who conducts the
operation or when it is conducted.
Failure to comply with these
requirements for review and
investigation of a product complaint in
a consistent way could lead to a failure
to ensure the quality of the dietary
supplement. For example, if you do not
have a procedure in place to determine
whether the product complaint involves
a possible failure of a dietary
supplement to meet any of its
specifications, you may not recognize
that a particular product complaint is
indicative that a problem has occurred
with one of your manufacturing
processes. That undiscovered problem
may lead to continued distribution of
product that is contaminated or
otherwise not consistent with your
specifications in the master
manufacturing record. Therefore, we
include in final subpart O a requirement
that you establish and follow written
procedures to fulfill the requirements of
subpart O (final § 111.553).
3. Written Procedures That Are Not
Required by This Final Rule
a. Written procedures for final subpart
E (‘‘Requirement to Establish a
Production and Process Control
System’’). In the CGMP proposal, we did
not specifically request comments on
whether we should require that you
establish and follow written procedures
to fulfill the requirements of proposed
§ 111.35 (‘‘What Production and Process
Controls Must You Use?’’), and we
received no specific comments
regarding whether we should establish
and follow such written procedures.
Given the strong support in the
comments for the use of written
procedures in a production and process
control system, we nonetheless
considered whether the requirements
that we establish in final subpart E,
Requirement to Establish a Production
and Process Control System, would
require written procedures.
Final subpart E requires that you
implement a system of production and
process controls that covers all stages of
manufacturing, packaging, labeling, and
holding of the dietary supplements and
that your system be designed to ensure
the quality of the dietary supplement
and that the dietary supplement is
packaged and labeled as specified in
your master manufacturing record (final
§§ 111.55 and 111.60); implement
quality control operations to ensure the
quality of dietary supplements and that
the dietary supplement is packaged and
labeled as specified in your master
manufacturing record (final § 111.65);
establish specifications (final § 111.70);
determine whether specifications are
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34773
met (final §§ 111.73 and 111.75); collect
representative samples (final § 111.80);
hold reserve samples of packaged and
labeled dietary supplements (final
§ 111.83); have quality control
personnel conduct all required material
reviews and make all required
disposition decisions (final § 111.87);
and adhere to certain requirements for
treatment, in-process adjustments, and
for reprocessing (final § 111.90).
In considering whether we should
require that you establish and follow
written procedures to fulfill the
requirements of final subpart E, we
evaluated whether requirements in
other subparts that address specific
operations for the production and
process control system substitute for the
requirement of written procedures in
final subpart E.
Final subparts F through M establish
specific requirements for
manufacturing, packaging, labeling, and
holding dietary supplements, including
requirements for quality control
operations (final subpart F);
components, packaging, labels, and
product that is received for packaging
and labeling as a dietary supplement
(final subpart G); establishing a written
master manufacturing record and batch
record (final subparts H and I);
laboratory operations (final subpart J);
manufacturing operations (final subpart
K); packaging and labeling operations
(final subpart L); and holding operations
(final subpart M). We require you to
establish and follow written procedures
to fulfill the requirements of final
subparts F, G, J, K, L, and M. Given
these requirements, we conclude it
would be redundant to require you to
establish and follow written procedures
to fulfill the requirements of final
§§ 111.55, 111.60, and 111.65 in subpart
E.
Final subpart J requires you to
establish and follow laboratory control
processes that include the use of criteria
for establishing appropriate
specifications (final § 111.315(a)); use of
sampling plans for obtaining
representative samples (final
§ 111.315(b)); use of criteria for selecting
appropriate examination and testing
methods (final § 111.315(c)); use of
criteria for selecting standard reference
materials used in performing tests and
examinations (final § 111.315(d)); and
use of test methods and examinations in
accordance with established criteria
(final § 111.315(e)). In addition, under
final § 111.303 you must establish and
follow written procedures for laboratory
operations. Given the requirements of
final subpart J, we conclude it would be
redundant to require you to establish
and follow written procedures to fulfill
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the requirements of final §§ 111.70,
111.75, and 111.80 in subpart E.
Final subpart M establishes
requirements for holding reserve
samples. Under final § 111.453, you
must establish and follow written
procedures for holding operations.
Given the requirements of final subpart
M, we conclude that it would be
redundant to require you to establish
and follow written procedures to fulfill
the requirements of final § 111.83 in
subpart E for reserve samples.
Final subpart F establishes
requirements for quality control
personnel to conduct a material review
and make a disposition decision (final
§ 111.113); approve any reprocessing
(final § 111.123(a)(5)); and document
any material review and disposition
(final § 111.140(b)(3)). In addition, as
discussed, under final § 111.103 you
must establish and follow written
procedures for quality control
operations. Given the requirements of
final subpart F, we conclude that it
would be redundant to require that you
establish and follow written procedures
to fulfill the requirements of final
§§ 111.87 and 111.90 in subpart E.
We conclude that it would be
redundant to require you to establish
and follow written procedures for each
of the requirements established in final
subpart E. We, therefore, do not require
you to establish and follow written
procedures to fulfill the requirements
established in subpart E.
b. Written procedures for preparing
the master manufacturing record (final
subpart H) and for preparing the batch
record (final subpart I). As discussed in
the 2003 CGMP Proposal (68 FR 12157
at 12203), a master manufacturing
record is analogous to a recipe that sets
forth the ingredients to use, the amounts
of ingredients to use, the tests to
perform, and the instructions for
preparing the quantity the recipe calls
for. This master manufacturing record
helps ensure that you manufacture each
ingredient or dietary supplement in a
consistent and uniform manner. If you
neglect to follow the master
manufacturing record, you might not
add all of the necessary components in
the appropriate strength or amount, and
this could result in a final product not
consistent with the master
manufacturing record. Thus, you must
follow a written master manufacturing
record in a consistent manner,
regardless of who conducts the
operation or when it is conducted.
However, we agree with the
comments that the specific requirements
for what must be in the master
manufacturing record make it
unnecessary to require written
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procedures for preparing the master
manufacturing record. Under final
subpart H, the master manufacturing
record must include written
instructions, including specifications for
each point, step, or stage in the
manufacturing process where control is
necessary to ensure the quality of the
dietary supplement and that the dietary
supplement is packaged and labeled as
specified in the master manufacturing
record; procedures for sampling, testing,
and examinations; specific actions
necessary to perform and verify points,
steps, or stages in the manufacturing
process where control is necessary to
ensure the quality of the dietary
supplement and that the dietary
supplement is packaged and labeled as
specified in the master manufacturing
record; special notations and
precautions to be followed; and
corrective action plans for use when a
specification is not met. With all of this
detail specified for the written
instructions the master manufacturing
record must include, we believe a
written procedure for developing a
master manufacturing record can be
optional. Therefore, we do not require
you to establish and follow written
procedures for preparing the master
manufacturing record.
A batch is prepared by following the
written instructions provided in the
master manufacturing record. The
master manufacturing record functions
as a written procedure for the
production of the batch. Therefore, we
do not require you to establish and
follow written procedures for the batch
production record because such
practices would be redundant to the
requirements for the master
manufacturing record in final subpart H.
c. Written procedures for records and
recordkeeping (final subpart P). Final
subpart P establishes general
requirements for making and keeping
records required in other subparts. We
did not request comments on written
procedures, nor did we receive any
comments that supported such a
requirement. Because we believe that
requiring written procedures to fulfill
subpart P requirements would be
redundant or unnecessary, we do not
require such written procedures.
d. Written procedures for product
recalls. We acknowledge that a product
recall by persons who manufacture,
package, label, or hold dietary
supplements must be conducted in a
consistent manner, regardless of who
conducts the operation or when it is
conducted. However, the final rule does
not establish any requirements for
product recalls. Therefore, we do not
require you to establish and follow
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written procedures for product recalls.
However, we encourage you to refer to
our ‘‘Guidance for Industry: Product
Recalls, Industry Removals and
Corrections’’ (Ref. 12) (available at
https://www.fda.gov/opacom/
7alerts.html).
D. Other Comments on Written
Procedures
(Comment 9) One comment stresses
the need for flexibility in requiring
written procedures, based on differences
between individual activities and
companies. The comment suggests
companies should be required to review
and determine the need for written
procedures at each critical step of their
operations and be prepared to defend
those determinations as necessary.
(Response) To the extent the comment
suggests we do not require any written
procedures specific to a particular
function or requirement, and allow
firms to decide when and when not to
include them, we disagree. We believe
that written procedures for the specific
operations we have identified should
not be optional. We have no objection
if firms decide to establish and follow
additional written procedures, beyond
those we require in this final rule.
Although we require written procedures
for entire subparts, or specific
requirements within certain subparts,
we provide flexibility for firms to
establish those written procedures that
will ensure the requirements are met.
(Comment 10) Some comments stress
the importance of written procedures in
enabling FDA to ensure compliance
with the dietary supplement CGMP
requirements.
(Response) We believe written
procedures will help us to ensure
compliance with these CGMP
requirements because they will clearly
communicate the steps the firm must
take to satisfy the requirements. During
an inspection, we observe the practices
that employees follow. However, to
ensure that a firm is consistently
complying with CGMP requirements,
our investigators need access to records
that both describe a firm’s processes and
procedures and demonstrate whether
the firm has been following them. Under
the final rule, we require you to make
and keep records of the written
procedures in each applicable subpart.
Such records would be available to us
under the requirements of final subpart
P, Records and Recordkeeping.
(Comment 11) Many comments object
to FDA’s stated reasons for not requiring
written procedures for most activities,
including concerns about cost control
and burden reduction. The comments
contend that written procedures
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actually save time and other resources
because they greatly facilitate employee
training and ensure that activities are
performed consistently and correctly.
Some comments assert most companies
already have written procedures in
place, so start-up costs associated with
such requirements would be minimal.
One comment notes written procedures
would be among the least costly of all
the procedural requirements proposed
by FDA.
(Response) We agree that requiring
that operations be conducted using
written procedures can save time and
other resources by facilitating employee
training and ensuring operations are
performed consistently and correctly.
Because following written procedures
can help ensure uniformity in the
process and ensure the quality of the
dietary supplement at every step,
periodic end product testing can be
sufficient to determine whether your
manufacturing process is controlled.
CGMP is premised upon quality
assurance at every step of the process.
It is less costly to establish and follow
written procedures than it would be to
test each finished batch for conformance
with specifications. As suggested by
these comments, our analysis (section
XXIV of this document) shows that the
overall costs are reduced, in part,
because requiring that certain
operations be conducted using written
procedures enables us to reduce
requirements for testing at the finished
batch stage.
(Comment 12) One comment states
training employees on the required
hygienic practices prior to their first day
of handling product is critical to
ensuring product safety.
(Response) The requirement to
establish and follow written procedures
to fulfill the requirements of subpart B
does not establish any fixed requirement
for when an employee must receive
such training relative to when the
employee handles product. However,
final § 111.12(c) requires that any
person engaged in manufacturing,
packaging, labeling, or holding, or in
performing any quality control
operations, must have the education,
training, or experience to perform the
person’s assigned functions. We
therefore assume that employees will
have the necessary education, training,
or experience for each operation that
they perform before they perform it.
(Comment 13) Some comments make
recommendations for what written
procedures should contain, including
general parameters that should be
included in all written procedures and
specific parameters that should be
included in specific written procedures.
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The general parameters include
identification of the company; title that
reflects the activities to be performed;
identification or control number with a
revision level code; effective date; the
number of pages in the procedure (e.g.,
by a procedure such as listing page
numbers using a convention such as
‘‘page 1 of 4’’); approval date and
signature(s); references to linked or
related procedures or forms; definitions
of technical terms and acronyms; list of
equipment, materials, and supplies
needed in performing the task; who has
the responsibility for performing each
task; when and where a task is to be
performed; concise step-by-step
instructions for performing the task; the
expected results from performing the
task; what data to collect; and how to
analyze, file, or report the collected
data. In the specific case of written
procedures for cleaning equipment and
utensils, some comments suggest the
written procedures include descriptions
of appropriate cleaning agents, methods
of cleaning, and the intervals and
schedules for cleaning equipment.
(Response) We agree the suggestions
provided by these comments are useful
to include in any written procedures.
However, to provide the flexibility
necessary to address diverse dietary
supplement manufacturing processes,
we are leaving details such as these to
the judgment of the company rather
than prescribing them within the final
rule.
(Comment 14) Some comments
request the final rule include
requirements for managing changes to
written procedures. One comment states
changes to written procedures should be
reviewed, justified, documented,
approved, and implemented in a
defined manner. The comments explain
that ‘‘Change control procedures’’ define
what is and what is not covered by the
written procedure and how proposed
changes will be identified or
recommended, processed, reviewed,
and approved.
(Response) As discussed in final
subpart F, the final rule requires that
quality control personnel approve all
written procedures. ‘‘All’’ written
procedures includes revisions to written
procedures. As discussed in this
section, the final rule requires you to
establish and follow written procedures
for quality control operations. We
believe that procedures for managing
changes to written procedures can be
addressed within the written procedures
for quality control operations.
(Comment 15) Some comments assert
the final rule should not require written
procedures for key operations because
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the rule should stay focused on end
results and not process.
(Response) We disagree. The essence
of good manufacturing practice that is
established by this final rule is a
production and process control system
that is designed to ensure the quality of
the dietary supplement.
E. What Other General Comments Did
We Receive?
(Comment 16) Some comments say
any final rule should not require written
procedures, should not propose a
definition of appropriate tests, and
generally should not include
requirements for procedures better left
to ‘‘normal business practices.’’ The
comments cited Executive Order 12866
and the Small Business Regulatory
Enforcement Flexibility Act (SBREFA).
The comment added that there is no
such requirement in the food CGMPs or
in the 1997 ANPRM.
(Response) We disagree the final rule
violates either Executive Order 12866 or
SBREFA and discuss this in section
XXIV of this document. We address
SBREFA’s regulatory flexibility issues
by staggering compliance dates so that
certain businesses would have 24 and
36 months, respectively, to comply with
the final rule. As for the assertion that
food CGMPs do not require written
procedures, we discuss the
requirements of food CGMPS in relation
to the requirements of these dietary
supplement CGMPs in section V of this
document. The comment’s assertion that
the 1997 ANPRM did not contain
written procedures is incorrect. The
industry draft that we published in the
1997 ANPRM had multiple written
procedures, including written
procedures for:
• Cleaning and maintaining
equipment and utensils used in the
manufacture of products;
• The receipt, identification,
examination, handling, sampling,
testing, and approval or rejection of raw
materials;
• Appropriate tests and/or
examinations to be conducted to assure
the purity, composition, and quality of
the finished product;
• The method for reprocessing
batches or operational start-up materials
that do not conform to finished goods
standards or specifications;
• The control procedures employed
for the receipt, storage, handling,
sampling, examination, and/or testing
that may be necessary to assure the
identity of labeling and the appropriate
identity, cleanliness, and quality
characteristics of packaging materials
for dietary products;
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• Ensuring correct labels, labeling,
and packaging materials are issued and
used for dietary products; and
• Describing the handling of all
written and oral complaints regarding a
product.
(62 FR 5700 at 5704 through 5706).
(Comment 17) In the analysis of
impacts in the 2003 CGMP Proposal (68
FR 12157 at 12222), we stated that we
had considered imposing fewer CGMP
requirements for the manufacture of
vitamins and minerals. Although this
issue arose as a discussion of regulatory
options that we had considered and
rejected, we received several comments
on this subject. Some comments state
we should not create different CGMP
standards based upon the type of dietary
ingredient. These comments state that
one set of appropriately flexible
standards would be more efficient and
less confusing to industry than separate
standards for each portion of the
industry. Some comments say that
different requirements for vitamins and
minerals would cause problems because
most people who use these products
take a multivitamin/mineral preparation
as their primary and sole dietary
supplement, so the risk of adverse
events arising from adulteration,
misidentification, or misformulation of
products would be much higher if
vitamins and minerals were subject to
fewer requirements compared to other
dietary supplements. Other comments
supported the concept of differing
standards. Some comments assert, in
order for the CGMP regulations to set
minimum quality standards for all
dietary supplements, we would have to
regulate each facet of the manufacture,
packaging, and storage of a dietary
supplement independently of product
type. These comments state reducing
the requirements for vitamin and
mineral manufacturers would not allow
the development of minimum quality
standards across the entire dietary
supplement industry.
(Response) The concept of fewer
requirements for vitamins and minerals
was simply one regulatory option we
considered as part of the 2003 CGMP
Proposal’s analysis of impacts (see 68
FR 12157 at 12220 through 12223). We
rejected it (id.). We disagree with the
comments that there should be fewer
CGMP requirements for vitamins and
minerals. Neither the 2003 CGMP
Proposal, nor this final rule, imposes
fewer requirements on vitamin or
mineral firms compared to firms that
make other types of dietary
supplements.
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V. What Legal Authority Comments Did
We Receive?
Many comments were submitted from
individuals, companies, and trade
groups concerning our legal authority
for this rule. Most of the comments
question the scope of the rule based on
the language in section 402(g) of the act
(21 U.S.C. 342(g)) stating that
‘‘regulations shall be modeled after
current good manufacturing practice
regulations for food.’’ Other comments
question our authority for records
access. Some comments assert that
certain provisions of the proposed rule
are unconstitutionally vague, and
therefore violate the Fifth Amendment.
A few comments disagree with our
rationale for why dietary supplements
are different than conventional food and
need separate CGMP requirements. We
address these comments immediately
below in this section.
A. Modeled After CGMP for Food
(Comment 18) Some comments
support our approach of proposing
requirements that are more
comprehensive than the CGMP
requirements for food. One comment
states that the current requirements for
food CGMP are less comprehensive than
the CGMP requirements in current use
by both the food and dietary
supplement industries and the current
‘‘best practices’’ should be incorporated
into the dietary supplement CGMP rule.
Several comments state that the
requirements for dietary supplement
CGMP do not need to be identical to the
requirements in existing food CGMP
regulations, that appropriate
manufacturing controls are needed for
dietary ingredients contained in dietary
supplements to protect the public
health, that some borrowing of drug
CGMP concepts may be necessary, and
that we should balance effective control
with necessary flexibility in the dietary
supplement CGMP rule. In addition, one
comment states that the USP
manufacturing guidelines, which
contain wording from the drug CGMP
requirements, are a model for dietary
supplement CGMP for many in
industry.
Several comments express concern
about not deviating too drastically from
the requirements in existing food CGMP
regulations. Although several comments
recognize that additional CGMP
provisions for dietary supplements,
such as those related to identity, purity,
strength, quality, and composition, are
needed, the comments say that we
should not regulate dietary supplement
manufacturing in the same manner as
drug manufacturing because it would
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entail overly burdensome methods for
production and process controls. Some
comments contend that some of the
proposed rule requirements exceed the
drug CGMP requirements.
Most of the comments assert that the
proposed dietary supplement CGMP
requirements are not modeled after the
CGMP regulations for food. The reasons
for this assertion vary. Some assert that
certain provisions in the proposed rule
were not found in, or differ from, the
provisions in part 110. Examples of
proposed requirements that comments
indicate exceeded food CGMP included
batch testing, packaging and labeling,
recordkeeping, consumer complaints,
and the use of validated methods. Other
comments state that the proposed
requirements exceeded those for food
because the proposed rule provided for
finished testing of certain substances
when used as dietary supplements, such
as garlic and ginger, whereas no such
testing is required under existing food
CGMP regulations when those same
substances are used as conventional
food. One comment says the rule was
modeled after juice hazard analysis and
critical control point (HACCP) and
therefore goes beyond existing food
CGMP regulations.
Some comments assert that the
proposed requirements exceed the
existing food CGMP regulations because
certain proposed provisions contained a
level of detail that is not in the food or
the drug CGMP regulations, or because
elements of a provision in the proposed
rule were similar to a provision in part
210 (21 CFR part 210) (drug CGMP
regulation). Other comments disagree
with our rationale that the proposed
rule was designed on the same
principles as the existing food CGMP
regulations to address the characteristics
and hazards specific to dietary
supplements, or to prevent adulteration
in preparing, packaging, or holding
dietary supplements. The comments
also disagree that we may include
provisions in the dietary supplement
CGMP final rule that were not found in
the food CGMP regulations at the time
DSHEA was enacted.
Several comments state that we
exceed our legal authority for the
proposed rule because it used too broad
a definition of ‘‘modeled after.’’ Some
comments offer their own definitions of
‘‘model;’’ others object to the use of the
noun form ‘‘model’’ and provide
dictionary definitions of the verb form
‘‘modeled.’’ A few comments assert that
the meaning of ‘‘model’’ is clear, despite
different dictionary meanings, and that
the statute is not ambiguous under
Chevron U.S.A. Inc. v. Natural
Resources Defense Council, 467 U.S.
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837 (1984) (‘‘Chevron’’). One comment
states that, even if the language is
ambiguous and our interpretation merits
deference, our interpretation is too
expansive and not based on a
permissible construction of the statute.
Another comment states that we did not
explain why our interpretation was
consistent with our congressional
mandate.
(Response) We agree with the
comments stating that the dietary
supplement CGMP requirements in this
final rule need not be identical to the
existing food CGMP regulations and that
a system of manufacturing controls
specific to dietary supplements is
needed. We do not agree that we
exceeded the scope of our authority
under section 402(g) of the act in issuing
the proposed requirements for dietary
supplement CGMP or these final
requirements. Our interpretation of the
language in section 402(g) of the act,
including the ‘‘modeled after’’ language,
as to what requirements of the act we
have authority to issue, is based on a
permissible construction of the statute.
The comments present the following
general questions: (1) Whether the
statute gives us authority to promulgate
CGMP requirements for dietary
supplements that are not identical to the
requirements in existing CGMP
regulations for food and (2) if so,
whether the requirements in this final
rule that differ from those in existing
CGMP regulations for food are fairly
encompassed within Congress’ direction
that the dietary supplement regulations
shall be ‘‘modeled after’’ food
regulations and, therefore, are based on
a permissible construction of the statute.
Under section 402(g)(1) of the act, a
dietary supplement is deemed to be
adulterated if it has ‘‘been prepared,
packed, or held under conditions that
do not meet current good manufacturing
practice regulations, including
regulations requiring, when necessary,
expiration date labeling, issued by the
Secretary under subparagraph (2).’’
Section 402(g)(2) of the act authorizes
the Secretary, by regulation, to
‘‘prescribe good manufacturing practices
for dietary supplements.’’ Congress
further provided that such regulations
‘‘shall be modeled after current good
manufacturing practice regulations for
food’’ and ‘‘may not impose standards
for which there is no current and
generally available analytical
methodology.’’
In construing the meaning of section
402(g) of the act, and, in particular, the
language in that section stating that
such regulations shall be ‘‘modeled after
current good manufacturing practice
regulations for food,’’ we are confronted
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with two questions. First, has Congress
directly and unambiguously spoken to
the precise question at issue? (‘‘Chevron
step one’’) (see Chevron, 467 U.S. at
842.) To find no ambiguity, Congress
must have clearly manifested its
intention with respect to the particular
issue (see Young v. Community
Nutrition Institute, 476 U.S. 974, 980
(1986)). If Congress has spoken directly
and plainly, we must implement
Congress’s unambiguously expressed
intent (see Chevron, 467 U.S. at 842–
843). Second, if the act is silent or
ambiguous with respect to a particular
issue in section 402(g) of the act, is our
interpretation based on a permissible
construction of the statute (‘‘Chevron
step two’’) (Chevron, 467 U.S. at 843;
FDA v. Brown & Williamson Tobacco
Corp., 529 U.S. 120, 132 (2000))? When
Congress leaves a gap for the agency to
fill by regulation, the regulation will
pass muster so long as it is not
‘‘arbitrary, capricious, or manifestly
contrary to the statute’’ (Chevron, 467
U.S. at 843–844).
We believe that the language in
section 402(g) of the act provides an
express delegation of authority to us to
promulgate a regulation to ‘‘prescribe
good manufacturing practices for dietary
supplements’’ so long as those
regulations are ‘‘modeled after the
current good manufacturing practice
regulations for food.’’ The express
language in section 402(g) of the act
contemplates broad, but not unlimited,
agency discretion as to what to include
in a dietary supplement CGMP
regulation.
Congress has also spoken to the
precise question of whether the dietary
supplement CGMP requirements must
be identical to the requirements in
existing food CGMP regulations. If
Congress had wanted dietary
supplement CGMP to be identical to
food CGMP, it easily could have
required that by statute. Indeed, if
Congress had intended for CGMPs for
dietary supplements to be the same as
food CGMPs, there would have been no
need for Congress to have addressed the
issue at all; as a type of food, dietary
supplements would otherwise be
governed by the food CGMPs. See
section (ff) of the act (21 U.S.C. 321(ff)).
Instead, the statute calls for us to issue
regulations that are ‘‘modeled after’’
CGMP regulations for food. The plain
meaning of a ‘‘model’’ or ‘‘modeled
after,’’ as discussed in the 2003 CGMP
Proposal (68 FR 12157 at 12165) and in
the comments, relates to a pattern, plan,
representation, or simulation. The use of
the term ‘‘modeled after’’ makes it clear
that the regulations need not be
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identical to the original, but instead are
contemplated to differ from the original.
Thus, the additional, independent
authority to promulgate CGMP
regulations for dietary supplements that
Congress provided in section 402(g) of
the act, without delineating what
requirements such a regulation could or
could not include, left us with
considerable authority to fill in the gaps
in ways that recognize the differences
between dietary supplements and other
foods that warrant different
manufacturing controls. A contrary
interpretation, as some comments
suggested, that the ‘‘modeled after’’
language means the requirements for
dietary supplement CGMP must be
precisely found in current part 110, or
other food CGMP regulations, would so
narrowly circumscribe our discretion as
to make it impossible to tailor the
regulation to fit the products it is
designed to address. Such an
interpretation would lead to a rule that
would ‘‘frustrate the success of the
regulation undertaken by Congress’’
because it would not take into
consideration the characteristics,
hazards, and manufacturing practices
specific to dietary supplements
(American Trucking Ass’ns v. U.S., 344
U.S. 298, 311 (1953)).4
Congress has also spoken to the
precise question of which requirements
CGMP ‘‘regulations for food.’’ The plain
meaning of ‘‘regulations’’ is plural (more
than one), and the plain meaning of
‘‘food’’ is as Congress defined in section
201(f) of the act, including articles
‘‘used for food or drink.’’ At the time
DSHEA was enacted, there were five
food CGMP regulations: Those for infant
formula (part 106), thermally processed
low-acid canned food (part 113),
acidified food (part 114), bottled water
(part 129), and general food (part 110,
often referred to as the ‘‘umbrella’’
regulations). All of these regulations
appear in Subchapter B of Chapter 1 of
Title 21 of the Code of Federal
Regulations, entitled ‘‘Food for Human
Consumption.’’ Nothing in the language
of section 402(g) or elsewhere suggests
that Congress meant to limit the term
CGMP ‘‘regulations for food’’ to only the
regulation in part 110. Thus, it is
4The Senate Report on DSHEA states that
Congress inserted section 402(g) because it
recognized that ‘‘dietary supplements may require
different manufacturing and quality controls’’ when
compared to food CGMP (S. Rep. No. 140, 103rd
Cong., 2d Sess., at 31 (1994)). However, the report
is not considered legislative history. Congress
issued a Statement of Agreement (140 Cong. Rec.
S14801 (Oct. 7, 1994), reprinted in 1994
U.S.C.C.A.N. 3523) that stated ‘‘it is the intent of the
chief sponsors of the bill * * * that no other
reports or statements be considered as legislative
history for the bill’’).
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consistent with our statutory authority
for us to look to all of our food CGMP
regulations—including infant formula,
low-acid canned foods, acidified foods,
and bottled water, as well as our general
food CGMP regulations—after which to
model our dietary supplement CGMP
regulations.
Congress has not spoken to the
precise question of what specific
requirements for dietary supplements
may be imposed under the ‘‘shall be
modeled after’’ language. Given this
ambiguity, therefore, under Chevron
step two, we may determine what
requirements to include in this final
rule for dietary supplement CGMP,
provided that our interpretation is not
arbitrary, capricious, or manifestly
contrary to the statute (Chevron, 467
U.S. at 844).
Accordingly, we considered the types
of requirements in the existing food
CGMP regulations and used those as
models for the dietary supplement
CGMP requirements. We considered
both the objectives and the means of
achieving the objectives in the existing
food CGMP regulations. These CGMP
food regulations include those for infant
formula (part 106), general food
(‘‘umbrella’’ regulations) (part 110),
thermally processed low-acid canned
food (part 113), acidified food (part
114), and bottled water (part 129). Each
of these food CGMP regulations
provides objectives and means upon
which we modeled the dietary
supplement CGMP regulations. Just as
the precise requirements of the other
food CGMP regulations are tailored to
the particular characteristics and
hazards of the foods and manufacturing
processes being addressed, the dietary
supplement CGMP requirements are
also so tailored.
For example, the infant formula
CGMP regulation is intended to ensure
that the ‘‘safety and nutritional
potency’’ of a formula are ‘‘built into the
manufacturing process’’ in order to
establish a quality control system to
make sure that infant formula products
are properly manufactured (47 FR 17016
at 17017, April 20, 1982). The specific
criteria in the regulations apply in
determining whether the infant formula
meets the safety, quality, and nutrient
requirements of the act (§ 106.1(a)). The
means to achieving the objectives in the
infant formula regulations include, for
example, requirements for ingredient
control (through a supplier’s guarantee
or certification or through analysis of
the ingredient) (§ 106.20); preparation of
a master manufacturing order and a
system to assure and verify the addition
of each ingredient (§ 106.25); either inprocess batch testing (§ 106.25(b)) or
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sampling and testing of each batch to
ensure nutrient requirements are met
(§ 106.30); and coding to enable ready
identification of lots during their sale
and distribution (§ 106.90).
The infant formula CGMP regulation
also includes numerous requirements
that manufacturers maintain records,
e.g., records on certain food-packaging
materials; records on nutrient premix
testing; certificate and guarantees from
premix suppliers for required nutrients;
records of results of testing conducted
by suppliers; records of tests to establish
the purity of each nutrient, the weight,
and amounts of nutrients; records to
ensure proper nutrient quality control;
records to ensure required nutrient
control at the final product stage;
distribution records; records on
microbiological quality and purity of
raw materials; and records of audits
(§ 106.100). The infant formula CGMP
regulation also requires manufacturers
to maintain procedures describing how
complaints will be handled, to follow
those procedures, and to investigate
when a complaint shows a possible
health hazard (§ 106.100(k)). Quality
control records must contain enough
information to permit a public health
evaluation of any batch of infant
formula (§ 106.100(o)). All required
records must be available for authorized
inspection (§ 106.100(l)).
Many provisions of the dietary
supplement CGMP final rule are similar
in objective and means and are
‘‘modeled after’’ the provisions of the
infant formula CGMP regulation. For
example, like the infant formula
regulation, the dietary supplement
CGMP regulation is designed to
establish a quality control system to
make sure that dietary supplements are
properly manufactured. The dietary
supplement regulation uses similar
means to ensure this goal, such as
requirements for ingredient control
(through supplier’s certificate of
analysis or testing or examination) (final
§ 111.75(a)); preparation of a master
manufacturing record (final § 111.205);
in-process batch monitoring (final
§ 111.75(b)) or batch testing or
examination (final § 111.75(c)); and
coding to provide a batch, lot, or control
number (final § 111.260(a)). Like the
infant formula CGMP regulations, the
dietary supplement CGMP final rule
contains recordkeeping requirements
related to packaging materials;
certificates of analysis from suppliers;
results of tests that you conduct, for
example, on ingredients or the finished
batch; and results of chemical,
microbiological, or other tests that you
conduct as necessary to prevent the use
of contaminated components (final
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§§ 111.95, 111.180(b)(2), 111.260(h),
111.325(b)(2), and 111.365(d)). Also
similar to the infant formula CGMP
regulation, the dietary supplement
CGMP final rule requires manufacturers
to maintain procedures for handling
complaints (final §§ 111.553 and
111.570(b)(1)); to investigate certain
complaints (final § 111.560(a)(2)); and to
keep records of complaints (final
§ 111.570(b)(2)). Required dietary
supplement records must also, as with
infant formula records, be available for
inspection by FDA (final § 111.610(a)).
The ‘‘umbrella’’ food CGMP
regulation in part 110 details practices
to ensure ‘‘(1) that food is manufactured,
processed, packed, and held under
conditions that are sanitary, and (2) that
such food is safe, clean, and
wholesome’’ (44 FR 33238 at 33239,
June 8, 1979). Promulgated primarily
under the adulteration provisions of
section 402(a)(3) and (a)(4) of the act, as
well as section 361 of the Public Health
Service Act (the PHS Act) (42 U.S.C.
264), the umbrella CGMP food
regulation requires a quality control
operation whose main purpose is ‘‘to
provide a systematic procedure for
taking all actions necessary to prevent
food from being adulterated within the
meaning of the act’’ (51 FR 22458 at
22461, June 19, 1986), as well as to
prevent the spread of food-borne
communicable diseases (44 FR 33239,
June 8, 1979) (see § 110.5(a)). Part 110
also ‘‘specifies requirements that must
be met to produce safe and wholesome
food’’ (51 FR 22461). These umbrella
food CGMP requirements not only
pertain to food safety, but also are
‘‘concerned with contamination by filth
or decomposition which may or may not
raise safety concerns’’ (51 FR 22458 at
22462).
The detailed requirements of the
umbrella food CGMP regulation
accomplish these objectives through a
variety of means. For example, there are
specific personnel provisions requiring
employees who may be sources of
microbial contamination to be excluded
from certain operations (§ 110.10(a));
persons working in contact with food,
food-contact surfaces, and foodpackaging materials to follow hygienic
practices (§ 110.10(b)); and that certain
personnel have sufficient education or
experience to produce clean and safe
food (§ 110.10(c)). The umbrella food
CGMP regulation also includes detailed
requirements concerning the grounds
surrounding a food plant and the design
of buildings and structures to protect
against contamination or to maintain
sanitary operations and produce safe
food (§ 110.20). Detailed provisions also
require that physical facilities be
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maintained in sanitary condition and in
sufficient repair to prevent food from
being adulterated (§ 110.35). Any water
that contacts food or food-contact
surfaces must be ‘‘safe and of adequate
sanitary quality’’ (§ 110.37(a));
plumbing, sewage, and other disposal,
as well as toilet facilities, must also
protect against contamination
(§ 110.37(b), (c), and (d)). Similarly,
equipment and utensils must be
designed and maintained to preclude
adulteration and food contact surfaces
must be maintained to protect food from
being contaminated by any source,
including unlawful indirect food
additives (§ 110.40(a)). All operations
for receiving, inspecting, transporting,
segregating, preparing, manufacturing,
packaging, and storing food must be
conducted using adequate sanitation
principles (§ 110.80). Appropriate
quality control operations must be used
to ensure that food is suitable for human
consumption and that food-packaging
materials are safe and suitable
(§ 110.80). Foods must be stored and
transported under conditions to protect
against physical, chemical, and
microbial contamination, as well as
against deterioration of the food and the
container (§ 110.93).
The provisions of the umbrella food
CGMP regulation serve as the model for
many dietary supplement CGMP
provisions. For example, the dietary
supplement CGMP requirements
concerning personnel and microbial
contamination (final § 111.10(a));
hygienic practices (final § 111.10(b));
and education, training, or experience
(final § 111.12) are very similar to
provisions in part 110. In addition, the
dietary supplement CGMP requirements
concerning the grounds, physical plant
facilities, cleaning materials, pest
control, water supply, plumbing, sewage
disposal, bathrooms, and trash disposal
(final §§ 111.15 and 111.20) closely
resemble the analogous part 110
requirements.
Because of the particular hazards
associated with low-acid canned foods
and with acidified foods, the CGMP
regulations for these foods contain
detailed provisions to ensure safe
manufacturing. Specifically, the CGMP
regulations for these foods protect the
public health against microbial
contamination from these foods. Part
113 sets out safe manufacturing,
processing, and packaging procedures
for low-acid foods in hermetically
sealed containers. The CGMP criteria in
this part apply in determining whether
the facilities, methods, practices, and
controls used by commercial processors
of such foods are operated ‘‘in a manner
adequate to protect the public health’’
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(§ 113.5). Processors of low-acid canned
foods must have a ‘‘scheduled process’’
that is established by a qualified person
and is ‘‘adequate under the conditions
of manufacture for a given product to
achieve commercial sterility’’ (§§ 113.3
and 113.83). ‘‘Commercial sterility’’ of
thermally processed food means a
condition achieved by applying heat to
render the food free of certain
microorganisms (§ 113.3). Part 113
requires that supervisors satisfactorily
complete training at a school approved
by FDA (§ 113.10).
Part 113 also contains extremely
detailed requirements on equipment
and procedures. For example, each
vessel used for pressure processing in
steam must be equipped with a mercury
thermometer that is tested for accuracy
at least once a year, or more frequently
if necessary, to ensure its accuracy
(§ 113.40(a)(1)). Critical factors
(variation of which may affect the
attainment of commercial sterility) must
be specified in the scheduled process
and must be measured and recorded on
processing records frequently enough to
ensure that the factors are within the
specified limits (at least every 15
minutes) (§§ 113.40(a)(13) and 113.83).
Observations and measurements of
certain operating conditions must be
made and recorded at intervals of
sufficient frequency to ensure that
commercial sterility of the food product
is being achieved (at least every hour)
(§ 113.40(g)(2)(ii)(c)). There must also be
a system to stop packaging operations
(or to segregate products) when the
packaging conditions fall below
scheduled processes
(§ 113.40(g)(2)(ii)(b)). Regular
observations of container closures are
required to be made and recorded
(§ 113.60). Each container must be
coded ‘‘to enable ready identification of
lots during their sale and distribution’’
(§ 113.60(c)).
Before using raw materials and
ingredients susceptible to
microbiological contamination, the lowacid food processor must ensure that
they are ‘‘suitable for use in processing
low-acid food’’ (§ 113.81(a)). Complete
records covering all aspects of the
establishment of the scheduled process
and of certain confirmation tests must
be maintained permanently (§ 113.83).
Scheduled processes must be readily
available to any duly authorized FDA
employee (§ 113.87(a)). Whenever any
process is less than the scheduled
process or when critical factors are not
in control, the low-acid food must be
reprocessed or set aside for further
evaluation as to public health
significance (§ 113.89). Unless the
evaluation demonstrates that the
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product is free of microorganisms of
potential public health significance, the
product either must be reprocessed to
render it commercially sterile or
destroyed (§ 113.89).
All process deviations involving a
failure to satisfy the minimum
requirements of the scheduled process
must be recorded and kept in a separate
file detailing the deviations and actions
taken (§ 113.89). Detailed information
on processing and production must be
entered on forms (§ 113.100(a)). Not
later than 1 working day after the actual
process, and before the food is shipped
or released for distribution, a qualified
representative of management must
review all processing and production
records for completeness and to ensure
that the product was subjected to the
scheduled process (§ 113.100(b)).
Records to identify the initial
distribution of the finished product
must be kept to facilitate segregation of
lots that may have become
contaminated or otherwise rendered
unfit for their intended use
(§ 113.100(d)). Records must be
maintained at the processing plant for at
least 1 year after the date of
manufacturing and at a reasonably
accessible location for another 2 years
(§ 113.100(e)).
Similarly, the CGMP regulation for
acidified food in part 114 requires
supervision by personnel trained at an
FDA-approved school (§ 114.10);
manufacturing in accordance with a
scheduled process established by a
qualified person (§§ 114.80 and 114.83);
processing sufficient to destroy the
vegetative cells of certain
microorganisms (§ 114.80(a)(1));
sufficient control, including frequent
testing and recording of results, to
ensure that the finished hydrogen-ion
concentration (pH) values are not higher
than 4.6 (§ 114.80(a)(2)); testing and
examinations of containers to ensure
that the food is suitably protected from
leakage or contamination
(§ 114.80(a)(4)); and coding to enable
ready identification of lots during their
sale and distribution (§ 114.80(b)).
Whenever any acidified food process
operation deviates from the scheduled
process or the pH of the finished
product exceeds 4.6, the processor must
reprocess it, process it under part 113
requirements, or set it aside for
evaluation as to any potential public
health significance (§ 114.89). Unless
the evaluation demonstrates that the
food has undergone a process that has
rendered it safe, the food must be fully
reprocessed to render it safe or be
destroyed (§ 114.89).
A record must be made of the
procedures used in the public health
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evaluation and the results of the
evaluation (§ 114.89). Records must be
kept of examinations of raw materials,
packaging materials, and finished
products, and of suppliers’ guarantees
or certifications that verify compliance
with our regulations (§ 114.100(a)).
Processing and production records
showing adherence to scheduled
processes must be maintained and must
have sufficient additional information
such as product code, date, container
size, and product, to permit a public
health hazard evaluation of the
processes applied to each lot, batch, or
other portion (§ 114.100(b)). Departures
from scheduled processes having a
possible bearing on public health or the
safety of the food must be recorded and
kept in a separate file or log, along with
the action taken to rectify the departure
and the product disposition
(§ 114.100(c)). Records must be kept
identifying initial distribution of the
finished product to facilitate segregation
of lots that may have become
contaminated or otherwise unfit for
their intended use. Copies of certain
required records must be kept at a
reasonably accessible location for 3
years from the date of manufacture
(§ 114.100). The criteria in the part 114
regulation, as well as those in part 110,
apply in determining whether an article
of acidified food is adulterated under
section 402(a)(3) of the act in that it has
been manufactured under such
conditions that it is unfit for food or
under section 402(a)(4) of the act in that
it has been prepared, packed, or held
under insanitary conditions whereby it
may have become contaminated with
filth, or whereby it may have been
rendered injurious to health (§ 114.5).
Many provisions of parts 113 and 114
also serve as models for provisions in
the dietary supplement final rule. In
many instances, the analogous provision
in the dietary supplement final rule
allows more flexibility in the means to
achieve the goal. For example, under
final § 111.13 qualified personnel must
be assigned to supervise the
manufacturing, packaging, labeling, or
holding of dietary supplements.
Although the supervisor must be
qualified by education, training, or
experience to supervise, the more
restrictive requirement of parts 113 and
114 to attend an FDA-approved school
is not included. The ‘‘scheduled
process’’ for low-acid and acidified food
manufacturing, processing, and packing
is analogous to the required ‘‘system of
production and process controls’’ that
dietary supplement manufacturers must
design and implement (final §§ 111.55
and 111.60(a)). Similarly, the ‘‘critical
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factors’’ required to be specified in the
scheduled process for low-acid and
acidified foods are akin to the
‘‘specifications’’ that dietary
supplement manufacturers must
establish for certain points in the
manufacturing process (final § 111.70).
Just as low-acid food processors must
establish procedures to ensure that
ingredients are suitable for use, so too
must dietary supplement manufacturers
establish component and finished
product specifications (final § 111.70(b)
and (e)). Just as containers for acidified
food must ensure suitable protection
from contamination, packaging that
comes into contact with dietary
supplements must be safe and suitable
for use (final § 111.70(d)). Dietary
supplement in-process points, like the
‘‘critical factors’’ for low-acid and
acidified food, must be monitored to
detect any deviation or unanticipated
occurrence that may result in
adulteration (final § 111.75(b)(2)).
Rejected dietary supplements must
also be held under quarantine (final
§§ 111.370 and 111.425); dietary
supplements which have been
reprocessed, treated, or which have had
in-process adjustments must meet all
established product specifications and
be approved before release (final
§ 111.90(c)). Similar to coding low-acid
or acidified foods, dietary supplements
must have assigned batch, lot, or control
numbers (final § 111.415(f)). The design,
calibrations, and cleaning of equipment
and utensils must also result in the
equipment and utensils being suitable
for their intended uses and not result in
contamination of components or dietary
supplements (final § 111.27). Written
procedures for the various controls are
required (see, e.g., final §§ 111.8, 111.25,
and 111.103), and required written
records (see, e.g., final §§ 111.14,
111.23, 111.35, and 111.95) must be
kept for 1 year past the shelf life date,
if shelf life dating is used, or 2 years
after the date of distribution of the last
associated batch of dietary supplement
(final § 111.605). All required dietary
supplement CGMP records must be
readily available for inspection and
copying by FDA (final § 111.610(a)).
Finally, the bottled water CGMP
regulation was promulgated to ensure
the safety and sanitary quality of these
products, which include all water
processed and bottled for human
consumption (38 FR 32563, November
26, 1973). The criteria in part 129, as
well as in part 110, apply in
determining whether the facilities,
methods, practices, and controls used to
process, bottle, hold, and ship bottled
drinking water conform with good
manufacturing practice ‘‘to assure that
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bottled drinking water is safe and that
it has been processed, bottled, held, and
transported under sanitary conditions’’
(§ 129.1). Part 129 requires plant
construction and design features, such
as a separate bottling room and an
enclosed room for washing and
sanitizing containers, to protect against
contamination (§ 129.20). All plant
equipment and utensils must be suitable
for their intended use (§ 129.40(a)).
Both the product water supply and
the operations water supply must be of
a ‘‘safe, sanitary quality’’ in
conformance with ‘‘the applicable laws
and regulations of the government
agency or agencies having jurisdiction’’
(§ 129.35(a)). Samples of source water
must be analyzed at least once a year for
chemical contaminants and once every
4 years for radiological contaminants
(§ 129.35(a)(3)). Source water from other
than a public water system must be
sampled and analyzed for
microbiological contaminants at least
once a week (id.). The product watercontact surfaces of all containers and
equipment must be clean and
adequately sanitized and protected from
contamination (§ 129.37(a) and (b)).
Filling, capping, closing, sealing, and
packaging of containers must be done so
as to preclude contamination of the
water (§ 129.37(d)). All product water
contact surfaces must be nontoxic and
in compliance with section 409 of the
act (21 U.S.C. 348) (concerning food
additives) (§ 129.40(a)(2)).
Numerous production processes and
controls for bottled water are also
required. For example, all treatment of
product water must be effective in
accomplishing its intended purpose and
in accordance with section 409 of the
act (§ 129.80(a)). The treatment
processes must be performed with
equipment and substances that will not
adulterate the product (§ 129.80).
Product water samples must be taken
before bottling and analyzed as often as
necessary to assure uniformity and
effectiveness of the processes performed
by the plant (§ 129.80(a)). Cleaning and
sanitizing solutions must be sampled
and tested to assure adequate
performance (§ 129.80(c)).
Each unit package from a batch or
segment of continuous production run
must be identified by a production code
(§ 129.80(e)). The plant must maintain
information on the kind of product,
volume, date, lot code, and distribution
of finished product to wholesale and
retail outlets (id.). During the process of
filling, capping, or sealing the
containers, performance must be
monitored and the filled containers
inspected to assure that they are sound,
properly capped or sealed, and coded
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and labeled (§ 129.80(f)). All containers
and closures must be sampled and
inspected to ascertain that they are free
from contamination (id.).
To assure that the plant’s production
of bottled water complies with
applicable standards, laws, and
regulations, the plant must analyze
product samples at specified intervals
(§ 129.80(g)). The methods used to
analyze the samples must be approved
by the government agency with
jurisdiction (§ 129.80(g)(3)). Records of
the date of sampling, type of product
sampled, production code, and results
of analysis must be maintained
(§ 129.80(g)(3)). All required records
must be maintained at the plant for at
least 2 years (§ 129.80(h)) and be
available for official review by FDA at
reasonable times (id.).
Provisions of the bottled water CGMP
regulation also serve as a model for
provisions of the dietary supplement
CGMP regulation. For example, water
that is used in a manner such that the
water may become a component of a
dietary supplement must at a minimum
comply with applicable Federal, State,
and local requirements and not
contaminate the dietary supplements
(final §§ 111.15(e)(2) and 111.365(c)).
Precautions that must be taken to
prevent contamination of components
or dietary supplements include
performing chemical, microbiological,
or other testing (final § 111.365(d)).
Filling, assembling, packaging, labeling,
and related operations must be
performed to protect the dietary
supplement against adulteration (final
§ 111.415). Equipment and utensils
must be suitable for their intended use
(final § 111.27(a)). Safe and adequate
cleaning compounds and sanitizing
agents must be used (final
§ 111.15(c)(1)). Representative samples
of each batch must be examined to
ensure that the product meets
established specifications (final
§ 111.415(g)). Each lot of packaged and
labeled dietary supplement must be
assigned a batch, lot, or control number
(final § 111.415(f)).
Moreover, our interpretation of
permissible requirements for the dietary
supplement CGMP regulation is also
consistent with the use of the terms
‘‘good manufacturing practice’’ and
‘‘current good manufacturing practice’’
in section 402(g) of the act. Although
these terms are not defined in the act,
GMP is generally used to refer to
methods used in, and the facilities and
controls used for, product
manufacturing and related activities.5
5Although the act does not define ‘‘current good
manufacturing practice,’’ the term is used elsewhere
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The umbrella food CGMP regulation, for
example, defines the ‘‘plant’’ covered by
the requirements of that regulation as
the facility used for, or in connection
with, ‘‘the manufacturing, packaging,
labeling, or holding of human food’’
(§ 110.3(k)). As we have described in
detail, the objectives of the existing food
CGMP regulations and the precise
means (or requirements) used to achieve
the objectives vary depending on the
particular hazards and characteristics of
the products and their manufacturing.
For example, the umbrella food CGMP
regulation is specifically designed to
ensure that food is manufactured,
processed, packed, and held under
sanitary conditions and that the food is
safe, clean, and wholesome. Low-acid
and acidified food CGMP requirements
focus on facilities, methods, practices,
and controls to protect the public health
against the particular risks of microbial
contamination from these foods. The
infant formula CGMP regulation is
aimed at ensuring both the safety and
nutritional potency of these special
foods. Infant formula is often the sole
item in the diet. An infant formula that
does not meet the requirements for
nutritional potency may cause a hazard
to the health of the infant (see 61 FR
36154, July 9, 1996). The bottled water
CGMP regulation embodies
requirements for facilities, methods,
practices, and controls used in
processing, bottling, holding, and
shipping of bottled water to ensure its
safety and sanitary quality.
Like the food CGMP regulations after
which they are modeled, the dietary
supplement CGMP final rule contains
criteria for facilities, methods, practices,
and controls used in manufacturing,
packaging, labeling, or holding dietary
supplements to ensure the quality of the
dietary supplement. Quality includes
consistently meeting the established
specifications for identity, purity,
strength, and composition of the dietary
supplement and limits on contaminants,
in addition to manufacturing the dietary
supplement under conditions to prevent
adulteration. As Congress recognized in
DSHEA, identity, purity, strength, and
composition are essential characteristics
in the statute (see, e.g., sections 501(a)(2)(B) (drug
CGMP) and 520(f)(1)(A) of the act (device CGMP)
(21 U.S.C. 351(a)(2)(B) and 21 U.S.C. 360j(f)(1)(A),
respectively). Case law supports the agency’s view
that ‘‘current’’ does not mean ‘‘actually prevailing
manufacturing practice’’ in an industry and that
such a practice need not be accepted by a majority
of manufacturers (National Ass’n of Pharmaceutical
Mfr’s v. Department of Health and Human Services,
586 F. Supp. 740, 752 (S.D.N.Y. 1984)).
Nevertheless, the requirements of this final rule
embody current practices of many food and dietary
supplement manufacturers, as reflected in the
comments supporting the provisions of the
proposed rule.
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for dietary supplements (see, e.g.,
section 403(s)(2) of the act (a dietary
supplement is misbranded if its labeling
fails to list the name and quantity of
each dietary ingredient and if it fails to
have the identity and strength or the
quality, purity, or compositional
specifications it is represented to meet)).
Yet without information about the
identity, purity, strength, or
composition, the manufacturer could
not know the final contents of the
dietary supplements it manufactures or
whether its processes are reliably and
consistently producing the correct
combination and amounts of ingredients
in a dietary supplement. Accordingly,
the final rule requires a manufacturer to
establish specifications for the identity,
purity, strength, and composition and
for limits on contaminants of the dietary
supplements it manufactures and ensure
that such specifications are consistently
met in the finished batch of dietary
supplement (§ 111.75(e)). Dietary
supplements, like infant formula, are
relied upon by consumers not only to be
safe, but also in many instances to
provide specific and important claimed
health benefits (see, e.g., section 403(r)
of the act). In the preamble to the 2003
CGMP Proposal, we discussed a number
of examples illustrating adulteration
and improper formulation of dietary
supplements caused by manufacturing,
packaging, or holding practices (68 FR
12157 at 12162 and 12163). These
dietary supplement CGMP requirements
will help to protect consumers against
similar types of adulteration and against
reliance on products that are not
properly formulated.
Generally recognized principles
underlying CGMP also support our
interpretation of section 402(g) of the
act. Our interpretation of permissible
CGMP regulations is reasonable based
on recognized principles for controlling
the quality of manufactured products in
general (Ref. 9). As many comments
asserted, if the dietary supplement
CGMP requirements are to be
meaningful, they must ensure quality in
the finished product (see, for example,
the discussion in section X of this
document of comments regarding the
production and process control system).
Controls to ensure quality include
planning processes to determine desired
product features or characteristics, a
system of controls to ensure that the
desired product will be consistently
produced, and making necessary
improvements to the process (section
2.6 of Ref. 9). Manufacturers must plan
what they intend to produce, institute
adequate controls to achieve the desired
outcome, and ensure that the controls
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work so that the desired outcome is
consistently achieved. If the outcome is
not consistently achieved, corrective
actions need to be implemented in order
to reach the desired outcome.
This final rule, like the other food
CGMP regulations, embodies the basic
concepts of controlling quality, i.e.,
planning, control, and improvement. As
discussed earlier in the ‘‘Overview of
CGMP’’ (section III.A of this document),
we have defined the term ‘‘quality’’ for
this dietary supplement CGMP
regulation to mean ‘‘that the dietary
supplement consistently meets the
established specifications for identity,
purity, strength, and composition and
has been manufactured, packaged,
labeled, and held under conditions to
prevent adulteration under section
402(a)(1), (a)(2), (a)(3), and (a)(4) of the
Federal Food, Drug, and Cosmetic Act.’’
Identifying the desired characteristics of
identity, purity, strength, and
composition of a dietary supplement, as
required in this final rule, is an essential
part of the planning process to
manufacture a dietary supplement.
Without identifying specifications for
each of these characteristics of a dietary
supplement, it is not possible to control
for, and repeatedly and reliably
produce, the desired end product.
Similarly, requirements for batch testing
ensure that there is consistency from
batch to batch. Packaging and labeling
requirements ensure that suitable
packaging is used and that the label
identified in the master manufacturing
record for the product is placed on the
finished product. In addition,
requirements related to consumer
complaints help to ensure that
manufacturers are made aware of
problems related to their manufacturing
processes, including those that may
result in illness or injury, so that they
can take corrective actions to prevent
any future problems from occurring.
The procedures for production and
process control in this final rule also
include as key elements measures to
prevent contamination that could
adulterate the product. Requirements to
protect against contamination during
the manufacturing, packaging, labeling,
and holding operations help ensure that
this aspect of ‘‘quality’’ is also achieved
for dietary supplements. In sum, this
final rule embodies principles for
controlling quality through
requirements designed to ensure both
that the dietary supplement meets its
established specifications for identity,
purity, strength, and composition and
that it is not adulterated.
The dietary supplement CGMP
requirements are also reasonable
because they take into consideration the
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different product forms in which these
products will be manufactured. Unlike
conventional foods, such as fruit,
vegetables, cereals, and dairy products,
dietary supplements will be sold in
tablet, capsule, powder, or softgel form.
They may also be sold as a concentrate,
metabolite, constituent, or extract of a
vitamin, mineral, herb, botanical, or
dietary substance. Because dietary
supplements are often sold in different
forms than conventional foods, different
processes and controls are needed to
manufacture dietary supplements than
to manufacture conventional foods. For
example, equipment must be able to
manufacture dietary supplements in
tablet or softgel form. Therefore, the
final rule requires that controls be
established to ensure that the equipment
functions in accordance with its
intended use (final § 111.30(e)) and will
consistently manufacture a product in
whatever form is desired. Consistent
with basic CGMP principles, ensuring
the quality of the dietary supplement
product requires that the manufacturer
establish precisely what it will produce
(specifications for its product), how it
will make the product (processes), and
which process controls and tests it will
use to ensure reliable, reproducible
results. These CGMP requirements will
help to achieve these results.
The dietary supplement CGMP
requirements are also reasonable when
viewed in the context of the act as a
whole. See Brown & Williamson, 529
U.S. at 133. Our mission is, in part, to
protect the public health by ensuring
that foods are safe, wholesome, sanitary,
and properly labeled (section
903(b)(2)(A) of the act) (21 U.S.C.
393(b)(2)(A))). Section 701(a) of the act
(21 U.S.C 371(a)) gives us the authority
to promulgate regulations for the
efficient enforcement of the act in order
to ‘‘effectuate a congressional objective
expressed elsewhere in the Act’’
(Association of American, Physicians
and Surgeons, Inc. v. FDA, 226 F. Supp.
2d 204 (D.D.C. 2002) (citing Pharm.
Mfrs. Ass’n. v. FDA, 484 F. Supp. 1179,
1183 (D. Del. 1980)). The final rule is
designed to help ensure that dietary
supplements consistently are
manufactured to produce the product
established by the manufacturer, to bear
the label identified in the master
manufacturing record, and to prevent
adulteration. The requirements are
written to facilitate efficient and
effective action to enforce their terms
when necessary.
Some provisions of the dietary
supplement CGMP final rule may be
similar to the existing drug CGMP
regulations. However, we have not
modeled these regulations after the drug
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CGMP regulations. Controls that relate
to certain product forms (e.g., tablets,
capsules, powder, softgel) are required
in this final rule based on the specific
characteristics of dietary supplements
and the hazards associated with these
forms, not, as some comments imply,
based on a desire to emulate drug CGMP
requirements. The act does not state that
there may not be similarities between
the dietary supplement CGMP
requirements and the CGMP
requirements for drugs or other nonfood products. Inasmuch as food CGMP
regulations and other CGMP regulations
are all based on CGMP principles, it is
neither surprising nor impermissible
that there are similarities between the
dietary supplement CGMP requirements
and drug or device CGMP requirements.
Although we do not agree that any of
the CGMP requirements exceed drug
GCMP requirements, even if a particular
requirement did, it is not prohibited
under the statute. As long as the CGMP
final rule is ‘‘modeled after’’ the food
CGMP regulations, we have satisfied the
statutory requirements. As noted, our
interpretation of ‘‘modeled after’’ means
that the dietary supplement CGMP final
rule provisions share similar objectives
and/or use similar means as the existing
food CGMP regulations. To the extent
that there are similarities to drug CGMP
regulations, those similarities are
appropriate and not prohibited by
section 402(g) of the act.
Consistent with our role ‘‘to fill in,
through interpretation, matters of detail
related to [the statute’s] administration,’’
Barnhart v. Walton, 535 U.S. 212, 225
(2002), we applied our scientific
expertise, policy judgment, and
experience to promulgate dietary
supplement CGMP requirements that
will protect the public health and
effectively implement our statutory
authority to prescribe dietary
supplement CGMP. See United States v.
Mead, 533 U.S. 218, 227–228 (2001);
Nationsbank of North Carolina v.
Variable Annuity Life Ins. Co., 513 U.S.
251, 256–58 (1995); Chevron, 467 U.S. at
844; Forester v. Consumer Product
Safety Com., 559 F.2d 774, 783 (D.C.
Cir. 1977).
B. Records Authority
(Comment 19) Some comments state
that requirements related to record
keeping and access to such records are
necessary to allow our inspectors to
assess the adequacy of a dietary
supplement manufacturer’s practices.
Additional comments state that access
to records is necessary to ensure that
CGMP requirements are followed and to
protect the public health. Several
comments identify specific types of
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records we should require in a final
rule, including written procedures,
batch and master manufacturing
records, distribution records, and lot
numbers. Another comment states that
training records should be required
because the qualifications and training
of employees affects product quality.
Other comments, however, state that
the record retention and access
requirements seem to be modeled after
drug CGMP and not food CGMP. Other
comments state that, even though
records may be necessary to ensure that
CGMP requirements are followed, we do
not have authority to require access to
and copying of such records. Some
comments assert the authority to
establish regulations for dietary
supplement CGMP does not imply there
is authority to inspect records. Several
comments state we cannot rely on
section 701 of the act because there is
not another section of the act that
authorizes us access to company records
for dietary supplement CGMP and
section 701(a) of the act does not itself
give us the authority we need to require
records inspection. Another comment
suggests that the absence of an express
grant of records inspection authority
means that records inspection is not
necessary for the efficient enforcement
of the act.
Some comments assert that we have
no record inspection authority under
section 704(a) of the act (21 U.S.C
374(a)). A few comments suggest that,
because records inspection authority
was not expressly granted in DSHEA’s
statutory language, as it was for OTC
drugs and medical devices, Congress
provided no authority for records
inspection for dietary supplement
CGMP. The comments state that we
have a longstanding interpretation that
section 704 of the act does not give us
access to a food manufacturer’s records.
Several comments state that it was
sufficient to have voluntary records
access, stating that many companies are
willing to provide access to records.
Other comments say that our record
inspection authority for dietary
supplement CGMP is limited to that
under section 306(a) of the Public
Health Security and Bioterrorism
Preparedness and Response Act of 2002
(Bioterrorism Act) (21 U.S.C. 350(c)),
i.e., when we have a ‘‘reasonable belief
that an article of food is adulterated and
presents a threat of serious adverse
health consequences * * *’’ Another
comment suggests an alternative
standard to that in section 306(a) of the
Bioterrorism Act of a ‘‘reasonable belief
that there is a public health hazard’’ for
when we may access records.
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One comment cites In the Matter of
Establishment Inspection of Medtronic,
Inc., 500 F. Supp 536 (D. Minn. 1980),
to support its assertion that we
exceeded our statutory inspection
authority in the dietary supplement
CGMP record requirements. One
comment states that a warrantless
inspection of dietary supplement CGMP
records and criminal consequences that
may be imposed under the act for failure
to comply with the act provide a
‘‘powerful argument against expanding
the Agency’s inspection authority any
further’’ and raise ‘‘serious
constitutional concerns.’’ Several
comments ask us to clarify our
jurisdiction for records inspection
requirements or delete proposed
§ 111.125(c).
Still other comments seek
confirmation that the confidential and
trade secret information obtained by us
under the rule would be protected from
disclosure under applicable statutes.
Among other things, the comments cite
the Trade Secrets Act, 18 U.S.C. 1905,
and the Freedom of Information Act
(FOIA), 5 U.S.C. 552(b)(4). Some
comments express concern that records
inspection would violate ‘‘rights to
privacy of corporate manpower’’ or
would compromise trade secrets. The
comments request the rule specifically
reconfirm our obligations under these
laws.
(Response) We disagree with the
comments suggesting that we have no
authority to require dietary supplement
manufacturers to maintain records to
comply with CGMP under section
402(g) of the act; that the absence of an
express grant of records authority means
records are not needed for the efficient
enforcement of the act; and that
Congress meant, by its silence, that we
have no authority to issue records
requirements. Clearly, just as Congress
is not expected to express ‘‘every single
evil sought to be corrected’’ in a grant
of authority to promulgate a rule, it can
not be expected to articulate every
requirement that is within an agency’s
delegated authority (American Trucking
Assoc. v. United States, 344 U.S. 298,
309–10 (1953)).
Agencies are expected to bring their
expertise to bear on what requirements
are necessary that will not ‘‘directly
frustrate the success of the regulation
undertaken by Congress’’ (id. at 311). In
this instance, Congress has not
expressed any specific intent regarding
recordkeeping for dietary supplements
but has directed FDA to use other food
CGMP regulations, which require
recordkeeping and FDA access to
records, as models for these regulations.
Congress has delegated substantial and
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sufficiently specific authority to us to
promulgate recordkeeping and access
regulations (Cf. United States v. Storer
Broadcasting, 351 U.S. 192, 202–03
(1956) (upholding a rule that established
limitations on broadcast licensing that
were ‘‘not specifically authorized by
statute’’)). As stated earlier in this
section, the ‘‘modeled after’’ language in
section 402(g) of the act is ambiguous
with respect to what specific CGMP
requirements we are to include in this
final rule. At the time Congress enacted
section 402(g) of the act there were
several food regulations that contained
recordkeeping and record access
requirements. We included records
requirements in the food CGMP
regulations for infant formula (part 106),
low acid food (part 113), acidified food
(part 114), and bottled water (part 129).
Accordingly, the directive in section
402(g) of the act is sufficient authority
for our recordkeeping requirements in
this final rule. In addition, our authority
to establish records requirements has
been upheld under other provisions of
the act, which lacked explicit
recordkeeping authority for FDA, where
we have found records to be necessary
(National Confectioners Assoc. v.
Califano, 569 F.2d 690, 693–94 (D.C.
Cir. 1978) (upholding requirements for
source coding and distribution records
based on the statutory scheme as a
whole)).
Moreover, records are an
indispensable component of CGMP. The
records required by this final rule
provide the foundation for the planning,
control, and improvement processes
that constitute a quality control system.
Implementation of these processes in a
manufacturing operation serves as the
backbone to CGMP. The records will
show what is to be manufactured; what
was, in fact, manufactured; and whether
the controls that the manufacturer put
in place to control the identity, purity,
strength, and composition and limits on
contaminants and to prevent
adulteration were effective. Further,
records will show whether and what
deviations from control processes
occurred, facilitate evaluation and
corrective action concerning these
deviations (including, where necessary,
whether associated batches of product
should be recalled from the
marketplace), and enable a
manufacturer to assure that the
corrective action was effective. Written
procedures also will help ensure that
personnel follow hygienic practices;
permit evaluation of whether
equipment, including software that may
run the equipment, performs as it is
intended; and help ensure that the
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equipment is properly maintained and
adequately cleaned.
The CGMP final rule establishes the
parameters for the production and
process control system in which dietary
supplements are to be manufactured.
The dietary supplement manufacturer
establishes the identity, strength, purity,
and composition of the supplement it
manufactures (final § 111.70);
determines whether the established
specifications are met (final § 111,73);
uses the tests it needs to ensure that
those characteristics are consistently
met (final §§ 111.75 and 111.315); and
identifies the steps necessary to ensure
that any necessary tests or examinations
are completed, reviewed, and recorded
in a timely fashion before the dietary
supplement is released for distribution
to the public (final §§ 111.110 and
111.325(b)(2)). The CGMP final rule also
requires that the manufacturer establish
written procedures for its quality
control operations to ensure the
personnel performing this function
provide proper review and oversight of
the production and process control
system, have the knowledge and
experience to identify and anticipate
possible problems in the manufacturing
of the dietary supplement, and ensure
corrective measures are taken promptly
when problems occur (final §§ 111.103
through 111.140). The final rule also
requires that the manufacturer establish
the ‘‘master recipe(s)’’ for the dietary
supplement(s) it manufactures so that
such recipe(s) can be followed for each
batch produced (final §§ 111.205
through 111.210). In sum,
manufacturers cannot operate without
records because critical elements in a
manufacturing process are entirely
dependent on information written or
captured in the form of a record.6 Such
records are also necessary to protect
consumers by enabling manufacturers to
identify and recall problematic products
as necessary and make necessary
corrections to deviations in their
processes.
The authority granted us under
sections 402(g) and 701(a) of the act not
only includes the authority to establish
record requirements, but also includes
access to such records. Without such
authority, the dietary supplement CGMP
requirements are, practically speaking,
not enforceable. Under section 402(g)(1)
of the act, the failure to meet any CGMP
requirements, including the failure to
have a record that is required by this
final rule, renders a dietary supplement
6It is also worth noting that standard references
used in many industries establish clear expectations
for documentation and recordkeeping practices for
assuring quality control in manufacturing
operations (Refs. 9 and 13).
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so manufactured to be adulterated as a
matter of law. The introduction or
delivery for introduction into interstate
commerce of an adulterated dietary
supplement is a prohibited act under
section 301(a) of the act (21 U.S.C.
331(a)), and acts done to an ingredient
in a dietary supplement, or to a dietary
supplement, while held for sale after
shipment in interstate commerce that
result in the ingredient or dietary
supplement being adulterated violates
section 301(k) of the act (21 U.S.C.
331(k)). Thus, in order for us to
determine whether the dietary
supplement product is adulterated and
whether a manufacturer has committed
a prohibited act, we must have access to
the manufacturer’s records that we are
requiring to be kept under section 402(g)
of the act.
In light of the foregoing, without
access to such records, we would not
know whether a manufacturer was
complying with the procedures and
processes required in this final rule. For
example, our investigator must have
access to the test results for the identity
of a dietary ingredient to determine
whether such ingredient meets the
manufacturer’s specification for
identity. The investigator needs to
understand, by reviewing a record, what
the software that runs a production
operation is set up to do and whether it
performs those functions to achieve the
desired product characteristics.
Observation of these processes alone, by
an investigator, would not allow that
investigator to evaluate compliance with
this final rule. Moreover, records often
cannot be thoroughly evaluated by the
investigator on site. In such cases,
records must be readily available to food
experts at the Center for Food Safety
and Applied Nutrition (CFSAN) and
agency consultants. We must have
accurate, reliable, and objective data
about the manufacturing specifications
to be able to achieve an enforceable rule.
We also disagree with comments
stating our records inspection authority
is limited to that provided by section
306(a) of the Bioterrorism Act. There is
no basis to conclude that Congress
intended to limit our authority to
inspect records, to enforce section
402(g) of the act, to the records
inspection authority under the
Bioterrorism Act. The Bioterrorism Act,
enacted almost 8 years after section
402(g), to address credible threats of
serious adverse health consequences or
death to humans and animals, required
recordkeeping to identify the immediate
previous sources and the immediate
subsequent recipients of food (21 U.S.C.
350c).
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There is nothing in the Bioterrorism
Act that reflects any Congressional
intent to modify section 402(g) of the
act. In fact, section 414(d)(1) of the act
(21 U.S.C. 350c(d)(1)), added by section
306(a) of the Bioterrorism Act, shows a
contrary intent. Section 414(d)(1)
provides that ‘‘This section shall not be
construed—(1) to limit the authority of
the Secretary to inspect records or to
require establishment and maintenance
of records under any other provision of
this Act.’’ Moreover, Congress, in the
legislative history to the Bioterrorism
Act, supported our general approach of
requiring recordkeeping pursuant to
authority in section 701(a) of the act in
combination with other provisions.7 We
are not relying on section 704 of the act
for its underlying authority to require
recordkeeping and records access in this
final rule. Those comments asserting
that we do not have such authority and
the underlying references, for example,
to past hearings on records inspection
authority under section 704 of the act,
are not controlling with regard to the
action we are taking under sections
402(g) and 701(a) of the act. When there
are other bases for jurisdiction and tools
to protect the public interest, we may
use what ‘‘will be the most effective in
advancing the Congressional objective’’
(U.S. v. Midwest Video Corp., 406 U.S.
649, 656 (1972)).
Some comments stated that our access
to dietary supplement records is not
consistent with constitutional
jurisprudence. We disagree. The
comment which expressed concern
about ‘‘constitutional issues’’ in the
context of an FDA inspection of records
during a warrantless FDA inspection
expressed concern about the criminal
liability that could be imposed on a
manufacturer under the act (citing
United States v. Dotterweich, 320 U.S.
277 (1944) and United States v. Park,
421 U.S. 658 (1975)). To the extent that
the comment asserts that the records
access established in this final rule
constitutes an improper search and
seizure under the Fourth Amendment,
we disagree.
The dietary supplement industry, as
the food industry as a whole, is a
7In discussing section 306 of the Bioterrorism Act
(Maintenance and Inspection of Records for Foods),
Congress stated, ‘‘The managers did not adopt a
Senate proposal to authorize the Secretary to
require the maintenance and retention of other
records for inspection relating to food safety,
because the Secretary has authority under section
701(a) of the [act] to issue regulations for the
‘efficient enforcement of this Act’ and this
authority, in combination with other provisions
(such as section 402 [of the act]), gives the Secretary
the authority to require appropriate record keeping
in food safety regulations.’’ (H.R. Conf. Rep. No.
107–481, at 135 (2002), (Ref. 14)).
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pervasively regulated industry that is
subject to warrantless inspections (see,
e.g., United States v. Biswell, 406 U.S.
311, 315 (1972) (‘‘In the context of a
regulatory inspection system of business
premises * * * the legality of the search
depends not on consent but on the
authority of a valid statute.’’); United
States v. New England Grocers Supply
Co., 488 F. Supp. 230, 238 (D. Mass.
1980) (holding that a warrantless
inspection under 21 U.S.C. 374 is ‘‘fully
consistent with the Fourth
Amendment’’); United States v. Acri
Wholesale Grocery Co., 409 F. Supp.
529, 533 (S.D. Iowa 1976) (holding that
a warrantless inspection, which
includes photographic activities,
conducted under 21 U.S.C. 374 does not
violate the Fourth Amendment); United
States v. Business Builders, Inc., 354 F.
Supp. 141, 143 (N.D. Okla. 1973) (‘‘the
statute takes the place of a valid search
warrant’’); United States v. Del Campo
Baking Mfg. Co., 345 F. Supp. 1371 (D.
Del 1972) (finding warrantless
inspection of food establishment lawful
under 21 U.S.C. 374)).
As explained earlier in this section,
we have ample authority, under sections
402(g) and 701(a) of the act, to require
that certain records be kept and
accessible to us upon inspection.
Records access is imperative to the
efficient enforcement of the dietary
supplement CGMP final rule, and we
are not prohibited from requiring access
to these records under sections 402(g)
and 701(a) of the act (See Permian Basin
Area Rate Cases, 390 U.S. 747, 780
(1968) (‘‘in the absence of compelling
evidence that such was Congress’
intention * * * [the court should not]
prohibit administrative action
imperative for the achievement of an
agency’s ultimate purposes.’’)).
We also disagree with the comment
suggesting that voluntary records access
is sufficient. In our experience, many
manufacturers are not willing, as the
comments suggest, to provide records
voluntarily to us (Ref. 15). Moreover, it
is often the case that the most
uncooperative manufacturers are the
very ones whose records and processes
are deficient. Without mandatory
requirements for agency access to
records required by the final rule, we
could not enforce and there would be
minimal incentives for manufacturers to
comply with the rule, which would
frustrate Congressional intent in
enacting section 402(g) of the act.
We also disagree with the comment
that cited In the Matter of Establishment
Inspection of Medtronic, Inc., 500 F.
Supp. 536 (D. Minn. 1980), to suggest
that our proposed recordkeeping
requirements exceed our statutory
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inspection authority. As already
discussed, we are not relying on section
704 of the act for our authority to
require access to dietary supplement
CGMP records. Thus, to the extent the
comment cited to Medtronic as an
example of the statutory authority for
inspection of device records under
section 704 of the act, Medtronic is not
pertinent to our authority for records
access in this final rule.
Finally, we disagree that the records
access in this final rule will violate any
protection a manufacturer has with
respect to protection of confidential
commercial or financial information or
trade secrets. Trade secrets and
commercial or financial information
that is privileged or confidential are
protected from disclosure under FOIA
and other laws (see, e.g., 21 U.S.C.
331(j), 18 U.S.C. 1905). Further, our
FOIA regulations set forth the specific
procedures for assuring such protection.
It was not clear from the comments
what was meant by ‘‘rights to privacy of
corporate manpower.’’ We note that
§§ 20.63 and 20.64 contain provisions
for the protection of personal privacy.
C. Public Health Service Act Authority
(Comment 20) One comment
acknowledges that we have authority
under the PHS Act to regulate intrastate
activities that may cause the spread of
communicable diseases. The comment
states that, in any situation in which we
need to exercise our authority over any
disease-causing substance within the
State where a component or dietary
supplement is manufactured, packed, or
held, we can and should exercise our
authority under the PHS Act. However,
the comment asserts that nothing in the
preamble clearly states whether we
believe that the final rule will be, in its
entirety, binding on manufacturers,
packers, and holders of dietary
supplements who are engaged solely in
intrastate commerce, and that we have
not requested comment on this specific
issue. The comment requests that we
clearly state that the final rule applies
only to interstate commerce, except for
activities that may spread
communicable diseases.
(Response) We address each of these
issues in turn.
1. The Communicable Disease Risk
Posed by Dietary Supplements
There are communicable disease risks
related to the manufacture of dietary
supplements that are appropriately
addressed not only under the act, but,
as the comment acknowledges, also
under the PHS Act. Microorganisms,
including Salmonella enterica
(Salmonella), Campylobacter jejuni, and
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enterohemorrhagic Escherichia coli
0157:H7 (EHEC), are well-known causes
of communicable diseases, and may be
present in dietary supplements and
their components. There are a number
of microorganisms that cause
communicable diseases and that may be
found in components or dietary
supplements. These microorganisms
cause serious effects and symptoms. For
example, Salmonella causes
salmonellosis, which affects the
gastrointestinal (GI) tract and is
characterized by diarrhea, fever,
abdominal cramps, headache, nausea,
and vomiting (Ref. 16). In a small
portion of healthy people (1 to 4
percent), infection spreads from the GI
tract into the blood stream, which can
be life-threatening. Persons with
immune compromising conditions (such
as cancer, Acquired Immunodeficiency
Syndrome (AIDS), autoimmune
disorders) are at greater risk of blood
stream infection (Ref. 16).
Campylobacteriosis, often due to
infection with Campylobacter jejuni, is
characterized by diarrhea, fever, and
abdominal cramps, which can be severe
(Ref. 17). These symptoms frequently
relapse, and the disease may become
chronic in immune compromised
persons. People with
campylobacteriosis are also at increased
risk of developing certain postinfectious complications, which will
prolong their recovery.
EHEC may cause infections with a
very low infectious dose (as low as 2 to
45 organisms), and may result in nonbloody and bloody diarrhea, hemolyticuremic syndrome (a cause of red blood
cell destruction, damage of blood vessel
walls, and, in severe cases, kidney
failure (especially in young children)),
thrombotic thrombocytopenic purpura
(i.e., a blood disorder characterized by
low platelets, low red blood cell count,
abnormalities in kidney function, and
neurological abnormalities (especially
in adults)), and death (Ref. 18).
Animal tissues (e.g., organs from
livestock), as well as botanicals, used as
components in dietary supplements
may contain EHEC, Salmonella, and
Campylobacter jejuni. In addition,
because the same microorganisms are
also present in the environment, they
may contaminate components during
manufacturing activities. Moreover,
people who harbor those pathogens
could transmit them to components and
dietary supplements during processing.
Therefore, components and dietary
supplements, as potential sources of
communicable diseases, may be
regulated under the PHS Act.
For these microorganisms (e.g., EHEC,
Salmonella, and Campylobacter jejuni)
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humans carry and transmit infections
through their feces or by direct contact
with other persons. For other
microorganisms, domestic and wild
animals serve as the reservoir, and
humans become infected when
contaminated tissues of infected
animals are used in dietary
supplements. For both categories of
microorganisms, dietary supplements
can also become contaminated
indirectly by human and animal fecal
contamination of water or through the
production or processing environment.
Dietary supplements may contain a
variety of components derived from
domestic and wild animals, such as
powders prepared from whole or partial
gecko, deer antler velvet, and organs,
such as cow liver and brain, pork
stomach, or sheep spleen from common
domestic livestock. Each of these tissues
may be contaminated with
microorganisms such as Salmonella,
Campylobacter jejuni, and EHEC. Even
clinically normal animals obtained from
safe sources may harbor these
communicable pathogens and result in
contaminated products (Ref. 19).
(Information on these animals and
potential pathogens can be accessed at
https://www.fsis.usda.gov/Science/
Microbiology/index.asp). Dietary
supplements also may contain
crustacean or molluscan shellfish or
components prepared from them, such
as glucosamine from shrimp
exoskeletons and oyster extract, that
may be contaminated with Vibrio
species, including V. parahaemolyticus.
Vibrio species are natural inhabitants of
shellfish harvest waters, and shellfish
are commonly naturally contaminated,
especially during times of the year when
harvest waters are warm (Refs. 20
through 23). V. parahaemolyticus most
often causes gastroenteritis
characterized by diarrhea, abdominal
cramps, nausea, vomiting, and fever
(Ref. 24).
Dietary supplements may also contain
botanicals (plants) that may harbor
microorganisms, including organisms
from animal feces (Salmonella and
Shigella spp., Escherichia coli), and
organisms arising from handling
(Staphylococcus aureus), harvesting,
processing, and transportation.
Components contaminated with
microorganisms must be treated to
prevent the finished dietary
supplements from being contaminated.
The processes used to manufacture
dietary supplements do not, by
themselves, always eliminate the
microorganisms. Studies show, for
example, that microorganisms, such as
EHEC and Salmonella, can even survive
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the tablet production process and
thereby expose consumers (Ref. 25).
The industry is aware of the dangers
of using components contaminated with
Salmonella and other microorganisms.
For example, in 2001, a component
manufacturer recalled 2,400 pounds of
pepsin contaminated with Salmonella.
As a result, a number of dietary
supplement manufacturers issued
recalls for their dietary supplements
that contained the pepsin. In the press
releases accompanying the recalls, the
dietary supplement manufacturers
warned consumers of the possible
dangers of Salmonella contamination,
and encouraged consumers to either
destroy or return the supplements (Ref.
26).
Therefore, because of the
communicable disease concerns
associated with dietary supplements, we
are asserting legal authority under the
PHS Act in support of the final rule. As
discussed in the following section of
this document, our authority under the
PHS Act is not limited to interstate
activities. It also covers intrastate
activities.
2. Activities For Which We Are
Asserting Legal Authority Under the
PHS Act
There are many opportunities for
components and dietary supplements to
become contaminated with
microorganisms that spread
communicable diseases. The final rule
requires firms to take all the necessary
precautions during the manufacture of a
dietary supplement to prevent such
contamination.
These precautions, for example,
include: Performing manufacturing
operations under conditions and
controls that protect against potential
microorganism growth; washing or
cleaning components that contain soil
or other contaminants; performing
microbiological testing, as necessary, to
prevent the use of contaminated
components; sterilization,
pasteurization, freezing, refrigeration,
and controlling pH, humidity, and water
activity (aw), or using other effective
means to remove, destroy, or prevent
the growth of microorganisms and
decomposition; and holding
components and dietary supplements
that can support the growth of
infectious microorganisms of public
health significance in a manner that
prevents them from becoming
adulterated.
Failure to properly clean components,
or take any other appropriate steps, such
as those listed in the previous
paragraph, could lead to pathogen
growth and the spread of communicable
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diseases. If, for example, a dietary
supplement manufacturer purchased an
animal-derived ingredient that harbored
Salmonella enterica, but failed to take
the steps necessary to inactivate the
pathogen, the consumption of the
dietary supplement could lead to the
spread of salmonellosis.
The final rule also requires firms to
take measures to exclude from certain
operations any sick persons who might
contaminate material, including
components, dietary supplements, and
contact surfaces used to manufacture,
package, label, or hold a dietary
supplement.
D. The Interstate Commerce Nexus for
the Final Rule
1. The PHS Act
(Comment 21) Several comments
assert that, although the PHS Act may
extend to some intrastate activities, its
reach is very limited. The comments
appear to conclude that the reach of the
PHS Act and the act extends only to
situations in which the finished dietary
supplement is shipped in interstate
commerce.
(Response) We do not agree that this
view is correct. The PHS Act extends to
intrastate commerce. Under section 361
of the PHS Act (42 U.S.C. 264), we may
‘‘make and enforce such regulations as
in [our] judgment are necessary to
prevent the introduction, transmission,
or spread of communicable diseases
from foreign countries into the States or
possessions, or from one State or
possession into any other State or
possession.’’
In Louisiana v. Mathews, 427 F. Supp.
174, 176 (E.D. La. 1977), the court
upheld FDA’s regulation that banned
the sale of small turtles to prevent the
spread of disease caused by turtles
harboring Salmonella and Arizona
microorganisms. The ban covered both
interstate and intrastate sales. The court
held that the intrastate ban is not only
authorized by the law, but, under
modern conditions of transportation and
commerce ‘‘is clearly reasonable to
prevent the interstate spread of disease’’
(id.).
We are authorized under the PHS Act
to regulate conduct that occurs within a
State to the extent necessary to prevent
the interstate spread of communicable
diseases. Such is the present case with
respect to the provisions of the dietary
supplement CGMP final rule for which
section 361 of the PHS Act provides
authority.
2. The Act
The act extends to the sale of a dietary
supplement that was manufactured and
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distributed entirely in one State, if the
supplement contains any ingredient or
uses any component that came from
outside of that State. Such a dietary
supplement is subject to section 301(k)
of the act, which prohibits ‘‘[t]he
alteration, mutilation, destruction,
obliteration, or removal of the whole or
any part of the labeling of, or the doing
of any other act with respect to, a food,
drug, device, or cosmetic, if such act is
done while such article is held for sale
(whether or not the first sale) after
shipment in interstate commerce and
results in such article being adulterated
or misbranded.’’ (emphasis added). See
also 21 U.S.C. 321(b)(3) (defining food
to include articles used as components
of food).
The interstate commerce prerequisite
under section 301(k) or section 304(a)
(21 U.S.C. 334(a)) of the act is
established when one or more
components used in the manufacture of
the product have crossed State lines.
This principle is known as ‘‘component
jurisdiction’’ (See, e.g., Baker v. United
States, 932 F.2d 813, 814–15 (9th Cir.
1991); United States v. Article of Food
* * * Coco Rico, Inc., 752 F.2d 11, 14
(1st Cir. 1985); United States v.
Dianovin Pharmaceuticals, Inc., 475
F.2d 100, 103 (1st Cir.), cert. denied, 414
U.S. 830 (1973) (‘‘appellants’ use of
components shipped in interstate
commerce to make vitamin K for
injection brought their activities within
§ 331(k)’’); United States v. Cassaro,
Inc., 443 F.2d 153, 155–56 (1st Cir.
1971); United Statesv. Detroit Vital
Foods, Inc., 330 F.2d 78, 81–82 (6th
Cir.), cert. denied, 379 U.S. 832 (1964);
United States v. Allbrook Freezing &
Cold Storage, Inc., 194 F.2d 937, 939
(5th Cir. 1952); United States v. VarelaCruz, 66 F.Supp.2d 274, 277–281 (D.
P.R. 1999)).
Nor does it matter that the interstate
product component comprises only a
minute part of the article, United States
v. Miami Serpentarium Laboratories,
[1981—1982 Transfer Binder] Food
Drug Cosm. L.Rep. (CCH) paragraph
38,164 at 38,930 (S.D. Fla. 1982); United
States v. 14 Cases * * * Naremco, 374
F.Supp. 922, 925 (W.D. Mo. 1974), or if
the interstate ingredient combines with
others to form a different product.
Detroit Vital Foods, 330 F.2d at 81;
United States v. 40 Cases * * *
Pinocchio Brand * * * Oil, 289 F.2d
343, 346 (2d Cir.), cert. denied, 368 U.S.
831 (1961).
Finally, we note that section 709 of
the act creates a presumption of
interstate commerce (see 21 U.S.C. 379a
(‘‘In any action to enforce the
requirements of this Act respecting a
device, food, drug, or cosmetic the
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connection with interstate commerce
required for jurisdiction in such action
shall be presumed to exist.’’)).
In conclusion, the final rule covers
not only finished products that have
moved in interstate commerce but also
products made from ingredients or
components that have moved in
interstate commerce. This is true
regardless of the amount of the
ingredient or component in the product
and regardless of whether the finished
dietary supplement has itself moved in
interstate commerce. The final rule also
covers products, components, and
ingredients that may contribute to the
spread of communicable disease,
regardless of whether the component,
ingredient, or product has itself moved
in interstate commerce.
3. Commerce Clause
(Comment 22) One comment states
that we must be ‘‘mindful of the limits’’
imposed on the regulation of intrastate
commerce by the Supreme Court in
United States v. Lopez, 514 U.S. 549
(1995). The comment asserts that we
may only regulate intrastate activity that
has a ‘‘substantial effect’’ on interstate
commerce and activity that ‘‘exerts a
substantial economic effect on interstate
commerce.’’
(Response) The final rule is consistent
with the Lopez decision. Among the
cases cited by the Court in Lopez as
support for its decision is Wickard v.
Filburn, 317 U.S. 111 (1942), which
involved the production and
consumption of homegrown wheat. In
that case, the Court explained:
‘‘although Filburn’s own contribution to
the demand for wheat may have been
trivial by itself, that was not enough to
remove him from the scope of federal
regulation where, as here, his
contribution, taken together with that of
many others similarly situated, is far
from trivial’’ (Lopez, 514 U.S. at 556).
The same is true for dietary supplement
manufacturers. Therefore, the
requirements of the final rule are
consistent with the Commerce Clause of
the Constitution.
E. Fifth Amendment
(Comment 23) Several comments
allege a number of the sections of the
proposed regulation are
unconstitutionally vague and violate the
Administrative Procedure Act (APA)
because the rule would be ‘‘contrary to
constitutional right, power, privilege, or
immunity.’’ The comments express
concern that if such terms are not
defined or deleted, there would be no
fair notice on what conduct is
prohibited and would result in
‘‘unbridled discretion’’ in how the rule
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will be enforced. The comments focus
on provisions containing words such as
‘‘adequate,’’ ‘‘qualified,’’ ‘‘readily
accessible,’’ ‘‘convenient,’’ ‘‘suitable,’’
‘‘appropriate,’’ and ‘‘necessary.’’ For
example, one comment notes that
proposed § 111.15(e) would require
physical plant plumbing to be of an
adequate size and design and to be
adequately installed and maintained.
The comment objects to the section on
the ground that ‘‘what constitutes
‘adequate’ in those contexts is left
undefined.’’
(Response) We disagree these terms
are vague or that the identified terms
should be deleted from the final rule.
The qualifying terms objected to in the
comments have been in use since the
umbrella food CGMP rule (part 110) was
first promulgated in 1969. For example,
this regulation included requirements
that: ‘‘[p]lant buildings and structures
shall be suitable in size;’’ there must be
‘‘sufficient space’’ for equipment and
storage materials; there must be
‘‘adequate lighting;’’ and protection
against pests must be provided ‘‘where
necessary’’ (see 34 FR 6977 at 6978,
April 26, 1969). The court in National
Association of Pharmaceutical
Manufacturers. v. Department of Health
& Human Services, 586 F.Supp. 704
(S.D.N.Y 1986), addressed the very
question of whether terms such as
‘‘adequate,’’ ‘‘appropriate,’’ ‘‘proper,’’
‘‘sufficient,’’ and ‘‘suitable,’’ in the drug
CGMP regulation were vague. The court
found that the drug CGMP regulation
containing such terms was ‘‘sufficiently
definite to give notice of the required
conduct to one who would avoid [their]
penalties, and to guide the judge in
[their] application * * *’’ (Id. at 753).
The court so held, in part, in light of the
fact that the drug CGMP statute was
upheld against a constitutional
vagueness attack in United States v. BelMar Laboratories, Inc., 284 F. Supp.
875, 883 (E.D.N.Y. 1968) (‘‘the phrase
‘current good manufacturing practice’ is
not strange to those in the trade to
whom the subject section is directed.’’).
Furthermore, the use of such ‘‘ordinary
terms to express ideas which find
adequate interpretation in common
usage and understanding’’ are not the
types of terms that have been held to be
unconstitutionally vague (Boyce Motor
Lines v. United States, 342 U.S. 337, 342
(1952)). Some of these very terms have
been in use for over 30 years in food
CGMP regulations.
No comments were submitted
objecting to the use of such terms, when
the umbrella food CGMP rule was
revised in 1986 (see 51 FR 22458, June
19, 1986). Also, when we began work on
the dietary supplement CGMP rule, we
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received and published for comment an
industry draft of a CGMP regulation for
dietary supplements. The industry draft
used many of the same terms. For
example, it provides in part: ‘‘Plumbing
shall be of adequate size and design and
adequately installed and maintained’’
(62 FR 5700 at 5703, February 6, 1997).
Thus, there has been sufficient common
usage of these terms in the food industry
and, in particular, the dietary
supplement industry to enable
manufacturers, and those who enforce
the requirements, to comprehend and
apply such terms ‘‘with a reasonable
degree of certainty’’ to their particular
operations (Boyce Motor Lines v. United
States, 342 U.S. at 340 (‘‘[F]ew words
possess the precision of mathematical
symbols, most statutes must deal with
untold and unforeseen variations in
factual situations, and the practical
necessities of discharging the business
of government inevitably limit the
specificity with which legislators can
spell out prohibitions [and therefore] no
more than a reasonable degree of
certainty can be demanded.’’)). The
same reasoning applies here. It
addresses ‘‘untold and unforeseen
variations in factual situations’’ and, as
such, ‘‘no more than a reasonable degree
of certainty can be demanded.’’
Agencies are permitted to, and indeed
must, use such qualifying terms to
address the variety of conditions that
exist at different companies. We do not
need to, nor could we, predict with
mathematical precision how many
inches or feet, for example, would be
‘‘adequate space’’ to allow for cleaning
a particular piece of equipment that
could be applied to every size of facility
and every operation (id.). Moreover,
defining such terms too precisely would
unduly restrict the application of the
regulation to a very narrow, limited set
of circumstances and not provide
industry with the needed flexibility to
address the number and variety of types
of manufacturing operations that
Congress intended for this rule to cover
(see Freeman United Coal Mining
Company v. Federal Mine Safety and
Health Review Commission, 108 F.3d
358, 363 (D.C. Cir. 1997) (citations
omitted) (upholding a regulation that
required equipment to be ‘‘maintained
in good repair,’’ the court rejected the
vagueness challenge: ‘‘specific
regulations cannot begin to cover all of
the infinite variety of [conditions at
firms and that] * * * [b]y requiring
regulations to be too specific [courts]
would be opening up large loopholes
allowing conduct which should be
regulated to escape regulation.’’); United
States v. Bel-Mar Laboratories, Inc., 284
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F. Supp. at 883 (rejecting a vagueness
challenge to the CGMP requirements for
drugs, noting that ‘‘[a]s a matter of fact,
there are responsible segments of
opinion within the industry itself which
oppose a greater degree of specificity in
this area.’’).
Finally, it is important to understand
that rules are not unconstitutionally
vague simply because they require
interpretation by regulated persons. For
example, courts have held that the term
‘‘insanitary conditions’’ in the act is not
unconstitutionally vague (See Golden
Grain Macaroni Co. v. United States,
209 F.2d 166, 168 (9th Cir. 1953) (citing
Boyce Motor Lines, supra); Berger v.
United States, 200 F.2d 818 (8th Cir.
1952)). In Berger, the court rejected the
claim that the term ‘‘insanitary
condition’’ is unconstitutionally vague
on the ground that it does not specify
the ‘‘degree of insanitation’’ required for
a violation (id. at 822). A law may
require a person to make ‘‘estimates of
the degree of dirtiness and lack of
sanitation’’ which may result in a
violation (id., see alsoBoyce Motor Lines
v. United States, 342 U.S. at 340 (It is
not ‘‘unfair to require that one who
deliberately goes close to an area of
proscribed conduct shall take the risk
that he may cross the line’’)). There are
sufficient protections under the act to
overcome any concerns related to how
it will be criminally enforced. We
disagree that such terms will lead to
‘‘unbridled discretion’’ on how the rule
is enforced.
In short, we find that the rule is not
unconstitutionally vague, and does not
violate section 706(2)(B) of the APA (5
U.S.C. 706(2)(B)).
F. Miscellaneous
(Comment 24) One comment states
that the proposed rule violates section
402(f)(1)(A)(i) and (f)(1)(A)(ii) of the act
(21 U.S.C. 342 (f)(1)(A)(i) and
(f)(1)(A)(ii)), which deems a dietary
supplement adulterated if it contains a
dietary ingredient that presents an
unreasonable risk of illness or injury
under conditions of use in labeling or
ordinary conditions of use, if none are
suggested or recommended in labeling.
Under section 402(f) of the act, the
Government bears the burden of proof to
show that a dietary supplement is
adulterated. The comment states that
the proposed rule reversed the
presumption under section 402(f) of the
act, and would revise the rule to require
us to first show a violation under
section 402(f) of the act before we could
take any enforcement action under
section 402(g). Another comment states
that, because the rule was intended to
enable manufacturers to be able to
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detect and avoid adulteration through
CGMP, the proposed rule created a
presumption that dietary supplements
are adulterated until proven otherwise.
(Response) The final rule does not
violate section 402(f) of the act. Section
402(f) and (g) of the act provide two
independent bases under which we may
take enforcement action against dietary
supplements. A dietary supplement may
be adulterated either because a
manufacturer has failed to follow a
CGMP requirement, or because a dietary
supplement presents an unreasonable
risk of illness or injury, or both. There
would be no reason to assert a second
basis for adulteration under section
402(g) of the act if one always had to
demonstrate adulteration under section
402(f) of the act as a prerequisite.
We also disagree with the comment
that the proposed rule creates a
presumption that the dietary
supplement is adulterated simply
because the proposed requirements
would enable a manufacturer to detect
and avoid adulteration. The
requirements for CGMP are prophylactic
and are designed in part to ensure that
all aspects of manufacturing, from
receipt through distribution, provide the
necessary controls and monitoring to
ensure the quality of the dietary
supplement, including that it is
manufactured, packaged, labeled, and
held in a manner to prevent
adulteration.
(Comment 25) One comment states
that, if there is reduced competition
through the enforcement of the rule,
there will be a secondary effect of
elimination of speech on dietary
supplement innovative uses.
(Response) The comment seems to
conclude that, if a dietary supplement
manufacturer is not able to stay in
business due to adverse enforcement
actions against it by us, or elects to not
go into business based on the possibility
of enforcement action by us, there will
be reduced competition due to fewer
products, less labeling, and
‘‘elimination of speech on innovative
uses.’’ To the extent that the comment
is suggesting that the dietary
supplement CGMP requirements are
unconstitutionally overbroad, this
argument is wholly without merit (Cf.
Wisconsin v. Mitchell, 508 U.S. 476,
488–89 (1993) (finding no merit to an
overbreadth argument that the
possibility of enhanced sentences based
on prior racially motivated speech or
associations constitutes an
impermissible chill on free speech)).
Manufacturing a dietary supplement in
a manner that violates the CGMP
requirements causes the product to be
adulterated, and therefore, unlawful.
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The fact that a manufacturer may not
stay in business, or elects not to enter
business, due to: (1) Our
implementation of CGMP requirements
or (2) our enforcement against a product
that violates CGMP requirements, does
not mean that we are somehow
prohibiting speech. In any event, there
is no First Amendment protection for
speech that concerns unlawful activity
under the first prong of the test set out
in Central Hudson Gas & Electric Corp.
v. Public Service Commission, 447 U.S.
557 (1980). Therefore, the comment’s
suggestion that there is elimination of
speech based on the rulemaking is not
supportable. The requirements in the
final rule do not infringe on a
manufacturer’s right to lawfully label
and market a dietary supplement.
VI. What Comments Did We Receive on
the General Provisions? (Subpart A)
A. Organization of Final Subpart A
Proposed subpart A contained five
provisions regarding the scope of the
proposed rule, definitions, and
exclusions. Table 2 of this document
lists the sections in final subpart A and
identifies the proposed sections that
form the basis of the final rule.
TABLE 2.—DERIVATION OF
SECTIONS IN FINAL SUBPART A
Final Rule
2003
CGMP
Proposal
§ 111.1
§ 111.3 what definitions
apply to this part?
§ 111.3
§ 111.5 Do other statutory provisions and
regulations apply?
sroberts on PROD1PC70 with RULES
§ 111.1 Who is subject
to this part?
§ 111.5
B. Who Is Subject to This Part? (Final
§ 111.1)
Section 111.1 explains who is subject
to the dietary supplement CGMP
requirements. In brief, final § 111.1(a)
states that you are subject to the dietary
supplement CGMP requirements if you
manufacture, package, label, or hold a
dietary supplement. This requirement
includes a dietary supplement you
manufacture but that is packaged or
labeled by another person, and a dietary
supplement that is imported, offered for
import in any State or Territory of the
United States, the District of Columbia,
or the Commonwealth of Puerto Rico.
Final § 111.1(b), however, excludes
certain persons from the rule.
Specifically, § 111.1(b) states that the
requirements pertaining to holding
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dietary supplements do not apply to you
if you are holding those dietary
supplements at a retail establishment for
the sole purpose of direct retail sale to
individual consumers. This section also
states that a retail establishment does
not include a warehouse or other storage
facility for a retailer or a warehouse or
other storage facility that sells directly
to individual consumers.
This exclusion represents specific
changes sought by the comments. We
provide detail on the comments and our
reasons for revising final § 111.1 in the
following paragraphs.
(Comment 26) Some comments
interpret the proposal as not applying to
persons who perform labeling
operations. For example, one comment
claims that proposed § 111.35(e), which
would require manufacturers,
packagers, and persons who hold
dietary supplements to establish
specifications, did not apply to
‘‘labelers’’ because the proposed
definition of ‘‘you’’ did not expressly
mention persons who label dietary
supplements.
(Response) We disagree with the
comments. Various provisions in the
proposal expressly mentioned or
pertained to labels and labeling
operations (see, e.g., proposed
§§ 111.20(c)(6) (which would require
your physical plant to have separate or
defined areas for packaging and label
operations), 111.30(a) (which would
impose certain requirements on
automatic, mechanical, or electronic
equipment used to ‘‘manufacture,
package, label, and hold’’ a dietary
supplement), 111.35(a) (which would
require you to implement a system of
production and process controls that
cover, among other things, all stages of
labeling dietary supplements), 111.37(a)
(which would require you to use a
quality control unit to ensure, among
other things, your label operations are
performed in a manner that prevents
adulteration and misbranding),
111.40(b) and (c) (which would impose
certain requirements on packaging and
labels you receive and on persons who
perform label requirements), and 111.70
(which would impose various
requirements on packaging and label
operations)). Although the proposed
definition of ‘‘you’’ and proposed
§ 111.1 did not include the word ‘‘label’’
or ‘‘labeling,’’ we considered label
operations to be part of a broader
manufacturing process, and it would be
illogical to interpret the proposal’s
specific references to label operations as
somehow being inapplicable to labelers
simply because a proposed definition of
‘‘you’’ or a general ‘‘scope’’ provision
did not mention labels or otherwise
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distinguish label operations from the
broader context of manufacturing.
In any case, to correct such
misinterpretation, we have revised
§ 111.1 to include the word ‘‘label.’’
Thus, under final § 111.1(a), you are
subject to the dietary supplement CGMP
requirements if you ‘‘manufacture,
package, label, or hold a dietary
supplement.’’ We also have made
corresponding changes to other sections
in this final rule; for example, we have
revised the definition of ‘‘you’’ in final
§ 111.3 to state that ‘‘you’’ means ‘‘a
person who manufactures, packages,
labels, or holds’’ a dietary supplement,
and we also have inserted the word
‘‘labeling’’ in the title to this final rule.
We have not explained this change in
the preamble each time it is made in the
codified provision.
In addition, we refer to ‘‘label’’ and
‘‘labeling’’ in the context of CGMP
requirements related to operations for
ensuring the correct label is on the
product. To help clarify that we are
referring to labeling requirements in this
final rule for labeling operations and
not, for example, to the labeling
requirements in part 101, we inserted
the word ‘‘operations’’ in the title of part
111 to read ‘‘Current Good
Manufacturing Practice in
Manufacturing, Packaging, Labeling, or
Holding Operations for Dietary
Supplements.’’
(Comment 27) Several comments ask
for clarification about the rule’s
applicability to different types of
businesses and practices. Some
comments ask for a clear listing of who
is subject to the rule, stating that it is
difficult to apply the rule’s specific
provisions. According to these
comments, the rule’s level of detail and
inflexibility does not account for
variations in manufacturing needs
within the entire industry.
Several comments on various
proposed sections ask who would be
responsible for complying with CGMP
requirements if more than one party was
involved in the manufacturing,
packaging, labeling, or holding of the
dietary supplement. For example, some
comments ask whether consultants are
subject to a specific proposed section;
others ask who would be responsible if
a firm employed another firm to handle
packaging or labeling operations.
Other comments request clarification
regarding the rule’s applicability to
distributors. Some comments claim that
a person who holds and sells packaged
products should not be subject to
dietary supplement CGMP
requirements. Other comments state that
dietary supplement CGMPs should
apply to distributors as well as
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manufacturers. These comments assert
many supplement distributors are
merely marketers who employ contract
manufacturers. The comments said that,
because marketers are the parties
providing supplements to consumers,
we should hold marketers responsible
for their products and require marketers
to ensure that their contract
manufacturers adhere to CGMP
requirements. These comments argue
we should not permit marketers to
transfer their responsibilities in
delivering safe supplements. Other
comments assert questions about the
rule’s applicability are underscored by
typical dietary supplement labeling
practices where the contact information
listed on the product label pertains to
the distributor/marketer instead of the
actual manufacturer.
Collectively, these comments raise a
basic question as to which party or
parties are responsible for complying
with the dietary supplement CGMP
requirements where more than one
party is involved in the manufacture,
packaging, labeling, or holding of that
dietary supplement.
(Response) In the 2003 CGMP
Proposal, we stated that it would apply
to a wide variety of activities associated
with the manufacture, packaging, and
holding of a dietary supplement,
including labeling, testing, quality
control, holding, and distribution (68 FR
12157 at 12175). We stated under
proposed part 111 you would need to
comply with those regulations directly
applicable to the operations that you
perform and provided examples (id.).
All activities may not be performed by
the same person. For example, a
manufacturer may contract with another
firm to package and label the dietary
supplement in the containers used for
distribution to consumers.
Alternatively, a distributor may contract
with one firm to manufacture a dietary
supplement, and another firm to
package and label the dietary
supplement that the distributor
ultimately distributes under its own
name.
Under this final rule, you must
comply with the CGMP requirements
that apply to your operations related to
the manufacture, packaging, labeling,
and holding of dietary supplements. It
is not practical to list all possible
contractual relationships that persons
may enter into in the manufacture of a
dietary supplement, or to list all
businesses or practices that may be
subject to the requirements of this final
rule in order for persons to know
whether they are subject to
requirements of this final rule. To
provide additional clarity about how
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this rule may apply to various persons,
we provide some examples in the
following paragraphs.
A manufacturer that manufactures a
dietary supplement, and then packages
and labels and distributes the dietary
supplement, is subject to all the
requirements in this final rule. If that
manufacturer contracts with another
person to package and label the dietary
supplement, then the packager/labeler is
responsible for complying with the
requirements for packaging and labeling
operations, in addition to other relevant
requirements. The packager/labeler, in
this example, would need to comply,
not only with the specific requirements
related to packaging and labeling
operations in subpart L, but also with
the general requirements related to
personnel, physical plant, quality
control, and other requirements that
apply to that firm’s operations. However
the packager/labeler would not need to
comply with requirements that do not
apply to it; for example, the packager/
relabeler would not have to conduct
testing on the finished batch of dietary
supplement since it does not
manufacture the finished batch of
dietary supplement.
A manufacturer who contracts with a
person to do packaging and labeling, but
who later distributes the packaged and
labeled product, is ultimately
responsible for the dietary supplement
it releases for distribution. The
manufacturer would be responsible for
the CGMP requirements for the
operations that it performs, including
those related to the release of the
product for distribution. For example,
the manufacturer must determine
whether the packaged and labeled
dietary supplement it receives from the
packager/labeler conforms to applicable
specifications (final § 111.127(d)), and
must approve the release of the
packaged and labeled dietary
supplement for distribution (final
§ 111.127(h)). Although the
manufacturer is not performing the
specific activities related to the
packaging and labeling operations done
by another person, the manufacturer has
an obligation to know what and how
such activities are performed so that it
can make decisions related to whether
the packaged and labeled product
conforms to applicable specifications
and whether to approve and release the
product for distribution.
Some manufacturers may sell their
finished batch of dietary supplement to
a packager/labeler that the packager/
labeler may package, label, and then
hold and distribute. The manufacturer
and packager/labeler would each be
responsible for complying with the
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applicable CGMP requirements related
to the operations that they perform. The
manufacturer would not be responsible
for the oversight of the packager/labeler,
since the packager/labeler is not under
the control of the manufacturer and has
control over the release of the packaged
and labeled dietary supplement.
A manufacturer may decide to hire a
contractor or a consultant for specific
operations within the scope of the
manufacturer’s responsibilities under
the final rule. For example, a
manufacturer may hire a person to
calibrate its equipment. The
manufacturer is responsible for
complying with the requirements
related to its responsibilities, e.g.,
calibration requirements in this
example, even though the manufacturer
has hired another person to perform that
job task.
In another example, a distributor who
purchases a packaged and labeled
dietary supplement and who then holds
the product in a warehouse for
distribution to another physical location
is subject to the requirements related to
its operations. The codified uses the
word ‘‘hold’’ since it is a broad term
which encompasses the activities of a
distributor. Thus, the distributor would
be responsible for complying with
requirements in subpart M, Holding and
Distributing, in addition to other
requirements related to its operations
(e.g., Personnel, Physical Plant and
Grounds).
In cases where a distributor contracts
with a manufacturer to manufacture a
dietary supplement that the distributor
then distributes under its own label, the
distributor has an obligation to know
what and how manufacturing activities
are performed so that the distributor can
make decisions related to whether the
packaged and labeled product conforms
to its established specifications and
whether to approve and release the
product for distribution.
(Comment 28) Some comments state
that the proposed rule requirements
would require the manufacturer to
report adverse events to us, but would
not require those who distribute the
product and whose name is likely to be
on the product label, to report adverse
events to us. The comments state that
reports of adverse events submitted by
consumers to those who distribute, but
do not make, dietary supplements could
be hidden from the public if such
persons are not required to submit those
reports to us.
(Response) The comments may have
misinterpreted the proposed rule. The
requirement to review and investigate a
product complaint is distinct from any
report about the product complaint to
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us. Reporting a complaint to us is not
covered by these CGMP requirements
and would be voluntary, unless the
complaint is subject to the statutorily
mandated reporting requirements for
‘‘significant adverse events’’ pursuant to
the ‘‘Dietary Supplement and NonPrescription Drug Consumer Protection
Act’’ (Public Law 109–462), signed into
law on December 22, 2006 (see
discussion in section XX of this
document).
Under the procedures that are set
forth in subpart O, Product Complaints
(see section XX of this document), a
distributor and a manufacturer are both
subject to the requirements related to
the review and investigation of a
product complaint that they receive.
(Comment 29) Some comments argue
against including minimum CGMPs
necessary for activities related to
manufacturing, packaging, labeling, or
holding dietary ingredients in the final
rule. Several comments argue the
proposed rule is overly broad and
inconsistent with congressional intent.
These comments question whether
Congress intended that CGMP apply to
persons involved in the manufacture,
packaging, labeling, and holding of
dietary ingredients. The comments also
argue that, if the rule applies to dietary
ingredient manufacturers, we would be
establishing precedent and that we lack
legal authority to regulate ingredients
rather than the finished products
themselves. The comments state that
neither food CGMP nor drug CGMP
offers precedent or guidance on
regulating ingredients. The comments
argue those who provide dietary
ingredients should be subject to the
existing general food CGMP
requirements in part 110 rather than to
the dietary supplement CGMP
requirements.
Several comments argue that many
dietary ingredients are used in regular
foods and in drugs as well as in dietary
supplements. The comments argue, for
some dietary ingredients, their use in
dietary supplements represents a very
small percentage of the dietary
ingredient’s worldwide usage. The
comments say we should allow those
who deal only with dietary ingredients
to operate under one set of regulations,
such as the general food CGMP
requirements in part 110. According to
these comments, we have not
demonstrated either a failure of the
current system or a compelling need to
create different regulations for raw
materials common to both the food and
dietary supplement industries. The
comments would revise the title of part
111 and proposed § 111.1 and make
conforming revisions throughout the
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proposed rule to limit the rule’s
applicability to dietary supplements.
In contrast, other comments say the
rule should apply to dietary ingredient
manufacturers as well as to dietary
supplement manufacturers. The
comments state that excluding those
who provide or supply dietary
ingredients would mean those who have
the greatest expertise in these goods
would not be subject to dietary
supplement CGMP requirements and
thus fail to cover a crucial step in
preventing the adulteration or
contamination of dietary supplements.
The comments argue that, for some
dietary ingredients (especially raw
botanical and agricultural goods), the
most critical point in ensuring an
ingredient’s quality and purity is at time
of harvest or creation, and that this is
particularly true with new or original
ingredients.
The comments state problems with
dietary supplements often arise from
substandard ingredients, and the
difficulty in testing the properties of
some botanical and other dietary
ingredients at the in-process or finished
product stage makes it necessary to
include dietary ingredient
manufacturers in the final rule.
Furthermore, these comments assert a
flexible testing scheme that they
recommend (which emphasizes
establishing specifications for
components, relying on certificates of
analysis from qualified suppliers,
qualifying component suppliers, and
establishing written procedures, with
testing of finished batches serving as a
check on the overall manufacturing
process) makes it important to regulate
dietary ingredient manufacturers.
Other comments suggest we issue a
separate or modified set of CGMP
requirements that would apply to
persons who manufacture, package,
label, or hold dietary ingredients. These
comments say the proposed rule does
not work for all dietary ingredients,
especially those converted from nonfood grade to food grade during the
manufacturing process. These
comments said the rule should be
modified for dietary ingredients.
(Response) Two issues seem to be
raised by these comments: (1) Whether
dietary ingredients are within the scope
of this final rule and (2) whether dietary
ingredient manufacturers are subject to
this final rule. Dietary ingredients are
included within the scope of this final
rule but dietary ingredient
manufacturers are not necessarily
subject to this rule. The definition of
‘‘component’’ in this final rule includes
‘‘any substance intended for use in the
manufacture of a dietary supplement
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including those that may not appear in
the finished batch of the dietary
supplement. Component includes
dietary ingredients (as described in
section 201(ff) of the act) and other
ingredients’’ (final § 111.3). The
proposed rule, § 111.3, recognized that
‘‘dietary ingredients’’ are ‘‘components’’
(68 FR 12157 at 12176) (describing how
dietary ingredients would fall within
the proposed definition of
‘‘component’’).
There are specific requirements in
this final rule that relate to components,
and thus dietary ingredients, that are
used in the manufacture of a dietary
supplement. For example, final
§ 111.70(b) requires you to establish
certain component specifications. Such
requirements would include
specifications for dietary ingredients as
‘‘components.’’ It is important to control
the components used in the
manufacture of dietary supplements to
ensure consistency and to ensure the
quality of the dietary supplement. Since
dietary ingredients are considered
components, the various requirements
apply to dietary ingredients as part of
the production and process control.
Therefore, we disagree to the extent
comments were suggesting that there
should be no CGMP requirements
related to the dietary ingredients used
by a manufacturer in the manufacture of
dietary supplements.
Dietary ingredients are included
within the meaning of ‘‘component.’’ In
those requirements in the proposed rule
where ‘‘component’’ encompasses
‘‘dietary ingredient’’ we are, in the final
rule, removing ‘‘dietary ingredient’’ in
those requirements and only refer to
‘‘component.’’ Given the scope of the
final rule, it is redundant to refer to both
‘‘component’’ and ‘‘dietary ingredient’’
where the latter is subsumed in the
former.
In response to comments that
questioned the need to include
manufacturers of dietary ingredients
within the scope of part 111, we have
made changes to the scope of the rule,
as applied to dietary ingredient
manufacturers. As we explain more
fully in our discussion of final
§§ 111.70, 111.73, 111.75, and 111.77
(see section X of this document), after
considering comments about the overall
production and process control system,
we revised the final rule’s approach to
ensuring product quality. This approach
emphasizes that it is important to
ensure the quality of the dietary
supplement throughout the production
and process control system. This
approach emphasizes establishing
specifications for components and
ensuring those specifications are met.
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You may rely on a certificate of analysis
for specifications (except for the identity
of the dietary ingredient) only if you
satisfy certain criteria, which include
qualifying the supplier of the
components. With this approach, the
goal of ensuring the quality of dietary
supplements can be achieved without
applying the rule specifically to persons
who manufacture, package, label, or
hold dietary ingredients that will be
further processed as a dietary
supplement by other persons.
Consequently, we revised § 111.1 by
deleting ‘‘dietary ingredient.’’ Therefore,
those who manufacture, package, label,
or hold dietary ingredients are not
subject to the final rule. To illustrate,
assume you manufacture a dietary
ingredient and sell that bulk dietary
ingredient to Company X. Company X
then utilizes the bulk dietary ingredient
in a dietary supplement. Under final
§ 111.1(a), you would not be subject to
these dietary supplement CGMP
requirements because you are not
manufacturing a dietary supplement,
rather you are manufacturing a dietary
ingredient for further incorporation into
a dietary supplement by Company X. If,
however, you sell herbs in bulk to
Company X, and Company X simply
packages the herbs into smaller units for
sale as a dietary supplement, you would
be subject to the dietary supplement
CGMP requirements because you are
manufacturing a dietary supplement
that Company X is simply packaging
and labeling, and not further processing
into a dietary supplement. In other
words, in the latter example, you would
have acted as a manufacturer whose
finished product is simply repackaged
or relabeled.
Under final § 111.1(a) persons
engaged solely in activities relating to
the harvesting, storage, or distribution of
raw agricultural commodities that will
be incorporated into a dietary
supplement by others are not included
within the scope of the rule as a dietary
supplement manufacturer. This is
because those persons simply ‘‘supply’’
a component (i.e., the raw agricultural
commodity) that another person will
process into a dietary supplement; thus
you do not manufacture, package, label,
or hold a dietary supplement.
Note, too, that if you manufacture and
supply a component directly to
consumers as a dietary supplement, you
would be considered a dietary
supplement manufacturer within the
scope of final § 111.1(a). Likewise, if
you manufacture a component and sell
part of the batch to another person who,
in turn, will further process the
component as a dietary supplement and
sell the remainder of the batch to
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consumers as a dietary supplement, you
would be subject to the dietary
supplement CGMP requirements, as a
manufacturer, for the product sold to
consumers and not subject to an
exclusion under final § 111.1(b),
discussed in this section. In other
words, final § 111.1(a) refers to the
nature of your activity, and simply
engaging in some activities that do not
bring you within the scope of the final
rule does not necessarily mean that all
your activities are outside the scope of
the final rule.
We do not agree, as some comments
suggested, that we need to issue a
separate or modified set of CGMP
requirements for dietary ingredients.
That is because there are adequate
controls established in this final rule for
the use of dietary ingredients used by
the manufacturer of a dietary
supplement. However, if you
manufacture, package, label, or hold
dietary ingredients that will be further
processed as a dietary supplement by
another person, you must comply with
food CGMP requirements in part 110. A
dietary ingredient is a food under
section 201(f) of the act, as a food, or as
a component of food. Because the final
rule gives manufacturers an incentive to
qualify suppliers of dietary ingredients,
persons who manufacture, package,
label, or hold dietary ingredients may
wish to familiarize themselves with
these dietary supplement CGMP
requirements and use them in
manufacturing, packing, labeling, or
holding operations for dietary
ingredients.
(Comment 30) Some comments argue
if the final rule ultimately covers dietary
ingredient suppliers then we should
clarify what constitutes a ‘‘consumer.’’
According to these comments, dietary
ingredient suppliers do not typically
supply their products directly to those
individuals who will ultimately
consume or ingest them. Thus,
‘‘consumers’’ of dietary ingredients are
other companies, not individuals. The
comments express concern about the
possible application of proposed
§ 111.95 which would require
procedures for handling complaints.
(Response) The final rule applies only
to persons who manufacture, package,
label, or hold dietary supplements and
are not subject to an exclusion in final
§ 111.1. However, as explained in the
previous response to comment 29, if a
dietary ingredient manufacturer also
supplies or sells a dietary ingredient as
a dietary supplement, such a
manufacturer would be subject to final
§ 111.1(a) and subject to all relevant
dietary supplement CGMP
requirements.
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Some comments expressed concern
about dietary ingredient manufacturers
having to comply with proposed
§ 111.95 on product complaints. If a
dietary ingredient manufacturer receives
a product complaint, we encourage the
manufacturer to evaluate the complaint
to determine if it may involve a problem
with the manufacture of the dietary
ingredient. In addition, we encourage
the dietary ingredient manufacturer to
notify the dietary supplement
manufacturer so that it can review the
complaint and investigate, as needed.
(Comment 31) Several comments
question the proposal’s applicability to
persons who sell packaged products or
seek clarification as to whether the rule
applies to dietary supplement
manufacturers that operate from homes
and those that distribute product to
other distributors.
(Response) To the extent that the
comments question whether retailers or
individuals who sell dietary
supplements directly to individual
consumers are subject to the dietary
supplement CGMP requirements, we
have revised the final rule by creating a
new § 111.1(b) which states that: ‘‘The
requirements pertaining to holding
dietary supplements do not apply to you
if you are holding those dietary
supplements at a retail establishment for
the sole purpose of direct retail sale to
individual consumers. A retail
establishment does not include a
warehouse or other storage facility for a
retailer or a warehouse or other storage
facility that sells directly to individual
consumers. ’’ This means, for example,
if you operate a storefront retail
establishment where you stock dietary
supplements on your shelves for
purchase by individual consumers, we
do not consider you to be ‘‘holding’’
those dietary supplements in a manner
that would require you to comply with
the holding provisions in this final rule.
Sale to individual consumers, where
you are not storing bulk dietary
supplements as one would in a
warehouse or storage facility, does not
fall within the manufacturing,
packaging, labeling, or holding activities
that would subject you to dietary
supplement CGMP requirements.
However, if you operate storefront
retail establishments, and those retail
establishments obtain their stocks from
your warehouse, we would consider
your warehouse operations to be
‘‘holding’’ dietary supplements and
expect your warehouse operations to
comply with the rule’s holding
requirements. Such distribution is no
different than other warehouse
operations that are normally subject to
CGMP requirements. Consequently, to
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distinguish between ‘‘holding’’ dietary
supplements for retail sale to consumers
and ‘‘holding’’ dietary supplements in a
warehouse for further distribution, final
§ 111.1(b) limits the exclusion to
persons holding dietary supplements
‘‘at a retail establishment for the sole
purpose of direct retail sale to
individual consumers.’’ Final § 111.1(b)
also makes it clear that a retail
establishment does not include a
warehouse or other storage facility that
a retailer uses to hold the dietary
supplements or an operation that sells
directly to consumers, but that itself
distributes the product to the consumer
from a warehouse or storage facility and
not from a storefront retail
establishment.
(Comment 32) Many comments
question the rule’s applicability to
various practitioners such as herbalists,
acupuncturists, naturopaths, and other
health care providers who prepare
individualized herbal formulas for
specific individuals on a case-by-case
basis. Most comments say such
practitioners should not be covered by
the rule. These comments give various
reasons to justify their position,
including:
• These practitioners do not broadly
sell products;
• These practitioners make very small
quantities of individualized formulas,
and can therefore be very selective as to
the quality of ingredients used;
• The testing and storage
requirements of each finished batch
cannot apply to a small dispensary
where several different modified herbal
formulas are prepared each day;
• Based on the projected costs to
implement CGMPs, it would be virtually
impossible for an individual
practitioner or university clinic to
develop the necessary quality control
unit, maintain reserve samples,
maintain the required paperwork, or
retrofit clinics to comply with the rule;
• Many States regulate or license
these practitioners, so further Federal
regulation is unnecessary;
• Some practitioners do not consider
themselves to be manufacturers;
• In an analogous situation,
compounding pharmacists are not
required to comply with drug CGMPs;
and
• Despite the growing number of such
practitioners, there is no proof that
greater harm has occurred to the general
public from the herbs these practitioners
sell.
(Response) We stated in the 2003
CGMP Proposal (68 FR 12157 at 12175)
that we declined to exempt herbalist
practitioners from the proposed rule.
We continue to believe that the risks of
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adulteration are not eliminated just
because the practitioner is an herbalist,
and therefore, such an exemption
should not be included in this final rule.
However, after further consideration, we
have determined that it would be
appropriate for us to consider the
exercise of our enforcement discretion
in deciding whether to apply the
requirements of this final rule to certain
health care practitioners, such as
herbalists, acupuncturists, naturopaths,
and other related health care providers.
We find it noteworthy that the
comments identified two potential
safeguards that could support the
exercise of our enforcement discretion
on whether to apply the requirements of
the final rule to certain practitioners: (1)
Adequate training in the professional
practice and (2) an individual client and
practitioner relationship. For example,
comments claimed that the practitioners
receive adequate training to formulate
dietary supplements and that they
provide the dietary supplements to
individuals in the course of a one-onone consultation on the premises of the
practitioner. One comment from a
practitioner states that she received her
training from an accredited 4-year
university and it included didactic and
clinical training in acupuncture and
Chinese herbs. Another comment from
an organization provides detailed
training guidelines for practitioners,
including 1,600 hours of training, 400
hours of which should include clinical
work. Moreover, many comments also
assert that the practitioners are different
from dietary supplement manufacturers
because they formulate the dietary
supplements in the course of a one-onone consultation at their premises. That
enables them to ensure the formulations
are made to meet the specific needs of
the individuals.
We believe that a one-on-one
consultation by a practitioner who is
adequately trained in their profession
may not necessitate the same types of
controls as we are establishing in this
final rule for manufacturing activities
that are on a larger scale. Such a
practitioner may make some
formulations in advance of the
consultation and still make the
formulations in very limited quantities
for the individual client. We believe that
it would be appropriate to consider the
exercise of our enforcement discretion,
on a case-by-case basis, to determine
whether to apply the requirements of
this final rule to such persons.
We do not expect the number of those
subject to the consideration of our
enforcement discretion to be very large.
Many products that are manufactured
by practitioners would not necessarily
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be considered to be dietary supplements
(e.g., certain products used by
traditional Asian medicine
practitioners). Further, we are not
considering exercising our enforcement
discretion with respect to practitioners
who prepare batches of herbs and sell
them to individual consumers without
determining whether the dietary
supplement is appropriate for each
consumer’s needs in a one-on-one
personal consultation, or those that
prepare batches of a dietary supplement
for which there is a known or suspected
safety concern.
(Comment 33) Several comments
asked us to exempt academic
institutions that provide training for
therapeutic disciplines that use, for
example, herbal formulas in their
practice regardless of whether the
dietary supplements they produce enter
into interstate commerce. Specifically,
these comments would revise the final
rule to state that it does not apply ‘‘to
academic institutions that provide
training in dispensing of nutritional or
herbal products and formulas related to
courses in therapeutic disciplines that
provide such products and formulas as
a part of their therapy, for example,
naturopathy, herbalism, traditional
Chinese medicine, and acupuncture.’’
(Response) Similar to what we stated
in response to comment 32, we believe
that it may be appropriate to consider
the exercise of our enforcement
discretion in circumstances where an
academic institution’s actions are
similar to those of a practitioner who is
adequately trained in their profession
and who provides dietary supplements
within the context of an individual
client and practitioner relationship. In
general, it is not our policy to inspect
an academic institution that provides
training for therapeutic disciplines that
use, for example, dietary supplements
in their practice. We intend to consider
the exercise of our enforcement
discretion in those situations where
there is a one-on-one consultation that
includes a practitioner with adequate
training. We intend to issue guidance to
further clarify how the agency intends
to exercise its enforcement discretion on
the application of this final rule to
certain academic institutions.
(Comment 34) Several comments
discuss the position taken by certain
nations, notably Australia and Canada,
that have developed CGMP
requirements and related guidance for
botanicals. According to these
comments, these nations recognize that
there are various types of practitioners
who sell herbs and herbal preparations
in a clinical setting, and do not consider
such persons to be manufacturers. The
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comments ask us to follow the example
of these nations.
(Response) We intend to consider the
positions taken by other nations to
inform us in our decisionmaking in any
future guidance on how we intend to
exercise our enforcement discretion on
the application of this final rule to
certain practitioners.
(Comment 35) Many comments say
we should define when a dietary
supplement will be said to have entered
interstate commerce. The comments
state herbal practitioners (and academic
institutions) often purchase source
herbs from outside their State, even if
they prepare these herbs for their
specific customers within the State.
These comments request we clarify that
the rule does not apply to herbs
purchased out of State if prepared for
local use. Other comments request
clarification regarding clients who have
moved across State lines, yet maintain
a relationship with an herbalist
practitioner.
(Response) In section V of this
document we explain the interstate and
intrastate issue related to the final rule.
(Comment 36) A few comments assert
individual practitioners and practitioner
organizations often are unaware of the
opportunity to comment on CGMP or
regulatory issues. Therefore, the
comments say these practitioners and
organizations often fail to provide
comment or otherwise participate in
rulemaking and say we should give
these practitioners and practitioner
organizations a chance to comment.
(Response) We provided many
opportunities for comment and,
therefore, we decline to adopt the
comments’ suggestion. As we discuss in
section I of this document, we
published an ANPRM concerning
dietary supplement CGMPs on February
6, 1997 (62 FR 5700); the 1997 ANPRM
provided an opportunity for public
comment. On March 7, 2003, we issued
a Talk Paper, along with other
background documents, announcing the
issuance of a proposed dietary
supplement CGMP rule. We made the
proposed rule available when it went on
display (before it published) in the
Federal Register on March 13, 2003 (68
FR 12157), and, again, provided an
opportunity for public comment. We
also held public meetings on April 29,
2003, in College Park, MD and on May
6, 2003, in Oakland, CA. We also held
a public meeting (via satellite downlink)
on May 9, 2003, with viewing sites at
our district and regional offices
throughout the country. Thus, we
provided numerous opportunities for
interested persons to learn about the
rule and to submit comments or
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otherwise participate in the rulemaking
process. Consequently, we decline to
provide yet another opportunity for
comment.
(Comment 37) The preamble to the
2003 CGMP Proposal noted that
comments submitted in response to our
1997 ANPRM state we should not
distinguish between dietary
supplements made in the United States
and those made in a foreign country (68
FR 12157 at 12174). Although we agreed
with the comments and made no
distinction between foreign and
domestic firms in the proposed rule, we
invited comment on how we might
ensure dietary ingredients and dietary
supplements exported to the United
States have been manufactured,
packaged, labeled, and held consistent
with part 111 (68 FR 12157 at 12175).
Several comments argue the rule
should apply to foreign firms as well as
domestic manufacturers to ensure a
‘‘level playing field’’ and to protect
American consumers. Some comments
say we should work with foreign
countries to harmonize our
requirements and thus avoid potential
trade disputes under international trade
agreements such as the General
Agreement on Tariffs and Trade. Other
comments suggest compliance by
foreign firms could be achieved through
the use of third party certification
programs, such as the dietary
supplement verification program
administered by USP, or the adoption of
importer verification provisions similar
to those used in our HACCP
requirements for seafood (see § 123.12).
In contrast, another comment says we
should inspect foreign firms to ensure
compliance, whereas other comments
claim we lack jurisdiction over foreign
firms.
(Response) We are amending
proposed § 111.1 to clarify the
regulation’s applicability to foreign
firms. We explain in this section how
we may enforce the rule against foreign
firms. We, however, are not making any
changes in response to the comments
calling for the harmonization of the rule
with foreign rules because this request
is beyond the scope of the final rule.
In response to comments, and for
clarification, we have revised final
§ 111.1(a) to clarify that the regulation
applies to the extent that you
manufacture, package, label, or hold a
dietary supplement, including a dietary
supplement imported or offered for
import in any State or Territory of the
United States, the District of Columbia,
or the Commonwealth of Puerto Rico.
With respect to the comments
requesting that we make clear our
position for enforcing the rule against
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foreign firms, we explain our position as
follows. Section 801(a) of the act (21
U.S.C. 381a) authorizes us to refuse
admission of an imported food if it
appears from the examination of such
samples or otherwise that such article
is, among other things, adulterated. A
foreign firm’s refusal to allow us to
obtain records via an inspection for
CGMP purposes, as required by final
§ 111.610 (for the dietary supplements
the foreign firm offers for import into
the United States), would create the
appearance that such imported dietary
supplements are adulterated under
section 402(g) of the act, and thus, could
lead to a refusal of admission under
section 801(a) of the act.
Foreign firms who ship to the United
States must operate under conditions
that satisfy our regulations, including
the requirement that records be made
available during the course of an FDA
inspection. We note that except in
circumstances where there is a public
health emergency or we receive
information that would indicate the
appearance of adulteration of products
shipped to the United States, foreign
inspections are generally scheduled
well, e.g., weeks, in advance. Thus, we
believe that taking action under section
801 of the act is appropriate if
companies do not accommodate our
inspectional request.
C. What Definitions Apply to This Part?
(Final § 111.3)
Section 111.3 defines various terms
that we use in the final rule and notes
that definitions or interpretations of
terms in section 201 of the act also
apply. In general, we adopted the
definitions that we proposed, although,
in some cases, we deleted words or
concepts as a result of other changes we
made to the final rule. We have added
a definition of ‘‘quality’’ for purposes
only of this final rule.
A recurring change we made is the
deletion of the words ‘‘dietary
ingredient’’ in several definitions. In
some cases, the use of the words
‘‘dietary ingredient’’ was redundant to
the use of ‘‘component’’ and thus not
necessary in the final rule. Because a
‘‘dietary ingredient’’ is subsumed within
the definition of ‘‘component,’’ as
explained in our response to comment
29, we deleted ‘‘dietary ingredient’’ in
those definitions where ‘‘component’’
was used to avoid redundancy.
In other provisions, we deleted
‘‘dietary ingredient’’ from the definition
because the use of those words was no
longer necessary given the narrowing of
the scope of the rule as it applies to
dietary ingredient manufacturers
(explained in the response to comments
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29 and 30). For example, we deleted
‘‘dietary ingredient’’ from the proposed
definition of ‘‘ingredient’’ that referred
to the ‘‘manufacture of a dietary
ingredient or dietary supplement’’ and
the ‘‘finished batch of the dietary
ingredient or dietary supplement.’’ We
did not need to state ‘‘manufacture of
the dietary ingredient’’ or refer to
‘‘finished batch of dietary ingredient’’
because dietary ingredient
manufacturers that only supply such
ingredients to other persons for
processing into a dietary supplement are
not subject to the final rule.
We discuss changes to the definitions,
other than the changes we have made
globally such as the deletion of ‘‘dietary
ingredients,’’ the change from ‘‘include,
but not limited to’’ to ‘‘includes’’ or
‘‘include,’’ the addition of labels and
labeling, and the deletion of the word
‘‘quality’’ from the phrase ‘‘identity,
purity, quality, strength, and
composition,’’ as well as comments
asking us to define more terms or to
delete certain definitions, in more detail
in the following paragraphs.
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1. Actual Yield
The final rule defines ‘‘actual yield’’
as ‘‘the quantity that is actually
produced at any appropriate step of
manufacture or packaging of a particular
dietary supplement.’’
We received no substantive comments
to the proposed definition.
2. Batch
The final rule defines ‘‘batch’’ as ‘‘a
specific quantity of a dietary
supplement that is uniform, that is
intended to meet specifications for
identity, purity, strength, and
composition, and that is produced
during a specified time period according
to a single manufacturing record during
the same cycle of manufacture.’’
This definition differs from the
proposed definition of ‘‘batch’’ by
stating that a batch is a specific quantity
of a dietary supplement that is
‘‘uniform.’’
We inserted the word ‘‘uniform’’ in
response to comments asking that we
define ‘‘lot’’ to be consistent with
‘‘batch.’’ We explain our reasons for
harmonizing the definitions and for
inserting ‘‘uniform’’ into the definition
of ‘‘batch’’ in the response to comment
42 of this document.
We discuss the comments on our
proposed definition of ‘‘batch’’ and our
changes to the definition in our
responses to the following comments.
(Comment 38) Several comments ask
us to clarify what the ‘‘same cycle of
manufacture’’ is in the definition of
‘‘batch.’’ One comment asks if it meant
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the same product made with the same
lot(s) of raw materials regardless of how
many days it took to produce the batch,
or if it meant a quantity produced in 1
day. The comment also asks whether
batches produced on consecutive days,
using the same formula, can be
considered to be the same batch with
respect to the proposed testing
requirements if the quality control unit
determined that different lots of raw
materials are equivalent (e.g., by
meeting all specifications).
(Response) The ‘‘same cycle of
manufacture’’ refers to a process during
which equipment remains dedicated to
the manufacture of the batch. The terms
do not limit you to any particular time
period or require you to operate
equipment continuously until you have
completed the ‘‘same cycle of
manufacture.’’ The ‘‘same cycle of
manufacture’’ also does not limit the
number of lots of components you use.
You may consider, as one batch, a
product produced using different lots of
raw materials where the production of
the batch is a continuous process on a
dedicated line. However, for each
component that you use in the
manufacture of the batch of dietary
supplement, you would need to
establish specifications under final
§ 111.70, determine whether these
specifications are met under final
§ 111.73, and ensure that these
component specifications are met using
the criteria under final § 111.75.
Further, you may not consider different
batches of product produced on
consecutive days using the same
formula to be the same batch for
purposes of testing requirements. The
term ‘‘different batches’’ suggests that
the production is not a continuous
process on a dedicated line.
3. Batch Number, Lot Number, or
Control Number
The final rule defines these terms as
‘‘any distinctive group of letters,
numbers, or symbols, or any
combination of them, from which the
complete history of the manufacturing,
packaging, labeling, and/or holding of a
batch or lot of dietary supplements can
be determined.’’
We received no substantive comments
on the definition. We added the word
‘‘and’’ before ‘‘or’’ to emphasize that the
history of each activity must be able to
be determined.
4. Component
The final rule defines ‘‘component’’ as
‘‘any substance intended for use in the
manufacture of a dietary supplement,
including those that may not appear in
the finished batch of the dietary
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supplement. Component includes
dietary ingredients (as defined in
section 201(ff) of the act) and other
ingredients.’’
The definition of component now
refers only to the manufacture of a
dietary supplement (whereas the
proposal also referred to the
manufacture of dietary ingredients). We
also made a nonsubstantive, editorial
revision in the last sentence to put
parentheses around the reference to
section 201(ff) of the act and to change
the word order so that ‘‘component’’
includes ‘‘dietary ingredients * * * and
other ingredients.’’ (The proposed
definition had ‘‘components’’ including
‘‘ingredients and dietary ingredients.’’)
(Comment 39) Some comments would
distinguish among ‘‘raw material,’’
‘‘components,’’ and ‘‘starting material’’
because the comments said that defining
‘‘component’’ to include all these
materials is confusing. One comment
adds that many starting materials are
not food grade or approved food
ingredients until they have been
processed. One comment states the term
‘‘raw material’’ is typically used to
describe the materials (such as dietary
ingredients, fillers, and processing aids)
that will be used to make the final
product. The comment further states
‘‘component’’ is typically used to
describe the specific items used to
assemble the finished product for the
end user. The components would
include packaging components such as
bottles, caps, and labels, as well as the
bulk dietary supplement. This comment
also suggests that we use the term
‘‘starting material’’ to distinguish
substances used in the manufacture of
dietary ingredients from substances
used in the manufacture of dietary
supplements.
(Response) We decline to revise the
rule as suggested by the comments.
There may be differences in how
components are referred to by certain
manufacturers and how we refer to it in
this final rule. However, for purposes of
this final rule we refer to all substances
used in the manufacture of dietary
supplements as ‘‘components,’’ whether
or not those substances appear in the
finished product.
Please note that, although ingredients
are ‘‘components’’ under our definition,
not all components are ingredients. For
example, a solvent used to make an
herbal extract is not an ingredient when
it is removed from the extract by a
process such as drying, because the
solvent was not intended to be present
in the finished dietary supplement.
However, the solvent would be a
‘‘component’’ because it was used in the
manufacture of the dietary supplement.
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As for materials that might not be
food grade or approved food ingredients
until processing, see the discussion in
response to comment 240 in section XII
of this document.
(Comment 40) Several comments
express concern that ‘‘component’’
could be interpreted to mean any
constituent present in a botanical
extract or other natural product. The
comments say a single botanical can
contain tens of thousands of
constituents or metabolites and that
chemists have not identified all
constituents of a single botanical.
According to the comments, the cost of
testing for all constituents would exceed
a product’s total annual revenues.
(Response) In general, we would
consider the botanical extract or the
other natural product to be the
‘‘component’’ as defined in this final
rule rather than consider that all the
various chemical substances contained
in the botanical extract or other natural
product are components. Thus, if you
are manufacturing a dietary supplement
that is intended to provide a certain
substance (e.g., vitamin C ) and you add
a natural product which is intended to
supply the vitamin C (e.g., vitamin C in
the form of rosehips), we would
consider the natural product (e.g.
rosehips that contain a certain amount
of vitamin C) to be a component which
must be listed in the master
manufacturing record. The component
specifications for the rosehips must
include a specification for the strength
of the substance (e.g., vitamin C) in
whatever amount you determine is
necessary to meet the specification for
the strength of the vitamin C in the
finished batch of dietary supplement.
Under final § 111.70, we expect you to
establish specifications for the natural
product and ensure that the
specifications are met. As an example
relevant to an extract, if you are
manufacturing a dietary supplement
that is intended to provide a certain
amount of vitamin C that derives from
the natural product rosehips, and the
substance that you purchase from a
supplier to add as a component is a
purified extract of rosehips (rather than
rosehips themselves), we would
consider the purified extract to be a
component (as an ingredient). The
component specifications for the
purified extract must include a
specification for the strength of the
substance (i.e., vitamin C) in whatever
amount you determine is necessary to
meet the specification for the strength of
the vitamin C in the finished batch of
dietary supplement. However, in this
example ‘‘rosehips’’ would not be
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considered a component, because
‘‘rosehips’’ is not what you added.
We did not receive any substantive
comments on the proposed definition.
5. Contact Surface
The final rule defines ‘‘contact
surface’’ as ‘‘any surface that contacts a
component or dietary supplement, and
those surfaces from which drainage onto
the component or dietary supplement,
or onto surfaces that contact the
component or dietary supplement,
occurs during the normal course of
operations.’’ The final rule lists
containers, utensils, tables, contact
surfaces of equipment, and packaging as
examples of ‘‘contact surfaces.’’
We did not receive any substantive
comments on the proposed definition.
We deleted ‘‘ordinarily’’ from
‘‘ordinarily occurs during the normal
course of operations’’ because
‘‘ordinarily’’ is redundant to ‘‘normal.’’
8. Lot
The final rule defines ‘‘lot’’ as ‘‘a
batch, or a specific identified portion of
a batch, that is uniform and that is
intended to meet specifications for
identity, purity, strength, and
composition; or, in the case of a dietary
supplement produced by continuous
process, a specific identified amount
produced in a specified unit of time or
quantity in a manner that is uniform
and that is intended to meet
specifications for identity, purity,
strength, and composition.’’
The final rule differs from the
proposed definition in that the proposed
definition of ‘‘lot’’ would have the batch
or specific identified portion of a batch
be intended to have ‘‘uniform identity,
purity, quality, strength, and
composition.’’
(Comment 42) One comment agrees
with the proposed definition for ‘‘lot,’’
but several other comments would
revise the definition to be more
consistent with the proposed definition
of ‘‘batch.’’ Specifically, the comments
note the proposed definition of ‘‘batch’’
would refer to a quantity of dietary
supplement that is ‘‘intended to meet
specifications for identity, purity,
quality, strength and composition,’’
whereas the proposed definition of ‘‘lot’’
would refer to a batch or specific
identified portion of a batch that is
‘‘intended to have uniform identity,
purity, quality, strength, and
composition.’’ The comments would
revise the definition of ‘‘lot’’ by deleting
the phrase ‘‘intended to have uniform’’
and inserting the phrase ‘‘intended to
meet specifications for’’ in order to
make the definitions of ‘‘batch’’ and
‘‘lot’’ consistent.
(Response) We agree that the
definitions for ‘‘batch’’ and ‘‘lot’’ should
be consistent, but we disagree with the
comments’ suggestion to delete the term
‘‘uniform’’ from the definition of ‘‘lot.’’
The attributes of a lot or batch should
be uniform throughout the lot or batch
and meet established specifications for
those attributes. If samples from a lot or
batch were tested for appropriate
specifications of identity, purity,
strength, and composition, the attributes
should be consistent throughout the
sample and be uniform from sample to
sample regardless of whether the test
samples are taken from the beginning,
middle, or end of the lot or batch.
Consequently, we revised the definition
of ‘‘lot’’ to state, in relevant part, that a
‘‘lot’’ is a batch or specific identified
portion of a batch that ‘‘is uniform and
that is intended to meet specifications
6. Ingredient
The final rule defines ‘‘ingredient’’ as
‘‘any substance that is used in the
manufacture of a dietary supplement
and that is intended to be present in the
finished batch of the dietary
supplement. An ingredient includes, but
is not necessarily limited to, a dietary
ingredient as defined in section 201(ff)
of the act.’’ We did not receive any
substantive comments on this
definition. We made a nonsubstantive,
editorial change to replace ‘‘finished
dietary supplement’’ with ‘‘finished
batch of the dietary supplement.’’
(Comment 41) One comment says we
should define ‘‘ingredient’’ better to
ensure consistent interpretation of
CGMP at all levels throughout the
dietary supplement industry.
(Response) We disagree with the
comment. We believe the definition is
adequate, including as it does both
dietary ingredients as described in
section 201(ff) of the act and other
ingredients that do not fit that
description, such as an emulsifier used
to establish a uniform dispersion in a
liquid dietary supplement or a color
additive used to color a capsule.
Moreover, the comment did not explain
or specify which aspects of the
proposed definition should be revised
or explain why the proposed definition
would lead to inconsistent
interpretations of CGMP.
7. In-Process Material
The final rule defines ‘‘in-process
material’’ as ‘‘any material that is
fabricated, compounded, blended,
ground, extracted, sifted, sterilized,
derived by chemical reaction, or
processed in any other way for use in
the manufacture of a dietary
supplement.’’
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for identity, purity, strength, and
composition’’ or, for dietary
supplements produced by a continuous
process, a specific identified amount
produced in a specified unit of time or
quantity in a manner that is uniform
and that is intended to meet
specifications for identity, purity,
strength, and composition.’’
Similarly, we revised the definition of
‘‘batch’’ so that it states, in relevant part,
that a ‘‘batch’’ is a specific quantity of
a dietary supplement ‘‘that is intended
to meet specifications for identity,
purity, strength, and composition.’’
These revisions make the definitions
of ‘‘batch’’ and ‘‘lot’’ consistent.
9. Microorganisms
The final rule defines
‘‘microorganisms’’ as ‘‘yeasts, molds,
bacteria, viruses, and other similar
microscopic organisms having public
health or sanitary concern.’’ It adds that
the definition includes species that: (1)
May have public health significance; (2)
may cause a component or dietary
supplement to decompose; (3) indicate
that the component or dietary
supplement is contaminated with filth;
or (4) otherwise may cause the
component or dietary supplement to be
adulterated.
(Comment 43) One comment would
revise the definition to identify specific
microorganisms that have public health
or sanitary concern (i.e., Salmonella
species, Escherichia coli, Pseudomonas
aeruginosa, and Staphylococcus
aureus). The comment says this would
be consistent with USP requirements.
(Response) We disagree with the
comment. A list of specific
microorganisms could easily become
outdated as new pathogens emerge, and
constantly issuing new rules to revise
the list would be both inefficient and
impractical.
(Comment 44) One comment
expresses concern that the proposed
definition for microorganisms would
include microorganisms that are a
natural part of the ecology of all natural
products. The comment says certain
levels of microorganisms are expected
on botanical raw materials (i.e., those
naturally occurring or introduced
through organic cultivation techniques)
and that many do not present a public
health risk. The comment expresses
concern that nonpathogenic
microorganisms that are not a public
health risk would be a ‘‘sanitary’’
concern that would render a product
adulterated. The comment argues there
should be little concern about the
presence of microorganisms that present
no public health consequence, and so
we should revise the definition
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accordingly. The comment further
discusses the difficulties in ‘‘sterilizing’’
botanicals to render them free of
microorganisms associated with
insanitary conditions. The comment
notes that some international
organizations have established ‘‘upper
limits’’ for these organisms for botanical
supplements, which, in the comment’s
opinion, represent more realistic
standards than trying to attain a
‘‘sterile’’ botanical supplement.
(Response) We disagree with the
comment. We do not interpret the
definition of ‘‘microorganism’’ as
making the presence of nonpathogenic
microorganisms that are not a public
health risk a ‘‘sanitary concern’’ that
would render a product adulterated.
Instead, we interpret the definition as
saying that microorganisms of public
health significance and microorganisms
presenting sanitary concerns are
‘‘microorganisms’’ under this rule.
These are the types of microorganisms
that may cause a component or dietary
supplement to become adulterated.
As for upper limits on microbial
contamination, the comment offered no
suggested limits, and we decline to
establish such limits in this rule. The
final rule requires manufacturers to
establish limits for those types of
contamination that may adulterate or
lead to adulteration of components or
dietary supplements. Thus, for example,
a manufacturer of a botanical dietary
supplement would have to determine
what, if any, microorganisms are likely
or certain to be present and establish
limits, as appropriate to prevent
adulteration of the finished batch of the
dietary supplement.
We have modified the word ‘‘have’’
with the word ‘‘may’’ to indicate that
the determination or evaluation of
whether there is a ‘‘public health
significance’’ is not made after the fact.
There does not have to be a factually
established determination of public
health significance for you to conclude
that the microorganisms ‘‘may
adulterate’’ the dietary supplement. The
change from ‘‘could cause’’ to ‘‘may
cause’’ is to be consistent with the
previous change to ‘‘may have.’’
10. Must
The final rule explains that the word
‘‘must’’ is ‘‘used to state a requirement.’’
(Comment 45) One comment would
revise the definition to say that the term
‘‘must’’ be used to state mandatory
requirements ‘‘unless shown to be
inapplicable or replaced by an
alternative demonstrated to provide at
least an equivalent level of quality
assurance.’’
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(Response) We decline to revise the
rule as suggested by the comment. The
comment’s revision would undermine
the reasons for issuing a rule. Rules
create enforceable requirements. It is not
clear, nor did the comment discuss, how
we could enforce the requirements in
this final rule if firms were able to avoid
a particular requirement by declaring
them to be ‘‘inapplicable’’ or
substituting alternatives which they felt
they had demonstrated were ‘‘at least an
equivalent level of quality assurance.’’
There would be inconsistency in the
general CGMP practices used within the
dietary supplement industry and
uncertainty as to whether the process
and production controls ensure the
quality of the dietary supplement.
Consequently, we decline to revise the
rule as suggested by the comment.
We have, however, made a
nonsubstantive, editorial change to the
definition so that ‘‘must’’ is used to state
‘‘a requirement.’’ The proposed
definition had referred to ‘‘mandatory
requirements.’’ Since a requirement by
its nature is mandatory, the word
‘‘mandatory’’ is unnecessary.
11. Pest
The final rule defines ‘‘pest’’ as ‘‘any
objectionable insect or other animal,
including birds, rodents, flies, mites,
and larvae.’’
We did not receive any substantive
comments on this definition. However,
on our own initiative, we made
nonsubstantive, editorial changes to
delete the words, ‘‘but not limited to’’
after ‘‘including’’ and to place the word
‘‘animals’’ in the singular.
12. Physical Plant
The final rule defines ‘‘physical
plant’’ as ‘‘all or any part of a building
or facility used for or in connection with
manufacturing, packaging, labeling, or
holding a dietary supplement.’’
We received no substantive comments
on this definition. The final rule is
substantially similar to the proposed
rule’s definition of ‘‘physical plant.’’ We
added ‘‘any’’ and placed ‘‘part’’ in the
singular to clarify that individual parts
of a building or facility are subject to the
CGMP requirements.
13. Product Complaint
The final rule defines ‘‘product
complaint’’ as ‘‘any communication that
contains any allegation, written,
electronic, or oral, expressing concern,
for any reason, with the quality of a
dietary supplement, that could be
related to current good manufacturing
practice. Examples of product
complaints are: Foul odor, off taste,
illness or injury, disintegration time,
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color variation, tablet size or size
variation, under-filled container, foreign
material in a dietary supplement
container, improper packaging,
mislabeling, or dietary supplements that
are superpotent, subpotent, or contain
the wrong ingredient, or contain a drug
or other contaminant (e.g., bacteria,
pesticide, mycotoxin, glass, lead).’’
This definition modifies the proposed
rule’s definition of ‘‘consumer
complaint,’’ which would define such a
complaint as any ‘‘communication that
contains any allegation, written or oral,
expressing dissatisfaction with the
quality of a dietary supplement related
to good manufacturing practices.
Examples of product quality related to
good manufacturing practices are: Foul
odor, off taste, superpotent, subpotent,
wrong ingredient, drug contaminant,
other contaminant (e.g., bacteria,
pesticide, mycotoxin, glass, lead),
disintegration time, color variation,
tablet size or size variation, under-filled
container, foreign material in a dietary
supplement container, improper
packaging, or mislabeling. For the
purposes of this regulation, a consumer
complaint about product quality may or
may not include concerns about a
possible hazard to health. However, a
consumer complaint does not include
an adverse event, illness, or injury
related to the safety of a particular
dietary ingredient independent of
whether the product is produced under
good manufacturing practices.’’
We explain the reasons for revising
the proposed definition in our response
to the following comments.
(Comment 46) Some comments would
broaden the definition of consumer
complaint to include complaints from
dietary ingredient suppliers. One
comment would change ‘‘consumer
complaint’’ to ‘‘customer complaint.’’
(Response) As discussed in section VI
of this document, the final rule does not
apply to those who only manufacture
dietary ingredients. However, we
encourage such firms that receive
complaints about a dietary supplement
to share those complaints with those in
the manufacturing chain associated with
that dietary supplement’s manufacture
so others may take corrective action as
needed. Those who engage in the
manufacture of a dietary supplement,
including manufacturing, packaging,
labeling, and holding operations, are
responsible for complying with this
final rule’s product complaint
requirements.
Furthermore, we encourage packagers,
labelers, and distributors who receive a
product complaint to notify those in a
dietary supplement’s manufacturing
chain about product complaints they
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receive or they, themselves, generate
that may relate to operations outside the
packagers’, labelers’, or distributors’
control. For example, a distributor who
purchases a dietary supplement in bulk
for packaging and labeling may
complain about product quality to the
dietary supplement manufacturer. The
manufacturer who receives the
complaint must then take appropriate
action to determine whether the
complaint involves a possible failure of
a dietary supplement to meet any CGMP
requirements. Thus, the final rule
revises the term ‘‘consumer complaint’’
to ‘‘product complaint’’ to emphasize
that the complaint is about the product
regardless of the complaint’s source.
(Comment 47) One comment
disagrees that ‘‘disintegration time’’ and
‘‘tablet size’’ are appropriate examples
of complaints about product quality
specifications.
(Response) We disagree with this
comment. Complaints about
disintegration time or tablet size could
indicate a problem with the production
and process control system that may
affect the quality of the dietary
supplement.
(Comment 48) Some comments
disagree with the proposed definition of
‘‘consumer complaint’’ because it
excluded an adverse event, illness, or
injury related to the safety of a
particular dietary ingredient. The
comments say there should be a
consistent approach for handling all
complaints, including adverse events.
One comment states consumers will not
be able to determine whether a product
quality issue related to CGMP caused an
adverse event. This comment expresses
concern that not classifying adverse
events as consumer complaints could
lead manufacturers to avoid
investigating certain adverse events and,
therefore, prevent them from
determining the appropriate cause and
implementing the associated corrective
action. The comments stress we should
not treat complaints related to CGMP
issues differently from other complaints
and urged us to classify all adverse
events as consumer complaints, whether
or not they might have been caused by
a particular dietary ingredient.
A few comments state the proposal,
which did not specifically address
adverse event reporting, but did address
the broader category of consumer
complaints and would require
companies to investigate ‘‘adverse event
reports,’’ may simply create more
confusion and may contradict the
overall objective of a comprehensive
adverse event reporting system. The
comments also state neither the food
CGMP regulations nor the 1997 ANPRM
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defined ‘‘consumer complaints.’’ The
comments say we should delete this
definition and deal with consumer
complaints separately as part of the new
CFSAN Adverse Event Reporting
System (CAERS).
One comment states we should define
the term ‘‘serious adverse dietary
supplement experience.’’ The comment
would define a ‘‘serious adverse dietary
supplement experience’’ as ‘‘any
adverse dietary supplement experience
occurring at any dose that results in any
of the following outcomes: death, a lifethreatening adverse dietary supplement
experience, inpatient hospitalization or
prolongation of existing hospitalization,
a persistent or significant disability/
incapacity, or a congenital anomaly/
birth defect. Important medical events
that may not result in death, be lifethreatening, or require hospitalization
may be considered a serious adverse
dietary supplement experience and,
based upon appropriate medical
judgment, they may jeopardize the
patient or subject and may require
medical or surgical intervention to
prevent one of the outcomes listed in
this definition.’’
(Response) We decline to include in
the definition of ‘‘product complaint’’
an adverse event related to the safety of
a particular dietary ingredient. The final
rule establishes CGMP requirements for
dietary supplements and does not focus
on whether dietary ingredients that
manufacturers may use in their dietary
supplements are inherently safe.
Nevertheless, we encourage firms to
investigate all complaints, regardless of
whether the complaints relate to CGMP.
Furthermore, mandatory reporting to
FDA of serious adverse events is now
required as a result of the enactment of
the ‘‘Dietary Supplement and NonPrescription Drug Consumer Protection
Act’’ (Public Law 109–462), signed into
law on December 22, 2006. In any event,
consistent with these CGMP
requirements, manufacturers must
establish limits on contamination, as
needed, for all ingredients or any
component they use in manufacturing a
dietary supplement.
We agree it may be unclear whether
a particular product complaint is related
to CGMP. Final § 111.560, relating to
product complaints, applies in
situations where the product complaint
involves a ‘‘possible failure of a dietary
supplement to meet any of its
specifications or any other requirements
of this part.’’ Thus, if a firm is unclear
whether a particular complaint it
receives relates to a CGMP issue, we
would consider that complaint to be
related to a ‘‘possible failure’’ to meet
CGMP. Consequently, the firm must
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comply with the requirements in
subpart O, unless the firm affirmatively
determines that the complaint is not
related to a ‘‘possible failure’’ to meet
CGMP, and therefore, is not a ‘‘product
complaint.’’ To make this clear, we
revised the definition so that it applies
to any ‘‘communication * * * that
could be related to good manufacturing
practice’’ rather than to be any
‘‘communication * * * that is related to
good manufacturing practice.’’
We disagree with comments that
suggested that the requirements for
product complaints would somehow
contradict the overall objective of the
CAERS. This final rule has no effect on
the mandatory or voluntary reporting of
adverse events. We agree some adverse
events may be related to a failure to
ensure the quality of the dietary
supplement as required by the final
rule. To the extent that an adverse event
is associated with CGMP, it would be
considered a ‘‘product complaint’’
under the final rule. The fact that it is
considered a product complaint does
not mean that such complaint could not
be voluntarily reported as an adverse
event through CAERS. Such a complaint
may be required to be reported under
the mandatory reporting requirements of
the ‘‘Dietary Supplement and NonPrescription Drug Consumer Protection
Act’’ (Public Law 109–462), signed into
law on December 22, 2006. We have
added ‘‘illness or injury’’ to the final
rule’s definition of ‘‘product complaint’’
as an example of a product problem
relating to CGMP to help clarify that
there may be some overlap in the type
of complaints related to product quality
that may also be considered an adverse
event.
As for defining ‘‘serious adverse
dietary supplement experience,’’ we
decline to add such a definition to the
final rule. We define certain terms in a
rule to give those terms a clear and
consistent meaning. None of the
provisions in this rule addresses or even
mentions ‘‘serious adverse dietary
supplement experiences,’’ so there
would be no advantage in codifying a
definition for the term in this final rule.
If, however, the comment meant to
narrow the definition of ‘‘consumer
complaint’’ to ‘‘serious’’ illness, or
injury, we decline to do so. If a
consumer reports an illness or injury,
which he or she attributes to consuming
a dietary supplement, the report may
indicate a problem with the production
and process control system for that
dietary supplement, even if the injury or
illness is not ‘‘serious’’ or severe.
We have, however, decided to delete
the last two sentences in the proposed
definition of ‘‘consumer complaint’’
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(now ‘‘product complaint’’ in the final
rule). These sentences explained, in
part, that a consumer complaint does
not include an adverse event, illness, or
injury related to the safety of a
particular dietary ingredient
independent of whether the product is
produced under CGMP. We deleted
those sentences because they are
unnecessary to include in the definition
and can be included as further
explanation of what the definition of
‘‘product complaint’’ means in the
preamble discussion.
The proposed definition of ‘‘consumer
complaint’’ used the phrase ‘‘expressing
dissatisfaction with the quality of a
dietary * * * supplement;’’ the final
rule uses the phrase ‘‘expressing
concern, for any reason, with the quality
of a dietary supplement.’’ This change is
to ensure that even if the consumer is
not actually dissatisfied with the
product, but has a concern with the
product, this is still handled as a
product complaint.
We made several editorial or
grammatical changes to the definition of
product complaint in this final rule for
simplicity and revised the order of the
listed examples of product complaints.
For example, the proposed definition of
‘‘consumer complaint’’ states the term
‘‘means communication that contains
any allegation * * *.’’ The final rule
defines ‘‘product complaint’’ as
meaning ‘‘any communication that
contains any allegation * * *.’’ Another
nonsubstantive change was to insert the
words ‘‘dietary supplements that are’’
before ‘‘superpotent, subpotent’’ to give
the reader a clear understanding as to
the article that is superpotent or
subpotent.
Finally, we added ‘‘electronic’’ as an
example of how a product complaint
could be communicated to ensure that
all forms of communication are
included and added ‘‘current’’ to modify
‘‘good manufacturing practice’’ for
consistency.
We discuss in section V of this
document, our general response to the
comment that stated that neither the
food CGMP regulations nor the 1997
ANPRM contains a definition of
‘‘consumer complaint,’’ is in our
discussion of whether this final rule
exceeds our authority or it has to be
identical to the food CGMP regulations.
More specifically, we acknowledge that
the industry draft that we published in
the 1997 ANPRM did not define
‘‘consumer complaint.’’ The industry
draft did contain provisions that would
be directed to ‘‘complaint files.’’ The
provisions for complaint files would
require the use of written procedures to
handle complaints, retention of records
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of complaints for a certain time period,
and the inclusion of specific
information in the record of a
complaint.
14. Quality
For purposes solely of this final rule
we have decided to define ‘‘quality.’’
Quality means that the dietary
supplement consistently meets the
established specifications for identity,
purity, strength, and composition and
limits on contaminants and has been
manufactured, packaged, labeled, and
held under conditions to prevent
adulteration under section 402(a)(1),
(a)(2), (a)(3), and (a)(4) of the act.
(Comment 49) Some comments asked
that we define ‘‘quality.’’ Some
comments claimed the proposal
described ‘‘quality’’ in terms of
‘‘identity,’’ ‘‘purity,’’ and
‘‘composition.’’ One comment would
define ‘‘quality’’ as ‘‘the total
characteristics of a product that bear on
its ability to satisfy stated (i.e., labeled)
or implied needs of identity, purity,
strength and composition.’’ Another
comment would define ‘‘quality’’ as
‘‘having the appropriate identity, purity,
and strength for the intended purpose.’’
Another comment would define quality
using all the other attributes of identity,
purity, strength and composition.
(Response) For purposes only of this
final rule, we have added a definition of
quality. This definition is not intended
to apply to CGMP requirements other
than those that apply to dietary
supplements. In section III of this
document, in the overview discussion,
we discuss the concept of ‘‘quality’’ as
it applies to these dietary supplement
CGMP requirements and the distinction
between the use of the term in the final
rule and in the proposed rule.
Because we have defined ‘‘quality’’ as
encompassing identity, purity, strength,
and composition, we have revised each
section with requirements for the
‘‘identity, purity, quality, strength, and
composition’’ to remove the word
‘‘quality.’’ The affected sections in this
final rule are: § 111.3 (definition of
batch); § 111.3 (definition of lot);
§ 111.65 (‘‘What are the requirements for
quality control operations?’’); § 111.70
(‘‘What specifications must you
establish?’’); § 111.75 (‘‘What must you
do to determine whether specifications
are met?’’); § 111.80 (‘‘What
representative samples must you
collect?’’); § 111.95 (‘‘Under this subpart
E, what records must you make and
keep?’’); § 111.105 (‘‘What must quality
control personnel do?’’); § 111.455
(‘‘What requirements apply to holding
components, dietary supplements,
packaging, and labels?’’); and § 111.515
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suitably disposed of?’’).
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15. Quality Control
The final rule defines ‘‘quality
control’’ as ‘‘a planned and systematic
operation or procedure for ensuring the
quality of a dietary supplement.’’ The
proposed rule defined ‘‘quality control’’
as ‘‘a planned or systematic operation
for preventing a dietary ingredient or
dietary supplement from being
adulterated.’’
(Comment 50) One comment suggests
revising the definition to use more
positive language. Specifically, the
comment would define ‘‘quality
control’’ as ‘‘a planned and systematic
operation or procedure for ensuring the
quality of dietary supplement
products.’’
(Response) We agree that the
comment’s suggested language conveys
a positive concept about quality
control’s role and value and adopt the
language in part. The final rule’s quality
control requirements will help ensure
compliance with other CGMP
requirements and, therefore, will help
ensure the quality of the dietary
supplement and that the dietary
supplement is packaged and labeled as
specified in the master manufacturing
record. We have defined the term
‘‘quality’’ in this final rule as including
preventing a dietary supplement from
being adulterated. Consequently, we
revised the definition of ‘‘quality
control’’ to state that ‘‘quality control’’
means a planned and systematic
operation or procedure ‘‘for ensuring the
quality of a dietary supplement.’’ We
deleted ‘‘for preventing a dietary
ingredient or dietary supplement from
being adulterated’’ in the proposed
definition since the concept of quality
includes preventing adulteration.
16. Quality Control Personnel
The final rule defines ‘‘quality control
personnel’’ as ‘‘any person, persons, or
group, within or outside your
organization, who you designate to be
responsible for your quality control
operations.’’
(Comment 51) Some comments seem
to suggest that the reference in the 2003
CGMP Proposal to a ‘‘quality control
unit’’ mandates a separate unit or
department with responsibility for all
quality control operations. One
comment explains many companies do
not have one quality control unit with
oversight of all operations within the
facility. This comment states companies
commonly have each separate section of
an operation perform both its function
and its own quality control. A few
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comments would clarify the definition
by indicating that a distinct or separate
unit need not perform the quality
control function. These comments say
the quality control function is best
performed by a person or persons
qualified by training, education, or
experience in the different processing
areas.
Many comments say we should
consider any individual carrying out a
quality control function to be part of the
quality control unit for purposes of this
rule.
(Response) We agree that the quality
control function is best performed by a
person or persons qualified by training,
education, or experience in relevant
areas. To the extent that the comments
interpreted the proposed definition as
requiring firms to have a separate
person or group whose sole function in
the company is to perform quality
control operations or that the quality
control functions are limited to those
who are employed within the firm, we
disagree. As discussed in the preamble
to the proposal, the quality control unit
should consist of as many people as
necessary to perform the quality control
operations (68 FR 12157 at 12252). We
have reconsidered the use of the term
‘‘unit.’’ In order to clarify that we do not
intend to require a separate division or
office be created, we instead use the
term ‘‘personnel.’’ Although we have
eliminated references to ‘‘unit,’’ we still
agree that personnel can be a person,
persons, or a group, and as many
persons as necessary, who perform the
quality control operations. The
manufacturer must identify the
appropriate person or persons to be
responsible for the quality control
operations associated with a particular
manufacturing operation. For example,
the manufacturer may designate one
individual as a packaging expert who is
responsible for the quality control
operations related to packaging,
designate a second individual as an
expert in deciding whether to accept or
reject incoming components, and
designate a third individual as an expert
in deciding whether in-process
specifications are met at certain control
points. The definition does not limit the
other activities that these designated
individuals may perform within the
manufacturing operations; thus, for
example, the packaging expert who
performs the quality control function for
packaged dietary supplements could
also have responsibilities in the actual
packaging operation. Quality control
responsibilities and specific activities
are distinct and separate from any other
responsibilities and specific activities
that an employee might perform for any
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other operation. In addition, the quality
control operations may be performed by
someone outside the organization (such
as a contractor).
To clarify these points and to prevent
potential misinterpretation of quality
control operations, we revised the
definition of ‘‘quality control unit.’’
Instead of a unit, quality control
personnel who perform quality control
operations may be a person, persons, or
group and may be ‘‘within or outside of
your organization.’’ We also added a
new § 111.12(b) to require you to
identify who is responsible for your
quality control operations. Under final
§ 111.12(b) each person who is
identified to perform quality control
operations must be qualified to do so
and have distinct and separate
responsibilities related to performing
such operations from those
responsibilities that the person
otherwise has when not performing
such operations. Throughout the
codified, we use the term ‘‘quality
control personnel’’ when referring to the
performance of specific quality control
operations. The term ‘‘quality control
personnel’’ refers to the person or
persons designated to perform the
particular quality control operation.
17. Representative Sample
The final rule defines ‘‘representative
sample’’ as ‘‘a sample that consists of an
adequate number of units that are drawn
based on rational criteria, such as
random sampling, and that are intended
to ensure that the sample accurately
portrays the material being sampled.’’
This definition is similar to the
proposed definition of ‘‘representative
sample.’’ We have added ‘‘an adequate’’
before ‘‘number’’ to emphasize that the
sample must be sufficient for its
purpose. We also made nonsubstantive
grammatical changes to insert ‘‘that are’’
between ‘‘and’’ and ‘‘intended.’’
(Comment 52) Some comments note
the proposed rule would use the terms
‘‘representative sample,’’ ‘‘reserve
sample,’’ and ‘‘representative reserve
sample’’ but would only define
‘‘representative sample.’’ The comments
ask us to clarify the distinction, if any,
between these terms.
(Response) A ‘‘reserve sample’’ is a
sample that is to be held or kept for a
designated time. It differs from a
‘‘representative sample’’ in the sense
that a representative sample is not
always kept; for example, one might
take a representative sample to test
product quality, but one would not
necessarily keep every tested sample.
To clarify this distinction, the final
rule now defines a ‘‘reserve sample’’ as
‘‘a representative sample of product that
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is held for a designated period of time.’’
We also revised the rule to refer solely
to a ‘‘reserve sample’’ rather than use
both ‘‘reserve sample’’ and
‘‘representative reserve sample.’’
18. Reprocessing
The final rule defines ‘‘reprocessing’’
as ‘‘using, in the manufacture of a
dietary supplement, clean,
uncontaminated components or dietary
supplements that have been previously
removed from manufacturing and that
have been made suitable for use in the
manufacture of a dietary supplement.’’
We modified the definition that, in part,
read ‘‘* * * dietary supplements that
have been previously removed from
manufacturing for reasons other than
insanitary conditions’’ by removing ‘‘for
reasons other than insanitary
conditions’’ to expand the scope of what
may be reprocessed. We explain the
reason for the latter change in our
response to the following comments. We
also changed ‘‘unadulterated’’ to
‘‘uncontaminated’’ to be consistent with
the revisions we have made in other
sections, including the definition of
quality.
(Comment 53) Some comments ask us
to clarify whether components or
dietary supplements that have been
successfully treated to reduce microbial
levels to acceptable levels can be
reprocessed. Some comments object to
the proposed definition of
‘‘reprocessing’’ because it did not
include components or dietary
supplements removed for insanitary
conditions, and several comments object
to the restrictions to reprocessing
described in proposed
§§ 111.35(i)(4)(iii) and 111.50(f),
because, they argue, the definition and
sections associated with reprocessing
would not permit the reprocessing of
previously insanitary ingredients even if
there are processes available that are
safe and effective in removing foreign
matter, microorganisms, or chemicals
that may have rendered the ingredient
‘‘insanitary.’’ One comment would
revise the definition as follows:
‘‘Reprocessing means using, in the
manufacture of a dietary supplement,
clean, unadulterated components * * *
or dietary supplements that have been
previously removed from manufacturing
for reasons other than insanitary
conditions or that have been
successfully reconditioned so that they
are suitable for use.’’
(Response) We agree that materials
can be treated, subjected to in-process
adjustments, or reprocessed when there
are suitable processes available, and we
revised the definition of ‘‘reprocessing’’
to reflect this. However, there must be
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appropriate oversight of the treatment,
in-process adjustments, and
reprocessing so the dietary supplement
will still meet required specifications.
Therefore, we added a conforming
requirement to final §§ 111.90(b) and
111.140(b)(3)(vi) to require oversight by
quality control personnel for any
reprocessing, treatment, or in-process
adjustment of a dietary supplement that
have been previously removed from
manufacturing and that have been made
suitable for use in the manufacture of a
dietary supplement (see sections X and
XI of this document).
19. Reserve Sample
The final rule contains a new
definition of ‘‘reserve sample.’’ ‘‘Reserve
sample’’ is defined as ‘‘a representative
sample of product that is held for a
designated period of time.’’ We explain
our reasons for creating this definition
in this section under the definition of
‘‘representative sample.’’
20. Sanitize
The final rule defines ‘‘sanitize’’ as
‘‘to adequately treat cleaned equipment,
containers, utensils, or any other
cleaned contact surface by a process that
is effective in destroying vegetative cells
of microorganisms of public health
significance, and in substantially
reducing numbers of other
microorganisms, but without adversely
affecting the product or its safety for the
consumer.’’
The final rule’s definition of
‘‘sanitize’’ differs from the proposal in
that the proposed definition would have
specified a reduction of 5 logs or 99.999
percent reduction of ‘‘representative
disease microorganisms of public health
significance’’ and ‘‘other undesirable
microorganisms’’ and would have
specified the use of heat or chemicals.
The preamble to the 2003 CGMP
Proposal explained that we based the
proposed definition of ‘‘sanitize’’ on the
definition of ‘‘sanitization’’ in the ‘‘Food
Code’’ (which is a model that gives food
control authorities a scientifically sound
technical and legal basis for regulating
the retail and food service segment of
the industry) because dietary
supplements are often consumed
without further processing, similar to
foods consumed in retail outlets (68 FR
12157 at 12179). The preamble to the
2003 CGMP Proposal also explained
that, to achieve the reduction levels in
the proposed definition, one would
need to validate control measures to
ensure they are both appropriate to their
operation and scientifically sound. The
preamble explained that in many cases,
manufacturers may rely on a written
certification from the equipment
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manufacturer or may obtain a written
scientific evaluation of a process,
especially in cases where two or more
control measures are used to accomplish
the 99.999 percent reduction in the
target pathogen, to ensure the process is
adequate to destroy microorganisms of
public health significance or to prevent
their growth.
(Comment 54) Many comments object
to the proposed text concerning the
application of heat or chemicals to a
food contact surface to yield a reduction
of 5 logs or 99.999 percent of
representative disease organisms of
public health significance. The
comments state the aspect of the
proposed definition is overly
prescriptive, beyond our legal authority,
and would not provide additional
public health benefits. Many comments
say it is inappropriate to use the
definition of sanitization from our Food
Code because retail and manufacturing
operations are distinct. A few comments
assert the process of manufacturing
dietary supplements shares more in
common with food or drug
manufacturing than with retail
operations. Most comments recommend
that we define ‘‘sanitize’’ in the manner
that was presented in the 1997 ANPRM
and consistent with the current food
CGMP definition at § 110.3 so that
‘‘sanitize’’ means ‘‘to adequately treat
dietary product contact surfaces by a
process that is effective in destroying
vegetative cells of microorganisms of
public health significance, and in
substantially reducing numbers of other
undesirable microorganisms, but
without adversely affecting the product
or its safety for the consumer.’’
One comment states that consistently
validating the effectiveness of the
sanitizing procedure is impractical and
recommended we state instead that
equipment, utensils, etc., should be
cleaned and sanitized in a manner that
keeps undesirable microorganisms and
other adulterants from contaminating all
components, ingredients, in-process
materials, and finished product. The
comment claims that, by this approach,
the microbial and analytical test results
of product produced on a facility’s
equipment, coupled with random
testing of final rinse water after cleaning
and sanitizing equipment and utensils,
would provide sufficient and
continuous evidence of a proper and
effective cleaning and sanitizing plan.
Two comments claim that the
proposed definition for sanitize denotes
‘‘validation methodology’’ found in drug
CGMP, and that we must base dietary
supplement CGMP on food rather than
on drug standards.
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Other comments express concern
about validating control measures to
ensure that they are scientifically sound
and appropriate to operations and the
economic burden to do the testing. A
few comments state it would be difficult
to show a 100,000-fold reduction on an
already cleaned surface, particularly if
the pre-sanitization level is at or near
the lower limit of the test method
employed.
One comment states the definition
required the manufacturer to
demonstrate a 100,000-fold reduction in
microbial count every time a food
contact surface is sanitized. A few
comments express concern that
processing lines would have to be
closed down each time they are
sanitized in order to test them, creating
a financial hardship especially on
smaller operations. Other comments ask
us to give companies the flexibility
necessary to monitor sanitation needs
based on individual products and
manufacturing operations to be
consistent with existing industry
practices and food and drug CGMPs.
One comment requests we clarify that
a sanitizing agent for use on food
processing equipment must be approved
in accordance with part 178, Indirect
Food Additives: Adjuvants, Production
Aids, and Sanitizers (21 CFR part 178)
and our expectations with respect to
what documentation would be
necessary to prove the effectiveness of
the sanitizer used. Two comments say
the proposed definition of sanitize
means that manufacturers must perform
validation studies to demonstrate that
the sanitizers they are using reduce the
microbial load on equipment by
100,000-fold, a requirement for a
‘‘sanitizer’’ under regulations issued by
the Environmental Protection Agency.
The comments say a sanitizer should
not be held to this standard for the
purpose of reducing microbial loads on
food product contact surfaces, and that
manufacturers of a solid dosage form
may not need to ‘‘sanitize’’ their
equipment because the processing
environment is not suitable for
microbial growth due to the low water
activity. One comment recommended
using the approach in the Food Code,
which specifies conditions under which
chemical sanitizers listed in § 178.1010
may be used, including the requirement
that they be used in accordance with the
Environmental Protection Agencyapproved manufacturer’s label use
instructions, and be used for dietary
supplements rather than imposing a
validation requirement on
manufacturers.
Some comments would divide the
definition of ‘‘sanitize’’ by creating
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separate definitions for ‘‘sanitize’’ and
‘‘sanitizing agent.’’ The comments
would define ‘‘sanitize’’ as meaning ‘‘to
adequately treat equipment, containers,
utensils, or any other dietary product
contact surface by applying a sanitizing
agent on cleaned food contact surfaces.’’
One comment would define ‘‘sanitizing
agent’’ as ‘‘cumulative heat or chemicals
that, when evaluated for efficacy, yield
a reduction of 5 logs, which is equal to
99.999 percent reduction, of
representative disease microorganisms
of public health significance and
substantially reduce the numbers of
other undesirable microorganisms, but
without adversely affecting the product
or its safety for the consumer.’’ Another
comment would define ‘‘sanitizing
agent’’ in a similar manner, except it
would omit references to a 5-log
reduction.
(Response) The proposed definition of
‘‘sanitize’’ was intended to give firms
the flexibility to monitor sanitation
needs based on their products and
operations. We did not intend to suggest
that manufacturers had to demonstrate a
100,000-fold reduction in microbial
count every time they sanitized a
contact surface, nor did we intend, as
some comments claimed, to have firms
close down processing lines every time
they were sanitized to test them for
microbial reduction. Rather, the
language of the proposed rule was
intended to make it clear that processes
used to sanitize contact surfaces should
be effective. However, we recognize that
the proposed definition caused
confusion as to our intent. The proposed
definition may have been interpreted as
proposing validation to ensure an area
was sanitized; however our intent was
simply to require that effective
sanitizers and sanitizing processes be
used, just as in food establishments.
Therefore, in order to clarify the
provision, we have revised the
definition of ‘‘sanitize’’ to be consistent
with § 110.3(o). The final rule defines
‘‘sanitize’’ as adequately treating
‘‘cleaned equipment, containers,
utensils, or any other cleaned contact
surface by a process that is effective in
destroying vegetative cells of
microorganisms of public health
significance, and in substantially
reducing numbers of other
microorganisms, but without adversely
affecting the product or its safety for the
consumer.’’ The final definition of
sanitize does not include any statements
about mechanisms that you may use to
achieve compliance because including
such nonbinding information is
inconsistent with our current practices
for establishing regulations.
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We note that the Environmental
Protection Agency has regulatory
authority over certain uses of sanitizers
as pesticide chemicals and we have
regulatory authority over certain uses of
sanitizers as food additives. Under
section 201(q)(1)(B) of the act, as
amended by the Food Quality Protection
Act (FQPA) (Public Law 104–170) and
the Antimicrobial Regulation Technical
Corrections Act (ARTCA) (Public Law
105–324), certain substances used as
food contact surface sanitizing solutions
are subject to the Environmental
Protection Agency’s regulatory authority
as pesticide chemicals. The
Environmental Protection Agency
recently codified tolerance exemptions
under section 408 of the act (21 U.S.C.
346a) for those food contact surface
sanitizing solutions that were
previously subject to our authority at
§ 178.1010 and transferred to the
Environmental Protection Agency’s
authority under FQPA and ARTCA (see
40 CFR 180.940 (69 FR 23113, April 28,
2004). Such pesticide chemicals must
comply with the Pesticide Tolerance
regulations in 40 CFR 180.940.
Sanitizers used on food packaging must
comply with our regulations at
§ 178.1010. For an in depth discussion
of appropriate sanitizers for food contact
surface use, see the Environmental
Protection Agency’s Pesticides;
Tolerance Exemptions for Active and
Inert Ingredients for Use in
Antimicrobial Formulations (Food
Contact Surface Sanitizing Solutions)
(69 FR 23113, April 28, 2004) and DIS/
TSS–4 Efficacy Data Requirements
Sanitizing Rinses (for previously
cleaned food-contact surfaces) (January
30, 1979) (Ref. 27) (available on the
Internet at https://www.epa.gov/
oppad001/dis_tss_docs/dis-04.htm).
21. Theoretical Yield
The final rule defines ‘‘theoretical
yield’’ as ‘‘the quantity that would be
produced at any appropriate step of
manufacture or packaging of a particular
dietary supplement, based upon the
quantity of components or packaging to
be used, in the absence of any loss or
error in actual production.’’
We received no substantive comments
on the proposed definition.
22. Water Activity
The final rule defines ‘‘water activity’’
as ‘‘a measure of the free moisture in a
component or dietary supplement and is
the quotient of the water vapor pressure
of the substance divided by the vapor
pressure of pure water at the same
temperature.’’
We received no substantive comments
on the proposed definition.
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23. We
The final rule explains that ‘‘we’’
means the United States Food and Drug
Administration.
The final rule’s definition is identical
to the proposed definition. We received
no substantive comments on the
proposed definition.
24. You
The final rule defines ‘‘you’’ as a
‘‘person who manufactures, packages,
labels, or holds dietary supplements.’’
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25. What Other Terms Did the
Comments Want Defined?
(Comment 55) Some comments ask us
to define ‘‘adulteration’’ (based on the
provisions of section 402 of the act),
‘‘dietary ingredient,’’ and ‘‘dietary
supplement’’ (based on the definition in
section 201(ff) of the act).
(Response) We decline to revise the
rule as suggested by the comments. The
terms have meaning within the context
of the act and case law. Further, under
final § 111.3 the act’s definitions and
interpretations ‘‘apply to such terms
when used in this part.’’ Thus, there is
no need for us to define the terms as
requested by the comments.
(Comment 56) Proposed § 111.35(e)(2)
would require a person to establish a
specification for any point, step, or stage
in the manufacturing process where
control is necessary to prevent
adulteration, and proposed § 111.35(f)
would require monitoring of the inprocess control points, steps, or stages
to ensure these established
specifications are met and to detect any
unanticipated occurrence that may
result in adulteration. Some comments
ask us to define the term ‘‘control point’’
as ‘‘any point, step or stage in the
manufacturing process where control is
necessary to prevent adulteration.’’
(Response) We decline to add a
definition of ‘‘control point’’ as
requested by the comments. Instead, we
revised final § 111.75(b) (formerly
proposed § 111.35(f)) to state that you
must monitor the in-process points,
steps, or stages where control is
necessary to ensure the quality of the
finished batch of dietary supplement;
this revision eliminates the need to
define ‘‘control point.’’
(Comment 57) Several comments
would have us define one or more of the
following terms: Identity, purity,
strength, and composition. Some
comments suggest specific text for the
definitions.
Similarly, some comments suggest
codifying the preamble description that
we used for these terms, i.e., the phrase
‘‘identity, purity, quality, strength, and
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composition’’ means that the production
on a batch-by-batch basis is consistent
with the master manufacturing record
and is what it is represented on the label
to be (identity); is without impurities
and is the desired product (purity); is
the identity, purity, and strength for its
intended purpose (quality); is the
concentration, that is, the amount per
unit of use intended (strength); and is
the intended mix of product and
product-related substances
(composition) (68 FR 12157 at 12176).
One comment says ‘‘identity’’ should
mean ‘‘a substance or product is what it
is represented on the label to be.’’
One comment says that it does not
seem appropriate to define the term
‘‘purity’’ to mean ‘‘without impurities.’’
The comment states it would be difficult
to consider an herbal extract as being
‘‘pure’’ because it is a mixture of
naturally occurring compounds in a
solvent. Another comment suggests the
term ‘‘purity’’ be defined to mean ‘‘free
from objectionable and/or deleterious
levels of impurities including, but not
limited to, heavy metals, pesticides,
mycotoxins, radioactivity, filth,
extraneous material, molds, yeasts and
bacteria.’’ Another comment suggests
defining the term ‘‘purity’’ as ‘‘having
the intended identity and composition
and being without significant
impurities.’’ However, the comment
does not explain what is meant by
‘‘without significant impurities.’’
One comment suggests defining the
term ‘‘strength’’ as ‘‘having the intended
concentration, that is, the amount of the
dietary ingredient per unit of use (tablet,
capsule, soft gel, teaspoon, or other
unit).’’ Another comment expresses
concern about the use of the term
‘‘strength’’ in relationship to
nonstandardized herbals because there
are no current industry standards for
these products. This comment suggests
we clarify the term ‘‘strength’’ so it
refers to having the correct amount of a
stated ingredient. One comment notes
St. Johns wort has a composition of
approximately 40 different constituents
in addition to the essential oil that
contains numerous constituents. The
comment asks which constituent it
should use to determine ‘‘strength.’’
Another comment would use the term
‘‘quantity’’ instead of ‘‘strength.’’
One comment would define
‘‘composition’’ as ‘‘having the intended
mix of components or ingredients,
including dietary ingredients.’’ Another
comment would delete ‘‘composition’’
from the rule because, the comment
claimed, an FDA investigator might
conclude that ‘‘composition’’ refers to
every constituent of every botanical.
According to this comment, there are
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many tests that could be used to identify
the botanical constituents, but that it
would be economically exhausting
considering the number of botanical
constituents, and it would not
contribute to quality or safety.
(Response) We decline to revise the
rule to define identity, purity, strength,
or composition. The exact way in which
the dietary supplement industry uses
these terms may vary, and defining
these terms could limit the flexibility
that is needed to accommodate such
variations.
Nevertheless, to elaborate on our
interpretation of identity, purity,
strength, and composition, and to
respond to the particular concerns
raised by some comments, we provide
the following information.
a. Identity. The ‘‘identity’’ of a dietary
supplement refers to the dietary
supplement’s consistency with the
master manufacturing record and/or that
it is the same as described in the master
manufacturing record.
b. Purity. The ‘‘purity’’ of a dietary
supplement refers to that portion or
percentage of a dietary supplement that
represents the intended product. For
example, amino acids generally can
exist in two forms (i.e., dextro (D-, or
right) and levo (L-, or left) forms) called
enantiomers. Enantiomers have the
same chemical formula and the same
chemical structure, but differ in their
three-dimensional orientation. If you
manufacture a dietary supplement to
provide the amino acid L-arginine, and
you determine that 90 percent of the
manufactured product is L-arginine and
10 percent of the manufactured product
is D-arginine, you could describe your
L-arginine product as ‘‘90 percent
pure.’’ As another example, if you
manufacture a mixture of triglycerides
that provides polyunsaturated fatty
acids in the diet, the manufactured
triglycerides may contain small amounts
of free fatty acids and sterols. The free
fatty acids and sterols could derive, for
example, from the source of the
triglycerides or could be byproducts of
the manufacturing process. If you
determine that 95 percent of the
manufactured product is the mixture of
the triglycerides that provides the
polyunsaturated fatty acids, and 5
percent of the product is free fatty acids
and sterols, you could describe the
purity of your product as ‘‘95 percent
pure.’’
Just as we use the term ‘‘purity’’ to
refer to the identity and amount of a
dietary supplement that is the desired
product, we use ‘‘impurity’’ to refer to
the identity and amount of a dietary
supplement that is not the desired
product. In the previous examples, we
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view the D-arginine that is present in
the product that is intended to be Larginine as an ‘‘impurity,’’ and we view
the free fatty acids and sterols that are
present in the product that is intended
to be a mixture of triglycerides that
provide polyunsaturated fatty acids in
the diet as ‘‘impurities.’’ For the
purposes of these examples, we do not
view these ‘‘impurities’’ as
‘‘contaminants.’’
If the comments were concerned that
the dietary supplement CGMP
requirements regarding a dietary
supplement’s ‘‘purity’’ mean that we
expect you to characterize each
constituent of a natural product to
determine whether each constituent is
present in a certain pre-established
quantity (i.e., purity specification) to
determine whether it contributes to the
‘‘purity’’ of the dietary supplement or
would be considered as an ‘‘impurity,’’
we do not consider such constituents to
be ‘‘components’’ of a dietary
supplement (see discussion of the
definition of component in this section).
For example, if you manufacture a
dietary supplement containing fish oil,
we would not consider the triglycerides,
which are constituents of the fish oil, to
be components. Likewise, we would not
consider particular fatty acids (such as
the polyunsaturated fatty acids
docosahexaenoic acid (DHA) and
eicosapentaenoic acid (EPA)), which are
constituents of the triglycerides, to be
components of the dietary supplement.
In this example, you would be required
to establish a purity specification for the
amount of triglycerides in the fish oil.
(Note that if you are manufacturing fish
oil to provide the fatty acids DHA and
EPA in the dietary supplement, the
component specifications for the fish oil
must include a strength specification for
DHA and EPA in whatever amount you
determine is necessary to meet the
specification for strength of DHA and
EPA in the dietary supplement.) We do,
however, expect you to set appropriate
limits on contaminants (e.g., toxic
substances) that are known to be
constituents of botanical extracts or
other natural products that are likely or
certain to contain constituents that are
harmful.
c. Strength. The strength of a dietary
supplement relates to its concentration.
By concentration, we mean the
quantitative amount per serving (for
example, weight/weight, weight/
volume, or volume/volume). Therefore,
for purposes of this final rule, strength
does not refer simply to the quantity of
an ingredient, rather it refers to the
amount of a stated ingredient per a
specified unit of measure.
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If the comments were concerned that
the ‘‘strength’’ of a dietary supplement
meant that you need to establish the
quantitative amount per unit of measure
of each constituent in a dietary
ingredient, such as a botanical extract or
natural product, we do not consider
such constituents to be ‘‘components’’
of a dietary supplement, unless you add
such constituents as components (as in
an extract) (see discussion of the
definition of component in this section).
We do not consider the rule’s
requirements on dietary supplement
strength as necessarily relating to the
individual constituents of such
products. Whether the requirements
regarding dietary supplement strength
apply to one or more constituents of
dietary ingredients in a dietary
supplement depends on what you are
manufacturing. For example, if you are
manufacturing vitamin C, and your
source of vitamin C is rosehips, you
would establish a strength specification
for vitamin C in the finished batch of
the dietary supplement (e.g., ‘‘x
milligrams (mg) of vitamin C per
tablet’’). You are required to ensure that
the dietary supplement does in fact
contain ‘‘x mg of vitamin C per tablet.’’
Alternatively, if you are manufacturing
rosehips and not vitamin C from
rosehips, the strength specification that
you establish for the finished batch of
the dietary supplement is the strength of
the rosehips themselves (i.e., the
concentration of rosehips in the final
product, such as ‘‘x mg of rosehips per
tablet’’). You are required to ensure that
the product does in fact contain ‘‘x mg
of rosehips per tablet.’’
We discuss the requirements to
establish and meet specifications in our
discussion of subpart E (see section X of
this document).
d. Composition. A dietary
supplement’s ‘‘composition’’ refers to
the specified mix of product and
product-related substances in a dietary
supplement. For example, a dietary
supplement manufactured to provide
vitamin C may contain, in addition to
vitamin C, a tablet coating agent and
substances used as binders. The
composition could be described as the
percent of the dietary supplement that
is vitamin C, the tablet-coating agent,
and each binder.
e. Other terms.
(Comment 58) Several comments
would revise the rule to define
‘‘manufacturer.’’ Many comments ask
whether the rule applies to certain types
of companies or professionals and said
a definition of ‘‘manufacturer’’ would
clarify the rule’s applicability.
Some comments suggest specific text
for a definition. For example, one
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comment would define ‘‘manufacturer’’
as ‘‘a person who formulates or changes
the composition or physical
characteristics of a dietary supplement
or who packages or labels the product
in a container for distribution’’ to clarify
that a company that does not
manufacture a specific dietary
supplement, but purchases a dietary
supplement in bulk and then packages
or labels the bulk dietary supplement
for sale to consumers, is still subject to
dietary supplement CGMP
requirements. The comment cites our
proposed definition of ‘‘manufacturer’’
in our infant formula CGMP proposal
(see 61 FR 36154 at 36209, July 9, 1996
(proposing to define a ‘‘manufacturer’’
as ‘‘a person who prepares, reconstitutes or otherwise changes the
physical or chemical characteristics of
an infant formula or packages or labels
the product in a container for
distribution’’)).
Other comments would define
‘‘manufacturer’’ to exclude a health care
practitioner or herbalist and noted the
Canadian Natural Health Product
regulations do not apply to health care
practitioners.
(Response) We decline to define
‘‘manufacturer’’ in the final rule. In
section III, footnote 1 of this document,
we explain that ‘‘manufacture’’ is a
broad term and is not limited to
production, packaging, or labeling
activities. Consequently, we prefer to
explain our interpretation of the final
rule in this preamble and to have the
codified provisions state general
principles rather than attempt to capture
subtleties in a definition of
‘‘manufacturer.’’
(Comment 59) Proposed § 111.35(e)(1)
through (e)(3) would require you to
establish specifications for identity,
purity, quality, strength, and
composition at receipt, in-process, and
finished batch stages, while proposed
§ 111.35(g)(1) would require you to test
each dietary supplement at the finished
batch stage before release for
distribution to confirm that
specifications are met, provided that
there are scientifically valid analytical
methods available to perform such
testing. If your quality control unit
determined that finished batch testing
could not be completed for any
specification because a scientifically
valid analytical method was not
available, proposed § 111.35(g)(2) and
(g)(3) would require you to perform
testing on components and at the inprocess stage to determine whether that
specification is met. The preamble to
the 2003 CGMP Proposal explained that
a scientifically valid analytical method
is one that is based on scientific data or
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results published in, for example,
scientific journals, references, text
books, or proprietary research (68 FR
12157 at 12198).
Several comments agree that
scientifically valid analytical methods
are those that are based on scientific
data or results published in scientific
journals, references, textbooks, or
proprietary research. However, several
comments ask us to define or better
explain the terms ‘‘test’’ or
‘‘scientifically valid analytical method’’
as used in the dietary supplement
CGMP final rule. One comment argues
that, because of the evolving nature of
methodology for ingredients used in
dietary supplements, we should give the
industry more guidance as to what can
be considered authoritative for the
purpose of compliance with CGMP.
Some comments state we should
acknowledge methods from the Institute
for Nutraceutical Advancement (INA),
American Herbal Pharmacopoeia (AHP),
European Pharmacopoeia, and the
World Health Organization (WHO) as
scientifically valid analytical methods.
One comment notes the USP establishes
scientifically valid procedures in its
compendia and encouraged us to
designate compendial procedures as
‘‘scientifically valid’’ by defining
‘‘scientifically valid’’ to include
compendial procedures. The comment
further argues that failure to
acknowledge compendial procedures as
scientifically valid would be
inconsistent with section 403(s)(2)(D) of
the act, which acknowledges the role of
compendia, by considering a dietary
supplement misbranded if the
supplement is covered by the
specifications of an official
compendium, is represented as
conforming to the specifications of an
official compendium, and fails to so
conform.
Other comments would define
‘‘validation’’ and ‘‘verification’’ and
directed us to ‘‘ANSI Standard A8402–
1994’’ (a description of validation and
verification standards).
(Response) We decline to define
‘‘test,’’ ‘‘scientifically valid analytical
method,’’ or ‘‘scientifically valid
method’’ in this final rule. As the
comments recognized, the analytical
methods for components are evolving. A
regulatory definition for ‘‘test,’’
‘‘scientifically valid analytical method,’’
or ‘‘scientifically valid method’’ could
become obsolete if we based it on
specific sources such as INA, AHP, or
USP that may or may not themselves
stay current or that may be modified in
a manner that did not enjoy widespread
support.
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The preamble to the 2003 CGMP
Proposal acknowledged that compendia
can have a role in establishing tests used
to determine whether specifications are
met. For example, we noted that
compendial standards may be
appropriate reference materials for use
in conducting tests or examinations (68
FR 12157 at 12208). However, we did
not list specific compendia that would
be suitable sources or scientifically
valid analytical tests, and are not listing
such compendia in this final rule. The
compendia identified in the comments,
i.e., INA, ANSI, AHP, and USP, may
include some methods that are based on
scientific data or results published in
scientific journals, references, textbooks,
or proprietary research, but also contain
some methods that are not based on
such data or results. Thus, whether or
not a method is scientifically valid is
not determined solely by its inclusion in
a compendium. Rather, it is the
responsibility of quality control
personnel to approve the use of those
scientifically valid tests that will ensure
a product’s identity, purity, strength,
and composition whether or not such
tests are contained in a particular
compendium.
We also decline to define ‘‘validation’’
and ‘‘verification’’ because the final rule
does not establish any requirements that
use these terms.
(Comment 60) One comment asks us
to define the terms ‘‘adequate,’’
‘‘sufficient,’’ and ‘‘qualified’’ and argues
that, without these definitions, an FDA
investigator may assert that something
or someone is not adequate, sufficient,
or qualified.
(Response) We decline to define
‘‘adequate,’’ ‘‘sufficient,’’ or ‘‘qualified’’
in this final rule. Deciding what is
‘‘adequate’’ or ‘‘sufficient,’’ or who is
‘‘qualified’’ must be done on a case-bycase basis, depending on the operations
and the particular facts. As explained in
section V of this document, we do not
need to, nor could we, predict with
mathematical precision how many
inches or feet, for example, would be
‘‘adequate space’’ to allow for cleaning
a particular piece of equipment that
could be applied to every size of facility
and every operation. Furthermore,
defining ‘‘adequate,’’ as defined in part
110, as ‘‘that which is needed to
accomplish the intended purpose in
keeping with good public health
practice’’ would still require context to
determine whether, in a particular
operation and based on a particular set
of facts the particular practice was
‘‘adequate.’’ Moreover, for terms such as
‘‘adequate,’’ ‘‘sufficient,’’ and
‘‘qualified,’’ where there has been
common usage in the food industry to
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enable manufacturers and FDA
investigators to comprehend and apply
such terms to a particular operation, we
do not believe a definition for these
terms is necessary.
(Comment 61) Several comments
would define the terms ‘‘certificate of
analysis,’’ ‘‘certificate of compliance/
conformance,’’ and ‘‘continuing product
guarantee.’’ Most comments include
these terms in a list of terms that they
want us to define to ensure consistent
interpretation of the rule throughout the
industry. One comment says a standard
for documentation, such as a certificate
of analysis, would put greater emphasis
on the firm’s responsibility to comply
with CGMP.
(Response) We decline to define these
terms as suggested by the comments. We
have included, in the codified, the use
of a certificate of analysis as an option
to determine whether certain
specifications have been met. The final
§ 111.75(a)(2)(ii)(B) requires that certain
information be provided in a ‘‘certificate
of analysis.’’ This provision states that
the certificate of analysis must include
a description of the test or examination
method(s) used, limits of the test or
examinations, and actual results of the
tests or examinations, provided you
satisfy certain other criteria.
As for the claim that a standard for
documentation, such as a certificate of
analysis, would emphasize a firm’s
responsibility to comply with CGMP,
we encourage firms who are excepted
from the scope of the rule in final
§ 111.1 and who supply dietary
ingredients and other components to
follow dietary supplement CGMP
requirements.
We decline to define ‘‘certificate of
compliance/conformance’’ or
‘‘continuing product guarantee’’ because
the final rule does not establish any
requirements that use these terms.
26. What Definitions Did the Comments
Want Us to Delete?
(Comment 62) Some comments would
delete certain definitions (e.g.,
‘‘component’’ and ‘‘ingredient’’) because
these terms do not appear in the food
CGMP, the 1997 ANPRM, or both.
(Response) We decline to delete any
definition for the reasons stated by the
comments. As discussed in section V of
this document, Congress did not require
dietary supplement CGMP requirements
to be identical to the food CGMP
requirements, so the mere fact that a
definition may not appear in a food
CGMP regulation does not mean we
must delete that definition from this
final rule, especially when the
comments offered no other justification
for deleting the definition. Definitions
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provide clarity and consistency in
interpreting various terms in a rule.
D. Do Other Statutory Provisions and
Regulations Apply? (Final § 111.5)
Final § 111.5 states: ‘‘In addition to
this part, you must comply with other
applicable statutory provisions and
regulations under the act related to
dietary supplements.’’ Proposed § 111.5
stated that, in addition to the dietary
supplement CGMP requirements, ‘‘you
must comply with other applicable
statutory provisions and regulations
under the act related to the
manufacturing, packaging or holding of
dietary ingredients or dietary
supplements.’’
Section 111.5 reminds you that other
statutory or regulatory requirements, not
included in the dietary supplement
CGMP requirements, may apply to your
particular products, operations, or
activities. In our further review of this
provision, we determined that we do
not need to elaborate on the individual
operations and have shortened the
provision to eliminate the references to
particular operations. You are required
to comply with other applicable
statutory and regulatory requirements,
and we have retained this provision to
ensure you understand that this final
rule does not relieve you of your
responsibilities to comply with other
applicable statutory and regulatory
requirements related to dietary
supplements.
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E. What Sections Did We Remove From
the Rule, and Why?
The final rule omits sections that were
in the proposed rule. Proposed § 111.2,
‘‘What Are These Regulations Intended
to Accomplish,’’ would have described
the rule’s purpose as establishing the
minimum CGMP you must use to the
extent that you manufacture, package, or
hold a dietary supplement. Proposed
§ 111.6, ‘‘Exclusions,’’ would have
excluded ‘‘persons engaged solely in
activities related to the harvesting,
storage, or distribution of raw
agricultural commodities that will be
incorporated into a dietary supplement
by other persons’’ from the dietary
supplement CGMP requirements.
1. ‘‘What Are These Regulations
Intended to Accomplish?’’ (Proposed
§ 111.2)
We elected to remove proposed
§ 111.2 from the final rule because we
realized that it created no enforceable
obligations and provided little, if any,
helpful information. The few comments
that address proposed § 111.2 either
disagreed with its general statement or
sought to weaken the provision; the
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comments’ arguments prompted us to
reconsider whether proposed § 111.2
was necessary at all, and, in the end, we
decided to delete the proposed section.
We describe the comments on proposed
§ 111.2 in the following paragraphs.
(Comment 63) Several comments
argue the proposed rule went beyond
the ‘‘minimum standards’’ mentioned in
proposed § 111.2. These comments also
assert the proposed rule lacked
flexibility.
(Response) We disagree with the
comments. In several instances, the
proposed requirement is practically
identical to requirements in the
umbrella food CGMP regulations. For
example, most of the proposed
requirements for personnel, physical
plants, and equipment and utensils
correspond to long-established, similar
requirements in the umbrella food
CGMP regulations in part 110. In other
instances, the proposed rule would
require a particular action or result
(such as establishing specifications for
components, in-process controls,
manufactured dietary supplements, and
packaged and labeled dietary
supplements under proposed
§ 111.35(e)), but gave firms the
flexibility and the responsibility to
decide what those specifications will be.
We have included flexibility where it is
appropriate to do so, and, after we
revised parts of the rule in response to
the comments, the final rule provides
more flexibility than the proposal. For
example, final § 111.75 sets forth criteria
for relying on a certificate of analysis to
ensure that certain specifications for
components are met and for when you
can test a subset of finished batches for
a select number of specifications; this
differs considerably from the proposal
which would have required testing all
batches for all specifications.
(Comment 64) One comment would
revise proposed § 111.2 to read as
follows: ‘‘These regulations recommend
general minimum current good
manufacturing practices that, when
modified by manufacturer product
specifications, will extend to the
manufacture, package, or holding of
dietary ingredients or dietary
supplements for that manufacturer.’’
(Response) We decline to revise the
rule as suggested by the comment.
Section 402(g) of the act states that ‘‘The
Secretary may by regulation prescribe
good manufacturing practices for dietary
supplements.’’ If a dietary supplement
has been prepared, packaged, labeled, or
held under conditions that do not meet
the final rule’s requirements, the dietary
supplement is deemed to be adulterated
under section 402(g)(1) of the act. Here,
the comment’s suggestion that dietary
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supplement CGMP requirements could
be ‘‘modified by manufacturer product
specifications’’ would create uncertainty
over whether manufacturers could
unilaterally ‘‘modify’’ their product
specifications to fit a batch that failed to
meet specifications or claim that a
violation was ‘‘cured’’ by a
manufacturer’s new product
specification. In any event, given that
we decided to omit proposed § 111.2
altogether, the change sought by the
comment is moot.
2. ‘‘Exclusions’’ (Proposed § 111.6)
As we stated earlier in this section,
proposed § 111.6 would exclude from
the dietary supplement CGMP
requirements persons who engage solely
in activities related to the harvesting,
storage, or distribution of raw
agricultural commodities that would be
incorporated into a dietary supplement
by other persons. However, as we
explained in our response to comment
27 of this document, we decided that
the exclusion was not necessary, given
the changes that we made to final
§ 111.1(a).
Nevertheless, we received several
comments on proposed § 111.6, and we
address those comments here.
(Comment 65) One comment would
revise the rule to exclude or use
different requirements for small
businesses. The comment suggested we
categorize small businesses by
employment levels or dollar sales and
adopt a tiered enforcement strategy
similar that used in other government
programs, such as those under the
Occupational Safety and Health Act, the
Americans with Disabilities Act, and the
Family Leave Act. Another comment
would exempt small businesses from
the specific requirements for testing if
those businesses produce annual batch
runs of 25,000 capsules and tablets.
(Response) We decline to exclude
small businesses from the final rule or
to have different criteria for such
businesses. As we stated in our response
to comments 1, 3, and 16, there is no
reason to assume that Congress meant to
apply different or lesser CGMP
requirements, or no CGMP requirements
at all, to dietary supplements made by
small businesses. Dietary supplement
CGMP requirements help to ensure the
quality of the dietary supplement and,
among other things, that a dietary
supplement meets its specifications,
that it contains the ingredients specified
in its master manufacturing record, and
that it is not contaminated. Consumers
should be able to expect that the dietary
supplements they purchase meet CGMP
requirements regardless of the
manufacturer’s size. However, to help
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businesses comply with dietary
supplement CGMPs, we are giving
businesses with fewer than 500
employees but 20 or more employees a
compliance date of 24 months after the
date of publication of this final rule, and
we are giving businesses with fewer
than 20 employees a compliance date of
36 months after the date of publication
of this final rule.
We carefully considered the size of a
business when developing these
regulations. The most common Small
Business Association size standard
applicable to manufacturers covered by
this final rule is 500 employees. Based
on comments and our knowledge of the
dietary supplement industry, we know
that there are a number of dietary
supplement manufacturers who fall
significantly below the standard of 500
employees. To accommodate these
manufacturers, we have established
different compliance dates as noted.
(Comment 66) One comment would
exempt ‘‘consolidators’’ (whom it
described as individuals who purchase
raw agricultural commodities for sale to
raw ingredient manufacturers) from the
rule. Some comments suggest expanding
the exclusion pertaining to harvesting,
storage, and distribution of raw
agricultural commodities to include
other common and basic raw botanical
processing activities, such as drying,
chopping, cutting, size reduction,
sifting, grinding, and storage. One
comment would delete the word
‘‘solely’’ to make the rule more flexible
and make it possible to exclude
producers, who do not manufacture a
distinct product, from the CGMP rule.
Another comment expresses concern
about potential safety issues that can
arise from the early stages of
manufacturing, such as the use of
improper handling of agricultural
commodities and the risk of
adulteration; the comment says
businesses involved in producing or
distributing raw agricultural
commodities should be subject to some
requirements under the rule. A few
comments ask us to draft guidance
documents to address activities such as
wildcrafting, plant identification, good
agricultural practices, and good
hygienic practices for wildcrafters
(persons who harvest plants grown in
the wild), and growers and brokers and
specific service providers (millers,
extractors). Some comments would
exempt individual wildcrafters because
wildcrafters deal in relatively small
amounts of material at a time and sell
their material to larger brokers who
combine materials from different
pickers together.
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(Response) As explained in our
responses to comments 29 and 30,
persons who only manufacture or
supply a component that will be further
processed as a dietary supplement by
another person are not within the scope
of this final rule. Thus, a ‘‘consolidator’’
who simply buys raw agricultural
commodities and then sells them to
dietary ingredient manufacturers would
not be subject to this final rule.
Similarly, persons engaged in drying,
chopping, cutting, size reduction,
sifting, and grinding of raw agricultural
commodities which they then sell to
others for processing into a dietary
supplement would not be subject to this
final rule. We note, however, that such
persons are not exempt from other
regulatory requirements. We remind
readers that a dietary ingredient is a
food under section 201(f)(3) of the act.
Consequently, a raw agricultural
commodity that is a dietary ingredient
is still subject to the umbrella food
CGMP requirements in part 110, and
activities such as drying, chopping, and
cutting are what we have long
considered to be types of food
processing.
As for ‘‘wildcrafters,’’ if they package
and label raw agricultural commodities
as dietary supplements or sell them to
consumers for use as a dietary
supplement, we would consider them to
be manufacturers of a dietary
supplement and subject to the rule. If,
however, the wildcrafter simply sells
the raw agricultural commodity to
another for incorporation into a dietary
supplement, it would not be subject to
this final rule, but might be subject to
the CGMP requirements in part 110.
Persons engaged in the harvesting,
storage, or distribution of raw
agricultural commodities, whether for
distribution as a dietary supplement or
for distribution as a dietary ingredient to
a dietary supplement manufacturer, may
want to read our guidance entitled
‘‘Guide to Minimize Microbial Food
Safety Hazards for Fresh Fruits and
Vegetables’’ available at https://
www.cfsan.fda.gov/~dms/
prodguid.html (Ref. 28). This guidance
addresses common areas of food safety
concern in the growing, harvesting,
sorting, packing, and distribution of
fresh produce, and contains principles
that would apply to raw agricultural
commodities, such as herbs and
botanicals.
As for the comment that would delete
the word ‘‘solely’’ from proposed
§ 111.6, we note that such a change is
no longer necessary since we are
deleting § 111.6. However, we caution
that only those persons or entities that
manufacture or supply components that
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will be further processed as a dietary
supplement by others are not subject to
the final rule. If you manufacture and
sell dietary supplements, in addition to
supplying components to others, you
would be subject to this final rule under
§ 111.1(a).
As for potential safety issues arising
from the early stages of manufacturing,
such as the use of improper handling of
agricultural commodities and the risk of
adulteration, the final rule, at § 111.75,
describes criteria that enable a
manufacturer of a dietary supplement to
rely on a certificate of analysis. One
criterion is that the manufacturer must
first qualify the firm providing the
component by establishing the
reliability of the firm’s certificate of
analysis through confirmation of the
results of the firm’s tests or
examinations. Firms that improperly
handle raw agricultural commodities,
such that the commodities that they
provide are adulterated, are not likely to
be qualified as suppliers of those
commodities.
In the future, we will consider the
requests to develop guidance for subsets
of agricultural and post-harvest
activities (such as for hygienic practice
for wildcrafters, identifying botanicals)
associated with dietary supplement
manufacturing, along with other
guidance we may find useful as they
relate to certain CGMP requirements for
dietary supplements.
VII. Comments on Personnel (Final
Subpart B)
A. Organization of Final Subpart B
Proposed subpart B contained three
provisions regarding personnel. Table 3
of this document lists the sections in
final subpart B and identifies the
proposed sections that form the basis of
the final rule.
TABLE 3.—DERIVATION OF
SECTIONS IN FINAL SUBPART B
Final Rule
2003
CGMP
Proposal
§ 111.8 What are the requirements under this
subpart B for written
procedures?
N/A
§ 111.10 What requirements apply for preventing microbial contamination from sick or
infected personnel and
for hygienic practices?
§ 111.10
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TABLE 3.—DERIVATION OF SECTIONS IN FINAL SUBPART B—
Continued
Final Rule
2003
CGMP
Proposal
§ 111.12 What personnel
qualification requirements apply?
§ 111.12
§ 111.13 What supervisor requirements
apply?
§ 111.13
§ 111.14 Under this subpart B, what records
must you make and
keep?
N/A
B. Highlights of Changes to the
Proposed Requirements for Personnel
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1. Revisions
The final provisions in subpart B
include revisions that clarify that the
final rule applies only to persons who
manufacture, package, label, or hold
dietary supplements unless subject to an
exclusion in § 111.1.
The final provisions also include
revisions that clarify the applicability of
the rule to persons who perform
labeling operations for dietary
supplements.
2. Changes After Considering Comments
The final rule:
• Requires you to establish and
follow written procedures to fulfill the
requirements of subpart B;
• Provides flexibility regarding the
requirement to exclude personnel who
might be a source of microbial
contamination (e.g., due to illness or
open lesions) so that such personnel
must be excluded only from operations
where such contamination may occur;
• Clarifies that the qualification of
personnel and supervisors may be done
through education, training, or
experience;
• Sets forth a new requirement that
you identify qualified personnel to
perform quality control operations and
requires that such personnel have
distinct and separate responsibilities
related to performing quality control
operations from those responsibilities
that the person otherwise has when not
performing quality control operations;
and
• Sets forth a new requirement to
make and keep records that document
training of personnel.
C. General Comments on Proposed
Subpart B
(Comment 67) Some comments assert
one or more proposed requirements are
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unconstitutionally vague under the Fifth
Amendment and arbitrary and
capricious under section 706(2)(B) of
the Administrative Procedure Act (APA)
and therefore should be deleted. The
comments focus on:
• Proposed § 111.12(a) which would
require ‘‘qualified employees’’ and
• Proposed § 111.13(a) which would
require ‘‘qualified personnel to
supervise.’’
In general, these comments say the
proposal’s failure to define the term
‘‘qualified’’ means that persons who are
subject to the rule could not discern the
meaning of the term. These comments
also say the proposal imposes no limits
on enforcement officers as to what
would satisfy the requirements and,
thus would represent an exercise of
unbridled discretion and disparate
decisionmaking. These comments argue
proposed § 111.12(b), which would
require employees to have ‘‘the training
and experience to perform the person’s
duties,’’ and proposed § 111.13(b),
which would require supervisors to be
‘‘qualified by training and experience to
supervise,’’ would suffice.
(Response) We are not deleting
§§ 111.12(a) and 111.13(a) as requested
by these comments. As discussed in
section V of this document, we disagree
that the terms in question are
unconstitutionally vague, need to be
defined, or may result in discriminatory
enforcement. There has been sufficient
common usage of these terms in the
food industry to enable manufacturers,
and those who enforce the
requirements, to comprehend and apply
such terms ‘‘with a reasonable degree of
certainty’’ to their particular operations
(see Boyce Motor Lines v. United States
342 U.S. at 340). Further, agencies are
permitted to use qualifying terms to
enable them to address a wide variety of
conditions at companies. For these
reasons, we have retained the use of the
terms in the final rule. The provisions
at issue also give firms the flexibility to
determine how to comply with the
regulations. We also explain in section
V of this document that the final rule
does not violate the APA.
D. What Are the Requirements Under
This Subpart for Written Procedures?
(Final § 111.8)
We received many comments that
recommended written procedures for
various provisions. We address the need
for written procedures generally in
section IV. We also respond to
individual comments on specific
provisions in the same section. Final
§ 111.8 requires you to establish and
follow written procedures to fulfill the
requirements of subpart B. Additionally,
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to ensure that we can evaluate firms’
compliance with their written
procedures, final § 111.14 requires that
a person who manufactures, packages,
labels, or holds dietary supplements
make and keep records of such
procedures. Such records would be
available to us under subpart P.
E. What Requirements Apply for
Preventing Microbial Contamination
From Sick or Infected Personnel and for
Hygienic Practices? (Final § 111.10)
The title of this provision has been
changed from proposed § 111.10 to
clarify that the requirements are related
to the prevention of microbial
contamination due to the health
condition of personnel and not other
sources.
1. Final § 111.10(a)
Final § 111.10(a) requires you to take
measures to exclude from any
operations any person who might be a
source of microbial contamination, due
to a health condition, where such
contamination may occur, of any
material including components, dietary
supplements, and contact surfaces used
in the manufacture, packaging, labeling,
or holding of a dietary supplement. This
provision is similar to proposed
§ 111.10. We added ‘‘due to a health
condition’’ for clarity.
(Comment 68) Several comments
suggest that employees who are sick
should be allowed to work in areas
where they will not come into contact
with components, dietary supplements,
or contact surfaces, and that the
requirements of proposed § 111.10 are
too strict. These comments say proposed
§ 111.10(a) is too broad in stating that
such persons be excluded ‘‘from
working in any operation.’’ These
comments explain that such persons
may be suitable for performing other
tasks, such as warehouse functions or
administrative work. These comments
would revise proposed § 111.10(a) so
that it is acceptable for such persons to
work so long as they will not be a vessel
for microbial contamination.
Other comments agree with proposed
§ 111.10(a), and state that employees
who are sick should be excluded from
the plant, even from areas where
products are not processed. These
comments state excluding such
personnel should be mandatory as the
microbes from an open sore, wound, or
other source of contamination could
contaminate the surrounding air,
personnel, etc. For example, if the
production area is a closed loop air
handling system, then contamination
could spread to the other areas through
the common air handling units/ducts.
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(Response) We agree that some tasks
may be suitable for a person who might
be a source of microbial contamination.
Certain warehouse functions or
administrative tasks may be appropriate
for such a person to do, provided that
these functions or tasks do not expose
components, dietary supplements, or
contact surfaces to microbial
contamination from the person, and
provided that the person would not
infect others who would then expose
components, dietary supplements, or
contact surfaces to microbial
contamination.
A requirement to exclude employees
from being present at work would limit
potential microbial contamination,
which is the basis of the point made by
some comments that employees who are
sick should be excluded from the plant.
However, the comments do not
persuade us to deny firms the flexibility
to determine whether it would be
appropriate for an employee who may
be a source of microbial contamination
to work in some areas of the physical
plant that are sufficiently separated
from areas where product
contamination could occur. When
considering whether an employee may
be permitted to work and whether he/
she represents a potential source of
microbial contamination, one should
look beyond the obvious potential
sources of contamination, and consider
possibilities such as the forms of
indirect contamination discussed by the
comments. Therefore, we are revising
proposed § 111.10(a) to require you to
take measures to exclude ‘‘from any
operations any person who might be a
source of microbial contamination, due
to a health condition, where such
contamination may occur, of any
material including components, dietary
supplements, and contact surfaces used
in the manufacture, packaging, labeling,
or holding of a dietary supplement.’’
As one measure to reduce potential
microbial contamination, final
§ 111.10(a)(1) requires you to exclude,
from working in any operations that
may result in contamination, any person
who, by medical examination, the
person’s acknowledgement, or
supervisory observation, is shown to
have, or appears to have an illness,
infection, open lesion, or any other
abnormal source of microbial
contamination, that may result in
microbial contamination of components,
dietary supplements, or contact
surfaces, until the health condition no
longer exists. Final § 111.10(a)(1) is
similar to proposed § 111.10(a)(1). We
have added that the person can
acknowledge that he or she may be a
source of microbial contamination. We
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are moving and modifying the
prepositional phrase concerning
‘‘working in any operation.’’ We also
have added the word ‘‘infection’’ to
clarify the sources of potential abnormal
contamination.
(Comment 69) Several comments
suggest employees who may be the
source of microbial contamination
should be permitted to work in areas of
the plant where they pose no risk of
contamination, and therefore should not
be excluded unless they pose such a
risk.
(Response) We agree with the
comments and are revising proposed
§ 111.10(a)(1) accordingly. Therefore,
you may allow persons with certain
health conditions to work in areas of a
plant where they pose no risk of
contamination even though they must
be excluded from other areas where they
would pose such a risk.
Final § 111.10(a)(2) requires you to
instruct your employees to notify their
supervisor(s) if they have, or if there is
a reasonable possibility that they have,
a health condition stated in
§ 111.10(a)(1) that could contaminate
any components, dietary supplements,
or any contact surface.
We did not receive comments specific
to proposed § 111.10(a)(2).
2. Final § 111.10(b)
Final § 111.10(b) requires, if you work
in an operation during which
adulteration of the component, dietary
supplement, or contact surface may
occur, you to use hygienic practices to
the extent necessary to protect against
contamination of components, dietary
supplements, or contact surfaces. Final
§ 111.10(b) lists nine hygienic practices,
such as wearing outer garments in a
manner that protects against
contamination, washing hands
thoroughly, and wearing, where
appropriate, hair nets, caps, beard
covers, or other effective hair restraints.
We did not receive any comments
concerning proposed § 111.10(b)(1)
(wearing outer garments in a manner
that protects against contamination),
§ 111.10(b)(2) (maintaining adequate
personal cleanliness), § 111.10(b)(3)
(washing hands thoroughly),
§ 111.10(b)(4) (removing all unsecured
jewelry and other objects that might fall
into components, dietary supplements,
equipment, or packaging and removing
hand jewelry that cannot be adequately
sanitized), § 111.10(b)(6) (wearing,
where appropriate, hair nets, caps,
beard covers, and other effective hair
restraints), § 111.10(b)(7) (not storing
clothing or other personal belongings
where components, dietary
supplements, or contact surfaces are
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34809
exposed or where contact surfaces are
washed), and § 111.10(b)(9) (taking any
other precautions necessary to protect
against contamination).
Proposed § 111.10(b)(5) would require
the hygienic practices that you use to
include maintaining gloves used in
handling components, dietary
ingredients, or dietary supplements in
an intact, clean, and sanitary condition
and ensuring that gloves be of an
impermeable material.
(Comment 70) One comment asks us
to clarify the requirements for the use of
gloves in proposed § 111.10(b)(5). The
comment says there are situations in
which gloves are ineffective or
cumbersome. The comment provides as
an example, if a person is packaging a
bulk material in fiber packs with metal
ring lids, bulky gloves can interfere with
the finer work such as attaching security
tabs, and thin, flexible gloves can be
easily damaged by the sharp edges of
the metal rings on the lid.
(Response) Final § 111.10(b)(5)
requires you to maintain gloves in an
intact, clean, and sanitary condition; it
does not require you to use gloves in
any specific situation. Although there is
no requirement for wearing gloves while
performing specific operations, you
must wear gloves when they are
necessary to protect against
contamination of any components,
dietary supplements, or contact
surfaces.
(Comment 71) Proposed § 111.10(b)(8)
would require that the hygienic
practices that you use, to the extent
necessary to protect against
contamination, include not eating food,
chewing gum, drinking beverages, or
using tobacco products in areas where
components, dietary ingredients, dietary
supplements, or any contact surfaces are
exposed, or where contact surfaces are
washed.
One comment would substitute the
word ‘‘processed’’ for the word
‘‘exposed’’ in proposed § 111.10(b)(8).
The comment says, although areas
where components, dietary
supplements, and contact surfaces are
exposed pose the greatest risk,
adulteration is also possible where these
items are held (i.e., stored in containers
and, thus, not exposed). Furthermore,
the comment explains the use of the
word ‘‘processed,’’ rather than
‘‘exposed,’’ would cover all areas
intended to be covered by CGMPs and
would alleviate the need to specify that
the requirement applies to areas where
contact surfaces are washed.
(Response) We decline to revise the
rule as suggested by the comment. We
believe the word ‘‘exposed’’ covers all
areas intended to be covered by the
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requirement, including areas where
contact surfaces are washed. We
consider an area where contact surfaces
are washed to ‘‘expose’’ the contact
surface. To avoid any confusion, we are
modifying § 111.10(b)(8) to say ‘‘* * *
any contact surfaces are exposed, or
where contact surfaces are washed.’’ As
written, the requirement to not eat,
chew gum, drink, or use tobacco
products in areas where components,
dietary supplements, and contact
surfaces are exposed gives firms
appropriate flexibility to determine
areas where employees may or may not
eat, chew gum, drink, or use tobacco
products.
F. What Personnel Qualification
Requirements Apply? (Final § 111.12)
Final § 111.12(a) requires you to have
qualified employees who manufacture,
package, label, or hold dietary
supplements. Final § 111.12(a) is similar
to proposed § 111.12(a), except that the
final rule includes an editorial change to
clarify that the requirement is to have
the qualified employees do the work
rather than merely to have qualified
employees.
(Comment 72) The 2003 CGMP
Proposal invited comment on whether
there is a minimum number of
employees needed to manufacture
dietary supplements (68 FR 12157 at
12183). Several comments state the final
rule should not include such a
minimum number because firms should
be able to decide for themselves how
many qualified personnel they need.
(Response) The final rule does not
stipulate a minimum number of
employees. However, there should be
enough employees to manufacture,
package, label, and hold dietary
supplements to ensure compliance with
the final rule. In general, CGMP suggests
the need for a minimum of two persons:
One to perform the work, and a second
to check the work performed to ensure
that a manufacturing deviation or an
unanticipated occurrence is not
overlooked.
(Comment 73) Some comments about
the proposed definition of ‘‘quality
control unit’’ say the quality control
function need not be performed by a
distinct or separate unit. These
comments say the quality control
function is best performed by a person
or persons qualified by training,
education, or experience in the different
processing areas.
(Response) As discussed, we have
revised the proposed definition and
substituted the term ‘‘personnel’’ for
‘‘unit.’’ (For the definition of quality
control personnel, see section VI of this
document.) We agree the quality control
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functions do not need to be performed
by a distinct or separate unit or person
and that a person who is qualified by
training, education, or experience can
serve a quality control function.
Therefore, we are adding a new
§ 111.12(b) to clarify that you must
identify who is responsible for quality
control operations. Under final
§ 111.12(b) each person identified must
be qualified to perform such operations,
and must have distinct and separate
responsibilities related to performing
such operations from those
responsibilities that the person
otherwise has when not performing
such operations. The quality control
personnel can have dual functions
within the facility but should separately
perform the different responsibilities.
Final § 111.12(c) requires that each
person engaged in manufacturing,
packaging, labeling, or holding, or in
performing any quality control
operations, have the education, training,
or experience to perform the person’s
assigned functions. Final § 111.12(c)
includes a revision associated with final
§ 111.12(b) by including persons who
perform quality control operations as
persons who also need to have the
education, training, or experience for
the assigned functions.
(Comment 74) Several comments state
we should revise the rule to allow for
any combination of ‘‘training or
experience.’’ These comments explain it
is not always possible for an employee
to have both ‘‘training and experience.’’
These comments would revise proposed
§ 111.12(b) to read, ‘‘each person
engaged in the manufacture of a dietary
product should have the proper
education, training, and experience (or
any combination thereof) needed to
perform the assigned functions.
Training should be in the particular
operations(s) that the employee
performs as they relate to the
employee’s functions.’’ Another
comment asks for guidance as to what
type of education, training, or
experience is required for an employee
to be considered qualified.
(Response) We agree with the point
made by the comments. We
acknowledge that some positions will
require an appropriate educational
background in addition to any on-thejob training. In the preamble to the 2003
CGMP Proposal (68 FR 12157 at 12183)
we noted ‘‘training’’ may be considered
a form of ‘‘education’’ and elected to
require that employees be qualified by
‘‘training and experience’’ rather than
‘‘education, training, and experience.’’
The 2003 CGMP Proposal used the
conjunction ‘‘and’’ because we
considered ‘‘experience’’ to be different
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from training, in that ‘‘experience’’ is
knowledge that a person gains over
time, e.g., as he or she becomes
increasingly familiar with a particular
action or piece of equipment.
These comments persuade us that the
rule would be clearer if we added
‘‘education’’ to the list of attributes that
are used to qualify an employee. We
also agree there are some employees
who could be qualified based solely on
their education or experience and other
employees who would become qualified
through, for example, on-the-job
training before they are left on their own
to perform their assigned duties. Rather
than revise the rule to list all three
attributes and then explain that an
employee can be qualified by any
combination of the attributes, we have
changed the conjunction from ‘‘and’’ to
‘‘or.’’ Additionally, on our own
initiative, we have replaced ‘‘person’s
duties’’ with ‘‘person’s assigned
functions.’’ This change reinforces the
principle that the employee’s training
relates to the functions that he or she is
assigned to perform.
We will consider whether it would be
useful to provide guidance on what type
of education, training, or experience
would be sufficient for an employee to
be properly qualified. We believe that
such education, training, or experience
may vary by job function and that it
would be difficult to provide generic
guidance that would be sufficient for all
specific job tasks. We decline to suggest
that training should be limited, as the
comments suggest, to the particular
operation(s) that the employee performs
as they relate to the person’s functions.
These CGMP requirements apply to
many types of manufacturing operations
of various size and complexity, so the
training may vary depending on the
circumstances and may include more
than the employee’s assigned functions.
(Comment 75) One comment states we
should provide training materials such
as texts, videos, Internet training, or
seminars, to help companies properly
train their employees.
(Response) We have no plans at this
time to provide companies with training
materials for their employees. We
expect that most companies already
have trained or will train their
employees and that where additional
training is needed to comply with these
regulations, companies will develop the
training materials that are appropriate
for the functions their employees
perform. We may consider providing
guidance in the future if circumstances
warrant such guidance.
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G. What Supervisor Requirements
Apply? (Final § 111.13)
Final § 111.13(a) requires you to
assign qualified personnel to supervise
the manufacturing, packaging, labeling,
or holding of dietary supplements. Final
§ 111.13(a) derives from proposed
§ 111.13(a).
We did not receive comments specific
to proposed § 111.13(a).
Final § 111.13(b) requires each
supervisor you use to be qualified by
education, training, or experience to
supervise. Final 111.13(b) derives from
proposed § 111.13(b) which would
require you and your supervisors to be
qualified by training and experience to
supervise.
(Comment 76) Several comments ask
us to revise the rule so that supervisors
may be qualified by any combination of
training or experience. These comments
would revise proposed § 111.13(b) to
read, ‘‘supervisors must be qualified by
education, training, and experience (or
any combination thereof) to supervise
the manufacturing, packaging, or
holding of dietary ingredients and
dietary supplements in compliance with
this rule.’’ One comment, however,
would make an exception for quality
control and sanitation supervisors,
stating we should require these
supervisors to have both training and
experience.
(Response) Consistent with the
change we made to proposed
§ 111.12(c), we are revising proposed
§ 111.13(b) to require the supervisors
you use to be qualified by ‘‘education,
training, or experience.’’ We
acknowledge that some supervisory
personnel may need a different range of
education, training, or experience than
others, and expect firms to determine
the appropriate balance of education,
training, and experience.
(Comment 77) Several comments say
our use of the phrase ‘‘you and the
supervisors you use’’ in proposed
§ 111.13(b) was unclear. According to
these comments, the term ‘‘you’’ as
defined in the proposal, is quite
expansive and could be read so broadly
as to require the Chief Executive Officer
(CEO) of a company be ‘‘qualified’’ to
supervise.
(Response) We agree that the phrase
‘‘you and the supervisors you use’’
could be clearer. Therefore, we are
revising proposed § 111.13(b) to say that
‘‘each supervisor whom you use’’ must
be qualified to supervise. Section
111.13(b) applies to any person who
supervises the manufacturing,
packaging, labeling, or holding of
dietary supplements, even if that person
also is an executive such as the CEO.
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Thus, final § 111.13(b) states, ‘‘Each
supervisor whom you use must be
qualified by education, training, or
experience to supervise.’’
(Comment 78) Several comments say
the term ‘‘to supervise’’ is ambiguous
and would revise the rule to clarify
what a supervisor must be qualified to
supervise: The manufacture, packaging,
or holding of dietary ingredients and
dietary supplements. Another comment
would revise proposed § 111.13(b) to
clarify what type of training and
experience are required so that firms
would have more guidance as to what
is expected to confirm that personnel
are qualified.
(Response) We decline to revise the
rule as suggested by the comments. We
disagree that the term ‘‘to supervise,’’
which is commonly used in the
industry, is ambiguous. These CGMP
requirements apply to many types of
manufacturing operations of various
size and complexity, and the training
must be suited to the circumstances.
H. Under This Subpart, What Records
Must You Make and Keep? (Final
§ 111.14)
As discussed in this section, the final
rule contains a new § 111.8 requiring
you to establish and follow written
procedures to fulfill the requirements of
subpart B. Those written procedures are
records. Therefore, we are adding a new
§ 111.14(a) requiring you to make and
keep records in accordance with subpart
P. Final § 111.14(b)(1) requires you to
make and keep a record of the written
procedures for fulfilling the
requirements of subpart B.
The preamble to the 2003 CGMP
Proposal invited comment on whether
we should require documentation and
records regarding each employee’s
training (68 FR 12157 at 12183). After
considering comments and for the
reasons discussed in the following
paragraphs, § 111.14(b)(2) requires you
to make and keep documentation of
training, including the date of training,
the type of training, and the person(s)
trained.
We also invited comment on whether
the final rule should contain
requirements for documentation about
consultants that you use (68 FR 12157
at 12183). We specifically suggested any
such requirement include the
consultant’s name, address,
qualifications, and a description of
services provided. After considering the
comments and for the reasons discussed
in the following paragraphs, the final
rule does not include any requirements
to make and keep records regarding
consultants.
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(Comment 79) Several comments state
employee training records are critical
and should be required under the final
rule. The comments explain that these
records should show the content of the
training, the date of the training, and the
signature of the employee trained. These
comments assert that a formal (written)
GMP training program is necessary to
track which employees have been
trained in the CGMP requirements.
These comments add, without a written
and documented training program, it is
likely that some employees may not
receive sufficient training, or in some
cases, any CGMP training at all. These
comments say successful quality control
programs are inextricably connected to
appropriate training programs, and
written documentation of employee
training is an important safeguard to
ensuring safe and accurately labeled
dietary supplements. These comments
also state it is already an industry
standard to document training.
Other comments question our ability
to evaluate whether a firm’s employees
have been adequately trained without
written documentation of the training.
(Response) As discussed more fully in
the discussion of subpart E in section X
of this document, the final rule focuses
on ensuring the quality of the dietary
supplement at every stage of the
production and process control system.
Such a system begins with the proper
training. We agree that documentation
of employee training is necessary to
track which employees have been
trained in which operations. Therefore,
final § 111.14(b)(2) requires you to keep
documentation of training, including
the date of the training, the type of
training, and the person(s) trained.
(Comment 80) One comment says we
should not require manufacturers to
document and keep records regarding
each employee’s training. The comment
says the rule should focus on end
results and not on process.
(Response) We disagree with the
comment. As we have explained in this
section, each person engaged in an
activity covered by these CGMP
regulations must have the education,
training, or experience to perform the
person’s assigned functions. Some
employees will be considered qualified
based in part on training taken as
company employees. To show that such
training is appropriate to the employee’s
functions and has in fact occurred, the
training must be properly documented.
This documentation is an important
aspect of ensuring adequate training
and, therefore, helping to ensure the
result of having qualified employees
who perform their functions properly.
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(Comment 81) Several comments state
the documentation of the training
program should include the title of the
person doing the training, an evaluation
of the employee’s understanding of the
training, and recommendations for the
frequency of refresher training. One
comment describes a specific method
for training and for tracking training.
The comments state an evaluation of the
employee’s understanding of the
training would ensure that employees
who receive training understand what
they have been taught.
(Response) We decline to require
specific additional documentation of
employee training. We believe a firm
should have some flexibility in how it
wants to document training.
(Comment 82) Several comments
respond to our question as to whether
the final rule should require
documentation about consultants,
including each consultant’s name,
address, qualifications, and a
description of services provided.
Several comments say that documenting
this information is useful and could be
done on a voluntary basis, but that such
information is not necessary to ensure
safe and accurately labeled supplements
and, thus, should not be required. One
comment notes that recommendations
from consultants may or may not be
used, and that a company should not
have to explain at a later date why such
decisions were made. Another comment
asserts that we and the company may
have different opinions on whether a
consultant is qualified and that the
consultant’s qualification is not our
concern if a product is not adulterated.
One comment says documenting the
name and services of the GMP
consultants should be required to
facilitate contact in case of need.
(Response) The proposal noted
documentation of the name, address,
qualifications, and services rendered for
each consultant may help you know
whom to contact and if questions arise
concerning the advice that the
consultant has given. Thus, our intent in
suggesting such documentation was to
help you rather than to make the
information available for us to
determine whether we agreed with you
that a particular individual was
qualified to be a consultant. However,
the comments persuade us that such
information is not necessary to help
ensure dietary supplement quality.
Therefore, the final rule does not require
documentation regarding consultants.
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VIII. Comments on Physical Plant and
Grounds (Final Subpart C)
A. Organization of Final Subpart C
Proposed subpart C contained two
provisions regarding physical plants.
Table 4 of this document lists the
sections in final subpart C and identifies
the corresponding proposed sections
that form the basis of the final rule.
TABLE 4.—DERIVATION OF
SECTIONS IN FINAL SUBPART C
2003 CGMP
Proposal
Final Rule
§ 111.15 What sanitation
requirements apply to
your physical plant
and grounds?
§ 111.15
§ 111.16 What are the
requirements under
this subpart C for written procedures?
N/A
§ 111.20 What design
and construction requirements apply to
your physical plant?
§ 111.20
§ 111.23 Under this subpart C, what records
must you make and
keep?
§ 111.15(d)(3)
and (e)(2)
C. General Comments on Proposed
Subpart C
B. Highlights of Changes to the
Proposed Requirements for Physical
Plant and Grounds
1. Revisions
The final rule:
• Reflects that the rule applies to
persons who manufacture, package,
label, or hold dietary supplements
unless subject to an exclusion in
§ 111.1.
• Requires you to have
documentation or otherwise be able to
show that water that is used in a manner
such that the water may become a
component of the dietary supplement,
e.g., when such water contacts
components, dietary supplements, or
any contact surface, meets applicable
Federal, State, and local requirements
and does not contaminate the dietary
supplement.
2. Changes After Considering Comments
The final rule:
• Includes requirements similar to the
food CGMP requirements in § 110.20(a)
for keeping the grounds bordering your
physical plant in a condition that
protects against contamination.
• Clarifies that sanitation supervisors
can be qualified by education, training,
or experience.
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• Modifies the minimum
requirements for water that is used in a
manner such that the water may become
a component of the dietary supplement,
e.g., when such water contacts
components, dietary supplements, or
any contact surface. Such water must, at
a minimum, comply with applicable
Federal, State, and local requirements
and not contaminate the dietary
supplement.
• Simplifies the sanitation
requirements for toxic materials,
bathroom facilities, and hand-washing
facilities.
• Simplifies and clarifies the design
requirements for floors, walls, and
ceilings; fans and other air-blowing
equipment; equipment that controls
temperature and humidity; and the use
of safety-type glass or glass-like
materials.
• Requires written procedures for
cleaning the physical plant and for pest
control.
• Requires that you make and keep
records of the written procedures.
Sfmt 4700
(Comment 83) Several comments say
we should have different sanitation
requirements for dietary ingredient
manufacturers than for dietary
supplement manufacturers. These
comments state that the manufacture of
synthetic or highly processed dietary
ingredients includes extensive
purification steps, especially toward the
end of the manufacturing process, and
that these steps remove contaminants
that may have been introduced at earlier
stages in the manufacturing process.
These comments consider some stages
of the dietary ingredient manufacturing
process to not be subject to the same
strict controls as those used for
manufacturing finished dietary
supplements.
(Response) As discussed in section VI
of this document (subpart A), the final
rule applies to persons who
manufacture, package, label, or hold
dietary supplements and who are not
subject to an exclusion in § 111.1, and
does not apply to establishments that
only manufacture dietary ingredients.
We addressed this comment in the
response to comment 29.
(Comment 84) Some comments assert
that one or more proposed requirements
are unconstitutionally vague under the
Fifth Amendment and are arbitrary and
capricious under section 706(2)(B) of
the APA. The comments would delete
the following proposed requirements:
• § 111.15(e), which would require
plumbing to be ‘‘of an adequate size and
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design and be adequately installed and
maintained;’’
• § 111.15(g), which would require
bathrooms to be ‘‘adequate’’ and
‘‘readily accessible; ’’
• § 111.15(h), which would require
hand-washing facilities ‘‘to be adequate,
convenient, and furnish running water
at a suitable temperature;’’
• § 111.15(h)(i), which would require
hand-washing and, where appropriate,
hand-sanitizing facilities ‘‘at each
location in your physical plant’’ where
good hygienic practices require
employees to wash or to sanitize or both
wash and sanitize their hands;
• § 111.20(a), which would require
your physical plant to ‘‘be suitable in
size, construction, and design to
facilitate maintenance, cleaning, and
sanitizing operations;’’ and
• § 111.20(d)(6), which would require
aisles or working spaces between
equipment and walls to be adequately
unobstructed and of adequate width.
In general, these comments assert the
2003 CGMP Proposal did not define
terms or phrases (such as ‘‘adequately’’
or ‘‘at each location’’) in a way that
persons who are subject to the rule can
discern the meaning of the term or
phrase. These comments argue that the
proposed rule imposes no limitations on
enforcement officers on the exercise of
their discretion and, thus, invites
exercise of unbridled discretion and
disparate decisionmaking.
(Response) As discussed in section V
of this document, we disagree that the
terms that the comments objected to in
the 2003 CGMP Proposal are
unconstitutionally vague, need to be
defined, or may result in discriminatory
enforcement. We are retaining the terms
in the final rule.
D. What Sanitation Requirements Apply
to Your Physical Plant and Grounds?
(Final § 111.15)
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1. Final § 111.15(a)
The preamble to the 2003 CGMP
Proposal (68 FR 12157 at 12184) stated
that we were not proposing
requirements similar to the food CGMP
requirements found in § 110.20(a) for
keeping the grounds bordering your
physical plant in a condition that
protects against contamination of
components or dietary supplements in
order to limit the burden to
manufacturers. However, we invited
comment on whether we should include
such requirements in a final rule. After
considering the comments, we have
drafted final § 111.15(a) to require you
to keep the grounds of your physical
plant in a condition that protects against
the contamination of components,
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dietary supplements, or contact
surfaces. The methods for adequate
ground maintenance include:
• Properly storing equipment,
removing litter and waste, and cutting
weeds or grass within the immediate
vicinity of the physical plant so that it
does not attract pests, harbor pests, or
provide pests a place for breeding;
• Maintaining roads, yards, and
parking lots so that they do not
constitute a source of contamination in
areas where components, dietary
supplements, or contact surfaces are
exposed;
• Adequately draining areas that may
contribute to the contamination of
components, dietary supplements, or
contact surfaces by seepage, filth or any
other extraneous materials, or by
providing a breeding place for pests;
• Adequately operating systems for
waste treatment and disposal so that
they do not constitute a source of
contamination in areas where
components, dietary supplements, or
contact surfaces are exposed; and
• If your plant grounds are bordered
by grounds not under your control, and
if those other grounds are not
maintained in the manner described in
this section, you must exercise care in
the plant by inspection, extermination,
or other means to exclude pests, dirt,
and filth or any other extraneous
material that may be a source of
contamination.
(Comment 85) Several comments say
the final rule should require the
maintenance of external areas similar to
the food CGMP requirement at
§ 110.20(a) for keeping the grounds
outside the facility adequately
maintained. These comments state that
such a requirement is basic, is equally
important to facilities that manufacture
conventional foods and to facilities that
manufacture dietary supplements, and
that there is no reason why this
requirement should differ from food
CGMPs. One comment asserts such a
requirement is basic to the industry and
it should not be dismissed as a burden
to the industry. Some comments also
assert that a provision similar to
§ 110.20(a) would help train staff and
would explain to plant maintenance
personnel what is required and why.
One comment says there should be
some minimum requirement for
sanitation and cleanliness in the area
surrounding the plant and that
requirements for drainage and trash
removal should be adequate.
(Response) We agree that a
requirement to maintain grounds is
equally important for facilities that
manufacture conventional foods and for
facilities that manufacture dietary
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34813
supplements. Although some
requirements in § 110.20(a) are not
strictly limited to drainage and trash
disposal, the comment suggesting the
requirements to maintain grounds be
limited to drainage and trash disposal
did not explain why, for example, it
would not be as important for a facility
that manufactures dietary supplements
to maintain roads, yards, and parking
lots so that they do not become a source
of contamination as it already is for
facilities that manufacture conventional
foods. Therefore, the final rule is adding
§ 111.15(a), which is similar to
§ 110.20(a) with editorial revisions
consistent with the rest of this final rule.
2. Final § 111.15(b)(1)
Final § 111.15(b)(1) (proposed
§ 111.15(a)) requires you to maintain
your physical plant in a clean and
sanitary condition. Final § 111.15(b)(2)
requires you to maintain your physical
plant in repair sufficient to prevent
components, dietary supplements, or
contact surfaces from becoming
contaminated.
We did not receive comments specific
to proposed § 111.15(a).
3. Final § 111.15(c)
Final § 111.15(c) (proposed
§ 111.15(b)) sets forth requirements for
cleaning compounds, sanitizing agents,
pesticides, and other toxic materials.
Final § 111.15(c) includes changes
that we are making for clarity and
consistency. We added other ‘‘toxic’’
materials because some paragraphs
within final § 111.15(c) simply refer to
the cleaning compounds, sanitizing
agents, and pesticides as ‘‘toxic
materials,’’ and because proposed
§ 111.15(b)(2) addressed the use and
storage of toxic materials that are not
within the general category of cleaning
compounds, sanitizing agents, or
pesticides.
Final § 111.15(c)(1) requires you to
use cleaning compounds and sanitizing
agents that are free from microorganisms
of public health significance and that
are safe and adequate under the
conditions of use. Final § 111.15(c)(1) is
similar to proposed § 111.15(b)(1),
except that we inserted ‘‘that are’’ before
‘‘safe and adequate.’’ We consider this
to be a nonsubstantive, editorial change.
Proposed § 111.15(b)(1) was, itself,
patterned after § 110.35(b)(1), which: (1)
Requires cleaning compounds and
sanitizing agents used in cleaning and
sanitizing procedures to be free from
undesirable microorganisms and safe
and adequate under the conditions of
use and (2) provides that compliance
may be verified by any effective means
including purchase of these substances
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under a supplier’s guarantee or
certification or examination of these
substances for contamination.
(Comment 86) Several comments ask
us to clarify our expectations with
respect to substantiating that a cleaning
compound or sanitizing agent is free
from microorganisms of public health
significance and is safe and adequate
under conditions of use. Some
comments suggest proposed
§ 111.15(b)(1) provide for the use of
certifications or guarantees from a
supplier because our investigators
otherwise may not recognize such
documents as evidence of compliance.
Several comments say it is not necessary
for a manufacturer to test these types of
products, and that a continuing product
guarantee, combined with a statement of
intended use from the manufacturer of
the cleaning compound or sanitizing
agent, should satisfy the requirements.
(Response) When assessing
compliance with final § 111.15(c)(1), we
would not treat a firm that
manufactures, packages, labels, or holds
a dietary supplement differently than
we would treat a facility that
manufactures, packages, labels, or holds
conventional foods. Therefore, we
intend to accept, as the comments
request, a supplier’s guarantee or
certification that a cleaning compound
or sanitizing agent is free from
microorganisms of public health
significance and is safe and adequate
under the conditions of use for the
purpose of determining compliance
with final § 111.15(c)(1).
Final § 111.15(c)(2) requires you to
not use or hold toxic materials in a
physical plant in which components,
dietary supplements, or contact surfaces
are manufactured or exposed, unless
those materials are necessary: (1) To
maintain clean and sanitary conditions,
(2) for use in laboratory testing
procedures, (3) for maintaining or
operating the physical plant or
equipment, or (4) for use in the plant’s
operations.
We did not receive comments specific
to proposed § 111.15(b)(2). We have
made a nonsubstantive edit to
§ 111.15(c)(2) by moving ‘‘contact
surfaces’’ to be the last item on the list.
Final § 111.15(c)(3) requires you to
identify and hold cleaning compounds,
sanitizing agents, pesticides, pesticide
chemicals, and other toxic materials in
a manner that protects against
contamination of components, dietary
supplements, or contact surfaces. Final
§ 111.15(c)(3) is similar to proposed
§ 111.15(b)(3).
We did not receive comments specific
to proposed § 111.15(b)(3), but replaced
‘‘toxic cleaning compounds’’ with
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‘‘cleaning compounds,’’ and added
‘‘other toxic materials.’’
4. Final § 111.15(d)
Final § 111.15(d) (proposed
§ 111.15(c)) sets forth requirements for
pest control. Section § 111.15(d) is
almost identical to proposed § 111.15(c).
Final § 111.15(d)(1) requires you to
not allow animals or pests in any area
of your physical plant. Final
§ 111.15(d)(1) allows guard or guide
dogs in some areas of your physical
plant if the presence of the dogs will not
result in contamination of components,
dietary supplements, or contact
surfaces. Final § 111.15(d)(2) requires
that you take effective measures to
exclude pests from your physical plant
and to protect against the contamination
of components, dietary supplements,
and contact surfaces on the premises by
pests. Final § 111.15(d)(3) requires that
you not use insecticides, fumigants,
fungicides, or rodenticides unless you
take precautions to protect against the
contamination of your components,
dietary supplements, or contact
surfaces.
(Comment 87) Several comments
claim proposed § 111.15(c) would
require that sealed equipment outside of
the plant (e.g. storage tanks, vessels,
piping) be enclosed to prevent pests
from roaming around these areas. The
comments say there is no need to shelter
outdoor equipment if it is properly
sealed. These comments state that
dietary supplements are sometimes
manufactured in extensive, highly
automated facilities in which large tanks
and vessels are interconnected via
piping, and that in these cases ‘‘the
physical plant’’ and ‘‘the equipment in
the plant’’ converge so that some or
much of the equipment is effectively
located outdoors. Thus, the comments
ask us to revise proposed § 111.15(c) to
clarify that it applies only to interior
areas of the physical plant.
(Response) Equipment such as that
described by the comments, if properly
sealed, should protect components,
dietary supplements, and contact
surfaces from contamination with pests.
Final § 111.15(d) does not require that
sealed equipment outside of the plant,
such as storage tanks, vessels, or piping,
be enclosed, e.g., inside a building.
Final § 111.15(d)(2) requires that you
take effective measures to exclude pests
from your physical plant and to protect
against the contamination of
components, dietary supplements, or
contact surfaces on the premises by
pests. Moreover, final § 111.15(a)
includes several requirements designed
to limit or exclude pests around all parts
of the exterior of your physical plant.
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Therefore, although you do not have to
enclose your outside equipment, you
must take measures to exclude pests
from areas outside of the plant.
5. Final § 111.15(e)
Final § 111.15(e) (proposed
§ 111.15(d)) sets forth requirements for
the water supply of your physical plant.
Final § 111.15(e)(1) requires that you
must provide water that is safe and
sanitary at suitable temperatures and
under pressure as needed for all uses
where water does not become a
component of the dietary supplement.
We did not receive comments specific
to proposed § 111.15(d)(1). We have
modified the phrase ‘‘safe and of
adequate sanitary quality’’ to read ‘‘safe
and sanitary.’’ To avoid confusion with
the definition of ‘‘quality’’ we have
adopted solely for purposes of this final
rule, we deleted the references to
‘‘quality’’ as it applies to water
standards. We consider this change to
be nonsubstantive and still require
water that is not a component of a
dietary supplement to meet a safe and
sanitary standard.
Final § 111.15(e)(2) requires that
water used in a manner such that the
water may become a component of the
dietary supplement, e.g., when such
water contacts components, dietary
supplements, or any contact surface,
must, at a minimum, comply with
applicable Federal, State, and local
requirements and not contaminate the
dietary supplement. Final § 111.15(e)(2)
derives from proposed § 111.15(d)(2)
which would require that water that
contacts components, dietary
supplements, or any contact surfaces
must, at a minimum, comply with the
applicable National Primary Drinking
Water (NPDW) regulations and any State
and local government requirements.
Final § 111.15(e)(2) includes changes we
are making after considering comments
discussed in the following paragraphs.
(Comment 88) Several comments state
the water quality that is required for
conventional foods is sufficient for
dietary supplements. The comments
argue that no additional water standards
are listed in the CGMPs for low-acid
canned foods in part 113 or in the
CGMPs for acidified foods in part 114.
These comments argue that, if ‘‘safe and
of adequate sanitary quality’’ is
sufficient to ensure the quality of the
water used in most food products, then
it is also adequate to ensure the quality
of the water used in dietary
supplements.
Other comments would revise the
final rule to allow different standards
and requirements for water that contacts
or is used in dietary supplements
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compared to water that contacts
components, including dietary
ingredients. These comments state
current food CGMP regulations require
only that water supplies that contact
food (defined to include ingredients and
raw materials) be ‘‘safe and of adequate
sanitary quality.’’ These comments say
that this would be consistent with the
act’s basis for CGMP requirements for
foods, i.e., that food is not prepared
‘‘under unsanitary conditions whereby
it may have become contaminated with
filth, or whereby it may have been
rendered injurious to health’’ (section
402(a)(4) of the act). Several comments
state the final rule should adopt a
similar rationale for components,
including dietary ingredients. These
comments explain that components,
including dietary ingredients, are not in
a form in which they will be consumed
and are subject to further processing
prior to consumption.
Several comments say that requiring
water used for cleaning contact surfaces
to meet Environmental Protection
Agency regulations is an unnecessary
burden for companies that do not have
access to municipal water. According to
these comments, potable water should
be sufficient.
(Response) In the preamble to the
2003 CGMP Proposal (68 FR 12157 at
12185), we stated that water should, at
a minimum, be potable and that water
that is ‘‘safe and of adequate sanitary
quality’’ should be potable. We also said
water that contacts components, dietary
supplements, or contact surfaces
should, at a minimum, meet the
Environmental Protection Agency’s
NPDW regulations and State, and local
requirements. We proposed to require
that water used in operations where
water contacts components, dietary
supplements, or any contact surfaces
meet the NPDW regulations because of
the potential for contamination if water
were used that did not adhere to the
microbial standards, for example, in the
NPDW regulations. Finally, we stated
these requirements were minimum
requirements and that water that is more
pure than that required under the
NPDW regulations may be desired.
The comments stated some
manufacturers may not have access to
municipal water, and therefore, that
meeting the NPDW regulations for
cleaning contact surfaces would be too
burdensome. These comments asserted
that potable water would be sufficient.
The comments do not provide a
definition of ‘‘potable water.’’ We have
defined ‘‘potable water,’’ in the
regulations on interstate conveyance
sanitation in 21 CFR part 1250 to be, in
part, water that meets the standards
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prescribed in the Environmental
Protection Agency’s NPDW regulations
in 40 CFR part 141.
We would consider it to be a rare
situation where a dietary supplement
manufacturer uses well water and has
no access to municipal water.
Nonetheless, to the extent that a
manufacturer uses water that is not
subject to Federal oversight, the
manufacturer would have to comply
with any State or local regulations that
apply to food manufacturing facilities
using such water in food processing.
Manufacturers that use water from a
municipal source, which is subject to
the Environmental Protection Agency
NPDW regulations, should not be
subject to a lesser standard in this final
rule than what is already required of
them by the Environmental Protection
Agency. Thus, to accommodate
manufacturers subject to the
Environmental Protection Agency’s
NPDW regulations for the water that
they use in the manufacture of dietary
supplements, as well as those dietary
supplement manufacturers who are not
subject to the Environmental Protection
Agency’s NPDW regulations, we are
modifying the rule to state water that is
used in a manner such that the water
may become a component of the dietary
supplement, e.g., when such water
contacts components, dietary
supplements, or any contact surface,
must, at a minimum, comply with
applicable Federal, State, and local
requirements and not contaminate the
dietary supplement. We decline to use
‘‘safe and of adequate safety’’ that some
comments state is sufficient because it
is for conventional foods. We believe
that requiring that water comply with
Federal, State and local requirements
and not contaminate dietary
supplements provides a clear standard
as to what is required.
(Comment 89) Some comments assert
that water that is used to manufacture
components or dietary ingredients
where such components or dietary
ingredients are subject to further
processing prior to consumption, should
be subject to the ‘‘safe and of adequate
sanitary quality’’ standard in § 110.37.
(Response) We acknowledge that such
components and dietary ingredients are
subject to the requirement in § 110.37. If
the manufacturers do not fall within the
scope of final § 111.1, such
manufacturers would be subject to the
CGMP requirements in part 110.
To the extent that such comments
request the ‘‘safe and of adequate
sanitary quality’’ language apply to
water used in the manufacture of a
dietary supplement, we decline to make
that change. Water that is safe and
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sanitary would not necessarily comply
with, for example, the NPDW
regulations. A requirement stating ‘‘safe
and of adequate sanitary quality’’ or, as
stated in the final rule, the requirement
of ‘‘safe and sanitary’’ could be seen as
a lesser standard than water that
complies with ‘‘applicable Federal,
State, and local requirements.’’ We want
to make clear that you must comply
with applicable Federal, State, and local
requirements related to the water that
you use for food processing that would
otherwise be required of you, and not to
some lesser standard that you may
consider is ‘‘safe and sanitary’’ when
water is used in a manner such that the
water may become a component of the
dietary supplement, e.g., when such
water contacts a component, dietary
supplement, or any contact surface.
Foreign manufacturers would need to
comply with the water standard
required in this final rule and achieve
the same level of performance as is
required of domestic manufacturers.
The water used in domestic or foreign
manufacturing must not contaminate
the dietary supplement. To clarify that
the water used, whether by a domestic
or foreign manufacturer, must not be a
source of contamination, we are adding
the words ‘‘and not contaminate the
dietary supplement’’ in final
§ 111.15(e)(2). We also want to make it
clear that water includes what is in the
water, e.g., any of its contaminants in
addition to H2O. For example, when we
speak of drinking water, we do not just
mean the H2O, we mean the iron, lead,
sulfur, and any other contaminants
contained in the water.
(Comment 90) Several comments
suggest water should meet some or all
standards of the USP monograph for
sterile, purified water and say that the
standard in the USP monograph is a
higher, and presumably safer, standard
than the NPDW standard. The
comments state the USP’s water
deionization and purification systems
requirements are already common in the
industry.
(Response) We do not discourage
firms from using water in dietary
supplement manufacturing that meets
USP standards, including deionized or
purified water, but we do not require, as
a CGMP, the use of USP standards. This
final rule sets forth minimum
requirements for persons who
manufacture, package, label, or hold a
dietary supplement. Thus, firms may
use water that exceeds our minimum
requirements.
(Comment 91) The preamble to the
2003 CGMP Proposal recognized that
foreign firms might not be subject to
Environmental Protection Agency water
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requirements or adhere to such
requirements, but also stated that water
quality is an important part of CGMP
(68 FR 12157 at 12185). Thus, in the
preamble to the 2003 CGMP Proposal,
we invited comment on how we might
ensure that foreign firms meet the same
water quality requirements as domestic
firms. Several comments respond to our
request for comments specific to the
applicability of the water standards to
foreign firms. Several comments
recommend we not distinguish between
domestic and foreign firms with regard
to water quality. The comments claim
all firms must compete on a ‘‘level
playing field.’’ These comments state
water quality standards vary from
country to country, and many countries
do not have requirements that are
comparable to those in the United
States. The comments say foreign
manufacturers should not be permitted
to import products into the United
States that do not meet the same safety
standards as domestic goods.
Other comments ask us to consider
the water quality requirement to be met
if the water complies with the NPDW
standard or any equivalent water quality
standard that is ensured by a foreign
public agency.
(Response) We agree that foreign firms
should be required to meet the water
safety and sanitary requirements
required of domestic firms and achieve
the same level of performance of
domestic firms. As discussed in this
section, foreign firms are required to
meet all requirements and would need
to comply with their own national or
local water safety requirements and not
contaminate the dietary supplement.
(Comment 92) One comment would
combine proposed § 111.15(d)(1) and
(d)(2) into a single paragraph. The
comment says the two proposed
paragraphs are redundant. Proposed
§ 111.15(d)(1) would require that you
provide water that is safe and of
adequate sanitary quality, at suitable
temperatures, and under pressure as
needed, in all areas where water is
necessary for: (1) Manufacturing dietary
ingredients or dietary supplements; (2)
making ice that comes in contact with
components, dietary ingredients, dietary
supplements, or contact surfaces; (3)
cleaning any surface; and (4) employee
bathrooms and hand-washing facilities.
Proposed § 111.15(d)(2) would require
that water that contacts components,
dietary ingredients, dietary
supplements, or any contact surface
must at a minimum comply with the
NPDW regulations prescribed by the
Environmental Protection Agency under
40 CFR part 141 and any State and local
government requirements.
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(Response) We disagree that proposed
§ 111.15(d)(1) and (d)(2) were
redundant. For example, as described in
the proposed sections, nonpotable water
that would have been ‘‘safe and of
adequate sanitary quality’’ for use in
flushing toilets may not have been ‘‘safe
and of adequate sanitary quality’’ for use
in the manufacture of a liquid dietary
supplement.
Final § 111.15(e)(1) requires that you
provide water that is safe and sanitary,
at suitable temperatures, and under
pressure as needed, for all uses where
water does not become a component of
the dietary supplement. Final
§ 111.15(e)(2) requires that water that is
used in a manner such that the water
may become a component of the dietary
supplement, e.g., when such water
contacts components, dietary
supplements, or any contact surface,
must, at a minimum, comply with
applicable Federal, State, and local
requirements and not contaminate the
dietary supplement. As an example of
how the requirements would apply,
water that contains lead at a level that
is 20 times higher than the maximum
accepted level in the Environmental
Protection Agency’s NPDW standards
for lead may not be safe for use in the
manufacture of dietary supplement that
is consumed in four 2-ounce portions
per day, but may be safe for use in
cleaning the floors of the physical plant.
Therefore, to emphasize that water that
is ‘‘safe and sanitary’’ may be different
depending on its use, the final rule
continues to separate § 111.15(e)(1) and
(e)(2) (formerly proposed § 111.15(d)(1)
and (d)(2)).
Additionally, to emphasize the
importance of the water that is used in
the manufacture of a dietary
supplement, where the water is used in
a manner such that the water may
become a component of the dietary
supplement, final § 111.23(c) (proposed
§ 111.15(d)(3)) requires you to have
documentation and keep records that
such water meets the requirements of
final § 111.15(e)(2). In contrast, there is
no corresponding requirement for
documentation in final § 111.23 that
other water, such as water that is used
to clean floors or used in employee
bathrooms, meets requirements of final
§ 111.15(e)(1).
(Comment 93) Several comments
state, if we retain a water standard
requirement based on the
Environmental Protection Agency
NPDW standard, then it is important to
include provisions recognizing the
acceptability of municipal water sources
and the frequency of testing required for
other water sources. Some comments
recommend water should meet the USP
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standard for purified water and point
out that the USP standard provides an
assurance of the water’s consistency and
provides a system that can be
monitored.
Several comments suggest we include
timetables for water testing or describe
water testing frequency requirements.
These comments state we should apply
something analogous to the proposed
requirements for infant formula which
would require manufacturers to conduct
the tests with sufficient frequency to
ensure that the water meets the
Environmental Protection Agency’s
NPDW standard, but not less frequently
than annually for chemical
contaminants, every 4 years for
radiological contaminants, and weekly
for bacteriological contaminants. Other
comments refer to the amendments to
the bottled water regulations at
§ 165.110 which require a minimum
yearly monitoring of source water and
finished bottled water products for
chemical contaminants for which
allowable levels have been established
in the bottled water quality standard.
(Response) Final § 111.23(c) requires
you to have documentation that water,
when used in a manner such that the
water may become a component of the
dietary supplement, e.g., when such
water contacts a component, dietary
supplement, or contact surface, meets
the requirements of final § 111.15(e)(2).
You must meet the requirement for final
§ 111.15(e)(2) at the point of use, rather
than at the point of delivery, i.e., at the
point the water may become a
component of the dietary supplement,
such as when the water contacts
components, dietary supplements, or
any contact surface (such as when the
water comes out of the faucet or comes
out of a spigot from a holding tank
where you store water). Thus, you must
ensure that the water used in a manner
such that the water may become a
component of the dietary supplement,
not the water source before it enters
your facility, meets the NPDW
regulations, or if not subject to the
NPDW regulations, that it meets any
other applicable Federal, State, and
local requirements and does not
contaminate the dietary supplement.
For example, if the water that enters
your facility is subject to the
Environmental Protection Agency
NPDW regulations, then the water must
comply with such requirements at the
point of use, i.e., when it contacts the
components, dietary supplement, or any
contact surface (such as when the water
comes out of the faucet or out of a spigot
from a holding tank where you store
water). You could rely on a certificate of
analysis under final § 111.75(a)(2)(ii)
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from the supplier of the water (e.g., the
municipality) to ensure that the water
entering your facility complies the
applicable Federal, State, and local
requirements. However, you must
ensure that nothing happens to the
water that may contaminate the water
once it enters your facility and before
the water may become a component of
the dietary supplement at the point of
use. Certain contaminants or
microorganisms may be introduced into
the water from the facility. Thus, you
may need to establish specifications and
procedures to prevent contamination
from pipes through which the water
travels in the facility or from vessels in
which the water is held in the facility
prior to use. You may need to test for
certain contaminants, e.g., lead or
microorganisms, at point of use to
ensure there is no contamination of the
water within your facility. Such tests
may not need to include all of the
chemical, microbiological, or
contaminant testing already certified by
the supplier to determine whether the
water entering your facility complies
with Federal, State and local
requirements. Rather, you would need
to evaluate what, if any, introductions of
contaminants are likely to occur within
your facility and determine whether
additional tests are needed to verify that
the water, at point of use, will comply
with Federal, State, and local
requirements and not contaminate the
dietary supplement. Alternatively, you
may decide not to rely on a certificate
of analysis and instead conduct your
own testing at point of use to determine
if the water complies with applicable
Federal, State, and local requirements.
We decline to set out testing
requirements or frequency of testing in
this final rule in lieu of giving
manufacturers the flexibility to decide
on the appropriate testing and frequency
of such testing to ensure that the water
meets the requirements in final
§ 111.15(e)(2). We may consider issuing
guidance, as needed, on our
recommendation for testing based on
water sources and the purposes for
which the water is used. If you rely on
a certificate of analysis from the
supplier of the water, we recommend
that you qualify your facility by
conducting appropriate tests at the point
of use to verify that no other tests are
necessary or that any additional tests
you have chosen are sufficient to
establish that the water that is used in
a manner such that the water may
become a component of the dietary
supplement, e.g., when such water
contacts components, dietary
supplements or any contact surface,
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meets the requirements of final
§ 111.15(e)(2). We also recommend that
you requalify your facility at the point
of use at appropriate intervals.
If you use water from a private source,
you must use water that complies with
any State and local requirement and
does not contaminate the dietary
supplement. You may need to perform
appropriate water treatment procedures,
including filtration, sedimentation, and
chlorination to satisfy final
§ 111.15(e)(2).
(Comment 94) Several comments
would delete proposed § 111.15(d)(2),
arguing that it is unnecessary to state a
requirement that water meet the
Environmental Protection Agency’s
NPDW standards. These comments state
that if water is used in processing or at
critical points in the cleaning process,
then a manufacturer will already have
established specifications for its
appropriate use.
(Response) We agree that a
manufacturer will need to establish
specifications, under final § 111.70(a),
for any point, step, or stage in the
manufacturing process where control is
necessary to ensure the quality of the
dietary supplement, and for water that
is used in a manner such that the water
may become a component of the dietary
supplement. For reasons set forth in
response to comment 88, final
§ 111.15(e)(2) establishes the minimum
standards for water that will be used in
a manner such that the water may
become a component the dietary
supplement, e.g., when such water
contacts components, dietary
supplements, or any contact surface.
Thus, we disagree that proposed
§ 111.15(e)(2) be eliminated.
6. Final § 111.15(f)
Final § 111.15(f) (proposed
§111.15(e)) sets forth requirements for
the plumbing of your physical plant.
Final § 111.15(f) requires your
plumbing to be of an adequate size and
design and be adequately installed and
maintained to: (1) Carry sufficient
amounts of water to required locations
throughout the physical plant; (2)
properly convey sewage and liquid
disposable waste from your physical
plant; (3) avoid being a source of
contamination to components, dietary
supplements, water supplies, or any
contact surface, or creating an
unsanitary condition; (4) provide
adequate floor drainage in all areas
where floors are subject to flooding-type
cleaning or where normal operations
release or discharge water or other
liquid waste on the floor; and (5) not
allow backflow from, or crossconnection between, piping systems
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34817
that discharge waste water or sewage
and piping systems that carry water
used for manufacturing dietary
supplements, for cleaning contact
surfaces, or for use in bathrooms and
hand-washing facilities.
We did not receive comments specific
to proposed § 111.15(e), other than
comments arguing that certain text was
unconstitutionally vague and arbitrary
and capricious. We address those
comments in section V of this
document.
7. Final § 111.15(g)
Final § 111.15(g) (proposed
§ 111.15(f)) sets forth requirements for
sewage disposal and requires you to
dispose of sewage into an adequate
sewage system or through other
adequate means.
We did not receive comments specific
to proposed § 111.15(f).
8. Final § 111.15(h)
Final § 111.15(h) (proposed
§ 111.15(g)(1)) sets forth requirements
for the bathrooms of your physical
plant. Final § 111.15(h) requires you to
provide your employees with adequate,
readily accessible bathrooms, and that
the bathrooms be kept clean and not be
a potential source of contamination to
your components, dietary supplements,
or contact surfaces.
(Comment 95) Several comments state
companies should be given flexibility in
designing their bathrooms. These
comments assert the food CGMP
requirements allow flexibility in
bathroom design, so the dietary
supplement CGMP rule should do the
same. The comments would delete
proposed § 111.15(g)(1) through (g)(3),
which pertained to: (1) Keeping the
bathrooms in good repair at all times; (2)
providing self-closing doors; and (3)
providing doors that do not open into
areas where components, dietary
ingredients, dietary supplements, or
contact surfaces are exposed to airborne
contamination, except where alternate
means have been taken to protect
against contamination.
(Response) We agree that it is
unnecessary to require specific
bathroom features such as those in
proposed § 111.15(g)(1) through (g)(3)
because you may be able to achieve
compliance through other means better
suited to your operations. Accordingly,
we are revising the rule by deleting
proposed § 111.15(g)(1) through (g)(3) as
requested by the comments. However,
we continue to believe that mechanisms
such as self-closing doors and doors that
do not open onto areas where
components, dietary supplements, or
contact surfaces are exposed to
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9. Final § 111.15(i)
Final § 111.15(i) (proposed § 111.5(h))
sets forth requirements for the handwashing facilities of your physical
plant. Final § 111.15(i) requires you to
provide hand-washing facilities that are
designed to ensure that an employee’s
hands are not a source of contamination
of components, dietary supplements, or
any contact surface, by providing
facilities that are adequate, convenient,
and furnish running water at a suitable
temperature.
Final § 111.15(i) differs from the
proposal in that the proposal would list
six specific features of a hand-washing
facility, such as effective hand-cleaning
and sanitizing preparations (proposed
§ 111.15(h)(2)), air driers, sanitary towel
service, or other suitable drying devices
(proposed § 111.15(h)(3)), and trash bins
that are constructed to protect against
recontamination (proposed
§ 111.15(h)(4)).
(Comment 96) Several comments state
we should give firms the flexibility to
design their hand-washing facilities.
According to these comments,
substituting the word ‘‘may’’ for the
word ‘‘must’’ would accomplish this.
The comments argue that, as with
bathrooms, an overall sanitation
requirement should be sufficient, and
that, as long as there is a strong and
enforceable standard, firms should have
the flexibility to adopt only those
measures that are needed to meet the
underlying requirement.
(Response) We agree that it is
unnecessary to require specific handwashing mechanisms because you may
be able to achieve compliance through
other means better suited to your
operations. However, we disagree that
an overall sanitation requirement would
be sufficient, because such a
requirement would not clearly state the
purpose of the requirement, which is to
ensure that an employee’s hands are not
a source of contamination of
components, dietary supplements, or
any contact surface.
We are revising proposed § 111.15(h)
(final § 111.15(i)) in the final rule in two
respects. First, the final rule states that
the hand-washing facilities are to be
designed to ensure that an employee’s
hands are not a source of contamination.
Second, final § 111.15(i) states that the
hand-washing facilities are to be
adequate, convenient, and furnish
running water at suitable temperatures
but does not provide the specific handwashing mechanisms detailed in the
2003 CGMP Proposal.
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10. Final § 111.15(j)
Final § 111.15(j) (proposed § 111.15(i))
sets forth requirements for trash
disposal at your physical plant. Final
§ 111.15(j) requires that you convey,
store, and dispose of trash to: (1)
Minimize the development of odors; (2)
minimize the potential for trash to
attract, harbor, or become a breeding
place for pests; (3) protect against
contamination of components, dietary
supplements, any contact surface, water
supplies, and grounds surrounding your
physical plant; and (4) control
hazardous waste to prevent
contamination of components, dietary
supplements, and contact surfaces.
(Comment 97) One comment suggests
deleting proposed § 111.15(i)(1)
concerning minimizing the
development of odors, because, the
comment claimed, minimizing odors is
not a ‘‘true’’ CGMP requirement.
(Response) We disagree that
minimizing the development of odors is
not part of CGMP. Odor from trash is
often an indication of problems with
microbial contamination, such as
decomposition, decay, and the growth
of harmful bacteria. In addition, odor
from trash can attract pests. By
conveying, storing, and disposing of
trash to minimize the development of
odors, you will help reduce the
potential for problems with microbial
contamination and pests.
11. Final § 111.15(k)
Final § 111.15(k) (proposed
§ 111.15(j)) sets forth requirements for
sanitation supervisors at your physical
plant. Final § 111.15(k) requires that you
assign one or more employees to
supervise overall sanitation. Each
supervisor must be qualified by
education, training, or experience to
develop and supervise sanitation
procedures. Final § 111.15(k) differs
from proposed § 111.15(j) in that the
proposal would require that each
supervisor be qualified by training and
experience.
(Comment 98) Several comments
suggest revising proposed § 111.15(j) to
state that sanitation supervisors may be
qualified by education, training, or
experience (or any combination thereof)
to develop and supervise sanitation
procedures. In contrast, several
comments say that sanitation
supervisors should be qualified by both
training and experience.
(Response) Consistent with our
response to comment 76 in section VII
of this document, final § 111.15(k)
provides that sanitation supervisors,
like other supervisors, must be qualified
by education, training, or experience to
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develop and supervise sanitation
procedures. As we also stated in
response to comment 76, we
acknowledge that some supervisory
personnel may need a different range of
education, training, or experience than
others. However, we have decided to
give firms the flexibility to decide the
appropriate amount of education,
training, or experience for a given job
function. If that includes a combination
of attributes, the firm should select and
train employees accordingly.
E. What Are the Requirements Under
This Subpart for Written Procedures?
(Final § 111.16)
We received many comments that
recommend written procedures for
various provisions. We address the need
for written procedures generally in
section IV of this document. We also
respond to comments on specific
provisions in the same section.
We are adding a new final § 111.16
entitled ‘‘What Are the Requirements
Under This Subpart for Written
Procedures?,’’ to require you to establish
and follow written procedures for
fulfilling certain requirements of
subpart C. You must establish and
follow written procedures for cleaning
the physical plant and for pest control.
F. What Design and Construction
Requirements Apply to Your Physical
Plant? (Final § 111.20)
Final § 111.20 addresses physical
plant design and construction
requirements.
1. Final § 111.20(a) and (b)
Final § 111.20(a) and (b) require that
any physical plant that you use in the
manufacturing, packaging, labeling, or
holding of dietary supplements: (1) Be
suitable in size, construction, and
design to facilitate maintenance,
cleaning, and sanitizing operations and
(2) have adequate space for the orderly
placement of equipment and holding of
materials as is necessary for
maintenance, cleaning, and sanitizing
operations and to prevent
contamination and mixups of
components and dietary supplements
during manufacturing, packaging,
labeling, or holding.
We did not receive comments specific
to proposed § 111.20(a) or (b), other than
comments arguing that certain text in
proposed § 111.20(b) was
unconstitutionally vague and arbitrary
and capricious. We address those
comments in this section and section V
of this document.
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2. Final § 111.20(c)
Final § 111.20(c) requires that any
physical plant you use in the
manufacturing, packaging, labeling, or
holding of dietary supplements provide
for the use of proper precautions to
reduce the potential for mixups or
contamination of components, dietary
supplements, or contact surfaces, with
microorganisms, chemicals, filth, or
other extraneous material.
Under final § 111.20(c) your physical
plant must have, and you must use,
separate or defined areas of adequate
size or other control systems, such as
computerized inventory controls or
automated systems of separation, to
prevent contamination and mixups of
components and dietary supplements
during the following operations: (1)
Receiving, identifying, holding, and
withholding from use, components,
dietary supplements, packaging, and
labels that will be used in or during the
manufacturing, packaging, labeling, or
holding of dietary supplements; (2)
separating, as necessary, components,
dietary supplements, packaging, and
labels that are to be used in
manufacturing from components,
dietary supplements, packaging, or
labels that are awaiting material review
and disposition decision, reprocessing,
or are awaiting disposal after rejection;
(3) separating the manufacturing,
packaging, labeling, and holding of
different product types including
different types of dietary supplements
and other foods, cosmetics, and
pharmaceutical products; (4) performing
laboratory analyses and holding
laboratory supplies and samples; (5)
cleaning and sanitizing contact surfaces;
(6) packaging and label operations; and
(7) holding components or dietary
supplements.
(Comment 99) Several comments
would change ‘‘computerized inventory
controls’’ to ‘‘adequate inventory
controls’’ in proposed § 111.20(c). The
comments say that a requirement to use
a computerized system is too
prescriptive and that inventory controls
that are not computerized may be
equally effective in achieving
compliance with proposed § 111.20(c).
(Response) These comments may have
misinterpreted proposed § 111.20(c).
Computerized inventory controls are an
example of the type of system that may
be appropriate; § 111.20(c) does not
require you to have a computerized
system in the first instance. Thus, final
§ 111.20(c) continues to use
computerized inventory controls as an
example of a central system.
(Comment 100) Several comments ask
us to clarify the degree of separation
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that is intended under proposed
§ 111.20(c) when it referred to ‘‘separate
or defined areas’’ of a physical plant.
These comments state that it is unclear
if we expect a firm not to manufacture
multiple products in a single room or
area. The comments state that, if this is
the case, this would be equivalent to the
drug CGMP requirements and would be
excessive. The comments argue that, if
the proper controls are in place,
manufacturing and packaging of
multiple products is possible in a single
room or area without compromising
product identity, quality, strength,
purity, and composition.
(Response) Final § 111.20(c) states
that you must have and use separate or
defined areas of adequate size or other
control systems, such as computerized
inventory controls or automated systems
of separation. The preamble of the 2003
CGMP Proposal explained that if your
physical plant does not allow for
physically separate areas, you could
develop an alternative approach for
segregating components and dietary
supplements at points when they are
received, stored, and rejected (68 FR
12157 at 12188). We interpret the
comments as asking whether alternative
approaches for segregating products
could be used, even if physically
separate areas were available in a
facility, so that different materials could
be processed in the same area. Final
§ 111.20(c) allows you to use ‘‘separate
or defined areas of adequate size or
other control systems;’’ thus, you can
comply with this requirement by
manufacturing multiple products in the
same room or area instead of using a
physically separate location, as long as
you have systems in place to prevent
contamination and mixups of
components and dietary supplements.
3. Final § 111.20(d)
Final § 111.20(d) requires that any
physical plant you use in the
manufacturing, packaging, labeling, or
holding of dietary supplements be
designed and constructed in a manner
that prevents contamination of
components, dietary supplements, or
contact surfaces.
Final § 111.20(d)(1) requires the
design and construction to include: (1)
Floors, walls, and ceilings that can be
adequately cleaned and kept clean and
in good repair; (2) fixtures, ducts, and
pipes that do not contaminate
components, dietary supplements, or
contact surfaces by dripping or other
leakage or condensate; (3) adequate
ventilation or environmental control
equipment, such as air flow systems,
including filters, fans, and other airblowing equipment, that minimize
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odors and vapors (including steam and
noxious fumes) in areas where they may
contaminate components, dietary
supplements, or contact surfaces; (4)
equipment that controls temperature
and humidity, when such equipment is
necessary to ensure the quality of the
dietary supplement; and (5) aisles or
working spaces between equipment and
walls that are adequately unobstructed
and of adequate width to permit all
persons to perform their duties and to
protect against contamination of
components, dietary supplements, or
contact surfaces with clothing or
personal contact.
Final § 111.20(d)(1)(i) through
(d)(1)(v) is similar to proposed
§ 111.20(d)(1), (d)(2), (d)(3), (d)(5), and
(d)(6), respectively. Additionally, as
explained in the following paragraphs,
we have made other changes to
proposed § 111.20(d)(1) (final
§ 111.20(d)(1)(i)) and proposed
§ 111.20(d)(5) (final § 111.20(d)(1)(iv)).
(Comment 101) Several comments
argue that the requirement of proposed
§ 111.20(d)(1) that floors, walls, and
ceilings be made of ‘‘smooth and hard
surfaces,’’ if read literally, could be
interpreted to prohibit the use of
ceilings with drop-in tiles. These
comments assert that, while there may
be areas in a manufacturing plant where
drop-in ceilings are inappropriate given
the height of the ceiling, the nature of
the product, or the type of operation
conducted in that area, such ceilings are
adequate in many areas of a
manufacturing facility, and certainly are
appropriate in places where product is
labeled or stored. The comments argue
that replacing such ceilings with
surfaces that are ‘‘smooth and hard’’ is
unnecessary. Several other comments
argue that they could find no precedent
in any food CGMP regulations for a
provision specifying ‘‘smooth and hard
surfaces’’ for ceilings, but did identify a
precedent in the section of drug CGMP
requirements relating to ‘‘aseptic
processing.’’ The comments state that
adopting such a drug CGMP
requirement is inappropriate for dietary
supplements.
The comments say the overall
purpose of proposed § 111.20(d)(1)
should be to ensure that facilities can be
kept in a clean and sanitary condition.
The comments would revise proposed
§ 111.20(d)(1) to require physical plants
to have surfaces that can be adequately
cleaned, but would give manufacturers
the flexibility to use appropriate
surfaces in different parts of a plant.
The comments also argue that the
rule’s specificity establishes a
conundrum for certain manufacturers to
conform to other Federal regulations,
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e.g., Occupational Safety and Health
Administration (OSHA) noise levels.
The comments argue that firms should
be allowed to simultaneously conform
to both OSHA and FDA requirements.
(Response) We agree that a smooth
and hard surface may not be necessary
in every case to prevent contamination
of the dietary supplement. However,
you may need floors, walls, and ceilings
that are constructed of smooth and hard
surfaces to prevent contamination of the
dietary supplement when, for example,
physical attributes of components (e.g.,
particle size or electrostatic charge)
would make it difficult to keep floors,
walls, and ceilings clean. Consequently,
we conclude that a requirement that the
physical plant have floors, walls, and
ceilings that can be adequately cleaned
and kept clean and in good repair to
prevent contamination of the dietary
supplement is sufficient. We are
revising final § 111.20(d)(1) to remove
the language concerning smooth and
hard surfaces. The final rule gives you
the flexibility to determine how best to
construct your facility in order to
prevent contamination and to ensure the
quality of the dietary supplements you
manufacture, package, label, or hold.
Section 111.20(d)(1)(ii) of the final
rule (proposed § 111.20(d)(2)) requires
your physical plant design and
construction to have fixtures, ducts, and
pipes that do not contaminate
components, dietary supplements, or
contact surfaces by dripping or other
leakage, or condensate. Final
§ 111.20(d)(1)(iii) (proposed
§ 111.20(d)(3)) pertains to adequate
ventilation or environmental control
equipment. We added ‘‘or other
leakage’’ to clarify that the requirement
relates to ‘‘leakage’’ regardless of
whether the leakage is in the form of
‘‘dripping.’’
(Comment 102) Proposed
§ 111.20(d)(5) would require your
physical plant design and construction
to include equipment that controls
temperature and humidity. Several
comments suggest adding a qualifier to
the temperature and humidity control
requirements so that controls are only
required as necessary to prevent
adulteration. The comments state there
is adequate evidence that temperature
and humidity do not stimulate
reproduction of microorganisms and
pests in dietary supplements. The
comments also argue that retesting older
ingredients stored in an uncontrolled
environment and subjected to heat,
cold, and ambient humidity produced
no evidence of reproduction of
microorganisms. According to the
comments, temperature and humidity
may present issues with raw,
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unprocessed botanical ingredients or
animal-derived ingredients, but there is
no proven issue with the powdered
botanical and animal derived
ingredients used by the dietary
supplement industry.
Several comments argue against
requiring temperature and heat controls,
asserting that most equipment used to
manufacture dietary supplements is
often cleaned with large amounts of hot
water, and therefore temperature and
humidity controls are not practical.
(Response) We agree that controls for
temperature and humidity should only
be required when necessary to ensure
the quality of the dietary supplement,
and we are revising final § 111.20(d)
accordingly. However, we disagree that
there is adequate evidence that
temperature and humidity do not
stimulate reproduction of
microorganisms in dietary supplements.
It is well-recognized that
microorganisms such as bacteria will
grow in a warm environment and that
microorganisms, such as molds, will
grow in a moist environment. In
addition, if the comments are suggesting
that this final rule should only include
requirements that derive from specific,
already known examples that the
absence of a requirement directly led to
a problem with a dietary supplement,
we disagree. CGMP requirements can
help prevent products from becoming
adulterated during the manufacturing
process, and, in certain cases,
controlling temperature and humidity
may be necessary to ensure the quality
of the dietary supplement.
With respect to the comments stating
that using hot water to clean equipment
makes control of temperature and
humidity impractical, we advise that a
firm unable to control temperature and
humidity in those parts of its facility
where control is necessary to ensure the
quality of the dietary supplement
because it uses hot water to clean
equipment would not be in compliance
with final § 111.20(c). The provision
requires that your physical plant have,
and that you use, separate and defined
areas of adequate size, or other control
systems, to prevent contamination
during operations such as cleaning
contact surfaces (final § 111.20(c)(5)).
Final § 111.20(d)(2) (proposed
§ 111.20(d)(4)) requires that, when fans
and other air-blowing equipment are
used, such fans and equipment be
located and operated in a manner that
minimizes the potential for
microorganisms and particulate matter
to contaminate components, dietary
supplements, or contact surfaces.
(Comment 103) Several comments
interpret proposed § 111.20(d)(4) as
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requiring fans and air-blowing
equipment. These comments state this
type of equipment is not always needed
and may, in some instances, be more
likely to cause adulteration than prevent
it. The comments ask us to clarify that
fans and other air-blowing equipment
are only required when they are
necessary to prevent adulteration.
(Response) Proposed § 111.20(d)(4)
was intended to require that any fans
and other air-blowing equipment you
use be located and operated in a manner
that minimizes the potential for
microorganisms and particulate matter
to contaminate components, dietary
supplements, or contact surfaces.
Nevertheless, given the comments’
misinterpretation, we are revising
proposed § 111.20(d)(4) (final
§ 111.20(d)(2)) to state that, ‘‘When fans
and other air-blowing equipment are
used,’’ those fans and equipment must
be located and operated in a manner
that minimizes the potential for
contamination by microorganisms and
particulate matter. This should clarify
that the rule does not mandate the use
of fans and air-blowing equipment.
(Comment 104) Some comments state
that exhaust and venting equipment
can, under certain circumstances, be a
source of microbial contamination. The
comments would revise proposed
§ 111.20(d)(4) to read: ‘‘Fans and other
air-blowing or exhaust and venting
equipment located and operated in a
manner that minimizes the potential for
microorganisms and particulate matter
to contaminate components, dietary
ingredients, dietary supplements, or
contact surfaces.’’
(Response) We decline to revise the
rule as suggested by these comments as
there is no need to do so. We consider
exhaust equipment and venting
equipment to be types of fans or airblowing equipment and therefore
covered by the term ‘‘fans and other airblowing equipment.’’
4. Final § 111.20(e)
Final § 111.20(e) (proposed
§ 111.20(e)) requires that any physical
plant that you use in the manufacturing,
packaging, labeling, or holding of
dietary supplements provide adequate
light in: (1) All areas where components
or dietary supplements are examined,
processed, or held; (2) all areas where
contact surfaces are cleaned; and (3)
hand-washing areas, dressing and locker
rooms, and bathrooms.
We did not receive any comments
specific to proposed § 111.20(e).
5. Final § 111.20(f)
Final § 111.20(f) (proposed
§ 111.20(f)) requires that any physical
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plant you use in the manufacturing,
packaging, labeling, or holding of
dietary supplements use safety-type
light bulbs, fixtures, skylights, or other
glass or glass-like materials when the
light bulbs, fixtures, skylights, or other
glass or glass-like materials are
suspended over exposed components or
dietary supplements in any step of
preparation, unless your physical plant
is otherwise constructed in a manner
that will protect against contamination
of components or dietary supplements
in case of breakage of glass or glass-like
materials.
We did not receive any comments
specific to proposed § 111.20(f). On our
own initiative, we are making clarifying
changes to final § 111.20(f) by:
• Adding ‘‘or glass-like materials’’
after the word ‘‘glass.’’ Although
proposed § 111.20(f) only specified
glass, its intent was to cover any
material that could shatter and
contaminate components, dietary
supplements, or contact surfaces.
Therefore, we are adding glass-like
material to final § 111.20(f) to cover
fixtures and skylights that use non-glass
materials (such as acrylic and
polycarbonate materials) but could still
contaminate components, dietary
supplements, or contact surfaces if
shattered or broken.
Further, we are stating that the
requirement applies when the light
bulbs, fixtures, skylights, or other glass
or glass-like materials are suspended
over exposed components or dietary
supplements in any step of preparation.
We made this change to prevent the rule
from being misinterpreted as requiring
firms to suspend light bulbs, fixtures,
skylights, or other glass over
components or dietary supplements in
every step of preparation.
6. Final § 111.20(g)
Final § 111.20(g) (proposed
§ 111.20(g)) requires that any physical
plant you use in the manufacturing,
packaging, labeling, or holding of
dietary supplements provide effective
protection against contamination of
components and dietary supplements in
bulk fermentation vessels. Such
protection includes: (1) Use of
protective coverings; (2) placement in
areas where you can eliminate
harborages for pests over and around the
vessels; (3) placement in areas where
you can check regularly for pests, pest
infestation, filth or any other extraneous
materials; and (4) use of skimming
equipment.
We did not receive comments specific
to proposed § 111.20(g). We have made
nonsubstantive, grammatical changes to
the provision by replacing ‘‘by any
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effective means’’ with ‘‘effective’’ before
the word protection and ‘‘including
consideration of’’ with ‘‘by, for
example:’’.
7. Final § 111.20(h)
Final § 111.20(h) (proposed
§ 111.20(h)) requires that any physical
plant you use in the manufacturing,
packaging, labeling, or holding of
dietary supplements use adequate
screening or other protection against
pests, where necessary.
(Comment 105) One comment argues
that proposed § 111.20(h) should be
deleted because it is redundant when
compared to proposed § 111.15(c) which
would require you to not allow animals
or pests in any area of your physical
plant, except for guard or guide dogs in
certain circumstances.
(Response) We disagree that final
§ 111.20(h) is redundant to proposed
§ 111.15(c) (final § 111.15(d)). Although
both paragraphs deal with pests, final
§ 111.20(h) establishes a design
requirement (i.e., a specific requirement
to use adequate screening or other
protection), while final § 111.15(d) sets
forth a sanitation requirement (i.e., to
not allow animals or pests in your
physical plant). Therefore, we are
retaining § 111.20(h) in the final rule.
G. Under This Subpart, What Records
Must You Make and Keep? (Final
§ 111.23)
Final § 111.23(a) requires you to make
and keep records required under this
subpart in accordance with subpart P.
Final § 111.23(b) requires that you
make and keep records of the written
procedures for cleaning the physical
plant and for pest control. This
provision was added to ensure that the
written procedures now required under
final § 111.16 are maintained as
required under subpart P.
Final § 111.23(c)(1) (proposed
§ 111.15(d)(3)) requires that you make
and keep records that water, when used
in a manner such that the water may
become a component of the dietary
supplement, meets the requirements of
final § 111.15(e)(2).
(Comment 106) Several comments
state there is no documentation
requirement for water in the food or
drug CGMPs. The comments, therefore,
say there should be not be such a
requirement in this final rule for dietary
supplements.
(Response) To the extent that the
comments assert we cannot include
such a requirement for documentation
in the dietary supplement CGMP
because there is no corollary
requirement in part 110, we have
responded to this issue in section V of
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34821
this document. The absence of a
provision in drug CGMP requirements
does not preclude us from requiring it
in this final rule establishing CGMP
requirements for dietary supplements
for which we have no pre-approval
scheme for ingredients used in such a
product.
(Comment 107) Several comments ask
us to clarify that, if a municipal water
supply is used in a facility, the
municipal water report is acceptable
documentation of water quality. These
comments say that a city’s yearly report
of its municipal water quality should be
sufficient documentation, and that
independent testing should not be
required. Several comments claim that
our officials made statements to this
effect during a public meeting held on
May 6, 2003.
The comments also assert that water
quality in a community is typically well
known due to public notification that is
required by the Environmental
Protection Agency or due to other
resources. These comments say that
municipal water supplies are also well
controlled as a result of Environmental
Protection Agency regulations, and that,
if water quality in a community or
country is suspect, we can move
aggressively to enforce the standards.
The comments argue that, overall, our
enforcement burden would be less than
requiring every company in the industry
to maintain and produce documentation
related to water quality.
(Response) A yearly municipal report
is a good starting point for documenting
water meets the requirements of final
§ 111.15(e), however, such a report
cannot stand on its own as the only
assurance that the water of the regulated
body (such as persons subject to this
final rule) complies with these
regulations. A municipal water report
offers reasonable assurance that the
water entering your plant satisfies the
requirements of the Environmental
Protection Agency’s NPDW regulations.
However, as discussed previously, the
requirement to show that the water that
is used in a manner such that the water
may become a component of the dietary
supplement, e.g., when such water
contacts components, dietary
supplements, or any contact surface,
meets the requirements of § 111.15(e)(2),
applies to water at the point of use, i.e.,
after it has passed through your
plumbing system.
If you use a municipal water supply,
you should take steps to ensure that you
are at all times aware of problems, such
as an acute problem with microbial
contamination or a long-term problem
associated with lead pipes that are
present in some parts of the city water
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supply, that may not be reflected in the
municipal water report.
IX. Comments on Requirements Related
to Equipment and Utensils (Subpart D)
A. Organization of Final Subpart D
Proposed subpart D contained two
provisions regarding equipment,
utensils, and automatic, mechanical, or
electronic equipment. Table 5 of this
document lists the sections in the final
rule and identifies the corresponding
sections in the 2003 CGMP Proposal
that form the basis of the final rule.
TABLE 5.—DERIVATION OF SECTIONS
IN SUBPART D
2003 CGMP
Proposal
Final Rule
§ 111.25 What are the
requirements under
this subpart D for written procedures?
§ 111.25(c)(1)
§ 111.25(e)(1)
§ 111.27 What requirements apply to the
equipment and utensils that you use?
§ 111.25(a), (b),
(d), and (e)
§ 111.30 What requirements apply to automated, mechanical, or
electronic equipment?
§ 111.30
§ 111.35 Under this subpart D, what records
must you make and
keep?
§§ 111.25(c)(1),
(c)(2), (d),
and (f),
§ 111.30(b)(2),
(b)(5), and (c)
§ 111.50(c)(4)
B. Highlights of Changes to the
Proposed Requirements for Equipment
and Utensils
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1. Revisions
The final rule includes revisions that
reflect the final rule applies to persons
who manufacture, package, label, or
hold dietary supplements unless subject
to an exclusion in § 111.1.
2. Revisions Associated With the
Reorganization
The revisions associated with the
reorganization include:
• Renumbering proposed § 111.25 as
final § 111.27 and correcting the
numbering of the sections misnumbered
in the 2003 CGMP Proposal;
• Requiring documentation and
backup files in a separate section for
recordkeeping requirements; and
• A nonsubstantive editorial change
to refer to ‘‘automated equipment’’
rather than ‘‘automatic equipment.’’
Although there is no practical difference
between these two terms, the term
‘‘automated’’ is the customary term.
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3. Changes After Considering Comments
The final rule:
• Requires you to establish and
follow written procedures to fulfill the
requirements of subpart D, including
written procedures for:
Æ Calibrating instruments and
controls;
Æ Calibrating, inspecting, and
checking automated, mechanical,
and electronic equipment; and
Æ Maintaining, cleaning, and
sanitizing, as necessary, equipment,
utensils, and other contact surfaces;
• Requires you to keep records of the
maintenance, cleaning, and sanitizing of
equipment either in equipment logs or
in batch records;
• Requires that quality control
personnel periodically review records of
calibrations, inspections, or checks of
automated, mechanical, or electronic
equipment rather than approve such
records when they are made;
• Specifies that software for a
computer controlled process is included
under automated, mechanical, or
electronic equipment; and
• Clarifies that the requirement to
retain backup files of software programs
and of data entered into computer
systems is for computer systems that
you use in the manufacture, packaging,
labeling, or holding of dietary
supplements.
C. General Comments on Proposed
Subpart D
(Comment 108) Some comments
claim one or more proposed
requirements are unconstitutionally
vague under the Fifth Amendment and
arbitrary and capricious under
§ 706(2)(B) of the APA. These proposed
requirements include:
• § 111.25(a)(1), which would require
that equipment and utensils be ‘‘of
appropriate design, construction, and
workmanship to enable them to be
suitable for their intended use and to be
adequately cleaned and properly
maintained’’; and
• § 111.25(a)(2), which would require
you to ‘‘use equipment and utensils of
appropriate design and construction so
that use will not result in the
contamination of components, dietary
ingredients, or dietary supplements.’’
In general, these comments assert the
proposed sections did not define terms
or phrases (such as ‘‘suitable’’ or
‘‘appropriate design’’) in a way that
persons who are subject to the rule can
discern the meaning of the term. These
comments also assert the proposed
sections do not limit enforcement
officers’ exercise of their discretion as to
what will satisfy the requirements and,
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thus, invite exercise of unbridled
discretion and disparate
decisionmaking.
(Response) As discussed in section V
of this document, we disagree that the
terms are unconstitutionally vague,
need to be defined, may result in
discriminatory enforcement, or violate
the APA. There has been sufficient
usage of these terms in the food industry
to enable manufacturers, and those who
enforce the requirements, to
comprehend and apply such terms.
Agencies are permitted to use qualifying
terms to enable them to address a wide
variety of conditions at companies.
D. What Are the Requirements Under
This Subpart for Written Procedures?
(Final § 111.25)
We received many comments that
recommend written procedures for
various provisions. We address the need
for written procedures generally in
section IV of this document. We also
respond to comments on specific
provisions in the same section. We are
adding final § 111.25 that requires you
to establish and follow written
procedures for certain requirements.
E. What Requirements Apply to the
Equipment and Utensils That You Use?
(Final § 111.27)
Final § 111.27 (proposed § 111.25)
sets forth various requirements for
equipment and utensils.
1. Final § 111.27(a)
a. Final § 111.27(a). Final § 111.27(a)
(proposed § 111.25(a)(1)) requires you to
use equipment and utensils that are of
appropriate design, construction, and
workmanship to enable them to be
suitable for their intended use and to be
adequately cleaned and properly
maintained. In order to correct the
misnumbering of this provision in the
2003 CGMP Proposal, this general
requirement has been broken out from
the remaining requirements of final
§ 111.27(a).
Final § 111.27(a)(1)(i) through (a)(1)(v)
provide examples of such equipment,
such as equipment used to hold or
convey (§ 111.27(a)(1)(i)), equipment
using compressed air or gas
(§ 111.27(a)(1)(iii)), and equipment used
in automated, mechanical, or electronic
systems (§ 111.27(a)(1)(v)).
Final § 111.27(a)(1) is similar to
proposed § 111.25(a)(1) except for two,
nonsubstantive editorial changes. The
first change replaces ‘‘automatic
equipment’’ with ‘‘automated
equipment’’ in what is now
§ 111.27(a)(1)(v) (proposed
§ 111.25(a)(1)(5)). Although there is no
practical difference between
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‘‘automatic’’ and ‘‘automated,’’ the latter
is the customary term.
(Comment 109) Some comments argue
that the proposal’s use of terms such as
‘‘appropriate design, construction, and
workmanship to enable them to be
suitable for their intended use’’ and
‘‘adequately cleaned and properly
maintained’’ are unconstitutionally
vague under the Fifth Amendment and
arbitrary and capricious under the APA.
(Response) We discuss those
comments generally in section V of this
document and, because we disagree that
the final rule violates either the Fifth
Amendment of the Constitution or the
APA, we have not revised § 111.27(a)(1)
except for the changes mentioned in the
previous paragraphs.
b. Final § 111.27(a)(2). Final
§ 111.27(a)(2) (proposed § 111.25(a)(2))
requires you to use equipment and
utensils of appropriate design and
construction so that use will not result
in the contamination of components or
dietary supplements with: (1)
Lubricants, (2) fuel, (3) coolants, (4)
metal or glass fragments, (5) filth or any
other extraneous material, (6)
contaminated water, or (7) any other
contaminants.
(Comment 110) Several comments
state we should recognize that
lubricants are an integral part of the
encapsulation of gelatin-enrobed
products and other dosage forms. These
comments state lubricants are not
potential contaminants, and in fact, help
move gelatin ribbons through
encapsulating machines. The comments
would revise proposed § 111.25(a)(2) to
read, ‘‘lubricants not intended for
product contact,’’ to clarify the rule’s
intent.
(Response) We decline to revise the
final rule as suggested by the comments.
Final § 111.27(a)(2) states that the use of
equipment and utensils must not result
in the contamination of components or
dietary supplements with lubricants. If
a lubricant used for encapsulation does
not result in contamination of the
components or dietary supplements
then the encapsulating machine
complies with final § 111.27(a)(2).
c. Final § 111.27(a)(3). Final
§ 111.27(a)(3) (proposed § 111.25(a)(3))
requires all equipment and utensils you
use to be: (1) Installed and maintained
to facilitate cleaning the equipment,
utensils, and all adjacent spaces; (2)
corrosion-resistant if the equipment or
utensils contact components or dietary
supplements; (3) made of nontoxic
materials; (4) designed and constructed
to withstand the environment in which
they are used, the action of components
or dietary supplements, and, if
applicable, cleaning compounds and
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sanitizing agents; and (5) maintained to
protect components and dietary
supplements from being contaminated
by any source.
We did not receive comments specific
to proposed § 111.25(a)(3). We have
substituted the phrase ‘‘in which they
are used’’ for ‘‘of their intended use’’ to
make clear the requirement applies to
equipment actually used in the
manufacture, packaging, labeling, or
holding of dietary supplements.
d. Final § 111.27(a)(4). Final
§ 111.27(a)(4) (proposed § 111.25(a)(4))
requires that the equipment and utensils
you use have seams that are smoothly
bonded or maintained to minimize
accumulation of dirt, filth, organic
material, particles of components or
dietary supplements, or any other
extraneous materials or contaminants.
Final § 111.27(a)(4) is similar to
proposed § 111.25(a)(4) and is analogous
to § 110.40(b) which requires that seams
on food-contact surfaces be smoothly
bonded or maintained so as to minimize
accumulation of food particles, dirt, and
organic matter and thus minimize the
opportunity for growth of
microorganisms. We have deleted the
phrase ‘‘to minimize the opportunity for
growth of microorganisms’’ as
unnecessary in this context as the
remaining wording of the provision
encompasses this concept. In
nonsubstantive editorial changes to final
§ 111.27(a)(4) we substitute ‘‘particles of
components or dietary supplements’’ for
‘‘component or dietary supplement
particles’’ to improve clarity, and reorder the list of extraneous materials or
contaminants.
(Comment 111) Several comments
argue that proposed § 111.25(a)(4) is
overly restrictive by requiring
equipment and utensils to ‘‘have seams
that are smoothly bonded or
maintained’’ to minimize
contamination. The comments would
revise the rule as follows: ‘‘Equipment
and utensils you use must be of proper
design and maintained to minimize
accumulation * * *.’’
(Response) We disagree that proposed
§ 111.25(a)(4) (final § 111.27(a)(4)) is
overly restrictive or that it requires a
particular design. Final § 111.27(a)(4)
requires seams that are smoothly
bonded or maintained to minimize
accumulation of dirt and gives firms the
flexibility to use any design they
choose, provided that the seams, by
design or maintenance, minimize
accumulation of contaminants.
e. Final § 111.27(a)(5). Final
§ 111.27(a)(5) (proposed § 111.27(a)(5))
requires that each freezer, refrigerator,
and other cold storage compartment you
use to hold components or dietary
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supplements: (1) Be fitted with an
indicating thermometer, temperaturemeasuring device, or temperaturerecording device that indicates, and
records, or allows for recording by hand,
the temperature accurately within the
compartment and (2) have an automated
device for regulating temperature or an
automated alarm system to indicate a
significant temperature change in a
manual operation.
(Comment 112) The preamble to the
2003 CGMP Proposal invited comment
as to whether we should require specific
target temperatures for dietary
ingredients or dietary supplements held
in freezers or cold storage (68 FR 12157
at 12190). Several comments assert there
is no need for us to specify storage
temperatures for dietary ingredients or
dietary supplements. The comments
state most dietary supplements and
dietary ingredients are shelf stable based
on their low water activity control,
which limits and slows chemical
degradation and microbiological growth.
Other comments say target temperatures
are not required where freezing is used
only to enhance the milling properties
(fracturing) of dried botanicals and not
to prevent microbial contamination.
(Response) We have not included any
specific target temperature requirements
in the final rule. Consequently, firms
should determine for themselves what
temperatures are needed to ensure that
the their dietary supplements are not
adulterated (see final § 111.70 regarding
the specifications you must establish).
f. Final § 111.27(a)(6). Final
§ 111.27(a)(6) (proposed § 111.25(a)(6))
requires the instruments or controls you
use in the manufacturing, packaging,
labeling, or holding of a dietary
supplement, and instruments or
controls that you use to measure,
regulate, or record temperatures, pH, aw,
or other conditions, to control or
prevent the growth of microorganisms
or other contamination, be accurate and
precise, adequately maintained, and
adequate in number for their designated
uses.
(Comment 113) One comment states
that proposed § 111.25(a)(6)(i)’s
requirements that instruments and
controls be ‘‘accurate and precise’’ goes
beyond ‘‘typical’’ calibration, and would
require full validation of all instruments
and controls. The comment argues that
it is unnecessary to require both
accuracy and precision for all
instruments and controls, and would
require precision only when necessary
to prevent contamination. The comment
states calibration to ensure accuracy of
instruments and controls is usually
sufficient to ensure control or
prevention of the growth of
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microorganisms or other contaminants
in most situations. The comment gives
an example where thermometers are
used to monitor temperature in a
warehouse where dietary supplements
are stored.
(Response) We disagree that proposed
§ 111.27(a)(6) requires full validation of
all equipment and controls. As
discussed in the preamble to the 2003
CGMP Proposal (68 FR 12157 at 12190),
accuracy means that the recorded
measurements are equal to the (true
value) of the thing being measured and
precision means that individual
measurements should be close to each
other when made under the same
conditions.
We also disagree that instruments
need not be precise. An instrument that
gives widely varying readings from one
use to the next cannot ensure product
quality over time. The degree of
accuracy and precision is determined by
the nature of the instrument or control
and the process to which it relates. We
have, however, made several
nonsubstantive, editorial changes to
§ 111.27(a)(6) as well as other edits to
conform to changes made throughout
the final rule. These are the
nonsubstantive editorial changes:
• Inserting a hyphen between
‘‘hydrogen’’ and ‘‘ion’’ and
• Revising the end of the paragraph
so that it discusses ‘‘instruments and
controls that you use * * * to control
or prevent the growth of
microorganisms or other contamination
* * *.’’ The proposal stated
‘‘instruments and controls that you use
* * * that control or prevent the growth
of microorganisms or other
contamination * * *’’. (In other words,
the final rule replaces ‘‘that’’ with ‘‘to’’.)
g. Final § 111.27(a)(7). Final
§ 111.27(a)(7) (proposed § 111.25(a)(7))
requires that the compressed air or other
gases you introduce mechanically into
or onto a component, dietary
supplement, or contact surface or you
use to clean any contact surface be
treated in such a way that the
component, dietary supplement, or
contact surface is not contaminated.
We received no comments specific to
proposed § 111.25(a)(7).
2. Final § 111.27(b)
Final § 111.27(b) (proposed
§ 111.25(b)(1)) requires you to calibrate
instruments and controls that you use in
manufacturing or testing a component
or dietary supplement. In order to
correct the misnumbering of this
provision in the 2003 CGMP Proposal,
this general requirement has been
broken out from the remaining
requirements of final § 111.27(b) and
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now has paragraphs (b) and (b)(1)
through (b)(3).
Final § 111.27(b)(1) through (b)(3)
(proposed § 111.25(b)(1) and (b)(2))
requires you to calibrate before first use,
and at the frequency specified in writing
by the manufacturer of the instrument
or control, or at routine intervals, or as
otherwise necessary to ensure the
accuracy and precision of the
instrument and control.
(Comment 114) Several comments
object to the level of detail regarding the
proposed calibration. Specifically, the
comments object to requiring that
manufacturers calibrate instruments and
controls ‘‘as specified in writing by the
manufacturer of the instrument and
control.’’ The comments say this
requirement is more prescriptive than
drug CGMP requirements. The
comments acknowledge that following
manufacturer specifications is likely to
be part of the calibration procedure, but
state that firms should have the
flexibility to modify their procedures as
necessary. These comments would
couple proposed § 111.25(b) with a
requirement to establish and follow
written procedures for calibrating
instruments and controls and redraft
proposed § 111.25(b) to mirror the drug
CGMP requirements, using language
such as ‘‘You must routinely calibrate
instruments and controls that control or
monitor critical parameters that you use
in manufacturing or testing a
component or dietary supplement.’’
(Response) We disagree that proposed
§ 111.25(b) is overly prescriptive,
exceeds drug CGMP requirements, or
requires what is claimed by the
comments. We discuss, generally, the
issue of whether this final rule ‘‘exceeds
drug CGMPs’’ in section V of this
document. It is standard practice to
calibrate an instrument before using it
for the first time. A requirement that
you calibrate as specified by the
manufacturer of the equipment, or at
routine intervals, or as otherwise
necessary to ensure the accuracy and
precision of the instrument and control,
provides ample flexibility. Calibration,
whether for instruments and controls
used in manufacturing or testing drugs,
devices, conventional foods, or dietary
supplements, helps ensure the accuracy
and precision of the instrument and
control. We do not prescribe how
frequently such calibration must be
done, but it must be done often enough
to ensure that instruments and controls
are operating within the correct
parameters. We are revising the 2003
CGMP Proposal (at § 111.27(b)(2)) to
clarify that the requirement relates to
the frequency of calibration.
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(Comment 115) Several comments
claim requirements relating to
calibration of instruments and controls
should be limited to those instruments
and controls that directly affect the
identity, purity, quality, strength, and
composition of a dietary supplement.
According to the comments, in most
manufacturing facilities, there are many
instruments and controls that do not
directly affect identity, purity, quality,
strength, and composition, and that
calibrating all instruments and controls
could easily become unduly
burdensome. The comments also would
limit the requirement for periodic
calibration of instruments and controls
to those instruments and controls
directly involved in the critical control
parameters of the process, i.e., those
parameters needed to meet
specifications or to ensure identity,
purity, quality, strength, and
composition. The comments suggest
that critical control parameters would
have to be established.
(Response) We decline to revise the
rule as suggested by the comments. The
requirement to calibrate instruments
and controls is limited to those
instruments and controls that you use in
testing a component or dietary
supplement or in manufacturing a
dietary supplement. Any such
equipment has the potential to affect,
directly or indirectly, the quality of the
dietary supplement.
(Comment 116) Some comments
would revise proposed § 111.25(b)(1) to
state that ‘‘calibration should be done,
where standards are available or where
it is necessary to meet product
specifications.’’
(Response) We decline to revise the
rule as suggested by the comments. It
would be customary for an equipment
manufacturer to have standards that can
be used to calibrate the equipment,
irrespective of the specific composition
of the dietary supplement that is
manufactured using that equipment.
Equipment that is not or cannot be
calibrated is unlikely to be in
compliance with the requirement of
final § 111.27(a)(6)(i) which requires
instruments used in the manufacturing,
packaging, labeling, and holding of
dietary supplements, and instruments
and controls that you use to perform
certain operations, be accurate and
precise.
(Comment 117) Some comments
would revise proposed § 111.25 from
the active voice to the passive voice.
These comments claim that the active
voice—i.e., requiring that ‘‘you’’
calibrate instruments and controls—
requires that the dietary supplement
manufacturer perform the calibration,
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when in fact such calibrations are often
performed by an outside service.
(Response) You may use an outside
service. We would not consider that
calibration done for you by an outside
service is any different than calibration
done by your employees, and it is you
(rather than an outside service) whom
we will hold responsible to ensure that
the calibration is performed.
Accordingly, we decline to revise the
provisions as suggested.
(Comment 118) Several comments say
calibration before first use should not be
required for certified, precalibrated
instrumentation. The comments state
precalibrated instrumentation is much
more expensive than noncalibrated
instrumentation, with the additional
expense attributed to the precalibration.
Several comments would revise
proposed § 111.25(b)(2) to read, ‘‘you
must calibrate, or be able to verify that
the calibration has been completed,
before first use,’’ instead of ‘‘you must
calibrate before first use.’’ The
comments state that performance test
results could be made available for this
verification.
(Response) As written, the
requirement that equipment be
calibrated before first use includes
calibration performed by a third party as
a precalibration because we would
consider that calibration performed by a
third party as no different from
calibration performed by one of your
own employees. Under final
§ 111.35(b)(3) you must have
documentation of the calibration.
If you purchase a precalibrated
instrument, we strongly recommend
that the vendor conduct the certification
onsite after installation. If not, we
strongly recommend that you verify that
the instrument remains calibrated after
it has been installed.
(Comment 119) Several comments ask
whether the proposed requirement to
calibrate ‘‘before first use’’ refers to the
first use after installation or the first use
after each start-up.
(Response) Final § 111.27(b)(1) refers
to the first use after installation and
does not require calibration after each
start-up.
(Comment 120) Some comments
would require that instruments and
controls be calibrated, but argue that the
final rule should not include detailed
procedures specifying calibration
methods. The comments said the rule
should stay focused on end results and
not process.
(Response) We disagree that the
regulations should not focus on process.
The essence of the CGMP requirements
established by these regulations is a
production and process control system,
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i.e., a process, that is designed to ensure
the quality of the dietary supplement.
The final rule gives firms the flexibility
to use different calibration methods as
long as the method used is established
in a written procedure.
3. Final § 111.27(c)
Final § 111.27(c) (proposed
§ 111.25(d)) requires that you repair or
replace instruments or controls that
cannot be adjusted to agree with the
reference standard.
We received no comments specific to
proposed § 111.25(d).
4. Final § 111.27(d)
Final § 111.27(d) (proposed
§ 111.25(e)) requires you to maintain,
clean, and sanitize, as necessary, all
equipment, utensils, and any other
contact surfaces used to manufacture,
package, label, or hold components or
dietary supplements. In order to correct
the misnumbering of this provision in
the 2003 CGMP Proposal, this general
requirement has been broken out from
the remaining requirements of final
§ 111.27(d) and now has paragraphs (d)
and (d)(1) through (d)(7).
a. Final § 111.27(d)(1). Final
§ 111.27(d)(1) requires that the
equipment and utensils be taken apart
as necessary for thorough maintenance,
cleaning, and sanitizing.
(Comment 121) Some comments argue
that individual manufacturing
operations will determine when
sanitizing agents are needed after
cleaning because of the wide variety of
processes in the industry. The
comments also say widespread use of
sanitizing agents is creating resistant
microbial strains, and incorporating
unnecessary sanitization processes
would contribute to this health concern.
Some comments recommend
manufacturers calibrate sanitizing
procedures to the particular process in
a declared fashion depending upon the
risk factors of their process and
materials. The comments set out several
standards for sanitation procedures.
(Response) Final § 111.27(d) requires
you to maintain, clean, and sanitize, as
necessary, equipment, utensils, and any
other contact surfaces, used to
manufacture, package, label, or hold
dietary supplements. The final rule thus
gives you discretion to decide when
sanitizers or sanitizing treatments, such
as heat, are necessary and does not
mandate the incorporation of
unnecessary sanitization processes.
Additionally, under final § 111.27(d)
you have flexibility to determine when
sanitizing is appropriate and to sanitize
only as necessary. We note that this
flexibility was also present in proposed
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§ 111.25(e)(1). Some comments
suggested calibrating sanitation
operations based on risk. The final rule
largely leaves it up to firms to decide
whether to sanitize or to just clean
without sanitizing, based on the risks
associated with the materials and
process used. However, under final
§ 111.27(d)(3), if you use wet
processing, if you determine that it is
necessary to clean a contact surface, you
must also sanitize that surface.
(Comment 122) Several comments
state the final rule should include a
requirement for validating cleaning
procedures. The comments argue that
testing requirements for finished dietary
supplements might not test for certain
contaminants that could arise as a result
of cleaning. One comment asserts these
potential contaminants would be
discovered in a properly designed and
executed cleaning validation protocol,
and that including these written
cleaning procedures in the final rule
would help prevent adulteration and
help ensure the identity, purity, quality,
strength, and composition of dietary
supplements.
(Response) We decline to require
specific cleaning validation procedures
in the final rule. Final § 111.27(d) and
the requirements for written procedures
under final § 111.25(c) are sufficient to
ensure the use of cleaning procedures to
ensure the quality of the dietary
supplement.
b. Final § 111.27(d)(2). Final
§ 111.27(d)(2) (proposed § 111.25(e)(2))
requires you to ensure that all contact
surfaces, used for manufacturing or
holding low-moisture components or
dietary supplements, are in a dry and
sanitary condition when in use. When
the surfaces are wet-cleaned, you must
sanitize them, when necessary, and
allow them to dry thoroughly before you
use them again.
We received no comments specific to
proposed § 111.25(e)(2). We have
substituted the phrase ‘‘when in use’’
for ‘‘at the time of use’’ for clarity.
c. Final § 111.27(d)(3). Final
§ 111.27(d)(3) (proposed § 111.25(e)(3))
requires you, if you use wet processing
during manufacturing, to clean and
sanitize all contact surfaces, as
necessary, to protect against the
introduction of microorganisms into
components or dietary supplements.
Final § 111.27(d)(3) also requires that:
• When cleaning and sanitizing is
necessary, you clean and sanitize all
contact surfaces before use and after any
interruption during which the contact
surface may become contaminated and
• If you use contact surfaces in a
continuous production operation or in
consecutive operations involving
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different batches of the same dietary
supplement, you must adequately clean
and sanitize the contact surfaces, as
necessary. In this provision, we
substituted ‘‘consecutive’’ for ‘‘back-toback,’’ a nonsubstantive change. We also
inserted ‘‘adequately’’ to make clear that
cleaning and sanitizing must be
adequate.
(Comment 123) Several comments
argue against using the term ‘‘sanitize’’
in proposed § 111.25(e)(3). The
comments state that, based on the
proposed definition of ‘‘sanitize,’’
§ 111.25(e)(3) would require evaluation
of any sanitation steps to ensure that the
level of log reduction is reached, for
example, by taking ‘‘before and after’’
swab samples. The comments would
revise proposed § 111.25(e)(3) to state
that equipment, utensils, etc. shall be
cleaned and sanitized in a manner that
keeps microorganisms and other
adulterants from contaminating all
components, ingredients, in-process
materials, and finished goods.
(Response) The final rule now defines
‘‘sanitize’’ as ‘‘to adequately treat
cleaned equipment, containers, utensils,
or any other cleaned product contact
surface by a process that is effective in
destroying vegetative cells of
microorganisms of public health
significance, and in substantially
reducing numbers of other
microorganisms, but without adversely
affecting the product or its safety for the
consumer.’’ The definition no longer
specifies a level of log reduction, so the
revised definition should eliminate the
comments’ concern as to any possible
need for ‘‘before and after’’ samples.
d. Final § 111.27(d)(4). Final
§ 111.27(d)(4) (proposed § 111.25(e)(4))
requires you to clean surfaces that do
not come into direct contact with
components or dietary supplements as
frequently as necessary to protect
against contamination. Final
§ 111.27(d)(4) relates to final
§ 111.27(d)(2) and (d)(3). For example,
you would not have to clean your
ceilings as often as you clean your
contact surfaces because your ceilings
normally do not touch components or
dietary supplements. However, you
would have to clean your ceilings as
frequently as necessary to prevent dust
or other contaminants from falling onto
your components, dietary supplements,
and contact surfaces.
We received no comments specific to
proposed § 111.25(e)(4). We substituted
‘‘do not come into direct contact with’’
for ‘‘do not touch’’ as a nonsubstantive
editorial revision.
e. Final § 111.27(d)(5). Final
§ 111.27(d)(5) (proposed § 111.25(e)(5))
requires that single-service articles
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(such as utensils intended for one-time
use, paper cups, and paper towels) be:
(1) Stored in appropriate containers and
(2) handled, dispensed, used, and
disposed of in a manner that protects
against contamination of components,
dietary supplements, or any contact
surface.
We received no comments specific to
proposed § 111.25(e)(5).
f. Final § 111.27(d)(6). Final
§ 111.27(d)(6) (proposed § 111.25(e)(6))
requires your cleaning compounds and
sanitizing agents to be adequate for their
intended use and safe under their
conditions of use.
(Comment 124) One comment would
delete proposed § 111.25(e)(6), stating it
is redundant to proposed § 111.15(b),
which would require you to use
cleaning compounds and sanitizing
agents that are free from microorganisms
of public health significance and safe
and adequate under the conditions of
use.
(Response) We disagree with this
comment. Proposed §§ 111.15(b)(1) and
111.25(e)(6) (now final §§ 111.15(b)(1)
and 111.27(d)(6), respectively) differed
in their requirements and their
applicability. Proposed § 111.15(b)(1)
would apply to cleaning compounds
and sanitizing agents used in the
physical plant and would require them
to be ‘‘safe and adequate under the
conditions of use.’’ In contrast,
proposed § 111.25(e)(6) would apply to
cleaning compounds and sanitizing
agents used on equipment, utensils, and
contact surfaces used to manufacture,
package, or hold components, dietary
ingredients, or dietary supplements, and
it would require such cleaning
compounds or sanitizing agents to be
‘‘adequate for intended use and safe
under condition [sic] of use.’’ By using
the phrase ‘‘adequate for intended use,’’
proposed § 111.25(e)(6) would have you
consider whether a particular cleaning
compound or sanitizing agent was
appropriate for the particular use to
which it was being applied.
Furthermore, depending on the
situation, a cleaning compound or
sanitizing agent that is appropriate for
use on a physical plant may be
inappropriate for use on equipment,
utensils, and contact surfaces. For
example, a powdered cleaning
compound might be suitable for
cleaning your physical plant’s floors,
but inappropriate for cleaning
equipment that mixes components. In
other words, the ‘‘conditions of use’’ can
also vary between final §§ 111.15(e)(1)
and 111.27(d)(6) and lead to different
conclusions regarding use of the same
cleaning compound.
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Additionally, on our own initiative,
we have made two editorial,
nonsubstantive changes to final
§ 111.27(d)(6). The final rule now states
that the cleaning compounds and
sanitizing agents must be adequate for
‘‘their’’ intended use and safe under
‘‘their conditions’’ of use.
g. Final § 111.27(d)(7). Final
§ 111.27(d)(7) (proposed § 111.25(e)(7))
requires you to store cleaned and
sanitized portable equipment and
utensils that have contact surfaces in a
location and in a manner that protects
them from contamination. We received
no comments specific to proposed
§ 111.25(e)(7).
F. Reorganization of Certain Paragraphs
in Proposed § 111.25
Proposed § 111.25 would impose
certain requirements relating to written
procedures for calibrating instruments
and controls (proposed § 111.25(c) and
(d)) and keeping calibration records
(proposed § 111.25(f)). The final rule
now contains a new recordkeeping
section (§ 111.35) that combines
elements of proposed § 111.25(c), (d),
and (f), as well as other sections. We
discuss comments on proposed
§ 111.25(c), (d), and (f) and describe
final § 111.35 in this section.
G. What Requirements Apply to
Automated, Mechanical, or Electronic
Equipment? (Final § 111.30)
Final § 111.30 sets forth requirements
for automated, mechanical, or electronic
equipment that you use to manufacture,
package, label, or hold a dietary
supplement.
1. Comments on the Organization and
Framework of Proposed § 111.30
(Comment 125) Some comments
would revise proposed § 111.30(a) to
replace ‘‘equipment to manufacture,
package, label, and hold’’ with
‘‘equipment to manufacture, package,
label, or hold.’’ The comments said that
the same piece of equipment will not
serve to manufacture, package, label,
and hold components or dietary
supplements.
(Response) We agree, and have
revised § 111.30 accordingly. Final
§ 111.30 also contains the following
changes:
• ‘‘Automatic’’ (as in ‘‘automatic
equipment’’) is replaced with
‘‘automated’’ as an editorial,
nonsubstantive change;
• The phrase ‘‘determine the
suitability of your equipment’’ has been
revised to read ‘‘determine the
suitability of the equipment * * *’’ in
§ 111.30(b) and has no substantive
impact; and
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• We have substituted the word
‘‘met’’ for ‘‘achieved’’ to comply with
‘‘plain language’’ initiatives and to be
consistent with other provisions.
We describe other changes to
proposed § 111.30 in the following
paragraphs.
(Comment 126) Several comments
support proposed § 111.30 particularly
with respect to computers. The
comments state computers are
susceptible to erroneous data input, are
subject to malfunctions and software
problems, and thus should be regulated
under the final rule.
One comment questions why we
organized proposed § 111.30 into two
paragraphs (a) and (b). The comment
claims there was no meaningful
difference between the two paragraphs.
Other comments say some proposed
requirements for automatic, mechanical,
and electronic equipment, such as the
proposed requirement for maintaining
backup files of data entered into
computer systems, would apply to
automatic, mechanical, and electronic
equipment that are not related to
CGMPs. The comments argue that
proposed § 111.30(b) would apply to
computers on which payroll records are
maintained, and that such a requirement
does not belong in these CGMPs.
(Response) We agree, in part, and
disagree, in part, with the comments.
We agree that computers used in the
manufacture, packaging, labeling, or
holding of dietary supplements should
be, and are, subject to final § 111.30.
We disagree, however, with those
comments that interpreted proposed
§ 111.30(a) and (b) as being the same or
interpreted proposed § 111.30 as
applying to equipment that has no
direct bearing on dietary supplements.
Proposed § 111.30(a) differed from
proposed § 111.30(b) in that paragraph
(a) would pertain to the operation and
suitability of your equipment within
your manufacturing process. In contrast,
proposed § 111.30(b) would apply to
calibration of your equipment and
controls you establish for your
equipment.
We disagree with those comments
that would interpret proposed
§ 111.30(b) as applying to payroll
computers or other equipment that has
no CGMP function. To prevent
misinterpretations of final § 111.30, we
have revised it to apply to equipment
‘‘that you use to manufacture, package,
label, or hold a dietary supplement’’ and
renumbered proposed § 111.30(a)(1),
(a)(2), (b)(1), (b)(3), and (b)(4) as
§ 111.30(a) through (e), respectively.
Proposed § 111.30(b)(2) which would
require you to make and keep written
records of equipment calibrations,
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inspections, and checks, and proposed
§ 111.30(b)(5) which would require you
to make and keep backup files of
software programs and data, are now
incorporated into final § 111.35, and we
discuss these provisions later in this
section.
(Comment 127) Several comments
would limit proposed § 111.30(a) and
(b) to automatic, mechanical, or
electronic equipment that actually
affects product specifications. The
comments argue that, in a modern
manufacturing facility, most, if not all,
equipment used to manufacture,
package, label, or hold any food product
is automatic, mechanical, or electronic.
The comments say that equipment, such
as forklifts, should not be required to be
designed or selected in a manner that
ensures that product specifications are
met, as would be required in proposed
§ 111.30(a)(1), or to be calibrated, as
would be required in § 111.30(b)(1).
(Response) As we stated previously,
we have revised § 111.30 so that it
applies to equipment ‘‘that you use to
manufacture, package, label, or hold a
dietary supplement.’’ This revision
should prevent the rule from being
interpreted as applying to forklifts or
other equipment that have no bearing on
the manufacture, packaging, labeling, or
holding of dietary supplements.
(Comment 128) Several comments
argue that proposed § 111.30 is
redundant to proposed § 111.25 and
could be removed without meaningful
effect. One comment argues that
proposed § 111.30(a) and (b) (i.e., that
all automatic, mechanical, and
electronic equipment be designed or
selected to ensure that product
specifications are consistently achieved
and operate satisfactorily within
operating limits required by the process)
are redundant to proposed § 111.25(a)(1)
(which would require that all
equipment be of appropriate design,
construction, and workmanship to
enable them to be suitable for their
intended use) and proposed
§ 111.25(a)(1)(v) (which would state that
‘‘equipment’’ includes automatic,
mechanical, or electronic systems). The
comment states that, for equipment to
be suitable for its intended use, the
equipment must operate satisfactorily
within operating limits and, by
extension, ensure that product
specifications are consistently achieved.
The comment states the separate
regulations for automatic equipment in
the drug CGMPs is less detailed despite
our efforts to present the 2003 CGMP
Proposal in ‘‘simplified language.’’
(Response) We disagree that proposed
§ 111.30 is redundant to proposed
§ 111.25 (final § 111.27). Although both
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proposed §§ 111.25 and 111.30
pertained to equipment, they differed in
their focus. Proposed § 111.25 would
focus on equipment design,
construction, maintenance, cleaning,
sanitizing, and calibration. In contrast,
proposed § 111.30 would focus on the
equipment’s operation or suitability
within your manufacturing process. For
example, proposed § 111.30(a)(2) would
require you to determine the suitability
of your equipment by ensuring that your
equipment is capable of operating
satisfactorily ‘‘within the operating
limits required by the process.’’ In
contrast, proposed § 111.25 had no
comparable suitability requirement
insofar as your manufacturing processes
were concerned. Thus, the proposed
sections are not redundant, and the final
rule retains both § 111.27 (proposed
§ 111.25) and § 111.30.
2. Comments Specific to Proposed
§ 111.30
a. Final § 111.30(a) and (b). Final
§ 111.30(a) (proposed § 111.30(a)(1))
requires you, for any automated,
mechanical, or electronic equipment
you use to manufacture, package, label,
or hold a dietary supplement, to design
or select the equipment to ensure that
dietary supplement specifications are
consistently met.
Final § 111.30(b) (proposed § 111.30
(a)(2)) requires you, for any automated,
mechanical, or electronic equipment
that you use to manufacture, package,
label, or hold a dietary supplement, to
determine the suitability of the
equipment by ensuring that the
equipment is capable of operating
satisfactorily within the operating limits
required by the process.
(Comment 129) Some comments argue
that the requirements of proposed
§ 111.30(a) might be impossible to meet
because, in many instances, dietary
supplement manufacturers cannot
predict, at the time of purchase, the
entire range of ingredients and products
for which a particular piece of
equipment might be used. The
comments argue that a particular piece
of equipment’s suitability for a
particular ingredient or product must be
evaluated at the time the need arises.
The comments would revise proposed
§ 111.30(a)(1). The words ‘‘Design and
select equipment to ensure’’ would be
replaced with the words ‘‘Use
equipment that ensures;’’ and proposed
§ 111.30(a)(2) would be revised to
replace the words ‘‘is capable of
operating’’ with the word, ‘‘operates.’’
(Response) We disagree with the
comments. Although a company may
not know the entire range of products
that a machine may be used for,
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proposed § 111.30(a)(1) and (a)(2) would
neither require you to determine all uses
of equipment at the time of purchase
nor prevent you from evaluating an old
machine for a new use (these provisions
are renumbered as final § 111.30(a) and
(b), respectively). Thus, even if you
chose to use old equipment for a new
use, you still must select that equipment
to ensure that dietary supplement
specifications are consistently met with
the new equipment use and determine
the suitability of the new equipment use
by ensuring that the equipment is
capable of operating satisfactorily
within the operating limits required by
the new process.
(Comment 130) Several comments
express concern that facilities and much
equipment in the industry are old and
lack historical documentation. These
comments ask us to clarify whether
manufacturers would have to establish
baseline information for old facilities
and equipment.
(Response) All equipment that you
use, regardless of whether it is old or
new, must be capable of doing what you
intend it to do. Just as you could
evaluate old equipment for a new use,
you can demonstrate that old equipment
does, in fact, do what you intend it to
do for uses that you developed before
these CGMP requirements were
established, and thereby comply with
final § 111.30(a) and (b).
(Comment 131) Several comments
argue that our statement in the preamble
to the 2003 CGMP Proposal that
‘‘systems need to be installed in a
manner that takes into account the
inherent limitations of the system,
tested under conditions that reflect
actual conditions of use’’ (68 FR 12157
at 12193) is vague and subject to
multiple interpretations.
(Response) We disagree with the
comment. The statement in question
should be read in context because the
preamble to the 2003 CGMP Proposal
described several conditions for
consideration. The preamble to the 2003
CGMP Proposal stated, in relevant part:
‘‘Some systems may work properly only
within a narrow range of environmental
conditions, such as temperature and
humidity, and some might be
particularly sensitive to electromagnetic
interference. The actual conditions of
use of a system should be considered as
early as possible in its design and
development. Systems need to be
installed in a manner that takes into
account the inherent limitations of each
system, tested under conditions of use,
and properly maintained to ensure that
they continue to function as expected
during their lifetime’’ (68 FR 12157 at
12193.) Thus, suitability under final
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§ 111.30(b) involves considerations of
how the equipment would be affected
by environmental conditions, whether
the equipment is appropriate for its
intended use, and whether the
equipment can be maintained properly
to ensure satisfactory operation.
(Comment 132) Several comments
argue that the requirement of proposed
§ 111.30(a)(2) to ‘‘determine the
suitability of your equipment by
ensuring that your equipment is capable
of operating satisfactorily within the
operating limits required by the
process’’ is vague and subject to many
interpretations. These comments assert
that this may cause an uneven playing
field among companies as they apply
differing standards to this requirement.
The comments also argue that the
vagueness of this requirement could
potentially cause uneven enforcement,
depending on the experience and
understanding of individual inspectors.
(Response) We disagree that proposed
§ 111.30(a)(2) (final § 111.30(b)) is vague
or may result in uneven enforcement.
There has been sufficient common usage
of terms such as ‘‘suitable,’’ ‘‘capable,’’
and ‘‘satisfactorily’’ in the industry to
enable firms, and those who enforce the
requirements, to comprehend and apply
such terms to particular operations.
Agencies may use qualifying terms to
enable them to address a wide variety of
conditions, and such terms provide the
flexibility needed for various
operations.
(Comment 133) Several comments
assert that proposed § 111.30(a)(2) is
without justification and overly
prescriptive when compared to
conventional food CGMPs.
(Response) As discussed in section V
of this document, the mere fact that a
dietary supplement CGMP requirement
has no counterpart in the food CGMP
regulations, or has more detail than a
counterpart in such regulations, does
not mean that it is overly prescriptive.
Rather, what is important is whether
proposed § 111.30(a)(2) (final
§ 111.30(b)) is necessary to ensure the
quality of the dietary supplements. For
example, the preamble to the 2003
CGMP Proposal (68 FR 12157 at 12193)
discussed how the incorporation of
software into the operation of automatic
equipment has both increased the
complexity of such equipment and
resulted in a process that may operate
differently for each execution, because a
software-based control system can be
configured at will by the operator or by
the system itself. Therefore, it is
essential that you ensure that automated
equipment is capable of operating
satisfactorily within the operating limits
required by the process.
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(Comment 134) Several comments
urge us to develop a separate guidance
document with respect to determining
the suitability and capability of
equipment used in the manufacture of
dietary supplements.
(Response) We believe that firms have
sufficient experience to determine
whether equipment is suitable and
capable of performing its intended
function. However, if we find that
guidance will be helpful, we will
consider whether to issue guidance at a
later date.
b. Final § 111.30(c). Final § 111.30(c)
(proposed § 111.30(b)(1)) requires you,
for any automated, mechanical, or
electronic equipment you use to
manufacture, package, label, or hold a
dietary supplement, to routinely
calibrate, inspect, or check the
equipment to ensure proper
performance. Final § 111.30(c) also
requires quality control personnel to
periodically review these calibrations,
inspections, or checks.
(Comment 135) Several comments
claim the requirement for the quality
control unit to approve calibrations,
inspections, or checks of equipment is
too prescriptive and that qualified
persons outside of the quality control
unit should be able to approve these
calibrations, inspections, or checks. The
comments also state the quality control
unit should perform audits of the
records generated to ensure the
appropriate calibrations, inspections, or
checks are being adequately performed
at the required intervals.
Other comments refer to related
requirements in proposed § 111.37(b)(8)
that the quality control unit review all
records for equipment calibrations,
inspections, or checks. The comments
state the requirements for oversight by
the quality control unit in proposed
§ 111.37(b)(8) are excessive and go
beyond requirements for both the drug
CGMPs and food CGMPs. One comment
would revise proposed § 111.37(b)(8) to
require a review of all records when
there is a negative impact on the dietary
supplement due to a calibration failure.
(Response) Final § 111.12(b) requires
that you identify who is responsible for
your quality control operations, and
each person who is designated to
perform quality control operations must
be qualified to do so and have distinct
and separate responsibilities related to
performing such operations from those
responsibilities that the person
otherwise has when not performing
such operations. Thus, you may identify
any person whom you believe is
qualified to approve calibrations,
equipments, or checks to perform
quality control operations.
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We disagree that the review by quality
control personnel should be limited to
circumstances when there has been a
calibration failure. One function of
quality control personnel is to provide
oversight to prevent problems with the
product that you distribute by finding
any problems with the equipment that
you use to produce the product rather
than to investigate the cause of a
problem with a product that you already
distributed. However, we agree that it is
sufficient to periodically review the
records of calibrations, inspections, or
checks of automated, mechanical, or
electronic equipment, for example, on
an annual basis, rather than to approve
each record when it is made. A periodic
review can uncover trends in the
performance of the equipment that have
the potential to adversely affect the
quality of the dietary supplement and
that may not be obvious by merely
approving each record when it is made.
Seeing such trends would enable quality
control personnel to recommend
corrective actions. This periodic review
is consistent with proposed
§ 111.37(b)(8) which would require the
quality control unit to ‘‘review’’ all
records for equipment calibration,
inspections, or checks rather than
‘‘approve’’ these records. Therefore, we
have revised the requirement that the
quality control unit approve
calibrations, inspections, or checks of
automatic, mechanical or electronic
equipment so that final § 111.30(c)
requires that quality control personnel
periodically review such operations
rather than approve them when they are
made.
Additionally, we have made a minor
change to § 111.30(c). The change
inserts the words ‘‘the equipment’’ after
‘‘Routinely calibrate, inspect, or check
* * *.’’ This insertion simply reiterates
that ‘‘the equipment’’ must be routinely
calibrated, inspected, or checked.
c. Final § 111.30(d). Final § 111.30(d)
(proposed § 111.30(b)(3)) requires you,
for any automated, mechanical, or
electronic equipment you use to
manufacture, package, label, or hold a
dietary supplement, to establish and use
appropriate controls for the equipment
(including software for a computercontrolled process) to ensure that any
changes to the manufacturing,
packaging, labeling, holding, or other
operations are approved by quality
control personnel and instituted only by
authorized personnel.
(Comment 136) The preamble to the
2003 CGMP Proposal invited comment
on whether we should regulate
computerized systems separately from
other automatic equipment, given the
broad range in sophistication,
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complexity, and computerization in
manufacturing equipment (68 FR 12157
at 12194).
Several comments state that
computers are susceptible to erroneous
data input and subject to malfunctions
and software problems and, thus,
should be regulated under the final rule.
(Response) We agree that computers
used in the manufacturing processes
should be regulated under the final rule.
As the preamble to the 2003 CGMP
Proposal stated the incorporation of
software into the operation of automatic
equipment has increased the complexity
of such equipment and resulted in a
process that may operate differently for
each execution, because a softwarebased control system can be configured
at will by the operator or by the system
itself (68 FR 12157 at 12193).
Additionally, final § 111.35(b)(5)
requires you to make and keep backup
files of software programs and data to
keep them secure from alterations,
inadvertent erasures, or loss. The issue
in the preamble to the 2003 CGMP
Proposal, however, was whether
computerized systems should be
regulated separately from other
equipment; in the absence of comments
supporting separate treatment for
computerized systems, we have
included computerized systems as
‘‘equipment’’ in final § 111.30(d).
We are, however, revising final
§ 111.30(d) in the following manner:
• We are inserting the words ‘‘for
automated, mechanical, and electronic
equipment (including software for a
computer controlled process)’’ after
‘‘Establish and use appropriate
controls.’’ This change simply reiterates
the types of equipment for which
appropriate controls must be established
and used, and makes it clear that
software is included under the rule and
• We are rephrasing the purpose of
§ 111.30(d). The proposal stated that
you must establish and use appropriate
controls ‘‘to ensure that your quality
control unit approves changes in the
master manufacturing record batch
control records, packaging operations,
and label operations, or changes to other
operations related to the equipment that
you use and that only authorized
personnel institute the changes.’’ The
final rule states that you must establish
and use appropriate controls for your
equipment ‘‘to ensure that any changes
to the manufacturing, packaging,
labeling, holding, or other operations
are approved by quality control
personnel and instituted only by
authorized personnel.’’
As revised, final § 111.30(d) shifts its
emphasis from the person(s) who must
approve or institute the changes to the
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types of changes that must be approved
and instituted. This shift in emphasis is
appropriate given that the final rule
addresses responsibilities of the quality
control personnel elsewhere.
d. Final § 111.30(e). Final § 111.30(e)
(proposed § 111.30(b)(4)) requires you,
for any automated, mechanical, or
electronic equipment you use to
manufacture, package, label, or hold a
dietary supplement, to establish and use
appropriate controls to ensure that the
equipment functions in accordance with
its intended use. Quality control
personnel must approve these controls.
We did not receive comments specific
to proposed § 111.30(b)(4).
3. Reorganization of Certain Paragraphs
in Proposed § 111.30
As we explained earlier in this
section, proposed § 111.30 would
impose certain requirements relating to
written records of equipment
calibrations, inspections, or checks
(proposed § 111.30(b)(2)) and making
and keeping backup files of software
programs and data (proposed
§ 111.30(b)(5)). The final rule now
contains a new recordkeeping section,
final § 111.35, that combines elements
of proposed § 111.30(b)(2) and (b)(5), as
well as other sections.
Additionally, proposed § 111.30(c)
would require you to keep records in
accordance with the written procedure
and recordkeeping requirements in
proposed § 111.125. Section 111.35 of
the final rule now incorporates
proposed § 111.30(c) as well. We
discuss final § 111.35 in the following
paragraphs.
H. Under This Subpart, What Records
Must You Make and Keep? (Final
§ 111.35)
Final § 111.35 describes the
recordkeeping requirements. It
represents a combination of proposed
§§ 111.25(c)(1) through (c)(2), (d)(1)
through (d)(7), and (f); 111.30(b)(2),
(b)(5), and (c); and 111.50(c)(4).
1. Final § 111.35(a)
Final § 111.35(a) states that you must
make and keep records required under
subpart D in accordance with subpart P.
Subpart P deals with records and
recordkeeping.
Final § 111.35(a) is broader than
proposed § 111.25(f), which stated that
you ‘‘must keep calibration records as
required by this section in accordance
with’’ the 2003 CGMP Proposal’s
recordkeeping section, and compared to
proposed § 111.30(c), which stated that
you must keep ‘‘automatic, mechanical,
or electronic equipment records
required by this section in accordance
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with’’ the 2003 CGMP Proposal’s
recordkeeping section. However, final
§ 111.35(a) has the same effect as
proposed §§ 111.25(f) and 111.30(c).
We did not receive any substantive
comments on proposed §§ 111.25(f) or
111.30(c).
2. Final 111.35(b)(1) and (b)(2)
Final § 111.35(b) combines the
various recordkeeping requirements that
were in proposed §§ 111.25(c) (written
procedures for calibrating instruments
and controls and documentation that
those procedures were followed and
that the calibration was performed),
111.25(d) (written procedures or
documentation for calibration, such as
the instrument or control calibrated and
the calibration date), 111.30(b)(2) and
(b)(5) (written records of equipment
calibrations, inspections, or checks, and
backup files of software and data,
respectively), and 111.50(b)(4)
(inclusion of date and time of
maintenance, cleaning, and sanitizing of
equipment and processing lines in the
batch record).
Specifically, final § 111.35(b)(1) states
that you must make and keep records of
‘‘written procedures for fulfilling the
requirements of this subpart,’’ including
written procedures for:
• Calibrating instruments and
controls that you use in manufacturing
or testing a component or dietary
supplement. This paragraph is similar to
proposed § 111.25(c). Although we did
not receive any substantive comment on
proposed § 111.25(c), we are rephrasing
the paragraph due to its reorganization
as part of final § 111.35. Additionally,
although proposed § 111.25(c) would
require you to document that the
written procedures for calibration were
followed each time a calibration is
performed, we are moving the
documentation requirement to final
§ 111.35(b)(3) which we discuss later in
this section.
• Calibrating, inspecting, and
checking automated, mechanical, and
electronic equipment. This paragraph is
similar to proposed § 111.30(b)(2),
although we are rephrasing the
paragraph due to its reorganization as
part of final § 111.35.
• Maintaining, cleaning, and
sanitizing, as necessary, all equipment,
utensils, and any other contact surfaces
that are used to manufacture, package,
label, or hold components or dietary
supplements. This paragraph relates to
final § 111.25(c) which requires you to
establish and follow written procedures
for such activities.
We did not receive any comments
specific to proposed §§ 111.25(c) or
111.30(b)(2).
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Final § 111.35(b)(2) (proposed
§ 111.50(c)(4)) requires you to make and
keep documentation, in individual
equipment logs, of the date of the use,
maintenance, cleaning, and sanitizing of
equipment, unless such documentation
is kept with the batch record.
(Comment 137) Proposed
§ 111.50(c)(4) would require that the
batch record include the date and time
of the maintenance, cleaning, and
sanitizing of the equipment and
processing lines used in producing the
batch. The preamble to the 2003 CGMP
Proposal also invited comment on
whether the person performing the
maintenance, cleaning, and sanitizing of
portable equipment and utensils should
document at the time of performance
the maintenance, cleaning, and
sanitizing (68 FR 12157 at 121928).
Several comments argue that the final
rule should require documentation at
the time of performance of equipment,
utensil, and contact surface
maintenance, cleaning, and sanitation
and should also require this
documentation to be kept as records.
The comments explain that such
recordkeeping is common practice in
the industry, is an important part of
batch history, and omitting such a
requirement would diminish the
industry standard. In addition, the
comments state that written records are
an effective way to ensure that there is
consistency in how employees are
trained and to assess compliance.
Several comments agree that
equipment maintenance, cleaning, and
sanitizing records should be kept and
state that this information should be
kept with individual pieces of
equipment, rather than in the batch
record as proposed § 111.50(c)(4) would
require. The comments say it is easier
and more efficient for some companies
to maintain equipment logs that can be
referenced when necessary.
Other comments say manufacturers
should have flexibility to design a
recordkeeping program suited to their
operations, and should have the option
of using an equipment log as it provides
an efficient way to document, trace, and
review equipment use, maintenance,
cleaning, and sanitization of equipment.
According to these comments, because
the 2003 CGMP Proposal would require
batch production records to identify all
equipment used during production, this
will allow for cross-referencing with the
equipment log, should the need occur.
The comments argue that the proposed
8Although the preamble to the 2003 CGMP
Proposal discussed this issue in relation to
proposed § 111.25 (‘‘What Requirements Apply to
the Equipment and Utensils You Use?’’), the same
principle applies to proposed § 111.50(c)(4).
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approach will be awkward for some
companies to comply with and would
not result in collection of information in
a logical order or location where it can
be easily referenced and reviewed, such
as on the production floor, or to provide
data for trend analysis. The comments
also contend requiring all information to
be maintained in the batch record will
be difficult in practice and place an
enormous burden on companies.
(Response) We agree that
documenting the cleaning, sanitizing,
and maintenance of equipment is
important. However, we have revised
the provision so that these records need
not be part of the batch record. Instead,
final § 111.35(b)(2) requires you to make
and keep documentation of the date of
use, maintenance, cleaning, and
sanitizing of equipment in individual
equipment logs, unless such
documentation is kept with the batch
record. By ‘‘equipment log,’’ we mean a
written record that includes information
about the history of a piece of
equipment. This history includes items
such as date of installation, routine
maintenance, repairs, and cleaning.
Additionally, final § 111.260 requires
you to identify the equipment and
processing lines used in producing the
batch and either provide a crossreference that will make it possible to
find the applicable equipment log as
needed or include documentation that
equipment was cleaned, sanitized, or
maintained (we discuss final § 111.260
in section XIV of this document). For
example, you may keep records
documenting that you cleaned
containers you will use for holding a
finished batch either in records
associated with the equipment you use
for cleaning, or with the applicable
batch record, depending on what is
most convenient and practical for your
operations.
(Comment 138) Several comments
state documenting the cleaning of
contact surfaces would be unnecessarily
labor-intensive because the term is so
broadly defined. Other comments argue
that documenting the cleaning of
utensils is unnecessary and
inappropriate. These comments support
requiring documentation for the
cleaning of large equipment, but claim
that requiring manufacturers to
uniquely identify each spoon, spatula,
container, and hose (or other general
cleaning) in order to document each
cleaning would be inappropriate and
create an enormous burden on the
manufacturer. According to these
comments, such a requirement would
slow and complicate the cleaning
process, making proper cleaning more
cumbersome. The comments assert that
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contamination from these sources has
not caused any recalls and is not
justified.
(Response) We disagree with these
comments. The final rule requires you
to document the work that was done,
but gives you the flexibility to decide
how to document that work was done.
For contact surfaces such as containers
you use to hold a finished batch, you
could, for example, record the cleaning
either on a single line that you provide
in your batch record, or as a line entry
in the log of the equipment that you use
to clean the containers, or in some other
way that suits your needs. These are not
labor-intensive requirements.
It is important that you have
procedures in place to know that small
items, such as spatulas, are clean when
you use them. For example, if you have
a log where you designate equipment
that has been cleaned, your batch record
could simply have a place to check that
you used equipment designated as
clean.
3. Final § 111.35(b)(3)
Final § 111.35(b)(3) (proposed
§ 111.25(d)(1) through (d)(7)) requires
you to make and keep documentation of
any calibration, each time the
calibration is performed, for instruments
and controls that you use in
manufacturing or testing a component
or dietary supplement. In the
documentation you must: (1) Identify
the instrument or control calibrated; (2)
provide the calibration date; (3) identify
the reference standard used, including
the certification of accuracy of the
known reference standard and a history
of recertification of accuracy; (4)
identify the calibration method used,
including appropriate limits for
accuracy and precision of instruments
and controls when calibrating; (5)
provide the calibration reading or
readings found; (6) identify the
recalibration method used, and reading
or readings found, if accuracy or
precision or both accuracy and
precision limits for instruments and
controls were not met; and (7) include
the initials of the person who performed
the calibration and any recalibration.
(Comment 139) Some comments
support proposed § 111.25(d). However,
other comments argue that the
documentation requirements are unduly
prescriptive. Some comments would
revise proposed § 111.25(d) to more
closely mirror the requirements in drug
CGMPs. Some comments suggest the
requirement to maintain written records
of calibrations should simply state ‘‘You
must maintain written records of
calibrations according to Sec. 111.125.’’
Other comments suggest detailed
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calibration requirements would not be
needed if the final rule included
requirements to establish and follow
written procedures.
(Response) The information required
under final § 111.35(b)(3) (proposed
§ 111.25(d)) is the minimum amount
necessary to provide sufficient
information concerning equipment
calibration. For example, some firms
may have more than one machine to
perform a given function; in those
situations, documentation that
identified the exact machine that was
calibrated would distinguish it from
other, seemingly identical, but
noncalibrated machines. Likewise, if the
maintenance instructions for a machine
called for calibration checks every
month, documenting the date of
calibration would show you whether
calibrations were done on schedule. As
another example, if a machine required
calibration according to a particular
standard, identifying the reference
standard would help verify that the
calibration was done correctly.
Thus, we disagree with those
comments claiming that proposed
§ 111.25(d) was too prescriptive. If, for
example, the final rule simply directed
you to document calibration, without
specifying what information should be
contained in that documentation, then
the resulting documentation could have
little or no value. For example, assume
that you have two identical pieces of
equipment, but only one had been
calibrated. If the documentation simply
said, ‘‘machine was calibrated,’’ you
would not know which machine had
been calibrated. As another example, if
you had a machine that had to be
recalibrated every year, and the
documentation merely said,
‘‘recalibration completed,’’ you would
not know whether the machine had
been recalibrated yesterday, last month,
last year, or 4 years ago.
With respect to the argument that
proposed § 111.25(d) should be revised
to resemble the drug CGMPs, we
disagree. We recognize that the drug
CGMPs are less detailed with respect to
documentation; for example, 21 CFR
211.68(a), ‘‘Automatic, mechanical, and
electronic equipment,’’ simply states, in
relevant part, ‘‘If such equipment is so
used, it shall be routinely calibrated,
inspected, or checked according to a
written program designed to assure
proper performance’’ and ‘‘Written
records of those calibration checks and
inspections shall be maintained.’’
However, the comments overlook the
fact that, from 1993 to 2003, the Center
for Drug Evaluation and Research
(CDER) issued periodic guidance, in the
form of ‘‘Human Drug CGMP Notes,’’
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34831
and those guidances offered advice on
various drug CGMP issues. With respect
to calibration, for example, the
December 1997 edition dealt with the
question of whether the drug CGMP
regulations require equipment to be
labeled with calibration dates. The
guidance identified various regulations
that would be applicable and also said
that: ‘‘During an inspection a firm
should be able to document when a
specific piece of equipment was last
calibrated/maintained, the results or
action, and when its next calibration/
maintenance is scheduled. The absence
of such documentation is a CGMP
deviation’’ (see CDER, ‘‘Human Drug
CGMP Notes,’’ December 1997, at page
3 (Ref. 29)).
This advice is comparable, in several
respects, to the information required by
final § 111.35(b)(3). For example, it
refers to a ‘‘specific piece of
equipment,’’ which is similar to final
§ 111.35(b)(3)(i)’s requirement to
identify the instrument or control
calibrated. It refers to the time when
calibration occurred; this is similar to
final § 111.35(b)(3)(ii)’s requirement to
provide the calibration date. Although
public distribution of ‘‘Human Drug
CGMP Notes’’ ended in 2003, and the
document was circulated only within
FDA from 2001 to 2003 (but was
available through FOIA), the guidances
offered the drug industry advice on
complying with the drug CGMPs, and
we have retained the guidances on our
Internet site. In other words, the drug
CGMP regulations did not have to be as
‘‘prescriptive’’ because the drug
industry learned about our
interpretations or expectations of the
drug CGMPs through guidance.
Here, in contrast, there is no
comparable history of issuing periodic
guidance to inform the dietary
supplement industry about specific
CGMP issues.
Yet, even if final § 111.35 is more
‘‘prescriptive’’ than the drug CGMPs,
that difference does not mean that we
must revise the rule to ‘‘mirror’’ the
drug CGMPs. The dietary supplement
industry is more diverse compared to
the drug industry, and so, at least with
respect to documenting calibration,
more—rather than less—detail is
appropriate.
We do note, however, that final
§ 111.35(b)(3) differs from proposed
§ 111.25(d) in the following respects:
• § 111.25(d) would require you to
identify specific calibration-related
information ‘‘in any written procedure
or at the time of performance,’’ final
§ 111.35(b)(3) requires documentation
‘‘each time the calibration is
performed.’’ Final section 111.35(b)(1)
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requires you to have records of the
written procedures for calibrating
instruments and controls, but does not
specify the contents of such written
procedures;
• § 111.25(d) would refer to
‘‘instruments and controls.’’ Final
§ 111.35(b)(3) now refers to
‘‘instruments and controls that you use
in manufacturing or testing a
component or dietary supplement.’’
This change clarifies the instruments
and controls that are subject to final
§ 111.35(b)(3) and is consistent with
final § 111.27(b), which requires you to
calibrate instruments and controls;
• The type of information that must
be documented under § 111.35(b)(3)(i)
through (b)(3)(vii) is essentially
identical to that in proposed
§ 111.25(d)(1) through (d)(7), but we
revised the sentence structure due to the
manner in which we reorganized final
§ 111.35;
• § 111.25(d)(6) would have you
identify the recalibration method used.
Final § 111.35(b)(3)(vi) requires you to
identify the recalibration method used
‘‘and reading or readings found.’’ The
addition of ‘‘reading or readings found’’
is consistent with the remainder of
proposed § 111.25(d)(6) (final
§ 111.35(b)(3)(vi)) which is a
simplification of the phrase ‘‘accuracy
or precision or both accuracy and
precision limits for instruments and
controls were not met.’’ One would only
know that limits were not met based on
a reading or readings; and
• § 111.25(d)(7) would require the
initials of the person who performed the
calibration. Final § 111.35(b)(3)(vii)
requires the initials of the person who
performed the calibration and any
recalibration. Arguably, recalibration is
a type of calibration, but we have added
‘‘any recalibration’’ to final
§ 111.35(b)(3)(vii) to ensure that
recalibrations are included in the rule.
(Comment 140) Several comments
would revise proposed § 111.25(d) to
read, ‘‘The following must be identified
* * *’’, rather than ‘‘you must
identify.’’ The comments explain that
calibrations and recalibrations are often
performed by the equipment
manufacturer, vendor, or other outside
service, rather than by the dietary
supplement manufacturer. The
comments argue that the proposal
requires that the calibration or
recalibration must be performed onsite
(i.e., at the plant manufacturing the
dietary ingredient or supplement) when
in fact many calibrations can, or even
must, be performed offsite.
(Response) We decline to revise the
paragraph as requested. As we discuss
in section VI of this document, the term
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‘‘you’’ can refer to someone with whom
you contract, but you are responsible for
ensuring that the calibration
requirements are met, and to have
documentation of the calibration, even
though the steps may be performed
offsite.
4. Final § 111.35(b)(4)
Final § 111.35(b)(4) (proposed
§ 111.30(b)(2)) requires you to make and
keep written records of calibrations,
inspections, and checks of automated,
mechanical, and electronic equipment
that is used to manufacture, package,
label, or hold a dietary supplement.
We did not receive comments specific
to proposed § 111.30(b)(2). We have
made nonsubstantive editorial changes
to the rule. For example, proposed
§ 111.30(b)(2) would require you to
‘‘make and keep’’ written records; final
§ 111.35(b)(4) omits the words ‘‘ make
and keep’’ because that requirement
appears earlier in § 111.35.
5. Final § 111.35(b)(5)
Final § 111.35(b)(5) (proposed
§ 111.30(b)(5)) requires you to make and
keep backup file(s) of current software
programs (and of outdated software that
is necessary to retrieve records that you
are required to keep in accordance with
subpart P, when current software is not
able to retrieve such records) and of data
entered into computer systems that you
use to manufacture, package, label, or
hold dietary supplements. Under final
§ 111.35(b)(5)(i), your backup file (e.g., a
hard copy of data you have entered,
diskettes, tapes, microfilm, or compact
disks) must be an exact and complete
record of the data you entered. Under
final § 111.35(b)(5)(ii), you must keep
your backup software programs and data
secure from alterations, inadvertent
erasures, or loss.
(Comment 141) Several comments
would limit the requirement for
maintaining backup files of data entered
into computer systems to those data
entered into computer systems that are
relied upon for compliance with
CGMPs. These comments argue that the
paragraph, as written, calls for a firm to
make and keep backup files of data
entered into computers on which
personnel payroll records are
maintained, and state that no such
requirement should be imposed.
Therefore, these comments would
replace the words ‘‘your computer
system’’ with the words ‘‘any of your
computer systems that are relied upon
for compliance with this part.’’
(Response) We have modified the
provision to clarify that the requirement
is for computer systems that you use to
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manufacture, package, label, or hold
dietary supplements.
(Comment 142) Several comments
argue that many software programs are
in a near constant state of revision and
that it is not a common business
practice for a firm in any industry to
maintain records of outdated software
programs, at least if the firm is still able
to use a revised program to access data
it entered using an outdated program.
The comments assert that, although the
drug CGMPs require the maintenance of
certain backup files of data entered into
computer systems, they do not require
the maintenance of backup files of
software programs.
(Response) Keeping backup copies of
software helps ensure that data can be
retrieved if the primary software
develops a problem. When we use the
term ‘‘backup,’’ we mean a second copy
of the software in question rather than
a copy of previous versions of the
software that are outdated, provided
that data can be retrieved. However, if
the data collected using outdated
software cannot be retrieved by the
newer software, there would still be a
need to maintain a primary copy and a
backup copy of the outdated software
used to collect or manage the data.
We have narrowed the requirement to
retain backup files of software to current
software and of outdated software that
is necessary to retrieve records that you
are required to keep in accordance with
subpart P, when current software is not
able to retrieve such records.
(Comment 143) Some comments
claim that, although the drug CGMPs
require the maintenance of certain
backup files of data entered into
computer systems, they do not require
the maintenance of backup files of
software programs. Several comments
also assert that it is not always possible
to keep backup files of the software
programs used in certain pieces of
equipment, because the equipment
manufacturer may be the only one
having access to the programming of its
equipment. The comments would delete
the words ‘‘software programs and’’
from proposed § 111.30(b)(5).
(Response) In most cases, we
anticipate that firms will have access to
backup copies of their software
programs. We acknowledge that in rare
instances, backup copies may not be
available and in these situations, we
will take that into account in reviewing
compliance with this provision. We
decline to revise the provision as
suggested.
6. Final § 111.35(b)(6)
Final § 111.35(b)(6) states that you
must make and keep ‘‘documentation of
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the controls that you use to ensure that
equipment functions in accordance with
its intended use.’’
The preamble to the 2003 CGMP
Proposal stated that we were not
proposing verification requirements for
automatic, mechanical, or electronic
equipment (68 FR 12157 at 12194).
However, we invited comment on
whether the final rule should require
such verification (id.). Verification
would ensure that the processes using
automatic, mechanical, and electronic
equipment consistently produce an
outcome that meets a predetermined
specification and any predetermined
quality characteristics. Verification
would show whether your automatic,
mechanical, or electronic processes will
consistently operate as they should.
(Comment 144) Several comments
argue against including equipment
verification requirements. The
comments argue that the verification
discussion in the preamble to the 2003
CGMP Proposal is difficult to
distinguish from drug validation. The
comments argue that validation should
be allowed to evolve in the dietary
supplement industry as it evolved in
drug CGMPs. According to these
comments, the dietary supplement
industry, being largely self regulated in
CGMPs to date and not generally
practicing verification, would be more
readily adaptable to, and better
controlled by, strict operating controls
and quality control checks including
sufficient input and output checks on
computer operated systems, than having
to digest the concept of verification and
implement verification processes. The
comments state that, in the future,
verification may be a means of offsetting
some of the extensive testing of finished
products.
Other comments state we should not
require verification of processes that use
automatic, mechanical, or electronic
equipment given the different processes
that dietary supplement manufacturers
use. The comments argue that although
dietary supplement manufacturers,
depending on the unique circumstances
of a particular manufacturing process,
may choose to verify processes using a
sound verification system, we should
not require verification.
Several comments ask us to clarify
whether we intended to require full
validation of equipment used to process
dietary supplements because terms such
as ‘‘suitability’’ and ‘‘capable,’’ which
we used in proposed § 111.30(a)(1) and
(a)(2), might be interpreted to require
validation. These comments state
validation is unnecessary and overly
burdensome for equipment used in
manufacturing dietary supplements.
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Several comments argue that
proposed § 111.30(a)(1) and (a)(2) have
the effect of establishing unnecessarily
formal, stringent, and expensive
validation requirements on equipment
design, selection, and capability. The
comment states that this language
represents a de facto ‘‘IQ/OQ/PQ’’
(installation qualification/operational
qualification/performance qualification)
requirement. According to these
comments, emphasis should instead be
directed to actual use and operation.
In contrast, several comments argue
we should require manufacturers to
develop and maintain data that
demonstrate that equipment is suitable
and that the production process
consistently delivers expected results.
The comments argue that one key CGMP
element is the requirement for systems
to operate consistently and to produce
an outcome that meets a predetermined
specification. According to these
comments, demonstration of system
capability is best achieved through
systems verification. The comments
explain that, in an industry where the
complexity of finished products often
precludes finished product testing, the
capability of the systems employed is of
paramount importance. The comments
state if the processes used fail to
produce a product meeting
predetermined specifications and
quality characteristics, then the product
should not be sold. The comments add
that, although verification imposes
additional costs on manufacturers,
frequently rejected product, adequate
rework procedures, and extensive inprocess and finished product testing
also would be costly.
Several comments also claim the use
of an appropriate verification system
may, under certain circumstances, allow
for lot testing as opposed to batch
testing. These comments state that, with
process verification and an appropriate
testing scheme, a manufacturer could
demonstrate that lot testing provides
sufficient assurance of quality and lack
of adulteration. The comments ask us to
address these alternatives in the final
rule. Many comments said written
records of verification should be
maintained. The comments offer several
suggestions on how this could be
accomplished, including using
statistical process control techniques or
other appropriate statistical tools.
(Response) We used the term
‘‘verification’’ rather than ‘‘validation’’
to signal that we did not expect that a
final rule would include requirements
for formal process validation
requirements, such as an IQ/OQ/PQ
requirement, for equipment. Regardless,
several comments interpreted our
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request for comments as a suggestion
that we were considering such formal
validation requirements. At this time,
we are not requiring formal process
validation for equipment. However, we
will monitor the development of
systems that evolve within this diverse
industry.
We disagree that proposed
§ 111.30(a)(1) and (a)(2) would have the
effect of establishing unnecessarily
formal, stringent, and expensive
validation requirements on equipment
design, selection, and capability, and
that the language would represent a de
facto ‘‘IQ/OQ/PQ’’ requirement for
equipment. Final § 111.30(e) requires
you to ensure equipment operates in
accordance with its intended use. We
agree with the comments that argued
that data demonstrating that equipment
is suitable, and that the production
process consistently delivers expected
results, are a key element of CGMP.
Therefore, final § 111.35(b)(6) requires
you to make and keep documentation of
the controls that you use to ensure that
the equipment functions in accordance
with its intended use. Examples of such
controls include temperature settings,
fill rates, and blending times that must
be set, checked, and adjusted as
necessary.
X. Comments on Requirement to
Establish a Production and Process
Control System (Final Subpart E)
A. Reorganization of Proposed § 111.35
Into Final Subpart E
In the 2003 CGMP Proposal, the
requirements for a production and
process control system were set forth in
§ 111.35. As shown in table 6 of this
document, we are reorganizing
proposed § 111.35 into subpart E. Table
6 lists the sections in final subpart E and
identifies the sections in the 2003
CGMP Proposal that form the basis of
the final rule.
TABLE 6.—DERIVATION OF SECTIONS
IN FINAL SUBPART E
Final Rule
2003 CGMP
Proposal
§ 111.55 What are the
requirements to implement a production and
process control system?
§ 111.35(a)
§ 111.60 What are the
design requirements
for the production and
process control system?
§ 111.35(b)
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TABLE 6.—DERIVATION OF SECTIONS
IN FINAL SUBPART E—Continued
2003 CGMP
Proposal
Final Rule
§ 111.65 What are the
requirements for quality control operations?
§ 111.35(c)
§ 111.70 What specifications must you establish?
§ 111.35(e), (f),
(g), and (k)
§ 111.73 What is your
responsibility for determining whether established specifications
are met?
§ 111.35 (f), (g),
and (h)
§ 111.75 What must you
do to determine
whether specifications
are met?
§ 111.35(e), (f),
(g), (h), (i),
(k), and (l)
§ 111.37
(b)(11)(iv)
§ 111.40(a)(2)
§ 111.77 What must you
do if established specifications are not met?
§ 111.50(d)(2),
(f), and (g)
§ 111.35(i)(4)(i)
and (i)(4)(ii)
§111.80 What representative samples must
you collect?
§ 111.37(b)(11)
§ 111.83 What are the
requirements for reserve samples?
§ 111.37(b)(12)
§ 111.50(h)
§ 111.83(b)(2)
§ 111.87 Who conducts
a material review and
makes a disposition
decision?
§ 111.35(i) and
(n)
§ 111.37(b)(5)
and (b)(14)
§ 111.40(a)(3)
§ 111.50(d)(1)
§ 111.85(a) and
(c)
§ 111.90 What requirements apply to treatment, in-process adjustments, and reprocessing when there is a
deviation or unanticipated occurrence or
when a specification
established in accordance with § 111.70 is
not met?
§ 111.35(i)(4)
§ 111.50(d)(1),
(f), and (g)
§ 111.65(d)
§ 111.95 under this subpart E, what records
must you make and
keep?
§ 111.35(m) and
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B. General Comments on Proposed
§ 111.35
(Comment 145) Several comments
emphasize the first step in ensuring
safe, high quality products is to use high
quality components that meet welldefined specifications. Some of these
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comments assert the 2003 CGMP
Proposal does not encourage
development of such specifications.
Several comments assert that a more
appropriate balance is needed between
an effective process control system and
a reasonable testing scheme that is
calculated to confirm the quality of
dietary supplements, and that it is
important to provide companies with
more flexibility in developing a specific
CGMP program that satisfies the
requirements. The comments stress it is
important to build quality into a
product throughout the entire
production process by relying on strong
process controls rather than by testing at
the finished batch stage. One comment
asserts that, in an appropriate process
control system, testing is a means to
monitor and ensure that the control
system is functioning as intended. Many
comments recommend the final rule
include rigorous in-process controls
plus a requirement for one identity test
of incoming components to ensure
quality and safety.
Many comments assert a certificate of
analysis can be a key element of the
manufacturing process provided that a
manufacturer certifies that a vendor
consistently supplies suitable product
through a combination of vendor audits
and product testing. (A certificate of
analysis is a document, provided by the
supplier of a component prior to or
upon receipt of the component, that
documents certain characteristics and
attributes of the component.) Comments
also assert that, with use of a certificate
of analysis from a properly qualified
supplier, the amount of required testing
could be reduced. One comment notes
that, although a certificate of analysis
may not be relied upon completely to
forgo testing of a received ingredient,
the extent of testing could be reduced to
take into account the history of the
supplier in providing quality
ingredients. This and other comments
recommend the dietary supplement
manufacturer conduct identity tests to
ensure that the correct component has
been received. A few comments note
that the drug CGMP regulations permit
the use of a supplier’s certificate of
analysis based upon certification of the
supplier by a program of complete
testing for conformance with the
certificate of analysis.
Several comments support the use of
a qualified supplier’s certificate of
analysis in lieu of testing at the finished
batch stage. One comment recommends
testing be strategically employed to
verify that other control procedures
have accomplished their intended
result; if other controls are adequate, a
statistically-based testing program
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should be permitted for finished batches
rather than the proposed requirement
for testing every batch for every
specification.
Many comments note that section
402(g)(2) of the act directs us to develop
dietary supplement CGMP requirements
that are modeled after the CGMP
regulations for food. These comments
point out that, because the food CGMPs
allow the use of a verified certificate of
analysis, it is unfair and illogical to
disallow a certificate of analysis in the
dietary supplement CGMP final rule.
One comment states the proposed
requirements for production and
process controls are more stringent than
the requirements for drug products.
Several comments stress that the most
critical aspect of a successful CGMP
system is effective process control,
which includes a requirement for
written procedures and documentation
for all key processing operations. Many
comments argue that effective process
control, including extensive written
procedures, should allow for a
decreased testing burden with respect to
the finished product. One comment
suggests we exempt manufacturers from
the requirement to test each batch of
finished product if they have a qualified
manufacturing process that meets
certain basic criteria, including a
requirement for written procedures for
each stage of the process and a written
plan for qualifying this process.
Several comments urge us to build
more flexibility into the testing
requirements, in both the type and
number of tests required and the
point(s) in the supply chain at which
they would be required. Some
comments recommend that the
frequency of testing be established
under a statistically valid method to
ensure that in-process controls are
adequate to guarantee production of a
safe and effective dietary supplement or
ingredient. Several comments
recommend we require manufacturers to
test incoming ingredients and raw
materials, in lieu of testing each
finished batch of product. These
comments state it is more prudent to
test to ensure that the materials used in
formulating a product are appropriate
and safe than to risk making an
adulterated product and, in so doing,
contaminate manufacturing equipment.
Several comments recommend we
allow manufacturers to employ skip-lot
testing as an alternative to testing each
finished batch of product. One comment
states that, with adequate process
controls in place, periodic or skip-lot
testing is sufficient, and notes that skiplot testing is acceptable under the
regulatory frameworks for herbal
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products in other countries, including
Canada and countries in the European
Union.
In summary, the comments suggest an
approach that stresses the importance of
establishing specifications for
components, relying on a certificate of
analysis from a qualified supplier for
certain specifications with qualification
of the suppliers, and establishing and
following written procedures. This
overall approach would focus on
building quality into a dietary
supplement throughout the production
and process control system. The role of
testing at the finished batch stage would
become a check on whether the overall
manufacturing process is, in fact, under
control.
(Response) Based upon a review of
the comments, we have reconsidered
the approach taken in the 2003 CGMP
Proposal. The 2003 CGMP Proposal
would require that all finished batches
of dietary supplements be tested at the
finished batch stage to ensure that the
products met specifications for identity,
purity, strength, and composition. The
2003 CGMP proposal recommended, but
would not require, testing of incoming
components to ensure that component
specifications, including identity, were
met. However, if a specification (such as
identity) could not be tested at the
finished batch stage, the proposed rule
would require a firm to test incoming
components for that specification and to
test for that specification at the inprocess stage as necessary to ensure that
products met specifications. We are
persuaded that, as an alternative to
testing each finished batch of product,
we can allow for the use of a statistically
sound sampling and testing program for
finished batches of dietary supplements
unless a manufacturer chooses to test
every batch. Such a sampling and
testing program is feasible when
controls are implemented earlier than
the final product stage in the
manufacturing process. Controls include
the use of a certificate of analysis from
a qualified supplier for specifications
other than the identity of a dietary
ingredient, and the establishment and
monitoring of in-process manufacturing
controls. We agree with the comments
that if we reduce the requirements for
testing at the finished batch stage, then
it is critical that you determine whether
components meet specifications. We
address this issue in the following two
ways: (1) Each manufacturer must
confirm the identity of each component
prior to use (you must test or examine
dietary ingredients to verify the identity,
but may rely on a certificate of analysis
to confirm the identify of components
other than dietary ingredients) and (2)
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each company must confirm other
required specifications for components
prior to use, either by relying upon a
certificate of analysis or by testing or
examining the component.
As the comments have suggested,
specifications for the ‘‘identity’’ of
components of dietary supplements are
critically important. These comments
included references to industry
proposals that supported identity
testing. The 1997 ANPRM (62 FR 5700)
included an industry proposed outline
of CGMP provisions which contained a
provision that required identity testing
as follows: ‘‘(iv) Each lot of raw material
shall undergo at least one test by the
manufacturer to verify its identity. Such
tests may include any appropriate test
with sufficient specificity to determine
identity, including chemical and
laboratory tests, gross organoleptic
analysis, microscopic identification, or
analysis of constituent markers.’’ (60 FR
5700 at 5705).
In January 2004, a group of trade
associations representing dietary
supplement manufacturers and others
submitted text of proposed CGMP
requirements to the docket as an
alternative to the 2003 CGMP Proposal.
This submission also included a
provision which required identity
testing as follows:
(1) For components, dietary ingredients, or
dietary supplements that you receive, you
must:
(i) conduct at least one test or examination
to verify that the specifications for identity
are met; * * *
(1996N–0417, EMC000261–02 at 20).
Both the 1997 ANPRM industry
outline and the January 2004 industry
docket submission included provisions
that allowed certificates of analysis to
establish specifications other than for
identity for ingredients and
components.
In the preamble to the 2003 CGMP
Proposal (68 FR 12157 at 12162) we
discussed a case in which Digitalis
lanata was labeled as plantain and, as
a result, a young woman experienced a
life-threatening abnormal heart function
after consuming a dietary supplement
containing D. lanata in lieu of plantain.
The problem occurred notwithstanding
the fact that certificates of analysis
furnished by the supplier provided
assurances that the component was
indeed plantain.
Because of the critical importance of
ensuring the proper identity of dietary
ingredients—they are the central
defining ingredients of a dietary
supplement—we are requiring each firm
that uses a dietary ingredient to perform
its own testing or examination for
identity of each dietary ingredient prior
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to use. This requirement is similar to the
proposed requirement set forth by
industry in both the 1997 ANPRM and
in the January 2004 industry comment
to the proposed rule. Firms may not rely
upon a certificate of analysis provided
by suppliers to determine the identity of
a dietary ingredient before use. We
recognize, however, that it may be
possible for a manufacturer to
demonstrate, through various methods
and processes in use over time for its
particular operation, that a system of
less than 100 percent identity testing
would provide no material diminution
of assurance of the identity of the
dietary ingredient as compared to the
assurance provided by 100 percent
identity testing. To provide an
opportunity for a manufacturer to make
such a showing and reduce the
frequency of identity testing of
components that are dietary ingredients
from 100 percent to some lower
frequency, we decided to provide, in an
interim final rule published elsewhere
in this issue of the Federal Register, a
procedure that allows for submission to,
and review by, FDA of an alternative to
the required 100 percent identity testing
of components that are dietary
ingredients, provided certain conditions
are met.
In the preamble to the 2003 CGMP
Proposal (68 FR 12157 at 12198), we
explained that we would not permit
firms to rely upon supplier
certifications. The decision was based,
in large part, on problems that have
occurred with faulty certificates in the
past. We have, however, reconsidered
our position on certificates for
specifications, other than for the
identity of the dietary ingredients, based
on comments discussing how firms have
taken steps to ensure that their
certificates are reliable. We believe that
the minimum criteria that we are
establishing for a certificate of analysis,
together with the requirement that a
firm relying on a certificate of analysis
must qualify a supplier and periodically
repeat that qualification process, can
prevent the problems that have occurred
with faulty certificates in the past.
Therefore, for component specifications,
other than the identity of a dietary
ingredient, including confirming the
identity of components that are not
dietary ingredients, we are permitting
firms to rely upon certificates of
analysis provided by suppliers, if the
certificates meet the requirements of the
final rule. Under final § 111.75(a), a firm
may rely upon a certificate of analysis
from its supplier of a component,
provided that certain criteria are met
which include the following: (1) The
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firm first qualifies the supplier by
establishing the reliability of the
supplier’s certificate of analysis through
confirmation of the results of the
supplier’s tests or examinations; (2) the
certificate of analysis includes a
description of the test or examination
method(s) used, limits of the test or
examinations, and actual results of the
tests or examinations; (3) the firm
maintains documentation of how it
qualified the supplier; (4) the firm
periodically reconfirms the supplier’s
certificate of analysis; and (5) the firm’s
quality control personnel review and
approve the documentation setting forth
the basis for qualification (and
requalification) of any supplier.
As we discussed in the preamble to
the 2003 CGMP Proposal, in-process
controls are necessary to ensure that
dietary supplements are manufactured
in accordance with their specifications
(68 FR 12157 at 12197). Under final
§ 111.75(b), firms must monitor the inprocess points, steps, or stages where
control is necessary to ensure the
quality of the finished batch of the
dietary supplement to: (1) Determine
whether the in-process specifications
are met and (2) detect any deviation or
unanticipated occurrence that may
result in a failure to meet specifications.
In addition, we have strengthened the
requirements for in-process controls by
requiring that quality control personnel
conduct all required material reviews
and make all required disposition
decisions using written procedures to
ensure that deviations or unanticipated
occurrences that occur are consistently
handled.
Because of the strengthened
requirements regarding component and
in-process specifications, the final rule
permits testing of a subset of finished
batches rather than requiring testing of
each finished batch. Consistent with
several suggestions in the comments, we
built more flexibility into the testing
requirements so that a firm may test a
subset of finished dietary supplement
batches that the firm identifies through
a sound statistical sampling plan for
selected specifications rather than test
every batch of the finished dietary
supplement for every specification.
Finally, quality control personnel must
review and approve any exceptions
from testing requirements that are
allowed under the rule and the basis for
such exceptions. This approach is
consistent with the comments that we
received and will achieve a high degree
of integrity in the manufacturing
process, while at the same time provide
flexibility to the industry.
Additional discussion on the
requirements for identity testing of
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dietary ingredients and the appropriate
reliance on a certificate of analysis for
components other than dietary
ingredients is found in this section in
response to comment 174.
C. Final Subpart E and Highlights of
Changes to the Proposed Regulations
The provisions in final subpart E
reflect that the final rule applies only to
persons who manufacture, package,
label, or hold a dietary supplement
unless subject to an exclusion in final
§ 111.1. The approach that we are
incorporating into the final rule requires
changes in most of the individual
paragraphs of proposed § 111.35.
D. What Are the Requirements to
Implement a Production and Process
Control System? (Final § 111.55)
Final § 111.55 requires you to
implement a system of production and
process controls that covers all stages of
manufacturing, packaging, labeling, and
holding of the dietary supplement to
ensure the quality of the dietary
supplement and that the dietary
supplement is packaged and labeled as
specified in the master manufacturing
record. Final § 111.55 derives from
proposed § 111.35(a).
(Comment 146) A few comments say
the production and process controls
outlined in proposed § 111.35 are
critical in ensuring that dietary
supplements meet specifications for
identity, purity, quality, strength, and
composition. One comment
recommends proposed § 111.35(a) be
revised to state ‘‘* * * that covers all
stages of manufacturing, packaging,
labeling, and holding of * * * dietary
supplements that occur in your facility
or for which you otherwise have
responsibility.’’ This comment explains
that the production of dietary
supplements is often broken up into
several stages which are under the
control of different entities. The
comment gives the following examples:
A marketing company may manufacture
and package a product itself; or it may
contract with one company to
manufacture and package the product;
or it may contract with one company to
manufacture the product and another
company to package the product; and
contract manufacturers and packagers
may subcontract portions of the
manufacturing or packaging.
(Response) We decline to revise the
rule as suggested by the comments. As
we discussed in response to comment
37 in section VI of this document, you
must comply with the CGMP
requirements that apply to your
operations related to the manufacturing,
packaging, labeling, and holding of
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dietary supplements. We decline to
include codified language that may not
capture all of the possible relationships
that exist in a given operation.
E. What Are the Design Requirements
for the Production and Process Control
System? (Final § 111.60)
Final § 111.60(a) requires that your
production and in-process control
system be designed to ensure that the
dietary supplement is manufactured,
packaged, labeled, and held in a manner
that will ensure the quality of the
dietary supplement and that the dietary
supplement is packaged and labeled as
specified in the master manufacturing
record. Final § 111.60(b) requires that
the production and in-process control
system include all requirements of
subparts E through L of part 111 and be
reviewed and approved by quality
control personnel. Final § 111.60(a) and
(b) derive from proposed § 111.35(b).
As discussed in section III of this
document, we are clarifying a number of
provisions that did not explicitly
identify labeling as an operation that is
covered by the rule. Final § 111.60 is
one such provision. Under proposed
§ 111.35(a) we would require that you
implement a system of production and
process controls that covers all stages of
manufacturing, packaging, labeling, and
holding of the dietary supplements. In
an oversight, proposed § 111.35(b)
would require your production and inprocess control system to be designed to
ensure that the dietary supplement is
manufactured, packaged, and held—but
not labeled—in a manner that would
prevent adulteration of the dietary
supplement. To correct this oversight,
final § 111.60 explicitly identifies
labeling as an operation that the design
of your production and process control
system must address.
(Comment 147) A few comments
recommend that the phrase ‘‘designed to
ensure’’ in proposed § 111.35(b) be
deleted because it requires that formal,
prospective studies (similar to a process
validation) must be performed and such
a requirement would be unduly
burdensome.
(Response) We disagree with the
comments’ interpretation of the
proposed regulation and decline the
request. Final § 111.60(a) relates to the
overall design of your production and
process control system. It does not
require validation based on scientific
studies, but rather that your process
contain all the controls necessary to
ensure the quality of your dietary
supplements and that the dietary
supplement is packaged and labeled as
specified in the master manufacturing
record. The process, for example, must
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ensure that the dietary supplement
meets all specifications established
under § 111.70(e).
F. What Are the Requirements for
Quality Control Operations? (Final
§ 111.65)
Final § 111.65 requires that you
implement quality control operations in
your manufacturing, packaging,
labeling, and holding operations for
producing the dietary supplement to
ensure that these operations are
performed in a manner that ensures the
quality of the dietary supplement and
that the dietary supplement is packaged
and labeled as specified in the master
manufacturing record. Final § 111.65
derives from proposed § 111.35(c).
Proposed § 111.35(c) referred to the
role of the quality control unit in
manufacturing, packaging, and label
operations—but not in holding
operations. This was an oversight. We,
therefore, revised proposed § 111.35(c)
to include ‘‘holding’’ as an operation
that is subject to the oversight of quality
control personnel for consistency with
final § 111.105 (proposed § 111.37(a)),
which provides for the performance of
quality control operations to ‘‘ensure
that your manufacturing, packaging,
label, and holding operations ensure the
quality of the dietary supplement and
that the dietary supplement is packaged
and labeled as specified in the master
manufacturing record.’’
(Comment 148) One comment
recommends proposed § 111.35(c) be
revised to state ‘‘ensures that the * * *
dietary supplement meets
manufacturing specifications for
identity, purity, quality, strength, and
composition.’’
(Response) We are not making this
change because it is unnecessary in the
context of the provisions of final
§ 111.65.
(Comment 149) One comment argues
that proposed § 111.35(c) is too wordy
and needs clarification. The comment
recommends it be revised to state ‘‘You
must use a quality control unit to ensure
that the dietary supplement meets
specifications for identity, purity,
quality, strength, and composition.’’
(Response) We disagree with this
comment. The change requested by the
comment would emphasize a single
responsibility of quality control
personnel (i.e., releasing final product)
and would obscure the fact that quality
control personnel have a role in the
design and conduct of most of your
operations.
(Comment 150) One comment
recommends proposed § 111.35(c) be
revised to state ‘‘ensures that the * * *
dietary supplement meets specifications
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for identity, purity, quality, strength,
and composition as appropriate to
protect the public health; and quality,
strength, and composition as
appropriate for the * * * product.’’
This comment states it is confusing and
unnecessary to require that all five of
these attributes be addressed for all
dietary supplements. The comment also
states the term ‘‘purity’’ requires
explanation because not all ingredients
or supplements are subject to the same
types of contamination.
(Response) We are not making any
changes in the provision as suggested by
this comment. The comment provides
no basis for the assertion that the
proposed requirement to use a quality
control unit to ensure that a dietary
supplement meets specifications for
identity, purity, strength, and
composition is confusing and
unnecessary. In section VI of this
document, we explain that purity means
that portion or percentage of a dietary
supplement that represents the intended
product.
G. What Specifications Must You
Establish? (Final § 111.70)
Final § 111.70 derives from proposed
§§ 111.35(e), (f), (g), and (k),
111.37(b)(11)(iv), and 111.70(c).
(Comment 151) Some comments state
proposed § 111.35(k), which would
require that you test or examine
components and dietary supplements
for those types of contamination that
may adulterate or lead to adulteration,
is more appropriate for, and should be
incorporated into, proposed § 111.35(e)
which would require, in part, that you
establish specifications for the identity,
purity, quality, strength, and
composition of components that you
receive and of dietary supplements that
you manufacture. The comments note
this suggestion would help simplify and
eliminate some redundancy in proposed
§ 111.35. One comment would revise
proposed § 111.35(k) to state ‘‘Purity
specifications for purchased or
manufactured components and dietary
supplements must be established for
those types of contamination which can
reasonably be expected to affect the
component, ingredient, or supplement
in question * * *.’’ According to the
comment not all ingredients or
supplements are subject to the same
types of contamination, and it would be
unduly burdensome to require that all
ingredients and supplements be tested
for all possible contaminants (as
opposed to all likely contaminants).
(Response) We agree that not all
ingredients or dietary supplements are
subject to the same types of
contamination. It would not be
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34837
practicable or necessary to require
testing for all possible contaminants for
every dietary supplement, or for every
component used to manufacture a
dietary supplement. As we explained in
the 2003 CGMP Proposal (68 FR 12157
at 12199 through 12200), the
manufacturer has the responsibility to
determine what types of contamination
are likely or certain to contaminate a
given product and to determine what
types of tests to conduct and when to
test for such contamination. We
explained that botanicals are likely or
certain to contain filth and
microorganisms of public health
significance based on the areas in which
they are harvested (id.). As another
example, fungal growth on a botanical
component can provide the
environment for mycotoxin production,
especially aflatoxin (id.). If fungal
growth is present, the manufacturer
would need to perform an appropriate
test that can detect the toxic substance.
We stated that the manufacturer must be
aware of potential contamination,
regardless of whether due to filth,
insects, microorganisms, or toxins and
to test or examine, as appropriate, the
components and dietary supplements
for those types of contamination that
may adulterate or that may lead to
adulteration (id.). Thus, the types of
contamination that we were referring to
in proposed § 111.35(k) are those that
are likely or certain to be present in or
on components received, based on the
nature of the product, its source,
handling prior to receipt by the facility,
or other reason, and not due to poor
manufacturing practices that resulted in
their presence in the first instance.
It is the responsibility of the
manufacturer to identify those
contaminants and to establish limits to
prevent adulteration under section
402(a)(1), (a)(2), (a)(3), and (a)(4) of the
act. For example, if you manufacture a
polysaccharide that derives from
seaweed, it is likely that you would
include a limit on cadmium, because
cadmium is a common contaminant that
can be present in marine-derived
ingredients. If you manufacture a
polysaccharide that has a composition
similar to seaweed-derived
polysaccharide, but derives from a landbased plant, it is not likely that you
would include a limit on cadmium,
because cadmium is not a common
contaminant of land-based plants.
Likewise, if you manufacture a mineral
that contains phosphates, it is likely that
you would include a limit on arsenic,
because phosphates are generally mined
and arsenic is a common contaminant
that can be present in ingredients that
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are mined. If you manufacture a mineral
that does not include ingredients that
are mined, it is not likely that you
would include a limit on arsenic.
We agree that controlling
contamination is critical to the quality
of the dietary supplement. However, we
do not agree that the types of
contamination addressed by proposed
§ 111.35(k) should be considered as a
purity specification. We have described
purity in this final rule to mean
something that you intend to be present
in the final product. As explained in
section VI of this document, purity
means that portion or percentage of a
dietary supplement that represents the
intended product. For example, you
may manufacture a dietary supplement
that uses a natural product such as fish
oil to provide triglycerides that are a
source of the polyunsaturated fatty acids
DHA and EPA. The purity refers to the
percent of the fish oil that is
triglycerides. (Note that if you are
manufacturing fish oil to provide the
fatty acids DHA and EPA in the dietary
supplement, the component
specifications for the fish oil must
include a strength specification for DHA
and EPA in whatever amount you
determine is necessary to meet the
specification for strength of DHA and
EPA in the dietary supplement.) If the
natural product also contains lead, or
other unwanted ingredients that may
adulterate or may lead to adulteration,
you would have to establish limits for
such contaminants. Thus, to distinguish
the proposed requirement in § 111.35(k),
which relates to contaminants that may
be present on or in the components that
you receive, from the requirements
related to specifications for desired
characteristics of identity, purity,
strength, and composition, we are
including a separate requirement on
establishing limits on such
contaminants for components that you
receive (final § 111.70(b)). We also
include a requirement for establishing
an in-process specification for any
point, step, or stage in the master
manufacturing record where control is
necessary to help ensure that
specifications are met, as necessary, for
limits on contamination. In addition, we
are including a requirement for such
limits on contaminants in the finished
batch of dietary supplement (or subset
of finished batches) (final § 111.70(e)) to
ensure that the manufacturing process
has not adversely affected such levels,
e.g., has not contributed an additional
source of such contaminant or failed to
remove the contaminant, when
necessary. Such limits would need to
ensure the quality of the dietary
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supplement, i.e., to ensure that the
dietary supplement has been
manufactured, packaged, labeled, and
held under conditions to prevent
adulteration under section 402(a)(1),
(a)(2), (a)(3), and (a)(4) of the act.
Thus, in addition to the presence of
contaminants that may be in or on
components that you receive, there may
be sources of contamination that you
need to control for in your facility. As
discussed in this section, you must
establish specifications under final
§ 111.70(a) and (c) to prevent
adulteration from such sources. The
specifications established under final
§ 111.70(a) and (c) may or may not
include limits on such contaminants. By
‘‘limits on those types of
contamination’’ in final § 111.70, we do
not mean contamination from, for
example, the presence of rodent pellets
or other filth that would constitute an
insanitary condition under section
402(a)(3) or (a)(4) of the act, if such filth
was present in your facility. You are not
allowed to establish specifications for
limits on contaminants that would
otherwise adulterate your product under
the act if such contaminants were
present.
Further, in proposed § 111.35(k), we
included a listing of the types of
contamination we considered to be
applicable to dietary supplements (68
12157 FR at 12258). We stated that the
types of contamination include: (1)
Filth, insects, or other extraneous
material; (2) microorganisms; and (3)
toxic substances. We have deleted the
listing of the types of contamination in
the final rule because the listing is
simply informative and establishes no
independent requirement. We received
several comments, discussed in the
following paragraphs, on the types of
contamination that may be present,
some which were solicited by us in the
2003 CGMP Proposal (68 FR 12157 at
12179 through 12181).
In the 2003 CGMP Proposal, we
solicited comment on whether we
should include in the final rule specific
requirements for manufacturing,
packaging, or holding animal-derived
dietary ingredients, because animalderived dietary ingredients present
important public health and safety
issues.
In the 2003 CGMP Proposal, the
example we used was an animal-derived
dietary ingredient potentially
contaminated with the agent that causes
bovine spongiform encephalopathy
(BSE), which is a type of transmissible
spongiform encephalopathy (TSE). TSEs
are fatal, neurodegenerative disorders,
which have been identified in humans
and a number of animal species (e.g.,
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cattle, sheep, goats, elk, deer, cats, and
mink), but primarily in ruminants
(cattle, sheep, elk, deer) (69 FR 42256,
July 14, 2004). Most scientists believe
that variant Creutzfeldt Jakob Disease
(vCJD), a progressive neurological
disease in humans, is caused by
consumption of cattle products
contaminated with the agent that causes
BSE (69 FR 42256 at 42257).
In the 2003 CGMP Proposal (68 FR
12157 at 12180), we stated that we had
communicated with the public and
manufacturers of FDA-regulated
products about appropriate steps to
increase product safety and minimize
the risk of products contaminated with
the BSE agent. We referenced a notice
in the Federal Register of August 29,
1994 (59 FR 44591), entitled ‘‘BovineDerived Materials; Agency Letters to
Manufacturers of FDA-Regulated
Products.’’ We sent letters to dietary
supplements manufacturers to alert
them to the developing concern about
TSEs in animals and Creutzfeldt-Jakob
Disease in humans. We recommended
they investigate the source of any
bovine and ovine material used in their
products. We suggested that
manufacturers develop plans to ensure,
with a high degree of certainty, that
bovine and ovine materials used in their
products were not from BSE countries
or from sheep flocks (foreign or
domestic) infected with scrapie. We
stated that our Center for Biologics
Evaluation and Research (CBER) had
developed guidances for industry that
describe steps manufacturers should
take to ensure the safety and suitability
for human use of animal-derived
biologics. We also stated that we were
considering whether the procedures that
CBER recommends for a product with
animal-derived materials, substances, or
tissues would be appropriate for dietary
ingredients and dietary supplements
that contain animal-derived materials,
substances, or tissues. We believed that
the use of an animal-derived material,
substance, or tissue in a dietary
supplement may raise many of the same
serious public health and safety issues
as animal-derived materials, substances,
or tissues, in a biologic. We invited
comment on whether there is a
scientific basis for us to treat animalderived dietary ingredients in a manner
different from, or that would offer less
protection than, what is recommended
for animal-derived biologics when the
same public health and safety risks may
be present.
(Comment 152) Several comments
state there should not be specific
requirements for manufacturing,
packaging, or holding animal-derived
dietary ingredients because BSE issues
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are not specific to dietary supplements,
and because other guidance and
regulations, issued by FDA and by the
U.S. Department of Agriculture (USDA),
already address BSE and public health.
Other comments state it would be
appropriate to include specific CGMP
requirements for BSE as long as the
requirements reflect the thinking in
currently existing regulations and
guidance.
Several comments do not support the
need for additional provisions regarding
the handling of imported animalderived ingredients because the
industry has already taken steps to
comply with the requirements or
recommendations issued by either
USDA or FDA. The comments state that
the regulations issued by USDA for meat
related products in the food industry
provide adequate control over the use of
animal tissues that might contain
microorganisms, specifically viruses, of
public health concern.
One comment argues that if purchases
of domestic raw tissues have been
inspected by USDA, it is unfair to
impose additional regulations simply
because these tissues are included in
dietary supplements. This comment
asserts it would be unfair to require
testing of animal-derived products given
the fact that there are no tests for BSE
available, and that reliance on USDA
and FDA is the best way to stop the
spread of BSE.
Another comment states that industry
trade associations have been working
actively with their member companies
to ensure adherence to the requirements
set forth in our various letters regarding
the need to develop plans ‘‘that ensure,
with a high degree of certainty’’ that
animal-derived ingredients are used
only in accordance with FDA and USDA
policies designed to protect against BSE.
The comment states that a summary of
industry procurement and handling
practices regarding animal-derived
ingredients (submitted to us) contains
lists of animal-derived ingredients used
by various companies, with examples of
the certificates of origin and other
documentation required for import of
any animal-derived materials. One
comment states that industry members
who handle animal-derived ingredients
already have implemented many of the
controls that originated either from
USDA or the dietary ingredient
suppliers in response to demands by
various governments or consumers, and
that such matters should remain with
USDA to avoid duplication of effort.
Some comments oppose any
recommendation that guidance issued
by CBER for ensuring the safety and
suitability for human use of animal-
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derived biologics apply to dietary
supplement products. One comment
includes a review of literature on BSE
and claims the review justifies not
applying the CBER guidances on BSE to
dietary supplement products under part
111.
(Response) For cattle derived
materials, you must comply with the
requirements of the interim final rule on
BSE set forth in § 189.5 (see 70 FR
53063, September 7, 2005) and any
subsequent modifications. Under the
interim final rule, no human food,
including dietary supplements, shall be
manufactured from, processed with, or
otherwise contain, prohibited cattle
materials as defined in the rule. In
addition, manufacturers and processors
of such food that is manufactured from,
processed with, or otherwise contains,
cattle material must make existing
records relevant to compliance available
to us for inspection and copying. For
both cattle-derived and other animalderived materials, you must comply
with all applicable provisions of this
final rule. For example, under final
§ 111.70, you must establish
specifications for any point, step, or
stage in the manufacturing process
where control is necessary to ensure the
quality of the dietary supplement. Thus,
you must establish specifications for
your animal-derived materials that are
necessary to ensure the quality of the
dietary supplement. Ensuring quality
includes preventing contamination that
may adulterate the product under
section 402(a)(1), (a)(2), (a)(3), or (a)(4)
of the act. In addition, you must take
actions to determine whether the
specifications are met (final § 111.73).
Therefore, if you used animal-derived
materials other than prohibited cattle
materials subject to the BSE interim
final rule, you would need to establish
specifications necessary to ensure the
quality of the dietary supplement.
The guidances issued by CBER are
still in effect for animal-derived
biologics, and we continue to
recommend that you use them as
appropriate for your products that
contain animal-derived ingredients.
(Comment 153) One comment agrees
with the provisions of proposed
§ 111.35(k) but requests that we provide
guidance to the industry on allowable
limits for the types of contamination
listed. Another comment asks us to
develop specific defect action levels
(DALs) for dietary supplements as more
information becomes available, rather
than rely on existing DALs from the
food industry.
(Response) In the 2003 CGMP
Proposal (68 FR 12157 at 12163), we
stated that we were not identifying
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DALs for the types of contaminants for
dietary ingredients because there are not
enough data available to identify an
appropriate DAL for most dietary
ingredients. These comments do not
provide data, or evidence that data are
available, to enable us to issue guidance
for DALs for specific contamination.
Therefore, we are not taking the action
requested by these comments. We
discuss DALs in this section in response
to comment 156.
(Comment 154) Some comments
suggest the provisions in proposed
§ 111.35(k), testing for contamination
that could adulterate a product, would
be more appropriate to include in
proposed § 111.35(e), which concerns
the establishment of specifications.
(Response) We agree with these
comments and are including
requirements to include limits on
contamination in final § 111.70. The
requirements set forth in final §§ 111.70
and 111.75 are consistent with this
comment. Under final § 111.70(b) you
must establish limits on those types of
contamination that may adulterate or
may lead to adulteration of the finished
batch of the dietary supplement to
ensure the quality of the dietary
supplement. Under final § 111.70(c) you
must establish in-process specifications
for any point, step, or stage in the
master manufacturing record where
control is necessary to help ensure that
specifications are met for the identity,
purity, strength, and composition of the
dietary supplements, and as necessary,
limits on contamination for those types
of contamination that may adulterate or
may lead to adulteration of the finished
batch of the dietary supplement. Under
final § 111.70(e), you must establish
product specifications for the identity,
purity, strength, and composition of the
finished batch of the dietary
supplement, and for limits on those
types of contamination that may
adulterate, or that may lead to
adulteration of, the finished batch of the
dietary supplement to ensure the quality
of the dietary supplement. As we
explained in the response to comment
151, by ‘‘limits on those types of
contamination’’ in final § 111.70, we do
not mean contamination from, for
example, the presence of rodent pellets
or other filth that would constitute an
insanitary condition under section
402(a)(3) or (a)(4) of the act, if such filth
was present in your facility. You are not
allowed to establish specifications for
limits on contaminants that would
otherwise adulterate your product under
the act if such contaminants were
present.
(Comment 155) Several comments
object to proposed § 111.35(k) because
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the provision would be more stringent
than the food or drug CGMP
requirements. Some point out that the
consumption levels for food are higher
than for dietary supplements. A few
comments argue that proposed
§ 111.35(k) is too broad as it requires
testing or examination for those
contaminants that ‘‘may’’ adulterate or
‘‘may lead to’’ adulteration, which could
be interpreted to mean testing for
unknown contaminants of every
description. The comments suggest that
this provision be revised to require
testing or examination for those types of
contamination that ‘‘may be present in
an amount or at a level’’ that may
adulterate or lead to adulteration or that
‘‘may reasonably be expected’’ to
adulterate or lead to adulteration. Other
comments agree that to test for all
possible contaminants would be
burdensome.
Several comments state that
manufacturers should be allowed to rely
on a supplier’s certificate of analysis
and that testing should not be required
for every potential contaminant. One
comment recommends that CGMPs
should be specific to the source and that
testing should depend on the nature of
the material.
Some comments note that for
botanicals it is sometimes nearly
impossible to identify and analyze all
naturally occurring substances.
(Response) The final rule does not
include any specific requirements to test
or examine components or dietary
supplements for contamination. Rather,
under final § 111.70(b), (c), and (e), you
are required to establish specifications
for limits on those types of
contamination that may adulterate or
may lead to adulteration of the finished
batch of the dietary supplement. Under
final § 111.73, you must determine
whether the specifications established
under § 111.70 are met. Final § 111.75(a)
through (d) sets forth the criteria you
must use to determine whether the
specifications that you establish under
final § 111.70(b), (c), and (e) are met.
Consistent with these comments, under
final § 111.75(a) you may rely on a
certificate of analysis (other than for the
identity of a dietary ingredient) from a
qualified supplier of components to
ensure that specifications that include
limits on contamination are met,
provided you satisfy the criteria set
forth in final § 111.75(a). This would
include, for example, relying on a
certificate of analysis to ensure that the
level of lead in each of your components
would not adulterate the dietary
supplement.
In determining compliance with the
requirements to set limits for those
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types of contamination that may
adulterate the dietary supplement or
lead to adulteration for received
components, we would not expect you
to set limits for every potential
contaminant or for every naturally
occurring constituent of a botanical.
Rather, we agree with the comments
that the substances you would consider
when determining whether to set limits
for particular types of contamination
would vary depending on the source of
a component, such as a plant source, an
animal source, a microbial source, or a
marine source.
(Comment 156) Some comments point
out that some compounds, such as
mycotoxins, that are toxic at higher
levels are detectable in nearly all plant
ingredients and are found in the food
supply. A few comments assert that
dietary ingredients should not contain
levels of certain toxic compounds that
are higher than reasonable or higher
than recognized maximum allowable
limits as opposed to the zero tolerance
for toxic compounds contained in the
2003 CGMP Proposal.
One comment requests clarification of
the term ‘‘toxic substances.’’ One
comment points out that information for
identifying potential adulterants is
provided in monographs. Another
comment requests clarification on
whether dietary supplement
manufacturers will be required to test
for toxins while food manufacturers,
who may use some of the same
ingredients, will not.
(Response) As the comments point
out, the food supply does contain some
degree of contaminants such as
mycotoxins that can be found, for
example, in certain grain. We do not
have a ‘‘zero tolerance’’ policy for such
unavoidable contaminants but we have
issued some regulations and guidance to
address certain common contaminants.
We also have issued a booklet entitled
‘‘Action Levels For Poisonous Or
Deleterious Substances In Human Food
And Animal Feed’’ (Ref. 30; available at
https://www.cfsan.fda.gov). The booklet
is a useful resource for manufacturers
who seek information about common
contaminants that may adulterate a
dietary supplement product or lead to
adulteration. Another resource is the
Foods Chemical Codex,9 which includes
9The Food Chemicals Codex (FCC) project is an
activity of the Food and Nutrition Board of the
Institute of Medicine. The FCC was intended to
provide standards for the purity of food chemicals
and thus promote uniform quality and ensure safety
in the use of such chemicals. The First Edition of
the resulting FCC, published in 1966, was limited
to chemicals added directly to foods to achieve a
desired technological function. Succeeding editions
upgraded the specifications for these substances
and added specifications for substances that come
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monographs on many substances, such
as salts that are used as sources of
minerals used in both dietary
supplements and conventional food.
These monographs include limits on
common contaminants, such as lead or
other heavy metals. In addition, the
regulations in 21 CFR part 109 provide
information about certain contaminants.
(Comment 157) One comment
recommends that all finished products
be tested for microorganisms. Another
comment contends the manufacturer
should be allowed to restrict testing to
the raw material if the facility and
equipment are monitored for
contamination. Some comments point
out that contaminants may be detectable
in raw materials but not in the finished
product.
(Response) We disagree that all
finished products must, as a matter of
course, be tested for contamination with
microorganisms. Whether it is necessary
to test the finished product for
microorganisms would depend, for
example, on the characteristics of your
product, the nature and source of your
components, the specifications you
establish for microbial contaminants in
your components and whether these
specifications are addressed in a
certificate of analysis, the in-process
specifications you establish, and the
nature of your manufacturing process.
However, these comments raise an
important point—i.e., that microbial
contamination could occur at your
facility even if an incoming component
is free of microorganisms. Final subpart
K discussed in section XVI of this
document, sets forth requirements for
your manufacturing operations. Many of
these requirements are designed to limit
the potential for contamination with
microorganisms.
(Comment 158) Some comments
would revise the requirements for
establishment of specifications for inprocess controls (proposed
§ 111.35(e)(2)) and the finished batch of
dietary supplements (proposed
§ 111.35(e)(3)), so that specifications for
attributes of quality, strength, and
composition are not required for a
product that does not purport to possess
such attributes.
(Response) We decline to reword the
provision as requested by these
comments. The requirement to establish
specifications for strength and
composition relate to the manufacturers’
responsibility to know what their
finished dietary supplement is
into contact with foods and some that are regarded
as foods, rather than as additives. The FCC is
available for purchase at 1–800–624–6242 or at
https://www.nap.edu.
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composed of so that their products are
consistently manufactured. Establishing
specifications and following these
CGMP requirements will help ensure
the quality of the dietary supplement.
The requirement to establish
specifications is not limited to when a
manufacturer purports that its product
possesses attributes of strength and
composition on the label. As discussed
in the 2003 CGMP Proposal (68 FR
12157 at 12162), the absence of
minimum standards has contributed to
the adulteration and misbranding of
dietary supplements because of
contaminants or because manufacturers
do not set and meet specifications for
their products, including specifications
for identity, purity, strength, and
composition and do not set and meet
limits on contaminants, when
necessary. The comment does not
persuade us otherwise. We note,
however, that the final rule’s
requirements to establish specifications
for components do, in fact, provide
flexibility so that you are not required
to establish a component specification
for certain attributes, such as the
strength of a tablet coating agent (see the
discussion of final § 111.70(b) in this
section).
(Comment 159) One comment asks for
guidance as to what constitutes an
official or scientifically valid standard
for specifications.
(Response) We are not aware of any
officially recognized standard for
specifications. Specifications are critical
standards that are proposed and
justified by the manufacturer for each
product that the manufacturer produces.
The manufacturer establishes the set of
criteria to which a product should
conform to be considered acceptable for
its intended use. In general, a
specification may include a list of tests,
references to analytical procedures, and
appropriate acceptance criteria that are
numerical limits, ranges, or other
criteria for the tests described.
(Comment 160) One comment asks
that we clarify whether every
specification sheet must include
separate, specific qualitative or
quantitative standards, and tests to be
established for each attribute, or
whether a specification sheet can be
modeled after a compendial monograph.
Some comments state that product
specification sheets should be modeled
after pharmacopoeia monographs other
than those listed in the preamble to the
2003 CGMP Proposal.
(Response) These CGMP requirements
do not establish any requirements to
have a ‘‘specification sheet.’’ Rather, the
final rule (final § 111.70(a)) requires you
to establish a specification for any point,
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step, or stage in the manufacturing
process where control is necessary to
ensure the quality of the dietary
supplement and that the dietary
supplement is packaged and labeled as
specified in the master manufacturing
record. We require that you establish
specifications for components (final
§ 111.70(b)), in-process production
(final § 111.70(c)), labels and packaging
(final § 111.70(d)), the finished batch of
dietary supplement (final § 111.70(e)),
product that you receive from a supplier
for packaging and labeling (final
§ 111.70(f)), and the packaging and
labeling for the finished packaged and
labeled dietary supplement (final
§ 111.70(g)). The general requirement for
establishing specifications in final
§ 111.70(a) includes specifications, not
otherwise required in final § 111.70(b)
through (g), that the manufacturer
determines are necessary to achieve
quality, i.e., that are necessary to meet
the identity, purity, strength, or
composition of the dietary supplement
or that are necessary to prevent
adulteration under section 402(a)(1),
(a)(2), (a)(3), and (a)(4) of the act.
Requirements to establish
specifications to control for
contamination are included in final
§ 111.70(a), (b), (c), and (e). As
discussed earlier, the specifications for
contaminants in final § 111.70(b) refer to
those types of contamination of a
component or dietary supplement that
may adulterate or that may lead to
adulteration that are due to
contaminants that may be present in or
on the components that you receive,
based on the nature of the product, its
source, its handling prior to receipt, or
other reason. Limits are established by
the manufacturer for such contaminants
at receipt.
The requirement to establish
specifications to control for
contamination under final § 111.70(a)
and (c) include specifications necessary
to prevent adulteration under section
402(a)(1), (a)(2), (a)(3), and (a)(4) of the
act as a result of what the manufacturer
may do or fail to do in its manufacturing
operation, and not as a result of
contaminants that are in or on the
components received. For example, it
may be critical that a certain piece of
equipment be cleaned and/or sanitized
after handling certain raw materials to
ensure that there is no microbial
contamination from microorganisms of
public health significance to
components processed on the
equipment. If the manufacturer failed to
establish a specification for cleaning
and/or sanitizing after handling those
raw materials before processing
components, the manufacturer would
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have failed to establish a specification
required by final § 111.70(a) or (c)
necessary to prevent a type of
contamination that may lead to
adulteration under section 402(a)(4) of
the act. We would consider it a failure
to follow CGMP requirements if a
manufacturer allowed conditions in the
manufacture of a dietary supplement
that would not ensure the quality of the
dietary supplement.
We have specified in final § 111.70(b)
that you must establish certain types of
specifications that are critical to
ensuring that you know what the
components are that you use in
manufacturing a dietary supplement
and that are necessary to ensure that the
dietary supplements you manufacture
meet their specifications for identity,
purity, strength, composition, and do
not exceed their limits for contaminants.
The identity, purity, strength, and
composition, and the limits that you
establish for contaminants, for a
finished batch of dietary supplement are
what we call ‘‘product specifications’’ in
final § 111.70(e). These product
specifications must be met in order for
you to ensure the quality of your
finished batch of dietary supplement. A
specification may include a list of tests,
references to analytical procedures, and
appropriate acceptance criteria that are
numerical limits, ranges, or other
criteria for the tests described. For
example, a specification for a
component may include information
about the test used to verify the identity
of the component and the range of test
results that are acceptable. Under final
§ 111.70(c), a specification for an inprocess control may include
information about the viscosity that
must be achieved during a batch
production of a liquid product and
information about the test or equipment
used to measure the viscosity. Under
final § 111.70(d), a specification for
packaging may include the specific type
or grade of plastic. Under final
§ 111.70(e), a specification for the
finished batch may include the
quantitative amount of a dietary
ingredient, such as vitamin C.
Under this final rule, the
manufacturer has the flexibility—and
the responsibility—to develop
specifications that are appropriate to the
circumstances, including whether
information in any particular
monograph is an appropriate model for
a given dietary supplement.
1. Final § 111.70(a)
Final § 111.70(a) requires you to
establish a specification for any point,
step, or stage in the manufacturing
process where control is necessary to
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ensure the quality of the dietary
supplement and that the dietary
supplement is packaged and labeled as
specified in the master manufacturing
record. Final § 111.70(a) derives from
the opening statement in proposed
§ 111.35(e).
As we discussed in the preamble to
the 2003 CGMP Proposal (68 FR 12157
at 12196), the points, steps, or stages
where specifications must be
established may include heating steps,
cooling steps, points where specific
sanitation procedures are needed,
product formulation control steps,
points where cross-contamination may
occur, and steps where employee and
environmental hygiene are necessary to
ensure the quality of the dietary
supplement. These specifications are
regulatory specifications addressed by
these CGMP regulations. The final rule
does not prevent you from establishing
additional, nonregulatory specifications
that are not at points, steps, or stages
where control is necessary to ensure the
quality of the dietary supplement. For
example, you could establish
specifications that largely address the
appearance of the dietary supplement in
an aesthetic sense. Such nonregulatory
specifications are not addressed by the
final rule.
(Comment 161) One comment notes
that labelers would not be subject to
proposed § 111.35(e).
(Response) Consistent with final
§ 111.1, persons who perform labeling
operations are, in fact, subject to the
final rule, including the requirements to
establish specifications. As discussed in
this section, the final rule includes an
explicit requirement that, if you receive
a product from a supplier for packaging
or labeling as a dietary supplement (and
for distribution rather than for return to
the supplier), you must establish
specifications to ensure that the product
that you receive is adequately identified
and is consistent with your purchase
order (final § 111.70(f)).
(Comment 162) One comment asks
whether the manufacturer determines
where control is ‘‘necessary’’ to prevent
adulteration.
(Response) In accordance with the
changes made to the section, the
manufacturer does determine where
control is necessary to ensure the
quality of the dietary supplement.
(Comment 163) Some comments
express concern that manufacturers who
must confirm the validity of subjective
criteria established as specifications
may set the specifications as low as
possible or set meaningless
specifications.
(Response) The specifications you
must establish under this final rule are
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designed to ensure the quality of the
dietary supplement that you
manufacture. It is not meaningless to
establish requirements that will ensure,
for example, the product meets the
established specifications for identity,
purity, strength, and composition, and
is within specified limits on
contaminants to prevent adulteration.
(Comment 164) Some comments
express concern that the language of
proposed § 111.35(e) may require
specifications beyond those already
required in the master manufacturing
record, as stated in proposed
§ 111.45(a)(1), to identify specifications
for the points, steps, or stages in the
manufacturing process where control is
necessary to prevent adulteration, or
may require specifications for attributes
that are not present at all stages. These
comments urge us to be flexible during
inspections as to what specifications are
appropriate.
(Response) Final § 111.70(a) provides
the manufacturer with flexibility in
determining what specifications may be
necessary for its operation. Moreover,
final § 111.70(a) through (g) provide the
manufacturer with flexibility to
determine what the specifications
require in order to ensure the quality of
the dietary supplement.
2. Final § 111.70(b)
Final § 111.70(b) requires you to
establish component specifications for
each component you use in the
manufacture of a dietary supplement.
Under final § 111.70(b)(1), you must
establish an identity specification for
each component that you use in the
manufacture of a dietary supplement. A
specification for identity may include
more than one attribute. For example, a
specification for the identity of a salt
used in the manufacture of a vitamin
and mineral supplement may include
the physical characteristics of the solid
(e.g., as a crystal or as a powder), the
color, and the state of hydration (e.g.,
with two or three molecules of water).
A specification for the identity of a
botanical may include the part of the
plant (e.g., roots or leaves), the color,
and whether the part of the plant is in
a native state or has been ground. Under
final § 111.70(b)(2), you must establish
component specifications that are
necessary to ensure that specifications
for the purity, strength, and composition
of dietary supplements manufactured
using the components are met. Under
final § 111.70(b)(3) you must establish
limits on those types of contamination
that may adulterate or may lead to
adulteration of the finished batch of the
dietary supplement to ensure the quality
of the dietary supplement. Final
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§ 111.70(b) derives from proposed
§ 111.35(e)(1) and (k). Final § 111.70(b)
is consistent with comments, already
discussed, that recommended the
provisions of proposed § 111.35(k),
regarding contaminants that could
adulterate a product, be incorporated
into proposed § 111.35(e). In addition,
as discussed previously with respect to
final § 111.55, final § 111.70(b) provides
that the required component
specifications you must establish for a
dietary supplement include identity,
purity, strength, and composition.
(Comment 165) A few comments state
it is appropriate and acceptable to
establish a requirement for a
specification for the identity and purity
of components, insofar as such
specifications are necessary to ensure
that components are not contaminated
with substances having public health
significance. However, these comments
argue that specifications for quality,
strength, and composition of
components should only be required for
the quality, strength, and composition
that a component is purported to
possess. One comment notes this would
provide the same requirement that is
currently established for drug products
and processing. Some comments
recommend that specifications should
be established ‘‘as appropriate’’ or
‘‘where control is necessary to assure
production of a quality product.’’
(Response) After considering the
comments that questioned the need to
establish specifications for the identity,
purity, quality, strength, and
composition of components, as well as
the general comments that led to the
overall approach that focuses on
building quality into a dietary
supplement at every stage of the
production and process control system
(see discussion in section IV of this
document), we are requiring in final
§ 111.70(b)(1) that you establish an
identity specification for components
that you use. This identity specification
is necessary to ensure that the finished
dietary supplement meets its
specification for identity because you
could not know what your final product
contains if you do not know what you
put into it. In addition, final
§ 111.70(b)(2) requires you to establish
those component specifications for
purity, strength, and composition that
are necessary to ensure that
specifications for the purity, strength,
and composition of dietary supplements
manufactured using the components are
met.
Final § 111.70(b)(2) provides
flexibility for you to determine which
component specifications other than
identity are, or are not, necessary to
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ensure that the final dietary supplement
meets its specifications. For example, it
is likely that you will need to establish
a specification for the strength of
vitamin C added as a component, that
you use to make a multivitamin
supplement, so that you will know how
much vitamin C to add to satisfy the
specification for the strength of the
vitamin C in the final product. Thus, if
you are manufacturing a vitamin C
tablet with a strength of 50 milligrams
(mg) per tablet, you must determine
how much vitamin C, of a given
strength, you must add in order to
produce tablets that will contain 50 mg,
after accounting for the theoretical yield
at each step in the manufacturing
process. However, you may not need to
establish a specification for the strength
of the tablet coating agent for that
multivitamin supplement, if your final
specifications include the amount of the
tablet coating agent as part of the
specifications for the composition, but
not the strength of the multivitamin
supplement. In most cases, a
specification for the composition of the
dietary supplement would be sufficient
to ensure that the tablet coating agent is
used within the established level.
(Comment 166) A few comments
express concern about how to determine
certain specifications for botanicals,
such as the strength of peppermint leaf.
The comments explain that a
specification for strength of peppermint
leaf could be based on a number of
different attributes. One comment
argues that establishing specifications
for all dietary ingredients may not
contribute to any assurance of product
quality and will not protect public
health. Some comments assert that
‘‘quality, strength, and composition’’ are
subjective with respect to botanical
ingredients for which no potency claim
is made, and, thus, these attributes
should not be included in the rule.
Another comment asserts proposed
§ 111.35(e)(1) goes beyond either food or
drug CGMPs and that the composition
of approximately 1,200 botanicals used
in the industry will be impossible to
determine in an economically feasible
manner.
(Response) To the extent that these
comments assert that this final rule
should not require you to establish
specifications for the strength and
composition of botanical ingredients,
we disagree. As explained in response
to comment 145, it is fundamental to
CGMPs that you know what
components are used to manufacture
your dietary supplement and to ensure
that the finished batch of dietary
supplement contains the established
identity, purity, strength, and
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composition. As explained in response
to comment 40, this final rule does not
require that you establish specifications
for the identity, purity, strength, or
composition of the various constituents
that are inherently present in a natural
product such as a botanical. However,
as previously discussed in section VI of
this document, depending on what you
are manufacturing, the product
specifications for the finished batch of
a dietary supplement may include a
specification, for example, of the
strength of a substance that is present in
the dietary supplement because it is a
constituent of a natural product that you
add as a component. For example, you
may establish a specification for the
amount of vitamin C in a dietary
supplement that you manufacture by
adding the component rose hips. If this
is the case, then the component
specifications for the natural product
must include a specification for the
strength of the constituent (e.g., vitamin
C) in whatever amount you determine is
necessary to meet the specification for
the constituent (vitamin C) in the
finished batch of dietary supplement.
(Comment 167) One comment asserts
it would be more appropriate for
proposed § 111.35(e)(1) to address
components ‘‘that you purchase’’ than
to address components ‘‘that you
receive,’’ because customers sometimes
provide the ingredient or product to be
processed and the customer, rather than
the manufacturer, establishes the
specifications.
(Response) Final § 111.70(b) (derived
from proposed § 111.35(e)(2)) requires
that component specifications be
established for each component that you
use in the manufacture of a dietary
supplement. Thus, the firm must
establish specifications for the
components it uses to manufacture a
dietary supplement, regardless of
whether it manufactures the
components itself or contracts with
another firm to manufacture the
components. The firm that conducts the
manufacturing operations, as explained
in section VI of this document, would
be responsible for complying with all
relevant CGMP requirements in this
final rule related to its operations.
(Comment 168) One comment asserts
that proposed § 111.35(e)(1) is
unnecessary because the requirements
for testing to meet the manufacturer’s
specifications are described elsewhere.
(Response) We disagree. The
requirements to establish specifications
are distinct from what you must do to
determine whether specifications are
met. Under the final rule (§ 111.73), you
have a responsibility to determine
whether the established specifications
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are met. What criteria you must use in
order to determine whether
specifications are met are set forth in
final § 111.75.
3. Final § 111.70(c)
Final § 111.70(c)(1) requires you, for
in-process production, to establish inprocess specifications for any point,
step, or stage in the master
manufacturing record where control is
necessary to help ensure that
specifications are met for the identity,
purity, strength, and composition of the
dietary supplements and, as necessary,
for limits on those types of
contamination that may adulterate or
may lead to adulteration of the finished
batch of the dietary supplement. Final
§ 111.70(c)(1) derives from proposed
§ 111.35(e)(2). Final § 111.70(c)(1)
includes a nonsubstantive, editorial
change that we are making for
consistency with other regulations in
part 111. This change is to refer to ‘‘inprocess specifications for any point,
step, or stage in the master
manufacturing record where control is
necessary’’ rather than ‘‘in-process
controls in the master manufacturing
record where control is necessary.’’
We also have added that you must
establish in-process specifications, as
necessary, for limits on those types of
contamination that may adulterate or
may lead to adulteration of the finished
batch of the dietary supplement. This
clarifies that if it is necessary to
establish limits on contaminants inprocess, due to contamination that may
occur in the facility you do so under
final § 111.70(c)(1). With a requirement
to set, as necessary, limits on
contamination in-process, aspects of the
production and process system from
receipt to finished product are covered
with respect to contamination. For
example, under final § 111.70(e) you
may determine that you need to
establish a microbiological specification
that the aerobic plate count of your
finished batch of the dietary supplement
will not exceed a certain number of
colony forming units per gram of
product. Under the written instructions
in your master manufacturing record
(final § 111.210(h)) and your written
procedures for manufacturing
operations (final § 111.353), you would
establish controls to prevent microbial
contamination at each point, step, or
stage in the manufacturing process
where control is necessary to prevent
microbial contamination. To ensure that
you will meet the microbiological
specification that you set for the
finished batch of the dietary
supplement, you may determine that it
is necessary to establish a specification
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for the aerobic plate count at an
intermediate stage of the in-process
production.
Final § 111.70(c)(2) requires you, for
in-process production, to provide
adequate documentation of your basis
for why meeting the in-process
specifications, in combination with
meeting component specifications, will
help ensure that the specifications are
met for identity, purity, strength, and
composition of the dietary supplements
and for limits on those types of
contamination that may adulterate or
may lead to adulteration of the finished
batch of the dietary supplement. Final
§ 111.70(c)(3) requires that quality
control personnel review and approve
the documentation you provide under
final § 111.70(c)(2). Final § 111.70(c)(3)
also derives in part from proposed
§ 111.37(b)(1) which would require the
quality control unit to approve or reject
all processes that may affect the
identity, purity, strength, or
composition of a dietary supplement.
In final § 111.70(c)(2), we are
requiring documentation that includes
the basis for why meeting the in-process
specifications, in combination with
meeting the component specifications
will help ensure the specifications for
the identity, purity, strength, and
composition of the dietary supplement
and limits on contamination are met.
Meeting in-process specifications alone
may not ensure the identity, purity,
strength, or composition of the dietary
supplement, but information about the
component specification may be needed
in order to put the results from the inprocess specification in perspective. For
example, if the manufacturer establishes
a component specification for lead that
it not be greater than ‘‘x’’ mg and
establishes a specification that all
piping that comes into contact with the
component be lead free in the facility,
and there are no other components or
equipment that would be a source of
lead, then there should be no added
lead from processing, provided that the
material only came in contact with the
lead-free pipes and only the other leadfree components and equipment are
used. Thus, we would not know by
looking solely at the in-process
specification whether the lead in the
final product is not greater than ‘‘x’’ mg.
We would need to evaluate the
component specification, in addition to
the in-process specification, to ensure
that the final product contains no
greater than ‘‘x’’ mg lead. To emphasize
the interplay of the specifications and
component specifications in ensuring
the specifications are met for the
identity, purity, strength, and
composition of dietary supplements,
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and, as necessary, for limits on
contamination, final § 111.70(c)(1) and
(c)(2) state ‘‘help ensure’’ rather then
‘‘ensure’’ the identity, purity, strength,
and composition of dietary supplements
and for limits on contamination.
(Comment 169) One comment asserts
monitoring and process controls are
more practical and effective than the
proposed requirements for in-process
testing, which the comment asserts are
overly broad and could impose an
undue burden on small businesses.
(Response) The comment’s objection
is unclear. The final rule requires that
you establish in-process specifications
for any point, step, or stage in the
master manufacturing record where
control is necessary in the
manufacturing process to help ensure
that specifications are met for the
identity, purity, strength, and
composition of the dietary supplement
and, as necessary, for limits on
contamination. You must monitor the
in-process points, steps, or stages, where
control is necessary to ensure the
quality of the finished batch of dietary
supplement, to determine whether the
in-process specifications are met and to
detect any deviation or unanticipated
occurrence that may result in a failure
to meet specifications (see final
§ 111.75(b)). The final rule does not
establish specific requirements for inprocess monitoring. The manufacturer
must determine any in-process
monitoring that is necessary to ensure
that the specifications are met for the
finished batch. Examples of such
monitoring include measuring pH or
viscosity.
4. Final § 111.70(d)
Final § 111.70(d) requires you to
establish specifications for dietary
supplement labels (label specifications)
and for packaging that may come in
contact with dietary supplements
(packaging specifications). Final
§ 111.70(d) derives from proposed
§ 111.35(e)(4). Further, § 111.70(d)
requires that packaging that may come
into contact with dietary supplements
must be safe and suitable for its
intended use and must not be reactive
or absorptive or otherwise affect the
safety or quality of the dietary
supplements, consistent with proposed
§ 111.35(e)(4). We deleted the phrase
‘‘comply with other statutory and
regulatory provisions’’ from proposed
§ 111.35(e)(4) because the requirement
was redundant to final § 111.5.
5. Final § 111.70(e)
Final § 111.70(e) requires you, for
each dietary supplement that you
manufacture, to establish product
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specifications for the identity, purity,
strength, and composition of the
finished batch of the dietary
supplement, and for limits on those
types of contamination that may
adulterate or may lead to adulteration of
the finished batch of the dietary
supplement, all to ensure the quality of
the dietary supplement. Final
§ 111.70(e) derives from proposed
§ 111.35(e)(3) and (k). Final § 111.70(e)
is consistent with comments, already
discussed, recommending that the
provisions of proposed § 111.35(k)
regarding contaminants that could
adulterate a product be incorporated
into proposed § 111.35(e).
6. Final § 111.70(f)
Final § 111.70(f) requires you, if you
receive a product from a supplier for
packaging or labeling as a dietary
supplement (and for distribution rather
than for return to the supplier), to
establish specifications to provide
sufficient assurance that the product
you receive is adequately identified and
is consistent with your purchase order.
Final § 111.70(f) derives from proposed
§ 111.35(e)(1) which would, in part,
require you to establish specifications
for dietary supplements that you
receive. Final § 111.70(f) includes
changes we are making after considering
comments.
(Comment 170) One comment notes
that labelers would not be subject to
proposed § 111.35(e). Other comments
request we clarify the roles of the
various parties in the ‘‘pre-consumer
supply chain’’ for dietary supplements.
One comment suggests that
manufacturers and packagers be
responsible for establishing
specifications only for the operations
occurring in their own facility or for
which they are otherwise responsible
(e.g., subcontracted operations), not for
upstream or downstream operations
over which they may not have any
control. This comment states that we
intended to relieve packagers from
establishing specifications for the
dietary supplements that they package,
and also states that such requirements
should not be in the CGMP regulations.
(Response) We have discussed, in
section VI of this document, who is
subject to the final rule under § 111.1 in
what the comment describes as the
‘‘pre-consumer supply chain’’ and do
not repeat that discussion. We agree that
packagers and labelers must establish
specifications for the dietary
supplements that they package and did
not intend to relieve them of complying
with relevant CGMP requirements. We
recognize that a firm that only packages
and labels a product may rely on
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information about the content of the
product that it receives from the
manufacturer. The information may
consist of an invoice, certificate,
guarantee, or other form of verification
as to what the product consists of so
that the packager or labeler has adequate
information about the dietary
supplement it receives to label the
product and to ensure that the product
is consistent with its purchase order.
Therefore, we are setting forth certain
requirements that distinguish a product
you receive for packaging or labeling as
a dietary supplement (and for
distribution rather than for return to the
supplier) from a product you
manufacture. One such requirement is
final § 111.70(f) which requires you to
establish specifications for a product
you receive for packaging or labeling as
a dietary supplement (and for
distribution rather than for return to the
supplier).
The inclusion of final § 111.70(f), or
any other provision that relates
explicitly to a product you receive for
packaging or labeling as a dietary
supplement, does not alter the fact that
such a product is no different from any
other dietary supplement as far as the
applicability of these CGMP
requirements.
Under final § 111.70(f), the
specifications you establish for a
product you receive for packaging or
labeling as a dietary supplement must
provide sufficient assurance that the
received product is adequately
identified and is consistent with your
purchase order. For example, you may
be purchasing tablets that provide 500
mg (strength) (quantitative amount per
serving) of vitamin C (identity).
Therefore, your purchase order would
need to include the identity and amount
of vitamin C per tablet to distinguish it
from other tablets of vitamin C that may
contain only 60 mg, or from other
vitamin tablets of 500 mg that you may
also purchase.
Final § 111.70(f) sets forth a
requirement for a product you receive
for packaging or labeling as a dietary
supplement that will be distributed by
you, rather than returned to the firm
from which you receive the product.
Thus, § 111.70(f) applies to product that
has left the control of the person who
manufactured the batch.
If you are a packager or labeler who
packages and labels for the
manufacturer and you will return the
packaged and labeled dietary
supplement to the manufacturer, we
would not consider that you are
‘‘receiving’’ product within the meaning
of final § 111.70(f). Thus, you would not
be subject to final § 111.70(f).
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(Comment 171) Some comments
assert that ‘‘packaging’’ should be
included with ‘‘manufacturing process,’’
but that a firm involved only in
‘‘holding’’ a product should not have to
set specifications.
(Response) Under final § 111.70(a), a
person who holds packaged and labeled
dietary supplements for distribution and
who does no manufacturing, packaging,
or labeling, would be required to
establish a specification for any point,
step, or stage in the manufacturing
process where control is necessary to
ensure the quality of the dietary
supplement. For example, a person may
need to establish a specification for the
temperature at which the product will
be held. However, a person who only
holds packaged and labeled dietary
supplements for distribution is not
required to establish component
specifications (final § 111.70(b)), inprocess specifications (final § 111.70(c)),
specifications for labels and for
packaging (final § 111.70(d)), product
specifications (final § 111.70(e)),
specifications for product received from
a supplier for packaging as a dietary
supplement (and for distribution rather
than for return to the supplier) (final
§ 111.70(f)), or specifications for the
packaging and labeling of the finished
packaged and labeled dietary
supplements (final § 111.70(g)) because
the person does not engage in any of
those activities. This is consistent with
the views expressed by the comments
regarding the applicability of proposed
§ 111.35(e) to persons who only hold
packaged and labeled dietary
supplements for distribution.
7. Final § 111.70(g)
Final § 111.70(g) requires you to
establish specifications for the
packaging and labeling of the finished
packaged and labeled dietary
supplements, including specifications
that ensure you used the specified
packaging and you applied the specified
label.
Final § 111.70(g) is a new provision
we are adding for clarity and
consistency. We had proposed to
require that you conduct a material
review and make a disposition decision
of any packaged and labeled dietary
supplements that do not meet
specifications (proposed § 111.70(c)).
We proposed minimum standards for
packaged and labeled dietary
supplements—i.e., we would require
that the quality control unit collect
representative samples of each batch of
packaged and labeled dietary
supplements to determine whether you
used the packaging specified in the
master manufacturing record and
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applied the label specified in the master
manufacturing record (proposed
§ 111.37(b)(11)(iv)). Final § 111.70(g)
includes the minimum standards that
we proposed to establish for packaged
and labeled dietary supplements in
proposed § 111.37(b)(11)(iv).
To make clear that the use of
packaging and labels for a final
packaged and labeled product must be
that which is specified in the master
manufacturing record, we have created
a separate provision (under final
§ 111.70(g)) requiring you to create the
relevant specifications to be met.
Final § 111.70(g) requires you to
establish specifications that ensure you
use the ‘‘specified packaging’’ and to
apply the ‘‘specified label’’ as we
proposed under proposed
§ 111.37(b)(11)(iv). We removed the
words ‘‘specified in the master
manufacturing record’’ as an editorial
change that we are making to simplify
the language of the requirement.
As already explained (see discussion
of final § 111.70(a)), the specifications
you establish under final § 111.70 are
regulatory specifications required by
these final CGMP requirements. The
final rule would not prevent you from
establishing additional, nonregulatory
specifications, such as specifications
that largely address the appearance of
the dietary supplement in an aesthetic
sense.
H. What is Your Responsibility for
Determining Whether Established
Specifications Are Met? (Final § 111.73)
Final § 111.73 requires you to
determine whether all specifications
you establish under final § 111.70 are
met. The criteria for determining
whether the specifications that you
establish under final § 111.70 are met
are set forth in final § 111.75. The
oversight by quality control personnel
for determining whether specifications
established under final § 111.70 are met
in accordance with the criteria
established under final § 111.75 and
under what conditions quality control
personnel can approve deviations from
specifications are set forth in final
§ 111.77 and final subpart F. Although
final § 111.73 requires you to determine
whether specifications are met, it is the
responsibility of quality control
personnel to conduct a material review
and make a disposition decision if a
specification established in accordance
with final § 111.70 is not met.
Final § 111.73 derives, in part, from
proposed § 111.35(f), (g), and (h). Final
§ 111.73 includes changes associated
with reorganization, and other revisions
associated with final § 111.70. Final
§ 111.73 neither includes any finished
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batch testing requirements that derive
from proposed § 111.35(g)(3) nor
specifies what you must do to determine
whether all specifications are met
because the requirements for what
means and methods you must use to
determine whether specifications are
met, including certain requirements for
testing, are set forth in final § 111.75.
The comments relevant to final
§ 111.73 are the general comments that
recommend an overall approach that
focuses on building quality into a
dietary supplement throughout the
production and process control system.
Because the primary focus of the
relevant comments is on the proposed
requirements for testing, we discuss
those comments when we describe the
derivation of the testing requirements in
final § 111.75.
I. What Must You Do to Determine
Whether Specifications Are Met? (Final
§ 111.75)
Final § 111.75 derives from proposed
§§ 111.35(f), (g), (h), (k), and (l);
111.37(b)(11); and 111.40(a) and (b).
Final § 111.75 describes the steps you
must take to determine whether
specifications are met.
(Comment 172) Many comments
assert that the CGMPs for dietary
supplements should place greater
emphasis on in-process controls and
HACCP principles. The comments state
FDA’s narrow focus on finished product
testing is not in line with the
philosophy of HACCP, in which
manufacturing steps are controlled and
verified so as to result in end products
that are safe, with minimal finished
product testing. One comment cites a
1997 document entitled ‘‘Hazard
Analysis and Critical Control Point
Principles and Application Guidelines’’
in which we state that ‘‘[A]n effective
HACCP system requires little endproduct testing, since sufficient
validated safeguards are built-in early in
the process.’’ (Ref. 31).
(Response) In the 1997 ANPRM, we
asked for comments on whether certain,
or all, of the requirements for
manufacturing and handling dietary
ingredients and dietary supplements
may be more effectively addressed by a
regulation based on the principles of
HACCP, rather than the system outlined
in the industry submission (62 FR 5700
at 5708). HACCP is a science-based,
systematic approach to preventing food
safety problems by anticipating how
such problems are most likely to occur
and by installing effective measures to
prevent them from occurring. The
HACCP concept is a systematic
approach to the identification and the
assessment of risk (likelihood of
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occurrence and severity), and control of
the biological, chemical, and physical
hazards associated with a particular
food production process or practice.
HACCP is a preventive strategy. It is
based on development by the food
producer of a plan that anticipates food
safety hazards and identifies the points
in the production process where a
failure would likely result in a hazard
being created or allowed to persist;
these points are referred to as critical
control points (CCPs).
Under HACCP, identified CCPs are
systematically monitored, and records
kept of that monitoring. Corrective
actions are taken when control of a CCP
is lost, including proper disposition of
the food produced during that period,
and these actions are documented.
Thus, the focus of a HACCP-based
approach is to anticipate food safety
hazards, take actions to prevent them,
and keep records of both the actions
taken to prevent problems and the
actions taken if a problem nonetheless
occurs.
As discussed in the preamble to the
2003 CGMP Proposal (68 FR 12157 at
12174), most of the comments that we
received to the ANPRM opposed basing
a CGMP regulation for dietary
supplements on HACCP principles.
Consistent with those comments, we
proposed certain requirements that,
although consistent with a HACCPbased approach, did not require a
HACCP-based approach. For example,
proposed § 111.65 would establish
requirements for manufacturing
operations, including several proposed
requirements to prevent contamination
of components or dietary supplements,
but would not require that you develop
a specific plan for the precautions that
you would take, or that you keep
records of any monitoring that was
directed solely at preventing specific
types of contamination.
In contrast to the specific focus of
HACCP to anticipate food safety
hazards, take actions to prevent them,
and keep records of both the actions
taken to prevent problems and the
actions taken if a problem nonetheless
occurs, CGMP requires that you take all
necessary steps to both prevent hazards
and ensure that the product that you
manufacture is what you established in
your specifications. The proposed
testing requirements were directed at
ensuring that a dietary supplement
meets all of its established
specifications, including specifications
for the identity, purity, strength, and
composition, rather than on ensuring
only that specific food safety hazards
that you take steps to prevent are not,
in fact, present in the dietary
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supplement. The comments that assert
that the CGMP requirements should
place greater emphasis on HACCP
principles and, in so doing, reduce the
requirements to test product at the
finished batch stage, did not explain
how the preventive measures that are
associated with a HACCP plan would be
effective at ensuring that a dietary
supplement is what you established it to
be in your specifications. Therefore, we
are not, as the comments request,
including additional HACCP
requirements as part of the overall
approach set forth in this final rule.
In the 2003 CGMP Proposal, we noted
that you may voluntarily choose to
implement a HACCP plan that meets the
requirements of the National Advisory
Committee on Microbiological Criteria
for Foods, but that proposed part 111
would still apply to you (68 FR 12157
at 12174). We also noted that any
HACCP plans that are intended to meet
the records requirements under
proposed part 111 would be treated as
records under the CGMP regulations.
(Comment 173) One comment states
that it supports a requirement that a
firm ensure that specifications have
been met and asserts that the 2003
CGMP Proposal failed to do so. This
comment asserts the specific testing
requirements in proposed § 111.35(g)(1)
and (g)(2) must be significantly
modified and suggests that a more
effective approach would be to establish
separate requirements for ensuring that
specifications are met in each of the four
categories addressed by proposed
§ 111.35(e): Goods received
(§ 111.35(e)(1)), in-process controls
(§ 111.35(e)(2)), manufactured goods
(§ 111.35(e)(3)), and labels and
packaging (§ 111.35(e)(4)).
(Response) The final rule is consistent
with this comment. Final § 111.70
requires you to establish certain
specifications (including specifications
for components, in-process controls, the
finished batch and packaging and
labels), and final § 111.75 sets forth the
requirements for what you must do to
determine whether those specifications
are met.
1. Final § 111.75(a)
Final § 111.75(a)(1) requires you,
before you use a component that is a
dietary ingredient, to conduct at least
one appropriate test or examination to
verify the identity of the dietary
ingredient. We recognize, however, that
it may be possible for a manufacturer to
demonstrate, through various methods
and processes in use over time for its
particular operation, that a system of
less than 100 percent identity testing
would provide no material diminution
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of assurance of the identity of the
dietary ingredient as compared to the
assurance provided by 100 percent
identity testing. To provide an
opportunity for a manufacturer to make
such a showing and reduce the
frequency of identity testing of
components that are dietary ingredients
from 100 percent to some lower
frequency, we decided to provide, in an
interim final rule published elsewhere
in this issue of the Federal Register, a
procedure that allows for submission to,
and review by, FDA of an alternative to
the required 100 percent identity testing
of components that are dietary
ingredients, provided certain conditions
are met.
Final § 111.75(a)(2) requires you,
before you use a component, to confirm
the identity of other components and
determine whether other applicable
component specifications established in
accordance with § 111.70(b) are met. To
do so, final § 111.75(a)(2) requires you
to either conduct appropriate tests or
examinations (final § 111.75(a)(2)(i)); or
rely on a certificate of analysis from the
suppler of the component that you
receive (final § 111.75(a)(2)(ii)). Final
§ 111.75(a)(2)(ii) sets forth the criteria
that you must satisfy in order to rely on
a certificate of analysis from a supplier:
• You must first qualify the supplier
by establishing the reliability of the
supplier’s certificate of analysis through
confirmation of the results of the
supplier’s tests or examinations;
• The certificate of analysis must
include a description of the test or
examination method(s) used, limits of
the test or examinations, and actual
results of the tests or examinations;
• You must maintain documentation
of how you qualified the supplier;
• You must periodically re-confirm
the supplier’s certificate of analysis; and
• Quality control personnel must
review and approve the documentation
setting forth the basis for qualification
(and re-qualification) of any supplier.
Final § 111.75(a)(1) and (a)(2) derive,
in part, from proposed § 111.35(g) and
(h) and proposed § 111.40(a)(2) and
(a)(3). Final § 111.75(a)(1) and (a)(2)
include changes that we are making
after considering comments to proposed
§§ 111.35 and 111.40(a).
(Comment 174) Many comments
assert that a certificate of analysis from
a properly certified supplier can be a
key element of the manufacturing
process, and reduce the need for testing
at the finished batch stage. Some
comments specifically recommend the
dietary supplement manufacturer
conduct identity tests to ensure that the
correct component has been received
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(also, see comment 145 of this
document).
Some comments recommend an
appropriate vendor qualification
program, including a combination of
vendor audits and product testing, to
alleviate the need for complete testing of
every lot of incoming components.
Several comments stress that a
meaningful certificate of analysis must
be based on the results of actual
analytical testing. One comment adds
that reliance on a supplier’s certificate
of analysis should be conditioned on a
qualification program whereby the
recipient independently verifies the
supplier’s ability to conduct tests and
verifies test results through
confirmatory testing.
Many comments provide suggestions
for ways in which manufacturers could
demonstrate the reliability of a
certificate of analysis, which include the
following: (1) Identity testing of
ingredients and components, (2)
maintenance of documentation of
appropriate test results, (3) appropriate
verification of the information provided
initially and at appropriate intervals,
and (4) documentation that any
suppliers have adequate CGMP
programs in place.
Some comments recommend that
vendor certification programs include
plant visits and inspections, while other
comments do not believe manufacturers
should be required to conduct plant
inspections. Other comments
recommend that vendor certification
programs include CGMP audits or
process reviews at supplier facilities;
verification of laboratory test results
against a certificate of analysis; and 100
percent inspection and testing of
incoming materials for a specified
period of time while reliability is being
assessed.
Some comments provide suggestions
for the types of information that should
be included on an acceptable certificate
of analysis, such as moisture, sieve
analysis, identity, and results of tests
against established raw material
specifications and specifications of any
compendia referenced on the label. One
comment suggests that a certificate of
analysis could be converted into sworn
affidavits to guarantee their reliability.
Some comments suggest that a system of
testing one batch for agreement with the
certificate of analysis, and then relying
on this information for future purchases,
would work well if the suppliers are
required to provide reliable and valid
certificate of analysis documents. One
comment suggests we issue guidelines
as to what should be included in a
properly verified certificate of analysis.
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Some comments address the
requirement in proposed § 111.40(a)(2)
to ‘‘Visually examine the suppliers
invoice, guarantee, or certification
* * * and perform testing, as needed, to
determine whether specifications are
met.’’ One comment agrees with this
proposed requirement and asserts that
the supplier’s certification is not
sufficient to ensure that appropriate
standards are met. Other comments,
however, disagree with this aspect of
the proposed requirement or ask for
further clarification. A few comments
assert that manufacturers should not
have to retest material already tested by
a supplier. Some comments note that a
certificate of analysis can be used for
ensuring received materials are
consistent with the purchase order, and
assert the certificate of analysis can be
an appropriate way to ensure
specifications are met without requiring
testing. One comment suggests the
phrase ‘‘perform testing, as needed’’ be
replaced with ‘‘perform testing, if
necessary’’ and that the CGMP
regulations allow for the use of a
certificate of analysis that has been
verified through a vendor certification
process. Another comment states that
the provisions requiring testing in
proposed § 111.40(a)(2) are more
burdensome than those required of food
and pharmaceutical products and cites
the drug CGMP provision that permits
the use of certificates of analysis in lieu
of testing for conformity with written
specifications. One comment supports
the idea of testing upon receipt in the
specific circumstance when testing
cannot be performed on the finished
product.
Several comments contend that there
is a conflict between the 2003 CGMP
Proposal and our position during our
stakeholder meetings. The comments
assert that, at the meetings, FDA
representatives recognized that a
verified certificate of analysis is
acceptable, provided it is based on
appropriate testing from suppliers who
are audited by their customers as to
their testing and manufacturing
practices.
A few comments say the 2003 CGMP
Proposal should allow more reliance on
strict chain of custody and
documentation requirements. Other
comments recommend that
manufacturers not be required to retest
previously tested incoming ingredients
if they arrive with the vendor’s seal
intact. Rather, the purchaser should be
able to rely on the vendor’s test results,
as presented in a verified certificate of
analysis, unless there has been a breach
in quality control during distribution
and subsequent manufacture. One
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comment notes the Canadian
regulations for Natural Health Products
allow periodic testing of ingredients if a
manufacturer has satisfactory evidence
that the raw materials sold to him/her
are consistently manufactured in
compliance with established
specifications.
(Response) We agree that CGMP
requires that a person who
manufactures a dietary supplement
conduct at least one appropriate test or
examination to verify the identity of
each dietary ingredient that will be used
in the manufacture of the dietary
supplement. For example, because some
botanicals require microscopic
examination and comparison to a
reference to be distinguished, and
because suppliers of such botanicals
may manufacture several of these
botanicals, it is important to verify that
a botanical that you receive from a
supplier is the correct botanical. In
some cases, a single test or examination
may be all that is needed to verify the
identity of a dietary ingredient; in other
cases, it may be necessary to conduct
more than one test or examination. It is
the responsibility of the manufacturer to
determine the appropriate test(s) or
examination(s) necessary to verify the
identity of a dietary ingredient.
The comments discussed the
importance of testing all components for
identity and did not appear to limit
their recommendation for conducting
identity tests to those components that
are dietary ingredients. Based on the
comments, we conclude that many firms
would conduct an identity test for most
ingredients and other components
rather than limit identity testing to
dietary ingredients. However, because
dietary ingredients are the central
defining ingredient of a dietary
supplement, final § 111.75(a) only
requires you to conduct tests or
examinations to verify the identity of
any component that is a dietary
ingredient. As discussed previously in
this section, we recognize, however, that
it may be possible for a manufacturer to
demonstrate, through various methods
and processes in use over time for its
particular operation, that a system of
less than 100 percent identity testing
would provide no material diminution
of assurance of the identity of the
dietary ingredient as compared to the
assurance provided by 100 percent
identity testing. To provide an
opportunity for a manufacturer to make
such a showing and reduce the
frequency of identity testing of
components that are dietary ingredients
from 100 percent to some lower
frequency, we decided to provide, in an
interim final rule published elsewhere
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in this issue of the Federal Register, a
procedure that allows for submission to,
and review by, FDA of an alternative to
the required 100 percent identity testing
of components that are dietary
ingredients, provided certain conditions
are met. For components other than
dietary ingredients you must confirm
the identity of the component and you
have the flexibility of relying on a
certificate of analysis, in lieu of
conducting a test or examination, to
confirm identity. The preamble to the
2003 CGMP Proposal discussed why we
were not proposing that you could rely
on a certificate of analysis, but did not
express a view as to whether the
establishment of minimum criteria for
how you would qualify the supplier,
and for what must be included on the
certificate of analysis, could alleviate
our concerns about whether the
certificate of analysis could ensure
certain attributes of dietary
supplements.
After considering the comments, we
also are persuaded that it is possible to
rely on a certificate of analysis from the
supplier, for attributes other than
identity of the dietary ingredient,
provided you satisfy certain minimum
criteria set forth in final
§ 111.75(a)(2)(ii). These criteria include
qualifying the supplier, maintaining
documentation of how you qualified the
supplier, periodically reconfirming the
supplier’s certificate of analysis, and
having quality control personnel review
and approve the documentation setting
forth the basis for qualifying the
supplier. These criteria also require that
the certificate of analysis, at a
minimum, includes a description of the
test or examination method(s) used,
limits of the tests or examinations, and
the actual results of the tests or
examinations. Under final
§ 111.75(a)(2)(ii)(A), to qualify the
supplier you must establish the
reliability of the supplier’s certificate of
analysis through confirmation of the
supplier’s tests or examinations.
Certain comments request that we
provide guidance on what should be
included in a certificate of analysis. As
stated earlier in this section, a certificate
of analysis is a document, provided by
the supplier of a component prior to or
upon receipt of the component, that
documents certain characteristics and
attributes of the component. Instead of
guidance, we are establishing, in final
§ 111.75(a)(2)(ii)(B), minimum criteria
that a certificate of analysis must meet
to satisfy these CGMP requirements. As
we gain experience in applying the
CGMP regulations, we will consider
whether it is appropriate to provide
guidance on certificates of analysis.
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(Comment 175) One comment asks if
a raw material contains an unknown
amount of excipients, is it necessary to
quantify the excipients or can a
company simply assess the active
material and rely on a vendor’s
specification for the excipient content?
(Response) To the extent that this
comment is asking whether it is
necessary to set a component
specification for the strength of
excipients that are present in a dietary
supplement, the final rule does not
require you to do so provided that such
a component specification is not
necessary to ensure that the
specifications for the purity, strength,
composition, or contamination limit for
the dietary supplement manufactured
using the excipients are met (final
§ 111.70(b)(2)). If such a strength
specification for an excipient is
necessary to ensure that the purity,
strength, or composition specifications
are met, or that a contamination limit is
met for the dietary supplement, you
could, as the comment suggested, rely
on a certificate of analysis for that
quantitative information provided that
you satisfy the criteria set forth in final
§ 111.75(a).
2. Final § 111.75(b)
Final § 111.75(b) requires that you
monitor the in-process points, steps, or
stages where control is necessary to
ensure the quality of the finished batch
of dietary supplement, to determine
whether the in-process specifications
are met, and to detect any deviation or
unanticipated occurrence that may
result in a failure to meet specifications.
Final § 111.75(b) derives from proposed
§ 111.35(f) with revisions associated
with final § 111.70(c)(1).
(Comment 176) A few comments
argue that it is not possible to monitor
in-process for those specifications
required under proposed § 111.35(e).
One comment states that a specification
such as identity is no longer identifiable
at an in-process stage. This comment
also notes any such requirement in
proposed § 111.35(e) would be
redundant, because proposed
§ 111.35(h) requires a firm to ensure,
through testing or examination, that all
established specifications are met.
Another comment contends that some
specifications are not met until
processing is complete, such as with
liquid extracts. A few comments
recommend that the requirement for
monitoring be limited to ensuring that
specifications established for in-process
controls under proposed § 111.35(e)(2)
and finished product under proposed
§ 111.35(e)(3) are met.
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One comment states it is not always
possible for a manufacturer to monitor
for strength and purity of raw materials
during in-process steps. The comment
suggests this proposed requirement be
removed or revised.
(Response) The comments may have
misunderstood what we refer to as ‘‘inprocess’’ specifications. Under final
§ 111.75(b), you must monitor the inprocess points, steps, or stages where
control is necessary to ensure the
quality of the finished batch of dietary
supplement, to determine whether the
in-process specifications are met, and to
detect any deviation or occurrence that
may result in a failure to meet
specifications. The in-process
specifications that you establish ensure
that, for example, the specification for
strength is achieved. If you must deliver
a certain amount of powdered vitamin
C to a mixture at a certain point in the
process in order to achieve a final
product that contains 60 mg of vitamin
C, a critical point in the process is
where ‘‘x’’ mg of vitamin C is added to
ensure that the final product contains 60
mg of vitamin C. You would monitor the
operation to ensure that ‘‘x’’ mg of
vitamin C is added. Your strength
specification may be tested at the end of
the process as a product specification,
but your in-process specification to
ensure the addition of ‘‘x’’ mg of
vitamin C is a specification that is
separate and distinct from the
specification that you establish for
strength, i.e., 60 mg vitamin C. You may
determine that in-process specifications
are met through a test or examination.
You could monitor for the vitamin C
product by checking the equipment you
use to mix the vitamin C-containing
product to ensure that the mixing
process was carried out during the time
period specified in the master
manufacturing record to ensure
uniformity in the finished batch. Other
examples could include a measurement,
such as checking pH during the course
of a process, or removing samples
during the course of a process to
conduct a test for viscosity. There may
be no need for certain in-process
specifications to ensure that
specifications for identity, purity,
strength, and composition of the
finished batch of dietary supplement are
met. If there are no in-process points,
steps, or stages at which any test or
examination is needed to ensure that the
identity specification for the finished
batch of dietary supplement is met, then
you would not need to establish an inprocess specification to ensure identity
in the finished batch, and, therefore,
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would not need to conduct in-process
monitoring for identity.
(Comment 177) One comment
requests clarification on what would be
considered ‘‘in-process’’ for materials
that are simply blended together to form
a final product. The comment asks how
a firm would test the samples if a final
material cannot be tested due to
interferences or lack of an available
method.
(Response) Examples of in-process
specifications when materials are
simply blended together are the mixing
time and speed.
(Comment 178) One comment points
out that in-process testing for
‘‘unanticipated occurrences’’ required
under proposed § 111.35(f) would be
difficult, because the manufacturer
would not know what to test for.
(Response) This comment may have
misunderstood the provision, which did
not propose to require that you test for
an unanticipated occurrence. Rather,
proposed § 111.35(i)(2) would require
you to review the results of any
monitoring, and conduct a material
review and make a disposition decision,
if there is any unanticipated occurrence
that adulterates or could result in
adulteration of a component or dietary
supplement. An example of such an
occurrence is leakage of extraneous
material from a pipe onto a component.
Quality control personnel, under final
§ 111.113(a)(3), must conduct a material
review and make a disposition decision
if there is such an unanticipated
occurrence during the manufacturing
operations.
(Comment 179) One comment
suggests that the provision is a HACCP
requirement and is unnecessary for
dietary supplements whose production
generally does not involve bacterial
contamination.
(Response) We disagree. It is not a
HACCP requirement because the
provisions deal with unanticipated
occurrences. Dietary supplement
production can involve bacterial
contamination as discussed in section V
of this document. The purpose of final
§ 111.75(b) is to ensure that the product
meets all specifications, which include
specifications associated with
contamination, and, therefore, is a
necessary provision.
3. Final § 111.75(c) and (d)
Final § 111.75(c) requires you, for a
subset of finished dietary supplement
batches, which you identify through a
sound statistical sampling plan (or for
every finished batch), to verify that your
finished batch of the dietary supplement
meets product specifications for
identity, purity, strength, composition,
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and limits on those types of
contamination that may adulterate or
that may lead to adulteration of the
finished batch of the dietary
supplement. Final § 111.75(c) also sets
forth the following verification
requirements:
• You must select one or more
established specifications for identity,
purity, strength, composition, and limits
on those types of contamination that
may adulterate or that may lead to
adulteration of the dietary supplement
that, if tested or examined on the
finished batch of the dietary
supplement, would verify that the
production and process control system
is producing a dietary supplement that
meets all product specifications (or only
those product specifications not
otherwise exempted from this provision
by quality control personnel under final
§ 111.75(d));
• You must conduct appropriate tests
or examinations on the specifications
selected in final § 111.75(c)(1);
• You must provide adequate
documentation of your basis for why
meeting the specification(s) selected
under final § 111.75(c)(1), through the
use of appropriate tests or examinations
conducted under final § 111.75(c)(2),
will ensure that your finished batch of
the dietary supplement meets all
product specifications for identity,
purity, strength, composition, and the
limits on those types of contamination
that may adulterate, or that may lead to
the adulteration of, the dietary
supplement; and
• Quality control personnel must
review and approve the documentation
that you provide under final
§ 111.75(c)(3).
Final § 111.75(c) requires you to
verify that your finished batch of dietary
supplement meets specifications for
identity, purity, strength, composition,
and limits that you established for those
types of contamination that may
adulterate or that may lead to
adulteration of the finished batch. You
may verify this by either testing or
examining: (1) Every finished batch for
each of these specifications or (2) a
subset of finished batches for the dietary
supplement. The subset of batches
tested must be identified using a sound
statistical sampling plan.
If you choose to test or examine a
subset of finished batches of dietary
supplement, you may test or examine
each subset of batches for identity,
purity, strength, composition, and limits
on contamination that you established.
Alternatively, you may determine that
you can select one, two, or three, or
other number of these specifications
that, if determined to be in compliance
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with specifications, would be able to
verify that the other untested
specifications are met. For example, you
may be able to substantiate that, if you
determine compliance with the
specification for the identity and
composition of a product for which no
contamination limits are needed, the
system is adequately controlling for the
purity and strength of the product,
without the need to test for compliance
with the specifications for purity and
strength. If so, you must document,
under final § 111.75(c)(3) your basis for
why this is so. Quality control
personnel must review and approve
such documentation under final
§ 111.75(c)(4).
Under final § 111.75(d), you may
determine, in the previous example, that
you could not verify, by testing for
compliance with the specifications for
identity and composition, that the
purity specification is met, and there
may be no scientifically valid method
for testing or examining the finished
batch to evaluate the purity in the
finished batch of dietary supplement. In
that case, you could exempt the
specification for purity from the
requirement in final § 111.75(c)(1) if you
can document why the purity
specification is met without such testing
or examination. You could do so
through, for example, documentation
that meeting component and
specifications for strength is sufficient,
or through documentation that inprocess monitoring is sufficient. Quality
control personnel must review and
approve such documentation (final
§ 111.75(d)).
Final § 111.75(c) and (d) derive from
proposed § 111.35(g) and (h) and
include changes that we are making
after considering comments.
(Comment 180) Several comments
assert that a more appropriate balance is
needed between an effective process
control system and a reasonable testing
scheme calculated to confirm the
quality of dietary supplements. The
comments stress it is important to build
quality into a product throughout the
entire production process by relying on
strong process controls rather than by
testing at the finished batch stage. One
comment asserts that in an appropriate
process control system, testing is a
means to monitor and ensure that the
control system is functioning as
intended. Several comments make a
specific recommendation that the final
rule include rigorous controls.
Some comments support the
requirement under proposed § 111.35(g)
to test each batch of finished product
when possible, and to perform testing of
components and in-process testing
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when testing the finished product is not
possible. Other comments object to the
proposed requirements for finished
product testing on the grounds that they
are overly burdensome, duplicative, and
unnecessary.
Some comments suggest that a more
practical approach to finished product
testing would be to conduct identity
testing of each component, combined
with certification of the vendor by a
program of complete testing for
conformance with a certificate of
analysis, as is allowed under the drug
CGMP regulations. Some comments
suggest manufacturers that have written
procedures for each stage of their
process, including raw material
certification, production, and finished
product analysis, and a written plan for
qualifying the process, should be
exempt from the proposed requirements
to test each finished batch. Some
comments urge us to give companies the
flexibility to devise testing procedures.
(Response) The approach in final
§ 111.75(c) and (d) is consistent with
these comments and is part of the
overall approach of this final rule,
which focuses on ensuring the quality of
the dietary supplement throughout the
production and process control system.
The concept behind final § 111.75(c)
and (d) is analogous to the overall
concept of proposed § 111.35(g). Under
proposed § 111.35(g) you could rely on
a combination of meeting component
specifications and in-process
specifications when you are unable to
test for a specification, provided you
satisfied certain criteria. Under the final
rule, you may rely on a combination of
meeting component specifications and
in-process specifications to verify that
your product meets specifications,
rather than test every batch to determine
whether specifications are met,
regardless of whether a test is available,
provided you satisfy certain criteria.
Thus, the final rule provides flexibility
that is needed to build adequate
controls early in the process to reduce
the need for end product testing on
every batch of finished dietary
supplement.
(Comment 181) One comment
expresses concern that the requirement
to use appropriate tests to determine
compliance with specifications could be
interpreted as requiring companies to
test dietary supplements not only for
compliance with company
specifications, but also for compliance
with any labeled specifications of the
ingredient suppliers, such as for
contaminants. The comment believes
this would be redundant and overly
burdensome.
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(Response) As we explain in section
XXIV of this document, we have made
changes to reduce the testing burden on
companies while still requiring steps
necessary to ensure the quality of
dietary supplements. For example,
under final § 111.75(a), instead of
testing or examination (other than for
identity of the dietary ingredients),
firms may rely upon supplier
certificates of analysis in certain
circumstances. Also, we recognize,
however, that it may be possible for a
manufacturer to demonstrate, through
various methods and processes in use
over time for its particular operation,
that a system of less than 100 percent
identity testing would provide no
material diminution of assurance of the
identity of the dietary ingredient as
compared to the assurance provided by
100 percent identity testing. To provide
an opportunity for a manufacturer to
make such a showing and reduce the
frequency of identity testing of
components that are dietary ingredients
from 100 percent to some lower
frequency, we decided to provide, in an
interim final rule published elsewhere
in this issue of the Federal Register, a
procedure that allows for submission to,
and review by, FDA of an alternative to
the required 100 percent identity testing
of components that are dietary
ingredients, provided certain conditions
are met. In addition, under final
§ 111.75(c), testing or examination for a
portion of the finished batches is an
option, and exemptions are provided for
in final § 111.75(d).
(Comment 182) One comment points
out that, if a product cannot be tested
for technical reasons at the final product
stage, then it also cannot be tested at the
final blending stage in the process,
because the nature and composition of
the product at both stages are virtually
the same. Another comment asks
whether a verification of content in the
final product will suffice if there is no
valid testing procedure.
(Response) Under final § 111.75(c),
you have flexibility to select one or
more established specifications for
identity, purity, strength, composition,
and limits on those types of
contamination that may adulterate or
that may lead to adulteration of the
dietary supplement that, if tested or
examined on the finished batch of the
dietary supplement, would verify that
the production and process control
system is producing a dietary
supplement that meets all product
specifications. Under final § 111.75(d),
you have flexibility to exempt one or
more product specifications from
verification requirements, provided that
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you satisfy the criteria established under
final § 111.75(d).
(Comment 183) Some comments
request that the rule include
requirements for dissolution,
disintegration, and bioavailability
testing for dietary supplements. These
comments note that, although a product
may contain the labeled amount, it may
not dissolve readily in the body or be
available for absorption.
(Response) We decline to revise the
rule as suggested by the comments. As
discussed in the preamble to the 2003
CGMP Proposal (68 FR 12157 at 12163),
tests for dissolution, disintegration, and
bioavailability of dietary supplements
are examples of areas where scientific
study is still evolving; thus it is
premature to impose requirements for
such tests. The comments provide no
specific information that would alter
this view or support the technical
feasibility of conducting such tests for
all types of dietary supplement
products. However, nothing in this final
rule would preclude a manufacturer
from establishing such requirements. A
manufacturer should have data to
support any specifications it establishes
for parameters such as dissolution,
disintegration, and bioavailability.
(Comment 184) One comment
questions the requirements in the 2003
CGMP Proposal that all manufacturers
quantify certain marker compounds in
their products. The comment offers two
reasons why such testing should not be
required for botanical products: Their
food-like composition and legal status,
and the assertion that scientifically
valid analytical methods may prove to
be irrelevant or even hinder the
development of superior products.
(Response) The final rule does not
require any specific testing
requirements, such as testing for marker
compounds. You would determine the
specific testing requirements, and
whether to use a marker compound in
those tests, depending on your product
and process. In the 2003 CGMP Proposal
(68 FR 12157 at 12172), we merely
discussed how a marker compound
could help you identify whether you
have a particular species of an herb to
differentiate, for example, between a
poisonous and nonpoisonous species.
4. Final § 111.75(e)
Final § 111.75(e) requires you, before
you package or label a product you
receive for packaging or labeling as a
dietary supplement (and for distribution
rather than for return to the supplier), to
visually examine the product and have
documentation to determine whether
the specifications that you established
under final § 111.70(f) are met. Final
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§ 111.75(e) derives from proposed
§ 111.35(e)(1) and (g) and from proposed
§ 111.40(a)(2).
(Comment 185) Some comments
request we clarify the roles and testing
obligations of the various parties in the
‘‘pre-consumer supply chain’’ for
dietary supplements. Some comments
argue that redundant tests should not be
required at every transaction point in
the pre-consumer supply chain. The
comments contend that any testing
already performed by a supplier,
manufacturer, or packager should
suffice, so long as other CGMP
certification, and chain of custody
standards, are met. Other comments
urge us to give companies the flexibility
to devise testing procedures and point
out that different testing is needed for
different roles in the supply chain.
One comment requests clarification of
the testing requirements applicable to
packagers/labelers. The comment states
it is unclear how a packager or labeler/
distributor could conduct testing of
component ingredients if all the firm
receives is a finished product for which
there is no scientifically valid testing
method.
(Response) As discussed in section VI
of this document, you are responsible
for the CGMP requirements that are
applicable to your operations. We agree
that redundant tests should not be
required. Further, we agree that it is the
responsibility of the manufacturer to do
component testing. The packager or
labeler does not need to do any required
component testing because the packager
or labeler does not receive components,
rather it receives a finished dietary
supplement. Under final § 111.70(f) if
you receive a product from a supplier
for packaging or labeling as a dietary
supplement (and for distribution rather
than for return to the supplier), you
must establish specifications to provide
sufficient assurance that the product
you receive is adequately identified and
is consistent with your purchase order.
Under final § 111.75(e), before you
package or label such a product, you
must visually examine the product and
have documentation to determine
whether the specifications that you
established under final § 111.70(f) are
met. Your documentation may consist of
an invoice, certificate, guarantee, or
other documentation from the supplier
to ensure that the product is adequately
identified and is the product that you
ordered. Final § 111.75(e) does not
require that the documentation consist
of the result of testing or examination by
the packager or labeler of such a
product.
As with final § 111.70(f), final
§ 111.75(e) applies to ‘‘product that you
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receive for * * * for distribution rather
than for return to the supplier’’ and,
thus, applies to product that has left the
control of the person who manufactured
the batch. If you are a packager or
labeler who packages and labels a
dietary supplement for the
manufacturer, and you will return the
packaged and labeled dietary
supplement to the manufacturer, we
would not consider that you are
‘‘receiving’’ product within the meaning
of final § 111.75(e). Thus, you would not
be subject to final § 111.70(f).
5. Final § 111.75(f)
Before you use packaging, final
§ 111.75(f)(1) requires you, at a
minimum, to conduct a visual
identification of the containers and
closures and review the supplier’s
invoice, guarantee, or certification to
determine whether packaging
specifications are met. Before you use
labels, final § 111.75(f)(2) requires you,
at a minimum, to conduct a visual
examination of the label and review the
supplier’s invoice, guarantee, or
certification to determine whether
labeling specifications are met. Final
§ 111.75(f)(1) and (f)(2) derive from
proposed § 111.40(b)(2) which, in part,
would require you, for packaging and
labels you receive, to conduct at least a
visual identification on the containers
and closures. Proposed § 111.40(b)(2)
also would require you, in part, for
packaging and labels you receive, to
quarantine the packaging and labels
until your quality control unit tests or
examines a representative sample to
determine whether specifications are
met. Consistent with changes that we
are making to the requirements for
packaging and labels that you receive
(see discussion of final § 111.160 in
section XII of this document), final
§ 111.75(f)(1) and (f)(2) include a
requirement analogous to proposed
§ 111.40(a)(2) which would require you
to visually examine the supplier’s
invoice, guarantee, or certification to
determine whether the components,
dietary ingredients, or dietary
supplements you receive are consistent
with your purchase order and to
perform testing, as needed, to determine
whether specifications are met.
6. Final § 111.75(g)
Final § 111.75(g) requires you, at a
minimum, to conduct a visual
examination of the packaging and
labeling of the finished packaged and
labeled dietary supplements to
determine whether you used the
specified packaging and applied the
specified label. Final § 111.75(g) derives
from proposed § 111.37(b)(11)(iv) which
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would require the quality control unit to
collect representative samples of each
batch of packaged and labeled dietary
ingredients or dietary supplements to
determine whether you used the
packaging specified in the master
manufacturing record and applied the
label specified in the master
manufacturing record. Final § 111.75(g)
is associated with final § 111.70(g)
which requires you to establish
specifications for the packaging and
labeling for the finished packaged and
labeled dietary supplements, including
specifications that ensure you used the
specified packaging and applied the
specified label.
7. Final § 111.75(h)
Final § 111.75(h)(1) requires you to
ensure that the tests and examinations
you use to determine whether the
specifications are met are appropriate
and scientifically valid methods. Final
§ 111.75(h)(1) derives from proposed
§ 111.35(h). Final § 111.75(h)(1)
includes editorial changes associated
with the reorganization and changes
that we are making after considering
comments.
Final § 111.75(h)(2) requires that the
tests and examinations you use include
at least one of the following: Gross
organoleptic analysis, macroscopic
analysis, microscopic analysis, chemical
analysis, or other scientifically valid
methods. Final § 111.75(h)(2) derives
from proposed § 111.35(l).
(Comment 186) Some comments
suggest that the tests listed in proposed
§ 111.35(l) be incorporated into
proposed § 111.35(h), relating to
appropriate test methods.
(Response) We agree with the
comment, and final § 111.75(h)(2)
combines these requirements as
requested.
(Comment 187) One comment states
that the list of tests should be deleted
because it is not sufficient to cover the
types of testing that will be required for
compliance with proposed § 111.35(g).
(Response) The comment does not
identify the types of tests that would not
be covered. We believe that final
§ 111.75(h)(2)(v)’s ‘‘catch-all’’ provision,
which requires that one of the tests that
you use be an ‘‘other scientifically valid
method’’ is sufficient to cover all other
types of testing required under this final
rule.
(Comment 188) One comment states
that the final rule should make clear
that organolepsis is an acceptable
method for identity testing. The
comment contends it is imperative for
the survival of small businesses that
organolepsis be allowed, coupled as
necessary with macroscopic and
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morphological examination and
comparison with voucher specimens or
photographs. Another comment requests
clarification of whether gross
organoleptic analysis alone can be a test
for releasing finished products. Some
comments assert that several
organizations have published relevant
methods that include macroscopic
methods that can be used in identifying
herbal ingredients.
(Response) Organolpetic analysis
would be an acceptable method under
the 2003 CGMP Proposal and remains
an acceptable method under the final
rule, which clarifies that the method
you use, including organoleptic
analysis, must be appropriate.
Organoleptic analysis may not be an
appropriate method of testing for certain
substances. This is particularly true
when the nature of the substance
decreases the reliability of organoleptic
analysis. For example, while
organoleptic analysis may be an
appropriate identity test for whole or
coarsely-cut botanical parts, it may not
be an appropriate identity test for
powdered or extracted botanicals
because of decreased reliability, or in
those instances where misidentification
of botanicals is known to occur.
Additionally, we recognize
‘‘macroscopic analysis’’ is one of the
tests or examinations you may select to
determine whether specifications are
met.
(Comment 189) One comment
remarks that the appropriateness of the
test depends on the material being
tested, and the method selected by the
manufacturer may be inappropriate.
One comment believes the methods
stated in proposed § 111.35(l)
(organoleptic, microscopy, chemical) for
establishment of identity and purity
would not be applicable to animal
products. This comment suggests that a
separate list of test methods should be
identified for those materials.
(Response) We agree that the
appropriateness of the test depends on
the material being tested. However, we
are not revising the rule to identify
methods that are, or are not, appropriate
for specific circumstances (such as the
case of animal-derived ingredients).
There are so many distinct
circumstances that such a list would be
neither practical nor useful. Beyond
that, the manufacturer is responsible for
choosing the appropriate test.
(Comment 190) One comment asks us
to clarify in the final rule the
requirement that methods be
scientifically valid applies only to
quantitative methods.
(Response) In proposed § 111.35(h),
we did not intend that the proposed
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requirement that you use scientifically
valid methods apply only to
quantitative methods, because we also
proposed that tests in accordance with
proposed § 111.35 must include at least
one of the following: (1) Gross
organoleptic analysis, (2) microscopic
analysis, (3) chemical analysis, or (4)
other appropriate test. To clarify that the
requirement that methods be
scientifically valid applies to all the
tests and examinations you use, rather
than to quantitative tests alone, final
§ 111.75(h)(1) does not use the term
‘‘analytical.’’
(Comment 191) One comment states
that the proposed definition of
‘‘appropriate test’’ (i.e., ‘‘a scientifically
valid analytical method’’) is extremely
onerous and violates congressional
intent. The comment believes that
mandating specific methods is
inappropriate, and dietary supplement
CGMPs should comply with Executive
Order 12866 and not impose additional
requirements on small businesses that
are better left to normal business
practices.
Several comments take issue with our
statement that we were not aware of a
situation where an appropriate
scientifically valid method is not
available when, in fact, valid test
methods are not always available for
testing dietary ingredients or dietary
supplements. One comment contends
the 2003 CGMP Proposal contains
conflicting information about available
test methods. For example, the preamble
to the 2003 CGMP Proposal states that
we are ‘‘not aware of a situation where
an appropriate scientifically valid
analytical method is not available,’’ and
our cost analysis does not address costs
of method development. At the same
time, however, we set out alternatives to
finished product testing in cases where
adequate methods are unavailable, and
we decline to require expiration dating
because there may not be adequate
methods available for assessing the
strength of a dietary ingredient. The
comment cites numerous ongoing efforts
in methods development by both
industry and government that illustrate
the lack of existing methods necessary
to confirm compliance with all quality
specifications.
(Response) These comments appear to
take our statements out of context. In
the 2003 CGMP Proposal, we stated: ‘‘If
an AOAC or FDA method is not
available, a scientifically valid
analytical method is one that is based
on scientific data or results published
in, for example, scientific journals,
references, text books, or proprietary
research. Although there may not be an
Association of Official Analytical
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Chemist (AOAC) or FDA method
available, we are not aware of a
situation where an appropriate
scientifically valid analytical method is
not available’’ (68 FR 12157 at 12198).
We also stated: ‘‘We recognize that
certain tests for identity, purity, quality,
strength, or composition for certain
finished product may not be available
due to complex finished matrices that
would make such testing impracticable’’
(68 FR 12157 at 12197). We disagree
that our statement acknowledging that
the available tests may not be
practicable in certain matrices is
inherently inconsistent with our
statement that we are not aware of a
situation where an appropriate
scientifically valid analytical method is
not available. One statement relates to
the availability of methods, the other
relates to the practicality of using an
available method in particular
circumstances.
In any case, under final § 111.75(d)(1)
you may exempt a product specification
from the verification requirements of
final § 111.75(c)(1) if you show that: (1)
The specifications selected to verify that
the product meets all product
specifications are not able to verify that
the control system is producing a
dietary supplement that meets the
exempted product specification and (2)
there is no scientifically valid method
for testing or examining the exempted
product specification at the finished
batch stage. Final § 111.75(c)(1) also
requires you to document why other
information, such as component and inprocess testing, will determine whether
the exempted product specification is
met without finished batch testing.
Although we agree that there may be
some circumstances where there is not
a scientifically valid method available
for finished product testing, we believe
that there would be some scientifically
valid method available for component
or in-process testing.
(Comment 192) One comment
encourages flexibility toward the
development of a quality system that is
based on a balance of prevention,
appraisal, and process verification
activities. Another comment asks
whether the industry should use
industry standards and tests now used.
A few comments request that we
clarify proposed § 111.35(h) to make it
clear whether the section recommends
or requires the use of available USP,
AOAC International (formerly
Association of Official Analytical
Chemists) or FDA methods. One
comment recommends that the final
rule give companies flexibility to use
the method(s) most suitable to the
ingredient they are testing and the
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specification they have set. The
comment adds that companies should
then be required to ensure, through
appropriate rationale and data, that the
method is indeed suitable and produces
accurate and reproducible results.
(Response) We agree that companies
should have the flexibility to adopt the
method most suitable to the ingredient
they are testing. As discussed in the
preamble to the proposal (68 FR 12157
at 12163 and 12208), official methods,
such as AOAC International methods,
are validated in collaborative studies
using several laboratories under
identical conditions and the AOAC
International methods are often cited as
‘‘official validated methods.’’ Other
method validations are conducted in a
single laboratory by repeating the same
test multiple times. In the case of
methods used to support specific
regulatory applications to FDA, data and
information about methods that are
developed and conducted in a single
laboratory by repeating the test multiple
times are sent to us, together with
appropriate samples and reference
materials so the test can be repeated in
an agency laboratory. Typical validation
characteristics include accuracy,
precision, specificity, detection limit,
quantitation limit, linearity, range, and
robustness.
The process of method validation
discussed in the previous paragraph is
a formal process for demonstrating that
procedures are suitable for their
intended use. Although many methods
that are scientifically valid have been
formally validated, other methods may
not have been subject to the formal
validation process, e.g., by collaborative
studies using multiple laboratories, but
nonetheless remain scientifically valid
because they are, in fact, suitable for
their intended use. For this reason, we
stated that the 2003 CGMP Proposal
would permit tests using methods other
than those that are officially validated
(68 FR 12157 at 12163). Consistent with
the view that we expressed in the 2003
CGMP Proposal, we believe a
scientifically valid method is one that is
accurate, precise, and specific for its
intended purpose. In other words, a
scientifically valid test is one that
consistently does what it is intended to
do.
Under final § 111.75(h)(1), you must
ensure the tests and examinations you
use to determine whether the
specifications are met are appropriate,
scientifically valid methods. Under final
§ 111.75(h)(2) the tests and
examinations you use must include at
least one of the following: (1) Gross
organoleptic analysis, (2) macroscopic
analysis, (3) microscopic analysis, (4)
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chemical analysis, or (5) other
scientifically valid methods.
(Comment 193) One comment
questions how a company would know
of all the available scientifically valid
methods when it deals with hundreds of
items. The comment states it cannot be
expected to have expertise in the assay
methodology for so many different
ingredients.
Several comments suggest we make
fuller use of available monographs and
other resources on test methods and
method development. These sources
include USP and AHP monographs,
AOAC International, the European
Pharmacopoeia, and the WHO. The
comments urge us to disseminate
information on these additional
resources.
Many comments assert that several
organizations have published relevant
analytical methods, such as
macroscopic, microscopic, and chemical
methods, that can be used in identifying
herbal ingredients. These comments
suggest that we should acknowledge
those methods and organizations as
authoritative sources of quality
standards.
(Response) In the preamble to the
2003 CGMP Proposal (68 FR 12157 at
12209), we acknowledged that validated
methods exist in official compendia for
vitamins, minerals, and several
botanicals, and we recommended you
use validated methods whenever such
methods are available. We explicitly
stated that you may use validated
methods that can be found in official
references, such as AOAC International,
USP, and others.
As discussed in this section (see
response to comment 196), we believe
that it is sufficient to provide in this
preamble general guidance on what we
consider to be scientifically valid tests,
such as those based on scientific data or
results published in, for example,
scientific journals, references, text
books, or proprietary research, and leave
it to the manufacturer to decide what
scientifically valid tests or examinations
to use in a given operation. In the
future, we may consider issuing
guidance as to sources of appropriate
tests or examinations, along with other
guidances that we may find useful that
relate to certain dietary supplement
CGMP.
(Comment 194) One comment states
the act prohibits us from imposing
testing requirements for which
scientifically valid methods are not
generally available, and other comments
believe that not all components have
scientifically valid identification tests.
Given the substantial ongoing efforts
towards method development, the
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comments believe that the proposed
requirements for testing would impose
standards on many products and
ingredients that cannot be met through
current and generally available
methods.
(Response) We disagree that the
statute prohibits us from imposing
testing requirements. Section 402(g)(2)
of the act states that dietary supplement
CGMP regulations ‘‘may not impose
standards for which there is no current
and generally available analytical
methodology.’’ We are not imposing
such standards. The manufacturer must
establish specifications for its product
and components, and we have provided
flexibility for how the manufacturer can
determine whether those specifications
are met. The manufacturer can test,
examine, rely on a certificate of analysis
(other than to verify the identity of
dietary ingredients), or, in the case of a
specification that is exempted from
periodic testing of a finished batch, rely
on other information that ensures that
such an exempted product specification
is met.
(Comment 195) One comment
requests clarification on the definition
of ‘‘examination’’ and asks whether it
includes monitoring of process
parameters as established in the master
manufacturing record. If so, the
comment questions whether this
practice would satisfy the requirement
now in final § 111.75(h)(1).
(Response) Under final § 111.75(h),
scientifically valid tests and
examinations include techniques such
as gross organoleptic analysis,
macroscopic analysis, chemical
analysis, and other scientifically valid
methods. As discussed in the response
to comment 169, monitoring in-process
parameters could encompass tests such
as measuring pH or viscosity. Such tests
would fall under ‘‘other scientifically
valid methods.’’
(Comment 196) One comment
contends that botanical identification is
largely ignored in the 2003 CGMP
Proposal. The comment states that
botanical identification forms the basic
foundation for botanical authenticity
and that manufacturers have a legal
responsibility to ensure the authenticity
of claimed ingredients. The comment
recommends that specific requirements
for authentication of botanical
ingredients be included in the final rule.
One comment points out the difficulty
in identifying and analyzing all
naturally occurring ingredients in herbs
and plants and suggests several
alternatives to testing for all such
ingredients. Another comment requests
that an herbal product containing 20
percent or more ethanol have relaxed
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testing requirements due to the
bacteriostata properties of ethanol. One
comment lists some alternatives for
testing naturally occurring ingredients.
One comment requests clarification
on the testing requirements for bovine
cartilage products. The comment states
there is no published method for
extracting chondroitin sulfate from
bovine cartilage. As a result, the
comment assumes that testing for
chondroitin sulfate would not be
required for these products.
(Response) We believe that it is
sufficient to provide in this preamble
general guidance about testing, such as
our discussion that scientifically valid
tests include official, validated methods
as well as tests based on scientific data
or results published in, for example,
scientific journals, references, text
books, or proprietary research. It is the
manufacturer’s responsibility to choose
which scientifically valid tests or
examinations to use in a given
operation. Therefore, the final rule does
not address the specific testing
circumstances described in these
comments, such as testing requirements
for an herbal product that contains 20
percent or more ethanol, or for bovine
cartilage products. The manufacturer is
responsible for establishing
specifications and meeting such
specifications, consistent with the
requirements in this final rule. In the
future, we may consider issuing detailed
guidance as to specific tests or
examinations, along with other
guidances that may be useful that relate
to certain dietary supplement CGMP.
With respect to the comments that
discuss botanical identification, we note
that the 2003 CGMP Proposal referred to
the draft report of the Dietary
Supplement Working Group of FDA’s
Food Advisory Committee (68 FR 12157
at 12161) (Ref. 32). The draft report
discusses the selection of the most
appropriate and reliable identity test
and the general principles for
consideration in setting performance
standards for such tests (Ref. 32). This
report may provide useful guidance.
8. Final § 111.75(i)
Final § 111.75(i) requires you to
establish corrective action plans for use
when an established specification is not
met. Final § 111.75(i) derives from
proposed § 111.35(i)(1).
(Comment 197) One comment asks
whether the proposed requirement to
establish corrective action plans for use
when an established specification is not
met (proposed § 111.35(i)(1)) would
apply to specifications for raw materials
and finished goods as well as to inprocess specifications.
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(Response) The requirement to
establish corrective action plans (final
§ 111.75(i)) applies to components, inprocess specifications, and to the
finished batch.
(Comment 198) One comment states
that corrective action plans would be
difficult to prepare for a variety of
situations, such as for complex
multivitamin and mineral formulas. One
comment recommends this requirement
be deleted. Another comment asserts
that establishment of corrective action
plans should be at the manufacturer’s
discretion.
(Response) We disagree that the final
rule should not require you to establish
corrective plans or that having such
plans should be at the manufacturer’s
discretion. The purpose of having
corrective action plans in place before a
problem occurs is to help you to deal
quickly and efficiently with problems as
they arise.
You may have a corrective action plan
to determine the steps to take if
something goes wrong such as not
meeting a specification. Moreover, a
corrective action plan may include steps
not only for dealing with an acute
problem, but also for dealing with steps
you would take to followup after the
acute problem is resolved. For example,
after you resolve an acute problem, such
as a failure to meet an in-process
specification, your corrective action
plan may include testing of every
finished batch, rather than a subset of
finished batches, for some period of
time to verify that the problem is
resolved.
We acknowledge that it may not be
practical to establish a corrective action
plan for all circumstances, because not
all circumstances are foreseeable.
However, the comment asserting that it
would be difficult to establish corrective
action plans for the variety of situations
that could come up for complex
multivitamin and mineral formulas
provided no basis for why
manufacturers of such formulas could
not anticipate specific situations that
present potential problems.
(Comment 199) Some comments
recommend that proposed § 111.35(i)(1)
state ‘‘Establish procedures,’’ rather than
‘‘Establish corrective action plans.’’
(Response) The comments did not
explain what, if any, practical difference
would exist between ‘‘procedures’’ and
‘‘corrective action plans.’’ A corrective
action plan is a procedure for which you
must have a record in the master
manufacturing record (final
§ 111.210(h)(5)). Because ‘‘corrective
action plans’’ is a term that is commonly
used in the industry, we have retained
it in the final rule.
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J. What Must You Do if Established
Specifications Are Not Met? (Final
§ 111.77)
1. Final § 111.77
As we explain in section II of this
document, we reorganized the final rule
to make it more ‘‘user-friendly’’ and to
clarify the rule’s applicability to certain
persons, items, or activities. Final
§ 111.77 is a new provision that clarifies
your responsibilities and identifies
those responsibilities in a more ‘‘userfriendly’’ fashion. We have identified in
final § 111.77 the consequences of not
meeting the specifications you establish
under subpart E and when you can
consider a treatment, in-process
adjustment, or reprocessing to correct a
failure to meet and established
specification for a component, dietary
supplement, packaging, or label.
Subpart F does identify these
consequences in several provisions
which deal with the responsibility of
quality control personnel to review and
approve or reject components, dietary
supplements, packaging, and labels. We
determined it would add clarity to state
the consequences for not meeting a
specification in the same subpart in
which the requirements to establish
specifications are located.
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2. Final § 111.77(a)
Final § 111.77(a) requires that for
specifications established under
§ 111.70(a), (b)(2), (b)(3), (c), (d), (e), and
(g) that you do not meet, quality control
personnel, in accordance with the
requirements in subpart F of this part,
must reject the component, dietary
supplement, package, or label unless it
approves a treatment, an in-process
adjustment, or reprocessing that will
ensure the quality of the finished
dietary supplement and that the dietary
supplement is packaged and labeled as
specified in the master manufacturing
record. No finished batch of dietary
supplements may be released for
distribution unless it complies with
final § 111.123(b).
This provision identifies those
specifications, if not fully met, that may
be able to be corrected by treatment, inprocess adjustment, or reprocessing and
approved by quality control personnel.
We emphasize, however, that even if,
for example, corrections are approved,
the finished batch of dietary supplement
can not be released for distribution
unless it is compliance with the
requirements of final § 111.123(b)
(discussed in section XI of this
document).
Final § 111.77(a) derives from the
following proposed provisions:
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• Proposed § 111.50(d)(2), which
would require the quality control unit
not to approve and release for
distribution any batch of dietary
supplement that does not meet all
specifications;
• Proposed § 111.50(f), which would
require you to not reprocess a batch that
deviates from the master manufacturing
record unless approved by the quality
control unit.
• Proposed § 111.50(g), which would
require that a reprocessed batch of
dietary supplement meet all
specifications and that the quality
control unit approve its release for
distribution.
• Proposed § 111.35(i)(4)(i), which
would require you, for any deviation or
unanticipated occurrence which
resulted in or could lead to adulteration
of the component, dietary supplement,
packaging, or label, to reject the
component, dietary supplement,
packaging, or label, unless the quality
control unit determines that in-process
adjustments are possible to correct the
deviation or occurrence.
• Proposed § 111.35(i)(4)(ii), which
would require you, for any deviation or
unanticipated occurrence which
resulted in or could lead to adulteration
of the component, dietary supplement,
packaging, or label, to not reprocess a
rejected component or dietary
supplement unless approved by the
quality control unit.
component in the manufacture of the
dietary supplement. This component
specification must be met and quality
control personnel are restricted in what
action must be taken if this specification
is not met.
3. Final § 111.77(b)
Final § 111.77(b) requires that for
specifications established under final
§ 111.70(b)(1) that you do not meet,
quality control personnel must reject the
component and the component must not
be used in manufacturing the dietary
supplement. Final § 111.77(b)
complements final § 111.70(b)(1) which
requires you to establish an identity
specification for components; final
§ 111.75(a)(1) which requires you to
conduct at least one appropriate test or
examination to verify the identity of any
component that is a dietary ingredient;
and final § 111.75(a)(2) which requires
you to confirm the identity of all other
components. As discussed earlier in this
section, many comments recommended
the final rule include a requirement for
an identity test of incoming components
to ensure quality and safety. We agree
with these comments and earlier
comments that point out it may not be
possible to confirm the identity of some
components after they have been
processed into the finished batch of the
dietary supplement. For these reasons,
we have concluded that, if the
component specification for identity is
not met, you may not use the
K. Comments on Shelf Life
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4. Final § 111.77(c)
Final § 111.77(c) requires that if you
do not meet the specifications
established under § 111.70(f), quality
control personnel must reject the
product and the product must not be
packaged or labeled for distribution as
a dietary supplement. As with final
§ 111.77(b), final § 111.77(c) limits the
actions you can take to package and
label product you receive for packaging
and labeling from a supplier for
packaging or labeling as a dietary
supplement (and for distribution rather
than for return to the supplier). Final
§ 111.77(c) complements final
§ 111.70(f), which requires you to
establish a specification for such
received product and final § 111.75(e),
which requires you to visually examine
the product, before you package or label
it, and have documentation to
determine whether the specifications
that you established under § 111.70(f)
are met. If you do not meet the
specifications under final § 111.70(f),
you must reject the product and not
package or label the product for
distribution as a dietary supplement.
In the preamble to the 2003 CGMP
Proposal (68 FR 12157 at 12203), we
stated that we had considered whether
to propose requirements for expiration
dating, shelf life dating, or ‘‘best if used
by’’ dating (referred to in this preamble
as shelf life or expiration dating). We
recognized that there are current and
generally available methods to
determine the expiration date of some
dietary ingredients, such as vitamin C.
However, we were uncertain whether
there are current and generally available
methods to determine the expiration
dating of other dietary ingredients,
especially botanical dietary ingredients.
We did not propose to require
expiration dating because we had
insufficient scientific information to
determine the biological activity of
certain dietary ingredients used in
dietary supplements, and such
information would be necessary to
determine an expiration date. Further,
because official validated testing
methods (e.g., AOAC International or
FDA) for dietary supplements are
evolving, especially for botanical dietary
ingredients, such methods are not
always available to assess the strength of
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a dietary ingredient in a dietary
supplement.
The preamble to the 2003 CGMP
Proposal emphasized that, if you use an
expiration date on a product, you
should have data to support that date
(68 FR 12157 at 12204). We
recommended that you have a written
testing program designed to assess the
stability characteristics of the dietary
supplement, and that you use the results
of the stability testing to determine
appropriate storage conditions and
expiration dates.
In the 2003 CGMP Proposal (68 FR
12157 at 12204), we invited comment
on whether any final rule should
contain provisions regarding expiration
dating and the feasibility of conducting
tests needed to support such dates. We
also invited comment on whether to
require expiration dating on certain
dietary ingredients and not others, for
example, require expiration dating of
vitamin, mineral, and amino acid, but
not of botanical dietary ingredients.
(Comment 200) Several comments
agree with our decision not to require
expiration dating on labels for dietary
supplements at this time, because of the
wide range of products and the need for
additional data. Most of these comments
state, however, that manufacturers
should be allowed to include a ‘‘best if
used by’’ date. One comment suggests
addressing the issue in a separate
rulemaking. Other comments support an
expiration date because consumers and
retailers expect one, and some markets
require one. Some comments state that
the expiration date or statement of
product shelf life will help ensure that
the product meets its label claims and
potency.
Many comments state an expiration
date on a label must be supported by a
rationale or data on stability testing.
Some of those comments suggest that
manufacturers should have flexibility in
the type of supporting data used.
Although label claims should be
confirmed by shelf life testing when
analytical methods exist, data could
come from a manufacturer’s experience
with the product or accelerated stability
testing on similar products with the
same storage container. One comment
points out that some manufacturers
already use stability testing. Another
comment recommends that we provide
a guidance document on supporting
data.
One comment suggests stringent
supporting data are not needed for a
‘‘best if used by’’ date, because that date
provides a recommended time frame to
ensure the best quality. Another
comment asserts that the discussion
about expiration dates in the 2003
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CGMP Proposal gives the impression
that the required level of supporting
data is similar to the requirements for
drug labeling, rather than the
requirements for food shelf life labeling.
Another comment recommends that a
general maximum shelf life of 4 or 5
years should be included in the rule,
with shortened or lengthened shelf lives
for individual products as data become
available.
(Response) These comments do not
provide data or information that would
reduce the uncertainty about the
feasibility of conducting tests to support
an expiration date and, thus, do not
persuade us to alter our position not to
require that you establish an expiration
date for your product. Indeed, the
comments generally concur with that
position. Because the final rule does not
require that you establish an expiration
date, we decline to offer guidance on the
type of data that are acceptable to
support an expiration date, other than to
repeat that any expiration date that you
place on a product label (including a
‘‘best if used by’’ date) should be
supported by data.
L. What Representative Samples Must
You Collect? (Final § 111.80)
Final § 111.80 sets forth requirements
to collect representative samples of
components, packaging, and labels
(final § 111.80(a)); in-process materials
(final § 111.80(b)); the finished batch of
dietary supplement (final § 111.80(c));
product you receive for packaging or
labeling as a dietary supplement (and
for distribution rather than for return to
the supplier) (final § 111.80(d)); and
packaged and labeled dietary
supplements (final § 111.80(e)). Final
§ 111.80(a) through (e) derive from
proposed § 111.37(b)(11)(i) through
(b)(11)(iv).
1. Final § 111.80(a)
Final § 111.80(a) requires you to
collect representative samples of each
unique lot of components, packaging,
and labels that you use to determine
whether the components, packaging,
and labels meet specifications
established in accordance with
§ 111.70(b) and (d), and as applicable,
final § 111.70(a) (and, when you receive
components, packaging, or labels from a
supplier, representative samples of each
unique shipment, and of each unique lot
within each unique shipment). Final
§ 111.80(a) derives from proposed
§ 111.37(b)(11)(i). Final § 111.80(a)
includes changes related to our review
of the proposed requirements for clarity.
We had used the term ‘‘shipment lot’’ in
several proposed requirements,
including § 111.35(g)(1)(i) (requirement
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to test components that you receive),
§ 111.37(b)(11)(i) (requirement to collect
representative samples of components
that you receive), § 111.40(a)(4)
(requirements for components that you
receive), § 111.40(b)(5) (requirements for
packaging and labels that you receive),
and § 111.50(c)(5) (requirement to
identify materials that you use in the
batch production record). Some of these
proposed requirements (e.g., those in
§§ 111.40(a)(4) and (b)(3) and
111.50(b)(5)) make clear that you must
be able to trace each lot of materials you
receive to each separate shipment that
contains that lot. To clarify and
emphasize this meaning of shipment lot,
we are revising proposed
§ 111.37(b)(11)(i) so that the
representative samples you collect must
come from ‘‘each unique shipment, and
of each unique lot within each unique
shipment.’’ We make analogous
revisions throughout the final rule as
necessary.
As discussed in this section, final
§ 111.70(b) sets forth the requirements
to establish specifications for
components, final § 111.73 requires you
to determine if the specifications
established are met, and final
§ 111.75(a) sets forth the criteria you use
to determine whether these
specifications are met. Likewise, final
§ 111.70(f) sets forth the requirements to
establish specifications for product that
you receive from a supplier for
packaging or labeling as a dietary
supplement (and for distribution rather
than for return to the supplier), final
§ 111.73 requires you to determine if
specifications established are met, and
final § 111.75(e) sets forth the criteria to
use to determine whether these
specifications are met.
For consistency with the regulations
in final §§ 111.70 and 111.75, we are
separating the requirement to collect
representative samples of components
(final § 111.80(a)) from the requirement
to collect representative samples of
product that you receive from a supplier
for packaging or labeling as a dietary
supplement (and for distribution rather
than for return to the supplier) (final
§ 111.(80)(d)).
We did not receive comments specific
to proposed § 111.37(b).
2. Final 111.80(b)
Final § 111.80(b) requires you to
collect representative samples of inprocess materials for each manufactured
batch at points, steps, or stages, in the
manufacturing process as specified in
the master manufacturing record, where
control is necessary to ensure the
identity, purity, strength, and
composition of dietary supplements, to
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determine whether the materials meet
specifications established under final
§ 111.70(c), and, as applicable, final
§ 111.70(a). Final § 111.80(b) derives
from proposed § 111.37(b)(11)(ii).
We did not receive comments specific
to proposed § 111.37(b)(11)(ii).
3. Final 111.80(c)
Final § 111.80(c) requires you to
collect representative samples of a
subset of finished batches of each
dietary supplement you manufacture,
which you identify through a sound
statistical sampling plan (or otherwise
every finished batch), before releasing
for distribution, to verify that the
finished batch of dietary supplement
meets product specifications established
in accordance with final § 111.70(e),
and, as applicable, final § 111.70(a).
Final § 111.80(c) derives from proposed
§ 111.37(b)(11)(iii). Final § 111.80(c)
includes changes associated with final
§ 111.75(c) which provides flexibility
for you to test or examine a subset of
finished batches you select through a
sound statistical sampling plan rather
than to test or examine all finished
batches. Under final § 111.75(c) the tests
or examinations you conduct at the
finished batch stage verify that your
process is in control.
We did not receive comments specific
to proposed § 111.37(b)(11)(iii).
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4. Final § 111.80(d)
Final § 111.80(d) requires you to
collect representative samples of each
unique shipment, and of each unique lot
within each unique shipment, of
product you receive for packaging or
labeling as a dietary supplement (and
for distribution rather than for return to
the supplier) to determine whether the
received product meets the
specifications established under final
§ 111.70(f), and, as applicable, final
§ 111.70(a). Final § 111.80(d) derives
from proposed § 111.37(b)(11)(i). We did
not receive comments specific to this
proposed requirement. However, we are
making changes to final § 111.80(d)
consistent with those described for final
§ 111.80(a).
5. Final § 111.80(e)
Final § 111.80(e) requires you to
collect representative samples of each
lot of packaged and labeled dietary
supplements to determine whether the
packaging and labeling of the packaged
and labeled dietary supplements meet
specifications established in accordance
with final §111.70(g), and, as applicable,
final § 111.70(a). Final § 111.80(e)
derives from proposed
§ 111.37(b)(11)(iv). Final § 111.80(e)
includes revisions associated with final
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§ 111.70(g), which requires you to
establish specifications for the
packaging and labeling of the finished
packaged and labeled dietary
supplements. Final § 111.70(g) includes
specifications that determine whether
you used the packaging specified in the
master manufacturing record and you
applied the label specified in the master
manufacturing record. Under final
§ 111.70(a) and (g) the parameters that
we proposed to specify under proposed
§ 111.37(b)(11)(iv) are the required
specifications for packaged and labeled
dietary supplements.
Final § 111.80(e) includes a change to
clarify the exact specifications by citing
the relevant sections. Final § 111.80(e)
also includes an editorial change in that
you are required to ‘‘determine
whether’’ specifications are met rather
than to ‘‘determine that’’ specifications
are met. We are making this change
because ‘‘determine that specifications
are met’’ may be interpreted as a
predetermined outcome, i.e., that
specifications will, in fact, be met.
We did not receive comments specific
to proposed § 111.37(b)(11)(iv).
M. What Are the Requirements for
Reserve Samples? (Final § 111.83)
Final § 111.83 sets forth requirements
to collect and hold reserve samples of
dietary supplements. Final § 111.83
derives from proposed §§ 111.37(b)(12),
111.50, and 111.83(b)(2).
Under proposed § 111.37(b)(12) we
would require holding reserve samples
as an operation performed by the quality
control unit. Under proposed
§ 111.50(h), we proposed that you
collect representative reserve samples of
each batch of dietary supplement.
Consistent with the changes that we are
making to final § 111.80, final § 111.83
does not specify who must collect and
hold the required reserve samples.
However, under final § 111.105(g),
quality control personnel retain
oversight of the collection and holding
of the required reserve samples. Because
the requirement to collect and hold
reserve samples is not an operation that
must be performed by quality control
personnel, we are including the
requirement to collect reserve samples
in subpart E as part of the elements of
a production and process control system
rather than in subpart F as part of the
requirements for quality control
personnel.
For consistency with terms used
elsewhere in the final rule, final
§ 111.83 requires that you ‘‘hold’’
reserve samples rather than ‘‘keep’’
them.
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1. Final § 111.83(a)
Final § 111.83(a) requires you to
collect and hold reserve samples of each
lot of packaged and labeled dietary
supplements that you distribute. Final
§ 111.83(a) derives, in part, from
proposed § 111.37(b)(12), which would
require the quality control unit to keep
the reserve samples and, in part, from
proposed § 111.50(h), which would
require you to collect representative
reserve samples from each batch of
dietary supplement.
(Comment 201) Several comments ask
for clarification of the requirements for
representative and reserve samples as
proposed in § 111.37(b)(11) and (b)(12).
One comment notes that proposed
§ 111.37(b)(11) does not indicate
whether representative samples are also
collected to serve as the reserve samples
described in proposed § 111.37(b)(12)
and asks whether the items in proposed
§ 111.37(b)(11)(i) through (b)(11)(iv) are
to be kept as reserve samples.
(Response) As discussed in section VI
of this document, we are adding a
definition of ‘‘reserve sample’’ to reduce
the potential for confusion between
requirements for reserve samples and
requirements for representative samples.
A reserve sample is a representative
sample that is held for a designated
period of time.
2. Final § 111.83(b)(1)
Final § 111.83(b)(1) requires the
reserve samples to be held using the
same container-closure system in which
the packaged and labeled dietary
supplement is distributed, or if
distributing dietary supplements to be
packaged and labeled, using a containerclosure system that provides essentially
the same characteristics to protect
against contamination or deterioration
as the one in which it is distributed for
packaging and labeling elsewhere. Final
§ 111.83(b)(1) derives from proposed
§ 111.83(b)(2) which we proposed to
include with the requirements for
holding and distributing. The final
sections that derive from proposed
§ 111.83(b)(2) are in subpart M (final
§ 111.465). However, we are duplicating
these requirements in final
§ 111.83(b)(1) for clarity and ease of use,
so that you have information about the
requirements for the container-closure
system for holding reserve samples of
packaged and labeled dietary
supplements in the same section as the
requirements to collect the samples.
3. Final § 111.83(b)(2)
Final § 111.83(b)(2) requires that
reserve samples be identified with the
batch, lot, or control number. Final
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§ 111.83(b)(2) derives from proposed
§ 111.37(b)(12)(i) with editorial changes
associated with the reorganization. We
have added ‘‘control number’’ to the
provision for consistency with other
provisions of the final rule which refer
to a ‘‘control number’’ in addition to a
‘‘batch or lot number.’’
We did not receive comments specific
to proposed § 111.37(b)(12)(i).
4. Final § 111.83(b)(3)
Final § 111.83(b)(3) requires that
reserve samples be retained for 1 year
past the shelf life date (if shelf life
dating is used), or for 2 years from the
date of distribution of the last batch of
dietary supplements associated with
those reserve samples, for use in
appropriate investigations. Final
§ 111.83(b)(3) derives from proposed
§ 111.37(b)(12) which would require the
quality control unit to keep the reserve
samples for 3 years from the date of
manufacture for use in appropriate
investigations including, but not limited
to, consumer complaint investigations
to determine, for example, whether the
dietary supplement associated with a
consumer complaint failed to meet any
of its specifications for identity, purity,
quality, strength, and composition, as
well as from proposed § 111.50(h)
which would require reserve samples to
be kept for 3 years from the date of
manufacture. We discuss the change
from 3 years to 2 years and the change
from ‘‘date of manufacture’’ to ‘‘the date
of distribution’’ in connection with the
recordkeeping requirements in subpart
P, in section XXI of this document.
Final § 111.83(b)(3) thus provides
flexibility in determining how long you
must hold reserve samples of packaged
and labeled dietary supplements.
Final § 111.83(b)(3) does not include
the proposed examples of investigations
that may require the use of reserve
samples because these examples are not
requirements.
(Comment 202) Many comments
address the requirement to keep the
reserve samples after manufacture and
recommend that expiration dates be a
factor when determining the amount of
time reserve samples should be kept and
maintained. Most of the comments
recommend holding reserve samples of
packaged and labeled dietary
supplements for 3 years from the date of
manufacture or, when an expiration
date has been established by the
manufacturer, for 1 year after the
expiration date. Other comments
recommend holding reserve samples for
time periods ranging from 6 months to
2 years after the expiration date.
(Response) The final rule contains
requirements similar to the suggestions
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made by the comments. The final rule
provides flexibility to hold reserve
samples for 1 year past the shelf life
date, when such dating is used. Any
shelf life date that you include on the
label of the product should be
supported by data.
5. Final § 111.83(b)(4)
Final § 111.83(b)(4) requires that
reserve samples consist of at least twice
the quantity necessary for all tests or
examinations to determine whether or
not the dietary supplement meets
product specifications. Final
§ 111.83(b)(4) derives from proposed
§ 111.37(b)(12)(ii) which would require
that the reserve samples consist of at
least twice the quantity necessary for
tests.
Final § 111.83(b)(4) provides that the
reserve samples may be used for
examinations or tests and to determine
whether or not the dietary supplement
meets product specifications, as a
revision associated with final § 111.75.
(Comment 203) One comment agrees
that twice the quantity necessary for
testing should be collected and held.
(Response) The final rule is consistent
with this comment.
N. Who Conducts a Material Review and
Makes a Disposition Decision? (Final
§ 111.87)
Final § 111.87 requires quality control
personnel to conduct all required
material reviews and make all required
disposition decisions. Final § 111.87
derives from a number of proposed
requirements for conducting a material
review and making a disposition
(§§ 111.35(i) and (n), 111.37(b)(5) and
(b)(14), 111.40(a)(3), 111.50(d)(1), and
111.85(a) and (c)). Under each of these
provisions, the quality control unit
would have an oversight role and would
review and approve all material reviews
and all disposition decisions. Under
some of these provisions (i.e.,
§§ 111.50(d)(1) and 111.85(a) and 85(c))
the quality control unit would conduct
the material review itself and make the
disposition decision.
(Comment 204) One comment
disagrees that the quality control unit
must conduct the material review and
make the disposition decision. The
comment argues that manufacturing
personnel are better qualified to conduct
the review and make disposition
decisions because they are often
engineers and have the relevant
expertise regarding the use of machinery
and people to produce a product. In
contrast, the comment asserts that
quality control unit personnel generally
are chemists with expertise only in
testing and little expertise in
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manufacturing. The comment asserts
that the quality control unit should not
be expected to make decisions
concerning manufacturing operations;
however, it should be informed of
changes so it can evaluate the results of
reprocessing on the finished product.
(Response) We agree, in part, with the
comments and the final rule simplifies
the provisions regarding a material
review and disposition decision.
Quality control personnel can conduct
the material review and disposition
decision by reviewing the underlying
information gathered or obtained by
other qualified personnel and then
making the final decision. Under the
final rule, we retain the principle that
qualified individuals other than quality
control personnel can contribute to the
quality control personnel’s material
review and disposition decision. The
final rule sets forth the following
requirements:
• Under final § 111.87, quality control
personnel must conduct all required
material reviews and make all required
disposition decisions;
• Under final § 111.103, you must
establish and follow written procedures
for conducting a material review and
making a disposition decision; and
• Under final § 111.140(b)(3)(vii),
documentation of a material review and
disposition decision and followup must
include the signature of the
individual(s) designated to perform the
quality control operations, who
conducted the material review and
made the disposition decision, and of
any qualified individual who provided
information relevant to that material
review and disposition decision.
Taken in total, the final rule
establishes a system in which you have
flexibility to develop procedures that
suit your organization, including having
qualified individuals, other than the
designated quality control personnel,
provide information relevant to the
material review and disposition
decision. For example, under final
§ 111.140(b)(3), you could have a
qualified individual in the production
department prepare a report that
includes all the required documentation
and information and provide a signed
copy of that report to designated quality
control personnel. An individual
designated to perform quality control
operations would then read that report,
add to it if necessary, conduct any
additional investigations if necessary,
and if he or she agrees with the report,
co-sign the report or an amended report
that includes additional documentation
or information, thus completing a
material review and disposition
decision.
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The final rule provides for the
participation of qualified individuals,
other than those designated to perform
quality control operations, in
conducting the material review. In
addition, as already discussed, under
final § 111.12(b) you may assign a
qualified individual who has
responsibilities for operations other
than quality control to perform quality
control operations, provided that the
individual has distinct and separate
responsibilities related to performing
quality control operations.
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O. What Requirements Apply to
Treatments, In-Process Adjustments,
and Reprocessing When There is a
Deviation or Unanticipated Occurrence
or When a Specification Established in
Accordance with § 111.70 Is Not Met?
(Final § 111.90)
1. Final § 111.90
Final § 111.90 is a unified provision
that clarifies your responsibilities
regarding treatment or in-process
adjustments to a component, and inprocess adjustments or reprocessing of a
dietary supplement, in a more ‘‘userfriendly’’ fashion. We have identified in
one provision the restrictions that apply
to these operations. Final § 111.90
derives from proposed §§ 111.35(i)(4)(i),
(i)(4)(ii), and (i)(4)(iii); 111.50(d)(1), (f),
and (g); and 111.65(d).
Final § 111.90 includes the following
changes we are making to the proposed
provisions for consistency and clarity:
• We are making revisions to make
the section consistent with the
definition of ‘‘reprocessing’’ in final
§ 111.3, which refers only to
‘‘components or dietary supplements
that have been previously removed from
manufacturing.’’
• We are adding ‘‘treatments’’ as a
step that quality control personnel
could approve, because that term better
describes actions that could be taken to
correct a deviation or unanticipated
occurrence with a component,
packaging, or label.
• We are clarifying that it is quality
control personnel who reject
components, packaging, or labels.
• We are clarifying that quality
control personnel approve the
treatment, in-process adjustment, or
reprocessing rather than determine
whether the treatment, in-process
adjustment, or reprocessing is possible.
• We are clarifying that, with respect
to labels, the provision applies to the
potential that a label not specified in the
master manufacturing record could be
used.
• We are making changes to be
consistent with the new provision, final
§ 111.77.
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(Comment 205) One comment
recommends deletion of proposed
§ 111.35(i)(4) and (i)(4)(i), arguing that
the principles of those sections are
covered under proposed § 111.35(i)(2)
and (i)(3).
(Response) We disagree with the
comment’s assertion. The requirements
of proposed § 111.35(i)(4) and (i)(4)(i)
are not covered by proposed
§ 111.35(i)(2) and (i)(3). All the sections
are related, but deal with different
aspects of corrective action. Proposed
§ 111.35(i)(2) and (i)(3) would require
the firm to conduct a material review
and make a disposition decision, while
proposed § 111.35(i)(4) would prohibit
the use of rejected ingredients unless
the quality control unit determines that
in-process adjustments are possible to
correct the deviations or occurrence. We
are making no changes as suggested by
this comment and the primary elements
of proposed § 111.35(i)(4) are retained in
final § 111.90.
(Comment 206) A few comments state
their support for the requirement that
the quality control unit have the
authority to determine whether
adjustments are possible to correct a
deviation.
(Response) We are retaining the
proposed requirement for quality
control personnel in final § 111.90.
2. Final § 111.90(a)
Final § 111.90(a) requires that you
must not reprocess a rejected dietary
supplement or treat or provide an inprocess adjustment to a component,
packaging, or label to make it suitable
for use in the manufacture of a dietary
supplement, unless: (1) Quality control
personnel conduct a material review
and make a disposition decision to
approve the reprocessing, treatment, or
in-process adjustment and (2) the
reprocessing, treatment, or in-process
adjustment is permitted by § 111.77.
Final § 111.90(a) derives from
proposed §§ 111.35(i)(4)(ii) and
111.50(d)(1). We revised this provision
to be consistent with the changes in
final § 111.77.
(Comment 207) Several comments
state their support for proposed
§ 111.35(i)(4)(ii), which would require
the quality control unit to approve the
reprocessing of any rejected component,
dietary ingredient, or dietary
supplement. However, not all comments
agree that the quality control unit
should have to conduct (under proposed
§ 111.50(d)(1)), rather than review and
approve, a material review and
disposition decision.
(Response) As discussed in this
section, by ‘‘conduct a material review
and make a disposition decision,’’ we
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do not intend to limit those who may
participate in a material review and
disposition decision to only those
persons acting in their capacity as
designated quality control personnel.
Others may assist quality control
personnel in gathering and considering
information relevant to the review and
decision, however the quality control
personnel have the responsibility to
conduct a material review and make
disposition decisions. Thus, we are
retaining in final § 111.90(a) the
requirements in proposed
§§ 111.25(i)(4)(ii) and 111.50(d)(1).
3. Final § 111.90(b)
Final § 111.90(b) requires that you
must not reprocess any dietary
supplement or treat or provide an inprocess adjustment to a component to
make it suitable for use in the
manufacture of a dietary supplement,
unless: (1) Quality control personnel
conduct a material review and make a
disposition decision based on a
scientifically valid reason and approve
the reprocessing, treatment, or inprocess adjustment and (2) the
reprocessing, treatment or in-process
adjustment is permitted by § 111.77.
Final § 111.90(b) derives from proposed
§§ 111.35(i)(4)(iii), 111.50(f), and
111.65(d). We revised this provision to
be consistent with the changes in final
§ 111.77.
(Comment 208) As discussed in
section VI of this document (discussion
of the definition of ‘‘reprocessing’’),
some comments object to the
restrictions in the definition of
reprocessing in proposed § 111.3
because the definition would not permit
the reprocessing of ingredients that may
have been removed because of
insanitary conditions even if there are
processes available that are safe and
effective in removing foreign matter,
microorganisms, or chemicals that may
have rendered the ingredient
‘‘insanitary.’’ These comments also
object to proposed § 111.35(i)(4)(iii) for
the same reasons. A few comments
argue that a manufacturer should be
able to reprocess a component or dietary
supplement if it has been rejected
because of contamination with
microorganisms or types of
contamination, such as heavy metals, if
the quality control unit approves the
reprocessing. These comments indicate
this is the industry practice, one based
on a scientific rationale for doing the
reprocessing and that ensures other
quality attributes of the product are not
affected.
Some comments state that the
requirement is more strict than the food
or drug CGMP requirements, noting that
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reprocessing is widely accepted and
allowed in the food CGMPs. Other
comments believe that the prohibition
in proposed § 111.35(i)(4)(iii) against
reprocessing materials contaminated
with microorganisms should be limited
to materials contaminated with healthhazardous microorganisms.
(Response) As we discussed in the
response to comment 53 for the
definition of ‘‘reprocessing,’’ we agree
with the comments that state that inprocess materials can be reprocessed
when there are suitable processes
available. However, as noted by the
comments, it is critical that there be
appropriate oversight of the
reprocessing so the quality of the dietary
supplement is not compromised. Final
§ 111.90(b) provides for the flexibility
requested by the comments, provided
that there is oversight by quality control
personnel.
(Comment 209) Proposed
§ 111.35(i)(4)(iii) mentions
‘‘microorganism or other contaminants,
such as heavy metals.’’ One comment
proposes that other contaminants, such
as pesticides and aflatoxin, should be
mentioned. Another comment suggests
that the final rule should specify limits
for heavy metals in dietary
supplements.
(Response) We decline to revise the
final rule as suggested by the comments.
It is impractical to provide an
exhaustive list of relevant types of
contamination, and a list that is longer,
but not exhaustive, is more likely to be
misunderstood as suggesting that the
only types of contamination that are
significant are the types of
contamination in the list. For that
reason, we have eliminated the
reference to contamination to clarify
that in any instance where it is
appropriate quality control personnel
must ensure that the disposition
decision is based on a scientifically
valid reason and also approve the
reprocessing.
(Comment 210) One comment notes
that in the May 9, 2003, satellite
broadcast concerning the 2003 CGMP
Proposal, we indicated that treating a
component or dietary supplement with
irradiation as a means to reduce or
eliminate the microbial load was
acceptable as long as the treatment was
part of the process for producing that
material. The comment asks for
confirmation that irradiation of
components or dietary supplements is
allowed under part 179 (21 CFR part
179), even though such treatments are
not listed in the table provided in
§ 179.26(b).
(Response) We are unable to provide
the requested confirmation. Under
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section 201(s) of the act, irradiation
intended for use in producing,
manufacturing, packing, processing,
preparing, treating, packaging,
transporting, or holding food is a food
additive that requires premarket review
and approval before it can be used in
food. Our Office of Food Additive Safety
is currently reviewing a food additive
petition for the use of irradiation on
dietary ingredients and dietary
supplements. Until that review process
is completed and we have authorized
this use of irradiation through a final
rule codified in part 179, irradiation of
dietary ingredients and dietary
supplements as a means to reduce or
eliminate microbial loads is not
permitted. However, you may use an
irradiated component (such as a spice
that is used to flavor a dietary
supplement) when the irradiation of
that component is allowed under
§ 179.26.
4. Final § 111.90(c)
Final § 111.90(c) requires that any
batch of dietary supplement that is
reprocessed, that contains components
that you have treated, or to which you
have made in-process adjustments to
make them suitable for use in the
manufacture of the dietary supplement
must be approved by quality control
personnel and comply with final
§ 111.123(b) before releasing for
distribution. Final § 111.90(c) derives
from proposed § 111.50(g).
Final § 111.90(c) also includes
conforming revisions to clarify that a
dietary supplement that contains a
component treated before use or
adjusted in-process, or that has had inprocess adjustments to make it suitable
for use in the manufacture of a dietary
supplement, must be approved by
quality control personnel and comply
with final § 111.123(b) before releasing
for distribution. We revised this
provision to be consistent with the
changes in final §§ 111.77 and
111.123(b).
Final § 111.90(c) also includes
revisions to reflect the final provisions
that relate to reprocessing and inprocess adjustments (see final
§§ 111.113, 111.120, and 111.155).
(Comment 211) One comment asserts
that a reprocessed product should be
retested to confirm that it meets product
specifications.
(Response) Under final § 111.75(c)
and (d) quality control personnel have
flexibility to determine whether tests or
examinations are necessary to ensure
that a reprocessed product meets
product specifications.
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P. Under This Subpart, What Records
Must You Make and Keep? (Final
§ 111.95)
1. Final § 111.95(a)
Final § 111.95(a) requires you to make
and keep records required under this
subpart in accordance with subpart P.
Final § 111.95(a) derives from proposed
§ 111.35(o). Some of the records
required under subpart E are set forth as
recordkeeping requirements in other
subparts of this final rule, such as those
related to receiving records for
components, packaging, and labels in
subpart G, and the results of testing or
examination in subpart J. The record
requirements not specifically required
in other related subparts are listed in
subpart E.
(Comment 212) One comment
supports the recordkeeping
requirements, states that the records
provide a valuable paper trail that will
allow manufacturers to identify and fix
problems in the process, and suggests
the requirements protect consumers
from adulterated and misbranded
products.
(Response) We agree. Under final
§ 111.95(a), a firm must make and keep
records required by subpart E in
accordance with subpart P. As
discussed in this section, firms are
required to keep the records necessary
for determining whether their products
are made in accordance with
specifications. This will help them
identify and correct any problems. In
addition, under subpart P, the records
must be kept for 1 year past the shelf life
date (if shelf life dating is used) or 2
years beyond the date of distribution of
the last batch of dietary supplements
associated with those records.
Moreover, firms must make their
records available to us for inspection
and copying, which will permit us to
determine whether firms are
manufacturing, packaging, labeling, and
holding dietary supplements in
accordance with the requirements of
this rule.
2. Final § 111.95(b)
Final § 111.95(b) specifies the records
you must make and keep under subpart
E. Under the reorganization several
recordkeeping requirements of proposed
§ 111.35 are set forth in other subparts.
Final § 111.95(b)(1) requires you to
make and keep records of the
specifications established. Final
§ 111.95(b)(1) derives from proposed
§ 111.35(o)(1).
Final § 111.95(b)(2) requires you to
make and keep records of your
qualification of a supplier for the
purpose of relying on the supplier’s
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certificate of analysis. Final
§ 111.95(b)(2) is a record that is required
under final § 111.75(a)(2)(B).
Final § 111.95(b)(3) requires you to
make and keep documentation for why
meeting in-process specifications, in
combination with meeting component
specifications, helps ensure that the
dietary supplement meets the
specifications for identity, purity,
strength, and composition and for limits
on those types of contamination that
may adulterate or may lead to
adulteration of the finished batch of the
dietary supplement. Final § 111.95(b)(3)
refers to records required under final
§ 111.70(c)(2).
Final § 111.95(b)(4) requires you to
make and keep documentation for why
the results of appropriate tests or
examinations for the product
specifications selected under final
§ 111.75(c)(1) ensures that the dietary
supplement meets all product
specifications. Final § 111.95(b)(4) is a
record that is required under final
§ 111.75(c)(3).
Final § 111.95(b)(5) requires you to
make and keep documentation for why
any component and in-process testing,
examination, or monitoring, and any
other information, will ensure that a
product specification that is exempted
under final § 111.75(d) is met without
verification through periodic testing of
the finished batch, including
documentation that the selected
specifications tested or examined under
final § 111.75(c)(1) are not able to verify
that the production and process control
system is producing a dietary
supplement that meets the exempted
product specification and there is no
scientifically valid method for testing or
examining such exempted product
specification at the finished batch stage.
Final § 111.95(b)(5) refers to a record
required under final § 111.75(d)(1). As
previously discussed in this section, we
are issuing an interim final rule,
published elsewhere in this issue of the
Federal Register, that sets forth a
procedure for requesting an exemption
from the requirement that the
manufacturer conduct at least one
appropriate test or examination to verify
the identity of any component that is a
dietary ingredient. Included in the
interim final rule is an amendment to
final § 111.95(b) adding a new
paragraph (b)(6) requiring the retention
of FDA’s response to a petition
submitted under § 111.75(a)(1)(ii) that
provides for an exemption from the
provision of § 111.75(a)(1)(i).
(Comment 213) One comment
recommends the recordkeeping
requirements of proposed § 111.35(m)
be moved to follow the requirements for
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appropriate test methods because these
requirements are related and probably
best understood without intervening
information.
(Response) Consistent with this
comment, the recordkeeping
requirements of proposed § 111.35(m)
are set forth in final subpart J instead of
subpart E.
TABLE 7.—DERIVATION OF SECTIONS
IN FINAL SUBPART F—Continued
Final Rule
2003 CGMP
Proposal
§ 111.113 What quality
control operations are
required for a material
review and disposition
decision?
§ 111.35(i)(2),
(i)(3), (i)(4)(i),
(i)(4)(ii), (j),
and (n)
§ 111.37(b)(3)
§ 111.37(c)
§ 111.40(a)(3)
and (b)(2)
§ 111.50(d)(1)
§ 111.65(d)
§ 111.70(c)
§ 111.117 What quality
control operations are
required for equipment, instruments, and
controls?
§ 111.30(b)(4),
(b)(6), (b)(7),
and (b)(8)
§ 111.120 What quality
control operations are
required for components, packaging, and
labels before use in
the manufacture of a
dietary supplement?
§ 111.35(i)(4)(i)
and (i)(4)(ii)
§ 111.37(b)(2)
and (b)(10)
§ 111.40(a)(3)
and (b)(2)
§ 111.50(e)(1)
§ 111.123 What quality
control operations are
required for the master
manufacturing record,
the batch production
record, and manufacturing operations?
§ 111.35(e)(2),
(f), (i)(2), and
(o)(2)
§ 111.37(b)(2),
(b)(4), (b)(5),
and (b)(11)(iii)
§ 111.45(c)
§ 111.50(d)(1)
and (d)(2)
§ 111.50(g)
§ 111.127 What quality
control operations are
required for packaging
and labeling operations?
§ 111.37(b)(2)
and (b)(10)
§ 111.40(a)(2)
and (a)(3)
§ 111.70(c), (d),
and (e)
§ 111.130 What quality
control operations are
required for returned
dietary supplements?
§ 111.37(b)(2)
and (b)(15)
§ 111.85(a)
§ 111.135 What quality
control operations are
required for product
complaints?
§ 111.95
§ 111.140 Under this
subpart F, what
records must you
make and keep?
§ 111.35(j)
§ 111.37(c) and
(d)
XI. Comments on Requirements for
Quality Control (Final Subpart F)
A. Organization of Final Subpart F
Proposed § 111.37 set forth
requirements for quality control
operations. Other proposed
requirements related to quality control
operations were set forth in other
sections. For example, proposed
§ 111.40(a) would require the quality
control unit to perform operations
associated with components that you
use in the manufacturing process.
Proposed § 111.45 would establish
requirements for the master
manufacturing record and would have
the quality control unit review and
approve each master manufacturing
record. Proposed § 111.50 would have
the quality control unit review batch
production records.
As shown in table 7 of this document,
the final rule reorganizes the
requirements related to quality control
operations into a distinct subpart (final
Subpart F—Production and Process
Control System: Requirements for
Quality Control Operations). Table 7
lists the sections in final subpart F and
identifies the proposed sections that
form the basis for the sections in the
final rule.
TABLE 7.—DERIVATION OF SECTIONS
IN FINAL SUBPART F
2003 CGMP
Proposal
Final Rule
§ 111.103 What are the
requirements under
this subpart F for written procedures?
N/A
§ 111.105 What must
quality control personnel do?
§ 111.37(a),
(b)(1), (b)(11),
and (b)(12)
§ 111.110 What quality
control operations are
required for laboratory
operations associated
with the production
and process control
system?
§ 111.37(b)(9)
and (b)(13)
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B. Highlights of Changes to the
Proposed Requirements for Quality
Control Operations
1. Revisions
The final rule:
• Reflects that the rule applies to
persons who manufacture, package,
label, or hold dietary supplements
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unless subject to an exclusion under
§ 111.1;
• Changes the requirement for a
quality control unit to a requirement for
quality control operations performed by
quality control personnel;
• Requires quality control personnel
to review and approve documentation
for why meeting in-process
specifications will ensure the
specifications for identity, purity,
strength, and composition of a dietary
supplement are met;
• Requires quality control personnel
to review and approve documentation
setting forth the basis for qualifying a
supplier of a component;
• Requires quality control personnel
to review and approve documentation of
your basis for why meeting certain
selected specifications in a subset of
finished batches will ensure your
finished batch of the dietary supplement
meets all product specifications for
identity, purity, strength, and
composition and limits on those types
of contamination that may adulterate, or
that may lead to the adulteration of, the
dietary supplement; and
• Requires quality control personnel
to review and approve documentation
for why a product specification
exempted from the verification
requirements in final subpart E is met
without verification through periodic
testing of the finished batch.
2. Changes Associated With the
Reorganization
The final rule:
• Reduces redundant provisions and
• Combines parts of various proposed
requirements that were scattered
throughout the 2003 CGMP Proposal.
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3. Changes After Considering Comments
The final rule:
• Incorporates a new requirement to
establish, and keep as a record, written
procedures for quality control
operations;
• Simplifies the requirements
associated with conducting a material
review and making a disposition
decision;
• Requires quality control personnel
to ensure that representative samples
are collected rather than collecting these
samples;
• Requires quality control personnel
to ensure that reserve samples are held
rather than quality control personnel
holding these samples;
• Requires quality control personnel
to ensure tests or examinations are
appropriate rather than conduct these
tests or examinations; and
• Requires review by quality control
personnel of all records for calibration
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of instruments, and for calibrations,
inspections, and checks of automatic,
mechanical, or electronic equipment to
be performed on a periodic basis rather
than at the time the record is made.
C. General Comments on Proposed
§ 111.37 (Final Subpart F)
(Comment 214) Some comments
support the use of a quality control unit
and recognize it as an important need in
manufacturing operations. Some
comments assert the quality control unit
may not have all the responsibilities
listed in proposed § 111.37 because
there may be some duties contracted out
to someone else, such as testing that
could be sent to a contract laboratory, or
some duties that may be better suited for
employees in other organizational units.
As an example, a few comments note
that the instrument and equipment
calibration functions in proposed
§ 111.37 may be better performed by
individuals responsible for the
equipment in their particular
operational area, by those in a unit
dedicated to equipment maintenance
and calibration, or possibly by a third
party, who is qualified by training and/
or experience, to do these functions.
Similarly, other comments note that
other groups with the appropriate
expertise may be assigned or required to
review and approve proposed changes
or procedures in manufacturing
operations or to conduct material
reviews and make disposition decisions.
These comments assert the quality
control unit should have overall
responsibility and oversight for quality
control functions but also should be
able to rely on the expertise of other
persons in the organization to
accomplish the tasks.
(Response) As already discussed with
respect to the definition of quality
control personnel in section VI of this
document, these comments may have
misunderstood the quality control unit’s
role under the proposed rule.
Consequently, we have added final
§ 111.12(b) in subpart B, discussed in
section VII of this document, to state
you must identify who is responsible for
your quality control operations. Each
person who is designated to perform
quality control operations must be
qualified to do so and have distinct and
separate responsibilities related to
performing such operations from those
responsibilities that the person
otherwise has when not performing
such operations.
The final rule requires quality control
personnel to ensure all appropriate tests
and examinations are conducted, and
review and approve the results of all
tests and examinations, but does not
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require that quality control personnel
conduct the tests or examinations. Thus,
you would not need to consider that an
individual who conducts tests or
examinations at a laboratory under
contract to your organization is
performing a quality control operation
that must be performed by quality
control personnel. However, you may
choose to designate that individual as
part of your quality control personnel
and require that the tests or
examinations conducted by that
individual be quality control operations.
Importantly, however, for the purposes
of this final rule, we consider that a
quality control operation performed by
an individual under contract to you or
by another third party is no different
than a quality control operation
performed by your employees who are
designated to perform such operation. If,
during the course of an inspection, we
find the requirements of this final rule
were not followed, we will hold you,
rather than the contractor or other third
party, responsible. The applicability of
this final rule to contractors is discussed
in detail in section VI of this document.
(Comment 215) Several comments
request that the quality control unit
focus on reviewing tasks performed by
others rather than on performing the
tasks itself.
(Response) We agree with these
comments and have revised several
provisions accordingly. For example, in
the 2003 CGMP Proposal we would
require the quality control unit to
perform appropriate tests and
examinations of incoming materials, inprocess materials, each finished batch of
dietary supplements, and each batch of
packaged and labeled dietary
supplements (proposed § 111.37(b)(13)).
Under the final rule, quality control
operations include ensuring appropriate
tests and examinations are conducted
(final § 111.110(b)) but do not include
conducting these tests and
examinations.
(Comment 216) One comment asks
whether we expect the quality control
unit to approve operational activities as
soon as they occur or collectively at the
end of the process. This and other
comments argue the quality control
function is usually accomplished by a
team of qualified persons with the
quality control unit having the overall
responsibility and authority to perform
a collective, post-processing, final
approval.
(Response) The time at which quality
control personnel conduct assigned
duties will vary by the specific
operation, the size and complexity of
the operation, and how quality control
functions are assigned to qualified
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persons. For example, the final rule
requires quality control personnel to
determine whether components
conform to specifications, and to release
components from quarantine before you
use them in the manufacture of a dietary
supplement (final § 111.120). However,
this final rule does not require, for
example, that quality control personnel
determine whether components
conform to specifications as soon as you
receive them, although it may be
common business practice to do so.
Regardless of when quality control
personnel perform their operations,
quality control personnel have the
ultimate responsibility for ensuring
manufacturing, packaging, labeling, and
holding operations are performed in a
manner that will ensure the quality of
the dietary supplement and that the
dietary supplement is packaged and
labeled as specified in the master
manufacturing record.
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D. What Are the Requirements Under
This Subpart for Written Procedures?
(Final § 111.103)
We received many comments that
recommend written procedures for
various provisions. We address the need
for written procedures generally in
section IV of this document. We also
respond to comments on specific
provisions in the same section.
Final § 111.103 requires that you
establish and follow written procedures
for the responsibilities of the quality
control operations. Final § 111.103
specifically identifies two of the written
procedures you must establish and
follow, i.e., written procedures for
conducting a material review and
making a disposition decision and for
approving or rejecting any reprocessing.
E. What Must Quality Control Personnel
Do? (Final § 111.105)
Final § 111.105 broadly captures the
responsibility of quality control
personnel to provide oversight for
manufacturing, packaging, labeling, and
holding operations. It requires quality
control personnel to ensure that your
manufacturing, packaging, labeling, and
holding operations ensure the quality of
the dietary supplement and that the
dietary supplement is packaged and
labeled as specified in the master
manufacturing record. Final § 111.105
derives from proposed § 111.37(a)
which would require you to use a
quality control unit to ensure your
manufacturing, packaging, labeling, and
holding operations in the production of
dietary supplements are performed in a
manner that prevents adulteration and
misbranding, including ensuring dietary
supplements meet specifications for
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identity, purity, quality, strength, and
composition.
This final rule focuses on ensuring
that the manufacturer establishes
specifications for its dietary
supplements; includes those
specifications in the master
manufacturing record; meets those
specifications and manufactures,
packages, labels, and holds the product
in a manner that will ensure the quality
of the dietary supplement; and that the
dietary supplement is packaged and
labeled as specified in the master
manufacturing record. Because of that
focus, the labeling requirements of the
final rule address the operation of
putting the label that is specified in the
master manufacturing record on the
product rather than the content of a
product label that meets all of the
labeling requirements of the act and our
implementing regulations. The failure to
put the label identified in the master
manufacturing record on the finished
product would be a violation of this
final rule. In addition, if the label on the
product does not correctly reflect the
ingredients, the label would misbrand
the product under section 403 of the act.
For purposes of this final rule, the
labeling operations are CGMP
requirements and relate to the label
identified in the master manufacturing
record. Therefore, we are deleting
‘‘misbranding’’ from proposed
§ 111.37(a) (final § 111.105) since the act
of misbranding other than applying a
label different from the one identified in
the master manufacturing record is not
considered a CGMP violation in the
context of this final rule. Any
misbranding is still a violation of the
act, however, and manufacturers must
comply with all applicable statutory and
regulatory requirements in addition to
the requirements of this final rule.
This series of changes emphasizes the
need to ensure the quality of a dietary
supplement and that the dietary
supplement is packaged and labeled as
specified in the master manufacturing
record. As discussed in detail in the rest
of this section, final § 111.105 also
requires that quality control personnel
perform certain operations and groups
of operations.
1. Final § 111.105(a)
Final § 111.105(a) requires that
quality control personnel approve or
reject all processes, specifications,
written procedures, controls, tests, and
examinations, and deviations from or
modifications to them, that may affect
the identity, purity, strength, or
composition of a dietary supplement.
Final § 111.105(a) derives from
proposed § 111.37(b)(1).
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(Comment 217) One comment
recommends revising proposed
§ 111.37(b)(1) by replacing ‘‘* * *
identity, purity, quality, strength, and
composition’’ with ‘‘* * * identity,
purity, quality, strength, or
composition.’’ The comment asserts the
quality control unit must be responsible
for approving or rejecting anything that
may affect one of these attributes.
(Response) We agree with this
comment. Under proposed
§ 111.37(b)(1) we had intended that the
quality control unit be responsible, for
example, for approving a test that would
establish the identity of a component
even if that test did not also establish
the strength of that component. Final
§ 111.105(a) changes ‘‘and’’ to ‘‘or’’ as
requested by this comment.
(Comment 218) One comment
recommends the quality control unit be
responsible for maintaining the master
copies of all current and approved
written procedures, for distributing
copies of approved written procedures
to relevant personnel, and for collecting
and destroying outdated Standard
Operating Procedures (SOPs) (except
designated historical SOP files).
(Response) This comment is
consistent with the underlying principle
that quality control personnel oversee
the design and conduct of the
operations associated with the
production of a dietary supplement.
After considering these comments, final
§ 111.105(a) requires quality control
personnel to approve all written
procedures that may affect the identity,
purity, strength, or composition of a
dietary supplement. With respect to the
other suggested duties of quality control
personnel, we are leaving the decision
as to who performs them, up to the
individual firm to best suit its overall
operations.
2. Final § 111.105(b), (c), d), and (e)
Final § 111.105(b) requires quality
control personnel to review and approve
the documentation setting forth the
basis for qualification of any supplier.
Final § 111.105(c) requires quality
control personnel to review and approve
the documentation setting forth the
basis for why meeting in-process
specifications, in combination with
meeting component specifications, will
help ensure that specifications for the
identity, purity, strength, and
composition of the dietary supplement
are met. Final § 111.105(d) requires
quality control personnel to review and
approve the documentation setting forth
the basis for why the results of
appropriate tests or examinations for
each product specification selected
under final § 111.75(c)(1) will ensure
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that the finished batch of the dietary
supplement meets product
specifications. Final § 111.105(e)
requires quality control personnel to
review and approve the basis and
documentation for why any product
specification is exempted from the
verification requirements in final
§ 111.75(c)(1), and for why any
component and in-process testing,
examination, or monitoring, or other
methods will ensure that such exempted
product specification is met without
verification through periodic testing of
the finished batch.
Final § 111.105(b), (c), (d), and (e) are
requirements associated with the
requirements established in final
§§ 111.70(c)(3) and 111.75(a)(ii)(2)(E),
(c)(4), (d)(1) and (d)(2).
3. Final § 111.105(f)
Final § 111.105(f) requires quality
control personnel to ensure that
required representative samples are
collected. Final § 111.105(f) differs
slightly from proposed § 111.37(b)(11)(i)
through (b)(11)(iv) which would require
the quality control unit to collect
representative samples of incoming
materials, in-process materials, each
finished batch of dietary supplements,
and each batch of packaged and labeled
dietary supplements.
After considering comments
requesting the quality control unit focus
on reviewing tasks performed by others
rather than on performing the tasks
themselves, the final rule does not
specify that quality control personnel
must collect representative samples.
Under final § 111.105(f), however,
quality control personnel retain
oversight of sample collection.
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4. Final § 111.105(g)
Final § 111.105(g) requires quality
control personnel to ensure that
required reserve samples are collected
and held. Final § 111.105(g) derives
from proposed § 111.37(b)(12) which
would require the quality control unit to
keep reserve samples.
After considering comments
requesting the quality control unit focus
on reviewing tasks performed by others
rather than on performing the tasks
themselves, the final rule does not
specify that quality control personnel
must keep reserve samples. Under final
§ 111.105(g), however, quality control
personnel retain oversight of sample
collection and holding.
5. Final § 111.105(h)
Final § 111.105(h) requires that
quality control operations for the master
manufacturing record, the batch
production record, and manufacturing
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operations include determining whether
all specifications established in
accordance with final § 111.70(a) are
met. Final § 111.105(h) derives from
proposed § 111.37(b)(2) which would
require that the quality control unit
determine whether all components,
dietary supplements, packaging, and
labels conform to specifications. Under
the final rule, we are identifying each of
the specifications subject to review by
quality control personnel under final
§ 111.77. The requirement for quality
control personnel to determine whether
specifications established under final
§ 111.70(a) are met is included for
consistency. This requirement is also
consistent with final § 111.73 which
requires that the production and process
control system must include a
determination of whether all of the
established specifications under final
§ 111.70(a) are met.
6. Final § 111.105(i)
Final § 111.105(i) requires quality
control personnel to perform other
operations required under subpart F.
Final § 111.105(i) is associated with the
reorganization. Under the 2003 CGMP
Proposal, proposed § 111.37(a) broadly
captured the responsibility of the
quality control unit to provide oversight
for your manufacturing, packaging,
labeling, and holding operations.
Proposed § 111.37(b) listed specific
operations that we would require the
quality control unit to perform. Final
§ 111.105 now captures the
responsibility of quality control
personnel to provide oversight for your
manufacturing, packaging, labeling, and
holding operations. The specific
operations that quality control
personnel must perform to provide that
oversight are set forth in final
§ 111.105(a) through (h) and in final
§§ 111.110, 111.113, 111.117, 111.120,
111.123, 111.127, 111.130, 111.135, and
111.140.
F. What Quality Control Operations Are
Required for Laboratory Operations
Associated With the Production and
Process Control System? (Final
§ 111.110)
Final § 111.110 sets forth the
minimum required operations that
quality control personnel must perform
with respect to laboratory operations
associated with the production and
process control system.
1. Final § 111.110(a)
Final § 111.110(a) requires that
quality control operations for laboratory
operations include reviewing and
approving all laboratory control
processes associated with the
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production and process control system.
Final § 111.110(a) derives, in part, from
proposed § 111.37(b)(9) which would
require that the quality control unit
review and approve all laboratory
control processes. For clarity, we are
adding that the laboratory operations
covered by final § 111.110 are those
associated with the production and
process control system. We want to
make clear that laboratory operations
such as those in your research and
development department are not subject
to final § 111.110.
We did not receive comments specific
to quality control operations under
proposed § 111.37(b)(9).
2. Final § 111.110(b)
Final § 111.110(b) requires that
quality control operations for laboratory
operations associated with the
production and process control system
include ensuring all tests and
examinations required under final
§ 111.75 are conducted. Final
§ 111.110(b) derives, in part, from
proposed § 111.37(b)(13) which would
require the quality control unit to
perform appropriate tests and
examinations of incoming materials, inprocess materials, each finished batch of
dietary supplements, and each batch of
packaged and labeled dietary
supplements.
Proposed § 111.37(b)(13) would list
the types of materials that must be
tested, including components,
packaging, labels, dietary ingredients,
and dietary supplements that you
receive; the batch production at the inprocess and finished batch stages; and
packaged and labeled dietary
supplements. This list would include
materials that, at a minimum, would be
tested under the 2003 CGMP Proposal.
Under the final rule, the minimum
requirements for testing or examination
of the materials listed in proposed
§ 111.37(b)(13) are set forth in final
§ 111.75. To simplify and clarify
proposed § 111.37(b)(13), final
§ 111.110(b) replaces this list with ‘‘all
tests and examinations required under
§ 111.75.’’
3. Final § 111.110(c)
Final § 111.110(c) requires that
quality control operations for laboratory
operations associated with the
production and process control system
include reviewing and approving the
results of all tests and examinations
required under final § 111.75. Final
§ 111.110(c) derives from proposed
§ 111.37(b)(9), which would require, in
part, that the quality control unit review
and approve all testing results. Final
§ 111.110(c) requires that quality control
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personnel review and approve the
results of examinations as well as tests.
This revision reflects the flexibility
provided in the final rule to use either
tests or examinations to determine
whether specifications are met,
provided that the test or examination is
an appropriate, scientifically valid
method.
As with final § 111.110(b), we provide
in final § 111.110(c) that the tests and
examinations are those required under
final § 111.75.
We did not receive comments specific
to quality control operations under
proposed § 111.37(b)(9).
G. What Quality Control Operations Are
Required for a Material Review and
Disposition Decision? (Final § 111.113)
Final § 111.113 derives from several
proposed provisions, including
§§ 111.35(i), (j), and (n); 111.37(b)(3);
111.40(a)(3) and (b)(2); 111.50(d)(1);
111.65(d); and 111.70(c). All these
proposed requirements are related to
one or more aspects associated with a
material review and disposition,
including the circumstances that require
a material review and disposition
decision, the documentation that must
be included in a material review and
disposition decision, any restrictions on
who must conduct the material review
and make the disposition decision, and
the need for oversight by the quality
control unit. As discussed in section X
of this document, we simplified the
provisions regarding a material review
and disposition decision (final
§ 111.87), emphasizing the importance
of oversight by quality control personnel
and retaining the principle that
qualified individuals other than those
who are designated quality control
personnel can contribute to the material
review and disposition decision. The
final rule sets forth the following
requirements for quality control
personnel that relate to final § 111.113:
• Under final § 111.87, quality
control personnel must conduct all
required material reviews and make all
required disposition decisions;
• Under final § 111.103, you must
establish and follow written procedures
for conducting a material review and
making a disposition decision; and
• Under final § 111.140(b)(3)(vii),
documentation of a material review and
disposition decision and followup must
include the signature of the individual,
designated to perform the quality
control operation, who conducted the
material review and made the
disposition decision and of any
qualified individual who provided
information relevant to that material
review and disposition decision.
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The final rule establishes a system in
which you have the flexibility to
develop procedures that suit your
organization, including having qualified
individuals, who are not designated to
perform the quality control operation,
provide information relevant to the
material review and disposition
decision. For example, under final
§ 111.140(b)(3), you could have a
qualified individual in the production
department assist quality control
personnel in conducting a material
review by preparing a report that
includes all the required documentation
and information and providing a signed
copy of that report to quality control
personnel. An individual who is
designated to perform the quality
control operation could then use that
report as part of the material review,
conduct any further investigations, as
necessary, and decide to accept, amend,
or reject the report.
1. Final § 111.113(a)
Under final § 111.113(a) quality
control personnel must conduct a
material review and make a disposition
decision if:
• A specification established in
accordance with § 111.70 is not met;
• A batch deviates from the master
manufacturing record, including when
any step established in the master
manufacturing record is not completed
and including any deviation from
specifications;
• There is any unanticipated
occurrence during the manufacturing
operations that adulterates or may lead
to adulteration of the component,
dietary supplement, or packaging, or
could lead to the use of a label not
specified in the master manufacturing
record;
• Calibration of an instrument or
control suggests a problem that may
have resulted in a failure to ensure the
quality of a batch or batches of a dietary
supplement; or
• A dietary supplement is returned.
Final § 111.113(a) is substantially
similar to proposed § 111.35(i)(3), which
would require, in part, that you make a
material disposition decision for any
component, dietary supplement,
packaging, or label:
• If a component, dietary supplement,
packaging, or label fails to meet
established specifications;
• If any step established in the master
manufacturing record is not completed;
• If there is any unanticipated
occurrence during the manufacturing
operations that adulterates or may lead
to adulteration of the component,
dietary supplement, packaging, or label;
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• If calibration of an instrument or
control suggests a problem that may
have caused batches of a dietary
supplement to become adulterated; or
• If a dietary supplement is returned.
Final § 111.113(a) also incorporates
elements from other proposed sections
regarding the circumstances that require
a material review and disposition
decision as follows:
• Proposed § 111.35(n), which would
require you, for any specification that is
not met, to conduct a material review
and disposition decision under
proposed § 111.35(i);
• Proposed § 111.40(a)(3), which
would require you, for components,
dietary ingredients, or dietary
supplements you receive, to conduct a
material review and make a disposition
decision if specifications are not met;
• Proposed § 111.40(b)(2), which
would require that for packaging and
labels you receive, you must conduct a
material review and make a disposition
decision if specifications are not met;
• Proposed § 111.50(d)(1), which
would require that if a batch deviates
from the master manufacturing record,
including any deviation from
specifications, the quality control unit
must conduct a material review and
make a disposition decision and record
any decision in the batch production
record;
• Proposed § 111.65(d), which would
require you to conduct a material review
and make a disposition decision in
accordance with proposed § 111.35(i)
for any component, dietary ingredient,
or dietary supplement that fails to meet
specifications or that is or may be
adulterated; and
• Proposed § 111.70(c), which would
require you to conduct a material review
and make a disposition decision of any
packaged and labeled dietary
supplements that do not meet
specifications.
In final § 111.113(a) we are
incorporating, into a single unified
provision, the various proposed
circumstances that would require a
material review and disposition
decision under the 2003 CGMP
Proposal. We included revisions
associated with final § 111.87 which
requires quality control personnel to
conduct any required material review
and make any required disposition
decision. We also included revisions
associated with final § 111.90 that relate
to the impact on labeling operations due
to deviations and unanticipated
occurrences.
In establishing final § 111.113(a)(1),
we are deleting the specific reference to
the articles (components, dietary
supplements, packaging, and labels)
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required to undergo a material review.
We are deleting these references, in part,
to simplify the provision. Under final
§ 111.113(a) quality control personnel
must conduct a material review and
make a disposition decision if any
specification established in accordance
with final § 111.70 is not met. It is not
necessary to repeat, in final § 111.113,
the list of specifications that is clearly
set forth in final § 111.70.
We did not receive comments specific
to quality control operations under
proposed §§ 111.35(i)(3) and (n),
111.40(a)(3) and (b)(2), 111.50(d)(1),
111.65(d), or 111.70(c).
2. Final § 111.113(b)
Final § 111.113(b)(1) requires that,
when there is a deviation or
unanticipated occurrence during the
production and in-process control
system that results in or could lead to
adulteration of a component, dietary
supplement, or packaging, or could lead
to the use of a label not specified in the
master manufacturing record, quality
control personnel must reject the
component, dietary supplement, or
packaging, or label unless it approves a
treatment, an in-process adjustment, or
reprocessing to correct the applicable
deviation or occurrence.
Final § 111.113(b)(1) derives from the
following proposed provisions:
• Proposed § 111.35(i)(4)(i) which, in
part, would require that, for any
deviation or unanticipated occurrence
which resulted in or could lead to
adulteration of the component, dietary
ingredient, dietary supplement,
packaging, or label, you reject the
component, dietary ingredient, dietary
supplement, packaging, or label, unless
the quality control unit determines that
in-process adjustments are possible to
correct the deviation or occurrence;
• Proposed § 111.35(i)(4)(ii) which, in
part, would require that, for any
deviation or unanticipated occurrence
which resulted in or could lead to
adulteration of the component, dietary
ingredient, dietary supplement,
packaging, or label, you not reprocess a
rejected component or dietary
supplement unless approved by the
quality control unit; and
• Proposed § 111.37(b)(3) which, in
part, would require the quality control
unit to approve or reject all dietary
ingredients, dietary supplements,
components, packaging, and labels.
For consistency with other provisions
in final subpart F, final § 111.113(b)(1)
requires that quality control personnel
‘‘reject’’ a component, dietary
supplement, packaging, or label. We
also included revisions that are
associated with final § 111.90.
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Final § 111.113(b)(2) requires that
when a specification established in
accordance with § 111.70 is not met,
quality control personnel must reject the
component, dietary supplement,
package, or label, unless quality control
personnel approve a treatment, an inprocess adjustment, or reprocessing, as
permitted in final § 111.77. This
provision has been added as a result of
the new provision, final § 111.77 which
provides for what happens when certain
specifications are not met, the
responsibilities of quality control
personnel, and the changes made to
final § 111.90.
(Comment 219) Several comments
request that the quality control unit
focus on reviewing tasks performed by
others rather than on performing the
tasks itself.
(Response) We agree, and final
§ 111.113(b) provides that quality
control personnel ‘‘approve’’ an inprocess adjustment rather than
‘‘determine whether’’ the in-process
adjustment is possible.
3. Final § 111.113(c)
Final § 111.113(c) requires the person
who conducts a material review and
makes the disposition decision, at the
time of performance, to document that
material review and disposition
decision. Final § 111.113(c) derives from
proposed § 111.35(j) which, in part,
would require that the person who
conducts the material review and makes
the disposition decision must, at the
time of performance, document every
material review and disposition
decision in proposed § 111.35(i).
As an editorial revision, final
§ 111.113(c) requires documentation of
‘‘that’’ decision rather than ‘‘every’’
decision. As a practical matter, under
final § 111.113(c) every material review
and disposition decision is documented.
We did not receive comments specific
to quality control operations under
proposed § 111.35(j).
H. What Quality Control Operations Are
Required for Equipment, Instruments,
and Controls? (Final § 111.117)
Final § 111.117 (proposed
§ 111.37(b)(6) through (b)(8)) sets forth
the minimum required operations that
quality control personnel must perform
with respect to equipment, instruments,
and controls.
1. Final § 111.117(a) through (c)
Final § 111.117(a) through (c) requires
the quality control operations for
equipment, instruments, and controls to
include:
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• Reviewing and approving all
processes for calibrating instruments
and controls;
• Periodically reviewing all records
for calibration of instruments and
controls; and
• Periodically reviewing all records
for calibrations, inspections, and checks
of automated, mechanical, or electronic
equipment.
Final § 111.117(a), (b), and (c) derive
from proposed § 111.37(b)(6), (b)(7), and
(b)(8) which would require the quality
control unit to:
• Review and approve all processes
for calibrating instruments or controls;
• Review all records for calibration of
instruments, apparatus, gauges, and
recording devices; and
• Review all records for equipment
calibrations, inspections, and checks.
Final § 111.117 includes the following
changes we are making for consistency
with the requirements, set forth in
subpart D, for equipment and utensils:
• We have deleted the terms
‘‘apparatus,’’ ‘‘gauges,’’ and ‘‘recording
devices’’ from proposed § 111.37(b)(7)
as they would fall under the terms
‘‘instruments and controls’’ in final
§ 111.117, and because subpart D does
not use the terms ‘‘apparatus,’’
‘‘gauges,’’ or ‘‘recording devices.’’
• We are characterizing the records
for equipment calibrations, inspections,
and checks as records for calibrations,
inspections, and checks of ‘‘automated,
mechanical, or electronic equipment,’’
because final § 111.30(c) requires you to
calibrate, inspect, or check ‘‘automated,
mechanical, or electronic equipment.’’
(Comment 220) One comment argues
the requirements for oversight by the
quality control unit in proposed
§ 111.37(b)(7) and (b)(8) are excessive
and go beyond requirements for both the
drug CGMPs and food CGMPs. The
comment recommends revising
proposed § 111.37(b)(7) and (b)(8) to
require a review of all records when
there is a negative impact on the
product due to a calibration failure.
Other comments refer to the related
requirements in proposed § 111.30(b)(1)
that the quality control unit approve
calibrations, inspections, or checks of
automatic, mechanical, or electronic
equipment. These comments assert the
requirement for the quality control unit
to approve such calibrations,
inspections, and checks of equipment is
too prescriptive and that qualified
persons outside of the quality control
unit should be able to approve these
calibrations, inspections, or checks.
These comments also assert the quality
control unit should perform audits of
the records generated to ensure the
appropriate calibrations, inspections,
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and checks are being adequately
performed at the required intervals.
(Response) As already discussed with
respect to proposed § 111.30(b)(1) (final
§ 111.30(c)), we disagree that the review
by quality control personnel should be
limited to circumstances when there has
been a calibration failure. One of the
oversight functions of quality control
personnel is to prevent problems with
the product you distribute by finding
any problems with the equipment you
use to produce the product rather than
to investigate the cause of a problem
with a product that you already
distributed. However, we agree it is
sufficient to review the records of
calibrations, inspections, and checks of
automated, mechanical, or electronic
equipment periodically, for example, on
an annual basis, rather than to approve
each record when it is made. A periodic
review can uncover trends in the
performance of the equipment that have
the potential to adversely affect the
quality of the dietary supplement and
that may not be obvious by merely
approving each record when it is made.
Seeing such trends would enable quality
control personnel to recommend actions
to correct the trend. Therefore, we have
revised the proposed requirement so
that under final § 111.117(c) quality
control personnel must review all
records of calibrations, inspections, and
checks of automatic, mechanical, or
electronic equipment on a periodic
basis. Likewise, we have revised the
rule so that the quality control
personnel’s review of all records of
equipment calibrations also is on a
periodic basis.
(Comment 221) A few comments
argue the review of calibration records
may be conducted by a qualified person
other than the quality control unit, such
as by a supervisor or by a separate
department dedicated to equipment
maintenance and calibration. These
comments assert the quality control unit
should approve calibration processes,
but review of completed calibration
records by the dedicated department is
sufficient to assure compliance with the
approved process.
(Response) As already discussed,
many comments about the quality
control unit may have misunderstood
the proposed definition of ‘‘quality
control unit’’ (now replaced by ‘‘quality
control personnel’’). Under final
§ 111.12(b), you must identify who is
responsible for your quality control
operations. Each person who is
identified to perform quality control
operations must be qualified to do so
and have distinct and separate
responsibilities related to performing
such operations from those
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responsibilities that the person
otherwise has when not performing
such operations. Thus, in the situation
described by these comments, you could
identify a qualified person in a
department dedicated to equipment
maintenance and calibration to perform
quality control operations for equipment
calibration. Neither the definition of
‘‘quality control personnel,’’ nor the
requirements of final § 111.12(b), would
preclude a person who performs
‘‘Operation X’’ from being identified as
the person who performs quality control
operations for ‘‘Operation X.’’ However,
we strongly recommend that the person
you identify to perform a given quality
control operation be a different person
than the person who performed the
operation that is subject to quality
control oversight.
2. Final § 111.117(d)
Final § 111.117(d) requires that
quality control operations for
equipment, instruments, and controls
include reviewing and approving
controls to ensure automated,
mechanical, or electronic equipment
functions in accordance with its
intended use. Final § 111.117(d) derives,
in part, from proposed § 111.30(b)(4)
(final § 111.30(e)) which would require
that, for any automated, mechanical, or
electronic equipment you use, you must
establish and use appropriate controls
and the controls are approved by your
quality control unit to ensure that the
equipment functions in accordance with
its intended use. We are clarifying the
proposed requirement related to quality
control personnel in final § 111.117(d).
We did not receive comments specific
to this responsibility of the quality
control unit in proposed § 111.30(b)(4).
I. What Quality Control Operations Are
Required for Components, Packaging,
and Labels Before Use in the
Manufacture of a Dietary Supplement?
(Final § 111.120)
Final § 111.120 sets forth the
minimum required operations that
quality control personnel must perform
with respect to components, packaging,
and labels before use in the manufacture
of a dietary supplement. Some of the
proposed provisions that form the basis
for final § 111.120 included
requirements for ‘‘dietary supplements
that you receive.’’ For example,
proposed § 111.40(a) would require you,
for components or dietary supplements
you receive, to visually examine
containers and documentation provided
by the supplier, quarantine the materials
until they are released by the quality
control unit, and identify the materials
in a manner that allows you to trace the
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shipment you receive to the product
that you manufacture and distribute.
The final rule separates these and other
requirements for quality control
operations for ‘‘product that you receive
from a supplier’’ for packaging or
labeling as a dietary supplement from
the analogous requirements for
components. Thus, the requirements for
quality control operations for product
you receive for packaging and labeling
as a dietary supplement (and for
distribution rather than for return to the
supplier) are found in final § 111.127
rather than final § 111.120.
1. Final § 111.120(a)
Final § 111.120(a) requires that
quality control operations for
components, packaging, and labels
include reviewing all receiving records
for components, packaging, and labels
before use. Final § 111.120(a) derives
from the following proposed provisions:
• Proposed § 111.37(b)(10) which, in
part, would require the quality control
unit to review and approve all
packaging and label records which
include, but are not limited to, crossreferencing receiving and batch
production records;
• Proposed § 111.40(a)(3) which, in
part, would require that you quarantine
dietary supplements until your quality
control unit reviews the supplier’s
invoice, guarantee, or certification; and
• Proposed § 111.50(e)(1) which, in
part, would require the quality control
unit to document its review of
component receiving records.
(Comment 222) One comment asserts
that the proposed requirement that the
review of the batch record by the quality
control unit include cross-referencing of
receiving records with the batch
production record is redundant and
should be mandatory only in cases
where a specification has not been met.
This comment asserts the quality
control unit has already reviewed and
approved components, packaging, and
labels prior to their release and has used
unique identifiers for these raw
materials as they are recorded on related
documentation and records, which
allow traceability back to this
documentation for review when
necessary. This comment also asserts all
material review and disposition
decisions must be documented and
these will include the unique identifiers
that tie them to particular raw or inprocess materials.
Another comment asserts that the
quality control unit should only need to
repeat a review of the receiving records
as a result of conducting an
investigation or a material review, as is
required for drugs, and to require
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otherwise would be redundant. This
comment also states requiring the
quality control unit to repeat its review
of the receiving records places a fairly
large burden on the quality control unit
because this re-review must be
performed for each and every batch
production record. The comments assert
the requirement should be completed
properly and only once.
(Response) In the preamble to the
2003 CGMP Proposal (68 FR 12157 at
12200), we stated that cross-referencing
receiving and batch production records
means the quality control unit must
verify that the batch record includes
certain documentation of the receiving
records for the components such as the
unique identifier assigned to the
shipment lot of components, testing
results, a material review and
disposition decision, if conducted, and
approval for use by the quality control
unit. We agree with the comments that
the review of records such as receiving
records (including proper
documentation of a unique identifier for
components, packaging, and labels), if
done properly the first time it is
performed, need not be repeated.
Therefore, the final rule does not
include any requirement for crossreferencing receiving records with the
batch production record as we would
require under proposed § 111.37(b)(10).
As noted, we have changed ‘‘quality
control unit’’ to ‘‘quality control
personnel.’’ We agree that crossreferencing receiving and batch
production records is an appropriate
step to take when conducting a material
review and making a disposition when,
for example, a specification is not met.
We encourage firms to include this
activity in the written procedures for
conducting a material review and
making a disposition decision.
2. Final § 111.120(b)
Final § 111.120(b) requires that
quality control operations for
components, packaging, and labels
include determining whether all
components, packaging, and labels
conform to specifications established
under § 111.70(b) and (d) before use.
Final § 111.120(b) derives from
proposed § 111.37(b)(2).
We did not receive comments specific
to quality control operations under
proposed § 111.37(b)(2). For clarity, we
have identified the specifications as
those required under final § 111.70(b)
and (d).
3. Final § 111.120(c)
Final § 111.120(c) requires that
quality control operations for
components, packaging, and labels
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include conducting any required
material review and making any
required disposition decision before
use. Final § 111.120(c) derives from the
following proposed provisions:
• Proposed § 111.40(a)(3) which, in
part, would require you to conduct a
material review and make a disposition
decision if specifications are not met for
components; and
• Proposed § 111.40(b)(2) which, in
part, would require you to conduct a
material review and make a disposition
decision if specifications are not met for
packaging and labels.
Final § 111.120(c) includes revisions
associated with final § 111.87 which
requires quality control personnel to
conduct any required material review
and make any required disposition
decision.
(Comment 223) One comment
recommends the quality control unit
have authority to allow usage of
material that has failed to meet
specifications if the defect will not
significantly affect the overall quality of
the finished product even if
reprocessing is not an option. The
comment gives an example of a material
that fails to meet particle size
specifications designed to maximize the
efficiency of processing of the material,
but ultimately does not impair strength,
and asserts the quality unit should have
the authority to release the material for
use.
(Response) The final rule provides for
a process in which quality control
personnel determine whether a
component meets specifications and
conduct a material review and make a
disposition decision if a component
does not meet one or more
specifications. The final rule does not
prohibit the use of a component that
does not meet all component
specifications other than the identity
specification. For example, under final
§ 111.120(d) quality control personnel
may approve an in-process adjustment
of a component to make it suitable for
use in the manufacture of a dietary
supplement (see discussion of final
§ 111.120(d) in the following
paragraphs). Under final § 111.123(b)
quality control personnel must not
approve and release for distribution any
batch of dietary supplement, including
any reprocessed batch, that does not
meet all product specifications or is not
a quality product. Thus, although a
disposition decision could be made
under final § 111.120(c) to use a
component even if it does not meet
certain specifications, that decision
should take into account whether the
failure for the component to meet
specifications will ultimately cause the
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dietary supplement to fail to meet
product specifications.
4. Final § 111.120(d)
Final § 111.120(d) requires that
quality control operations for
components, packaging, and labels
include approving, or rejecting, any
treatment and in-process adjustments of
components, packaging, or labels to
make them suitable for use in the
manufacture of a dietary supplement.
Final § 111.120(d) derives from the
following proposed provisions:
• Proposed § 111.35(i)(4)(i) which, in
part, would require that you reject the
component, packaging, or label, unless
the quality control unit determines that
in-process adjustments are possible to
correct the deviation or occurrence and
• Proposed § 111.35(i)(4)(ii) which
would have prohibited you from
reprocessing a rejected component
unless approved by the quality control
unit.
Final § 111.120(d) includes a revision
associated with final § 111.90(c), and
refers to ‘‘treatment and in-process
adjustments to make them suitable for
use in the manufacture of a dietary
supplement’’ (see discussion of final
§ 111.90(c) in section X of this
document).
(Comment 224) Several comments
request the quality control unit focus on
reviewing tasks performed by others
rather than on performing the tasks
itself.
(Response) Final § 111.120(d)
includes a revision that quality control
personnel ‘‘approve’’ a treatment rather
than ‘‘determine that’’ the treatment is
possible.
(Comment 225) A few comments
support the proposed requirement that
the quality control unit have the
authority to approve reprocessing
measures.
(Response) These comments are
consistent with proposed § 111.35(i) and
(i)(4)(ii) and final § 111.120(d), as
applicable to quality control personnel.
(Comment 226) One comment states
that the decision to reprocess a material
belongs within the particular
operational unit, and that the role of the
quality control unit should be to
approve the results of the reprocessing.
(Response) We disagree that the role
of quality control personnel should be
limited to approving the results of
reprocessing or, in this case, of the
treatment or in-process adjustments of
components, packaging, or labels. An
underlying principle of these CGMP
requirements is that quality control
personnel oversee the design and
conduct of manufacturing, packaging,
labeling, and holding operations. A
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decision about when reprocessing is, or
is not, appropriate requires oversight.
As already discussed, under final
§ 111.12(b) you must identify who is
responsible for your quality control
operations. Each person who is
identified to perform quality control
operations must be qualified to do so
and have distinct and separate
responsibilities related to performing
such operations from those
responsibilities that the person
otherwise has when not performing
such operations.
5. Final § 111.120(e)
Final § 111.120(e) requires that
quality control operations for
components, packaging, and labels
include approving and releasing from
quarantine all components, packaging,
and labels before they are used. Final
§ 111.120(e) derives from the following
proposed provisions:
• Proposed § 111.40(a)(3) which, in
part, would require that you quarantine
components until your quality control
unit approves the components and
releases them from quarantine and
• Proposed § 111.40(b)(2) which, in
part, would require that you quarantine
packaging and labels until your quality
control unit approves the packaging and
labels and releases them from
quarantine.
We did not receive comments specific
to quality control operations under
proposed § 111.40(a)(3) or (b)(2).
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J. What Quality Control Operations Are
Required for the Master Manufacturing
Record, the Batch Production Record,
and Manufacturing Operations? (Final
§ 111.123)
Final § 111.123 sets forth the
minimum required operations that
quality control personnel must perform
with respect to the master
manufacturing record, the batch
production record, and manufacturing
operations.
1. Final § 111.123(a)(1)
Final § 111.123(a)(1) requires that
quality control operations for the master
manufacturing record, the batch
production record, and manufacturing
operations include reviewing and
approving all master manufacturing
records and all modifications to the
master manufacturing records. Final
§ 111.123(a)(1) derives from duplicate
proposed requirements, in proposed
§§ 111.37(b)(4) and 111.45(c), with no
changes other than the editorial changes
associated with the reorganization.
We did not receive comments specific
to quality control operations under
proposed §§ 111.37(b)(4) or 111.45(c),
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but have combined them as final
§ 111.123(a)(1).
2. Final § 111.123(a)(2)
Final § 111.123(a)(2) requires that
quality control operations for the master
manufacturing record, the batch
production record, and manufacturing
operations include reviewing and
approving all batch production-related
records. Final § 111.123(a)(2) derives
from proposed § 111.37(b)(5), which
would require, in part, the quality
control unit to review and approve all
batch production-related records.
Proposed § 111.37(b)(5) explicitly
stated, in part, that the batch record
would include, but not be limited to,
cross-referencing receiving and batch
production records.
(Comment 227) One comment
expresses concern that proposed
§ 111.37(b) does not state specifically
that the complete batch history,
including batch record, analytical
records, quality control records, yields,
and packaging records should be
reviewed and approved by the quality
control unit before the batch is shipped.
The comment believes these are
important requirements that should be
clearly stated.
(Response) Proposed § 111.37(b)(5)
would require that the quality control
unit ‘‘review and approve all batch
production-related records, including
but not limited to * * *’’ We disagree
with the comment that this proposed
provision would not include what the
comment describes. To the extent that
the comments interpreted the list of
records to mean that only the partial
listing of records was required, we have
modified final § 111.123(a)(2) to require
quality control personnel to review all
batch production-related records. We do
not emphasize any particular aspect of
the batch production record. This
reduces the potential to misinterpret the
requirement as being limited to the
specific items cited.
(Comment 228) As already discussed
in detail with respect to final
§ 111.120(a), some comments assert the
proposed requirement that the review of
the batch record by the quality control
unit include cross-referencing of
receiving records with the batch
production record is redundant to other
requirements that the quality control
unit review receiving records for
components, packaging, and labels. In
general, these comments assert the
requirement should be completed
properly and only once.
(Response) We agree with the
comments that the review of records,
such as receiving records, if done
properly the first time that it is
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34869
performed, need not be repeated.
Therefore, the final rule does not
include any requirements for crossreferencing receiving records with the
batch production record as we would
require under proposed § 111.37(b)(5).
3. Final § 111.123(a)(3)
Final § 111.123(a)(3) requires that
quality control operations for the master
manufacturing record, the batch
production record, and manufacturing
operations include reviewing all
monitoring required under subpart E.
Final § 111.123(a)(3) derives from the
following proposed provisions:
• Proposed § 111.35(f) which would
require you to monitor the in-process
control points, steps, or stages to ensure
that specifications established under
proposed § 111.35(e) are met and to
detect any unanticipated occurrence
that may result in adulteration;
• Proposed § 111.35(e)(2) which
would require you to establish a
specification for any point, step, or stage
in the manufacturing process where
control is necessary to prevent
adulteration, including the in-process
controls in the master manufacturing
record where control is necessary to
ensure the identity, purity, quality,
strength, and composition of dietary
supplements;
• Proposed § 111.35(i)(2) which
would require you to review the results
of the monitoring required under
proposed § 111.35(f) and conduct a
material review if an established
specification is not met or if there is any
unanticipated occurrence that
adulterates or could result in
adulteration;
• Proposed § 111.35(o)(2) which
would require you to make and retain
records to ensure you follow the
requirements of proposed § 111.35,
including the actual results obtained
during the monitoring operation; and
• Proposed § 111.37(b)(5) which
would require the quality control unit to
review and approve all batch
production-related records.
Under the final rule, the results of the
monitoring required under proposed
§ 111.35(f) must be kept in the batch
record (see the discussion of the batch
record in section XIV of this document).
Quality control personnel must review
the results of the required monitoring.
(Comment 229) One comment
suggests the phrase ‘‘review the results
of the monitoring required by this
section’’ be deleted from proposed
§ 111.35(i)(2) because it is unnecessary
and can be read as narrowing any final
rule. This comments points out the only
required monitoring in the proposal
appears in § 111.35(f) related to
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monitoring of in-process control points,
steps, or stages, and that such
monitoring would not necessarily find
all failures in specifications, for
example, specifications related to raw
materials or labels.
(Response) We disagree with the
comment that the quoted language
narrows the final rule. Monitoring that
relates to in-process control points,
steps, or stages would be required under
proposed § 111.35(f) and is now
required in final § 111.123(a)(3).
However, in practice, a manufacturer
must monitor its entire operation to
ensure that the requirements of the final
rule are met. For example, under final
§ 111.73, a manufacturer must
determine whether specifications
established under final § 111.70 are met
and under final § 111.75(a) and (f) a
manufacturer must use certain criteria
to determine whether specifications for
components and labels, respectively, are
met. Thus, there are sufficient controls
in other requirements to ensure the
entire production and process controls
are functioning as intended.
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4. Final § 111.123(a)(4)
Final § 111.123(a)(4) requires that
quality control operations for the master
manufacturing record, the batch
production record, and manufacturing
operations include conducting any
required material review and making
any required disposition decision. Final
§ 111.123(a)(4) derives from the
following proposed provisions:
• Proposed § 111.37(b)(5) which, in
part, would require the quality control
unit to approve a material review and
disposition decision related to batch
production records; and
• Proposed § 111.50(d)(1) which, in
part, would require, if a batch deviates
from the master manufacturing record,
including any deviation from
specifications, the quality control unit
to conduct a material review and make
a disposition decision.
We did not receive comments specific
to quality control operations under
proposed §§ 111.37(b)(5) or 111.50(d)(1).
5. Final § 111.123(a)(5)
Final § 111.123(a)(5) requires that
quality control operations for the master
manufacturing record, the batch
production record, and manufacturing
operations include approving or
rejecting any reprocessing. Final
§ 111.123(a)(5) derives from proposed
§ 111.37(b)(5) which would require the
quality control unit to approve any
reprocessing. For consistency with other
provisions in this final rule (such as
final § 111.90), final § 111.123(a)(5)
includes a revision that quality control
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personnel must approve—or reject—any
reprocessing.
We did not receive comments specific
to quality control operations under
proposed § 111.37(b)(5).
6. Final § 111.123(a)(6)
Final § 111.123(a)(6) requires that
quality control operations for the master
manufacturing record, the batch
production record, and manufacturing
operations include determining whether
all in-process specifications established
in accordance with § 111.70(c) are met.
Final § 111.123(a)(6) derives from the
following proposed provisions:
• Proposed § 111.35(f) which would
require you to monitor the in-process
control points, steps, or stages to ensure
specifications are met (including the inprocess specifications required under
proposed § 111.35(e)(2)) and
• Proposed § 111.37(a) which, in part,
would require the quality control unit to
ensure your manufacturing, packaging,
labeling, and holding operations are
performed in a manner that prevents
adulteration, including that such
operations ensure the dietary
supplement meets its specifications for
identity, purity, quality, strength, and
composition.
Final § 111.123(a)(6) is consistent
with the overall approach, set forth in
final §§ 111.70, 111.73, and 111.75, that
focuses on ensuring the quality of the
dietary supplement throughout the
production and process control system.
We did not receive comments specific
to quality control operations under
proposed §§ 111.35(e)(2) or (f), or
111.37(a).
7. Final § 111.123(a)(7)
Final § 111.123(a)(7) requires that
quality control operations for the master
manufacturing record, the batch
production record, and manufacturing
operations include determining whether
each finished batch conforms to product
specifications established in accordance
with final § 111.70(e). Final
§ 111.123(a)(7) derives from proposed
§ 111.37(b)(2) which, in part, would
require the quality control unit to
determine whether all dietary
supplements conform to specifications.
We did not receive comments specific
to quality control operations under
proposed § 111.37(b)(2).
8. Final § 111.123(a)(8)
Final § 111.123(a)(8) requires that
quality control operations for the master
manufacturing record, the batch
production record, and manufacturing
operations include approving and
releasing, or rejecting, each finished
batch for distribution, including any
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reprocessed finished batch. Final
§ 111.123(a)(8) derives from the
following proposed provisions:
• Proposed § 111.37(b)(5) which, in
part, would require the quality control
unit to approve batch production
records for releasing finished batches for
distribution;
• Proposed § 111.50(d)(2) which
would require the quality control unit to
not approve and release for distribution
any batch that does not meet all
specifications; and
• Proposed § 111.50(g) which would
require the quality control unit to not
approve and release for distribution any
reprocessed batch of dietary supplement
that does not meet all specifications.
We did not receive comments specific
to the proposed provisions cited above.
9. Final § 111.123(b)
Final § 111.123(b) requires that
quality control personnel must not
approve and release for distribution:
• any batch of dietary supplement for
which any component in the batch does
not meet its identity specification;
• any batch of dietary supplement,
including any reprocessed batch, that
does not meet all product specifications
established in accordance with
§ 111.70(e);
• any batch of dietary supplement,
including any reprocessed batch, that
has not been manufactured, packaged,
labeled, and held under conditions to
prevent adulteration under section
402(a)(1), (a)(2), (a)(3), and (a)(4) of the
act; and
• any product received from a
supplier for packaging or labeling as a
dietary supplement (and for distribution
rather than for return to the supplier) for
which sufficient assurance is not
provided to adequately identify the
product and to determine that the
product is consistent with your
purchase order.
Final § 111.123(b) derives from the
following proposed provisions:
• Proposed § 111.50(d)(2) which
would require the quality control unit to
not approve and release for distribution
any batch of dietary supplement that
does not meet all specifications;
• Proposed § 111.50(g) which would
require that a reprocessed batch of
dietary supplement meet all
specifications and that the quality
control unit approve its release for
distribution; and
• Proposed § 111.37(b)(11)(iii) which
would require the quality control unit to
collect representative samples of each
batch of dietary supplement
manufactured to determine, before
releasing for distribution, whether the
dietary supplement meets its
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specifications for identity, purity,
quality, strength, and composition.
The final provision clarifies all of the
responsibilities of quality control
personnel and includes provisions
consistent with changes made to final
§§ 111.73, 111.77, and 111.90.
We did not receive comments specific
to those aspects of proposed
§§ 111.50(g) and 111.37(b)(11)(iii) that
are relevant to final § 111.123(b). We
discuss in the following paragraphs
comments we received to proposed
§ 111.50(d)(2).
(Comment 230) Several comments
object to proposed § 111.50(d)(2)
because it would prohibit the release of
any batch that does not meet all
specifications. Other comments suggest
the prohibition should apply to meeting
‘‘release specifications’’ or ‘‘essential
manufacturer specifications’’ rather than
‘‘all specifications’’ because in-process
deviations and minor deviations may
not affect product quality.
(Response) A finished dietary
supplement that is ready for release for
distribution must meet component
specifications for identity established
under final § 111.70(b) and all product
specifications established for the batch
under final § 111.70(e) and must be
manufactured in a manner to prevent
adulteration under section 402(a)(1),
(a)(2), (a)(3), and (a)(4) of the act. The
final rule does not prevent you from
establishing additional specifications
that do not affect the identity, purity,
strength, composition, or contaminant
levels of your finished dietary
supplement. Such a specification is not
a component specification for identity
or a product specification that is
required under the final rule. Final
§ 111.123(b) would not preclude you
from releasing a product that fails to
meet a specification that is not a
component specification for identity or
a product specification established
under final § 111.70 provided quality
control personnel approve such release.
Final § 111.123(b) would not preclude
you from releasing a product that you
are permitted to release under final
§ 111.77.
(Comment 231) Some comments note
that proposed § 111.50(d)(2) would not
allow the quality control unit to conduct
an investigation, and make a disposition
decision, of the failure of a batch to
meet specifications. These comments
assert proposed § 111.50(d)(2) therefore
restricts the provision in proposed
§ 111.50(d)(1) which would require that,
if a batch deviates from the master
manufacturing record, including any
deviation from specifications, the
quality control unit must conduct a
material review and make a disposition
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decision. The comments argue the
quality control unit should have the
authority to release products with minor
deviations.
(Response) As discussed previously
(see discussion of final § 111.90 in
subpart E in section X of this
document), we acknowledge that some
specifications, such as component, other
than for identity, and in-process
specifications, that are not met may be
able to be corrected by a treatment or an
in-process adjustment. Quality control
personnel would need to conduct a
material review and disposition
decision for any such specification not
met. If there are specifications for any
point, step, or stage in the
manufacturing process where control is
necessary to ensure the quality of the
dietary supplement and that the dietary
supplement is packaged and labeled as
specified in the master manufacturing
record (final § 111.70(a)), you must
determine whether these specifications
are met (final § 111.73).
Final § 111.123(b) does not preclude
you, for example, from releasing a
product that was the subject of a
material review because sampling
procedures had not been followed if, as
a corrective action, the appropriate
samples were collected and subjected to
appropriate tests and examinations.
K. What Quality Control Operations Are
Required for Packaging and Labeling
Operations? (Final § 111.127)
Final § 111.127 sets forth the required
operations that quality control
personnel must perform with respect to
packaging and labeling operations.
1. Final § 111.127(a) and (b)
Final § 111.127(a) and (b) set forth
requirements for product you receive for
packaging or labeling as a dietary
supplement (and for distribution rather
than for return to the supplier).
Final § 111.127(a) and (b) apply to
product that has left the control of the
person who manufactured the batch; for
example, the purchase of dietary
supplements in bulk for packaging or
labeling by a person who will distribute
the packaged and labeled dietary
supplements under a private label. If
you are a packager or labeler who
operates under contract to the
manufacturer, and you will return the
dietary supplement to the manufacturer,
we would not consider that you are
‘‘receiving’’ product within the meaning
of final § 111.127(a) and (b). We would
consider you to be no different than an
operating unit of the manufacturer. In
section VI of this document (subpart A),
we discuss in detail the scope of this
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34871
final rule and its applicability to
contractors.
a. Final § 111.127(a). Final
§ 111.127(a) requires that quality control
operations for packaging and labeling
operations include reviewing the results
of any visual examination and
documentation to ensure that
specifications established under final
§ 111.70(f) are met for product you
receive for packaging or labeling as a
dietary supplement (and for distribution
rather than for return to the supplier).
Final § 111.127(a) derives from the
following proposed provisions:
• Proposed § 111.40(a)(2) which
would require you to visually examine
the supplier’s invoice, guarantee, or
certification to ensure that dietary
supplements you receive are consistent
with your purchase order and perform
testing, as needed, to determine whether
specifications are met and
• Proposed § 111.40(a)(3) which
would, in part, require you to
quarantine dietary supplements you
receive until your quality control unit
reviews the supplier’s invoice,
guarantee, or certification and performs
testing, as needed, of a representative
sample to determine that specifications
are met.
Final § 111.127(a) includes revisions
associated with final §§ 111.70(f) and
111.75(e) which set forth requirements
for all products you receive from a
supplier for packaging or labeling as
dietary supplements (and for
distribution rather than for return to the
supplier). As discussed in section X of
this document, under final § 111.70(f) if
you receive such product, you must
establish specifications to provide
sufficient assurance that the product
you receive is adequately identified and
is consistent with your purchase order.
In addition, under final § 111.75(e)
before you package or label such
products, you must visually examine
the products and have documentation to
determine whether the specifications
that you established under final
§ 111.70(f) are met. The documentation
you have to satisfy the requirements of
final § 111.75(e) is not limited to a
supplier’s invoice, guarantee, or
certification and, thus, final § 111.127(a)
incorporates the standard set by final
§ 111.75(e) (i.e., documentation) rather
than the proposed standard of the
supplier’s invoice, guarantee, or
certification. In addition, consistent
with final § 111.75(e), final § 111.127(a)
requires quality control personnel to
review the results of the visual
examination but not otherwise review
the results of tests or examinations.
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We did not receive comments specific
to quality control operations under
proposed § 111.40(a)(2) or (a)(3).
b. Final § 111.127(b). Final
§ 111.127(b) requires that quality control
operations for packaging and labeling
operations include approving, and
releasing from quarantine, all products
you receive for packaging and labeling
as a dietary supplement (and for
distribution rather than for return to the
supplier) before the products are used
for packaging and labeling. Final
§ 111.127(b) derives from proposed
§ 111.40(a)(3) which, in part, would
require you to quarantine dietary
supplements that you receive until your
quality control unit reviews the
supplier’s invoice, guarantee, or
certification and performs testing, as
needed, of a representative sample to
determine that specifications are met,
and approves and releases the dietary
supplements from quarantine before you
use them.
As with final § 111.127(a), final
§ 111.127(b) includes revisions
associated with changes made in final
§§ 111.70(f) and 111.75(e).
We did not receive comments specific
to quality control operations under
proposed § 111.40(a)(3).
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2. Final § 111.127(c)
Final § 111.127(c) requires that
quality control operations for packaging
and labeling operations include
reviewing and approving all records for
packaging and label operations. Final
§ 111.127(c) derives from proposed
§ 111.37(b)(10) which, in part, would
require the quality control unit to
review and approve all packaging and
label records.
We did not receive comments specific
to quality control operations under
proposed § 111.37(b)(10).
3. Final § 111.127(d)
Final § 111.127(d) requires that
quality control operations for packaging
and labeling operations include
determining whether the finished
packaged and labeled dietary
supplement conforms to specifications
established in accordance with final
§ 111.70(g). Final § 111.127(d) derives
from the following proposed provisions:
• Proposed § 111.37(b)(2) which, in
part, would require the quality control
unit to determine whether all dietary
supplements conform to specifications
and
• Proposed § 111.37(b)(11)(iv) which,
in part, would require the quality
control unit to collect representative
samples of each batch of packaged and
labeled dietary supplements to
determine that you used the packaging
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specified in the master manufacturing
record and applied the label specified in
the master manufacturing record.
For clarity, final § 111.127(d)
identifies the specifications as those
established in final § 111.70(g).
We did not receive comments specific
to quality control operations under
proposed § 111.37(b)(2) or (b)(11)(iv).
4. Final § 111.127(e)
Final § 111.127(e) requires that
quality control operations for packaging
and labeling operations include
conducting any required material
review and making any required
disposition decision. Final § 111.127(e)
derives from the following proposed
provisions:
• Proposed § 111.70(c) which would
require you to conduct a material review
and make a disposition decision of any
packaged and labeled dietary
supplement that does not meet
specifications and
• Proposed § 111.40(a)(3) which, in
part, would require you, if
specifications are not met for a received
dietary supplement, to conduct a
material review and make a disposition
decision.
Final § 111.127(e) includes revisions
associated with final § 111.87 which
requires quality control personnel to
conduct any required material review
and make any required disposition
decision.
We did not receive comments specific
to quality control operations under
proposed §§ 111.70(c) or 111.40(a)(3).
5. Final § 111.127(f) and (g)
Final § 111.127(f) requires that quality
control operations for packaging and
labeling operations include approving
or rejecting any repackaging of a
packaged dietary supplement. Final
§ 111.127(g) requires that quality control
operations for returned dietary
supplements include approving or
rejecting any relabeling of a packaged
and labeled dietary supplement. Final
§ 111.127(f) and (g) derive from the
following proposed provisions:
• Proposed § 111.37(b)(10) which, in
part, would require the quality control
unit to approve any repackaging and
relabeling and
• Proposed § 111.70(d) which would
require the quality control unit to
approve and document any repackaging
or relabeling of a dietary supplement.
For consistency with other provisions
in this final rule (such as final § 111.90),
final § 111.127(f) and (g) provide that
quality control personnel must clearly
choose between approving—or
rejecting—any repackaged or relabeled
dietary supplements.
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We did not receive comments specific
to quality control operations under
proposed §§ 111.37(b)(10) or 111.70(d).
6. Final § 111.127(h)
Final § 111.127(h) requires that
quality control operations for packaging
and labeling operations include
approving for release, or rejecting, any
packaged and labeled dietary
supplement (including a repackaged or
relabeled dietary supplement) for
distribution. Final § 111.127(h) derives
from the following proposed provisions:
• Proposed § 111.37(b)(10) which, in
part, would require the quality control
unit to approve the release of packaged
and labeled dietary supplements for
distribution; and
• Proposed § 111.70(e) which, in part,
would require the quality control unit to
approve or reject the release of any
repackaged or relabeled dietary
supplement.
We did not receive comments specific
to quality control operations under
proposed §§ 111.37(b)(10) or 111.70(e).
L. What Quality Control Operations Are
Required for Returned Dietary
Supplements? (Final § 111.130)
Final § 111.130 sets forth the
minimum required operations quality
control personnel must perform with
respect to returned dietary supplements.
Final § 111.130 modifies proposed
§ 111.85 which set forth requirements
for returned dietary ingredients and
dietary supplements, including
requirements for quality control
operations for returned dietary
supplements. We did not explicitly
include quality control operations with
respect to returned dietary supplements
under proposed § 111.37 but did
include quality control operations in
proposed § 111.85 for returned dietary
supplements. The provisions of the final
rule that pertain to returned dietary
supplements are set forth in final
subpart N. However, we are duplicating
these requirements in subpart F to make
clear that once returned products are
back within your control, quality
control personnel must perform
appropriate operations before the
products are redistributed, if they are
approved for redistribution. Any
returned dietary supplements that are
reprocessed must be returned to your
production and process control system,
and, therefore, must be properly
reviewed by quality control personnel.
1. Final § 111.130(a)
Final § 111.130(a) requires that
quality control operations for returned
dietary supplements include conducting
any required material review and
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making any required disposition
decision. Final § 111.130(a) differs
slightly from proposed § 111.85(a)
which, in part, would require the
quality control unit to conduct a
material review and make a disposition
decision for any returned dietary
supplement.
(Comment 232–233) Some comments
support the proposed requirement to
specify that it is the quality control unit
that conducts the material review and
makes the disposition decision
regarding returned dietary supplement
products.
(Response) These comments are
consistent with proposed § 111.85(a)
which is being incorporated into final
§ 111.130(a).
2. Final § 111.130(a)(1) and (a)(2)
Final § 111.130(a)(1) requires that
quality control operations for returned
dietary supplements include
determining whether tests or
examination are necessary to determine
compliance with product specifications
established in accordance with final
§ 111.70(e).
Final § 111.130(a)(2) requires that the
review and disposition decision for
returned dietary supplements include
review of the results of any tests or
examinations that are conducted to
determine compliance with product
specifications established in accordance
with final § 111.70(e).
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3. Final § 111.130(b)
Final § 111.130(b) requires that
quality control operations for returned
dietary supplements include approving
or rejecting any salvage and
redistribution of any returned dietary
supplement. Final § 111.130(b) derives
from proposed § 111.37(b)(15) which, in
part, would require the quality control
unit to approve the distribution of
returned dietary supplements. As
discussed in the preamble to the 2003
CGMP Proposal, ‘‘salvage’’ means to
return to distribution without
reprocessing (68 FR 12157 at 12215).
For consistency with other regulations
in this final rule (such as final § 111.90),
final § 111.130(e) provides that quality
control personnel must clearly choose
between approving—or rejecting—any
salvage and redistribution.
(Comment 234) Some comments
support the proposed requirement to
specify that it is the quality control unit
who approves, or rejects, a returned
dietary supplement for redistribution.
(Response) These comments are
consistent with proposed § 111.37(b)(15)
which is being incorporated into final
§ 111.130(b).
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4. Final § 111.130(c)
Final § 111.130(c) requires that
quality control operations for returned
dietary supplements include approving
or rejecting any reprocessing of any
returned dietary supplement. Final
§ 111.130(c) derives from proposed
§ 111.37(b)(15) which, in part, would
require the quality control unit to
approve the reprocessing of returned
dietary supplements. For consistency
with other provisions of this final rule
(such as final § 111.90), final
§ 111.130(c) provides that quality
control personnel must clearly choose
between approving—or rejecting—any
reprocessing.
(Comment 235) One comment argues
that the responsibility to decide whether
a returned dietary supplement is
reprocessed belongs with qualified
persons in manufacturing operations,
and the only responsibility of the
quality control unit is to approve the
reprocessed product for distribution.
(Response) We disagree with the
comment. An underlying principle of
these CGMP requirements is that quality
control personnel oversee the design
and conduct of manufacturing,
packaging, labeling, and holding
operations. A decision about when
reprocessing is, or is not, appropriate
requires oversight.
5. Final § 111.130(d)
34873
M. What Quality Control Operations Are
Required for Product Complaints? (Final
§ 111.135)
Final § 111.135 requires that quality
control operations for product
complaints include reviewing and
approving decisions about whether to
investigate a product complaint and
reviewing and approving the findings
and followup action of any investigation
performed.
Final § 111.135 derives from proposed
§ 111.95 which would set forth
requirements for consumer complaints
(now ‘‘product complaints’’), including
requirements for quality control
operations for consumer complaints. We
did not explicitly include quality
control operations with respect to
consumer complaints under proposed
§ 111.37 but did include quality control
operations in proposed § 111.95 for
review and investigation of consumer
complaints. The final rule’s product
complaint requirements are now set
forth in final subpart O. However, we
have duplicated the requirements for
quality control operations for product
complaints in subpart F to make clear
that your investigation of the product
complaint has the potential to uncover
a problem with your production and
process control system and, therefore,
quality control personnel must exercise
appropriate oversight of your
investigation of any product complaint.
N. What Records Must You Make and
Final § 111.130(d) requires that
Keep? (Final § 111.140)
quality control operations for returned
Final § 111.140 sets forth the
dietary supplements include
requirements for records that quality
determining whether the reprocessed
control personnel must make and keep.
dietary supplement meets product
1. Final § 111.140(a)
specifications and either approving for
release, or rejecting, any returned
Final § 111.140(a) requires quality
dietary supplement that is reprocessed.
control personnel to make and keep
Final § 111.130(d) derives from the
records required under subpart F in
following proposed provisions:
accordance with subpart P. Final
§ 111.140(a) derives from proposed
• Proposed § 111.37(b)(2) which, in
§ 111.37(d) with editorial revisions
part, would require the quality control
associated with the reorganization.
unit to determine whether all dietary
Other than comments that generally
supplements conform to specifications;
opposed the requirements to make and
and
• Proposed § 111.65(d) which, in part, keep records, and to have records
available for inspection and copying by
would require you, if a material review
FDA when requested (see the discussion
and disposition decision allows you to
in section V of this document), we did
reprocess a dietary supplement, to
not receive comments specific to
ensure it meets specifications and is
proposed § 111.37(d).
approved by the quality control unit.
For consistency with other regulations 2. Final § 111.140(b)(1)
in this final rule (such as final § 111.90),
The final rule (final § 111.103)
final § 111.130(d) provides that quality
requires you to establish and follow
control personnel must clearly choose
written procedures for the
between approving—or rejecting—a
responsibilities of the quality control
reprocessed dietary supplement.
operations, including written
We did not receive comments specific procedures for conducting a material
review and making a disposition
to quality control operations under
decision and for approving or rejecting
proposed §§ 111.37(b)(2) or 111.65(d).
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reprocessing. The written procedures
are records. Therefore, final
§ 111.140(b)(1) requires you to make and
keep a record of the written procedures
for the responsibilities of the quality
control operations.
3. Final § 111.140(b)(2)
Final § 111.140(b)(2) requires written
documentation, at the time of
performance, that quality control
personnel performed the review,
approval, or rejection requirements
under subpart F. Final § 111.140(b)(2)(i)
requires quality control personnel to
record the date that the review,
approval, or rejection was performed.
Final § 111.140(b)(2)(ii) requires quality
control personnel to record the
signature of the person performing the
review, approval, or rejection. Final
§ 111.140(b)(2) derives from proposed
§ 111.37(c) with revisions associated
with the reorganization.
We did not receive comments specific
to proposed § 111.37(c).
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4. Final § 111.140(b)(3)
Final § 111.140(b)(3) requires quality
control personnel to document any
material review and disposition
decision and followup and include the
documentation in the batch record.
Final § 111.140(b)(3) derives from
proposed § 111.35(j) with revisions
associated with the reorganization and a
revision, associated with final § 111.87
which requires quality control
personnel to conduct the material
review and make the disposition
decision.
Final § 111.140(b)(3) details the type
of information that must be included as
part of this documentation. Five
paragraphs derive from proposed
§ 111.35(j)(1) through (j)(5), with
editorial changes associated with the
reorganization. One paragraph is
associated with final § 111.90(b) which
requires that you not reprocess any
component or dietary supplement that
is rejected or treat a component or make
an in-process adjustment to make it
suitable for use in the manufacture of a
dietary supplement, unless quality
control personnel conduct a material
review and make a disposition decision
that is based on a scientifically valid
reason and approve the reprocessing,
treatment, or in-process adjustment.
Another paragraph derives, in part, from
proposed § 111.37(c)(2) which would
require the signature of the quality
control unit person performing the
requirement.
The documentation that must be
included under final § 111.140(b)(3) is
as follows:
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• Section 111.140(b)(3)(i)—
Identification of the specific deviation
or the unanticipated occurrence;
• Section 111.140(b)(3)(ii)—A
description of your investigation into
the cause of the deviation from the
specification or the unanticipated
occurrence;
• Section 111.140(b)(3)(iii)—An
evaluation of whether the deviation or
unanticipated occurrence has resulted
in or could lead to a failure to ensure
the quality of the dietary supplement or
a failure to package and label the dietary
supplement as specified in the master
manufacturing record;
• Section 111.140(b)(3)(iv)—
Identification of the action(s) taken to
correct, and prevent a recurrence of, the
deviation or the unanticipated
occurrence;
• Section 111.140(b)(3)(v)—An
explanation of what you did with the
component, dietary supplement,
packaging, or label;
• Section 111.140(b)(3)(vi)—A
scientifically valid reason for any
reprocessing of a dietary supplement
that is rejected, or the treatment or inprocess adjustment of a component that
is rejected; and
• Section 111.140(b)(3)(vii)—The
signature of the individual(s) designated
to perform the quality control operation,
who conducted the material review and
made the disposition decision, and of
each qualified individual who provided
information relevant to that material
review and disposition decision.
We did not receive comments specific
to proposed § 111.35(j).
XII. Comments on the Production and
Process Control System: Requirements
for Components, Packaging, and Labels,
and for Product that You Receive for
Packaging or Labeling as a Dietary
Supplement (Final Subpart G)
A. Organization of Final Subpart G
In the 2003 CGMP Proposal, the
requirements for production and
process controls related to components,
packaging, dietary ingredients, labels,
and dietary supplements that you
receive were set forth in proposed
§ 111.40. As shown in table 8 of this
document, we are reorganizing the
requirements related to components,
packaging, labels, and product that you
receive for packaging and labeling as a
dietary supplement, into a distinct
subpart (final Subpart G—Production
and Process Control System:
Requirements for Components,
Packaging, and Labels, and for Product
that You Receive for Packaging or
Labeling as a Dietary Supplement).
Table 8 lists the sections in final subpart
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G and identifies the sections in the 2003
CGMP Proposal that form the basis of
the final rule.
TABLE 8.—DERIVATION OF SECTIONS
IN FINAL SUBPART G
Final Rule
2003 CGMP
Proposal
§ 111.153 What Are the
requirements under
this subpart G for written procedures?
N/A
§ 111.155 What requirements apply to components of dietary supplements?
§ 111.40(a)(1)
through (a)(5)
§ 111.35(d)(1)
throug (d)(5)
§ 111.160 What requirements apply to packaging and labels received?
§ 111.35(e)(4)
§ 111.40(a)(2)
and (b)
§ 111.165 What requirements apply to a product received for packaging or labeling as a
dietary supplement
(and for distribution
rather than for return
to the supplier)?
§ 111.40(a)
§ 111.170 What requirements apply to rejected components,
packaging, and labels,
and to rejected products that are received
for packaging or labeling as a dietary supplement?
§ 111.74
§ 111.180 Under this
subpart G, what
records must you
make and keep?
§ 111.40(c)(1)(i)
through
(c)(1)(iv) and
(c)(2)
§ 111.35(d)(4)
B. Highlights of Changes to the
Proposed Requirements for
Components, Packaging, and Labels,
and Product That You Receive for
Packaging or Labeling as a Dietary
Supplement
1. Revisions
The final rule:
• Applies to persons who
manufacture, package, label, or hold a
dietary supplement unless subject to an
exclusion in § 111.1.
• Includes requirements that apply to
components, including components that
are dietary ingredients, regardless of
whether you receive the components or
manufacture them yourself (final
§§ 111.70(b) and 111.75(a)).
• Separates the requirements for
product you receive from a supplier for
packaging or labeling as a dietary
supplement (and for distribution rather
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than for return to the supplier) (final
§ 111.165) from the requirements for
components (final § 111.155).
E. What Requirements Apply to
Components of Dietary Supplements?
(Final § 111.155)
2. Changes After Considering Comments
The final rule applies only to persons
who manufacture, package, label, or
hold dietary supplements unless subject
to an exclusion under final § 111.1. The
effect of this revision is that the
requirements that derive from proposed
§ 111.40(a) for components you receive
now apply to all components, whether
you receive them or manufacture them
yourself.
The final rule separates the
requirements for product you receive
from a supplier for packaging or labeling
as a dietary supplement (and for
distribution rather than for return to the
supplier) (final § 111.165) from the
analogous requirements for components,
packaging, and labels (final § 111.155).
The final rule incorporates a new
requirement to establish and follow
written procedures for fulfilling the
requirements for components,
packaging, labels, and product you
receive from a supplier for packaging or
labeling as a dietary supplement for
distribution rather than for return to the
supplier.
C. General Comments on Proposed
§ 111.40 (Final Subpart G)
(Comment 236) One comment states
that many companies use an electronic
material resource planning system to
control the status of inventory, and
assert this type of system provides
suitable controls to ensure only
materials that are approved by the
quality control unit are used. The
comment notes only the quality control
unit has the authority to release any
material in quarantine and asks whether
such a system would comply with the
requirements of the proposed
regulation.
(Response) Based on the limited
information provided by the comment,
it appears the electronic inventory
system that the comment describes
would comply with the requirements of
final § 111.155(c)(3) to quarantine
components until quality control
personnel release them for use in
manufacture, provided that appropriate
controls are established and used to
ensure the system functions in
accordance with its intended use as
required by final § 111.30(e). We are
making no changes based on this
comment.
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D. What Are the Requirements Under
This Subpart for Written Procedures?
(Final § 111.153)
We received many comments that
recommended written procedures for
various provisions. We address the need
for written procedures generally in
section IV of this document. We also
respond to individual comments on
specific provisions in the same section.
Final § 111.153 requires you to
establish and follow written procedures
for fulfilling the requirements of subpart
G. Under final § 111.180(b)(1), as a
conforming requirement, we require you
to make and keep records of such
written procedures. Such records would
be available to us under the
requirements in Subpart P—Records
and Recordkeeping.
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1. Proposed § 111.35(d)
In proposed § 111.35(d), we would
require that any substance, other than a
‘‘dietary ingredient’’ within the meaning
of section 201(ff) of the act, that is
subject to section 409 of the act, be: (1)
Authorized for use as a food additive
under section 409 of the act; or (2)
authorized by a prior sanction
consistent with § 170.3(l) (21 CFR
170.3(l)); or (3) if used as a color
additive, subject to a listing that, by the
terms of that listing (including a listing
for use in coloring foods generally),
includes the use in a dietary
supplement; or (4) GRAS for use in a
dietary supplement. We also proposed
that any claim that a substance is GRAS
must be supported by a citation to the
agency’s regulations or by an
explanation for why there is general
recognition of safety of the use of the
substance in a dietary supplement.
Further, under § 111.35(d)(5), we
proposed to require that you comply
with all other applicable statutory and
regulatory requirements under the act.
We received several comments
objecting to one or more of the
provisions of proposed § 111.35(d) and
to our statement in the preamble to the
2003 CGMP Proposal regarding how we
would apply the provisions of proposed
§ 111.35(d)(4). After considering these
comments, we have deleted the
requirements in § 111.35(d) in this final
rule.
(Comment 237) Several comments
recommend proposed § 111.35(d) be
deleted because the statute already
requires that ingredients, other than
‘‘dietary ingredients,’’ be approved as a
food additive or a color additive, or be
GRAS. Some comments assert that
proposed § 111.35(d) and proposed
§ 111.5 already require compliance with
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all other applicable statutory and
regulatory requirements under the act,
and therefore, there is no need to refer
to food additive, color additive, and
GRAS requirements. Some comments
assert that proposed § 111.35(d) is
unnecessary because there is no such
requirement in the food CGMPs. Other
comments assert this proposed
requirement should be deleted because
it is only tangentially related to the
manufacturing process, and CGMP
should be focused on setting minimum
standards for manufacturing systems
and steps in the production and
distribution of dietary supplements that
are required to produce safe and
accurately labeled products. Other
comments assert that because the drug
CGMPs do not have such a requirement,
dietary supplement CGMPs should not
have such a requirement.
Other comments did not object to the
principle underlying proposed
§ 111.35(d), i.e., that we need to ensure
GRAS substances used in dietary
supplements are GRAS under the
manufacturer’s specified use. However
many comments disagreed, for various
reasons, with the proposed requirement
in § 111.35(d)(4) that a claim that a
substance is GRAS must be supported
by a citation to our regulations or by an
explanation for why there is general
recognition of safety of the use of the
substance in a dietary supplement.
(Response) We agree that proposed
§ 111.35(d) is unnecessary because there
are already existing statutory and
regulatory requirements related to the
lawful use of ingredients used in dietary
supplements. We do not have to repeat
those requirements in this final rule.
Ensuring the ingredients you use to
manufacture a dietary supplement are
lawful under the applicable statutory
and regulatory requirements is the
responsibility of the dietary supplement
manufacturer.
For the reasons set forth in the
previous paragraphs, we are deleting
proposed § 111.35(d)(4) from the final
rule. Because we are deleting this
provision, it is unnecessary to respond
to the various comments related to the
documentation that proposed
§ 111.35(d)(4) would have required, or
whether we could not have included
such requirements in the dietary
supplement CGMP final rule because
the requirements are not in food or drug
CGMP regulations.
We also agree that proposed
§ 111.35(d)(5) is redundant to proposed
§ 111.5 and final § 111.5 and are
therefore not repeating proposed
§ 111.35(d)(5) in final § 111.35.
Although we are deleting § 111.35(d)
from the final rule, there were several
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comments that we received, and
respond to in the following paragraphs,
that seemed to question whether
existing statutory and regulatory
requirements apply to the use of
ingredients in a dietary supplement.
(Comment 238) One comment
suggests components not found in
finished goods in a material amount
should not be subject to the same GRAS
requirements as those found in a
material amount. Another comment
states dietary supplements are excluded
from the food additive definition in
section 201(s) of the act, and that
components that constitute the dietary
supplement are also excluded from the
food additive definition. The comment
suggests that, under proposed
§ 111.35(d), we are erroneously trying to
maintain food additive authority for
dietary supplements.
(Response) The assertion that dietary
supplements and all of their
components are not subject to the food
additive provisions of the act’s
definition is incorrect. We do maintain
authority over the use of certain
substances, as color additives, food
additives,10 or GRAS substances that
may be used in manufacturing dietary
supplements.
The food additive definition in
section 201(s) of the act excludes ‘‘an
ingredient described in paragraph (ff) in,
or intended for use in, a dietary
supplement.’’ Thus, a ‘‘dietary
ingredient’’ described in section
201(ff)(1) of the act is not a ‘‘food
additive.’’ Nor can the use of a dietary
ingredient be considered to be GRAS,
since the GRAS status itself is an
exception to the definition of a food
additive. However, ingredients that may
be used in a dietary supplement, other
than those excepted in section 201(s),
are subject to our regulatory authority as
a food additive, unless their use is
GRAS or authorized by a prior sanction.
Thus, it is incorrect to say, as the
comment asserts, that dietary
supplements and all of their
components are not subject to the food
additive definition.
We also disagree that components not
found in finished goods in a material
amount should not be subject to the
same GRAS requirements as those found
in a material amount. It is not clear what
the comment meant by ‘‘material
amount.’’ A food additive means ‘‘any
substance the intended use of which
results or may reasonably be expected to
result, directly or indirectly, in its
10Although
we refer to the term ‘‘food additive’’
in the preamble, the reader should also consider
color additives and substances prior-sanctioned for
such use as being relevant to the discussion.
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becoming a component or otherwise
affecting the characteristics of any food’’
if the use of such substance is not GRAS
(section 201(s) of the act).11 We have
discretion to determine whether an
ingredient is one where the agency
would find the presence to be ‘‘de
minimis’’ (Monsanto v. Kennedy, 613
F.2d 947, 956 (D.C. Cir. 1979)).
However, whether the agency would
find it appropriate to exercise such
discretion with respect to the use of a
particular ingredient is beyond the
scope of this final rule.
(Comment 239) Several comments
questioned whether certain ingredients
would be considered GRAS. One
comment stated excipients regularly
used in pharmaceuticals for many years
and safely used in dietary supplements
may not be considered GRAS for use in
foods, approved for use as a food
additive, or considered a dietary
ingredient. An example provided was
‘‘croscarmellose sodium’’ used for
disintegration. The comment asks
permission to use any recognized
excipient, an excipient that is
monographed in a recognized
compendium, used in drug products, or
shown to be in use prior to the
implementation of the final rule. Other
comments stated proposed § 111.35(d)
would be overly burdensome since
many ingredients are GRAS for broad
food use, have been used in dietary
supplements without specific
recognition as a GRAS use, and should
be permitted. Other comments state
substances listed in the USP National
Formulary, Food Chemical Codex, the
American Pharmaceutical Associations
Handbook of Pharmaceutical Excipients,
and FDA’s inactive ingredient guide are
considered GRAS based on a history of
common use even though there is no
listing of these substances as GRAS.
(Response) The GRAS status of
specific uses of excipients cannot be
treated as a general class and is beyond
the scope of this final rule. It is possible
that the data needed to support safe uses
as an excipient in a drug may be widely
known among experts and form a basis
for a consensus that use in a dietary
supplement is safe. However, use of
drugs containing the excipient may be
short term or may be intermittent,
leading to far less exposure than routine
use in some dietary supplements. As
human exposure increases, not only
does the safety profile of the intended
excipient become more important, but
the purity specifications also become
11It is important to note that it is the use of the
substance, not the substance itself, that must be
GRAS. The amount of a substance in the food is a
critical factor in determining whether the use
would be GRAS.
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more critical. We advise persons who
need more information about the basis
for concluding that a use of a substance
is GRAS to consult § 170.30 and our
GRAS Proposal to establish a
notification program for the use of
GRAS substances (62 FR 18938, April
17, 1997).
(Comment 240) Some comments
assert it is not feasible to require that
starting materials used by bulk
ingredient manufacturers be GRAS or
approved food additives. The comments
state many ingredients are not food
grade substances or approved for use in
food until after processing. One
comment states raw materials may
become dietary ingredients after
processing, but the materials from
which the dietary ingredient is derived
are not considered to be a GRAS
ingredient, a dietary ingredient, or a
dietary supplement. The comment gives
examples of Ginkgo biloba leaves or
Saw palmetto or cartilage. The comment
asks us to consider natural products
(from animal, mineral, or vegetable
origin) to be included in the rule as
potential raw materials for nutritional
supplements. Another comment
expresses concern that a soy isolate,
from which natural vitamin E is
derived, would not be considered a
GRAS substance.
(Response) These comments seem to
be concerned about the regulatory status
of substances used as raw materials in
the manufacture of a dietary ingredient
or dietary supplement. An important
consideration, however, is whether such
materials become a component of the
dietary ingredient or dietary
supplement.
Dietary ingredient manufacturers who
manufacture dietary ingredients for
further processing by another person
into a dietary supplement are outside
the scope of this final rule. However,
such manufacturers are still subject to
other applicable statutory and
regulatory provisions. For example, if
you are a dietary ingredient
manufacturer that uses a material in the
manufacture of a dietary ingredient, and
the material becomes part of the dietary
ingredient, we would consider it to be
part of the dietary ingredient and
subject to the exception to the food
additive definition in section 201(s)(6)
of the act. However, because the
material becomes a component of the
dietary ingredient, you are subject to the
applicable statutory and regulatory
requirements that would apply to the
dietary ingredient, including the safety
of the dietary ingredient.
If you use a material, other than a
dietary ingredient, in the manufacture of
a dietary supplement, that becomes a
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part of the dietary supplement, you are
subject to the applicable statutory and
regulatory requirements that apply to
the use of such material, including its
safety for such use. In this case, the use
of the material would be subject to
regulation as a food additive (unless it
is GRAS or prior-sanctioned).
Alternatively, if you use material in
the manufacture of a dietary ingredient
or a dietary supplement that does not
become part of the dietary ingredient or
dietary supplement, then we would not
consider the material to be a food.
(Comment 241) Several comments
state the color additive provision would
be too restrictive if it only allowed
colors listed for use in a dietary
supplement, rather than colors listed for
use in foods generally. Some comments
note none of the color additives
currently approved generally for ‘‘food’’
use is approved specifically for dietary
supplements within the food category.
Another comment argues we gave no
rationale for requiring a categorical
listing under specific color additives for
dietary supplements. The comment
states color additives are not used in
any greater amount in supplements than
in foods and, if anything, are probably
used less because supplements are
consumed in smaller amounts than
foods and less color additive must be
used to achieve the desired effect. One
comment notes it was not familiar with
any evidence to indicate that a color
additive (whether it is certified or
exempt) found by us to be safe for use
in foods is not safe in dietary
supplements.
(Response) We acknowledge that the
combination of proposed § 111.35(d)(3)
and several color additive listings is
confusing and could lead to incorrect
conclusions about whether specific
color additives may lawfully be used in
a dietary supplement. As the comments
point out, some listings for color
additives (such as for the certified colors
FD&C Blue No. 1 (21 CFR 74.101) and
FD&C Red No. 40 (21 CFR 74.340)) list
the color additive ‘‘for coloring foods
(including dietary supplements)
generally’’ (i.e., the listings specifically
identify dietary supplements as a food
category in which the color additive
may be used). In contrast, some listings
for color additives (such as for annatto
extract (21 CFR 73.30) and for betacarotene (21 CFR 73.95)) list the color
additive ‘‘for coloring foods generally’’
(i.e., without specifically identifying
dietary supplements as a food category
in which the color additive may be
used). In general, the terms of either of
these two kinds of listings (i.e., ‘‘for
coloring foods (including dietary
supplements) generally’’ and ‘‘for
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coloring foods generally’’) mean we saw
no need for restriction of the use of the
color additive when FDA approved the
listing of that color additive. Thus, a
color additive listed for use in food
generally may be used in a dietary
supplement.
Although most listings of color
additives provide for the use of the color
additive in food generally, some listings
for color additives restrict the use of the
color additive in terms of the food
category in which it may be used. For
example, under 21 CFR 73.125 sodium
copper chlorophyllin may be safely
used to color citrus-based dry beverage
mixes in an amount not exceeding 0.2
percent in the dry mix, and the terms of
this listing would not include the use in
a dietary supplement. We list a color
additive with restrictions such as these
when for example, the person who
submits a petition for us to approve the
listing of a color additive only requests
a specific use, or when the available
data and information only support the
safety of a limited consumption of the
color additive.
2. Final § 111.155(a)
Final § 111.155(a) (proposed
§ 111.40(a)(1)) requires you to visually
examine each immediate container or
grouping of immediate containers in a
shipment you receive for appropriate
content label, container damage, or
broken seals to determine whether the
container condition may have resulted
in contamination or deterioration of the
components. Final § 111.155(a) is
substantially similar to proposed
§ 111.40(a)(1) which would require you,
for components you receive, to visually
examine each container or grouping of
containers in a shipment for appropriate
content label, container damage, or
broken seals to determine whether the
container condition has resulted in
contamination or deterioration of the
components. Because you do not receive
shipments for components you make,
we are revising proposed § 111.40(a) so
that it applies only to shipments of
components you receive. We have
added the word ‘‘immediate’’ to identify
the container as the one in contact with
the dietary supplement or component.
We also have changed ‘‘has resulted’’ to
‘‘may have resulted’’ since in some
cases you may not be able to make a
final determination from a visual
inspection alone whether the container
condition has resulted in contamination
or deterioration of the components.
(Comment 242) One comment
supports the proposed requirements of
proposed § 111.40(a) as an effective
guideline for the inspection of
purchased ingredients.
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(Response) The provisions of final
§ 111.155(a) are requirements, not
guidelines, as stated by the comment.
3. Final § 111.155(b)
Final § 111.155(b) (proposed
§ 111.40(a)(2)) requires you to visually
examine the supplier’s invoice,
guarantee, or certification in a shipment
you receive to ensure that the
components are consistent with your
purchase order. Final § 111.155(b) is
substantially similar to proposed
§ 111.40(a)(2) which would require you
to visually examine the supplier’s
invoice, guarantee, or certification to
ensure the components are consistent
with your purchase order and perform
testing, as needed, to determine whether
specifications are met. As with final
§ 111.155(a), final § 111.155(b) clarifies
that the invoice, guarantee, or
certification comes in the shipment you
receive.
Final § 111.155(b) does not include
any requirements related to testing
components. Final § 111.75(a) sets forth
the requirements to test or examine
components; final §§ 111.110 and
111.120 set forth requirements for
quality control personnel to ensure that
appropriate tests or examinations are
conducted, review the results of any
tests or examination, determine whether
components conform to specifications,
and approve the components before
they are used in the manufacture of a
dietary supplement. Given this set of
requirements, it would be redundant to
set forth requirements regarding testing
for components in final subpart G.
We did not receive comments specific
to the requirements of proposed
§ 111.40(a)(2).
4. Final § 111.155(c)
Final § 111.155(c) (proposed
§ 111.40(a)(3)) requires you to
quarantine components before you use
them in the manufacture of a dietary
supplement until:
• You collect representative samples
of each unique lot of components (and,
for components that you receive, of each
unique shipment, and of each unique lot
within each unique shipment);
• Quality control personnel review
and approve the results of any test or
examinations conducted on
components; and
• Quality control personnel approve
the components for use in the
manufacture of a dietary supplement,
including approval of any treatment
(including in-process adjustments) of
components to make them suitable for
use in the manufacture of a dietary
supplement, and release them from
quarantine.
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Final § 111.155 modifies proposed
§ 111.40(a)(3) which would require:
• You to quarantine components until
your quality control unit reviews the
supplier’s invoice, guarantee, or
certification;
• The quality control unit to perform
testing, as needed, of a representative
sample to determine that specifications
are met;
• You to conduct a material review
and make a disposition decision if
specifications are not met; and
• The quality control unit to approve
and release the components from
quarantine before you use them.
Final § 111.155(c) includes revisions
related to the following changes to other
provisions already discussed.
• Under final § 111.110, quality
control personnel ensure that all
appropriate tests and examinations are
conducted, and review and approve the
results of tests and examinations
conducted on components, but quality
control personnel are not required to
conduct the tests or examinations;
• Under final § 111.80(a), we
establish the convention in this final
rule of referring to ‘‘each unique lot
within each unique shipment’’ rather
than ‘‘each shipment lot;’’
• The requirements to conduct a
material review and make a disposition
decision are already set forth in final
§§ 111.87, 111.113, and 111.120 and,
therefore, are not repeated in final
§ 111.155; and
• Under final § 111.90(c), any batch of
dietary supplement that is reprocessed,
that contains components that you have
treated, or to which you have made inprocess adjustments to make them
suitable for use in the manufacture of
the dietary supplement, must meet all
product specifications for the dietary
supplement and be approved by quality
control personnel before being released
for distribution.
(Comment 243) Some comments
address the requirement to quarantine
components before you use them and
assert that it is not feasible to quarantine
incoming materials in a continuous
extraction and purification operation,
such as one built adjacent to a soy
crushing or vegetable oil refinery to
receive a continuous side stream flow
from that operation. One comment
explains that in such operations,
quarantine and quality control approval
occurs later in the process after the
material has been isolated and
concentrated in a stable matrix suitable
for holding. One comment suggests
proposed § 111.40(a)(3) state
‘‘quarantine components or dietary
supplements as applicable * * *’’.
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(Response) We decline to revise
proposed § 111.40(a)(3) as suggested by
the comments. The comment describes
a situation where a manufacturer of a
dietary supplement is also
manufacturing a dietary ingredient or
other component but only provides
limited information. It appears that,
however, the procedures described for
quarantine of the isolated, stable matrix,
with subsequent evaluation by quality
control personnel before release for use
in the manufacture of the dietary
supplement, would satisfy the
requirements of final § 111.155(c),
provided quality control personnel are
able to determine that all specifications
for the component are met.
(Comment 244) One comment states
that plant personnel who are not
formally part of the manufacturer’s
quality control unit can conduct the
quality control functions required for
the release of materials from quarantine
before use.
(Response) As already discussed with
respect to the definition of quality
control personnel (see section VI of this
document), these comments may have
misunderstood the role of the quality
control unit (now quality control
personnel). To clarify that role, final
§ 111.12(b) states you must identify a
qualified person who is responsible for
your quality control operations.
(Comment 245) One comment
suggests components that cannot be
used in a short time should be retested
at least yearly.
(Response) We are making no changes
to the provision after considering this
comment. Whether any tests or
examinations must be repeated over
time, or whether the information in a
certificate of analysis remains valid over
time, is a matter to be decided by the
manufacturer based on the established
characteristics and shelf life of the
component.
5. Final § 111.155(d)
Final § 111.155(d)(1) (proposed
§ 111.40(a)(4)) requires you to identify
each unique lot within each unique
shipment of components you receive
and any lot of components that you
produce in a manner that allows you to
trace the lot to the supplier, the date
received, the name of the component,
the status of the component (e.g.,
quarantined, approved, or rejected), and
to the dietary supplement you
manufactured and distributed. Final
§ 111.155(d)(2) requires you to use this
unique identifier whenever you record
the disposition of each unique lot
within each unique shipment of
components that you receive and any lot
of components that you produce.
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Final § 111.155(d)(1) and (d)(2) are
substantially similar to proposed
§ 111.40(a)(4) which would require you
to identify each lot of components in a
shipment in a manner that allows you
to trace the shipment to the supplier,
the date received, the name of the
component, and the status (e.g.,
quarantined, approved, or rejected), and
to trace the shipment lot to the dietary
supplement you manufactured and
distributed. Proposed § 111.40(a)(4) also
would require you to use this unique
identifier whenever you record the
disposition of each shipment lot
received.
Final § 111.155(d)(1) and (d)(2)
include revisions associated with final
§ 111.80(a).
We did not receive comments specific
to proposed § 111.40(a)(4).
6. Final § 111.155(e)
Final § 111.155(e) (proposed
§ 111.40(a)(5)) requires you to hold
components under conditions that will
protect against contamination and
deterioration and avoid mixups.
We did not receive comments specific
to proposed § 111.40(a)(5).
F. What Requirements Apply to
Packaging and Labels Received? (Final
§ 111.160)
1. Final § 111.160(a)
Final § 111.160(a) (proposed
§ 111.40(b)(1)) requires you to visually
examine each immediate container or
grouping of immediate containers in a
shipment for appropriate content label,
container damage, or broken seals to
determine whether the container
condition may have resulted in
contamination or deterioration of the
packaging and labels. Final § 111.160(a)
is similar to proposed § 111.40(b)(1)
with the addition of the word
‘‘immediate’’ to identify the container as
the container that is in contact with the
packaging or labels and substituting
‘‘may have’’ for ‘‘has’’ before the word
‘‘resulted’’ as discussed in this section.
We did not receive comments specific
to proposed § 111.40(b)(1).
2. Final § 111.160(b)
Final § 111.160(b) requires you to
visually examine the supplier’s invoice,
guarantee, or certification in a shipment
to ensure the packaging or labels are
consistent with your purchase order.
Final § 111.160(b) is a new requirement
that is analogous to proposed
§ 111.40(a)(2). We are requiring in final
§ 111.160(b), that, as part of your visual
identification, you compare what was
received, based on the supplier’s
invoice, guarantee, or certification, with
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your purchase order so you can ensure
your specifications for packaging and
labels are met. This is consistent with
what you would do with respect to
components and dietary supplements
you receive. Without final § 111.160(b),
the review by quality control personnel
under final § 111.120(a) would be a
matter of performing receiving
operations rather than performing
quality control operations; as already
discussed in this section, some
comments asserted the quality control
unit should focus on reviewing the work
of others rather than conducting the
operations themselves. Thus, final
§ 111.160 is consistent with these
comments.
3. Final § 111.160(c)
Final § 111.160(c) requires you to
quarantine packaging and labels before
you use them in the manufacture of a
dietary supplement until:
• You collect representative samples
of each unique shipment, and of each
unique lot within each unique
shipment, of packaging and labels and,
at a minimum, conduct a visual
identification of the immediate
containers and closures;
• Quality control personnel review
and approve the results of any tests or
examinations conducted on the
packaging and labels; and
• Quality control personnel approve
the packaging and labels for use in the
manufacture of a dietary supplement
and release them from quarantine.
Final § 111.160(c) is similar to
proposed § 111.40(b)(2) which would
require that:
• You quarantine packaging and
labels until your quality control unit
tests or examines a representative
sample to determine that specifications
are met;
• You conduct at least a visual
identification of the containers and
closures;
• If specifications are not met, you
conduct a material review and make a
disposition decision; and
• Your quality control unit approve
and release packaging and labels from
quarantine before you use them.
Final § 111.160(c) includes revisions
that reflect the following change already
discussed in this final rule:
• Refers to ‘‘each unique lot within
each unique shipment’’ rather than
‘‘each shipment lot’’.
We did not receive comments specific
to proposed § 111.40(b)(2).
4. Final § 111.160(d)
Final § 111.160(d)(1) requires you to
identify each unique lot within each
unique shipment of packaging and
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labels in a manner that allows you to
trace the lot to the supplier, the date
received, the name of the packaging and
label, the status of the packaging and
label (e.g., quarantined, approved, or
rejected), and to the dietary supplement
you distributed. Final § 111.160(d)(2)
requires you to use this unique
identifier whenever you record the
disposition of each unique lot within
each unique shipment of packaging and
labels. Final § 111.160(d) derives from
proposed § 111.40(b)(3) which would
require you to identify each shipment
lot of packaging and labels in a manner
that allows you to trace the shipment lot
to the supplier, the date received, the
name of the packaging and label and the
status (e.g., quarantined, approved, or
rejected) and to trace the shipment lot
to the dietary supplement manufactured
and distributed. Proposed § 111.40(b)(3)
also would require that you use this
unique identifier whenever you record
the disposition of each shipment lot
received.
Final § 111.160(d) includes revisions
that reflect the following changes
already discussed in this final rule:
• Reference to ‘‘each unique lot
within each unique shipment’’ rather
than ‘‘each shipment lot.’’
• As a clarification, final
§ 111.160(d)(2) refers to the ‘‘dietary
supplement that you distributed’’ rather
than to the ‘‘dietary supplement
manufactured and distributed’’ to avoid
a narrow—and incorrect—interpretation
of ‘‘manufactured.’’ Under proposed
§ 111.40(b)(3), we used the term
‘‘manufactured’’ in a broad sense that
includes any aspect of the
manufacturing process rather than a
narrow sense that applied to
manufacturing operations for producing
a batch of dietary supplement. Both
proposed § 111.40(b)(3) and final
§ 111.160(e) address the need to trace
the packaging and labels that you use to
the product that you distribute,
regardless of whether your role in the
manufacturing process includes the
production of the batch or includes only
packaging a dietary supplement you
receive from a supplier.
(Comment 246) One comment
believes packaging and labels are rarely
the source of quality problems. This
comment suggests proposed
§ 111.40(b)(3) allow the use of packaging
approved by the quality control unit
without the need to use a specific lot
identification number. The comment
explains that this type of flexibility is
needed when they have dozens of short
run lots each day and use less than a
carton of packaging supplies for each
run.
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(Response) This comment may have
misinterpreted proposed § 111.40(b)(3).
Under proposed § 111.40(b)(3) (final
§ 111.160(d)) you must assign the
identifier to each unique lot within each
unique shipment of packaging and
labels when you receive them rather
than each time that you use them. This
number would stay the same for each of
the short runs described by the
comment. We are making no changes to
the requirement.
5. Final § 111.160(e)
Final § 111.160(e) requires you to
hold packaging and labels under
conditions that will protect against
contamination and deterioration, and
avoid mixups. Final § 111.160(e) is
identical to proposed § 111.40(b)(4).
We did not receive comments specific
to proposed § 111.40(b)(4).
G. What Requirements Apply to a
Product Received for Packaging or
Labeling as a Dietary Supplement (and
for distribution rather than for return to
the supplier)? (Final § 111.165)
Final § 111.165 (proposed § 111.40(a))
sets out actions you must take when you
receive a product for packaging and
labeling and for distribution. Final
§ 111.165 includes editorial changes
associated with the reorganization and
revisions that reflect changes we are
making to other sections of the final
rule.
Final § 111.165 sets forth
requirements for ‘‘product that you
receive from a supplier for packaging or
labeling as a dietary supplement (and
for distribution rather than for return to
the supplier)’’ rather than for ‘‘dietary
supplements that you receive.’’
The final rule separates the
requirements in proposed § 111.40(a) for
product that you receive from a supplier
for packaging or labeling as a dietary
supplement (and for distribution rather
than for return to the supplier) (final
§ 111.165) from the analogous
requirements for components,
packaging, and labels (final § 111.155).
1. Final § 111.165(a)
Final § 111.165(a) requires you to
visually examine each immediate
container or grouping of immediate
containers in a shipment of product you
receive for packaging or labeling as a
dietary supplement (and for distribution
rather than for return to the supplier) for
appropriate content label, container
damage, or broken seals to determine
whether the container condition may
have resulted in contamination or
deterioration of the received product.
Final § 111.165(a) is substantially
similar to proposed § 111.40(a)(1)
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which, in part, would impose this
requirement for dietary supplements
you receive. We have added the word
‘‘immediate’’ to identify the container as
the container that is in contact with the
product you receive for packaging or
labeling as a dietary supplement and
substituted ‘‘may have’’ for ‘‘has’’ before
the word ‘‘resulted’’ as explained in this
section.
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2. Final § 111.165(b)
Final § 111.165(b) requires you to
visually examine the supplier’s invoice,
guarantee, or certification in a shipment
of the received product to ensure the
received product is consistent with your
purchase order. Final § 111.165(b) is
substantially similar to proposed
§ 111.40(a)(2) which, in part, would
establish a similar requirement for
dietary supplements that you receive.
3. Final § 111.165(c)
Final § 111.165(c) requires you to
quarantine the received product until:
• You collect representative samples
of each unique shipment, and of each
unique lot within each unique
shipment, of received product;
• Quality control personnel review
and approve the documentation to
determine whether the received product
meets the specifications that you
established under § 111.70(f); and
• Quality control personnel approve
the received product for packaging or
labeling as a dietary supplement and
release the received product from
quarantine.
Final § 111.165(c) is similar to
proposed § 111.40(a)(3) which, in part,
would require that:
• You quarantine dietary
supplements that you receive until your
quality control unit reviews the
suppliers invoice, guarantee, or
certification;
• The quality control unit performs
testing, as needed, of a representative
sample to determine that specifications
are met;
• You conduct a material review and
make a disposition decision if
specifications are not met; and
• The quality control unit approves
and releases the dietary supplements
that you receive from quarantine before
you use them.
Final § 111.165(c) includes revisions
that reflect that under final § 111.75(e)
before you package or label a product
you received for packaging or labeling
as a dietary supplement, you must
visually examine the product and have
documentation to determine whether
the specifications you established under
§ 111.70(f) are met, but not otherwise
examine or conduct tests.
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4. Final § 111.165(d)
Final § 111.165(d)(1) requires that you
identify each unique lot within each
unique shipment of received product in
a manner that allows you to trace the lot
to the supplier, the date received, the
name of the received product, the status
of the received product (e.g.,
quarantined, approved, or rejected), and
to the product you packaged or labeled
and distributed as a dietary supplement.
Final § 111.165(d)(2) requires you to use
this unique identifier whenever you
record the disposition of each unique lot
within each unique shipment of the
received product. Final § 111.165(d)
derives from proposed § 111.40(a)(4)
which would require you, in part, to
identify each lot of dietary supplements
in a shipment in a manner that allows
you to trace the shipment to the
supplier, the date received, the name of
the dietary supplement, and the status
(e.g., quarantined, approved, or
rejected), and to trace the shipment lot
to the dietary supplement manufactured
and distributed. Proposed § 111.40(a)(4)
also would require you to use this
identifier whenever you record the
disposition of each shipment lot
received.
Final § 111.165(d) includes a revision
associated with final § 111.80 referring
to ‘‘each unique lot within each unique
shipment’’ rather than ‘‘each shipment
lot.’’
5. Final § 111.165(e)
Final § 111.165(e) requires you to
hold the received product under
conditions that will protect against
contamination and deterioration, and
avoid mixups. Final § 111.165(e) derives
from proposed § 111.40(a)(5) with
editorial changes associated with the
reorganization.
H. What Requirements Apply to
Rejected Components, Packaging, and
Labels, and to Rejected Products That
Are Received for Packaging or Labeling
as a Dietary Supplement? (Final
§ 111.170)
Final § 111.170 requires you to clearly
identify, hold, and control under a
quarantine system for appropriate
disposition any component, packaging,
and label, and any product you receive
for packaging or labeling as a dietary
supplement (and for distribution rather
than for return to the supplier), that is
rejected and unsuitable for use in
manufacturing, packaging, or labeling
operations. Final § 111.170 is
substantially similar to proposed
§ 111.74 which would require you to
clearly identify, hold, and control under
a quarantine system any component,
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dietary supplement, packaging, and
label that is rejected and unsuitable for
use in manufacturing, packaging, or
labeling operations.
We did not receive comments specific
to proposed § 111.74. Final § 111.170
includes revisions associated with the
series of provisions that distinguish a
product you receive for packaging or
labeling as a dietary supplement (and
for distribution rather than for return to
the supplier) from a dietary supplement
you manufacture.
I. Under This Subpart, What Records
Must You Make and Keep? (Final
§ 111.180)
Final § 111.180 sets forth the
requirements to make and keep records
associated with components, packaging,
labels, and product you receive for
packaging and labeling as a dietary
supplement. Final § 111.180 derives
from proposed § 111.40(c).
1. Final § 111.180(a)
Final § 111.180(a) requires you to
make and keep records required under
subpart G in accordance with subpart P.
Final § 111.180(a) derives from
proposed § 111.40(c)(2), with editorial
changes associated with the
reorganization.
We did not receive comments specific
to the requirements set forth in final
§ 111.180(a).
2. Final § 111.180(b)(1)
Final § 111.153 requires you to
establish and follow written procedures
to fulfill the requirements of subpart G.
These written procedures are records.
Therefore, final § 111.180(b)(1) requires
you to make and keep a record of the
written procedures for fulfilling the
requirements of subpart G.
3. Final § 111.180(b)(2)
Final § 111.180(b)(2) requires you to
make and keep receiving records
(including records such as certificates of
analysis, suppliers’ invoices, and
suppliers’ guarantees) for components,
packaging, and labels, and for products
you receive for packaging or labeling as
dietary supplements (and for
distribution rather than for return to the
supplier). Final § 111.180(b)(2) derives
from proposed § 111.40(c)(2) with
editorial changes associated with the
reorganization. Final § 111.180(b)(2)
also includes revisions associated with
the series of provisions that distinguish
a product you receive for packaging or
labeling as a dietary supplement (and
for distribution rather than for return to
the supplier) from a dietary supplement
you manufacture. Because the final rule
provides that you may rely, under
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certain circumstances, on a certificate of
analysis to ensure that some component
specifications are met (final
§ 111.75(a)(2)(ii)) and that you may rely,
in part, on documentation to determine
whether specifications for received
products are met, we specifically
identify a certificate of analysis and
common forms of documentation as
being ‘‘receiving records’’ for purposes
of this rule.
(Comment 247) One comment on
proposed § 111.40(c)(2) points out the
recordkeeping requirements of any final
rule will be a costly burden for a
company that produces multiple
ingredient products in several packaging
configurations and will be much greater
than the burden for a company that
produces batches of single ingredient
products in one packaging
configuration.
(Response) We acknowledge that
companies that produce multiple
ingredient products in several packaging
configurations will have more records to
keep than companies that produce
single ingredient products in one
packaging configuration. However, these
records are necessary to be able to
determine the source of the component,
packaging, and labels, so that if
adulteration of the dietary supplement
occurs, the records will show the source
of the material so that its use can be
stopped.
4. Final § 111.180(b)(3)
Final § 111.180(b)(3) requires you to
make and keep documentation that the
requirements of subpart G were met.
Under final § 111.180(b)(3)(i), the
person who performs the required
activity must document, at the time of
performance, that the required operation
was performed. Under final
§ 111.180(b)(3)(ii), the documentation
must include:
• The date that the components,
packaging, labels, or products you
receive for packaging or labeling as a
dietary supplement were received;
• The initials of the person
performing the required operation;
• The results of any tests or
examinations conducted on
components, packaging, or labels, and of
any visual examination of product you
receive for packaging or labeling as a
dietary supplement; and
• Any material review and
disposition decision conducted on
components, packaging, labels, or
products that you receive for packaging
or labeling as a dietary supplement.
Final § 111.180(b)(3) differs from
proposed § 111.40(c)(1)(i) through
(c)(1)(iv), by referring to ‘‘required
operation’’ rather than ‘‘requirement.’’
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Additionally as a conforming revision
associated with final § 111.75(a) which
requires appropriate tests and
examinations, final § 111.180(b)(3)
requires you to include in the
documentation the results of any
examinations as well as tests. Final
§ 111.180(b)(3) also includes revisions
associated with the series of changes
that distinguish a product that you
receive for packaging or labeling as a
dietary supplement (and for distribution
rather than for return to the supplier)
from a dietary supplement that you
manufacture.
(Comment 248) A few comments note
proposed § 111.40(c) requires the
signature of the person performing the
requirement, whereas other sections of
the 2003 CGMP Proposal, such as
proposed § 111.50(c)(2), only require the
initials of the person performing the
requirement. One comment requests the
format for the requirement to document
the person performing the step be made
consistent throughout the regulations.
(Response) We agree that the identity
of the person performing a requirement
should be required throughout the final
rule and that this can be accomplished
through initials except for operations
that are performed by quality control
personnel. Therefore, we are revising
the requirements so that a signature
(and not initials) is required for any
operation performed by quality control
personnel (see final § 111.140). Because
§ 111.40(c)(1)(ii) is not a quality control
operation, we also revised proposed
§ 111.40(c)(1)(ii) (final § 111.180(b)(3))
to require the initials, rather than the
signature, of the person performing the
required operation. Initials are required
for other circumstances that do not
involve quality control operations,
including final § 111.180(b)(3).
However, whenever this final rule
requires initials, a signature is also
acceptable, because a signature would
achieve the goal of identifying the
person who performed the requirement.
XIII. Comments on the Production and
Process Control System: Requirements
for the Master Manufacturing Record
(Final Subpart H)
A. Organization of Final Subpart H
In the 2003 CGMP Proposal, the
requirements for the master
manufacturing record were set forth in
proposed § 111.45. As shown in table 9
of this document, we are setting forth
the requirements for the master
manufacturing record in a distinct
subpart (final Subpart H—Production
and Process Control System:
Requirements for the Master
Manufacturing Record). Table 9 lists the
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sections in final subpart H and
identifies the proposed provisions that
form the basis for the final rule.
TABLE 9.—DERIVATION OF SECTIONS
IN FINAL SUBPART H
Final Rule
2003 CGMP
Proposal
§ 111.205 What is the
requirement to establish a master manufacturing record?
§ 111.45(a)(1),
(a)(2), and (d)
§ 111.210 What must the
master manufacturing
record include?
§ 111.45(b)
The requirements in final subpart H
are set forth from the perspective of the
manufacture of a batch of a dietary
supplement. You must comply with all
requirements that pertain to your
activity. However, you must comply
with the requirement to prepare and
follow a ‘‘master manufacturing record’’
regardless of whether you manufacture
a batch, or whether you package or label
product you receive from a supplier for
packaging or labeling as a dietary
supplement (and for distribution rather
than for return to the supplier). If you
are a packager or labeler, you only need
to include those parts relevant to your
process. For example, if you are a
labeler, under final § 111.210(c) you
would not need to include an accurate
statement of the weight or measure of
each component to be used because you
would be starting from packages already
filled.
B. Highlights of Changes to the
Proposed Requirements for the Master
Manufacturing Record
1. Revisions
The final rule:
• Includes revisions that reflect that
the final rule applies to persons who
manufacture, package, label, or hold
dietary supplements unless subject to an
exclusion in § 111.1;
• Includes revisions so the
requirements for the master
manufacturing record are consistent
with final § 111.70(a) which requires
you to establish a specification for any
point, step, or stage in the
manufacturing process where control is
necessary to ensure the quality of the
dietary supplement and that the dietary
supplement is packaged and labeled as
specified in the master manufacturing
record; and
• Includes a revision associated with
final § 111.75(h), which provides for the
use of either tests or examinations for
complying with the requirements of part
111.
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2. Changes Associated With the
Reorganization
The proposed requirement
(§ 111.45(c)) that the quality control unit
approve each master manufacturing
record and any modifications to a
master manufacturing record is set forth
as final § 111.123(a) in subpart F, rather
than in final subpart H, with the
changes we made to the definition of
‘‘quality control unit’’ to ‘‘quality
control personnel’’ as explained in
section VI of this document (subpart A).
3. Changes After Considering Comments
The final rule:
• Retains a requirement to state any
intentional overage of a dietary
ingredient but does not require an
explanation for such an overage;
• Provides flexibility to include either
a representative label, or a crossreference to the physical location of the
actual or representative label if an actual
label is not provided; and
• Provides flexibility for what must
be included in written instructions
when operations are not conducted
manually.
C. General Comments on Proposed
§ 111.45 (Final Subpart H)
1. Comments on Written Procedures
We received many comments that
recommended written procedures for
various provisions. We address the need
for written procedures generally in
section IV of this document. We also
respond to individual comments on
specific provisions in the same section.
As discussed in section IV of this
document, we do not require you to
establish and follow written procedures
for preparing a master manufacturing
record.
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2. Comments That Support Proposed
§ 111.45
(Comment 249) A few comments
support the proposed requirements for
the master manufacturing record. One
comment states that properly recorded
quality control measures, such as the
batch production and master
manufacturing records, will aid
manufacturers in producing dietary
supplements in a consistent and
uniform manner, as well as serve as
tools to assess possible sources of
contamination and flaws in the
production process. Another comment
asserts the master manufacturing and
batch production records probably have
the second greatest impact on overall
product quality, surpassed only by the
quality of the ‘‘people’’ manufacturing
the product.
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(Response) We agree the master
manufacturing record requirements in
the 2003 CGMP Proposal are important
for reasons that include those expressed
in the comments. Establishing a master
manufacturing record will help to
ensure the quality of the dietary
supplement. The proposed requirements
for the master manufacturing record
have been codified as subpart H in this
final rule.
D. What Is the Requirement to Establish
a Master Manufacturing Record? (Final
§ 111.205)
Final § 111.205 (proposed § 111.45(a)
and (d)) sets forth the requirement to
prepare and follow a written master
manufacturing record.
1. Final § 111.205(a)
Final § 111.205(a) requires you to
prepare and follow a written master
manufacturing record for each unique
formulation of dietary supplement that
you manufacture, and for each batch
size, to ensure uniformity in the
finished batch from batch to batch. Final
§ 111.205(a) is similar to proposed
§ 111.45(a) which would require you to
prepare and follow a written master
manufacturing record for each type of
dietary supplement you manufacture
and for each batch size to ensure
uniformity from batch to batch.
(Comment 250) Some comments
suggest the phrase ‘‘to ensure uniformity
from batch to batch’’ be changed to ‘‘to
ensure that specifications are met from
batch to batch.’’ One comment states the
term ‘‘uniformity’’ could be interpreted
to mean that two batches would be
exactly the same, down to the minutest
detail. The comment expresses concern
about how batches of herbal products
will meet this standard of ‘‘uniformity’’
from batch to batch.
(Response) These comments may have
misinterpreted the term ‘‘uniformity’’ as
we used it in proposed § 111.45(a).
Uniformity means that the
specifications you establish for identity,
purity, strength, and composition of the
finished batch must be the same
throughout a given batch, e.g., at the
beginning, middle, and end of a
production run. To emphasize this, we
have revised the requirement so it is
clear that the uniformity relates to ‘‘the
finished batch.’’ Whether two batches
must be exactly the same, down to the
minutest level, would depend on the
specifications the manufacturer
establishes for the finished batch under
final § 111.70(e). Although a finished
batch must meet those specifications
‘‘from batch to batch,’’ it is up to the
manufacturer to determine what those
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specifications will be. We are making no
changes to the requirement.
(Comment 251) Some comments
assert that the proposed requirement to
prepare a separate record ‘‘for each
batch size’’ is burdensome, particularly
for smaller firms who specialize in
custom blended products. These
comments would revise the rule so the
master manufacturing record includes a
master formula with instructions for
how to adjust the amount of ingredients
to add depending on the batch size,
with the actual amounts included in the
applicable batch record.
(Response) We disagree with these
comments. Requiring a separate master
manufacturing record for each batch
size will lessen the likelihood of
mistakes that can happen when a
formula is ‘‘multiplied up’’ or ‘‘divided
down,’’ particularly in light of the
requirement that quality control
personnel review and approve each
master manufacturing record (final
§ 111.123(a)). Moreover, it is not clear
that the scenario described in the
comments would lessen any burden,
because a new ‘‘formula,’’ based on the
master formula, would still need to be
prepared for each batch.
In essence, these comments suggest
shifting the burden from a requirement
to prepare a master manufacturing
record to a requirement to prepare a
batch record. Under final § 111.123,
quality control personnel review the
master manufacturing record before that
record is used, but review the batch
record only after the batch is prepared.
Shifting the requirement in the manner
suggested by these comments would
defeat the purpose of having quality
control personnel review and approve
each ‘‘formula.’’ We are not making the
suggested changes to proposed
§ 111.45(a).
We are changing the word ‘‘type’’ to
‘‘unique formulation’’ to clarify that the
requirement for a master manufacturing
record applies to each different dietary
supplement whether it is a different
strength, includes any different
ingredients, is a capsule or tablet, or
includes minor variations.
2. Final § 111.205(b)(1)
Final § 111.205(b)(1) requires that the
master manufacturing record identify
specifications for each point, step, or
stage in the manufacturing process
where control is necessary to ensure the
quality of the dietary supplement and
that the dietary supplement is packaged
and labeled as specified in the master
manufacturing record. Final
§ 111.205(b)(1) derives from proposed
§ 111.45(a)(1). We received no
comments specific to proposed
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§ 111.45(a)(1). We revised this section to
include changes that we made to
§ 111.70(a).
3. Final § 111.205(b)(2)
Final § 111.205(b)(2) requires that the
master manufacturing record establish
controls and procedures to ensure that
each batch of dietary supplement you
manufacture meets the specifications
identified in accordance with
§ 111.205(b)(1). Final § 111.205(b)(2)
derives from proposed § 111.45(a)(2)
with grammatical changes and changes
associated with the reorganization. We
did not receive comments specific to
proposed § 111.45(a)(2).
4. Final § 111.205(c)
Final § 111.205(c) requires you to
make and keep master manufacturing
records in accordance with subpart P.
Final § 111.205(c) derives from
proposed § 111.45(a) and (d), and
clarifies that you must prepare and keep
the master manufacturing records. We
did not receive comments specific to
proposed § 111.45(d), and comments
relevant to § 111.45(a) are discussed in
the response to comment 250.
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E. What Must the Master Manufacturing
Record Include? (Final § 111.210)
Final § 111.210 sets forth the
requirements for what the master
manufacturing record must include.
Final § 111.210 derives from proposed
§ 111.45(b).
1. Final § 111.210(a)
Final § 111.210(a) requires that the
master manufacturing record include
the name of the dietary supplement to
be manufactured and the strength,
concentration, weight, or measure of
each dietary ingredient for each batch
size. Final § 111.210(a) derives from
proposed § 111.45(b)(1).
(Comment 252) One comment
supports listing the weight or measure
for each ingredient but believes that
including the strength and
concentration is unnecessary. This
comment also suggests that the identity
of each ingredient can be controlled
using a unique item number identifier,
along with a brief description of the
ingredient.
(Response) Proposed § 111.45(b)(1)
would require the master manufacturing
record to include strength,
concentration, weight, or measure of
each dietary ingredient for each batch
size. We did not intend that all would
be required. The purpose of this
requirement is to ensure the correct
dietary ingredient and amount are used
in a given batch. To the extent that
weight or measure best describes what
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that dietary ingredient is and how much
is to be used in a given batch, the
manufacturer could use weight or
measure. To the extent that a
manufacturer determines, for a
particular dietary ingredient, strength,
or concentration would best describe
what is to be used in a given batch, the
manufacturer could use those instead.
We are giving firms the flexibility to use
the measure that they determine best
describes the amount of dietary
ingredient to use in their batch. For
example, assume you are manufacturing
a million tablets of a vitamin C product
in 250 mg tablets and the only other
ingredients in your product are starch,
microcrystalline cellulose, and
dicalcium phosphate. Under proposed
§ 111.45(b)(1) (final § 111.210(a)) your
master manufacturing record would
state: ‘‘Vitamin C 250 mg, 1,000,000
tablets.’’ As another example, if you are
manufacturing 100 liters of a liquid
dietary supplement that provides tuna
oil as a dietary ingredient, and the only
other ingredients are alpha-tocopherols
for use as an antioxidant, then your
master manufacturing record would
state: ‘‘Tuna oil, 100 liters.’’
The unique identifier comment states
‘‘the identity of each dietary ingredient
can be controlled instead with the use
of a unique item identifier, along with
a brief description of the ingredient.’’ It
is not clear what the comment meant by
‘‘a brief description of the ingredient.’’
If the ‘‘brief description of the
ingredient’’ includes the identity, then it
would comply with the final rule. Firms
are free to use unique identifiers in
addition to the identity. If, however, the
comment means something other than
identity, the comment fails to explain
how the identity will be controlled to
prevent manufacturing errors. In the
absence of such an explanation, we have
no basis to make the requested change.
Moreover, under final § 111.205(c) the
master manufacturing record is a record
you must make and keep in accordance
with final § 111.610 in final subpart P.
Under final § 111.610, the master
manufacturing record must be available
during the record retention period for
inspection and copying by us when we
request that you do so. A master
manufacturing record that does not
identify the dietary ingredient and the
weight or measure of the dietary
ingredient would not allow an FDA
investigator to determine, for example,
how your master manufacturing record
relates to the finished dietary
supplement and to the product label of
that dietary supplement.
(Comment 253) One comment
recommends the weight or measure be
expressed per unit or portion, or per
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unit of weight or measure of the
product, for each batch size.
(Response) The final rule does not
prescribe the units you must use. Thus,
firms have the flexibility to include this
information in the way that best suits
their product.
2. Final § 111.210(b)
Final § 111.210(b) requires that the
master manufacturing record include a
complete list of components to be used.
Final § 111.210(b) is identical to
proposed § 111.45(b)(2). We did not
receive comments specific to proposed
§ 111.45(b)(2).
3. Final § 111.210(c)
Final § 111.210(c) requires that the
master manufacturing record include an
accurate statement of the weight or
measure of each component to be used.
Final § 111.210(c) is identical to
proposed § 111.45(b)(3). We did not
receive comments specific to proposed
§ 111.45(b)(3).
4. Final § 111.210(d)
Final § 111.210(d) requires that the
master manufacturing record include
the identity and weight or measure of
each dietary ingredient that will be
declared on the Supplement Facts label
and the identity of each ingredient that
will be declared on the ingredients list
of the dietary supplement. Final
§ 111.210(d) is similar to proposed
§ 111.45(b)(4). We have removed the
phrase ‘‘in compliance with section
403(s) of the act’’ as it is unnecessary in
the context of compliance with the
dietary supplement CGMP
requirements. The manufacturer must
still comply with section 403(s) and
failure to do so will result in a
misbranding violation, not a CGMP
violation under this final rule.
(Comment 254) One comment
supports having the identity and weight
or measure of each dietary ingredient as
required by proposed § 111.45(b)(4), but
asserts it is unnecessary for the verbiage
to identically match the corresponding
label statements. This comment also
asserts that the ingredients can be
controlled in the master manufacturing
record by use of a unique identifier,
instead of the ingredient name, along
with a brief description of the
ingredient.
(Response) We disagree for the
reasons stated in response to comment
252 and decline to revise the provision
in this manner.
5. Final § 111.210(e)
Final § 111.210(e) requires that the
master manufacturing record include a
statement of any intentional overage
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amount of a dietary ingredient. Final
§ 111.210(e) derives from proposed
§ 111.45(b)(5) which would require you
to explain any intentional excess
amount of a dietary ingredient.
(Comment 255) Some comments
request us to modify this requirement.
Several comments note that a
manufacturer may design products with
overage levels adjusted so the product
always tests at least 100 percent of the
amount claimed on the label throughout
the declared shelf life. One comment
states it should be sufficient to identify
any overage amount, rather than having
to explain it.
(Response) We understand that some
firms design products using an
additional amount of certain ingredients
to ensure the product meets its
specifications for the amount of the
ingredient during the expected shelf life
of the product. We agree it is not
necessary to include the reason for
adding the intentional excess amount.
We also understand it would be more
appropriate to refer to the additional
amount as an ‘‘overage’’ amount rather
than an ‘‘excess’’ amount, because
‘‘overage’’ is commonly used in the
industry to convey the practice that is
now the subject of final § 111.260(e).
Therefore, we have revised proposed
§ 111.45(b)(1) to use the term ‘‘overage’’
rather than ‘‘excess’’ and to delete the
proposed requirement to include the
reason for the intended overage. As
discussed in the preamble to the 2003
CGMP Proposal (68 FR 12157 at 12203),
the amount of overage should be limited
to the amount needed to meet the
amounts listed in accordance with final
§ 111.210(d).
6. Final § 111.210(f)
Final § 111.210(f) requires that the
master manufacturing record include a
statement of theoretical yield of a
manufactured dietary supplement
expected at each point, step, or stage of
the manufacturing process where
control is needed to ensure the quality
of the dietary supplement, and the
expected yield when you finish
manufacturing the dietary supplement,
including the maximum and minimum
percentages of theoretical yield beyond
which a deviation investigation of a
batch is necessary and material review
is conducted and disposition decision is
made. Final § 111.210(f) derives from
proposed § 111.45(b)(6). We revised the
section to state ‘‘beyond which a
deviation investigation of a batch is
necessary’’ rather than ‘‘beyond which a
deviation is performed’’ for clarity.
(Comment 256) One comment
suggests the term ‘‘maximum and
minimum percentages’’ in proposed
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§ 111.45(b)(6) be replaced with the term
‘‘normal range.’’
Another comment recommends
proposed § 111.45(b)(6) be replaced
with: ‘‘A statement of theoretical yield
of a manufactured dietary ingredient or
dietary supplement expected at
appropriate phases of manufacturing.’’
This comment states the detail in this
proposed requirement should be
eliminated because the manufacturer
should decide where and when to
include a statement about theoretical
yield.
(Response) Final § 111.210(f) clearly
communicates when it is necessary to
conduct a material review and make a
disposition decision. The comment’s
suggestions do not improve the
communication or clarify this point.
Final § 111.210(f) gives firms the
flexibility to decide what steps, in the
manufacturing process, are points,
steps, or stages where control is needed
to ensure the quality of the dietary
supplement. A statement about
theoretical yield is necessary at each
such point, step, or stage including at
the finished batch stage so that you will
know, when you manufacture a batch,
whether the process is proceeding as
expected or whether something is
wrong. For example, your master
manufacturing record could state the
theoretical yield after mixing a series of
components is 100 percent, because
nothing about the additional step would
remove any material from the
production system. When
manufacturing the batch, a yield of less
than 100 percent would tell you
something was wrong, for example, if
there was an obstruction that prevented
a component that was being delivered
by automated equipment from actually
entering the production vessel. For a
process such as recrystallization,
knowing the theoretical yield is critical,
because if the expected yield is not
achieved at a given step it may mean
that the process did not proceed as
intended.
(Comment 257) One comment argues
it is not possible for the majority of
supplement products, especially
botanicals, to provide 100 percent of the
claimed amount of the botanical,
because botanicals are inherently of
uneven consistency, density, and
particle size. This comment
recommends that we allow for
variability in yield, especially for
botanicals.
(Response) Final § 111.210(f) does not
specify what the yield must be, so no
revision is necessary. It is the
manufacturer’s responsibility to
manufacture the product in a way that
will ensure that a product contains what
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the manufacturer has established in its
specifications and its master
manufacturing record. The
manufacturer must establish
specifications for the identity, purity,
strength, and composition and limits on
contamination and other specifications
the manufacturer decides are necessary
to ensure the quality of the dietary
supplements that it makes, and design
and implement a production and
process control system that will ensure
those specifications are met. In the
situation described by the comment, it
is the manufacturer’s responsibility to
design and implement a production and
process control system that will ensure
the quality of the dietary supplement
regardless of the problems presented by
the nature of the ingredients.
7. Final § 111.210(g)
Final § 111.210(g) requires that the
master manufacturing record include a
description of packaging and a
representative label, or a cross-reference
to the physical location of the actual or
representative label. Final § 111.210(g)
derives from proposed § 111.45(b)(7),
which would require a description of
packaging and a copy of the label to be
used.
(Comment 258) One comment
supports the proposed requirement that
the master manufacturing record
contain a copy of the dietary
supplement label. Other comments
contend that the proposed requirement
to include a copy of the label is neither
appropriate nor necessary. Some
comments state that companies often do
not have a label available to include in
the master manufacturing record and
believe that a description of the
packaging or label in the master
manufacturing record should be
sufficient. Another comment, by a
company that produces many different
brands for each bulk product, asserts
that updating labels in the record would
be burdensome and suggests wording
similar to that used by USP, for which
a positive identification of all labeling
used is permitted. One comment asks
whether the packaging and label copy
requirements can be in separate
documents cross-referenced in the
master manufacturing record, because
some companies treat tablet
manufacturing and packaging as two
separate and distinct operational
elements. This comment explains that
the master manufacturing record
includes the specifics required to
manufacture the tablets, but the actual
description of packaging and label copy
requirements are contained in separate
documents cross-referenced to the
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master manufacturing record by a
product part number.
(Response) We understand there may
be some circumstances where it would
be impractical to have actual copies of
labels in the master manufacturing
record. If an actual label is not available,
you may include a representative label
in the master manufacturing record. A
representative label could be a graphic
representation of the label, including
the exact statements that would be on
the product label, or a detailed
description of the statements and other
information (such as pictures or
graphics) that will be on the actual
label. The representative label must be
an accurate representation of the label
that will be affixed to the dietary
supplement distributed. We also agree
that it would be acceptable to crossreference the physical location of the
actual or representative label.
Finally, because the actual or
representative label is a record that you
must make and keep in accordance with
final § 111.610 in final subpart P, it
must be readily available during the
retention period for inspection or
copying by FDA. Thus, we are revising
proposed § 111.45(b)(6) (final
§ 111.210(g)) as discussed above.
(Comment 259) One comment states
that a company that manufactures a
dietary supplement under contract to
another company would not have access
to the product label.
(Response) Under final § 111.210(g) a
company that manufactures a dietary
supplement under contract could
comply with the requirement by, for
example, providing the name and
address of the company who contracted
for the manufacture of the batch as the
cross-reference to the physical location
of the label.
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8. Final § 111.210(h)(1)
Final § 111.210(h)(1) requires that the
master manufacturing record include
written instructions for specifications
for each point, step, or stage in the
manufacturing process where control is
necessary to ensure the quality of the
dietary supplement and that the dietary
supplement is packaged and labeled as
specified in the master manufacturing
record. Final § 111.210(h)(1) is similar
to proposed § 111.45(b)(8)(i) which
would require that the master
manufacturing record include written
instructions for specifications for each
point, step, or stage in manufacturing
the dietary supplement necessary to
prevent adulteration. Final
§ 111.210(h)(1) includes changes that we
are making for consistency with final
§ 111.70(a).
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We did not receive comments specific
to proposed § 111.45(b)(8)(i).
9. Final § 111.210(h)(2)
Final § 111.210(h)(2) requires that the
master manufacturing record include
written instructions for procedures for
sampling, and a cross-reference to
procedures for tests or examinations.
Final § 111.210(h)(2) derives from
proposed § 111.45(b)(8)(ii), which
would require that the master
manufacturing record include written
instructions for sampling and testing.
(Comment 260) A few comments
object to including certain written
instructions for sampling and testing
procedures in the master manufacturing
record. One comment states that this
documentation, such as laboratory
testing procedures, would be a
burdensome task and should be
maintained separate from the master
manufacturing record and be retrievable
by appropriate cross-referencing
information.
(Response) As we discussed in the
preamble to the 2003 CGMP Proposal
(68 FR 12157 at 12204), the written
instructions are similar to a recipe. As
such, the written instructions must
include instructions related to
procedures for sampling plans so you
can collect appropriate samples for tests
or examinations. We agree, however,
that it is not necessary for the master
manufacturing record to include written
instructions for tests or examinations.
Accordingly, we have revised the
provision to permit the master
manufacturing record to include a crossreference to the procedures for tests or
examinations. The final rule includes a
requirement that you establish and
follow written procedures for laboratory
operations, including for tests and
examinations that you conduct to
determine whether specifications are
met (final § 111.303). In essence, these
written procedures for tests and
examinations would constitute the
written instructions that we proposed
under § 111.45(b)(8)(ii) for testing
procedures. This requirement for
written procedures is generally
described in section IV of this
document.
10. Final § 111.210(h)(3)
Final § 111.210(h)(3) requires that the
master manufacturing record include
written instructions for specific actions
necessary to perform and verify each
point, step, or stage in the
manufacturing process where control is
necessary to ensure the quality of the
dietary supplement and that the dietary
supplement is packaged and labeled as
specified in the master manufacturing
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record. Final § 111.210(h)(3) derives
from proposed § 111.45(b)(8)(iii) which
would require that the master
manufacturing record include written
instructions for specific actions
necessary to perform and verify each
point, step, or stage necessary to meet
specifications and otherwise prevent
adulteration. Final § 111.210(h)(3)
includes changes for consistency with
final § 111.70(a).
Final § 111.210(h)(3)(i) requires that
the specific actions include verifying
the weight or measure of any
component and verifying the addition of
any component. Final § 111.210(h)(3)(ii)
requires that, for manual operations, the
specific actions include: (1) One person
weighing or measuring a component
and another person verifying the weight
or measure and (2) one person adding a
component and another person
verifying the addition. Final
§ 111.210(h)(3)(i) and (h)(3)(ii) derive
from proposed § 111.45(b)(8))(iii).
(Comment 261) Some comments
suggest the requirement to have more
than one person involved in performing
and verifying each point, step, or stage
in the manufacturing process is overly
prescriptive and that alternative,
reliable methods for verifying the
weighing and addition of components
should be permitted. One comment
explains many manufacturers use bar
code systems to identify the weight and
identity of components both before and
after weighing. In such cases, a
computer generated weight record and
corresponding bar code can be created
and affixed to the container by one
individual as reliable verification of the
material’s contents and weight.
Likewise, the addition of components to
a blender can be adequately controlled
and verified by one person through
scanning technology that allows reliable
verification of the identity and weight of
components added to a blender without
the need for a second person.
(Response) These comments describe
a system partially under the control of
automated equipment. Final § 111.30
establishes a series of requirements for
automated equipment. We agree that,
with such requirements in place for an
automated system such as that
described by the comments, the
requirement to verify the weight or
measure of a component, or to verify the
addition of a component, can be
achieved without requiring that one
person do the weighing or measuring
and another person verify the weighing
or measuring and without requiring that
one person add the component and
another person verify the addition.
Therefore, final § 111.210(h)(3) provides
both that the written instructions must
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include verifying the weight or measure
of any component and verifying the
addition of any component and that, for
manual operations, the written
instructions must include: (1) One
person weighing or measuring a
component and another person
verifying the weight or measure and (2)
one person adding a component and
another person verifying the addition.
The final rule makes clear that there
must be a verification step and gives
firms flexibility, when the weighing or
addition is not done manually, to
determine how they would accomplish
the verification.
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11. Final § 111.210(h)(4)
Final § 111.210(h)(4) requires that the
master manufacturing record include
written instructions for special
notations and precautions to be
followed. Final § 111.210(h)(4) derives
from proposed § 111.45(b)(8)(iv). We did
not receive comments specific to
proposed § 111.45(b)(8)(iv).
12. Final § 111.210(h)(5)
Final § 111.210(h)(5) requires that the
master manufacturing record include
written instructions for corrective action
plans for use when a specification is not
met. Final § 111.210(h)(5) derives from
proposed § 111.45(b)(8)(v).
(Comment 262) Several comments
argue pre-established corrective action
plans are not useful for complex failure
scenarios, and that the quality control
unit should instead approve corrective
action procedures on a case-by-case
basis. One comment suggests the rule
should refer to ‘‘procedures’’ rather than
specifying ‘‘corrective action plans.’’
(Response) We acknowledge that
corrective action plans would be
focused on each point, step, or stage
where control is necessary to ensure the
quality of the dietary supplement. We
also acknowledge that it may not be
practical to establish a corrective action
plan for all foreseeable circumstances.
In circumstances such as the complex
failure scenario described by the
comments, the documentation of the
material review and disposition
decision (rather than the corrective
action plan) would identify the action
taken to correct, and prevent a
recurrence of, the deviation and discuss
what you did with the batch (final
§ 111.140(b)(3)(iv) and (b)(3)(v)).
However, we disagree that the fact that
it may not be practical to establish a
corrective action plan for all foreseeable
circumstances means you could not
establish a corrective action plan at each
point, step, or stage where you can, in
fact, predict a scenario and provide a
plan for action when that scenario
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presents itself. Therefore, for any
circumstance you can predict, final
§ 111.210(h)(5) requires that you
establish corrective action plan.
F. Quality Control Responsibility
(Proposed § 111.45(c))
In proposed § 111.45(c) we would
require the quality control unit to
review and approve each master
manufacturing record and any
modifications to a master manufacturing
record. As part of the reorganization,
this requirement is set forth under final
§ 111.123(a) in subpart F for quality
control personnel. There is no reason to
repeat the requirement in final subpart
H and, thus, it does not appear in final
subpart H.
XIV. Comments on the Production and
Process Control System: Requirements
for the Batch Production Record (Final
Subpart I)
A. Organization of Final Subpart I
In the 2003 CGMP Proposal, the
proposed requirements for the batch
production record were set forth in
§ 111.50. As shown in table 10 of this
document, we are setting forth the
requirements for the batch production
record in a distinct subpart (final
Subpart I—Production and Process
Control System: Requirements for the
Batch Production Record) that contains
the requirements that derive from
proposed § 111.50. In addition, we are
moving some proposed requirements
from §§ 111.35 and 111.37 into final
subpart I. Table 10 lists the sections in
final subpart I and identifies the
provisions that form the basis for the
final rule.
TABLE 10.—DERIVATION OF SECTIONS
IN FINAL SUBPART I
Final Rule
2003 CGMP
Proposal
§ 111.255 What is the
requirement to establish a batch production
record?
§ 111.50(a), (b),
and (i)
§ 111.260 What must the
batch record include?
§ 111.35(i)(2),
(j), (m), and
(o)(2)
§ 111.37(b)(3),
(b)(5), and
(b)(9)
§ 111.50(c)(1)
through
(c)(11),
(c)(13),
(c)(14), (d)(2),
(e), and (g)
§ 111.70(b)(6),
(e), and (g)
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The requirements in final subpart I
are set forth from the perspective of the
manufacture of a batch of a dietary
supplement. However, you must comply
with the requirement to prepare and
follow a ‘‘batch production record’’ or a
‘‘batch record’’ regardless of whether
you manufacture a batch or whether you
package or label product you receive
from a supplier for packaging or labeling
as a dietary supplement (and for
distribution rather than for return to the
supplier). As discussed in section VI of
this document, if you are a packager or
labeler, you only need to include those
parts relevant to your process. For
example, if you are a labeler under final
§ 111.260(e) you would not need to
include the identity and weight or
measure of each component used,
because you would be starting from
packages that already had been filled.
B. Highlights of Changes to the
Proposed Requirements for the Batch
Production Record
1. Revisions
The final rule:
• Includes revisions that reflect that
the final rule applies to persons who
manufacture, package, label, or hold
dietary supplements unless subject to an
exclusion in § 111.1.
• Does not use the term ‘‘shipment
lot’’ when referring to components.
2. Changes Associated With the
Reorganization
• Several provisions derive in whole
or in part from proposed §§ 111.35,
111.37, or 111.70.
• Several requirements in proposed
§ 111.50 are redundant to requirements
set forth in other subparts and are not
repeated in subpart I.
• Several proposed requirements for
reprocessing are moved to final § 111.90
in final subpart E.
• The proposed requirement to
collect reserve samples of each batch of
dietary supplement is moved to final
§ 111.83 in subpart E, where we clarify
that the requirement relates to each lot
of packaged and labeled dietary
supplement rather than to a finished
batch awaiting packaging and labeling.
3. Changes After Considering Comments
The final rule:
• Provides flexibility for firms to
document information about the
maintenance, cleaning, and sanitizing of
equipment used in producing the batch
in either the batch production record or
in individual equipment logs that it
cross-references in the batch production
record.
• Provides flexibility for firms to
include in the batch production record
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either the results of any testing or
examination performed, or a crossreference to the results of any testing or
examination.
C. What Is the Requirement to Establish
a Batch Production Record? (Final
§ 111.255)
Final § 111.255(a) requires you to
prepare a batch production record every
time you manufacture a batch of a
dietary supplement. Final § 111.255(b)
requires that the batch production
record include complete information
relating to the production and control of
each batch. Final § 111.255(a) and (b)
derive from proposed § 111.50(a), with a
nonsubstantive revision that divides the
proposed requirements into two
separate paragraphs.
Final § 111.255(c) requires your batch
production record to accurately follow
the appropriate master manufacturing
record and you to perform each step in
the production of the batch. Final
§ 111.255(c) derives from proposed
§111.50(b).
Final § 111.255(d) requires you to
make and keep batch production
records in accordance with subpart P.
Final § 111.255(d) derives from
proposed § 111.50(i) with editorial
changes associated with the
reorganization.
We did not receive comments specific
to proposed § 111.50(a), (b), or (i).
D. What Must the Batch Record Include?
(Final § 111.260)
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1. Final § 111.260(a)
Final § 111.260(a) requires the batch
production record to include the batch,
lot, or control number: (1) Of the
finished batch of dietary supplement
and (2) that you assign in accordance
with § 111.415(f) for each lot of
packaged and labeled dietary
supplement from the finished batch of
dietary supplement, and for each lot of
dietary supplement, from the finished
batch of dietary supplement, that you
distribute to another person for
packaging or labeling.
Final § 111.260(a) derives, in part,
from proposed § 111.50(c)(1), which
would require the batch, lot, or control
number in the batch production record.
Consistent with comments that
requested that we clarify responsibilities
when more than one party is involved
with the manufacturing, packaging,
labeling, or holding of a dietary
supplement (see section VI of this
document), we have added the
requirements of final § 111.260(a)(1),
(a)(2)(i), and (a)(2)(ii) to ensure that you
are able to determine the manufacturing
history and control of the packaged and
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labeled dietary supplement from all
stages of manufacturing through
distribution, and to be consistent with
other provisions of this final rule. In the
discussion of subpart L (section XVII of
this document), we explain in detail
final § 111.410(d), which requires you to
be able to determine the complete
manufacturing history and control of the
packaged and labeled dietary
supplement through distribution. In that
same section, we explain final
§ 111.415(f) which requires you to
assign a batch, lot, or control number to
each lot of packaged and labeled dietary
supplement from a finished batch and
each lot of dietary supplement from a
finished batch that you distribute to
another person for packaging and
labeling. In that way, these batch, lot, or
control numbers can be used to
determine the manufacturing history
and control of the batch. However, you
can determine how you track the batch,
lot, or control number of the packaged
and labeled dietary supplement, or
dietary supplement you send to another
person for packaging and labeling, to a
distributed dietary supplement.
We did not receive comments specific
to proposed § 111.50(c)(1). We respond
to comments relevant to final subpart L
in section XVII of this document.
2. Final § 111.260(b)
Final § 111.260(b) requires that the
batch production record include the
identity of equipment and processing
lines used in producing the batch and
derives from proposed § 111.50(c)(3).
We did not receive comments specific
to proposed § 111.50(c)(3).
3. Final § 111.260(c)
Final § 111.260(c) requires that the
batch production record include the
date and time of the maintenance,
cleaning, and sanitizing of the
equipment and processing lines used in
producing the batch, or a cross-reference
to records, such as individual
equipment logs, where this information
is retained. Final § 111.260(c) derives
from proposed § 111.50(c)(4).
(Comment 263) Many comments
argue that it is not necessary or
appropriate to retain the records of
maintenance, cleaning, and sanitizing
equipment and processing lines in the
batch production record. These
comments request that the final rule
provide flexibility to retain such records
in individual equipment files or log
books for easy access. One comment
recommends the requirement to retain
such records be set forth within subpart
D.
(Response) As discussed in section IX
of this document (final § 111.35(b)(2)),
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we agree with these comments.
Consistent with final § 111.35(b)(2),
final § 111.260(c) provides flexibility to
retain the records of maintenance,
cleaning, and sanitizing equipment and
processing lines in either the batch
production record or another record you
cross-reference in the batch production
record.
4. Final § 111.260(d)
Final § 111.260(d) requires that the
batch production record include the
unique identifier you assigned to each
component (or, when applicable, to a
product you receive from a supplier for
packaging or labeling as a dietary
supplement), packaging, and label used.
Final § 111.260(d) derives from
proposed § 111.50(c)(5), which would
require that the batch record include the
shipment lot unique identifier of each
component, dietary supplement,
packaging, and label used. Consistent
with the convention we are establishing
under final §§ 111.80(a), 111.155, and
111.160, final § 111.260(d) does not use
the term ‘‘shipment lot.’’
We did not receive comments specific
to proposed § 111.50(c)(5).
5. Final § 111.260(e) and (f)
Final § 111.260(e) requires that the
batch production record include the
identity and weight or measure of each
component used and derives from
proposed § 111.50(c)(6).
Final § 111.260(f) requires that the
batch record include a statement of the
actual yield and a statement of the
percentage of theoretical yield at
appropriate phases of processing. Final
§ 111.260(f) derives from proposed
§ 111.50(c)(9).
(Comment 264) A few comments
argue that the requirements in proposed
§ 111.50(c)(6) are not applicable to
continuous operations and that yield
information required in proposed
§ 111.50(c)(9) is irrelevant for quality
control in continuous operations used
for producing dietary ingredients. One
of these comments also discusses
‘‘continuous operations,’’ such as a
continuous operation built adjacent to a
soy crushing or vegetable oil refinery to
receive a continuous side stream flow
from that operation (see the discussion
of final § 111.155(c) in section XII of this
document). This comment explains that
in such operations, quarantine and
quality control approval occurs after the
material has been isolated and
concentrated in a stable matrix suitable
for holding.
(Response) Based on the limited
information provided by these
comments, it appears that they are
describing the manufacture of a ‘‘dietary
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ingredient’’ or other component that
will subsequently be used in the
manufacture of a dietary supplement.
Therefore, in this scenario, the identity
and weight or measure of the stable
matrix must be taken. The statement of
the actual yield and the theoretical yield
refers to the batch in which the stable
matrix is added as a component.
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6. Final § 111.260(g)
Final § 111.260(g) requires that the
batch production record include the
actual results obtained during any
monitoring operation. Final § 111.260(g)
derives from proposed § 111.35(o)(2)
which would require you to make and
retain records of the actual results
obtained during monitoring of the inprocess production. Consistent with the
reorganization we are specifying that the
records of monitoring be located in the
batch production record, because the
monitoring is associated with the batch
production.
We did not receive comments specific
to proposed § 111.35(o)(2).
7. Final § 111.260(h)
Final § 111.260(h) requires that the
batch production record include the
results of any testing or examination
performed during the batch production,
or a cross-reference to such results.
Final § 111.260(h) derives from
proposed § 111.50(c)(10) which would
require you to record the actual results
of any testing performed during
production of the batch.
(Comment 265) A few comments
object to the requirement in proposed
§ 111.50(c)(10) that actual test results be
included in the batch production
record. These comments state test
results are typically retained in other
records, such as laboratory records, and
that it would be duplicative to include
such results in the batch production
record. One comment states the ‘‘actual’’
(original record of) test results may not
be available to the manufacturer when
the testing is performed electronically or
an outside laboratory does the testing.
This comment adds for test results
obtained in-house, original records are
typically kept as part of the master
laboratory records and cross-referenced
in batch records.
(Response) After considering these
comments, we are providing flexibility
to either include the results of tests or
examinations in the batch production
record, or provide a cross-reference to
such results. We note that final
§ 111.260(h) does not require that you
have the original documentation of the
test results. If an outside laboratory has
performed testing for you, you must
obtain a copy of the test results and
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include these in your batch production
record or in another appropriate record
that you can cross-reference and make
readily available for inspection.
8. Final § 111.260(i)
Final § 111.260(i) requires that the
batch production record include
documentation that the finished dietary
supplement meets specifications
established in accordance with
§ 111.70(e) and (g). Final § 111.260(i)
derives from proposed § 111.50(c)(11).
We have made a change to identify
which required specifications the
dietary supplement must meet.
We did not receive comments specific
to proposed § 111.50(c)(11).
9. Final § 111.260(j)
Final § 111.260(j) sets forth the
requirements for documentation you
must make and include in the batch
production record, at the time of
performance, of the manufacture of the
batch. Final § 111.260(j) derives from
proposed § 111.50(c)(2) and (c)(7).
a. Final §111.260(j)(1). Final
§ 111.260(j)(1) requires documentation,
at the time of performance, of the date
on which each step of the master
manufacturing record was performed.
Final §111.260(j)(1) derives from
proposed § 111.50(c)(2). We did not
receive comments specific to proposed
§ 111.50(c)(2).
b. Final §111.260(j)(2). Final
§ 111.260(j)(2) requires documentation,
at the time of performance, of the
initials of the persons performing each
step in the master manufacturing record.
Final § 111.260(j)(2) derives from the
second part of proposed
§ 111.50(c)(2),(c)(7) and (c)(8).
(Comment 266) One comment asks
whether the persons responsible for
batch production must be identified by
name or by position.
(Response) The requirement is for the
initials of the name of the person rather
than for identification of the position.
Requiring that the record include the
initials of the person(s) performing each
step in the master manufacturing record
means that the person performing the
step is the person who physically
initials the batch record at the time the
person performs the step. The intent is
for the person to acknowledge that he or
she performed the requirement rather
than to merely provide information that
would identify that person.
(Comment 267) One comment asks
whether we will allow electronic
signatures for batch production records,
laboratory test results, and quality
control unit documentation. The
comment notes that many companies
have fully computerized, automated
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production and quality control
management systems that utilize
password-protected (or otherwise
secure) means of entering data at key
quality control steps.
(Response) The use of electronic
signatures is governed by our
regulations in part 11, which control
whether electronic signatures are
permitted. Our guidance entitled
‘‘Guidance for Industry Part 11,
Electronic Records; Electronic
Signatures—Scope and Application,’’
available at https://www.fda.gov/cder/
guidance/5667fnl.htm, discusses the use
of electronic signatures (Ref. 33).
c. Final § 111.260(j)(2)(i) through
§ 111.260(j)(2)(iv). Final
§ 111.260(j)(2)(i) requires you to
document at the time of performance
the initials of the person responsible for
weighing or measuring each component
used in the batch, and final
§ 111.260(j)(2)(ii) requires you to
document at the time of performance
the initials of the person responsible for
verifying the weight or measure of each
component used in the batch. Final
§ 111.260(j)(2)(i) and (j)(2)(ii) derive
from proposed § 111.50(c)(2)(i) and
(c)(7), respectively.
Final § 111.260(j)(2)(iii) requires you
to document, at the time of
performance, the initials of the person
responsible for adding the component to
the batch; and final § 111.260(j)(2)(iv)
requires you to document, at the time of
performance, the initials of the person
responsible for verifying the addition of
components to the batch. Final
§ 111.260(j)(2)(iii) derives from
proposed § 111.50(c)(2)(ii) and final
§ 111.260(j)(2)(iv) derives from proposed
§ 111.50(c)(8).
We did not receive comments specific
to proposed § 111.50(c)(2)(i) and
(c)(2)(ii) or § 111.50(c)(7) and (c)(8).
10. Final § 111.260(k)
Final § 111.260(k) sets forth the
requirements for documentation you
must make and include in the batch
production record, at the time of
performance, of the packaging and
labeling operations. Final § 111.260(k)
derives from proposed § 111.70(g)
which we discuss in the following
paragraphs.
In final § 111.260(k)(3), we are
eliminating proposed § 111.70(g)(4)
which would require that the
documentation include any material
reviews and disposition decisions for
packaging and labels, because it would
be redundant to final
§ 111.180(b)(4)(ii)(D).
a. General comments on proposed
§ 111.70(g).
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(Comment 268) Some comments
assert that the requirement of proposed
§ 111.70(g) that all packaging releases be
placed in the batch production record is
unnecessary. According to the
comments, most packaging material lots
are used in multiple batches. The
comments assert that a requirement for
this disposition information to be
copied into each batch production
record is unnecessary as long as lot
traceability exists and this information
is kept in a central file.
(Response) These comments may have
misinterpreted proposed § 111.70(g). It
would require that the documentation
in the batch production record for
packaging and label operations include:
(1) The identity and quantity of the
packaging and labels used and
reconciliation of any discrepancies
between issuance and use, (2) the
examination conducted in accordance
with proposed § 111.70(b)(7), (3) the
conclusions reached from retests
conducted in accordance with proposed
§ 111.70(e), and (4) any material reviews
and disposition decisions for packaging
and labels. None of these proposed
requirements would require that
‘‘packaging releases’’ be included in the
batch record.
The requirements for documentation
for packaging you receive are set forth
in final § 111.180(b) in subpart G.
b. Final § 111.260(k)(1). Final
§ 111.260(k)(1) requires the
documentation of packaging and
labeling operations to include the
unique identifier you assigned to
packaging and labels used, the quantity
of the packaging and labels used, and,
when label reconciliation is required,
reconciliation of any discrepancies
between issuance and use of labels.
Final § 111.260(k)(1) derives from
proposed § 111.70(g)(1) which would
require that the documentation include
the identity and quantity of the
packaging and labels used and
reconciliation of any discrepancies
between issuance and use. For
consistency with other provisions of
this final rule, such as final
§ 111.160(e)(1), final § 111.260(k)(1)
requires ‘‘the unique identifier you
assigned to packaging and labels used,’’
rather than ‘‘the identity of packaging
and labels used.’’ Final § 111.260(k)(1)
also includes changes we are making
after considering comments.
(Comment 269) Some comments
assert comprehensive label
reconciliation should not be required if
appropriate electronic controls are
instituted to ensure that correct labels
are used during labeling operations. The
comments state this alternative is
permitted for labeling operations for
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drug products, which are generally
identical or similar in nature to labeling
operations for dietary supplements. As
such, the comments assert the same
flexibility should be afforded to dietary
supplement manufacturers. Some
comments specifically suggest changing
the language of proposed § 111.70(g)(1)
to read ‘‘The identity and quantity of the
packaging and labels used and either
reconciliation of any discrepancies
between issuance and use or use of
appropriate electronic or
electromechanical equipment to
conduct a 100-percent examination for
labeling during or after completion of
finishing operations.’’
(Response) We agree that label
reconciliation need not be required for
cut or rolled labels if a 100-percent
examination for correct labels is
performed by appropriate electronic or
electromechanical equipment during or
after completion of finishing operations.
Thus we have made two changes in this
final rule in addition to the changes in
final § 111.260(k)(1) that provide there
must be label reconciliation when such
reconciliation is required either to
account for discrepancies or to ensure
the use of the label that is specified in
the master manufacturing record. First,
we have revised the final rule in subpart
L (for packaging and labeling
operations) to provide that you need not
conduct label reconciliation if a 100percent examination for correct labels is
performed by appropriate electronic or
electromechanical equipment during or
after completion of finishing operations
(see discussion of final § 111.410(b) in
subpart L in section XVI of this
document). Second, final
§ 111.260(k)(1), requires you to include
documentation in the batch production
of reconciliation of any discrepancies
between issuance and use of labels only
when label reconciliation is required.
c. Final § 111.260(k)(2). Final
§ 111.260(k)(2) requires the
documentation of packaging and
labeling operations to include an actual
or representative label, or a crossreference to the physical location of the
actual or representative label specified
in the master manufacturing record.
Final § 111.260(k)(2) derives from
proposed § 111.50(c)(12) which would
require that the batch production record
include copies of all container labels
used and the results of examinations
conducted during the label operation to
ensure that the containers have the
correct label.
(Comment 270) A few comments ask
that we clarify the container labels that
proposed § 111.50(c)(12) is referring to.
Specifically, these comments ask
whether proposed § 111.50(c)(12) is
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referring to finished product labels, bulk
material labels, or in-process container
labels. One comment asserts proposed
§ 111.50(c)(12) is unnecessary for
ensuring the dosage form of dietary
supplements meets specifications.
One comment finds proposed
§ 111.50(c)(12) confusing, because it
does not specify what is meant by ‘‘label
operation.’’ This comment notes that
during the course of manufacturing
operations, containers holding inprocess materials are often labeled but
the comment assumes that proposed
§ 111.50(c)(12) does not require the
retention of copies of in-process
container labels, which would not add
significant value toward the assurance
of a quality product.
In general, these comments ask for
clarification of proposed § 111.50(c)(12),
and suggest it be deleted.
(Response) Proposed § 111.50(c)(12)
referred to the product label that would
be affixed to the containers that hold the
packaged and labeled dietary
supplement. We did not receive any
comments that a related requirement (in
proposed § 111.45(b)(7) in the master
manufacturing record) was confusing or
needed clarification. We therefore
believe that the requirement that the
batch production record include a label
will be clearer if we state the
requirement in a way that is similar to
the requirement in proposed
§ 111.45(b)(7). However, because
comments to proposed § 111.45(b)(7)
persuaded us to provide flexibility for
(1) having a representative label rather
than an actual label and (2) crossreferencing the physical location of the
actual or representative label that is
specified in the master manufacturing
record, we are providing the same
flexibility for having a label in the batch
production record. Therefore, we are
revising the proposed requirement that
the batch production record include
‘‘copies of all container labels used’’ so
that, under final § 111.260(k)(2), the
batch production record must include
an actual or representative label, or a
cross-reference to the physical location
for the actual or representative label that
is specified in the master manufacturing
record.
However, we are not requiring in final
§ 111.260(k)(2) that the batch
production record include the results of
examinations conducted during the
label operation to ensure that the
containers have the correct label that is
specified in the master manufacturing
record, because this would be
redundant to final § 111.260(k)(3).
d. Final § 111.260(k)(3). Final
§ 111.260(k)(3) requires that the
documentation of packaging and
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labeling operations include the results
of any tests or examinations conducted
on packaged and labeled dietary
supplements (including repackaged or
relabeled dietary supplements), or a
cross-reference to such results. Final
§ 111.260(k)(3) combines the proposed
requirements of proposed § 111.70(g)(2)
which would require that the
documentation include the results of
examinations conducted in accordance
with proposed § 111.70(b)(7), and
proposed § 111.70(g)(3) which would
require that the documentation include
the conclusions from retests conducted
in accordance with proposed § 111.70.
For consistency with other requirements
for documentation that must be in the
batch record, final § 111.260(k)(3)
requires you to include ‘‘the results of
any tests or examinations,’’ rather than
‘‘the examination’’ (proposed
§ 111.70(g)(2)) and ‘‘conclusions’’
(proposed § 111.70(g)(3)). Final
§ 111.260(k)(3) also includes editorial
revisions associated with combining
proposed § 111.70(g)(2) and (g)(3).
We did not receive comments specific
to proposed § 111.70(g)(2) or (g)(3).
11. Final § 111.260(l)
Final § 111.260(l) sets forth the
requirements for documentation quality
control personnel must make at the time
of performance and that must be
included in the batch production
record. Final § 111.260(l) derives from
proposed §§ 111.35(i)(2), (j), (m), (o)(2);
111.37(b)(3), (b)(5), and (b)(9);
111.50(c)(1) through (c)(11), (c)(13),
(c)(14), (d)(2), (e), and (g); 111.70(b)(6);
and 111.70(g).
a. Final § 111.260(l)(1). Final
§ 111.260(l)(1) requires quality control
personnel to document at the time of
performance the review of the batch
production record. Final § 111.260(l)(1)
derives from the following proposed
regulations:
• § 111.50(d), which would require
that the quality control unit review in
accordance with § 111.37(b)(5) the batch
production record established in
§ 111.50(c); and
• § 111.50(e), which would require
that the quality control unit document
at the time of performance in
accordance with § 111.37(c), the review
performed in accordance with
§ 111.50(d).
Final § 111.260(l)(1) includes editorial
changes associated with the
reorganization. We did not receive
comments specific to proposed
§ 111.50(d) or (e).
b. Final § 111.260(l)(1)(i). Final
§ 111.260(l)(1)(i) requires the
documentation by quality control
personnel to include review of any
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monitoring operation required under
subpart E. Final § 111.260(l)(1)(i)
derives from proposed § 111.35(i)(2)
which would require that you review,
among other things, the results of the
monitoring of the in-process control
points, steps, or stages to ensure
specifications are met. As discussed in
section XI of this document (final
§ 111.123(a)(3)), the final rule requires
quality control personnel to review the
required monitoring.
We did not receive comments specific
to proposed § 111.35(i)(2).
c. Final § 111.260(l)(1)(ii). Final
§ 111.260(l)(1)(ii) requires the
documentation by quality control
personnel to include the review by
quality control personnel of the results
of any tests or examinations, including
tests or examinations conducted on
components, in-process materials,
finished batches of dietary supplements,
and packaged and labeled dietary
supplements. Final § 111.260(l)(1)(ii)
derives from the following proposed
provisions:
• Proposed § 111.50(e)(1) which
would require that the documentation
by the quality control unit include
review of component, dietary
ingredient, and dietary supplement
receiving records, including review of
testing and examination results and
• Proposed § 111.37(b)(9) which
would require, in part, the quality
control unit to review all testing results.
(Comment 271) A few comments
assert that the proposed requirement
that the quality control unit review
receiving records as part of its review of
the batch record is redundant and
should be eliminated. One comment
argues that it is unnecessarily
burdensome to require the quality
control unit to re-review and crossreference all receiving records, noting
that the quality control unit already has
performed a review of these records
when the components or dietary
supplements were received, approved,
and released for use. The comment
asserts the quality control unit should
only have to repeat this review if it is
conducting an investigation or a
material review.
(Response) We agree with the
comments. Therefore, final
§ 111.260(l)(1)(ii) retains the
requirements of proposed
§§ 111.37(b)(9) and 111.50(e)(1) to
review the results of testing and
examination, but does not require
quality control personnel to document,
as part of the review of the batch record,
receiving records for components and
dietary supplements.
d. Final § 111.260(l)(2). Final
§ 111.260(l)(2) requires that the
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documentation by quality control
personnel include that quality control
personnel approved or rejected any
reprocessing or repackaging. Final
§ 111.260(l)(2) derives from proposed
§ 111.50(c)(14) which would require
that the batch production record include
the signature of the quality control unit
to document its review of the batch
production record and any approval for
reprocessing or repackaging. For
consistency with other provisions in
this final rule (such as final § 111.90),
final § 111.260(l)(2) includes a revision
that quality control personnel must
clearly choose between approving—or
rejecting—any reprocessing or
repackaging.
We did not receive comments specific
to proposed § 111.50(c)(14).
e. Final § 111.260(l)(3). Final
§ 111.260(l)(3) requires the
documentation by quality control
personnel to include that it approved
and released, or rejected, the batch for
distribution, including any reprocessed
batch. Final § 111.260(l)(3) derives from
the following proposed regulations:
• Proposed § 111.37(b)(5) which
would require, in part, the quality
control unit to review the batch
production record to approve the batch
for release for distribution;
• Proposed § 111.50(d)(2) which
would require the quality control unit
not to approve and release for
distribution any batch of dietary
ingredients or dietary supplement that
does not meet all specifications; and
• Proposed § 111.50(g) which would
require, in part, the results of the
reevaluation by the quality control unit
to be documented in the batch
production record.
For consistency with other provisions
of this final rule (such as final § 111.90),
final § 111.260(l)(3) requires that quality
control personnel must clearly choose
between approving—or rejecting—the
batch for distribution. We did not
receive comments specific to those parts
of proposed §§ 111.37(b)(5) or
111.50(d)(2) that we are setting forth in
final § 111.260(l)(3).
f. Final § 111.260(l)(4). Final
§ 111.260(l)(4) requires the batch
production record to include
documentation, at the time of
performance, that quality control
personnel approved and released, or
rejected, the packaged and labeled
dietary supplement, including any
repackaged or relabeled dietary
supplement. Final § 111.260(l)(4)
derives from the following proposed
regulations:
• Proposed § 111.37(b)(3) which
would require, in part, that the quality
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control unit approve or reject all dietary
supplements and
• Proposed § 111.70(e) which would
require, in part, that any repackaged or
relabeled dietary supplement meet all
specifications and that the quality
control unit must approve or reject their
release for distribution.
We did not receive comments specific
to those parts of proposed
§§ 111.37(b)(3) or 111.70(e) that we are
setting forth in final § 111.260(l)(4).
12. Final § 111.260(m)
Final § 111.260(m) requires the batch
production record to include
documentation, at the time of
performance, of any required material
review and disposition decision. Final
§ 111.260(m) derives from the following
proposed provisions:
• Proposed § 111.50(c)(13) which
would require that the batch production
record include any documented review
and disposition decision and
• Proposed § 111.35(j) which would
require that the person who conducts
the material review and makes the
disposition decision document that
activity, at the time of performance, in
the batch production record.
We did not receive comments specific
to proposed §§ 111.35(j) or
111.50(c)(13).
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13. Final § 111.260(n)
Final § 111.260(n) requires that the
batch production record include
documentation, at the time of
performance, of any reprocessing. We
have added this requirement in
conjunction with the requirement for
written procedures for the quality
control operations for approving or
rejecting any reprocessing, discussed
generally in section IV of this document.
E. Review of Batch Production Record
Deviations (Proposed § 111.50(d)(1),
(e)(2), (e)(3), and (e)(4))
Proposed §111.50(d)(1) would
require, if a batch deviates from the
master manufacturing record, including
any deviation from specifications, the
quality control unit to conduct a
material review and make a disposition
decision and record any decision in the
batch production record. Under final
§ 111.87 quality control personnel must
conduct any required material review
and make any required disposition
decision; under final § 111.113(a)(2)
quality control personnel must conduct
a material review and make a
disposition decision if a batch deviates
from the master manufacturing record,
including any deviation from
specifications. Given the requirements
of final §§ 111.87 and 111.113, it would
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be redundant to include proposed
§ 111.50(d)(1) in final subpart I.
Proposed § 111.50(e)(2) would require
that the review of the batch production
record and documentation by the
quality control unit include
identification of any deviation from the
master manufacturing record that may
have caused a batch or any of its
components to fail to meet
specifications identified in the master
production record. Proposed
§ 111.50(e)(3) would require that the
review of the batch production record
and documentation by the quality
control unit include records of
investigations, conclusions, and
corrective actions performed in
accordance with proposed § 111.50(d).
Proposed § 111.50(e)(4) would require
that the review of the batch production
record and documentation by the
quality control unit include the identity
of the person qualified by training and
experience who performed the
investigation in accordance with
§ 111.50(d).
Each of these requirements is already
included in final § 111.140(b)(3) which
sets forth the requirements for the
documentation that quality control
personnel must include for any required
material review and disposition
decision. In addition, under final
§ 111.260(m), the batch production
record must include documentation of
any required material review and
disposition decision. Given the
requirements of final §§ 111.140(b)(3)
and 111.260(m), it would be redundant
to include proposed § 111.50(e)(2),
(e)(3), and (e)(4) in final subpart I, and
we are not including them.
TABLE 11.—DERIVATION OF SECTIONS
IN FINAL SUBPART J
Final Rule
2003 CGMP
Proposal
§ 111.303 What are the
requirements under
this subpart J for written procedures?
N/A
§ 111.310 What are the
requirements for the
laboratory facilities
that you use?
§ 111.60(a)
§ 111.315 What are the
requirements for laboratory control processes?
§ 111.60(b)(1)
§ 111.320 What requirements apply to laboratory methods for testing and examination?
§ 111.60(c) and
(d)
§ 111.325 Under this
subpart J, what
records must you
make and keep?
§ 111.60(b)(2)
and (b)(3)
B. Highlights of the Changes to the
Proposed Requirements for Laboratory
Operations
1. Revisions
The final rule applies to persons who
manufacture, package, label, or hold
dietary supplements unless subject to an
exclusion in § 111.1.
2. Changes Associated With the
Reorganization
XV. Comments on Production and
Process Control System: Requirements
for Laboratory Operations (Final
Subpart J)
This subpart contains fewer details,
compared to the 2003 CGMP Proposal,
regarding the requirements for
collecting representative samples and
for testing, because these details are set
forth elsewhere in this final rule (i.e., in
final §§ 111.75 and 111.80) and would
be redundant in final subpart J.
A. Organization of Final Subpart J
3. Changes After Considering Comments
In the 2003 CGMP Proposal, the
proposed requirements for production
and process controls for laboratory
operations were set forth in proposed
§ 111.60(a) through (d). As shown in
table 11 of this document, we are
reorganizing the requirements for
laboratory operations into a distinct
subpart (final Subpart J—Production
and Process Control System:
Requirements for Laboratory
Operations). Table 11 lists the sections
in final subpart J and identifies the
proposed sections that form the basis of
the final rule.
The final rule:
• Includes a new requirement to
establish and follow written procedures
for laboratory operations, including
written procedures for the tests and
examinations you conduct to determine
whether or not specifications are met.
• Requires you to identify and use the
appropriate ‘‘scientifically valid
method,’’ rather than an appropriate
‘‘validated testing method,’’ for each
established specification for which
testing or examination is required to
determine whether the specification is
met.
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for specifications other than the identity
of a dietary ingredient.
C. What Are the Requirements Under
This Subpart for Written Procedures?
(Final § 111.303)
We received many comments that
recommended written procedures for
various provisions. We address the need
for written procedures generally in
section IV of this document. We also
respond to individual comments on
specific provisions in the same section.
Final § 111.303 requires you to
establish and follow written procedures
for laboratory operations, including
written procedures for the tests and
examinations you conduct to determine
whether specifications are met.
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D. What Are the Requirements for the
Laboratory Facilities That You Use?
(Final § 111.310)
Final § 111.310 requires you to use
adequate laboratory facilities to perform
whatever testing and examinations are
necessary to determine whether: (1)
Components that you use meet
specifications; (2) in-process
specifications are met as specified in the
master manufacturing record; and (3)
dietary supplements that you
manufacture meet specifications. Final
§ 111.310(a) is substantially similar to
proposed § 111.60(a). The requirement
for ‘‘adequate laboratory facilities’’ is to
ensure that the facilities used are
designed and suitable for carrying out
the necessary tests and examinations.
Other CGMP requirements of this final
rule would apply to the manufacturer’s
laboratory facilities, such as Subpart C—
Physical Plant and Grounds, and
Subpart D—Equipment and Utensils,
and should be considered in assessing
the adequacy of the laboratory facilities.
If the tests and examinations are carried
out by an outside laboratory, you will be
responsible for ensuring that the test
and examinations are adequately
performed.
(Comment 272) One comment states
that proposed § 111.60(a) would be
highly disruptive to the dietary
supplement industry and would impose
a great burden on companies that
traditionally rely on certification of
ingredient suppliers. Some comments
assert it would be redundant to require
testing by companies who are suppliers
of dietary ingredients, as well as by
companies who receive the dietary
supplements, to determine whether the
dietary ingredients meet specifications.
(Response) The final rule already
includes changes that address the
concerns raised by these comments. As
discussed in section X of this document
regarding final § 111.75(a), the final rule
permits the use of certificates of analysis
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E. What Are the Requirements for
Laboratory Control Processes? (Final
§ 111.315)
Final § 111.315 sets forth the
minimum laboratory control processes
that you must establish and follow.
These laboratory control processes must
be reviewed and approved by quality
control personnel.
1. Final § 111.315(a)
Final § 111.315(a) requires the
laboratory control processes you
establish and follow to include the use
of criteria for establishing appropriate
specifications. Final § 111.315(a) is
identical to proposed § 111.60(b)(1)(ii).
We did not receive comments specific
to proposed § 111.60(b)(1)(ii).
2. Final § 111.315(b)
Final § 111.315(b) requires you to
establish and follow laboratory control
processes that are reviewed and
approved by quality control personnel,
including the use of sampling plans for
obtaining representative samples, in
accordance with subpart E, of: (1)
Components, packaging, and labels; (2)
in-process materials; (3) finished
batches of dietary supplements; (4)
product you receive for packaging or
labeling as a dietary supplement (and
for distribution rather than for return to
the supplier); and (5) packaged and
labeled dietary supplements. Final
§ 111.315(b) derives from proposed
§ 111.60(b)(1)(iii)(A) through
(b)(1)(iii)(E).
Final § 111.315(b) combines the
proposed requirements of
§ 111.60(b)(1)(iii)(A) and (b)(1)(iii)(D) for
consistency with final § 111.80(a) which
combines the requirements to collect
representative samples of components,
packaging, and labels. However, for
consistency with other requirements
established by this final rule, we are
separating the requirements to collect
representative samples of ‘‘dietary
supplements received’’ (which the final
rule refers to as ‘‘product that you
receive for packaging or labeling as a
dietary supplement (and for distribution
rather than for return to the supplier,’’
or ‘‘received product’’)) from the
requirements to collect representative
samples of components.
(Comment 273) Some comments note
that proposed § 111.60(b)(1)(iii) restates
the requirements, already contained in
proposed § 111.37(b)(11)(i) through
(b)(11)(iv), that the quality control unit
collect representative samples. These
comments request proposed
§ 111.60(b)(1)(iii) be deleted, because it
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is more appropriately described as a
quality control function rather than as a
laboratory function.
(Response) We disagree that the
proposed requirement to use a sampling
plan is more appropriately described as
a quality control function than as a
laboratory function. Under both the
proposed and the final rule, the
sampling plans that are part of the
laboratory control operations are subject
to approval by quality control personnel
(‘‘unit’’ in the proposed rule) but are not
developed by quality control personnel.
We are making no changes based on this
comment.
(Comment 274) One comment asserts
sampling can be better accomplished at
the point of packaging rather than at a
laboratory remote from the packaging
operation.
(Response) This comment
misinterprets proposed
§ 111.60(b)(1)(iii) which proposed to
establish a process (i.e., the use of a
sampling plan) rather than to direct that
a particular operating unit (such as a
laboratory) collect samples. We are
making no changes based on this
comment.
3. Final § 111.315(c)
Final § 111.315(c) requires the
laboratory control processes you
establish and follow include use of
criteria for selecting appropriate
examination and testing methods. Final
§ 111.315(c) is identical to proposed
§ 111.60(b)(1)(i).
(Comment 275) One comment
recommends that a contract laboratory
hired by a person who is subject to the
final rule be able to determine the
specific type of test that is most
appropriate.
(Response) Nothing in the final rule
would preclude you from relying on the
recommendation of the contract
laboratory in selecting an appropriate
test or examination. However, the
manufacturer of the dietary supplement
has the responsibility to comply with
these CGMP requirements, including the
requirement to select appropriate tests,
regardless of who conducts the tests.
4. Final § 111.315(d)
Final § 111.315(d) requires the
laboratory control processes you
establish and follow to include use of
criteria for selecting standard reference
materials used in performing tests and
examinations. Final § 111.315(d) derives
from proposed § 111.60(b)(1)(iv).
(Comment 276) Several comments
support the use of standard reference
materials. Some comments distinguish
between a reference standard (which
they describe as a highly purified
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compound that is well characterized
and is used in quantitative assays for
single chemical entities) and a reference
material (which they describe as similar
to a reference standard but with less
specificity). These comments urge us to
recognize the difference between
reference standards and reference
materials and to require the use of both
in the final rule.
(Response) The comments that
request we recognize a difference
between certain types of reference
materials are consistent with proposed
§ 111.60(b)(1)(iv) and with statements
that we made in the preamble to the
2003 CGMP Proposal. We distinguished
two general types of reference materials:
(1) Compendia reference standards that
do not require characterization and (2)
noncompendia standards that should be
of the highest purity that can be
obtained by reasonable effort and that
should be thoroughly characterized to
ensure their identity, purity, quality,
and strength. We recommended you use
compendia reference standards
whenever possible, and that you
establish appropriately characterized inhouse materials prepared from
representative lots if no compendia
reference standard exists.
We also discussed reference materials
from the perspective of the type of test
or examination. For organoleptic
examinations, we described an
authenticated plant reference material
as material that has been authenticated
as the correct plant species and correct
plant part(s) by a qualified plant
taxonomist. For microscopic and
chemical tests (including calibration
tests), we described a reference material
as a highly purified compound that is
well characterized.
To the extent that the comments are
recommending that both compendia
reference standards and noncompendia
reference standards comply with any
final rule, this final rule would allow for
the use of both compendia reference
standards and noncompendia reference
standards. However, to the extent that
the comments are requesting this final
rule require that both types of reference
materials be used, we disagree. We see
no reason to require, for example, that
a firm with access to compendia
standards be required to develop
noncompendia standards. Likewise,
given that we have acknowledged that
noncompendia standards may be used,
we see no reason to require the use of
compendia standards in all
circumstances.
(Comment 277) One comment
expresses confusion about the preamble
discussion of proposed § 111.60(b)(1)(iv)
and suggests the preamble specify that
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reference standards be established
appropriate to the assay procedure for
which they are used.
(Response) Reference materials
should be appropriate to the assay
procedure for which they are used.
(Comment 278) Several comments
recommend we acknowledge certain
reference materials as authoritative
sources for botanical ingredients, such
as American Herbal Pharmacopoeia,
European Pharmacopoeia, and the
World Health Organization, in part
because other sources include only a
limited number of botanicals as
supplements. In the comments’ view,
explicit acknowledgment by FDA would
encourage manufacturers to use
independent standards, increase CGMP
compliance, and show that validation is
not limited to quantitative chemical
methods.
(Response) We decline to
acknowledge certain reference materials
as authoritative sources for botanical
ingredients. Such a request is outside
the scope of this final rule.
(Comment 279) One comment
believes we should designate USP to
develop appropriate standards.
(Response) This comment is outside
the scope of this final rule.
5. Final § 111.315(e)
Final § 111.315(e) requires that the
laboratory control processes you must
establish and follow include use of test
methods and examinations in
accordance with established criteria.
Final § 111.315(e) derives from
proposed § 111.60(b)(1)(vi).
We did not receive comments specific
to proposed § 111.60(b)(1)(vi).
F. What Requirements Apply to
Laboratory Methods for Testing and
Examination? (Final § 111.320)
1. Final § 111.320(a)
Final § 111.320(a) requires you to
verify that laboratory examination and
testing methodologies are appropriate
for their intended use. Final § 111.320(a)
is identical to proposed § 111.60(c).
(Comment 280) One comment states
that this decision should be made by a
qualified person, whether in-house or at
a contract laboratory.
(Response) We agree. Nothing in the
final rule would preclude you from
relying on the judgment of a qualified
person at a contract laboratory to satisfy
the requirements of final § 111.320(a).
We would not consider that a
recommendation from a contract
laboratory is any different from a
recommendation from an operating unit
of the manufacturer. However, the
manufacturer of the dietary supplement
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has the responsibility to comply with
these CGMP requirements, including the
requirement to select appropriate tests,
regardless of who conducts the tests.
(Comment 281) One comment
suggests modifying proposed § 111.60(c)
to add ‘‘reference materials and/or
reference standards’’ to the list of
elements that must be verified to be
appropriate for their intended use.
(Response) If reference materials and
reference standards are used as part of
the test or examination method, then
such materials and standards are
already required to be verified under the
language in proposed § 111.60(c). Thus,
there is no need for the modification
and we decline to modify the language
of final § 111.320(a).
2. Final § 111.320(b)
Final § 111.320(b) requires you to
identify and use the appropriate
scientifically valid method for each
established specification for which
testing or examination is required to
determine whether the specification is
met. Final § 111.320(b) derives from
proposed § 111.60(d) which would
require you to identify and use an
appropriate validated testing method for
each established specification for which
testing is required to determine whether
the specification is met. Final
§ 111.320(b) includes a provision
associated with final § 111.75(h) which
provides flexibility to use examinations
as well as tests to determine whether
specifications are met.
(Comment 282) Many comments
express concern about the amount of
testing required for the validation of the
appropriate test method. Several
comments object to the use of the terms
‘‘validations’’ and ‘‘validated’’ which
they assert have a specific meaning in
a pharmaceutical context and would be
overly burdensome in this rule. Other
comments assert that methods already
recognized as official standards do not
need to be ‘‘validated,’’ but simply
‘‘verified’’ as to suitability. Some
comments suggest substituting
‘‘scientifically valid testing method’’ for
‘‘appropriate validated testing method.’’
One comment suggests ‘‘qualifications’’
replace ‘‘validations.’’ Another
comment suggests test methods need
not be validated if they are ‘‘proven to
be suitable under actual conditions of
use.’’ Another comment suggests adding
‘‘established by the manufacturer’’ after
‘‘appropriate validated test method.’’
One comment recommends the final
rule give companies the flexibility to
adopt the method most suitable to the
ingredient they are testing, regardless of
whether the method is, or is not, an
‘‘official method’’ such as those
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established by AOAC International or
FDA.
(Response) In the preamble to the
2003 CGMP Proposal (68 FR 12157 at
12208), we stated that test method
validation determines whether a newlydeveloped or existing test method is
accurate, precise, and specific for its
intended purpose and involves
evaluating the test method on multiple
occasions or in multiple test facilities.
We explained that official methods,
such as AOAC International methods,
are validated in collaborative studies
using several laboratories under
identical conditions and that the AOAC
International methods are often cited as
‘‘official validated methods.’’ We also
explained that other method validations
are conducted in a single laboratory by
repeating the same test multiple times.
Typical validation characteristics
include accuracy, precision, specificity,
detection limit, quantitation limit,
linearity, range, and robustness.
The process of method validation
discussed above is a formal process for
demonstrating that procedures are
suitable for their intended use.
Although all methods that are formally
validated are considered ‘‘scientifically
valid,’’ other methods that are based on
scientific data or results published in,
for example, scientific journals,
references, text books, or proprietary
research can be scientifically valid even
if they are not formally ‘‘validated’’ in
collaborative studies (68 FR 12157 at
12198).
We agree that companies should have
flexibility to adopt the method most
suitable to the ingredient they are
testing. Consistent with the view that
we expressed in the preamble to 2003
CGMP Proposal (68 FR 12157 at 12198),
we believe that a scientifically valid
method is one that is accurate, precise,
and specific for its intended purpose. In
other words, a scientifically valid
method is one that consistently does
what it is intended to do.
Because we acknowledge that
methods that are based on scientific
data or results published in, for
example, scientific journals, references,
text books, or proprietary research can
be scientifically valid even if they are
not formally ‘‘validated,’’ we are
revising proposed § 111.60(d). Under
final § 111.320(b) you must identify and
use an appropriate ‘‘scientifically valid
method’’ (rather than a ‘‘validated
method’’) for each established
specification for which testing or
examination is required to determine
whether the specification is met.
However, we continue to recommend
that you use tests and examinations that
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already have been validated when such
tests are available.
(Comment 283) One comment
specifically asks how much
modification of a validated method is
allowed before the method must be revalidated by the laboratory. The
comment cites an example of moisture
testing in which the testing method
needs to be modified to provide a more
valid moisture reading.
(Response) In the preamble to the
2003 CGMP proposal (68 FR 12157 at
12209), we recommended that, if you
modify an officially validated method,
you document the reason for the
modification and have data to show that
the modified method produces results
that are at least as accurate and reliable
as the established method for the
material being tested. We also
recommended that you have complete
records of any testing and
standardization of laboratory reference
standards, reagents, and standard
solutions that you use in your laboratory
operations. We are making no changes
to these recommendations in this final
rule.
(Comment 284) Several comments
request the final rule incorporate by
reference authoritative sources of
compendial methods.
(Response) We decline this request for
the reasons discussed in response to
comments 193 and 196.
G. Appropriate Test Method Validation
(Proposed § 111.60(b)(1)(v))
Proposed § 111.60(b)(1)(v) would
require the laboratory control processes
you establish and follow to include the
use of appropriate test method
validations. Because the final rule does
not require that you use a validated
method for any tests or examinations
that you conduct, we are removing
proposed § 111.60(b)(1)(v).
H. Under This Subpart, What Records
Must You Make and Keep? (Final
§ 111.325)
Final § 111.325 sets forth the
requirements for records that quality
control personnel must make and keep.
1. Final § 111.325(a)
Final § 111.325(a) requires you to
make and keep records required under
subpart J in accordance with subpart P.
Final § 111.325(a) derives from
proposed § 111.60(b)(3), which would
require you to keep laboratory
examination and testing records in
accordance with proposed § 111.125.
Because final § 111.303 requires you to
establish and follow written procedures
for laboratory operations, the records
you must make and keep under final
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§ 111.325 are not limited to laboratory
examination and testing records, but
also include the written procedures.
Final § 111.325(a) also includes editorial
revisions associated with the
reorganization and editorial revisions
for consistency with the recordkeeping
requirements in subparts P.
We did not receive comments specific
to proposed § 111.60(b)(3).
2. Final § 111.325(b)(1)
The final rule includes a new
requirement (final § 111.303) that you
establish and follow written procedures
for laboratory operations, including
written procedures for the tests and
examinations you conduct to determine
whether specifications are met. Those
written procedures are records.
Therefore, final § 111.325(b)(1) requires
you to make and keep a record of the
written procedures for laboratory
operations, including written
procedures for the tests and
examinations that you conduct to
determine whether specifications are
met.
3. Final § 111.325(b)(2)
Final § 111.325(b)(2) sets forth
requirements for documenting that you
followed the laboratory methodology
established in accordance with this
subpart. Final § 111.325(b)(2)(i) requires
that the person who conducts the testing
and examination document, at the time
of performance, that laboratory
methodology established in accordance
with this subpart is followed. Final
§ 111.325(b)(2)(ii) requires that the
documentation include the results of the
testing and examination. Final
§ 111.325(b)(2) derives from proposed
§ 111.60(b)(2) with revisions associated
with the reorganization.
(Comment 285) One comment states
that, without appropriate
documentation, there would be no
assurance that the appropriate testing
was indeed performed and that the
product’s identity, purity, quality,
strength, and composition are what they
are represented to be.
(Response) We agree and have
retained the requirement in this final
provision.
XVI. Comments on the Production and
Process Control System: Requirements
for Manufacturing Operations (Final
Subpart K)
A. Organization of Final Subpart K
In the 2003 CGMP Proposal, the
requirements for manufacturing
operations were set forth in § 111.65. As
shown in table 12 of this document, we
are establishing the requirements for
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manufacturing operations in a distinct
subpart (final Subpart K—Production
and Process Control System:
Requirements for Manufacturing
Operations). In addition, we are
incorporating some requirements from
proposed § 111.74 relating to rejected
components, dietary supplements, and
packaging and labels into final subpart
K. Table 12 lists the sections in final
subpart K and identifies the proposed
sections that form the basis of the final
rule.
TABLE 12.—DERIVATION OF SECTIONS
IN FINAL SUBPART K
2003 CGMP
Proposal
Final Rule
§ 111.353 What are the
requirements under
this subpart K for written procedures?
N/A
§ 111.355 What are the
design requirements
for manufacturing operations?
§ 111.65(a)
§ 111.360 What are the
requirements for sanitation?
§ 111.65(b)
§ 111.365 What precautions must you
take to prevent contamination?
§ 111.65(c)
§ 111.370 What requirements apply to rejected dietary supplements?
§ 111.74
§ 111.375 Under this
subpart K, what
records must you
make and keep?
N/A
(Comment 286) Some comments
support proposed § 111.65 as a ‘‘good
model’’ for an appropriate level of
flexibility, noting that proposed § 111.65
clearly states the requirements and
presents relevant factors that must be
considered when determining how to
best meet the requirements of the rule.
(Response) We acknowledge these
comments and utilize many elements of
proposed § 111.65 in final § 111.355.
E. What Are the Design Requirements
for Manufacturing Operations? (Final
§ 111.355)
The final rule:
• Applies to persons who
manufacture, package, label, or hold
dietary supplements unless subject to an
exclusion in § 111.1 and
• Reflects changes relevant to this
subpart that we are making to final
subpart C concerning water standards.
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C. General Comments on Manufacturing
Operations
We received many comments that
recommended written procedures for
various provisions. We address the need
for written procedures generally in
section IV of this document. We also
respond to individual comments on
specific provisions in the same section.
We are including a new provision,
final § 111.353, to require that you
establish and follow written procedures
for manufacturing operations.
1. Revisions
2. Changes Made After Considering
Comments
The final rule requires written
procedures for manufacturing
operations.
20:59 Jun 22, 2007
The final rule sets forth in final
§ 111.90, rather than in subpart K, the
requirements for in-process adjustments
or reprocessing.
D. What Are the Requirements Under
This Subpart for Written Procedures?
(Final § 111.353)
B. Highlights of Changes to the
Proposed Requirements for
Manufacturing Operations
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Reorganization
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Final § 111.355 requires you to design
or select manufacturing processes to
ensure that product specifications are
consistently met. Final § 111.355
derives from proposed § 111.65(a)
which would require you to design or
select manufacturing processes to
ensure that dietary supplement
specifications are consistently achieved.
Final § 111.355 refers to ‘‘product
specifications’’ rather than ‘‘dietary
supplement specifications’’ to conform
with final § 111.70(e). We have
substituted the word ‘‘met’’ for
‘‘achieved’’ to comply with plain
language initiatives and to be consistent
with other provisions.
We did not receive comments specific
to proposed § 111.65(a).
F. What Are the Requirements for
Sanitation? (Final § 111.360)
Final § 111.360 requires you to
conduct all manufacturing operations in
accordance with adequate sanitation
principles. Final § 111.360 derives from
proposed § 111.65(b). We did not
receive comments specific to proposed
§ 111.65(b).
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G. What Precautions Must You Take to
Prevent Contamination? (Final
§ 111.365)
Final § 111.365 requires you to take
all necessary precautions during the
manufacture of a dietary supplement to
prevent contamination of components
or dietary supplements. Final § 111.365
derives from proposed § 111.65(c)(1)
through (c)(11).
1. Final § 111.365(a)
Final § 111.365(a) requires that the
necessary precautions include
performing manufacturing operations
under conditions and controls that
protect against the potential for growth
of microorganisms and the potential for
contamination. Final § 111.365(a)
derives from proposed § 111.65(c)(1).
(Comment 287) One comment
contends that the requirement in
proposed § 111.65(c)(1) to protect
‘‘against the potential for growth of
microorganisms,’’ does not take into
account processes that have a kill step.
The comment recommends that
proposed § 111.65(c)(1) be revised to be
more consistent with § 110.80(b)(2) and
state, ‘‘performing manufacturing
operations under such conditions and
controls as are necessary to minimize
the potential for the growth of
undesirable microorganisms, or for the
contamination of the product.’’
(Response) We decline to modify final
§ 111.365(a) as requested by the
comment because the provision
accomplishes what is requested by the
comment. We defined ‘‘microorganism’’
in the 2003 CGMP Proposal similar to
how we describe ‘‘undesirable
microorganisms’’ in § 110.3(i). Further,
we decline to use the words ‘‘minimize
the potential for growth’’ instead of
‘‘protect against the potential for
growth’’ because the word ‘‘minimize’’
suggests a lesser standard than ‘‘protect
against’’ the potential for growth of
microorganisms.
We would consider that you are not
complying with the final rule if you do
not perform manufacturing operations
under conditions and controls that
protect against the potential for growth
of microorganisms and the potential for
contamination, regardless of whether
you use a kill step. Although a kill step
may be necessary in some
circumstances, it is not a substitute for
conditions and controls that protect
against the potential for growth of
microorganisms and the potential for
contamination. Therefore, we decline to
make the change requested by this
comment.
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2. Final § 111.365(b)
Final § 111.365(b) requires that
necessary precautions include washing
or cleaning components that contain
soil or other contaminants. Final
§ 111.365(b) is identical to proposed
§ 111.65(c)(2). We did not receive
comments specific to proposed
§ 111.65(c)(2).
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3. Final 111.365(c)
Final § 111.365(c) requires that the
necessary precautions include using
water that, at a minimum, complies
with the applicable Federal, State, and
local requirements and does not
contaminate the dietary supplement
when the water may become a
component of the finished batch of
dietary supplement.
The proposed requirements would set
forth parallel requirements for water
that is used in the manufacture of a
dietary supplement for both your
physical plant (proposed § 111.15(d)(2))
and for manufacturing operations
(proposed § 111.65(c)(3)). Thus,
proposed § 111.15(d)(2) would require
that water that contacts components,
dietary ingredients, dietary
supplements, or any contact surface
must, at a minimum, comply with the
NPDW regulations prescribed by the
Environmental Protection Agency under
40 CFR part 141 and any State and local
requirements.
As discussed in section VIII of this
document (final § 111.15(e)(2) in
subpart C), we are revising proposed
§ 111.15(d)(2) to require in the final rule
that water, used in the manufacture of
a dietary supplement in a manner such
that the water may become a component
of the dietary supplement, i.e., when
such water contacts components,
dietary supplements, or any contact
surface, must, at a minimum, comply
with applicable Federal, State, and local
requirements and not contaminate the
dietary supplement. Given the parallel
nature of proposed § 111.65(c)(3) and
proposed § 111.15(d)(2), we are revising
proposed § 111.65(c) to be consistent
with the revisions we are making to
proposed § 111.15(d)(2) (final
§ 111.15(e)(2)).
Final § 111.365(c) also includes
grammatical changes consistent with the
structure of final § 111.365.
(Comment 288) One comment asks
that the words ‘‘or equivalent quality
water’’ be added to ‘‘water that meets
the National Primary Drinking Water
regulations’’ in proposed § 111.65(c)(3)
to allow for ingredients manufactured in
facilities outside the United States.
(Response) As stated in response to
comment 91, dietary supplements
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manufactured in a foreign country
would be subject to the requirements of
this final rule. Although the
Environmental Protection Agency
NPDW regulations would not apply to a
foreign manufacturer, the foreign
manufacturer would need to use water
that is of a standard required in this
final rule and that achieves the same
level of performance required of
domestic manufacturers. The water used
by the foreign facility must not
contaminate the dietary supplement that
is manufactured. We decline to add ‘‘or
equivalent water quality’’ because that
would suggest domestic firms would not
need to follow whatever Federal, State,
and local requirements are applicable.
(Comment 289) One comment
recommends that proposed
§ 111.65(c)(3) be revised to be consistent
with proposed § 111.15(d)(1), which
would require you to provide water that
is safe and of adequate sanitary quality,
at suitable temperatures, and under
pressure as needed, in all areas where
water is necessary for: (1)
Manufacturing dietary ingredients or
dietary supplements; (2) making ice that
comes in contact with components,
dietary ingredients, dietary
supplements, or contact surfaces; (3)
cleaning any surface; and (4) employee
bathrooms and hand-washing facilities.
(Response) We do not agree with the
comment that we should be consistent
in the water requirement related to
proposed § 111.15(d)(1) and the
requirement in proposed § 111.65(c)(3).
The requirement in proposed
§ 111.15(d)(1) describes a variety of
manufacturing operations where water
is used. For example, water that is safe
and of adequate sanitary quality, as
described in the proposed rule, for
purposes of manufacturing dietary
supplements or that comes into contact
with a dietary supplement would be
water that would have been required to
comply with the requirement in
proposed § 111.15(d)(2). Under the
proposed rule and under the final rule,
if such water is subject to
Environmental Protection Agency
NPDW, then the water must meet
Environmental Protection Agency
NPDW requirements at point of use.
Proposed § 111.15(d)(1) has been
revised and simplified in final
§ 111.15(e)(1) to require you to provide
water that is safe and sanitary, at
suitable temperatures, and under
pressure as needed, for all uses where
water does not become a component of
the dietary supplement. Water that is
safe and sanitary for cleaning the floor
in a facility would not need to meet
standards for drinking water, but such
water could not be a source of
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contamination of the dietary
supplement. The standard ‘‘safe and
sanitary’’ in final § 111.15(e)(1) allows
some flexibility for the manufacturer in
deciding what water it can use in
various operations for which no other
requirements in this final rule apply.
The requirements of final § 111.365(c)
are consistent with the changes in final
§ 111.15(e).
4. Final § 111.365(d)
Final § 111.365(d) requires that the
necessary precautions you take during
the manufacture of a dietary supplement
to prevent contamination of components
or dietary supplements include
performing chemical, microbiological,
or other testing, as necessary to prevent
the use of contaminated components.
Final § 111.365(d) derives from
proposed § 111.65(c)(4).
(Comment 290) One comment asserts
that requirements for testing belong in
proposed § 111.25 (proposed
requirements for equipment and
utensils) rather than in proposed
§ 111.65 (proposed requirements for
manufacturing operations).
(Response) In our discussion of
proposed § 111.65(c)(4) in the 2003
CGMP Proposal (68 FR 12157 at 12210),
we stated that you consider identifying
those areas in the processing and
production areas where chemical,
microbial, or other forms of
contamination are most likely to occur.
We also stated that chemical, microbial,
or other testing is necessary to identify
areas where sanitation measures have
not been adequate or where products
may become adulterated. These remarks
reflect that the proposed requirement in
proposed § 111.65(c)(4) is directed to
facilities rather than to equipment and
utensils. For example, under proposed
§ 111.65(c)(4), we encouraged you to
establish a testing program that
monitors levels of microorganisms at
key places in your physical plant where
you process and produce your products.
Thus, we disagree with the comment
that the testing requirements belong in
proposed § 111.25 and are not making
any changes in final § 111.365(d).
5. Final § 111.365(e)
Final § 111.365(e) requires that the
necessary precautions you take during
the manufacture of a dietary supplement
to prevent contamination of components
or dietary supplements include
sterilizing, pasteurizing, freezing,
refrigerating, controlling hydrogen-ion
concentration (pH), controlling
humidity, controlling water activity
(aw), or using any other effective means
to remove, destroy, or prevent the
growth of microorganisms, and prevent
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decomposition. Final § 111.365(e)
derives from proposed § 111.65(c)(5).
(Comment 291) One comment asserts
that only sanitary practices are needed
to prevent microbial contamination or
decomposition, and, therefore, requests
that we clarify the processes listed in
proposed § 111.65(c)(5) are optional.
(Response) We disagree with this
comment. Good sanitary practices are
important, but they are not the only
precaution to take to prevent a
component or dietary supplement from
contamination with microorganisms. In
the preamble to the 2003 CGMP
Proposal, we gave the example of bovine
colostrum, which is the lacteal secretion
that precedes milk after a cow gives
birth and is a substance that is used in
dietary supplements. We also stated that
we consider that bovine colostrum
likely presents the same potential health
risks as bovine milk, which can contain
pathogenic organisms capable of
causing diseases in man such as
tuberculosis, undulant fever, or
gastrointestinal disease and, thus, must
be pasteurized (21 CFR 1240.61). Under
final § 111.365(e) you must sterilize or
pasteurize bovine colostrums, or take
other steps, to remove or destroy
microorganisms that could be present in
bovine colostrum. Under final
§ 111.365(e) we list various ways that,
depending upon the particular situation,
would be effective in removing,
destroying, or preventing the growth of
microorganisms and preventing
decomposition. You must decide for
your given operation what means to use
to remove, destroy, or prevent the
growth of microorganisms and prevent
deterioration of your components and
dietary supplements so that you ensure
the quality of the dietary supplement.
(Comment 292) Some comments
recommend adding ‘‘irradiating’’ to the
list of practices to prevent the growth of
microorganisms in proposed
§ 111.65(c)(5) similar to the industry
CGMP provision, ‘‘Production and
Process Controls,’’ section (d)(5),
published in the 1997 ANPRM.
(Response) We decline to revise the
provision as suggested by these
comments. We are not adding
‘‘irradiating’’ to the list of practices
because, at this time, irradiation of
dietary ingredients and dietary
supplements, as a means to reduce or
eliminate microbial loads, is not
permitted. CFSAN is currently
reviewing the use of irradiation for the
control of microbial contamination on
dietary supplements and ingredients
(including dietary ingredients) used in
the manufacture of dietary supplements
(68 FR 25048, May 9, 2003). If we
authorize this use of irradiation you
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34897
could then use irradiation in
compliance with that rule to comply
with final § 111.365(e) as an ‘‘other
effective means.’’
implement them if they are necessary to
prevent contamination of components
or dietary supplements. Final
§ 111.65(h) retains this same language.
6. Final § 111.365(f)
Final § 111.365(f) requires that the
necessary precautions you take during
the manufacture of a dietary supplement
to prevent contamination of components
or dietary supplements include holding
components and dietary supplements
that can support the rapid growth of
microorganisms of public health
significance in a manner that prevents
the components and dietary
supplements from becoming
adulterated. Final § 111.365(f) derives
from proposed § 111.65(c)(6). We did
not receive comments specific to
proposed § 111.65(c)(6).
9. Final § 111.365(i)
Final § 111.365(i) requires that the
necessary precautions you take during
the manufacture of a dietary supplement
to prevent contamination of components
or dietary supplements include using
effective measures to protect against the
inclusion of metal or other foreign
material in components or dietary
supplements. Compliance with this
requirement must include consideration
of the use of: (1) Filters or strainers, (2)
traps, (3) magnets, or (4) electronic
metal detectors. Final § 111.365(i)
derives from proposed § 111.65(c)(9).
(Comment 294) One comment
contends it is sufficient to require in
proposed § 111.65(c)(9) that
manufacturers inspect their equipment
before and after use to determine if any
piece is missing, and if so, the entire
batch should be disposed of. The
comment states metal detection devices
are not 100 percent effective and that
inspection of equipment before and after
use would be preferable.
(Response) We disagree with the
comment. As discussed in the 2003
CGMP Proposal, the purpose behind
proposed § 111.65(c)(9) is to ensure that
no metal or foreign material becomes a
source of possible contamination and
not to establish mechanisms to be used
after contamination has or is suspected
to have occurred (68 FR 12157 at
12211). The source of metal
contamination is not limited to
manufacturing equipment. For example,
metal contamination could occur
through using utensils such as metal
brushes during processing of natural
products. It would be impractical to
determine whether contamination has
occurred by examining the brush.
7. Final § 111.365(g)
Final § 111.365(g) requires that the
necessary precautions you take during
the manufacture of a dietary supplement
to prevent contamination of components
or dietary supplements include
identifying and holding any
components or dietary supplements, for
which a material review and disposition
decision is required, in a manner that
protects components or dietary
supplements that are not under a
material review against contamination
and mixups with those under a material
review. Final § 111.365(g) is
substantially similar to proposed
§ 111.65(c)(7). We did not receive
comments specific to proposed
§ 111.65(c)(7).
8. Final § 111.365(h)
Final § 111.365(h) requires that the
necessary precautions you take during
the manufacture of a dietary supplement
to prevent contamination of components
or dietary supplements include
performing mechanical manufacturing
steps (such as cutting, sorting,
inspecting, shredding, drying, grinding,
blending, and sifting) by any effective
means to protect the dietary
supplements against contamination.
Final § 111.365(h) derives from
proposed § 111.65(c)(8). Such steps
must include consideration of: (1)
Cleaning and sanitizing contact
surfaces, (2) using temperature controls,
and (3) using time controls.
(Comment 293) One comment
suggests that the time controls required
in proposed § 111.65(c)(8)(iii) are not
always necessary.
(Response) As written, proposed
§ 111.65(c)(8) acknowledges that time
controls are not always necessary,
because the provision requires that you
consider using time controls, and
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10. Final § 111.365(j)
Final § 111.365(j) requires that the
necessary precautions you take during
the manufacture of a dietary supplement
to prevent contamination of components
or dietary supplements include
segregating and identifying all
containers for a specific batch of dietary
supplements to identify their contents
and, when necessary, the phase of
manufacturing. Final § 111.365(j)
derives from proposed § 111.65(c)(10).
We did not receive comments specific to
proposed § 111.65(c)(10).
11. Final § 111.365(k)
Final § 111.365(k) requires that the
necessary precautions you take during
the manufacture of a dietary supplement
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to prevent contamination of components
or dietary supplements include
identifying all processing lines and
major equipment used during
manufacturing to indicate their
contents, including the name of the
dietary supplement and the specific
batch or lot number and, when
necessary, the phase of manufacturing.
Final § 111.365(k) derives from
proposed § 111.65(c)(11).
(Comment 295) One comment
suggests continuous processes should be
excluded from the requirement in
proposed § 111.65(c)(11) to identify
specific batch or lot numbers. The
comment explains that in continuous
bulk operations for manufacturing
dietary ingredients, the batch or lot
number often is not identified until after
the materials have been blended and
moved into a storage bin.
(Response) We are making no changes
to proposed § 111.65(c)(11) in final
§ 111.365(k) because the comment
describes a situation where the
manufacturer is manufacturing a dietary
ingredient, and the final rule does not
apply to the manufacture of a ‘‘dietary
ingredient’’ within the meaning of
section 201(ff) of the act.
Final § 111.370 requires you to clearly
identify, hold, and control under a
quarantine system for appropriate
disposition any dietary supplement that
is rejected and unsuitable for use in
manufacturing, packaging, or label
operations. Final § 111.370 derives from
proposed § 111.74 which would require
that you clearly identify, hold, and
control under a quarantine system any
component, dietary ingredient, dietary
supplement, packaging, and label that is
rejected and unsuitable for use in
manufacturing, packaging, or label
operations. Because the requirements
regarding components, packaging, and
labels that are rejected and unsuitable
for use are already set forth in final
§ 111.170, final § 111.370 addresses only
the requirements for dietary
supplements.
We did not receive comments specific
to proposed § 111.74.
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I. Under This Subpart, What Records
Must You Make and Keep? (Final
§ 111.375)
In order to ensure that records are
maintained as required under subpart P,
we are adding a new § 111.375. This
section requires that you make and keep
records of the written procedures you
establish for manufacturing operations.
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XVII. Comments on the Production and
Process Control System: Requirements
for Packaging and Labeling Operations
(Final Subpart L)
A. Organization of Final Subpart L
In the 2003 CGMP Proposal, the
requirements for packaging and labeling
operations were set forth in § 111.70. As
shown in table 13 of this document, the
final rule reorganizes the requirements
related to quality control operations into
a distinct subpart (final Subpart L—
Production and Process Control System:
Requirements for Packaging and
Labeling Operations). Table 13 lists the
sections in final subpart L and identifies
the proposed sections that form the
basis of the final rule.
TABLE 13.—DERIVATION OF SECTIONS
IN FINAL SUBPART L
2003 CGMP
Proposal
Final Rule
§ 111.403 What are the
requirements under
this subpart L for written procedures?
N/A
§111.410 What requirements apply to packaging and labels?
H. What Requirements Apply to
Rejected Dietary Supplements? (Final
§ 111.370)
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These written procedures are required
under final § 111.353.
§ 111.70(a),
(b)(6), and (f)
§ 111.415 What requirements apply to filling,
assembling, packaging, labeling, and
related operations?
§ 111.70(b)
§111.420 What requirements apply to repackaging and relabeling?
§ 111.70(d) and
(e)
§111.425 What requirements apply to a packaged and labeled dietary supplement that is
rejected for distribution?
§ 111.74
§ 111.430 Under this
subpart L, what
records must you
make and keep?
§ 111.70(g) and
(h)
B. Highlights of Changes to the
Proposed Requirements for Packaging
and Labeling Operations
1. Revisions
The final rule:
• Reflects that the final rule applies to
persons who manufacture, package,
label, or hold dietary supplements
unless subject to an exclusion in
§ 111.1.
• Reflects that the labeling
requirements of the rule address the
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operation of putting the label specified
in the master manufacturing record on
the final product.
• Clarifies the applicability of the rule
to labeling operations.
2. Changes Associated With the
Reorganization
We are moving to final § 111.260(k) in
subpart I the requirements for the
documentation, in the batch production
record, of packaging and labeling
operations (proposed § 111.70(g)).
3. Changes After Considering Comments
The final rule:
• Requires you to establish and
follow written procedures for packaging
and labeling operations.
• Provides for an exception to the
requirements for label reconciliation for
cut or rolled labels if a 100-percent
examination for correct labels is
performed by appropriate electronic or
electromechanical equipment during or
after completion of finishing operations.
• Clarifies the requirement for
‘‘retesting or re-examining’’ any
repackaged or relabeled dietary
supplements, i.e., consistent with final
§ 111.75(g) you must examine a
representative sample of each batch of
repackaged or relabeled dietary
supplements to determine whether
repackaged or relabeled dietary
supplements meet all specifications
established in accordance with
§ 111.70(g).
C. General Comments on Proposed
Requirements for Packaging and
Labeling Operations
(Comment 296) Some comments
assert that the proposed packaging and
labeling requirements are unnecessarily
stringent for dietary ingredients,
because the potential for abuse is
primarily at the final product stage.
(Response) To the extent that the
comment is saying that a dietary
ingredient manufacturer who
manufactures, packages, labels, and
holds a dietary ingredient that is further
processed and incorporated into a
dietary supplement by another person
should not have to comply with the
packaging and labeling requirements in
subpart L, we agree. We are modifying
the scope of the rule as to who is subject
to the CGMP requirements, as discussed
in section VI of this document (subpart
A). The final rule applies to persons
who manufacture, package, label, or
hold dietary supplements unless subject
to an exclusion in § 111.1.
(Comment 297) Several comments
assert that it is imperative that a dietary
supplement contain what it purports on
its label. Some comments state that the
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amounts of ingredients listed on the
label must accurately reflect what is in
the package.
(Response) To the extent that the
comments are suggesting that there need
to be requirements for labeling
operations as part of CGMP to ensure
that the label applied to the dietary
supplement is the label specified in the
master manufacturing record for the
finished product, we agree. To the
extent that the comments suggest that
CGMP requirements should ensure the
quality of the dietary supplement
manufactured, we also agree. If
consumers believe that dietary
supplements contain the ingredients as
labeled, as with any other product they
purchase, then CGMP requirements
should help to ensure that dietary
supplements are manufactured
consistently to ensure the quality of the
dietary supplement and to help ensure
the proper identity and amount of
ingredients identified on the label.
D. General Comments on Requirements
for What Must Be on the Product Label
Rather Than for Labeling Operations
(Comment 298) Some comments
express disappointment that the 2003
CGMP Proposal does not address
product claims included on product
labels. These comments state that, if
FDA is not going to review label claims,
it should, at a minimum, require the
following statement be placed on
dietary supplement products: ‘‘This
product has not been reviewed for safety
and efficacy by the FDA.’’ These
comments assert that such a statement
should be included on all dietary
supplement products, regardless of
whether the product makes structure/
function claims. These comments also
recommend that dietary supplement
labeling encourage consumers to share
information about their use of the
dietary supplements with their
pharmacists and physicians and
encourage consumers to seek the input
of a health care provider if symptoms
that prompted use of the dietary
supplement are not resolved.
One comment requests we establish
specific label content to include on
dietary supplement labels. The
comment asserts that the technology
and mechanical tools exist to produce
expanded labeling for dietary
supplements efficiently and costeffectively. The comment asserts that
the content should include a complete
listing of ingredients, relative
percentages, batch or lot number,
intended use, safety information,
directions, and product information.
Specifically, the comment supports the
labeling recommendations of the U.S.
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Department of Health and Human
Services (HHS), Office of the Inspector
General (OIG) ‘‘Dietary Supplement
Labels: Key Elements,’’ March 2003,
publication no. OEI–01–01–00120,
available at https://oig.hhs.gov/oei/
reports/oei–01–01–00120.pdf) (Ref. 34).
The comment endorses the HHS/OIG
recommendations, with the addition of
batch or lot number on the label. The
comment also endorses the OIG’s
proposed label presentation which calls
for: (1) A standardized format with
similar types of information in a similar
order across supplements; (2) distinct
product features to assist consumers in
distinguishing supplements from other
health care products; (3) readability,
with language and visual cues that are
easily understood by consumers; (4)
balance to present information in a fair
and balanced format that omits
marketing and sales pitches; and (5)
constructive use of space whereby
innovative packaging is employed to
expand label space.
Several comments address whether
we should permit manufacturers to state
on their products that the manufacturer
of the product is in compliance with
FDA CGMP requirements. Several
comments assert that a CGMP statement
on labels should not be allowed. These
comments assert that the proposed
‘‘made in a CGMP facility’’ language is
fraught with potential misuse, and that
the potential for confusion is
overwhelming. These comments state
that the rule also should be modified to
exclude other similar statements such as
‘‘produced using good laboratory
practices,’’ ‘‘produced using good
practices,’’ or ‘‘produced in compliance
with USP good manufacturing
practices.’’ According to these
comments, similar statements currently
appear on dietary supplement labels
and also may be misleading. These
comments assert that CGMP
requirements are not voluntary and
should not be marketed as such.
Some comments state that a voluntary
label statement that a dietary
supplement complies with CGMP
should be allowed. According to these
comments, there are several third party
organizations such as USP and National
Nutritional Foods Association (NNFA)
that have proposed or established CGMP
requirements as rigorous as, or more
rigorous than, those proposed by FDA.
These comments assert that a voluntary
statement that characterizes the nature
of the GMP compliance should be
allowed.
(Response) The comments related to
requests about specific label content,
such as ingredient listing, relative
percentage of ingredients, intended use,
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safety information, label format, use of
label space, and directions and product
information are outside the scope of this
final rule. Further, with respect to
requiring specific statements about
dietary supplement product, such as,
‘‘This product has not been reviewed for
safety and efficacy by the FDA,’’ or
‘‘This product has been produced using
good manufacturing practice,’’ we have
stated previously that the manufacturer
is responsible for ensuring that any
voluntary labeling statements on its
dietary supplement products are
truthful and not misleading (68 FR
12157 at 12164). We would review the
lawfulness of such statements under
sections 403(a)(1) and 201(n) of the act.
We did not propose to require any
specific statements. We stated that an
unqualified statement such as
‘‘produced in compliance with dietary
supplement current good manufacturing
practice requirements,’’ without more,
could suggest a product may be safe and
effective or somehow superior to other
dietary supplement products that are
subject to the same CGMP requirements
(id.). Further, we stated that such a
statement would likely be considered
misleading by us under sections
403(a)(1) and 201(n) of the act, but that
including language clarifying to
consumers that all dietary supplements
must be manufactured in compliance
with CGMP requirements and that such
compliance does not mean that the
dietary supplement is safe or effective
may be a way to cure that unqualified
statement (id.). Thus, we are not
prohibiting voluntary statements on the
dietary supplement label, provided that
such statements are truthful and not
misleading.
(Comment 299) Some comments
assert that the labeling standards found
in the 2003 CGMP Proposal should be
uniformly applied across manufacturers,
regardless of size, because consumers
are unlikely to differentiate between
small companies and large ones when
selecting dietary supplements. These
comments assert that we should,
therefore, only allow 1 year for labeling
compliance for all manufacturers
regardless of their size.
Some comments assert that small
manufacturers are more likely to suffer
competitively if their labels lack
important ingredient and other
information relative to labeling
employed by their larger competitors.
These comments argue that enhanced
labeling is a cost-effective packaging
feature and should not represent a
significant cost burden when
outsourced to a qualified printpackaging vendor. Moreover, labels
already represent a budgeted cost item
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for dietary supplement producers.
Labels with additional content would
add little to manufacturer overhead.
(Response) These comments may have
misinterpreted the 2003 CGMP
Proposal. The CGMP requirements do
not impose any requirements for the
specific content of the label. We discuss
the requirements necessary to determine
the complete manufacturing history and
control of a packaged and labeled
dietary supplement through distribution
in this subpart in our discussion on
final § 111.410(d). To the extent that
businesses with fewer than 500
employees want to comply with the
CGMP requirements for labeling
operations in a shorter timeframe than
what we are allowing in this final rule,
such businesses may do so. However, to
assist businesses with fewer than 500
employees in complying with dietary
supplement CGMPs, we are giving
businesses with fewer than 500 but 20
or more employees a compliance date of
24 months after the date of publication
of this final rule, and we are giving
businesses with fewer than 20
employees a compliance date of 36
months after the date of publication of
this final rule.
E. What Are the Requirements Under
This Subpart for Written Procedures?
(Final § 111.403)
We received many comments that
recommended written procedures for
various provisions. We address the need
for written procedures generally in
section IV of this document. We also
respond to individual comments on
specific provisions in the same section.
Final § 111.403 requires you to
establish and follow written procedures
for packaging and labeling operations.
Under final 111.430(b), relating to
records you must make and keep, we
require that you make and keep records
of such written procedures.
F. What Requirements Apply to
Packaging and Labels? (Final § 111.410)
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1. Final § 111.410(a)
Final § 111.410(a) requires that you
take necessary actions to determine
whether the packaging for dietary
supplements meets specifications so
that the condition of the packaging will
ensure the quality of your dietary
supplements. Final § 111.410(a) is
similar to proposed § 111.70(a) which
would require you to take necessary
actions to ensure that each packaging
container for holding dietary ingredients
or dietary supplements meets
specifications so that the condition of
the packaging container will not
contaminate your dietary supplements
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or cause them to deteriorate. We have
made changes to be consistent with final
§ 111.70 and the definition of ‘‘quality’’
by substituting the phrase ‘‘ensure the
quality of your dietary supplement’’
instead of using the words
‘‘contamination’’ and ‘‘deterioration’’
which would be encompassed in the
definition of ‘‘quality.’’ We are deleting
the words ‘‘container’’ and ‘‘holding’’
from final § 111.410(a) to emphasize
that all packaging must meet
specifications and ensure the quality of
the dietary supplement.
(Comment 300) One comment
requests the removal of the word ‘‘each’’
from proposed § 111.70(a) because the
inclusion of the word mandates that
each and every container, rather than a
representative sample, be inspected.
(Response) Because the final rule only
requires the use of representative
samples to ensure compliance, as
provided in final § 111.80, to reduce the
potential for confusion, we are deleting
the word ‘‘each’’ and making associated
grammatical revisions.
(Comment 301) Some comments
request we clarify our expectations
under proposed § 111.70(a) with respect
to substantiating that packaging
containers meet specifications and will
not contaminate dietary supplements.
The comments assert that it is not
necessary for a manufacturer to test
these types of products proactively, and
that a continuing product guarantee
combined with a statement of intended
use from the manufacturer of the
packaging material should suffice to
meet the proposed requirements. The
comments assert this is consistent with
expected practice in other industries
that FDA regulates.
(Response) Final § 111.410(a)
reiterates the requirement of final
§ 111.70(d) to establish packaging
specifications and the requirement of
final § 111.75(f)(1) to determine whether
packaging specifications are met. Under
final § 111.75(f)(1), to determine
whether packaging meets its
specifications, you must conduct a
visual identification of the containers
and closures and review the supplier’s
invoice, guarantee, or certification.
Thus, the final rule does not require that
you test packaging proactively, and does
allow you to rely on documentation
such as a continuing product guarantee
combined with a statement of intended
use from the manufacturer of the
packaging.
As we discussed in the preamble to
2003 CGMP Proposal (68 FR 12157 at
12212), proposed § 111.70(a) would
require you to take into account factors
such as whether your product is
sensitive to light when setting
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specifications for packaging. Other
factors to consider include whether your
product is sensitive to moisture or could
interact with certain kinds of packaging.
(For other requirements related to
packaging, see final §§ 111.70(d), (f), (g),
and 111.160.)
2. Final § 111.410(b)
Final § 111.410(b) requires you to
control the issuance and use of
packaging and labels and reconciliation
of any issuance and use discrepancies,
except that label reconciliation is not
required for cut or rolled labels if a 100percent examination for correct labels is
performed by appropriate electronic or
electromechanical equipment during or
after completion of finishing operations.
Final § 111.410(b) derives from
proposed § 111.70(f)(1) which would
require you to control the issuance and
use of packaging and labels and
reconciliation of any issuance and use
discrepancies.
(Comment 302) Some comments
assert that comprehensive label
reconciliation should not be required if
appropriate electronic controls are
instituted to ensure that correct labels
are used during labeling operations. The
comments state this alternative is
permitted for labeling operations for
drug products, which are generally
identical or similar in nature to labeling
operations for dietary supplements. As
such, the comments assert that the same
flexibility should be afforded to dietary
supplement manufacturers.
(Response) We agree with these
comments and the revisions are
reflected in final § 111.410(b) (proposed
§ 111.70(f)(1)).
3. Final § 111.410(c)
Final § 111.410(c) requires you to
examine, before packaging and labeling
operations, packaging and labels for
each batch of dietary supplement to
determine whether the packaging and
labels conform to the master
manufacturing record. Final § 111.410(c)
derives from proposed § 111.70(f)(2). We
did not receive comments specific to
proposed § 111.70(f)(2).
4. Final § 111.410(d)
Final § 111.410(d) requires you to be
able to determine the complete
manufacturing history and control of the
packaged and labeled dietary
supplement through distribution. We
are revising the language of proposed
§ 111.70(b)(6) and including in final
§ 111.410 the similar requirement stated
in proposed § 111.70(b)(6). Section
111.410 is where we chose to place this
requirement because it is likely that you
will affix the batch, lot, or control
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number that you used for the finished
batch of dietary supplement on the
immediate container or on the product
label as the means to trace the product
through distribution, although this is
not required. Other means are
acceptable besides the use of a batch,
lot, or control number.
(Comment 303) Some comments
assert that we do not propose in the
2003 CGMP Proposal the affixing of a lot
number to the container of product
marketed to the consumer. These
comments assert that all the
recordkeeping in the 2003 CGMP
Proposal is of little value unless issues
can be traced back from the individual
container, perhaps received from a
customer complaint, to a specific batch.
These comments state that such labeling
should be a requirement.
(Response) We agree that it is
necessary to be able to trace a dietary
supplement in distribution to a specific
batch or lot of product. We disagree that
we did not provide any requirements in
the 2003 CGMP Proposal that would
require you to be able to trace a
distributed dietary supplement to a
specific batch or lot.
In proposed § 111.70(b)(6) we stated
that a batch, lot, or control number is
necessary for you to trace the
manufacturing history for a particular
batch, which will help you investigate
and correct any safety problems for a
batch or to recall a dietary supplement.
We discussed the fact that, without such
a batch, lot, or control number,
consumers would be unable to
determine which product was the
subject of a recall and they would not
know which product to stop using, or
there would be a need to recall more
product than otherwise may be
necessary (68 FR 12157 at 12212).
We also proposed several other
requirements related to the need to be
able to trace the components, packaging,
and labeling used in the manufacture of
a dietary supplement with the
distributed dietary supplement. Under
proposed § 111.40(a) (with respect to
components and dietary supplements)
and proposed § 111.40(b)(3) (with
respect to packaging and labeling) we
would require you to identify each lot
of product received in a shipment in a
manner to allow you to trace the
shipment lot to the dietary supplement
manufactured and distributed. In the
preamble to the 2003 CGMP Proposal
(68 FR 12157 at 12202), we stated that
using a unique identifier throughout the
manufacturing process will make it
possible to track and account for
components and dietary supplements
received to any necessary investigation
of consumer complaints. In proposed
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§ 111.50(c)(1) we provided that the
batch production record must include a
batch, lot, or control number, and in
proposed § 111.50(c)(5) we provided
that the batch production record must
include the shipment lot unique
identifier of each component, dietary
ingredient, dietary supplement,
packaging, and label used. Further, in
proposed § 111.85(d), we required that
you conduct an investigation if a
returned dietary supplement implicates
associated batches. Thus, we proposed
to require that you be able to trace a
dietary supplement through
distribution. However, we did not
require you to use a specific
mechanism, such as affixing a batch, lot,
or control number to the immediate
container or product label. Under the
2003 CGMP Proposal, the manufacturer
would have flexibility to determine the
method to trace its product in
distribution to the batch, lot, or control
number assigned to the finished batch
or lot of dietary supplement.
In final § 111.415(f), we require you to
assign a batch, lot, or control number to:
(1) Each lot of packaged and labeled
dietary supplement from a finished
batch of dietary supplement and (2)
each lot of dietary supplement, from a
finished batch of dietary supplement,
that you distribute to another person for
packaging or labeling. We do not require
you to affix this batch, lot, or control
number to the immediate container or
the product label. Instead, we provide
flexibility for you to determine how you
track the batch, lot, or control number
you assign to each lot of packaged and
labeled dietary supplement from a
finished batch of dietary supplement,
and each lot of dietary supplement from
a finished batch of dietary supplement
you distribute to another person for
packaging or labeling, to distributed
dietary supplements. To clarify that we
do not require you to affix a batch, lot,
or control number on the immediate
container or product label, final
§ 111.410(d) provides that you must be
able to determine the complete
manufacturing history and control of the
packaged and labeled dietary
supplement through distribution by a
method of your choice. For example, a
dietary supplement manufacturer may
make one type of product that it
distributes to a select few customers and
may be able to trace its dietary
supplement using dates on distribution
records to such customers, or may use
different containers or labeling, other
than a batch, lot, or control number that
is affixed to the label.
We are retaining the use of a unique
identifier in final §§ 111.155(d),
111.160(d), and 111.260(a), (d), and (k).
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34901
These requirements relate to the
tracking of a component, packaging,
labeling, or dietary supplement
throughout the manufacturing process.
The use of a batch, lot, or control
number or other unique identifier, as
required, for product in the
manufacturing process is needed for
tracking components, packaging, and
labels used to manufacture, package, or
label a dietary supplement so that once
a batch is identified, the components,
packaging, and labels used in a batch
will also be known. But by contrast,
when the distribution of a final product
may be distributed to a few select
customers, or where every unique batch
is placed in a different type of container,
there may not be a need to use batch,
lot, or control numbers affixed to the
immediate container or product labels
to be able to trace the product.
This final rule will enhance the
benefits of the new statutory
requirement for mandatory reporting to
FDA of serious adverse events as the
result of the enactment of the ‘‘Dietary
Supplement and Non-Prescription Drug
Consumer Protection Act’’ (Public Law
109–462), signed into law on December
22, 2006. This final rule will facilitate
the additional traceback activities taking
place as a result of the additional
serious adverse events discovered
through mandatory reporting. We will
evaluate such mandatory reports for
patterns or ‘‘signals’’ of problems with
particular products so that further harm
to consumers may be prevented by
removing the products and, in some
cases, related products from the
marketplace. This cannot be done
without first quickly and accurately
identifying the products of interest. To
efficiently determine which specific
products or group of products are
associated with the serious (or nonserious) adverse event report, traceback
ability is crucial. This final rule
includes requirements that will provide
the information needed to quickly and
accurately conduct a sufficient
traceback. The provisions that require
maintenance of records for production
processes include records such as batch
records, unique identifiers, and master
manufacturing records. The
recordkeeping provisions of this final
rule give us access to those records, so
we will have an enhanced ability to
investigate the serious adverse events
reported to us, using records such as
information on ingredients, processing,
storage, composition, and distribution.
This enhanced ability to track
information related to serious adverse
events will increase both the accuracy
and the speed of the response to such
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events, which may in many cases
reduce the number of illnesses or deaths
associated with unsafe dietary
supplements.
G. What Requirements Apply to Filling,
Assembling, Packaging, Labeling, and
Related Operations? (Final § 111.415)
Final § 111.415 requires that you fill,
assemble, package, label, and perform
other related operations in a way that
ensures the quality of the dietary
supplement and that the dietary
supplement is packaged and labeled as
specified in the master manufacturing
record. Final § 111.415 also requires that
you do these functions using any
effective means you choose, including:
(1) Cleaning and sanitizing all filling
and packaging equipment, utensils, and
dietary supplement packaging, as
appropriate; (2) protecting
manufactured dietary supplements from
contamination, particularly airborne
contamination; (3) using sanitary
handling procedures; (4) establishing
physical or spatial separation of
packaging and label operations from
operations on other components and
dietary supplements to prevent mixups;
(5) identifying, by any effective means,
filled dietary supplement containers
that are set aside and held in unlabeled
condition for future label operations, to
prevent mixups; (6) assigning a batch,
lot, or control number to each lot of
packaged and labeled dietary
supplement from a finished batch of
dietary supplement and each lot of
dietary supplement from a finished
batch of dietary supplement that you
distribute to another person for
packaging or labeling; (7) examining a
representative sample of each batch of
the packaged and labeled dietary
supplement to determine whether the
dietary supplement meets specifications
established in accordance with final
§ 111.70(g); and (8) suitably disposing of
labels and packaging for dietary
supplements that are obsolete or
incorrect to ensure that they are not
used in any future packaging and
labeling operations.
Final § 111.415 derives from proposed
§ 111.70(b). We revised the section to be
consistent with other revisions.
(Comment 304) Some comments
request clarification as to what
specifications we are referring to in
proposed § 111.70(b)(7). The comments
state that if we are referring to
specifications required by proposed
§ 111.35(e), then we should indicate so
in any final rule. The comment asserts
that, if we intend this provision to mean
that persons who simply package, label,
and store dietary supplements must
conduct full product testing, then
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proposed § 111.70(b)(7) is unwarranted
and unreasonable.
The comments assert that full product
testing should not be required for
companies that merely package, label,
and store finished products. The
comments assert that in-route
contamination from the facility of a
supplier or manufacturer to the facility
of a packager, labeler, or distributor
facility is unlikely to occur if the proper
environmental conditions are
maintained as required by other
provisions of the 2003 CGMP Proposal.
The comments assert that the
responsibility for raw material and
finished product testing should lie
solely with the companies that handle
the raw materials and dietary
ingredients and that perform
manufacturing duties. According to the
comments, assuming the supplier/
manufacturer complies with the final
rule and adequately performs the
required testing, reasonable cost/benefit
analysis would dictate that redundant
testing not be performed. Therefore, the
comments assert that those who perform
packaging and labeling operations
should only be required to test those
areas of contamination that are likely to
occur during the shipment, or in the
receipt, identification, packaging, and
holding areas of production operations
(e.g., surface contamination).
The comments state it is our duty to
ensure that the industry is complying
with any final rule, not the duty of
certain segments of the industry to
ensure that other segments of the
industry are complying. Since in-route
contamination is unlikely and rare,
consumers would enjoy little or no
benefit from redundant testing at a
tremendous cost to the industry,
particularly small businesses.
(Response) The term ‘‘specifications’’
in proposed § 111.70(b)(7) included any
specifications that you established for
packaged and labeled dietary
supplements under proposed
§ 111.35(e). In final § 111.415(g), we
identify the specifications as those you
establish in accordance with final
§ 111.70(g). In final § 111.70(g), we
require you to establish specifications
for the packaging and labeling for the
finished packaged and labeled dietary
supplements. We distinguish these
specifications (final § 111.70(g)) from
product specifications you must
establish for a finished batch that you
manufacture (final § 111.70(e)). The
specifications that you establish and
follow ensure that your product is what
you establish in your master
manufacturing record. As discussed in
sections VI and section XII of this
document, a master manufacturing
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record for a firm that only packages and
labels the dietary supplement would
include specifications that are
applicable to its operations and would
not include specifications related to, for
example, components.
H. What Requirements Apply to
Repackaging and Relabeling? (Final
§ 111.420)
1. Final § 111.420(a)
Final § 111.420(a) provides that you
may repackage or relabel dietary
supplements only after your quality
control personnel have approved such
repackaging or relabeling. Final
§ 111.420(a) is similar to proposed
§ 111.70(d) with a restructuring of the
provision for clarity. We did not receive
comments specific to proposed
§ 111.70(d).
2. Final § 111.420(b) and (c)
Final § 111.420(b) requires you to
examine a representative sample of each
batch of repackaged or relabeled dietary
supplements to determine whether the
repackaged or relabeled dietary
supplements meet all specifications
established in accordance with
§ 111.70(g). Final § 111.420(c) requires
that quality control personnel approve
or reject each batch of repackaged or
relabeled dietary supplement prior to its
release for distribution. Final
§ 111.420(b) and (c) derive from
proposed § 111.70(e) which would
require you to retest or re-examine any
repackaged or relabeled dietary
supplements. Proposed § 111.70(e) also
would require that any repackaged or
relabeled dietary supplements meet all
specifications and that the quality
control unit approve or reject their
release for distribution.
(Comment 305) Some comments
assert that the proposed requirement
that directs companies to retest or reexamine any repackaged or relabeled
dietary supplement unnecessarily
restricts the ability of the quality control
unit to make an appropriate disposition
decision. These comments assert that
testing would not be necessary, for
example, when a packager repackages a
multiple vitamin softgel from a 500count bottle to a 60-count bottle. The
comments also assert that it would be
costly to retest such product, and that
such testing would not benefit
consumer health and safety. The
comments would revise proposed
§ 111.70(e) to give the quality control
unit the authority to make an
appropriate disposition decision, e.g., to
assess the repackaged dietary
supplement for conformity to
specifications.
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(Response) We agree that there are
circumstances, such as those described
by these comments, when testing would
not be necessary. However, we disagree
that it would not be necessary to
‘‘examine’’ a representative sample of
the repackaged and relabeled dietary
supplement to determine whether the
required specifications are met, i.e., that
you used the specified packaging and
applied the specified label. If no
examination of a representative sample
took place, there would be no basis for
the determination. We believe that final
§ 111.420(b) makes this clear.
I. What Requirements Apply to a
Packaged and Labeled Dietary
Supplement That Is Rejected for
Distribution? (Final § 111.425)
Final § 111.425 requires you to clearly
identify, hold, and control under a
quarantine system for appropriate
disposition any packaged and labeled
dietary supplement that is rejected for
distribution. Final § 111.425 derives
from proposed § 111.74 which would
require you to clearly identify, hold, and
control under a quarantine system any
component, dietary ingredient, dietary
supplement, packaging, and label that is
rejected and unsuitable for use in
manufacturing, packaging, or label
operations. Under the final rule, the
requirements of proposed § 111.74 for
components, packaging, and labels are
being set forth in final § 111.170, and
the requirements for a finished batch of
dietary supplement are set forth in final
§ 111.370. Although the proposal did
not include any packaged and labeled
dietary supplement rejected for
distribution, we are making this change
to be consistent with the principle that
rejected components, dietary
supplements, packaging, or labels
unsuitable for the distribution supply
include finished product already
packaged and labeled.
J. Under This Subpart, What Records
Must You Make and Keep? (Final
§ 111.430)
1. Final § 111.430(a)
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Final § 111.430(a) requires you to
make and keep records required under
this subpart in accordance with subpart
P. Final § 111.430(a) derives from
proposed § 111.70(h) with revisions
associated with the reorganization. We
did not receive comments specific to
proposed § 111.70(h).
2. Final § 111.430(b)
As discussed in this section, final
§ 111.403 requires you to establish and
follow written procedures for packaging
and labeling operations. The written
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procedures are records. Therefore, final
§ 111.430(b) requires you to make and
keep records of the written procedures
for packaging and labeling operations.
XVIII. Comments on Holding and
Distributing (Final Subpart M)
A. Organization of Final Subpart M
In the 2003 CGMP Proposal, the
requirements for holding operations
were set forth in §§ 111.80, 111.82, and
111.83 in subpart F; the requirements
for distribution operations were set forth
in proposed § 111.90 in subpart F. As
shown in table 14 of this document, the
final rule moves the requirements
related to holding and distributing
operations to a new subpart (final
Subpart M—Holding and Distributing).
Table 14 lists the sections in the final
rule and identifies the sections that form
the basis of the final rule.
TABLE 14.—DERIVATION OF SECTIONS
IN FINAL SUBPART M
2003 CGMP
Proposal
Final Rule
§ 111.453 What are the
requirements under
this subpart M for written procedures?
N/A
§ 111.455 What requirements apply to holding
components, dietary
supplements, packaging, and labels?
§ 111.80
§ 111.460 What requirements apply to holding
in-process material?
§ 111.82
§ 111.465 What requirements apply to holding
reserve samples of dietary supplements?
§ 111.83(b)(1)
and (b)(2)
§ 111.470 What requirements apply to distributing dietary supplements?
§ 111.90
§ 111.475 Under this
subpart M, what
records must you
make and keep?
N/A
1. Revisions
The final rule includes changes that
reflect that the scope of the final rule
applies to persons who manufacture,
package, label, or hold dietary
supplements, unless subject to an
exclusion in § 111.1.
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2. Changes Associated With the
Reorganization
Final § 111.465 in subpart M
duplicates the requirement of final
§ 111.83(b)(3) to retain reserve samples
of dietary supplements for 1 year past
the shelf life date (if shelf life dating is
used) or for 2 years from the date of
distribution of the last batch of dietary
supplements associated with the reserve
samples. We are duplicating this
requirement in this subpart because we
believe that it will be useful to include
the length of time that you must hold
reserve samples in each place of the
codified where it is logical to look for
this information.
3. Changes After Considering Comments
The final rule:
• Does not require that you collect
reserve samples of components;
• Provides flexibility as to the
container-closure system used to hold
reserve samples of dietary supplements;
• Includes a new requirement for
written procedures; and
• Includes a new requirement to
make and keep records of product
distribution and written procedures.
C. General Comments on Proposed
§§ 111.80, 111.82, 111.83, and 111.85
B. Highlights of Changes to the
Proposed Requirements for Holding and
Distributing
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(Comment 306) One comment
requests that factory sealed finished
products, which have been specifically
manufactured to be held and
transported in a variety of conditions, be
excluded from the requirements for
holding. Another comment states that
there are many types of companies or
individuals in the supply chain who
may ‘‘hold’’ a dietary supplement after
final production, packaging, and
labeling is complete. This comment
seeks clarification that brokers,
distributors, or wholesalers would be
subject only to the proposed
requirements for holding in proposed
§ 111.90.
(Response) If you hold a dietary
supplement, you are subject to all
applicable requirements of these CGMP
regulations related to your operation.
For example, if you are a wholesaler,
you would be subject to the
requirements in final § 111.470 for the
dietary supplements you are holding for
distribution as well as other applicable
requirements, such as those related to
personnel, physical plant and grounds,
equipment and utensils, quality control,
returned dietary supplements, and
product complaints. We decline to list
all of the requirements that would be
applicable because individual
operations may vary. However, we
provide the following examples of
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requirements that would, or would not,
apply in some specific circumstances.
For example, if the dietary supplements
that you hold require refrigeration, your
refrigeration equipment must comply
with the requirements to be fitted with
an indicating thermometer, temperaturemeasuring device, or temperaturerecording device that shows the
temperature accurately within the
compartment, and have an automated
device for regulating temperature or an
automatic alarm system to indicate a
significant temperature change in a
manual operation. However, you would
not be required to establish
specifications for the finished batch of
the dietary supplement, for product that
is received for packaging or labeling, or
for packaged and labeled dietary
supplements or to determine whether
such specifications are met if you only
hold the product and do not perform
any other functions.
D. What Are the Requirements Under
This Subpart for Written Procedures?
(Final § 111.453)
We received many comments that
recommended written procedures for
various provisions. We address the need
for written procedures generally in
section IV of this document. We also
respond to individual comments on
specific provisions in the same section.
We are including a new provision,
§ 111.453 ‘‘What are the requirements
under this subpart M for written
procedures?’’ which requires you to
establish and follow written procedures
for holding and distribution operations.
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E. What Requirements Apply to Holding
Components, Dietary Supplements,
Packaging, and Labels? (Final § 111.455)
1. Final § 111.455(a)
Final § 111.455(a) requires you to
hold components and dietary
supplements under appropriate
conditions of temperature, humidity,
and light so that the identity, purity,
strength, and composition of the
components and dietary supplements
are not affected. Final § 111.455(a)
derives from proposed § 111.80(a)
which would require that you hold
components, dietary ingredients, and
dietary supplements under appropriate
conditions of temperature, humidity,
and light so that the identity, purity,
quality, strength, and composition of the
components, dietary ingredients, and
dietary supplements are not affected.
We did not receive comments specific
to proposed § 111.80(a).
2. Final § 111.455(b)
Final § 111.455(b) requires you to
hold packaging and labels under
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appropriate conditions so that the
packaging and labels are not adversely
affected. Final § 111.455(b) derives from
proposed § 111.80(b) with modifications
for consistency with other provisions
addressing packaging and labels.
We did not receive comments specific
to proposed § 111.80(b).
3. Final § 111.455(c)
Final § 111.455(c) requires you to
hold components, dietary supplements,
packaging, and labels under conditions
that do not lead to the mixup,
contamination, or deterioration of
components, dietary supplements,
packaging, and labels. Final § 111.455(c)
derives from proposed § 111.80(c).
We did not receive comments specific
to proposed § 111.80(c).
F. What Requirements Apply to Holding
In-Process Material? (Final § 111.460)
1. Final § 111.460(a)
Final § 111.460(a) requires you to
identify and hold in-process material
under conditions that protect against
mixups, contamination, and
deterioration. Final § 111.460(a) is
similar to proposed § 111.82(a) with a
grammatical change (i.e., a change from
‘‘that will protect them’’ to ‘‘that
protect’’).
We did not receive comments specific
to proposed § 111.82(a).
2. Final § 111.460(b)
Final § 111.460(b) requires you to
hold in-process material under
appropriate conditions of temperature,
humidity, and light. Final § 111.460(b)
is identical to proposed § 111.82(b).
(Comment 307) One comment asserts
it would be impractical, unnecessary,
and extremely burdensome to maintain
reserve samples of in-process materials.
The comment asserts that collecting and
holding samples of in-process materials
would duplicate the requirement to
collect and hold reserve samples of
finished dietary supplements and
require significant additional
documentation, time, and storage space.
(Response) This comment may have
misinterpreted proposed § 111.37(b)(11)
(final §111.80(g)) which included
requirements for collecting
representative, rather than reserve,
samples of in-process materials. The
representative sample is used for those
tests or examinations conducted to
determine whether the batch meets
specifications. A representative sample
is held for only a short period of time,
i.e., the time between the collection and
the test or examination. Neither the
2003 CGMP Proposal nor this final rule
includes a requirement to maintain a
reserve sample of in-process materials.
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G. Proposed Requirement for Holding
Reserve Samples of Components
(Proposed § 111.83(a))
Proposed § 111.83(a) would require
you to hold any collected reserve
samples of components or dietary
ingredients in a manner that protects
against contamination and deterioration.
(Comment 308) One comment
requests the final rule not require that
manufacturers of dietary supplements
collect and hold reserve samples of
components. The comment asserts that
all components can be traced back to
their source (i.e., the vendor or
manufacturer of the material) for a more
in-depth investigation if a dietary
supplement comes under investigation
due to a product complaint.
(Response) We agree with this
comment. Therefore, the final rule
contains no requirement for holding
reserve samples of components, only
finished dietary supplements, and, thus,
proposed § 111.83(a) has no counterpart
in the final rule.
H. What Requirements Apply to Holding
Reserve Samples of Dietary
Supplements? (Final § 111.465)
1. Final § 111.465(a)
Final § 111.465(a) requires you to
hold reserve samples of dietary
supplements in a manner that protects
against contamination and deterioration.
Under final § 111.465(a)(1) this includes
holding the reserve sample under
conditions consistent with product
labels or, if no storage conditions are
recommended on the label, under
ordinary storage conditions. Final
§ 111.465(a)(1) derives from proposed
§ 111.83(b)(1) which would require you
to hold reserve samples under
conditions of use recommended or
suggested in the label of the dietary
supplement and, if no conditions of use
are recommended or suggested in the
label, then under ordinary conditions of
use.
Final § 111.465(a)(1) refers to
‘‘conditions consistent with product
labels’’ rather than to ‘‘conditions of use
recommended or suggested in the label
of the dietary supplement’’ and refers to
‘‘storage conditions’’ rather than
‘‘conditions of use.’’ This change is to
reflect that the ‘‘conditions of use’’
referenced in the 2003 CGMP Proposal
referred to the typical storage of the
dietary supplement and not the
consumption of the product by the
consumer.
We did not receive comments specific
to proposed § 111.83(b)(1).
Under final § 111.465(a)(2) the
manner in which you hold reserve
samples of dietary supplements
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includes using the same containerclosure system in which the packaged
and labeled dietary supplement is
distributed, or if distributing dietary
supplements to be packaged and
labeled, using a container-closure
system that provides essentially the
same characteristics to protect against
contamination or deterioration as the
one in which you distribute the dietary
supplement for packaging and labeling
elsewhere. Final § 111.465(a)(2) derives
from proposed § 111.83(b)(2) which
would require that the manner in which
you hold reserve samples of dietary
supplements include using the same
container-closure system in which the
dietary supplement is marketed or in
one that provides the same level of
protection against contamination or
deterioration.
(Comment 309) One comment states a
substantial amount of its product is
shipped in bulk for packaging
elsewhere. As a result, one often does
not know the packaging being used to
market the dietary supplement or how
the packaged product is being stored.
This comment recommends we revise
the proposed regulation to require using
the same container-closure system in
which the dietary supplement is
marketed ‘‘if known and if not in a
typical market container-closure
system.’’
(Response) We acknowledge that
some manufacturers of dietary
supplements will distribute product in
bulk and will not know the packaging
used to market the dietary supplement.
In addition, if you ship products in
bulk, any commitment you make to your
customer about the quality of the
product you shipped would relate to the
container you used to ship the bulk
product. To address these points we
provide in final § 111.465(a)(2) that you
have the flexibility to use a containerclosure system that provides essentially
the same characteristics to protect
against contamination or deterioration
as the one in which it is distributed for
packaging and labeling elsewhere. For
example, if you distribute product in
bulk using a polyethylene bottle that
can hold 50 kilograms of the product,
and there is an air space above the
product, you would hold the reserve
samples in a polyethylene bottle with an
air space. However, you would use a
bottle that is sized to fit the amount that
you are holding in reserve.
2. Final § 111.465(b)
Final § 111.465(b) requires you to
retain reserve samples for 1 year past
the shelf life date (if shelf life dating is
used), or for 2 years from the date of
distribution of the last batch of dietary
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supplements associated with the reserve
samples, for use in appropriate
investigations. Final § 111.465(b)
derives from proposed § 111.37(b)(12),
which proposed, in part, that you must
keep reserve samples for 3 years from
the date of manufacture. Proposed
§ 111.37(b)(12) is now final
§ 111.83(b)(3) with a change to 2 years
for the retention period and with
changes that we are making consistent
with comments that requested that the
time frame for retaining reserve samples
be linked to a shelf life date (or other
form of expiration dating) when such a
date is established. We discuss the
reasons for the change from 3 years to
2 years and the change from ‘‘date of
manufacture’’ to ‘‘the date of
distribution’’ in section XXI of this
document. In essence, final § 111.465(b)
duplicates final § 111.83(b)(3) because
we believe it will be useful to include
the length of time you must hold reserve
samples in each place in the codified
where it is logical to look for this
information.
I. What Requirements Apply to
Distributing Dietary Supplements?
(Final § 111.470)
Final § 111.470 requires you to
distribute dietary supplements under
conditions that will protect the dietary
supplements against contamination and
deterioration. Final § 111.470 derives
from proposed § 111.90.
We did not receive comments specific
to proposed § 111.90.
J. Under This Subpart, What Records
Must You Make and Keep? (Final
§ 111.475)
In the 2003 CGMP Proposal, we
invited comment on whether we should
require you to make and keep records
on the distribution of dietary
supplements that you manufacture,
package, or hold.
(Comment 310) Some comments
assert that written records of product
distribution would provide the ability to
trace the shipment of each finished
batch in the event of a product recall.
One comment expresses the view that
the ability to quickly and efficiently
recall a product is an important
safeguard in ensuring public health in
the event of a serious problem. Another
comment points out that the scope of
recall would likely be much broader if
records of product distribution were not
available to pinpoint distribution.
(Response) We agree with these
comments. Therefore, final § 111.475
requires you to make and keep records
of product distribution in accordance
with subpart P. In addition, we are
adding a provision to complement final
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34905
§ 111.453 to ensure that records are
maintained of the written procedures
you establish for holding and
distributing operations. As discussed,
comments stressed that such procedures
must be available to us during the
course of an inspection.
(Comment 311) One comment asserts
that the final rule should not include a
requirement for records of product
distribution, because such records are
already common industry practice. This
comment also points out that neither the
food CGMPs in part 110 nor the
agency’s 1997 ANPRM have
requirements for records of product
distribution.
(Response) To the extent that the
comment asserts that a practice that is
a common industry practice should not
be a requirement in the final rule, we
disagree. CGMP includes those practices
that may be commonly used in industry.
In fact, the reason that such practices
may be common in industry is because
they are already considered to be CGMP.
As we noted in the preamble to the 2003
CGMP Proposal (68 FR 12157 at 12221),
however, not all dietary supplement
establishments follow CGMP and,
therefore, may not be keeping records of
product distribution. Thus, in this final
rule we do not exclude practices we
consider to be CGMP and already may
be used by some in industry.
The industry outline we published in
the 1997 ANPR suggested (under
Warehousing, Distribution, and PostDistribution Procedures) that the CGMP
rule require adequate distribution
records to be maintained and retained
for at least 1 year beyond the expected
product shelf life, whereby an effective
product recall can be achieved should
one become necessary. Therefore, we
disagree that the 1997 ANPRM did not
suggest a requirement to make and
retain records of product distribution.
XIX. Comments on Returned Dietary
Supplements (Final Subpart N)
A. Organization of Final Subpart N
In the 2003 CGMP Proposal, the
requirements for returned dietary
supplements were set forth in proposed
§ 111.85. As shown in table 15 of this
document, we are reorganizing
proposed § 111.85 into a distinct
subpart (final Subpart N—Returned
Dietary Supplements). Table 15 lists the
sections in final subpart N and
identifies the proposed sections that
form the basis of the final rule.
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TABLE 15.—DERIVATION OF SECTIONS
IN FINAL SUBPART N
2003 CGMP
Proposal
Final Rule
§ 111.503 What are the
requirements under
this subpart N for written procedures?
N/A
§ 111.510 What requirements apply when a
returned dietary supplement is received?
§ 111.85(a)
§ 111.515 When must a
returned dietary supplement be destroyed,
or otherwise suitably
disposed of?
§ 111.85(b) and
(c)
§ 111.520 When may a
returned dietary supplement be salvaged?
§ 111.37(b)(15)
§ 111.525 What requirements apply to a returned dietary supplement that quality control personnel approve
for reprocessing?
§ 111.50(g)
§ 111.530 When must an
investigation be conducted of your manufacturing processes
and other batches?
§ 111.85(d)
§ 111.535 Under this
subpart N, what
records must you
make and keep?
§ 111.50(g)
§ 111.85(e) and
(f)
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B. Highlights of Changes to the
Proposed Requirements for Returned
Dietary Supplements
1. Revisions
The final rule includes:
• Revisions that reflect that the final
rule applies to persons who
manufacture, package, label, or hold
dietary supplements unless subject to an
exclusion in § 111.1.
• A provision (final § 111.520) that
we are adding for consistency, so that
the final rule for returned dietary
supplements clearly sets forth the
requirements for a positive outcome
(i.e., when you may salvage a returned
dietary supplement) as well as a
negative outcome (i.e., when you must
destroy or otherwise suitably dispose of
a returned dietary supplement); and
• A provision (final § 111.525) we are
adding for consistency, so that the final
rule for returned dietary supplements
clearly sets forth the requirements for
reprocessed materials.
2. Changes After Considering Comments
The final rule:
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• Includes a new requirement to
establish and follow written procedures
to fulfill the requirements for returned
dietary supplements;
• Includes a revised description of
the conditions that preclude you from
salvaging a returned dietary
supplement; and
• Provides flexibility for firms to
salvage a returned dietary supplement
without conducting tests to demonstrate
that the dietary supplement meets all
specifications, provided that quality
control personnel conduct a material
review and make a disposition decision
to approve the salvage.
C. General Comments on Proposed
§ 111.85
(Comment 312) Several comments
request we clarify the roles of the
various parties in the ‘‘pre-consumer
supply chain’’ for dietary supplements.
(Response) We have discussed, in
section VI of this document, who is
subject to the final rule in what the
comment describes as the ‘‘preconsumer supply chain’’ and do not
repeat that discussion here. The
requirements for returned dietary
supplements do not distinguish between
those returned to a person who
manufactures a finished batch and those
returned to a person whose role in the
manufacturing process is limited to
operations such as packaging, labeling,
or holding.
Any reprocessing operations, other
than repackaging or relabeling, by a
packager or labeler who receives a
product for packaging or labeling as a
dietary supplement would make that
packager or labeler subject to all
relevant regulatory requirements under
this final rule, as explained in section VI
of this document. A packager or labeler
that only conducts repackaging or
relabeling operations may conclude that
a product was returned for reasons
related to a problem with the
manufacture of the product it received
for packaging or labeling, and therefore
cannot be salvaged. In such a case,
under final § 111.515 the packager or
labeler would have to destroy or
otherwise suitably dispose of the dietary
supplement. Under final § 111.515, the
packager or labeler may contact the
manufacturer to determine if the
packager or labeler could suitably
dispose of the dietary supplement by
sending it back to the manufacturer for
possible reprocessing (see discussion of
final § 111.515 in this section). A
manufacturer who receives a dietary
supplement returned by a packager or
labeler would be required to comply
with the requirements of final subpart N
for returned dietary supplements,
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including requirements for any
reprocessing of the returned dietary
supplements.
D. What Are the Requirements Under
This Subpart for Written Procedures?
(Final § 111.503)
We received many comments that
recommended written procedures for
various provisions. We address the need
for written procedures generally in
section IV of this document. We also
respond to individual comments on
specific provisions in the same section.
Final § 111.503 requires you to
establish and follow written procedures
to fulfill the requirements of subpart N.
Under final § 111.535(b)(1) we are
requiring you to make and keep records
of such written procedures. Such
records would be available to us under
the requirements in subpart P.
E. What Requirements Apply When a
Returned Dietary Supplement is
Received? (Final § 111.510)
Final § 111.510 requires you to
identify and quarantine returned dietary
supplements until quality control
personnel conduct a material review
and make a disposition decision. Final
§ 111.510 is similar to proposed
§ 111.85(a).
We did not receive comments specific
to proposed § 111.85(a).
F. When Must a Returned Dietary
Supplement Be Destroyed, or Otherwise
Suitably Disposed Of? (Final § 111.515)
Final § 111.515(a) requires that you
destroy, or otherwise suitably dispose
of, any returned dietary supplement,
unless the outcome of a material review
and disposition decision is that quality
control personnel either: (1) Approve
the salvage of the returned dietary
supplement for redistribution or (2)
approve the returned dietary
supplement for reprocessing. Final
§ 111.515(a) derives from the following
proposed sections:
• Proposed § 111.85(b) which would
require that you not salvage returned
dietary supplements unless: (1)
Evidence from their packaging (or, if
possible, an inspection of the premises
where the dietary ingredients and
dietary supplements were held)
indicates that the dietary ingredients
and dietary supplements were not
subjected to improper storage
conditions and (2) tests demonstrate
that the dietary ingredients or dietary
supplements meet all specifications for
identity, purity, quality, strength, and
composition; and
• Proposed § 111.85(c) which would
require that you destroy or suitably
dispose of the returned dietary
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ingredients or dietary supplements if
such dietary ingredients and dietary
supplements do not meet specifications,
unless the quality control unit conducts
a material review and makes a
disposition decision to allow
reprocessing.
Final § 111.515(a) includes editorial
changes and other changes made after
considering comments.
(Comment 313) Several comments
assert it is unnecessary to conduct
testing for all specifications for every
returned product because products may
be returned for reasons unrelated to
product quality. For example, products
may be returned due to overstocking,
ordering the wrong quantity, going out
of business, or failing to pay for the
product on time. In addition, several
comments assert that many returned
products are intact, show no signs of
mishandling, and are within the time
limits for shelf life. These comments
assert that a material review and
disposition decision by the quality
control unit to restock the material
without retesting may be acceptable in
these types of situations. Some
comments assert that proposed
§ 111.85(b) is more restrictive than
CGMP requirements for drug products,
and suggest that testing need be
conducted only when some doubt has
been cast upon the identity, purity,
quality, strength, or composition of the
product, or if the product was returned
for some other GMP-related problem.
Some comments contend that
proposed §§ 111.35(i)(3)(v) and 111.85
would make it difficult to salvage any
returned product because companies
receiving returns often cannot verify the
conditions under which such products
were held. One comment refers to a
stakeholder meeting when we indicated
that the extent of testing requirements
would depend upon the reason such
products were returned. The comments
state that the rule should allow
flexibility as to when returned products
must be tested.
Some comments specifically suggest
the approach used in the USP (revised
in 2nd supplement USP 26). These
comments suggest that proposed
§ 111.85(b) be revised as follows: ‘‘If the
conditions under which returned
products have been held, stored, or
shipped before or during their return, or
if the condition of the product, its
container, carton or labeling, as a result
of storage or shipping, cast doubt on the
safety, identity, strength, quality, or
purity of the product, the returned
product should be destroyed unless
examination, testing or other
investigations prove the product meets
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appropriate standards of safety, identity,
strength, quality, or purity.’’
These comments assert that
inspection of the condition of the
returned product could be used to
determine that a product can be
returned to inventory, and this
inspection could be covered by internal
procedures and based on experience in
testing product stored under conditions
that include extremes in heat and
humidity without affecting the
container or closure system.
(Response) As already discussed in
this section, the final rule includes a
new requirement that you establish and
follow written procedures for handling
returned dietary supplements. The final
rule also retains the requirement that
quality control personnel (formerly
‘‘unit’’ in the proposed rule) conduct a
material review and make a disposition
decision regarding all returned dietary
supplements (see discussion of final
§ 111.113(a)(5) in section XI of this
document). We agree with the
comments that it is not necessary to
conduct testing for all specifications for
every returned product, because
products may be returned for reasons
unrelated to the quality of the dietary
supplement. Final § 111.130 provides
for quality control personnel to
determine whether tests or
examinations are necessary for returned
dietary supplements to determine
compliance with product specifications.
Therefore, final § 111.515 does not
include a testing requirement. We
believe the combination of written
procedures and oversight by quality
control personnel is adequate to
determine the appropriate disposition of
a returned dietary supplement, without
requiring a test in every case to
demonstrate that the dietary supplement
meets specifications for identity, purity,
strength, and composition.
In final § 111.515(a) we generally
accept the comments’ suggestions and
reflect the approach of the USP for
returned products. Thus, you must
destroy or otherwise suitably dispose of
the returned dietary supplement, unless
the outcome of the material review and
disposition decision is that quality
control personnel approve the salvage of
the returned dietary supplement for
redistribution or approve the
reprocessing of the returned dietary
supplement. We provide flexibility on
how quality control personnel may
conduct a material review and make a
disposition decision and do not require
testing in every case. We respond in
section V of this document to the
comment asserting that the proposed
CGMPs exceed the drug CGMPs.
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34907
G. When May a Returned Dietary
Supplement Be Salvaged? (Final
§ 111.520)
Final § 111.520 permits the salvage of
a returned dietary supplement only if
quality control personnel conduct a
material review and make a disposition
decision to allow the salvage. Final
§ 111.520 is a conforming provision we
are adding for consistency, so that the
final requirement for returned dietary
supplements clearly sets forth a positive
outcome (i.e., when you may salvage a
returned dietary supplement) as well as
a negative outcome (i.e., when you must
destroy or otherwise suitably dispose of
a returned dietary supplement). Final
§ 111.520 is consistent with final
§ 111.130 (proposed § 111.37(b)(15))
which requires quality control
personnel to approve the distribution of
returned dietary supplements.
H. What Requirements Apply to a
Returned Dietary Supplement That
Quality Control Personnel Approve for
Reprocessing? (Final § 111.525)
Final § 111.525(a) requires you to
ensure that any returned dietary
supplements that are reprocessed meet
all product specifications established in
accordance with final § 111.70(e). Final
§ 111.525(b) requires quality control
personnel to approve or reject the
release for distribution of any returned
dietary supplement that is reprocessed.
As with final § 111.520, final § 111.525
is a provision we are adding for
consistency. Final § 111.525 is
consistent with final § 111.90(c).
I. When Must an Investigation Be
Conducted of Your Manufacturing
Processes and Other Batches? (Final
§ 111.530)
Final § 111.530 requires that, if the
reason for a dietary supplement being
returned implicates other batches, you
must conduct an investigation of your
manufacturing processes and each of
those other batches to determine
compliance with specifications. Final
§ 111.530 derives from proposed
§ 111.85(d) which would require that if
the reason for a dietary supplement
being returned implicates associated
batches, you must conduct an
investigation of your manufacturing
processes and those other batches to
determine compliance with
specifications. Final § 111.530 includes
a nonsubstantive editorial change of
‘‘associated’’ to ‘‘each of those other
batches’’ for clarity.
We did not receive comments specific
to proposed § 111.85(d).
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determine whether specifications are
met.
J. Under This Subpart, What Records
Must You Make and Keep? (Final
§ 111.535)
5. Final § 111.535(b)(4)
Final § 111.535 sets forth the
requirements to make and keep records
for returned dietary supplements. Final
§ 111.180 derives from proposed
§ 111.85(e) and (f).
We did not receive comments specific
to proposed § 111.85(e) or (f).
1. Final § 111.535(a)
Final § 111.535(a) requires you to
make and keep records required under
subpart N in accordance with subpart P.
Final § 111.535(a) derives from
proposed §111.85(f) and includes
changes associated with the
reorganization.
2. Final § 111.535(b)(1)
As discussed in this section, the final
rule includes a new requirement (final
§ 111.503) that you establish and follow
written procedures to fulfill the
requirements of subpart N. Those
written procedures are records.
Therefore, final § 111.535(b)(1) requires
you to make and keep a record of the
written procedures for fulfilling the
requirements of subpart N.
3. Final § 111.535(b)(2)
Final § 111.535(b)(2) requires you to
make and keep a record of any material
review and disposition decision on a
returned dietary supplement. Final
§ 111.535(b) derives from proposed
§ 111.85(e), with revisions associated
with the reorganization.
Final § 111.535(b)(4) requires you to
make and keep a record of
documentation of the re-evaluation by
quality control personnel of any dietary
supplement that is reprocessed and the
determination by quality control
personnel of whether the reprocessed
dietary supplement meets product
specifications established in accordance
with § 111.70(e). Final § 111.535(b)(4) is
related to final § 111.525. Under final
§ 111.525, you must ensure that any
returned dietary supplements that are
reprocessed meet all product
specifications you established under
§ 111.70(e) and quality control
personnel must approve or reject the
release for distribution of any returned
dietary supplement that is reprocessed.
XX. Comments on Product Complaints
(Final Subpart O)
A. Organization of Final Subpart O
In the 2003 CGMP Proposal, the
requirements for consumer complaints
were set forth in § 111.95. As shown in
table 16 of this document, we are
reorganizing proposed § 111.95 into
three provisions in a new subpart (final
Subpart O—Product Complaints). Table
16 lists the sections in final subpart O
and identifies the provisions that form
the basis for the final rule.
TABLE 16.—DERIVATION OF SECTIONS
IN FINAL SUBPART O
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4. Final § 111.535(b)(3)
Final § 111.535(b)(3) requires you to
make and keep a record of the results of
any testing or examination conducted to
determine compliance with product
specifications established under
§ 111.70(e). Final § 111.535(b) derives
from proposed § 111.85(e) which would
require you to establish and keep
records on any testing conducted to
determine compliance with established
specifications in the master
manufacturing record for the type of
dietary supplement that was returned.
Final § 111.535(b)(3) includes the
following revisions:
• Consistent with final § 111.70(e),
final § 111.535(b)(3) substitutes
‘‘product specifications established
under § 111.70(e)’’ for ‘‘established
specifications in the master
manufacturing record for the type of
dietary ingredient or dietary supplement
that was returned.’’
• Consistent with final § 111.75(c),
final § 111.535(b)(3) provides flexibility
to use either tests or examinations to
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2003 CGMP
Proposal
Final Rule
§ 111.553 What are the
requirements under
this subpart O for written procedures?
N/A
§ 111.560 What requirements apply to the review and investigation
of a product complaint?
§ 111.95(a), (b),
(c), and (d)
§ 111.570 Under this
subpart O, what
records must you
make and keep?
§ 111.95(e) and
(f)
B. Highlights of Changes to the
Proposed Requirements for Product
Complaints
1. Revisions
The final rule:
• Includes changes that reflect the
final rule applies to persons who
manufacture, package, label, or hold
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dietary supplements unless subject to an
exclusion in § 111.1.
• Uses the term ‘‘product complaint’’
rather than ‘‘consumer complaint,’’ and
the definition of ‘‘product complaint’’
does not include an explanation about
the types of complaints that may or may
not be covered by the CGMP
regulations. The definition does,
however, include examples of product
complaints.
2. Changes After Considering Comments
The final rule modifies the process for
handling product complaints as follows:
• A qualified person investigates any
product complaint that involves a
possible failure of a dietary supplement
to meet any requirements of part 111,
without an intermediate step of having
quality control personnel first determine
whether the complaint should be
investigated;
• Quality control personnel review
and approve all decisions made by a
qualified person about whether to
investigate a product complaint and the
findings and followup action of any
investigation performed rather than
conduct the investigation and followup;
and
• The review and investigation of the
product complaint extends to all
relevant batches and records, without
identifying specific records, and specific
batches, that must be included in the
review and investigation.
C. General Comments on Proposed
§ 111.95 (Final Subpart O)
(Comment 314) Some comments
express general support for the
proposed procedures for consumer
complaints. Other comments request
proposed § 111.95 be deleted. Most of
these comments point out that we had
announced the development of
CFSAN’s Adverse Event Reporting
System (CAERS) for reporting to FDA
adverse events attributed to food
products and suggest that this new
system would be the appropriate
mechanism for handling complaints
about dietary supplements.
(Response) We disagree with these
comments. Because the problem giving
rise to the complaint may be associated
with a failure in manufacturing,
packaging, labeling, or holding, it is
CGMP for a firm that receives a product
complaint to review it and investigate,
if necessary, regardless of whether we
are notified about the complaint. An
important goal of the firm’s review and
investigation is to determine whether
there is a problem with the production
and process control system for the
manufacture, packaging, labeling, or
holding of the dietary supplement. That
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goal would not be achieved merely by
notifying us. A firm subject to any of the
requirements of this final rule, whether
such firm is a manufacturer, packager,
labeler, or holder, is responsible for the
requirements in subpart O for a product
complaint it receives.
(Comment 315) Some comments
assert that the proposed requirements
for consumer complaints do not go far
enough and urge that any final rule
require any complaints that involve an
adverse event be referred to us. The
comments stress accurate reporting of
adverse events is essential to long term
evaluations of a product’s safety.
(Response) Mandatory reporting
requirements to us regarding adverse
events related to dietary supplements
are outside the scope of this rulemaking.
This final rule addresses the internal
processes and controls that persons who
manufacture, package, label, or hold
dietary supplements must follow.
Mandatory reporting to FDA of serious
adverse events, however, is now
required as a result of the enactment of
the ‘‘Dietary Supplement and NonPrescription Drug Consumer Protection
Act’’ (Public Law 109–462) signed into
law on December 22, 2006. The new law
requires manufacturers, packers, or
distributors of such products to submit
reports to FDA about serious adverse
events involving such products based
on specific information that they receive
from the public. Serious adverse events
are defined in the law as those events
that result in death, a life-threatening
situation, an inpatient hospitalization, a
persistent or significant disability or
incapacity, or a congenital anomaly or
birth defect or one that requires medical
or surgical intervention to prevent such
serious outcomes (based on reasonable
medical judgment).
As discussed in the preamble to the
2003 CGMP Proposal (68 FR 12157 at
12217), however, we continue to
strongly recommend that firms that
receive product complaints, that are not
‘‘serious adverse events,’’ notify us
about any illness or injury, because, for
example, we may have additional
expertise or data that may be helpful in
investigating the complaint or
determining whether the problem
applies to more than one product. In
light of the requirement in the final rule
to establish and follow written
procedures for handling product
complaints, we encourage you to
include our recommendations in the
written procedures that you develop for
handling product complaints (see
discussion of final § 111.553 in this
section).
(Comment 316) Some comments raise
questions about who would be subject
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to the proposed requirements regarding
consumer complaints. Some comments
state the section should apply only to
manufacturers of dietary supplements,
not to manufacturers of dietary
ingredients. Other comments are
concerned that distributors who merely
put their label on the finished product
may be held responsible for keeping
records of adverse events caused by
failures to follow CGMPs during the
manufacture of the supplements.
(Response) The final rule only applies
to persons who manufacture, package,
label, or hold a dietary supplement. We
discuss the scope of this final rule in
detail in section VI of this document.
In most cases, the person who
receives a product complaint from a
consumer will be the manufacturer,
packager, or distributor of the dietary
supplement. A distributor (also a
‘‘holder’’ under this final rule) who
receives a product complaint must
review and investigate that complaint to
determine whether the complaint relates
to a failure of the processes under the
control of the distributor, such as
conditions of temperature, humidity,
and light that could affect the identity,
purity, strength, or composition of the
dietary supplement. If the distributor
concludes the problem is unrelated to
any process under the control of the
distributor, the distributor should
contact the manufacturer. Under the
final rule, any person in the
manufacturing chain who receives a
product complaint—regardless of the
source—must comply with the
requirements in this subpart O.
(Comment 317) One comment
suggests proposed § 111.95, which
describes requirements for consumer
complaints, could be combined with
proposed § 111.85 which describes
requirements for returned dietary
supplements.
(Response) We decline to adopt this
suggestion. In this final rule, we are
incorporating the requirements for
returned dietary supplements into a
distinct subpart (final subpart N) that
sets forth requirements for returned
dietary supplements. The procedures
described in final subpart O, which
relate solely to the handling of product
complaints rather than returned dietary
supplement products, are quite different
from those described in final subpart N,
which addresses the handling, review,
and possible reprocessing of returned
product.
(Comment 318) Some comments
assert the proposed requirements for
complaints are different from those for
food CGMPs.
(Response) We are making no changes
to the requirements after considering
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34909
these comments. We responded in
section V of this document to similar
comments asserting that certain aspects
of the proposed regulations are different
from those for other food CGMP
requirements.
D. What Are the Requirements Under
This Subpart for Written Procedures?
(Final § 111.553)
We received many comments which
recommended written procedures for
various provisions. We address the need
for written procedures generally in
section IV of this document. We also
respond to individual comments on
specific provisions in the same section.
Final § 111.553 requires that you
establish and follow written procedures
to fulfill the requirements of this
subpart O. Under final § 111.570(b)(1)
we require you to make and keep
records of such procedures. Such
records would be required to be made
available to us under the requirements
in subpart P.
We encourage you to include in your
written procedures the recommendation
made in the 2003 CGMP Proposal for
you to consult with a health care
provider if you receive complaints that
involve serious illness or injury. Even if
the complaints are not required to be
submitted to FDA under the newly
enacted ‘‘Dietary Supplement and NonPrescription Drug Consumer Protection
Act’’ (Public Law 109–462), we
encourage your company to notify us
about the product complaints.
Manufacturers and distributors should
be aware that this newly enacted law,
which requires reporting to FDA of
‘‘serious adverse events,’’ contains new
mandatory provisions that require
record retention of adverse event reports
separate from the requirements in this
CGMP final rule concerning product
complaints.
E. What Requirements Apply to the
Review and Investigation of a Product
Complaint? (Final § 111.560)
1. Final § 111.560(a)(1)
Final § 111.560(a)(1) requires a
qualified person to review all product
complaints to determine whether the
product complaint involves a possible
failure of a dietary supplement to meet
any of its specifications, or any other
requirements of part 111, including
those specifications and other
requirements that, if not met, may result
in a risk of illness or injury. Final
§ 111.560(a)(1) derives from proposed
§ 111.95(a).
We did not receive comments specific
to proposed § 111.95(a).
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2. Final § 111.560(a)(2), (b), and (c)
Final § 111.560(a)(2) requires a
qualified person to investigate any
product complaint that involves a
possible failure of a dietary supplement
to meet any of its specifications, or any
other requirements of part 111,
including those specifications and other
requirements that, if not met, may result
in a risk of illness or injury. Final
§ 111.560(b) requires that quality control
personnel review and approve decisions
by the qualified person about whether
or not to investigate a product
complaint and the findings and
followup action of any investigation
performed. Final § 111.560(c) requires
that the review and investigation extend
to all relevant batches and records.
(Comment 319) Some comments
characterize the requirements of
proposed § 111.95 as a confusing and
difficult scheme to review, investigate,
and resolve customer complaints. These
comments state the 2003 CGMP
Proposal would require extensive
human resources, recordkeeping, and
decisionmaking.
(Response) We disagree that the 2003
CGMP Proposal would require extensive
human resources, recordkeeping, or
decisionmaking. The comments
provided no rationale for such
assertions. The 2003 CGMP Proposal
sets forth basic steps, i.e., review,
evaluation, and followup, that one
would need to take to appropriately
address a product complaint. For those
product complaints for which there is a
reasonable possibility of a relationship
to an adverse event, the 2003 CGMP
Proposal would require that an
investigation be done by the quality
control unit because we believe such an
event would need more careful review
and followup.
To address the comments that found
proposed § 111.90 confusing, we have
made the following changes in the final
rule to simplify the procedures for
handling product complaints:
• We replaced the proposed
procedure in which a qualified person
determines whether a complaint should
be investigated by the quality control
unit with a procedure in which a
qualified person investigates any
product complaint that involves a
possible failure of a dietary supplement
to meet any requirements of part 111.
• We require an oversight function by
quality control personnel for the review
and evaluation of product complaints,
but do not require that quality control
personnel do any investigations. This is
consistent with other changes that we
are making in response to comments
that requested that the quality control
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unit focus on reviewing tasks performed
by others rather than on performing the
tasks itself.
• We refer to ‘‘any product complaint
that involves a possible failure of a
dietary supplement to meet any of its
specifications, or any other
requirements of this part [part 111],
including those specifications and other
requirements that, if not met, may result
in a risk of illness or injury’’ rather than
to ‘‘a reasonable possibility of a
relationship between the quality of a
dietary supplement and an adverse
event.’’ This is consistent with changes
that we are making to the definition of
the term ‘‘product complaint’’ in final
§ 111.3 (see section VI of this
document).
• We continue to require that the
review and investigation of the product
complaint extend to all relevant batches
and records but simplify the language of
the requirement by removing the details,
i.e., that the investigation must include
the batch records associated with the
dietary supplement involved in the
consumer complaint and not specifying
that the investigation must extend to
other batches of dietary supplement.
Rather, we require that the investigation
must extend to all relevant batches and
records.
The final rule provides firms
flexibility on how to use its human
resources. Nothing in subpart O would
preclude a qualified person among
designated quality control personnel to
be designated to actually review product
complaints and conduct investigations
of any product complaint. If an
individual is so designated and
conducts the investigation, reviews and
approves the findings, and conducts
followup actions of any investigation
performed, final § 111.560(b) would not
apply.
(Comment 320) Some comments
object to the requirement in proposed
§ 111.95(c) that consumer complaints
are to be investigated only when there
may be a relationship between product
quality and an adverse event. These
comments suggest this provision be
extended to any possible relationship
between dietary supplements and
adverse events, including those that
might be independent of whether the
product is produced under CGMPs.
These comments consider there should
be consistent procedures for handling
product complaints, regardless of
whether the complaints relate to
product quality.
(Response) The action requested in
these comments is outside the scope of
this rule, which specifically addresses
CGMP requirements to ensure the
quality of the dietary supplement
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product. However, we encourage firms
to investigate all product complaints in
a consistent way, regardless of whether
the complaints relate to the quality of
the dietary supplement.
(Comment 321) Some comments
request clarification of statements made
or terms used in the preamble to the
2003 CGMP Proposal regarding the
handling of product complaints. In the
preamble discussion of proposed
§ 111.95(c), we stated a consumer
complaint about adverse effects ‘‘after
consuming several dietary
supplements’’ is worthy of quality
control unit investigation. One comment
asks about the meaning of ‘‘several’’ and
whether this example means that a
manufacturer is responsible for
consumers who take more than the
recommended dosage.
(Response) In our discussion of
proposed § 111.95(c) we addressed a
situation where a consumer had
symptoms on more than one occasion
rather than a situation where a
consumer took more than the
recommended dosage. However, firms
must investigate any complaint of
illness or injury even if a consumer
reports that he/she has consumed more
than the amount recommended on the
product label to determine if the
complaint is related to CGMP.
F. Under This Subpart, What Records
Must You Make and Keep? (Final
§ 111.570)
1. Final § 111.570(a)
Final § 111.570(a) requires you to
make and keep the records required
under subpart O in accordance with
subpart P. Final § 111.570(a) derives
from proposed § 111.95(f)(2) with
changes associated with the
reorganization.
We did not receive comments specific
to proposed § 111.95(f)(2).
2. Final § 111.570(b)(1)
Final § 111.570(b)(1) requires you to
make and keep a record of the written
procedures for fulfilling the
requirements of subpart O. Final
§ 111.553 requires written procedures
for fulfilling the requirements of subpart
O. Those written procedures are
considered a record under final
§ 111.570(b)(1).
3. Final § 111.570(b)(2)
Final § 111.570(b)(2) requires you to
make and keep a written record of every
product complaint that is related to
CGMP. Final § 111.570(b)(2) derives
from proposed § 111.95(e) which would
require that you ‘‘* * * make and keep
a written record of every consumer
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complaint that is related to good
manufacturing practices. For the
purposes of the regulations in this part,
a consumer complaint about product
quality may or may not include
concerns about a possible hazard to
health. However, a consumer complaint
does not include an adverse event,
illness, or injury related to the safety of
a particular dietary ingredient
independent of whether the product is
produced under good manufacturing
practices.’’
As a revision for consistency with the
definition of ‘‘product complaint’’ in
final § 111.3, final § 111.570(b)(2) does
not include the two full sentences from
proposed § 111.95(e), as quoted in the
previous paragraph.
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4. Final § 111.570(b)(2)(i)
Final § 111.570(b)(2)(i) requires that
the person who performs the
requirements of subpart O, at the time
of performance, document and record
the performance. Final § 111.570(b)(2)(i)
is similar to proposed § 111.95(f)(1) with
changes associated with the
reorganization.
5. Final § 111.570(b)(2)(ii)
Final § 111.570(b)(2)(ii) requires that
the written record of the product
complaint include: (1) The name and
description of the dietary supplement;
(2) the batch, lot, or control number of
the dietary supplement, if available; (3)
the date the complaint was received and
the name, address, or telephone number
of the complainant, if available; (4) the
nature of the complaint including, if
known, how the product was used; (5)
the reply to the complainant, if any; and
(6) findings of the investigation and
followup action taken when an
investigation is performed. Final
§ 111.570(b)(2) is similar to proposed
§ 111.95(e)(1) through (e)(6) and
includes a change we are making after
considering comments to proposed
§ 111.95(e)(4) (discussed in the
following paragraphs) which would
have required that the consumer
complaint written record include ‘‘The
nature of the complaint including how
the consumer used the product.’’ On our
own initiative, we also made a change
to include the date the complaint was
received.
(Comment 322) One comment notes
proposed § 111.95(e)(4) would require
the written record of consumer
complaints to include ‘‘how the
consumer used the product.’’ The
comment notes this information may
not always be available and suggests the
words ‘‘where known’’ should be added.
(Response) We agree that there can be
circumstances where the firm that
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receives the product complaint may not
know how the product was used. For
example, a consumer may make a
complaint by leaving a telephone
message before or after business hours
and neither describe how the product
was used, nor leave contact information
so that the firm could followup with the
consumer. To address this comment, we
provide in the final rule that the written
record of the product complaint include
‘‘the nature of the complaint including,
if known, how the product was used.’’
(Comment 323) Some comments
request clarification of statements made
or terms used in the preamble to the
2003 CGMP Proposal regarding the
handling of product complaints. In our
discussion of proposed § 111.95(e) we
recommended that consumer
complaints and investigations be
reported to us when consumption of a
dietary supplement may be related to ‘‘a
serious adverse event.’’ Some comments
note that ‘‘serious’’ is not defined.
(Response) The term ‘‘serious adverse
event’’ is widely used in the industries
we regulate. Our current forms for
reporting ‘‘serious adverse events’’ via
the MedWatch program do not define
the term, but instead list outcomes that
were attributed to an adverse event.
These outcomes include death, lifethreatening, hospitalization (initial or
prolonged), disability, congenital
anomaly, required intervention to
prevent permanent impairment/damage,
and ‘‘other.’’ As discussed in this
section, however, there is a new
statutory requirement for mandatory
reporting to FDA of serious adverse
events enacted in the ‘‘Dietary
Supplement and Non-Prescription Drug
Consumer Protection Act’’ (Public Law
109–462). The new law does define
‘‘serious adverse events’’ as those events
that result in death, a life-threatening
situation, an inpatient hospitalization, a
persistent or significant disability or
incapacity, or a congenital anomaly or
birth defect or one that requires medical
or surgical intervention to prevent such
serious outcomes (based on reasonable
medical judgment). The law also has
specific provisions for how these
serious adverse events are to be
submitted to FDA and record retention
for records relating to these and other
adverse event reports. We anticipate
issuing guidance on implementation of
the new statutory provisions. We
encourage firms who are unsure as to
whether the nature of a reported adverse
event should be reported to FDA to
contact us for assistance.
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XXI. Comments on Records and
Recordkeeping (Final Subpart P)
A. Organization of Final Subpart P
In the 2003 CGMP Proposal, the
requirements for records and
recordkeeping were set forth in
proposed § 111.125. As shown in table
17 of this document, we are
reorganizing the requirements for
records and recordkeeping into a
distinct subpart (final Subpart P—
Records and Recordkeeping). Table 17
lists the sections in final subpart P and
identifies the proposed provisions that
form the basis for the final rule.
TABLE 17.—DERIVATION OF SECTIONS
IN FINAL SUBPART P
Final Rule
2003 CGMP
Proposal
§ 111.605 What requirements apply to the
records you make and
keep?
§ 111.125(a)
and (b)
§ 111.610 What records
must be made available to FDA?
§ 111.125(b)
and (c)
B. Highlights of Changes to the
Proposed Requirements for Records and
Recordkeeping
1. Revisions
The final rule reflects that it applies
to persons who manufacture, package,
label, or hold a dietary supplement
unless subject to an exclusion in
§ 111.1.
2. Changes After Considering Comments
This final rule requires you to keep
written records required by this subpart
for either 1 year past the shelf life date,
if shelf life dating is used, or 2 years
beyond the date of distribution of the
last batch of dietary supplements
associated with those records (final
§ 111.605(a)).
C. General Comments on Proposed
§ 111.125
(Comment 324) Some comments
support the requirements in proposed
§ 111.125 because documentation helps
to ensure CGMPs are consistently
followed and retention of records
provides an effective trail when
subsequent problems need to be
identified and corrected.
Another comment asserts the
recordkeeping requirements would
represent a large burden for companies
that manufacture vitamin and mineral
supplements with a large number of
active ingredients.
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(Response) We agree that records are
useful in identifying manufacturing
problems and tracking the source of
failures in CGMPs.
We understand the burden on
manufacturers may be heavier for
manufacturers who use many dietary
ingredients and discuss the burden of
the recordkeeping requirements in
sections XXVIII and XXIV of this
document. However, we do not believe
that a manufacturer who elects to put
several components into one finished
batch of dietary supplement would
necessarily have a larger burden than
one who, instead, elects to manufacture
multiple dietary supplements each
containing one component. We believe
that the requirements, for example, for
ensuring the identity, purity, strength,
and composition of each component in
a dietary supplement need to be the
same for a dietary supplement
containing one ingredient or component
and one containing multiple ingredients
or components. To the extent the
comment is suggesting that the
recordkeeping requirements for those
who manufacture multivitamin/mineral
dietary supplements (containing
components) are too large and should be
less, the comment provided no basis for
such a change.
D. What Requirements Apply to the
Records That You Make and Keep?
(Final § 111.605)
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1. Final § 111.605(a)
Final § 111.605(a) requires you to
keep written records for 1 year past the
shelf life date, if shelf life dating is used,
or 2 years beyond the date of
distribution of the last batch of dietary
supplements associated with those
records. Final § 111.605(a) derives from
proposed § 111.125(a).
(Comment 325) Several comments
suggest that the requirement in
proposed § 111.125(a) to keep records
for 3 years beyond the date of
manufacture should be modified. One
comment favors record retention for 3
years beyond the date of manufacture or
for the shelf life of the product,
whichever is longer. Some comments
state the rule should require
establishment of an expiration date and
that the manufacturer should have the
option of retaining records for 1 year
beyond the expiration date, when an
expiration date has been established by
the manufacturer. Some comments
point out that under section 306(a) of
the Bioterrorism Act, FDA is authorized
to issue recordkeeping regulations with
a record retention period of ‘‘not longer
than two years.’’ One comment,
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therefore, asserts CGMP records should
not be kept for more than 2 years.
(Response) We believe a record
retention period for records related to
CGMP requirements should correlate
generally with the length of time that
product complaints are likely to arise
related to the manufacture of a dietary
supplement. Such correlation will
increase the likelihood that, if a problem
with a dietary supplement is identified
that may be associated with a violation
of CGMP, the dietary supplement
manufacturer, packager, labeler, or
holder will have access to the CGMP
records associated with that dietary
supplement. In addition, we will have
access to such records at inspection.
We have modified the final rule to
require a record retention period of 2
years beyond the date of distribution of
the last batch of dietary supplements
associated with those records or 1 year
past the shelf life date, if shelf life
dating is used.
A significant portion of the dietary
supplement industry use shelf life
dating. It is likely that if there are
product complaints related to a product
these will arise during the shelf life of
these products. To ensure there is
adequate time to examine the records,
determine if there are related
manufacturing problems, and
implement corrective actions, it is
necessary to require the retention of
records for 1 year past the shelf life date.
This will help ensure that
establishments have access to such
records to perform the necessary CGMP
actions.
For those dietary supplements
without shelf life or expiration dating,
we believe that 2 years from the date of
distribution is a reasonable estimate of
the time needed to retain records in
order to address CGMP problems
identified in product complaints.
It is important to note that, as
discussed in this section, the term
‘‘shelf life dating,’’ includes shelf life
dating as well as expiration dating and
‘‘best if used by’’ dating.
We disagree with the comment that
suggests we require an expiration date
on all products. Many products will not
have a determinable expiration date due
to the state of knowledge about these
products. We believe the manufacturer
is in the best position to determine if its
product requires an expiration date.
(Comment 326) One comment
requests clarification of the ‘‘date of
manufacture.’’ The comment asserts if
an expiration date is shown on the label
of a product, the date of manufacture
should be considered to be the date on
which the expiration date is based. The
comment gives an example of vitamin C
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tablets having a 2-year shelf life. The
comment explains if the tablets are
compressed, tested, and approved for
packaging in August 2003, they would
generally be assigned an expiration date
of August 2005 regardless of the date of
packaging. The comment argues if the
tablets are held and later packaged in
February 2004, records for this batch
should only have to be kept for 1 year
beyond the expiration date (i.e., August
2006), rather than 3 years beyond the
packaging date (i.e., February 2007).
(Response) In the scenario described
in the previous paragraph, where an
expiration date (shelf life) has been
determined, records for this batch must
only be kept for 1 year beyond the
expiration date (i.e., shelf life date). The
packaging date in the scenario has no
effect on the amount of time records
must be kept. However, in the final rule,
we have decided that it is more
appropriate to determine the record
retention period from the date of
distribution rather than the ‘‘date of
manufacture.’’ The date on which the
manufacturer completes the
manufacture of a batch of a dietary
supplement (the date of manufacture)
does not necessarily indicate the
availability of the dietary supplement
product in the marketplace. It is
possible that such product could be
held for a period of time before entry
into the marketplace and possible
consumer consumption. A more
accurate time period for entry is
calculated by the date of distribution.
Final § 111.605(a)(2) requires that
manufacturers, packagers, labelers, and
holders keep their records for 2 years
from the date of distribution of the last
batch of dietary supplement associated
with those records. For products with a
shelf life date, the records associated
with those dietary supplements are
required to be kept for 1 year past the
shelf life date of that particular dietary
supplement. Packagers and labelers that
return the product to the manufacturer
for distribution are not required to keep
separate records under this subpart.
2. Final § 111.605(b)
Final § 111.605(b) requires you to
keep records as original records, true
copies (such as photocopies, microfilm,
etc.), or as electronic records. Final
§ 111.605(b) derives from proposed
§ 111.125(b).
We did not receive comments specific
to proposed § 111.125(b).
3. Final § 111.605(c)
Final § 111.605(c) requires that all
electronic records comply with part 11
(21 CFR part 11). Final § 111.605(c)
derives from proposed § 111.125(b).
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(Comment 327) One comment
believes part 11 should only apply to
records that do not have paper
counterparts.
(Response) This comment is beyond
the scope of this CGMP rulemaking.
(Comment 328) One comment
suggests the proposed requirement that
CGMP electronic records must comply
with part 11 should be deleted because
the FDA guidelines on part 11 have not
yet been finalized.
(Response) Part 11 applies to
electronic CGMP records. Therefore,
final § 111.605(c) requires that all
electronic records, including electronic
signatures, must comply with part 11.
We have finalized guidance for
industry. The guidance entitled ‘‘Part
11, Electronic Records; Electronic
Signatures Scope and Application,’’ sets
out our enforcement policies with
respect to certain aspects of part 11 (Ref.
33). The guidance is available at https://
www.fda.gov/cder/guidance/
5667fnl.htm. The guidance applies to
any CGMP electronic records and
signatures.
E. What Records Must Be Made
Available to FDA? (Final § 111.610)
1. Final § 111.610(a)
Final § 111.610(a) requires you to
keep records, or copies of such records,
required by this final rule, readily
available during the retention period for
inspection and copying by FDA when
requested. Final § 111.610(a) derives
from proposed § 111.125(c). We
responded in section V of this document
to comments that we received on FDA’s
statutory authority to inspect and copy
records. We made one editorial,
nonsubstantive change from the
language in proposed § 111.125(c). We
removed the word ‘‘authorized’’ to
prevent any confusion regarding
whether some authorization other than
the statutory authority that provides the
legal basis for this final rule is necessary
for our access to inspect and copy
records.
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2. Final § 111.610(b)
Final § 111.610(b) requires that if you
use reduction techniques, such as
microfilming, you must make suitable
reader and photocopying equipment
readily available to us. Final
§ 111.610(b) derives from proposed
§ 111.125(b).
We did not receive any comments
specific to proposed § 111.125(b) and
final § 111.610(b).
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XXII. Other Comments and
Miscellaneous
A. Comments on Guidance Documents
To Be Used With the Final Rule
In the 2003 CGMP Proposal, we
invited comment on the usefulness of
guidance documents, education,
training, or other approaches and
potential sources of education and
training that would assist industry
efforts to implement the 2003 CGMP
Proposal, if finalized as proposed (68 FR
12157 at 12163).
(Comment 329) A few comments state
booklets, videos, seminars, and other
training would be useful on topics such
as sanitation, recordkeeping, quality
assurance methods, microbiological
testing, and botany. Another comment
states a subset of CGMPs that focuses on
plant authenticity, purity, proper
handling, and hygiene should be
developed for parties who exclusively
deal with bulk raw agricultural
commodities (with the exception of
individual wildcrafters). If such CGMPs
are not developed, the comment
requests we develop guidance
documents on the identification,
cultivation, and handling of botanicals.
The same comment also notes guidance
specifically is needed on the use of
microscopy to identify plants.
(Response) We acknowledge these
comments and, in the future, we may
issue guidance that relates to certain
dietary supplement CGMP
requirements.
B. Comments on Consideration for
Other CGMP Programs
(Comment 330) One comment asserts
several existing dietary supplement
CGMP programs (e.g., those developed
by the NNFA, NSF International, ANSI,
and USP) are well designed and
represent useful examples for us to
follow. The comment notes section
12(d) of the National Technology
Transfer and Advancement Act directs
Federal agencies to use such voluntary
consensus standards whenever possible,
as long as the standards are consistent
with Federal law and are practical. The
comment recommends we include
standards from these existing CGMP
programs where suitable in the final
rule.
(Response) In the development of the
2003 CGMP Proposal and this final rule,
we carefully considered the comments
that recommended aspects of other
CGMP programs. For example, as
discussed previously, the 1997 ANPRM
for this rule contained the entire text of
an outline presented to us by
representatives of the dietary
supplement industry. Furthermore,
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34913
where comments recommended aspects
of other CGMP programs, we considered
those recommendations and, in some
cases, incorporated certain
recommendations into requirements in
this final rule (e.g., the use of a
certificate of analysis).
In 2006, ANSI updated its Standard
173 (ANSI Standard 173) regarding
dietary supplements (Ref. 35). ANSI
Standard 173 contains provisions for
dietary supplement CGMP that are
based, in part, on the industry
submission to FDA in November 1995,
which the agency published as part of
its 1997 ANPRM. We considered
comments to the 1997 ANPRM, many of
which commented on the provisions of
the industry submission, and the
comments to the 2003 CGMP Proposal
in the course of developing this CGMP
final rule. We have considered the
provisions contained in the updated
ANSI Standard 173 and many of the
specific provisions contained in ANSI
Standard 173 are similar to provisions
adopted in this final rule. For example,
both the ANSI standard and this CGMP
final rule have similar requirements on
written procedures, personnel
qualifications, record retention, and
quality control. However, we
determined that adopting the entire
ANSI Standard 173 would be
impracticable. There are key provisions
which reflect major differences between
the latest ANSI Standard 173 and the
CGMP final rule. Many of these
differences are in the product testing
environment. For example, the ANSI
standard contains different product
testing frequency and production stage
requirements. We have extensively
discussed the justification for the
particular testing requirements adopted
in this CGMP final rule, which we
believe are no more burdensome than
the ANSI Standard 173 requirements.
For example, the ANSI Standard 173
contains testing methods for metal or
microbiological contaminants not
included in the final rule. We found that
providing flexibility for manufacturers
to choose their own specific test
methods was a more efficient way of
reaching the goals of the CGMP final
rule than specifying and requiring
particular tests. We support, however,
the use of the ANSI Standard 173 testing
methods by manufacturers, where
appropriate, in complying with the
requirements of this rule.
(Comment 331) Another comment
states CGMPs that reflect common
elements and areas of uniqueness
should be placed in subcategories of
CGMPs as is the case with the current
food CGMP model. The comment
recommends we follow a similar
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approach and establish subcategories of
CGMPs for dietary supplements (e.g., for
vitamin-mineral and probiotic tablets).
(Response) In the 1997 ANPRM, we
asked for comment about whether broad
CGMP regulations would be adequate,
or whether it would be necessary to
address the operations of particular
segments of the dietary supplement
industry (68 FR 12157 at 12174). Based
on the comments received to the 1997
ANPRM, we were persuaded that a
broad final rule is preferable to multiple
regulations focused on particular
segments of the dietary supplement
industry, or to general CGMP provisions
plus subcategories applicable to
segments of the dietary supplement
industry. We stated in the 2003 CGMP
Proposal that we would consider
whether we needed to re-evaluate our
decision to establish one set of
requirements for all dietary
supplements (id.). This comment did
not provide any basis to persuade us to
re-evaluate the decision we made that a
broad CGMP rule was appropriate.
Thus, in this final rule, we are
establishing one set of requirements for
all persons who manufacture, package,
label, or hold dietary supplements and
not subject to an exclusion under final
§ 111.1.
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C. Comments on Public Involvement
1. Public Involvement
(Comment 332) Several comments
express general concerns with our
public involvement process. Several
comments state additional public
meetings and workshops are necessary
to permit FDA, industry, and other
stakeholders to work together to seek a
more workable solution to dietary
supplement CGMPs and to resolve
differences of opinion. One comment
states the differences of opinion
identified by the comment process will
not be meaningfully resolved without
active and forthright communication
with stakeholders. According to the
comment, we should establish a forum
prior to the publication of the final rule
to communicate our perception of these
differences of opinion. In another
comment, a trade association expresses
disappointment that our 2003 CGMP
Proposal disregards industry efforts to
draft CGMPs over the last decade.
Another comment contends the
proposal was rushed and the comment
period was established without
publication of a core economic analysis
to support it.
(Response) We disagree with these
comments. We believe there has been
sufficient public involvement given the
public meetings that were held and the
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opportunity for comment during the
comment periods provided. We discuss
the public involvement in section I of
this document. Further, the 2003 CGMP
Proposal did contain an economic
analysis. We received extensive
comments on the economic analysis in
the 2003 CGMP Proposal. We have
made several changes to the economic
analysis of this final rule in response to
these comments as discussed in section
XXIV of this document. Furthermore,
we have made various changes in
response to comments to the CGMP
requirements in this final rule.
D. Comments on Implementation and
Enforcement
(Comment 333) Several comments
suggest postponing the effective date of
the rule for 24 months to allow a
voluntary inspection and compliance
program to take effect in the interim.
One comment recommends adoption of
a voluntary program similar to that of
OSHA regulations in Title 29 of the
Code of Federal Regulations, where
companies would invite FDA inspection
without penalty or cost unless a serious
violation occurs. In cases of serious
violation, companies would have the
option to voluntarily correct the
problem and inform the public before
the effective date of the rule.
(Response) We disagree with these
comments regarding the establishment
of a voluntary compliance period. The
effective date of this final rule is 60 days
after the date of its publication in the
Federal Register. However, as discussed
in sections VI and XXIV of this
document, we have staggered
compliance dates to 12 months, 24
months, and 36 months, respectively,
after the final rule’s publication date for
businesses of over 500 employees,
businesses with under 500 employees
but 20 or more employees, and
businesses with less than 20 employees.
(Comment 334) Several comments
indicate they want differential treatment
under the final rule based on the
seriousness of a violation, others ask for
strict enforcement, and others ask how
FDA would enforce against those who
continually adulterate dietary
supplements.
(Response) We consider these
comments to be outside the scope of this
final rule. In general, we would provide
guidance on our enforcement policy
through the issuance of guidance
documents if we determine that any
variance from full enforcement is
warranted.
(Comment 335) Another comment
expresses concern the 2003 CGMP
Proposal works at ‘‘cross purposes’’
with recent regulations associated with
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bioterrorism. The comment
recommends these rules be harmonized
to reduce costs and increase efficiencies
for manufacturers.
(Response) It is not clear what the
comment means when it states the 2003
CGMP Proposal works at ‘‘cross
purposes’’ with the regulations issued
under the Bioterrorism Act or that we
should ‘‘harmonize’’ the regulations
issued under the Bioterrorism Act with
the final rule establishing dietary
supplement CGMP requirements. We
have made every effort to consider the
regulations issued under the
Bioterrorism Act and their relationship
to this final rule. There are different
purposes to the Bioterrorism Act and
these CGMP requirements; however, we
have harmonized to the extent possible.
(Comment 336) One comment states
the 1-year compliance period for large
firms is reasonable as long as we modify
the rule to better reflect existing CGMPs
already in practice among responsible
companies. The comment also notes the
3-year compliance period for small
firms may be reasonable, but urges us to
enforce compliance of basic food GMP
requirements, which some of these firms
may not be observing.
(Response) The effective date for this
final rule is 60 days after its date of
publication in the Federal Register,
though we are staggering the
compliance dates as described in
sections VI and XXIV of this document.
Dietary supplement products in the
marketplace must already be in
compliance with all other statutory and
regulatory provisions that affect dietary
supplements.
E. Removal of References to Part 112
The 2003 CGMP Proposal (68 FR
12157 at 12175) had proposed the
heading and table of contents for part
112. Proposed part 112 had the heading
‘‘Restrictions for Substances Used in
Dietary Supplements.’’ At the time, we
said that it was necessary to amend part
112 because at that time the proposed
rule for dietary supplements containing
ephedrine alkaloids (62 FR 30678, June
4, 1997) had not been finalized and
included proposed revisions to part 111.
The 2003 CGMP Proposal for dietary
supplement CGMPs proposed using part
111 and proposed the relocation of the
‘‘Restrictions for Substances Used in
Dietary Supplements’’ to part 112. Since
the issuance of the 2003 CGMP
Proposal, the final rule for dietary
supplements containing ephedrine
alkaloids has been finalized (69 FR
6788, February 11, 2004) and has been
included in 21 CFR part 119. Thus,
there is no need to reserve part 112 in
this final rule. The references to part
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112 have been removed from the final
rule.
XXIII. Paperwork Reduction Act of
1995
This final rule contains information
collection requirements that are subject
to review by the Office of Management
and Budget (OMB) under the Paperwork
Reduction Act of 1995 (44 U.S.C. 3501–
3520). The title, description, and
respondent description of the
information collection requirements are
given in the following paragraphs, with
estimates of the one-time burden of
establishing written procedures and the
annual recordkeeping burden. Included
in the burden estimates are the time for
reviewing instructions, searching
existing data sources, gathering and
maintaining the data needed, and
completing and reviewing each
collection of information.
Title: Current Good Manufacturing
Practice in Manufacturing, Packaging,
Labeling, or Holding Operations for
Dietary Supplements
Description: Section 402(g) of the act
gives us explicit authority to issue a rule
establishing current good manufacturing
practice requirements for dietary
supplements. Section 402(g)(1) of the
act states that a dietary supplement is
adulterated if ‘‘it has been prepared,
packed, or held under conditions that
do not meet current good manufacturing
practice regulations.’’ Section 402(g)(2)
of the act authorizes us to, by regulation,
‘‘prescribe good manufacturing practices
for dietary supplements.’’ Under section
701(a) of the act (21 U.S.C. 371), FDA
may issue regulations necessary for the
efficient enforcement of the act. Other
relevant legal authority is discussed in
section V of this document.
We did not receive any direct
comments on the Paperwork Reduction
Act analysis of the 2003 CGMP
Proposal. Many comments on the
estimated costs of the 2003 CGMP
Proposal stated that we underestimated
the annual number of batches of dietary
supplements produced. Due to a
contractor’s error, we did underestimate
the number of batches produced. This
final paperwork reduction analysis
corrects for this error. The final analysis
also has been revised from the analysis
of the 2003 CGMP Proposal in order to
incorporate the effects of revisions to
the proposed regulation, including
reorganization.
Records are an indispensable
component of CGMP. The records
required by this final rule provide the
foundation for the planning, control,
and improvement processes that
constitute a quality control system.
Implementation of these processes in a
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manufacturing operation serves as the
backbone to CGMP. The records will
show what is to be manufactured; what
was, in fact, manufactured; and whether
the controls that the manufacturer put
in place to control the identity, purity,
strength, and composition and limits on
contaminants and to prevent
adulteration were effective. Further,
records will show whether and what
deviations from control processes
occurred, facilitate evaluation and
corrective action concerning these
deviations (including, where necessary,
whether associated batches of product
should be recalled from the
marketplace), and enable a
manufacturer to assure that the
corrective action was effective. Further,
records will show whether and what
deviations from control processes
occurred, facilitate evaluation and
corrective action concerning these
deviations (including, where necessary,
whether associated batches of product
should be recalled from the
marketplace), and enable a
manufacturer to assure that the
corrective action was effective. In
addition, by requiring records, we will
be able to ensure that you follow CGMPs
so that you ensure the quality of your
dietary supplements during
manufacturing, packaging, labeling, or
holding operations. The final rule
establishes the minimum manufacturing
practices necessary to ensure that
dietary supplements are manufactured,
packaged, labeled, or held in a manner
that will ensure the quality of the
dietary supplements during
manufacturing, packaging, labeling or
holding operations.
The records requirements of this final
rule include written procedures and
records pertaining to: (1) Personnel; (2)
sanitation; (3) calibration of instruments
and controls; (4) calibration, inspection,
or checks of automated, mechanical, or
electronic equipment; (5) maintaining,
cleaning, and sanitizing equipment and
utensils and other contact surfaces; (6)
water used that may become a
component of the dietary supplement;
(7) production and process controls; (8)
quality control; (9) components,
packaging, labels and product received
for packaging and labeling; (10) master
manufacturing and batch production;
(11) laboratory operations; (12)
manufacturing operations; (13)
packaging and labeling operations; (14)
holding and distributing operations; (15)
returned dietary supplements; and (16)
product complaints.
Description of Respondents:
Manufacturers, dietary supplement
manufacturers, packagers and repackagers, labelers and re-labelers,
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34915
holders, distributors, warehousers,
exporters, importers, large businesses,
and small businesses.
The recordkeeping requirements of
the final rule are set forth in each
subpart. In table 18 of this document we
list the one-time burdens associated
with establishing written procedures. In
table 19 of this document we list the
annual burdens associated with
recordkeeping. In each table, where the
same records are mentioned in more
than one provision of a subpart, we list
the burden under the provisions
corresponding to the heading, ‘‘Under
this subpart, what records must you
make and keep?’’ For some provisions
listed in table 19, we did not estimate
the annual frequency of recordkeeping
because recordkeeping occasions consist
of frequent brief entries of dates,
temperatures, monitoring results, or
documentation that specific actions
were taken. Information might be
recorded a few times a day, week, or
month. When the records burden
involves frequent brief entries, we
entered one as the default for the annual
frequency of recordkeeping. For
example, many of the records listed
under final § 111.35 in table 19, such as
final § 111.35(b)(2) (documentation, in
individual equipment logs, of the date
of the use, maintenance, cleaning, and
sanitizing of equipment), involve many
short sporadic entries over the course of
the year, varying across equipment and
plants in the industry. We did not
attempt to estimate the actual number of
recordkeeping occasions for these
provisions, but instead entered an
estimate of the average number of hours
per year. We entered the default value
of 1 as the annual frequency of
recordkeeping for these and similar
provisions. For final § 111.35, the entry
for annual frequency is 1 as a default
representing a large number of brief
recordkeeping occasions.
In many rows of tables 18 and 19 of
this document, we list a burden under
a single provision that covers the
written procedures or records described
in several provisions. The burden of the
master manufacturing record listed in
table 18 under final § 111.210 includes
the burden for final § 111.205 because
the master manufacturing record must
include those written procedures.
Similarly, the burden of the batch
production records listed in table 19
under final § 111.260 includes the
burden for records listed under final
§ 111.255 because the batch production
records must include those records.
The annual frequency for batch
production records (and other records
kept on a batch basis in table 19 of this
document) equals the annual number of
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batches. The estimated burden for
records kept by batch includes both
records kept for every batch and records
kept for some but not all batches. We
use the annual number of batches as the
frequency for records that will not
necessarily be kept for every batch, such
as test results or material review and
disposition records, because such
records are part of records, if they are
necessary, that will be kept for every
batch.
We estimate the burden of this
collection of information as follows:
TABLE 18.—ESTIMATED ONE-TIME BURDEN TO ESTABLISH WRITTEN PROCEDURES1
21 CFR Section
Number of
Recordkeepers
Annual Frequency
per Recordkeeping
Hours per
Record
Total Records
Total Hours
111.14
15,000
1
15,000
3.6
54,000
111.23
15,000
1
15,000
1
15,000
111.35
400
1
400
36
14,400
111.95
250
1
250
68
17,000
111.140
300
1
300
10.7
3,210
111.180
200
1
200
10
2,000
111.210
250
1
250
12
3,000
111.325
150
1
150
45
6,750
111.375
260
1
260
9
2,340
111.430
250
1
250
12.6
3,150
111.475
15,000
1
15,000
2.1
31,500
111.535
200
1
200
6
1,200
111.570
240
1
240
12
2,880
Total
1There
156,430
are no capital costs or operating costs associated with the collection of information under this final rule.
TABLE 19.—ESTIMATED ANNUAL RECORDKEEPING BURDEN1
21 CFR Section
Number of
Recordkeepers
Annual Frequency
per Recordkeeping
Total Annual
Records
Hours per
Record
Total Hours
15,000
4
60,000
1
111.23
15,000
1
15,000
0.2
3,000
111.35
400
1
400
12.5
5,000
111.95
250
1
250
45
11,250
111.140
240
1,163
279,120
1
279,120
111.180
240
1,163
279,120
1
279,120
111.210
240
1
240
111.260
145
1,408
204,160
1
204,160
111.325
120
1
120
15
1,800
111.375
260
1
260
2
520
111.430
50
1
50
12.6
630
111.475
15,000
1
15,000
0.4
6,000
111.535
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111.14
110
4
440
13.5
5,940
111.570
240
600
144,000
0.5
72,000
2.5
Total
1There
60,000
600
929,140
are no capital costs or operating costs associated with the collection of information under this final rule.
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The burden estimates in tables 18 and
19 of this document are based on our
institutional experience with other
CGMP requirements and on data
provided by Research Triangle Institute
(RTI) in the ‘‘Survey of Manufacturing
Practices in the Dietary Supplement
Industry,’’ OMB Control Number 0910–
0422, expiration date April 4, 2000
(Refs. E1 and E2).
The estimates in both tables of the
number of firms affected by each
provision of the rule are based on the
percentage of manufacturers, packagers,
labelers, holders, distributors, and
warehousers that reported in the survey
that they have not established written
SOPs or do not maintain records that
would be required under the final rule.
Because we do not have survey results
for general warehouses, we entered the
approximate number of facilities in that
category for those provisions covering
general facilities. For the dietary
supplement industry, the survey
estimated that 1,460 firms would be
covered by this final rule, including
manufacturers, packagers, labelers,
holders, distributors, and warehousers.
The time estimates include the burden
involved in documenting that certain
requirements are performed and in
recordkeeping. We used an estimated
annual batch production of 1,408
batches per year to estimate the burden
of requirements that are related to the
number of batches produced annually,
such as final § 111.260, ‘‘What must the
batch production record include?’’ The
estimate of 1,408 batches per year is
near the midpoint of the number of
annual batches reported by survey
firms.
The length of time that CGMP records
must be maintained is set forth in final
§ 111.605. Tables 18 and 19 of this
document reflect the estimated burdens
for written procedures, record
maintenance, periodically reviewing
records to determine if they may be
discarded, and for any associated
documentation for that activity for
records that will be required under part
111. We have not included a separate
estimate of burden for those sections
that require maintaining records in
accordance with final § 111.605, but
have included those burdens under
specific provisions for keeping records.
For example, final § 111.255(a) requires
that the batch production records be
prepared every time a batch is
manufactured, and final § 111.255(d)
requires that batch production records
be kept in accordance with final
§ 111.605. The estimated burdens for
both § 111.255(a) and (d) are included
under final § 111.260 (what the batch
record must include).
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The information collection provisions
of this final rule have been submitted to
OMB for review.
Prior to the effective date of this final
rule, we will publish a document in the
Federal Register announcing OMB’s
decision to approve, modify, or
disapprove the information collection
provisions in this final rule. An agency
may not conduct or sponsor, and a
person is not required to respond to, a
collection of information unless it
displays a currently valid OMB control
number.
XXIV. Analysis of Impacts
A. Introduction
FDA has examined the impacts of this
final rule under Executive Order 12866.
Executive Order 12866 directs agencies
to assess all costs and benefits of
available regulatory alternatives and,
when regulation is necessary, to select
regulatory approaches that maximize
net benefits (including potential
economic, environmental, public health
and safety, and other advantages;
distributive impacts; and equity).
Executive Order 12866 classifies a rule
as significant if it meets any one of a
number of specified conditions,
including: Having an annual effect on
the economy of $100 million, adversely
affecting a sector of the economy in a
material way, adversely affecting
competition, or adversely affecting jobs.
A regulation is also considered a
significant regulatory action if it raises
novel legal or policy issues. FDA has
determined that this final rule will be an
economically significant regulation
under Executive Order 12866 because it
will have an annual effect on the
economy of more than $100 million.
The Small Business Regulatory
Enforcement Fairness Act of 1996
(Public Law 104–121) defines a major
rule for the purpose of congressional
review as being likely to cause one or
more of the following: An annual effect
on the economy of $100 million; a major
increase in costs or prices; significant
adverse effects on competition,
employment, productivity, or
innovation; or significant adverse effects
on the ability of U.S.-based enterprises
to compete with foreign-based
enterprises in domestic or export
markets. In accordance with the Small
Business Regulatory Enforcement
Fairness Act, OMB has determined that
this final rule will be a major rule for
the purpose of congressional review.
FDA has examined the impacts of this
final rule under the Regulatory
Flexibility Act (5 U.S.C. 601–612). If a
rule has a significant economic impact
on a substantial number of small
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34917
entities, the Regulatory Flexibility Act
requires agencies to analyze regulatory
options that would lessen the economic
effect of the rule on small entities. FDA
finds that this final rule will have a
significant economic impact on a
substantial number of small entities.
The Unfunded Mandates Reform Act
of 1995 (Public Law 104–4) requires
cost-benefit and other analyses for rules
that would cost more than $100 million
in a single year. The current (2005)
inflation-adjusted statutory threshold is
$122 million. This final rule qualifies as
a significant rule under the statute.
1. Summary of the Economic Analysis
We carry out the cost-benefit analyses
required for significant rules in the
Final Regulatory Impact Analysis, in
section XXIV.B of this document. We
perform the Final Regulatory Flexibility
Analysis of the effects on the final rule
on small businesses in section XXIV.C
of this document. We estimate that,
once it is fully implemented 36 months
after the date of publication, the
quantifiable annual benefits from the
final rule will be about $44 million. The
benefits able to be quantified are
generated by more consistently
produced dietary supplements which
will increase product safety, which
reduces the number of acute illnesses
and product recalls. In addition, the
final rule may generate benefits that we
lack sufficient data to quantify. These
benefits we cannot quantify arise from
dietary supplements manufactured
under a system to ensure quality, which
leads to a reduction in the number of
chronic illnesses and conditions.
The final rule will lead to quantifiable
costs of $16 million in the first year it
takes effect, $120 million in the second
year, and $190 million in the third year.
After 3 years, the annual costs will be
about $164 million. If we annualize the
benefits and costs over 20 years at a 3
percent rate of discount, the annualized
quantifiable benefits are $40 million and
annualized quantifiable costs are $153
million. These annualized benefits
include only those that we are able to
quantify. The total annualized benefits
may be larger than our estimate of $40
million in quantifiable benefits because
of the benefits that we are not able to
quantify.
We have determined, based on
information contained in this regulatory
impact analysis as well as information
contained elsewhere in the preamble,
that the benefits of this final rule justify
the costs.
The final rule will have a significant
economic effect on small businesses. We
estimate that the annual costs will be
about $46,000 for an establishment with
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fewer than 20 employees and $184,000
for an establishment with 20 to 499
employees.
2. Summary of Comments on the
Economic Analysis
We received numerous substantive
comments on the economic analysis of
the 2003 CGMP Proposal. In general,
comments from the dietary supplement
industry state that we underestimated
the cost of the 2003 CGMP Proposal.
Specific comments from the industry
target the 2003 CGMP Proposal’s testing
requirements, which the comments
characterize as ‘‘burdensome.’’ Many
comments address our estimate of the
number of batches of dietary
supplements firms produce in a year.
Many comments express the fear that, as
a result of this 2003 CGMP Proposal, the
prices consumers pay for dietary
supplements would increase
dramatically. Nearly all economic
comments mention potential adverse
effects of the 2003 CGMP Proposal on
small businesses, stating that many
firms would have to stop
manufacturing. A few comments state
that, if made final, the 2003 CGMP
Proposal would make dietary
supplements more expensive than
pharmaceuticals. Other comments
address the following topics:
• FDA’s other assumptions, including
the number of tests required for each
batch and the number of tests already
being performed.
• Development of analytical methods.
• Equipment and capital investment
costs.
• Recordkeeping costs.
• FDA’s estimation of benefits.
We will summarize comments on
individual substantive issues under the
appropriate subject headings and
respond.
B. Final Regulatory Impact Analysis
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1. The Need for the Final Current Good
Manufacturing Practice Rule
The final rule is needed because
establishments that manufacture,
package, label, or hold dietary
supplements may not have sufficient
market incentives to use controls to
ensure that the characteristics of the
supplements are what consumers would
choose to buy if they had full or
adequate information. Dietary
supplements have the characteristics of
both experience goods and credence
goods.12 In terms of the acute illnesses
12An experience good is a product or service
where product characteristics such as quality or
price are difficult to observe in advance, but these
characteristics can be ascertained upon
consumption. A credence good is a good whose
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discussed below, it may be difficult for
consumers to identify the attributes of
dietary supplements before the actual
consumption of the good. Therefore, it
may be difficult, in the absence of some
regulation of dietary supplement
manufacturing practices, for consumers
to differentiate between products
produced under good manufacturing
practices, and those that are not, at the
point of purchase in the marketplace. In
terms of dietary supplements as
credence goods, consumers may never
have adequate information on product
characteristics even after the
consumption of the good, making it
difficult for consumers to determine
what benefits each product offers.
Because problems can be undetectable,
establishments may not adopt the
necessary practices to ensure product
attributes are as they are intended
unless required to do so by regulation.
Of course, the characteristics of
dietary supplements, as a type of food
product, argue for some sort of
Government intervention in this market
in order to alleviate the specific market
failures that lead to the types of
problems with dietary supplements that
this rule addresses. There are many
types of interventions that may be used
to address market failure; FDA has
examined the options and has
determined that specific CGMPs are
necessary for dietary supplements. The
rest of this regulatory impact analysis,
and particularly section III.A of this
document, discusses why FDA has
concluded that specific CGMPs are
necessary for dietary supplements.
(Comment 337) We received several
comments on the need for the 2003
CGMP Proposal. Four comments
specifically support the proposal,
stating, in part, that they are pleased we
are addressing the issue of dietary
supplement manufacturing. In addition,
one comment states that the 2003 CGMP
Proposal was a good step toward
providing assurance that dietary
supplements are as safe as prescription
and OTC drugs.
Other comments express concern
about the 2003 CGMP Proposal. One
comment generally supports it, but
expresses concern that the statements
we make regarding market incentives to
prevent adulteration and misbranding
are inaccurate and misleading. The
comment points out that the incentive
exists for firms to prevent adulterated
products from entering the marketplace
because of their desire to avoid damage
to their reputations. In addition,
utility impact is difficult or impossible for the
consumer to ascertain even after consumption of
the good.
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adulterated products are already illegal
to market. Two other comments support
the 2003 CGMP Proposal only with
modifications, and another comment
supports CGMP regulations, provided
they reflect the current ‘‘best practices
of leading manufacturers.’’ Two
comments assert that a ‘‘more rigorous’’
enforcement program would be more
effective than dietary supplement CGMP
requirements in preventing adulteration.
Two comments state that a regulation
would serve no useful purpose because
of the ‘‘low level of harm identified in
the industry.’’
One comment states that the 2003
CGMP Proposal spells out design
standards rather than performance
standards. According to the comment,
the 2003 CGMP Proposal spells out
procedures a firm must follow rather
than defining a specific outcome, such
as a specified level of contamination.
This comment maintains that we should
set a performance standard and then
allow manufacturers flexibility in how
that standard is reached. Another
comment states that, although certain
dietary supplement ingredients may
cause concern, this concern did not
justify imposing ‘‘overbearing’’ and
‘‘broad’’ CGMP regulations for an entire
industry. Another comment asserts that
the CGMPs as presented in the 2003
CGMP Proposal would serve as an anticompetitive tool by allowing dominant
manufacturers to increase their
dominance and make it more difficult
for new firms to enter the industry.
(Response) Those comments that
disagreed with our analysis provided no
data or evidence to support the
comment. Without such data or
evidence, we have no basis upon which
to revise our analysis and continue to
use the analysis. Thus, we have not
made any changes based on these
comments.
Whether or not these provisions are
performance or design standards is a
theoretical issue. Instead of specifically
choosing either design or performance
standards for all provisions of the rule,
FDA has chosen to provide flexibility to
manufacturers whenever possible. For
example, providing for the use of ‘‘safe
and sanitary’’ water sources gives
manufacturers flexibility in deciding the
best way to assure that ‘‘safe and
sanitary’’ water is used in the
manufacture of their products. There are
many areas of the rule where more than
one way is given to comply with a
particular provision. This flexibility
allows manufacturers to choose the
appropriate means to comply with the
provision that is the most cost-effective
for them.
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We agree with the comments that
point out that existing statutes and
regulations, concern for brand names,
and voluntary industry standards
provide some product safety and
quality. Nonetheless, continuing
problems in the industry provide
evidence for the need for this final rule.
From 2000 through 2005, there were a
total of 75 recall actions in the dietary
supplement industry, including class 1,
2, and 3 recalls of vitamins and minerals
and herbal and botanical supplements.
We will discuss these recalls, which
accounted for about 4 percent of the
1,937 FDA food recall actions in 2000
through 2005, later in this document.
Most of these recalls occurred because
establishments failed to adhere to
product manufacturing or labeling
specifications.
For a class 1 recall, there is a
reasonable probability of serious
adverse health consequences or death;
for a class 2 recall, exposure to the
product may cause temporary or
medically reversible adverse health
consequences; for a class 3 recall,
exposure to the product is not likely to
cause adverse health consequences. Full
compliance with the provisions of this
final rule could have prevented most of
the recalls. We note also recall
classifications only track acute hazards,
not long-term quality problems. Results
from ConsumerLab.com and other
independent laboratory results provide
further evidence of a need for this final
rule (Refs. E3 through E6). Statistical
sampling methods were not used to
collect the data reported in these
analyses. Therefore, although this
information provides anecdotal
evidence of problems, the data may not
be representative of overall industry
practices. The information serves as
additional evidence of the existence of
problems.
Although the final rule will increase
the monetary cost of entering the dietary
supplement industry, the industry will
remain highly competitive with more
than a thousand competing producers
and thousands more potential entrants.
2. Regulatory Options
We considered several regulatory
options for dealing with current
manufacturing, packaging, labeling, and
holding practices that may not ensure
the quality of the dietary supplement.
The options considered include: (1) No
new regulatory action, (2) fewer
requirements for vitamins and minerals,
(3) more restrictive regulations than the
final rule, (4) HACCP without the other
elements of the final rule, (5) final
product testing only, (6) a final rule for
high-risk products or hazards only, and
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(7) the 2003 CGMP Proposal.13 As a
result of comments on the 2003 CGMP
Proposal and our reconsideration of our
position on several provisions, this final
rule differs from the 2003 CGMP
Proposal.
(Comment 338) We received few
comments on the option of fewer
requirements for vitamins and minerals,
and the comments submitted did not
support this option. One comment
supports one set of CGMPs that would
apply to the entire industry rather than
fewer requirements for vitamins and
minerals than for botanicals. Another
comment states that having fewer
requirements for vitamins and minerals
would not be wise because of the large
number of people who take
multivitamin or mineral supplements.
One comment supports more
restrictive CGMP requirements,
including further testing and quality
assurance requirements.
We received two comments that
support HACCP without other elements
of the final rule. One comment echoes
an earlier comment made about
stressing outcomes and points to the
HACCP systems in the juice and seafood
industries as a way of ensuring effective
quality control design. The comment
asserts that the detailed manufacturing
controls and testing requirements
spelled out in the 2003 CGMP Proposal
may actually stifle innovation. Another
comment echoes these thoughts, adding
that a HACCP approach could work in
tandem with a more traditional
specification and test approach.
We received one comment that
specifically discusses requiring only
final product testing, but received
numerous comments on final product
testing in general. The specific comment
did not support reliance on final
product testing only, stating it is not the
best or most appropriate control. In
addition, the comment claims it is not
technically feasible in many cases and
is economically burdensome, a point
repeated in other general comments
about final product testing. In addition,
numerous comments point out that a
firm cannot ‘‘test in quality,’’ meaning
that ensuring the quality of the dietary
supplement will not be achieved
13Options 1 through 6 were discussed in detail in
the 2003 CGMP Proposal (68 FR 12157 at 12221
through 12223; March 13, 2003) and analyses of
costs were provided when possible. The principles
of the options discussion have not changed and are
still relevant for purposes of the requirements of the
final rule. The 2003 CGMP proposal also included
an Analysis of Impacts which contained some
errors from a contractor’s report. We have corrected
the analysis and have recalculated the costs of the
2003 CGMP Proposal. These corrections and
recalculations are discussed in section XXIV.B.9 of
this document.
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34919
through rigorous end-product testing,
which emphasizes the wrong stage of
production, but by ensuring quality
through an effective process control
system.
Few comments discuss regulation of
only high-risk products. Those that did
note that some ingredients would be of
public health concern and it would be
preferable to test these ingredients only
rather than all ingredients.
(Response) The comments on the
regulatory options did not provide
evidence to directly support or oppose
those options but instead addressed
particular issues such as testing or
coverage.
We took the comments on specific
issues into account in the analysis of
this final rule. We discuss them below
in the relevant parts of the analysis.
One comment supporting HACCP
stated that the detailed manufacturing
and testing requirements of the 2003
CGMP Proposal would, compared with
HACCP, stifle innovation. Although
regulations that impose costs can divert
resources away from innovation, the
costs of this final rule represent less
than 1 percent of industry revenues (see
table 35 of this document). Because
research and development expenditures
account for a small fraction of total
expenditures, any reduced expenditures
on research and development associated
with this final rule will be a small
fraction of 1 percent of revenues. Thus,
it seems unlikely that this rule would
have the effect of stifling innovation. As
we explained in the economic analysis
of the 2003 CGMP Proposal, the HACCP
option would not specify detailed
manufacturing requirements but would
also fail to ensure product quality (68
FR 12157 at 12222). In section X.I of this
document, we discuss why HACCP is
not appropriate for dietary supplements.
The comment supporting HACCP failed
to provide any data or any evidence to
support its conclusion. Without such
data or evidence, we have no basis upon
which to revise our analysis and
continue to use the analysis.
3. Coverage of the Final Rule
The final rule applies to
establishments that manufacture,
package, label, or hold dietary
supplements. Tables 20 and 21 of this
document list the estimated number of
covered manufacturers, packagers,
labelers, holders, and other
establishments subject to the final rule.
Table 20 shows the number of
establishments categorized as
manufacturers, repackagers or
relabelers, holders whose primary
business is dietary supplements, and
other (although not including other
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holders and distributors). Table 21
shows our estimate of the number of
general warehouses, wholesalers, and
others that hold dietary supplements,
but are not otherwise involved in the
industry.
TABLE 20.—COVERED ESTABLISHMENTS BY TYPE OF OPERATION FROM THE DIETARY SUPPLEMENT ENHANCED
ESTABLISHMENT DATABASE (DS–EED)
No. of
Establishments
Establishment Type
Manufacturer
Percent of
Establishments
1,228
84.1
26
1.8
114
7.8
92
6.3
1,460
100.0
Repackager; relabeler
Holder
Establishments not already classified
Total
TABLE 21.—COVERED ESTABLISHMENTS THAT HOLD DIETARY SUPPLEMENTS
Type of Holders
NAICS Code
No. of
Establishments
General grocery wholesalers or drug wholesalers
424410
4,036
General warehouse
493110
4,415
42420
7,418
Drug wholesalers
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Total
15,869
We consulted several sources to
estimate the number of establishments
reported in this document. The number,
1,460, is the estimated number of
establishments in the DS-EED that
manufacture, package, label, or hold
dietary supplement products in the
United States. In the analysis of the
2003 CGMP Proposal, we included an
additional 106 U.S. establishments that
supplied dietary ingredients. Because
those establishments are not covered in
this final rule, we exclude them from
the total. RTI developed the DS-EED
using FDA’s Official Establishment
Inventory and supplemented that source
with information from trade
organizations, trade shows, and
electronic databases (Refs. E1 and E2).
To estimate the total number of
establishments that could hold dietary
supplements but do not consider dietary
supplements as their primary business,
we first looked for a count of
establishments that had North American
Industrial Classification System
(NAICS) codes for wholesalers of
groceries or drugs. Next we looked for
a count of firms that met the description
of warehouses for groceries or drugs. We
did not find a category devoted
exclusively to food and drug
warehousing, so we concluded that
general warehousing most closely
corresponded to the set of
establishments that would hold dietary
supplements. The results are shown in
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table 21 of this document. This total
differs from the total reported in the
analysis of the 2003 CGMP Proposal
because the new classification system
allows us to identify more
establishments that would not hold
dietary supplements and therefore
exclude them from the total.
Foreign firms that export dietary
supplements to the United States must
satisfy the requirements of this final
rule. We do not have data on the
number of foreign firms that export
dietary supplements to the United
States. The small number of foreign
products in the FDA dietary supplement
sales database suggests that relatively
few foreign firms export dietary
supplements to the United States (Ref.
E7). The foreign firms that will be most
affected by the final rule are suppliers
of dietary ingredients. Although
suppliers of dietary ingredients are not
directly covered by the final rule, the
need of manufacturers to meet the
ingredient specifications required by the
final rule will indirectly affect foreign
suppliers (as well as domestic
suppliers).
No comments were received on the
economic analysis of the coverage of the
2003 CGMP Proposal.
4. Baseline Practices
a. Consumption. Baseline risks
depend on baseline consumption of
dietary supplements. Total sales in 2004
were about $20 billion (Ref. E8).
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Vitamins and minerals accounted for
about 42 percent of sales. Sales of herbal
supplements, which have not grown in
recent years, were half as large as sales
of vitamin and minerals, accounting for
about 21 percent of the total. Amino
acids, proteins, animal extracts, tea-like
supplements, and other supplements
not otherwise classified accounted for
the remainder of sales.
There were no comments on the
consumption baseline.
b. Manufacturing. We contracted with
RTI to conduct a survey of the dietary
supplement industry to learn about both
baseline (existing) manufacturing
practices and the existing standards
used for manufacturing dietary
ingredients and dietary supplements
(Ref. E2). A sample of 966 dietary
supplement establishments from the DSEED database was selected from an
estimated eligible population of 1,566
firms in the industry (the total number
of dietary supplement establishments
included 106 ingredient manufacturers,
who are now excluded from the
requirements of the final rule). The
eligibility criteria and the response rate
for the survey are fully explained in the
final report on the survey (Ref. E2). We
further classified the target firms by
product and by size. The product
categories were: (1) Vitamins and
minerals; (2) amino acids and proteins;
(3) herbals and botanicals, including
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extracts; and (4) supplements not
already classified.
The Small Business Administration
classifies companies as ‘‘small’’ based
on the size of the entire company,
including both parent and subsidiaries.
If firms that manufacture dietary
supplements have fewer than 500
employees, they are classified as small.
In addition, for purposes of this
analysis, we classify firms with fewer
than 20 employees as very small.
34921
We received 238 completed surveys.
Table 22 of this document shows the
number of completed surveys by
product and by size of establishment.
TABLE 22.—NUMBER OF COMPLETED SURVEYS BY SAMPLING STRATA
Size
Very Small (fewer
than 20 employees)
Small (20 to 499
employees)
Large (500 or more
employees)
Unknown
Total
Vitamins and minerals
19
39
13
1
72
Amino acids, proteins
8
7
0
5
20
Herbals and botanicals, including extracts
58
25
0
30
113
Supplements not already
classified
14
13
2
4
33
Total
99
84
15
40
238
(Comment 339) We received two
comments on manufacturers’ baseline
practices. One comment expresses
concern that, as the information is over
3 years old, it may no longer represent
current industry practices. The second
comment questions the way we
calculated the number of dietary
supplement establishments that do not
follow any CGMP models. In the 2003
CGMP Proposal, we state that survey
data reflect that 36 percent of surveyed
establishments do not follow any CGMP
models. The comment points out that
26.5 percent of firms responded ‘‘no’’ to
the question, ‘‘Does this plant follow a
published GMP model for the dietary
supplement products produced at this
plant?’’ Furthermore, of the 63 that
answered ‘‘no,’’ ‘‘at least’’ 29 of the
firms provided responses indicating the
reason they do not follow a published
GMP is that they did not manufacture
dietary supplement products.
(Response) Although the survey
responses are now over 6 years old, they
represent the best information we have
on the industry and its practices. We
have, however, adjusted our estimated
costs to reflect the correction of the
results from the original survey.
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5. Baseline Risk
The current number of illnesses
caused by poor dietary supplement
manufacturing practices requires data
linking illnesses to poor practices.
Because these data do not exist, we
looked for other information to provide
indirect evidence on the problem. We
looked at many sources for information,
including medical and other literature
on adverse events, information from
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poison control centers, reports to the
agency, newspaper and magazine
articles, and surveys of users. The
literature review was conducted using
Medline, Healthstar, Aidsline, Cancerlit,
and OldMedline (Ref. E9). We found
evidence of many adverse events
associated with dietary supplements.
For example, in 2003, the American
Association of Poison Control Centers
received 24,412 reports on events
associated with herbal dietary
supplements and 57,801 reports on
events associated with vitamin and
mineral supplements, with 8,653 of the
herbal and 5,669 or the vitamin and
mineral reports treated in health care
facilities (Ref. E10). In addition, we have
received many voluntary reports of
illnesses caused by dietary supplements
(Ref. E11).14
The vast majority of these events and
those described in other sources we
consulted, however, are reported as
associated with the ingredients used in
the products themselves, not with
contamination or other results of poor
manufacturing processes. Most of the
reports from poison control centers on
vitamins and minerals, for example,
involved inappropriate ingestion by
children (Ref. E10). We have no direct
evidence on how many illnesses can be
attributed to manufacturing processes.
14Mandatory reporting to FDA of serious adverse
events is now required as a result of the enactment
of the ‘‘Dietary Supplement and Non-Prescription
Drug Consumer Protection Act’’ (Public Law 109–
462), signed into law on December 22, 2006. The
new law requires manufacturers, packers, or
distributors of such products to submit reports to
FDA about serious adverse events involving such
products based on specific information that they
receive from the public.
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The anecdotal evidence described
elsewhere in the preamble suggests that
many illnesses could have been caused
by poor manufacturing processes, but
there are only a few examples of
evidence that explicitly link illnesses to
manufacturing processes. Examples of
illness that were linked directly to poor
manufacturing practices include
vitamin D toxicity from excessive
vitamin D in multivitamins and cardiac
glycoside poisoning from botanical
dietary supplements contaminated with
Digitalis lanata (Ref. E12).
With no direct evidence on the
number of illnesses caused by poor
manufacturing practices, we had to use
an indirect approach. We based the
approach on our recall records. Class 1
and class 2 recalls all involve defective
products that could have caused illness
if ingested. Although the recall data
cannot be linked directly to illness data,
we have found anecdotes, surveys, and
some medical literature on illnesses that
could be caused by avoidable dietary
supplement manufacturing mistakes.
We have recall data that show that
manufacturing mistakes exist, so we can
construct a plausible link between
manufacturing mistakes and potential
illnesses or injuries. The number of
illnesses associated with a
manufacturing problem leading to a
recall is both variable and uncertain,
and could be anything from zero to
quite large. Based on data from FDA
food and dietary supplement recalls, we
concluded that one reported illness per
recall is a plausible average, so we
assumed that a recall could be a proxy
for a single reported illness associated
with a defective product.
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Because there are no active
surveillance systems for identifying
adverse health events related to dietary
supplements, we assume that the total
number of illnesses caused by poor
manufacturing practices is substantially
greater than the number reported.15
Based on data for drug and vaccine
reporting rates in other studies, one
study concluded that for dietary
supplements, reported illnesses
represent approximately 1 percent of
total illnesses (Ref. E13). We use the
associated multiplier, 100, in our
baseline estimate and assume that
reporting adverse health events due to
poorly manufactured dietary
supplements occurs at the same rate as
reporting adverse health events caused
for other reasons by dietary
supplements. Other reporting rates and
associated multipliers are, however,
plausible. For some hazards that lead to
severe events only, we have used a
multiplier of 10; the Centers for Disease
Control and Prevention have used a
multiplier of 38 for Salmonella
infections and similar food-related
illnesses. We show the sensitivity of
benefits to the choice of multiplier
below.
From 1990 through 1999, we received
reports on an annual average of 11.8
class 1 and class 2 recalls of dietary
supplements related to manufacturing
problems. If we assume that each recall
is a proxy for a reported illness, then the
total number of illnesses per year is
approximately 1,180. We recognize that
our procedure generated uncertain
estimates of the number of illnesses.
With a multiplier of 10, the estimated
number of illnesses per year is 118; with
a multiplier of 40, the total number of
illnesses per year is 472.
We estimate that the monetary value
of the health losses for the hazards
listed in table 23 of this document as a
weighted average of the values attached
to the different health outcomes
associated with each hazard. We
estimate the health losses or fatal cases
as the monetary value of a statistical
life, defined as the willingness to pay
for a small change in the probability of
death. We estimate the health losses for
non-fatal illnesses as the sum of: (1) The
imputed value of lost productivity, (2)
the imputed value of pain and suffering,
and (3) actual expenditures on medical
treatment. We measured lost
productivity (defined to include
household and market productivity)
indirectly with measures of functional
state, which includes measures of
physical function. We estimated the
losses caused by pain and suffering with
a symptom-problem index. We combine
the functional losses with the pain and
suffering into a single index of lost
quality-adjusted life years (measured by
the Quality of Well-Being Index). We
then convert the quality-adjusted life
years to dollars by multiplying the
index numbers by the dollar value of a
quality-adjusted life year. We used
direct measures of medical costs, such
as payments to physicians and
hospitals. We obtained data on the cost
of a hospital day and other medical
costs from the Health Care Cost and
Utilization Project’s Nationwide
Inpatient Sample, administered by the
HHS Agency for Healthcare Research
and Quality (Ref. E14).
Table 23 of this document contains
summaries of our measures of the health
costs potentially caused by known
instances of hazards associated with
poor dietary supplement manufacturing
processes for the decade 1990 through
1999. We estimated the health loss per
day for the different levels of illness
severity by summing the lost
productivity (as measured by functional
state) and the loss from pain and
suffering (as measured by the symptomproblem index). These losses per day
can be interpreted as the difference
between a day of normal health and a
day of suffering from the health
conditions caused by these defective
products. The numerical scale is a
relative baseline that rests on the notion
of a quality-adjusted life day (QALD).
The QALD for a day of normal health
equals 1; the QALD for death equals 0.
The loss of QALDs per illness equals the
daily loss multiplied by the number of
days the illness lasts. We converted
QALDs to dollars by multiplying the
index numbers by the dollar value of a
QALD. We computed the monetary
value of a QALD using three values
derived from three different values for a
quality-adjusted life year: $100,000,
$300,000, and $500,000. These yield
values per day of $274, $822, and
$1,370. Our base measures use $822; we
show the effects of using other values in
the sensitivity analysis.
TABLE 23.—SUMMARY OF HEALTH EFFECTS BASED ON POTENTIAL ILLNESS ASSOCIATED WITH RECALLS BETWEEN 1990
AND 1999
Number of
Recalls
Recall Class
Expected Value
of Illness
Expected Value of Illness Times
Number of Recalls
Chemical
2
1
$489
$489
Digitalis
1
33
$37,442
$1,235,599
Ephedra
1
1
$177,237
$177,237
Hypervitaminosis A
1
2
$1,264
$2,528
Hypervitaminosis D
2
1
$1,366
$1,366
Lead poisoning (class 1)
1
1
$15,591
$15,591
Lead poisoning (class 2)
2
40
$10,436
$417,451
Niacin
sroberts on PROD1PC70 with RULES
Copper salts
2
2
$5,802
$11,603
Pyridoxine (Vitamin B6)
2
1
$12,085
$12,085
15Mandatory reporting to FDA of serious adverse
events is now required as a result of the enactment
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of the ‘‘Dietary Supplement and Non-Prescription
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Drug Consumer Protection Act’’ (Public Law 109–
462), signed into law on December 22, 2006.
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34923
TABLE 23.—SUMMARY OF HEALTH EFFECTS BASED ON POTENTIAL ILLNESS ASSOCIATED WITH RECALLS BETWEEN 1990
AND 1999—Continued
Number of
Recalls
Recall Class
Expected Value
of Illness
Expected Value of Illness Times
Number of Recalls
Selenium poisoning (class 1)
1
1
$755,338
$755,338
Selenium poisoning (class 2)
2
6
$1,288
$7,731
Stannous fluoride
1
1
$1,266
$1,266
Superpotent zinc
2
1
$389
$389
Botulism (class 1)
1
1
$494,683
$494,683
Botulism (class 2)
2
1
$2,044
$2,044
Klebsiella Pneumonia
1
1
$774,178
$774,178
Salmonella (class 1)
1
4
$15,298
$61,191
Salmonella (class 2)
2
4
$778
$3,110
Lactose intolerance
2
1
$396
$396
Undeclared sulfites
1
1
$723
$723
Yellow #5 sensitivity
2
5
$723
$3,616
Yellow #6, red #40, blue #2
2
1
$1,595
$1,595
2
1
$4,241
$4,241
1
7
$1,135
$7,946
Biological
Allergenic
Physical
Glass fragments
Other
L-tryptophan (Eosinophilia-Myalgia Syndrome
(EMS))
sroberts on PROD1PC70 with RULES
Total
118
The hazards that occurred between
1990 and 1999 are not necessarily the
same hazards that would occur today.
For example, botulism is rare and may
no longer be a hazard associated with
dietary supplements, but recalls
involving botulism represent generic
examples of adulteration that could
occur with other substances in the
absence of good manufacturing
practices. Also, we base our cost
estimates on information from 1999, so
it is appropriate to estimate benefits
from the same time.
(Comment 340) We received a
comment that took issue with the way
the recalls are counted. The comment
asserts it is more appropriate to count
each recall action as a separate recall,
regardless of the number of different
products affected.
The same comment criticizes the
inclusion of the outbreak of
Eosinophilia-Myalgia Syndrome (EMS)
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in the table of what is characterized as
‘‘ordinary’’ recalls, since this case is
analyzed separately as an example of a
‘‘rare catastrophic event.’’ The comment
states that the outbreak of Digitalis
should also have not been included in
the recall list because it also was a rare
event. The comment asserts that FDA
announcements and media attention
should have led to full reporting of any
adverse events.
Other comments generally refer to risk
associated with dietary supplements.
One comment states that botanical
supplements pose minimal risk if
dispensed directly to a patient rather
than used in an unsupervised setting,
and that toxicology and adverse event
reports indicate that end-of-process
adulteration in herbal clinics is rare. By
contrast, another comment states that
adverse events related to dietary
supplement use led to hospital
admissions at one location and that
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$3,992,397
reports of misbranded and adulterated
dietary supplements are common.
(Response) We are not changing the
way we count recalls. Each different
recall will continue to be counted as a
separate recall. How recalls are counted,
however, does not affect the analysis.
The method used in this analysis
corresponds to an average of about one
reported illness per recall action. A
particular event can lead to many recall
actions. If we changed the way we
counted recalls so as to reduce the
number of baseline recalls to correspond
to events, the average reported illnesses
per recall would rise in proportion. The
estimated benefits would not change.
We are no longer including the
outbreak of EMS in our analysis of
benefits. The product recalls associated
with EMS occurred several years after
the outbreak that we are now excluding.
The continued benefit associated with
preventing EMS is associated with
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sroberts on PROD1PC70 with RULES
incorporating quality controls aimed at
such hazards.
6. Benefits
The benefits of this final rule come
from ensuring the quality of dietary
supplements. Dietary supplements
should contain the listed ingredients in
the listed amounts in product forms that
disintegrate and dissolve. Dietary
supplements should not contain any
contaminants that would adulterate the
product under section 402(a)(1), (a)(2),
(a)(3), or (a)(4) of the act.
Estimating the benefits of preventing
adulteration and contamination is
straightforward, at least in theory. These
benefits are the value of reducing the
risk of the acute illnesses and longerterm complications associated with
physical, chemical, and microbiological
contamination (see table 23 of this
document). The direct value of
preventing recalls is another source of
benefits from preventing adulteration
and contamination. We estimate the
benefits of preventing adulteration and
contamination by first estimating (based
on recall data) the number and kinds of
illnesses prevented, and then placing a
value on preventing those illnesses. We
include the recall costs avoided by
industry as additional benefits of
preventing adulteration and
contamination.
Estimating the value of ensuring the
quality of the dietary supplements and
that they are manufactured according to
their specifications is difficult in
practice because we lack the necessary
data on what is missing and how what
is missing affects public health. Some
dietary supplements have authorized
health claim labeling that allows them
to state their products may reduce the
risk of chronic illnesses or conditions.
Ensuring that those supplements are
manufactured consistently according to
the appropriate specifications will
increase their effectiveness in reducing
the risk of chronic illnesses. In this
analysis, we describe those benefits but
are not able to quantify them.
The benefits from the final rule, then,
will be:
• Reduced health costs associated
with a reduced number of acute
illnesses (quantified),
• Fewer product recalls (quantified),
and
• Reduced health costs associated
with a reduced number of chronic
illnesses and conditions (not
quantified).
This final rule could also enhance the
benefits of the ‘‘Dietary Supplement and
Non-Prescription Drug Consumer
Protection Act’’ (Public Law 109–462),
which requires mandatory reporting to
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FDA of serious adverse events. This
final rule includes requirements that
will provide the information needed to
quickly and accurately conduct a
sufficient traceback in the case of an
adverse event. This enhanced ability to
track information related to serious
adverse events will increase both the
accuracy and the speed of the response
to such events, which may in many
cases reduce the number of illnesses or
deaths associated with unsafe dietary
supplements.
(Comment 341) We received many
comments on the estimated benefits.
Although we did receive comments that
stated the rule would benefit consumers
by enhancing public confidence in
dietary supplements, many comments
state that the estimated benefits in the
2003 CGMP Proposal were overstated.
In addition, one comment states that our
estimates of benefits are double
counted, because the outbreak of EMS
was included in the measure of benefits
from preventing a large catastrophic
event as well as total benefits of
reduction of illnesses measured by
recalls. Furthermore, comments critical
of the benefits state the search cost
model used in the analysis is not
applicable or the benefits of reduced
search costs do not exist, we lack
evidence with which to base the
estimate of reduced health care costs
from elimination of rare catastrophic
events, and recalls will not fall to zero
as a result of implementing CGMPs.
(Response) We agree with the
comment that benefits were overstated
because of the inclusion of the outbreak
of EMS. We no longer include the value
of preventing that or similar outbreaks
in our estimate of benefits. Although we
do not agree with the comments on the
applicability of the search model as a
measure of benefits, the empirical
difficulties associated with quantifying
those benefits have led us to replace the
search model with a qualitative
description.
We now explain each of the three
sources of benefits: Reduced acute
illnesses, fewer recalls, and reduced
chronic illnesses and conditions.
a. Reduced health costs associated
with a reduced number of acute
illnesses. The final rule will help ensure
the quality of dietary supplements,
which will lead to improved safety of
dietary supplements, reducing the
probability of acute illness or deaths
caused by manufacturing problems. We
estimated the reduction of acute
illnesses by using our recall records as
evidence of possible illnesses; class 1
and class 2 recalls of dietary
supplements all involved adulterated
products that could have caused illness
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if ingested. In the 2003 CGMP Proposal,
we estimated the reduction of illnesses
from preventing catastrophic events by
using the public health effects of the
outbreak of EMS that resulted from
consumption of contaminated Ltryptophan. We agree with comments
questioning the applicability of this
outbreak to CGMP, so we are no longer
including the value of preventing this
outbreak as a benefit of this rule.
We estimated the annual expected
health benefits for acute illnesses
prevented by taking the values of
preventing particular illnesses and
weighing them by their likely incidence
as indicated by recall data. The acute
illnesses prevented that we use to
estimate benefits are not actual
illnesses, but statistical illnesses
(defined as the probability of illness
multiplied by the population at risk)
prevented by the reduction in risk
associated with this final rule. These
recalls indicate recurring failures to
ensure the quality of dietary
supplements. Although each class 1 and
2 recall is estimated to have resulted in
some illnesses (which may have
triggered the recall), there may also be
other manufacturing problems that did
not lead to recalls but that did lead to
illness. Both situations are part of the
baseline number of illnesses and deaths
estimated.
We computed the expected health
benefits from preventing a single illness
(of any type) associated with a recall as
a weighted average of all potential
illnesses. We then calculated the
average health benefits of preventing a
single illness associated with a non-fatal
class 1 or a class 2 recall as:
Health costs prevented = (QALY x value
per QALY) + medical costs
We define QALY as the average qualityadjusted life year per illness; as
explained earlier, we computed the
average by weighting the quality
adjusted life years lost for the
probability of each health outcome by
the expected frequency of that outcome.
To estimate the number of acute
illnesses prevented, we started with the
average number of recalls per year for
the decade 1990 through 1999. The
yearly averages for the decade were six
class 1 recalls and seven class 2 recalls.
As discussed previously, we then
assumed that these recalls represented
about 1 percent of all acute illnesses
caused by the manufacturing problems
leading to the recalls. With that
assumption, we estimated that the
recalls represented about 530 acute
illnesses from class 1 recalls and 650
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acute illnesses from class 2 recalls.16
The illnesses used to estimate the
benefits of the final rule represent a
sample of acute illnesses that could
occur without this final rule. We assume
that the benefits computed for the
average year from the decade 1990
through 1999 represent the annual
average benefits we should expect in the
future. We do not assume that the acute
illnesses prevented in the future will be
identical to those that occurred during
1990 through 1999.
TABLE 24.—HEALTH BENEFITS ESTIMATED USING RECALL DATA
FROM 1990 THROUGH 1999
Estimated annual number
of acute illnesses prevented (530 class 1 and
650 class 2 recalls)
1,180
Dollar estimate of average
health benefit for preventing an acute illness
associated with a class
1 or class 2 recall
$33,800
Estimated dollar estimate
of annual health benefits
$40 million
sroberts on PROD1PC70 with RULES
The estimated benefits are indeed
sensitive to the choice of years. For 2000
through 2005, there were 75 recalls: 29
class 1, 25 class 2, and 21 class 3. The
annual averages for 2000 through 2005
are therefore 4.8 class 1, 4.2 class 2, and
3.5 class 3 recalls. We estimate that
about 80 percent of the class 1 and class
2 recalls were related to manufacturing
problems (for 1990 through 1999 over
95 percent of class 1 and class 2 recalls
stemmed from manufacturing
problems). With an average of 9 class 1
and class 2 recalls per year, our baseline
estimate of total associated illnesses
using 2000 through 2005 data is 900 (9
x 100). If this final rule prevents 80
percent of these events, then 720
illnesses will be prevented. We do not
use this estimate to calculate baseline
benefits for this final rule because we do
not have a comparably recent estimate
of costs. If the reduced number of recalls
16In the uncertainty analysis in section XXIV.B.11
of this document, we used a probability distribution
to represent the uncertainty associated with the
number of illnesses. We modeled the number of
illnesses prevented for each class as the average
number of recalled products plus a negative
binomial distribution representing unknown cases.
The negative binomial distribution estimates the
number of failures (unknown cases) that will occur
before some number of successes (known cases) for
a given probability of success. In the negative
binomial distribution, we assumed that the
numbers of recalls represented reported cases and
that the probability of reporting equaled 1 percent
(Ref. E13). The mean estimated number of illnesses
is 100 times the reported number of recalls.
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reflects increased controls in the
industry, then the benefits and costs of
this final rule will be lower than what
we have estimated.
(Comment 342) We received
comments critical of the estimates of
reduced illness due to recalls. One
comment points out that drugs, despite
having stringent CGMP requirements,
have a higher rate of recalls than dietary
supplements, thus providing evidence
that such requirements do not
necessarily reduce recalls. Expanding
on this thought, other comments state
that we seem to assume that new CGMP
requirements will reduce human error
to zero and no more recalls will occur,
which is said to be unrealistic.
Other comments express concern
about the 100-fold multiplier used to
estimate the costs related to recallassociated illnesses. The comment states
that we, besides referencing Walker
(2000) (Ref. E13 of this document (Ref.
E16 in the 2003 CGMP Proposal)),
provided no other information to
substantiate the use of the 100-fold
multiplier and therefore are being
arbitrary. Any other number could be as
accurate. In addition, other comments
state that it is difficult to believe that the
multiplier would be applicable to
recalls associated with Klebsiella
pneumonia and selenium poisoning,
and L-tryptophan, because the severity
of the illnesses would certainly have
been associated with the highly
publicized recalls; that is, they would
not have gone unreported.
Some comments present recalculated
benefits. One comment estimates
benefits from fewer illnesses as a result
of the 2003 CGMP Proposal to be $10.9
million, rather than our estimate in the
analysis of the 2003 CGMP Proposal of
$39 million. This new estimate was
arrived at by taking into account what
was characterized as double-counted
benefits which, as mentioned earlier,
were characterized as the inclusion of
EMS in the measure of benefits from
preventing a large catastrophic event as
well as total benefits of reduction of
illnesses measured by recalls. Another
comment re-estimates the benefits as
$16 million. This estimate was
calculated assuming 100 percent of
potential illnesses related to Klebsiella
pneumonia were classified as severe
(with none classified as deaths), and 50
percent of illnesses associated with the
selenium recall were classified as
serious and none were classified as
deaths. This comment also disagrees
with the assumption that 3 percent of
the 100 potentially ill from the recall
associated with undeclared ephedra
would have died. Furthermore, this
comment adjusts the benefits to take
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34925
into account recalls that this comment
felt were erroneously included in the
calculation of benefits from reduced
illnesses.
(Response) We have not seen any new
data or other information that would
lead us to change the 100-fold
multiplier for our basic estimate. We
recognize that the multiplier is
uncertain; different multipliers lead to
different estimated numbers of illnesses
and different estimated benefits. With a
multiplier of 10, estimated benefits are
10 percent of our baseline; with a
multiplier of 40, estimated benefits are
40 percent of our baseline. The
estimated benefits of this final rule,
thus, move in proportion to the assumed
multiplier. We recognize this
uncertainty and show how it affects the
estimated benefits in the sensitivity
analysis. The multiplier implicitly
assumes that the more severe illnesses
are more likely to be reported; the
average reporting rate for all adverse
events is assumed to be about 1 percent.
The average incorporates higher
reporting rates for more severe illnesses,
and lower reporting rates for less severe
illnesses.
The comments on the severity weights
for Klebsiella pneumonia and ephedra
did not persuade us to change these
estimates. We based the estimates on the
outcomes for severe events associated
with these hazards. The Klebsiella
weights come from the medical
literature (Ref. E9); the ephedra weights
are based on adverse events involving
ephedrine alkaloids.
The comparison of drug recalls to
dietary supplement recalls does not
provide data that would cause us to
change our analysis. The drug industry
is far larger than the dietary supplement
industry and any such comparison
would have to account for that
difference as well as other differences.
Expenditures on prescription drugs
exceeded $200 billion in 2004.
(Comment 343) We received many
comments regarding the use of the
outbreak of EMS in 1989 as a basis for
estimating health benefits from
preventing a catastrophic event. The
majority of the comments assert that
CGMPs would not have prevented the
outbreak. One comment expands this
assertion by stating our claim that
testing requirements would reduce the
probability that contaminated
ingredients would be released to the
public is incorrect, because it was not
known what, if any, contaminants
caused the outbreak. Secondly, the
comment states that our claim that
complaint files would allow for fast
identification of an adverse health event
is also incorrect because the victims of
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EMS did not know the L-tryptophan
was the cause of their illnesses.
Two other comments question the
periodicity for a cycle of potential
catastrophic events due to dietary
supplements. One comment suggests a
period of 70 years rather than our 30
years. The other comment does not
suggest a period but rather states that,
since we have no data to support the
cycle of 30 years, and we admit it is
difficult to know how likely rare events
are, it is possible that the total projected
benefit could be zero.
Lastly, other comments state that the
benefits from preventing a rare
catastrophic event are double-counted.
These comments state these benefits are
double-counted because they are also
included in the estimation of benefits
from reduced recalls.
(Response) As stated previously, we
are no longer including estimated
benefits from preventing a rare
catastrophic event in the analysis of
benefits. We continue to include the
benefits of preventing statistical cases of
EMS in the annual health benefits,
because several recalls of L-tryptophan,
which could be associated with EMS
took place during the 1990 through 1999
period.17
b. Fewer products recalled.
Implementation of the final rule will
reduce the number of adulterated
products distributed to the public,
which will reduce the number of
products recalled. Process controls and
better recordkeeping will increase the
ability of establishments to produce
dietary supplements according to
specifications and to identify problems
before distribution. If adulterated
products are caught before they are
distributed or earlier in the production
process, they will not need to be
recalled.
To estimate the direct benefits from
fewer recalled adulterated dietary
supplements, we estimate the number of
annual recalls of dietary supplements
that would be prevented by adherence
to CGMP requirements in the final rule.
From 1990 to 1999, FDA received
reports on 195 recalls related to
manufacturing problems, an average of
19.5 recalls per year (Ref. E9). The
average figure reported here includes
class 3 recalls. The number of units of
dietary supplements for each recalled
product varied, so we used a
distribution per recall of 1,000 units to
34,000 units (Ref. E9). Product price
(updated to 2004) also varies, with most
prices falling between $6 per unit and
$11 per unit; we used a most likely
price of $8.50 per unit. We include an
adjustment for the goodwill lost by the
establishment as a result of the recall.
We multiply the direct cost of the recall
by two in order to include the lost
goodwill. We also adjust for recalls that
would likely not be prevented by the
final rule. The result is an estimated
savings of $1.8 million in direct costs
and $1.8 million in goodwill, for a total
savings of about $3.6 million per year.
(Comment 344) We received several
comments on our estimates of the
reduction in recalls. As noted
previously, a comment generally states
that drugs, despite having stringent
CGMP requirements, have a higher rate
of recalls than dietary supplements,
thus providing evidence that CGMPs do
not necessarily reduce recalls. Again,
other comments state that we seem to
hold the unrealistic assumption that the
final rule will reduce human error to
zero and no more recalls will occur.
Another comment points out that the
assumption that the final rule would
cause the discovery of all adulteration is
inconsistent with the requirement that
firms keep complaint files. If the rule
eliminates adulteration, the comment
states, then there should be no
complaints to report.
(Response) We do not believe that
recalls will fall to zero. We assume that
the recalls identified as being
preventable by this final rule will fall to
zero, but that mistakes and other
hazards will continue to generate
recalls. In the sensitivity analysis,
however, we show the effects of a lower
level of effectiveness in preventing
recalls associated with manufacturing
problems.
c. Reduced health costs associated
with a reduced number of chronic
illnesses and conditions. We cannot
quantify the value of ensuring that
dietary supplements contain everything
in the established specifications (and
nothing that is not in the specifications)
because we lack the necessary data on
what is missing and how what is
missing affects public health. The
public health benefits are derived from
the reduced number of chronic illnesses
and conditions. These benefits may
arise from known nutritional effects or
from uncertain nutritional effects.
d. Benefits from known nutritional
effects. Many of the nutritional benefits
of vitamins and minerals are known and
well-documented. For example, the
Dietary Guidelines for Americans, 2005
states that dietary supplements can be
used to help meet the recommended
intakes of vitamin B12, folic acid, and
vitamin D (Ref. E15). The Institute of
Medicine’s Dietary Reference Intakes
include statements that supplements
can be sources of several vitamins and
minerals (Ref. E16). We have recognized
the use of supplements in authorized
health claims for calcium and
osteoporosis (§ 101.72) and folic acid
and neural tube defects (§ 101.79).
In table 25 of this document, we list
some of the health benefits associated
with the consumption of various dietary
supplements.
TABLE 25. SELECTED HEALTH BENEFITS FROM CERTAIN DIETARY SUPPLEMENTS
Dietary Supplement
User
Benefit
Women of child-bearing age
Reduces the risk of neural tube defects
Calcium
Children and adults
Reduces the risk of osteoporosis
Iron
Adolescent females and women of child-bearing age
Reduces the risk of anemia
Vitamin D
Children and adults; persons with dark skin, or with too little
exposure to sunlight
Reduces the risk of osteoporosis
Vitamin B12
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Folic acid
Persons over the age of 50
Reduces the risk of anemia
17We recognize, however, that the presence of Ltrypotophan only indicates a small probability of
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EMS. The estimates in table 23 of this document
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probability of EMS.
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e. Benefits from uncertain nutritional
effects. We do not know the full range
of effects (or lack of effects) of most
dietary supplements. Vitamins and
minerals with known nutritional effects
in supplement form may have other
effects that we have yet to discover. Our
uncertainty is particularly large with
respect to the nutritional effects of
herbal and botanical supplements. The
evidence is still too mixed and
incomplete to determine the effects of
most of these substances. If, however,
herbal dietary supplements do indeed
have significant beneficial effects on the
risk of chronic illnesses and conditions,
then if the final rule ensures that the
supplements consistently meet their
specifications, we should add those
benefits to those from supplements
having known nutritional effects.
The benefits of this final rule that we
can identify are those associated with
the known effects. The product
deficiency might be, for example, that
packages contain some percentage less
or more of the necessary ingredient
(such as calcium) than what is listed on
the label. The relationship between the
shortage or excess amount of the
ingredient and the probability of
chronic illness would also have to be
taken into account in order to determine
the risk associated with the product
deficiencies. The increase in the
probability of chronic illnesses may be
negligible, less than, the same, or more
than the shortage or excess in the
amount of the ingredient. The increase
in the probability of chronic illness
would also depend on how long the
supplement contained a shortage or
excess amount of the ingredient.
Suppose, for example, that a calcium
supplement contains 10 percent less
calcium than it should for 1 year. If the
average consumer takes calcium
supplements for 20 years, would the 1year deficiency of 10 percent increase
the probability of osteoporosis by more
or less than 0.5 percent (10 percent x (1/
20))?
If we could determine the change in
the number of chronic illnesses
prevented by dietary supplements as a
result of this final rule, we could
estimate benefits by multiplying the
additional number of chronic illnesses
prevented by the value of preventing
those illnesses. The values consumers
place on preventing illness differ across
illnesses and across consumers, and are
related to the reasons they use dietary
supplements. We will illustrate the
method with two examples: Calcium
and osteoporosis and folic acid and
neural tube defects.
Calcium and osteoporosis. Many
consumers take calcium supplements to
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reduce the probability of osteoporosis,
which afflicts as many as 10 million
people over age 50 (about 8 million
women and 2 million men). An
additional 34 million men and women
may be at risk for developing
osteoporosis (Ref. E17). If ensuring that
calcium supplements contain what they
should reduces the risk of osteoporosis,
the total osteoporosis health benefits
associated with the final rule will be the
number of cases prevented multiplied
by the health costs per case. We
estimated the health costs per case as
the sum of the direct medical costs, the
value of functional disability, and the
value of the pain and suffering
associated with the illness. Cases range
in severity from mild to severe. A mild
case, for example, might lead to a loss
of utility (measured as quality-adjusted
life years—a year of life adjusted for the
individual’s health status) of 0.14 per
year for 9 years. If we apply a discount
rate of 7 percent to the years the
condition lasts, the loss of qualityadjusted life years is about 0.9 (6.5
discounted years x 0.14 lost utility per
year). In other rulemakings we have
used a range of values for a qualityadjusted life year; the range has been
from $100,000 to $500,000, with a
medium monetary value of $300,000 (68
FR 41434, July 11, 2003). With a value
per year of $300,000, the value of
preventing a mild case is about
$270,000 (0.9 x $300,000).
A severe case, by contrast, can lead to
fractures and permanent disability.
Also, osteoporosis in women can occur
at early ages and last decades. If
someone suffers from osteoporosis for
30 years, the discounted quality
adjusted life years lost would be 6.9
(12.4 discounted years x 0.56 lost utility
per year). We estimate that medical
costs for a severe case can be over
$17,000. The value of preventing a
severe, long-lasting case is therefore
about $2.1 million ((6.9 x $300,000) +
$17,000).
Folic acid and neural tube defects.
Many women of child-bearing age take
dietary supplements to help ensure their
own health, and the health of their
children should they become pregnant.
For example, 40 percent of women aged
18 to 45 take supplements containing
folic acid, which may reduce the
probability that children will be borne
with neural tube defects (Ref. E18).
Neural tube defects affect the spine
(spina bifida) and the brain
(anencephaly). About 3,000 pregnancies
are affected each year (Ref. E18).
The benefit of ensuring that folic acid
supplements contain what they should
equals the population at risk multiplied
by the reduction in the probability of
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neural tube defects, multiplied by the
value of preventing a neural tube defect.
Neural tube defects involve large
medical expenses, and either early
death or permanent disability. The
lifetime medical costs alone are between
$400,000 and $500,000 for spina bifida
(Ref. E19, with values updated). In
recent rulemakings, we have used $5
million as the value of a statistical life,
defined as the willingness to pay for
reductions in small risks of premature
death. Preventing a statistical death
from anencephaly would therefore
generate benefits of $5 million to $6.5
million. For spina bifida, one estimate is
that an average case leads to a loss of
more than 15 quality-adjusted life years,
for a monetized loss of close to $5
million for a non-fatal case if valued at
$300,000 per quality adjusted life year
(Ref. E20). The value of preventing a
case of spina bifida, then, is the sum of
medical costs and the value of a saving
the quality-adjusted life years, or about
$5 million ($450 million value of
quality adjusted life years + $500,000
direct medical costs).
Estimating the total benefits of this
final rule requires estimates of the
numbers of chronic illnesses and
conditions whose incidence can be
further reduced by ensuring that dietary
supplements contain what they should.
Because we have no information on the
baseline number of chronic illnesses
caused by deficient or excessive
ingredients, or on the change in the
likelihood of chronic illness that will
occur as a result of the provisions of this
final rule, we cannot estimate the full
benefits of ensuring that dietary
supplements contain what they should.
Our quantified benefits for this final
rule must therefore consist entirely of
the benefits from reducing the risks of
acute illnesses and reducing the number
of product recalls. The total benefits
will be larger by an amount we are not
able to quantify.
(Comment 345) We received many
comments about the estimated benefits
as measured by the value of
hypothetical search time.
(Response) We are no longer using the
search model.
f. Total benefits. The total benefits
from the final rule are the sum of the
value of health benefits from fewer
acute illnesses, the value of fewer
product recalls, and the value of the
health benefits from fewer chronic
illnesses. Table 26 of this document
shows the total benefits.
(Comment 346) One comment states
that our total estimated benefits could
be as little as $21 million.
(Response) Our current estimate of
total quantified benefits is $44 million
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per year, once the final rule takes full
effect. In addition, as discussed
previously, there are benefits to this rule
that have not been quantified. The
unqualified benefits estimate is the
mean of a range of estimates based on
assumptions about reporting rates and
the effectiveness of the final rule.
In the analysis of benefits for this rule
there are two large uncertainties:
Quantified underreporting of acute
illnesses and injuries and nonquantified
benefits associated with chronic
illnesses. Despite the best efforts by
public health authorities, there will
always be underreporting of illness and
injuries. Where fatalities are concerned,
unless there are litigation problems or
the potential for the spread of infectious
disease, there is no incentive to do
extensive forensic work to determine
whether a fatality is related to the
ingestion of a dietary supplement. This
leads to reporting most fatalities under
the most general International
Classification of Diseases codes. We
acknowledge the large uncertainties in
our estimate because of these factors.
The degree of prevention of chronic
illnesses due to preventing super- or
subpotent dietary supplements depends
on two factors, both of which are highly
uncertain. The first factor concerns
product benefit: How many dietary
supplements have any beneficial effect
on chronic illnesses and how strong are
those effects? Recent work in this area
so far has examined only a few dietary
supplements, with mixed results. Of
course, ensuring the potency of an
ingredient that has adverse effects or has
adverse interactions with drugs would
subtract from the benefits. The second
factor is the incidence and effects of
subpotency and superpotency across
products and over time: How much of
a difference in the product need there be
to generate a substantial adverse health
effect? Because of these uncertainties, it
is virtually impossible to make any sort
of quantitative statement about likely
effects of a regulation ensuring against
superpotency and subpotency.
Because of the uncertainties in
estimating the benefits associated with
both chronic and acute illnesses
associated with manufacturing practices
for dietary supplements, the decision to
implement regulatory requirements
becomes an exercise in weighing
quantitative and qualitative benefits to
public health against expenditure of
scarce resources. By choosing to go
forward with this rule, FDA is
exercising precaution with respect to
uncertain risks.
In the uncertainty and sensitivity
analyses in section XXIV.B.11 of this
document, we show how uncertainty
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and different assumptions generate
higher or lower quantifiable benefits.
Using plausible assumptions about the
uncertain variables, we estimate that
total quantified benefits (using 1990
through 1999 data) most likely fall
within a range of $8 million to $64
million per year.
TABLE 26.—SUMMARY OF ANNUAL
BENEFITS
Benefits
Mean
Fewer acute illnesses
$40 million
Fewer product recalls
$4 million
Fewer chronic illnesses
Not quantified
Total quantified benefits
$44 million
7. Costs
The same changes in manufacturing
practices that produce benefits also have
opportunity costs. Due to the increased
expenditures of complying with this
final rule, firms may spend fewer
resources on potentially costly activities
such as worker safety, product
development and marketing, or
voluntary testing of the efficacy of their
products. The final rule will require
dietary supplement establishments to
adopt some new practices in order to
manufacture, package, label, or hold
their products in compliance with
CGMP requirements. In some cases,
establishments will make capital
improvements to the physical plant, add
or replace equipment or controls,
perform additional maintenance,
establish written procedures, keep
records, carry out tests, monitor
production and process controls, or
execute a variety of additional tasks that
they may not have previously
performed. Not all firms will comply;
some will go out of business or move
their plants to other countries and not
sell their product in the United States.
We estimated the additional costs of
production associated with the final
rule and the leading regulatory options
using the survey to estimate baseline
manufacturing practices (Ref. E2).
a. Description of the costs. To estimate
costs for the dietary supplement
industry, we initially divided the
industry into four product categories
and three size categories. Because the
survey showed that there were only a
few establishments in some categories,
we consolidated the size and product
into three size categories. The size
categories were:
• Very small (fewer than 20
employees),
• Small (20 to 499 employees), and
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• Large (500 or more employees).
Although this consolidation glosses
over the important differences across
products, the purpose is to estimate the
broad average costs of the rule.
For each size category, we constructed
a cost model that included every
provision of the final rule. We then
attached a cost to each provision that
had an additional activity associated
with it. Most provisions did not have
costs attached to them, because they
were either descriptive or the costs were
included elsewhere.
The costs will be the marginal, or
additional, costs of the activities
producers undertake in response to the
provisions of the final rule. In the cost
model, we expressed the cost as cost per
unit, with the unit being the
establishment, the number of
employees, or the annual number of
batches produced or affected.
b. Summary of general comments on
costs. We received many comments on
the costs of the 2003 CGMP Proposal.
Many of the comments were general in
nature and addressed the belief that our
economic analysis underestimated the
total costs of the 2003 CGMP Proposal,
both first year costs and annual costs.
Numerous comments point to the rule’s
testing requirements as the main cause
of the high costs. Comments also state
that the analysis underestimates costs of
hiring new workers, capital equipment,
and holding and distributing costs. In
addition, some comments point out that
the economic analysis did not include
estimates of costs of holding reserve
samples and tracking product
complaints.
As a result of the 2003 CGMP
Proposal, comments assert, product
choice would decline, prices of existing
products would increase, and many
businesses, particularly small
businesses, would be forced to shut
down. One comment states there could
be a decrease in spending on research
and development. Some comments state
that the burden on business could be
alleviated by allowing the use of
certificates of analysis for incoming raw
materials and using a statistical, or more
flexible, testing regime instead of
requiring final product testing on all
batches.
A comment from a trade association
representing ingredient suppliers and
manufacturers in the dietary
supplement industry accepts our
assumptions on the following variables:
• The number of control points,
• The average number of ingredients
per product, and
• The average cost per test.
Other comments, however, state that
the average number of ingredients is
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higher than estimated and that the
average cost per test is higher than
estimated; one comment from a
manufacturer states that its average cost
was 2.5 times our estimate. These
comments came from self-described
small firms.
(Comment 347) One comment states
that we failed to consider start-up costs.
(Response) We include start-up costs
(also referred to as set-up or one-time
costs) throughout this analysis.
(Comment 348) Many comments on
the regulatory impact analysis targeted
our estimates of firms’ batches per year.
Nearly all comments about batches state
that our batch estimates are too low. For
example, an industry trade groups
claims our estimate of 309 batches per
year for large firms is ‘‘implausibly
low.’’ The same comment states that the
distribution of the number of batches
per firm of 309, 554, and 223 for large,
small, and very small firms is ‘‘illogical’’
because it does not make sense that
large firms would have fewer batches
per year than small firms.
(Response) Due to a contractor’s error,
we used an inaccurate estimate of the
annual number of batches in the
analysis of the 2003 CGMP Proposal.
The analysis of the final rule corrects for
this error. The corrected mean numbers
of batches per firm are 444 for very
small, 2,436 for small, and 1,164 for
large firms. The corrected estimates of
the number of batches continue to show
that small firms produce more batches
than large firms. Comments from selfdescribed small firms suggest that this
distribution of batches is reasonable.
These comments state that small firms
produce many small batches of product
using machinery with smaller capacity
than that used by large firms. Very small
firms produce the fewest number of
batches per firm of the three size
categories because of their much lower
output.
(Comment 349) One comment states
that we used faulty data in the economic
analysis.
(Response) In accordance with our
information quality guidelines, we have
used the best available data in this
analysis. As explained in the response
to comment 348, the survey results used
in the analysis of the 2003 CGMP
Proposal included an inaccurate
estimate of the number of batches of
dietary supplements produced. We use
the corrected estimate in the analysis of
this final rule.
(Comment 350) Some comments
dispute the estimated testing costs. In
particular, comments question our
assumptions on:
• The number of tests required per
batch,
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• The number of tests already being
performed,
• The costs to perform specific
analytical tests, and
• The development of analytical
methods.
(Response) The final rule reduces the
number of required tests. In the final
rule, we account for tests where no
analytical methods have been
developed. We now require fewer tests,
although we anticipate that some testing
will take place associated with the
creation of certificates of analysis
required for component specifications
and as verification for process controls.
We now assume that the tests will be:
• One identity test for each shipment
lot of incoming dietary ingredients (e.g.,
vitamin C);
• Tests of subsets of shipment lots by
supplier firms to create certificates of
analysis for identity of other
components (e.g., sugar);
• Tests of subsets of shipment lots for
other specifications in the certificates of
analysis;
• Tests of subsets of batches of
dietary supplements for microbial,
chemical, or physical contaminants;
• Tests of subsets of batches of
dietary supplements for specifications;
and
• Tests for meeting requirements that
water used to manufacture dietary
supplements complies with Federal,
State, and local requirements and does
not contaminate the dietary supplement.
We are not changing our estimate of
the current prevalence of testing, which
is based on the survey of manufacturers
(Ref. E2). We would only revise this
estimate in light of new data of
comparable quality to that provided by
the survey.
(Comment 351) We did receive two
comments favorable to recordkeeping,
stating that master and production batch
records were good to adopt and that
associated costs will be minimal. One of
the comments states that the level of
detail may be unrealistic for a small
firm, but also states that any final
regulation could be made more flexible
for small manufacturers.
Although there were favorable
comments, we received several
comments critical of the recordkeeping
requirements. These comments make
general statements that the economic
analysis underestimates the
recordkeeping burden and some added
that these requirements go beyond the
CGMPs for food. In addition, several of
the comments include firms’ own
estimates of costs of complying with the
recordkeeping requirement. Comments
estimate costs in the range of $11,000 to
$64,000.
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(Response) The recordkeeping
requirements in the final rule differ
from the 2003 CGMP Proposal; revised
estimates are included in this final
regulatory impact analysis and
paperwork reduction analysis.
(Comment 352) We received a
favorable comment regarding the
requirements for physical plant and
equipment, saying that, although the
costs would be moderate, the result
would be higher quality products.
Another comment states that, although
not unrealistic, the provision would be
very costly.
Other comments are more critical.
One comment estimates that renovation
expenses would amount to
approximately $600 million over the
entire industry, as opposed to our
estimate of $45 million. This comment
states that the reason our estimates in
the 2003 CGMP Proposal were too low
is that we apply a reduction factor
which assumes that 18 percent of very
small firms, 10 percent of small firms
and 1 percent of large firms will have to
make capital improvements. It is more
appropriate, the comment states, to
assume that most facilities will need to
renovate about 10 percent of their plant,
regardless of firm size. In addition, the
requirement that plants have smooth,
hard surfaces on all floors, walls, and
ceilings is unrealistic and would add
quite a bit of cost. The comment asserts
no company will have such surfaces
throughout the plant and this is not a
requirement in either the food or drug
CGMP requirements. Other comments
echo the belief that capital expenditures
would be greater than our estimates and
would be excessively burdensome. One
comment estimates this cost at
approximately $83,000 per facility.
The comment also estimates that a
large firm that needs to expand its
capacity could expect to incur costs of
$240,000, as opposed to the $2,000 that
the comment says we estimated for large
firms. In addition, it is pointed out that
equipment costs could be burdensome
to small firms, which likely do not have
well-equipped labs. This thought is
affirmed by other comments that
estimate that new equipment could cost
anywhere from $50,000 to $1 million,
with annual costs estimated between
$15,000 and $100,000. In addition,
expansion of laboratory space is
estimated at $200 per square foot, as
opposed to the agency’s estimate of $50
per square foot. Lastly, one comment
suggests we work with the Internal
Revenue Service to allow for more rapid
depreciation of facility costs to help
small businesses make facility upgrades.
(Response) In the analysis of the 2003
CGMP Proposal, we estimated the
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number of firms needing to make capital
expenditures associated with the rule as
a distribution, with the parameters of
the distribution determined by the size
of the facility. We assume that if a firm
does make a capital investment in
response to the rule, it would affect
about 10 percent of the plant. With an
estimated cost of $50 per square foot,
and the average size of a very small
plant of about 25,000 square feet, the
cost per very small establishment
making a capital investment would be
about $125,000. With the average size of
a small plant of about 70,000 square
feet, the cost per small establishment
making a capital investment would be
about $350,000. With the average size of
a large plant of about 600,000 square
feet, the cost per large establishment
making a capital investment would be
about $3 million (Ref. E2). We assume
that most facilities will not need to
make capital investments to meet the
sanitation requirements of this final rule
as, according to the survey results, most
establishments already meet the
sanitation standards of this final rule.
This would not be possible if their
facilities were inadequate. We note that
the final rule does not require smooth
and hard surfaces throughout the plant.
We estimated the capital costs as the
costs of minor renovations to help meet
sanitation requirements, not as the cost
of, for example, expanding the size of a
laboratory or some other technically
sophisticated change. Although some
facilities may choose to expand
laboratories, the testing requirements of
this final rule should be able to be met
by existing laboratory facilities within
or outside of the manufacturing
facilities.
Working with the Internal Revenue
Service on depreciation is beyond the
scope of our authority. We will provide
advice on financing capital
improvements through our small
business representatives in the Office of
Regulatory Affairs.
(Comment 353) Many comments
address costs resulting from what
industry describes as the exhaustive
testing requirements outlined in the
2003 CGMP Proposal. Comments point
out that the requirement to test every
ingredient would be very costly for
firms large and small, with many firms
stating that they risk going out of
business. In addition, several comments
add that the testing requirements would
do little to enhance product quality.
Many comments assert that allowing the
use of a certificate of analysis would
reduce the amount of tests performed on
a shipment of incoming raw materials,
reducing redundant testing, and also
reducing the risk that a firm may go out
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of business. Other comments state that
allowing statistical testing regimes
would also cut down on testing costs.
(Response) As we already have
discussed in this section, we have
reduced the amount of required testing
in this final rule. The final rule requires
testing the identity of every incoming
dietary ingredient. However, the final
rule allows for use of certificates of
analysis in place of identity tests of
other components and other tests of
incoming dietary ingredients and other
components. The final rule also allows
sound statistical testing regimes for
finished products. We recognize,
however, that it may be possible for a
manufacturer to demonstrate, through
various methods and processes in use
over time for its particular operation,
that a system of less than 100 percent
identity testing would provide no
material diminution of assurance of the
identity of the dietary ingredient as
compared to the assurance provided by
100-percent identity testing. To provide
an opportunity for a manufacturer to
make such a showing and reduce the
frequency of identity testing of
components that are dietary ingredients
from 100 percent to some lower
frequency, we decided to provide, in an
interim final rule published elsewhere
in this issue of the Federal Register, a
procedure that allows for submission to,
and review by, FDA of an alternative to
the required 100-percent identity testing
of components that are dietary
ingredients, provided certain conditions
are met.
(Comment 354) One comment states
that our cost estimates are based on the
assumption of only two ingredient tests,
an assumption which the comment calls
into question. For multivitamins, one
comment estimates about 8 separate
tests and 16 separate assays, depending
on the nutrients present.
(Response) In the analysis of this final
rule, we assume one identity test per
incoming shipment lot of dietary
ingredients based on the revisions made
to the final rule compared with the 2003
CGMP Proposal.
(Comment 355) Many comments
include individual estimates of testing
costs. For example, two comments
estimate an average cost of about $100
per test, and other comments estimate
averages as high as $360, as opposed to
our estimate of about $60 per test.
Several other comments claim that the
costs of finished product testing alone
would be ‘‘at least 100 times’’ greater
than our estimates; other comments
state that testing costs would almost
equal the costs of manufacturing. One
comment estimates testing costs for
firms of all sizes at $245 million, as
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opposed to our estimate of $24 million,
although another contains estimates as
high as $13.6 million annually for one
firm. Two comments concede that some
finished product testing may be
necessary.
In addition, some comments state that
our estimate of finished and raw
material testing is off by a multiple of
three to six. One comment states that,
for companies that have products which
contain a large number of ingredients
expensive to test, very large costs will
be incurred. This comment also states
that our cost estimates do not include
in-process testing, which they claim the
rule would clearly require. Specifically,
our analysis suggests that an average of
2.5 in-process tests per batch are likely
to be needed at critical control points.
In addition, the comment maintains that
our analysis showed that additional
testing may be required for an average
of 2.5 components of herbal products
and 7.5 components of vitamin
products, but our estimates do not
include costs of the tests. Finally,
comments point out that, if the
production system is properly
controlled, then a ‘‘reduced schedule’’
of final product testing is justified and
that focusing excessive resources on
end-product testing does not constitute
GMP. Quality controls should be built
into the production and process system
from the beginning of the manufacturing
process.
A comment also states that our
estimates of firms that already test are
inaccurate. The comment asserts that
our estimates are overstated and they
also think we have understated that
proportion of finished batches not
currently being tested. In addition, the
comment claims that ‘‘even large firms
that are testing 90 percent of their
products are unlikely to be performing
the exhaustive level of testing required
by the 2003 CGMP Proposal, namely
testing every component of every batch
of finished product.’’
The comments point out that our cost
estimates do not include estimates for
the cost of developing methods of
analysis for ingredients. At a minimum,
one comment states this estimate should
be $2 million (the cost of 100 methods
at a minimum of $20,000 each). Several
comments point out that often there are
no existing scientifically valid analytical
methods to test finished products,
especially botanical products. Another
comment states that costs of analytical
testing are at least three times our
estimate, and could be as high as eight
times our estimate. Because of this,
many comments call for the use of a
certificate of analysis in place of
analytical testing.
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Another comment states some
unintended consequences could occur
in the industry due to the testing
requirements, including stress on the
current contract laboratory facilities and
in-house laboratories, and also increases
in holding costs, due to changes in turnaround time at outside labs. Other
comments point to the loss of product
choice that could occur if the testing
requirements force manufacturers to go
out of business or discontinue certain
products.
(Response) In response to comments,
we have revised the testing
requirements in the final rule. We also
have revised our estimates of the costs
of testing. In what follows, we describe
the estimated number and costs of tests
required by this final rule.
The final rule requires tests for
identity for each incoming shipment lot
of dietary ingredient. Estimating the
number of tests per batch is
complicated, because the tests are
required on the shipment lots and we
have data only on the number of batches
of dietary supplements produced. For
example, if a shipment lot of some
dietary ingredient is used in six batches
of final products, it would need to be
tested for identity only once. The
number of required identity tests per
batch of final product will equal the
number of dietary ingredients per batch,
divided by the average number of
batches per shipment lot (to account for
the production of multiple batches of
dietary supplements from single lots of
components). In addition to the required
identity tests, a subset of other
components will be tested for identity
(these tests are likely to be the
responsibility of suppliers and need
only be done once per batch no matter
how many recipients of those batches).
The quantity and quality of evidence
on the variables used to estimate the
number of tests varies greatly. In this
section, we explain the evidence and
assumptions we used to construct the
formulas for the number of tests.
Number of dietary ingredients. We
based our measure of the number of
dietary ingredients per product on a
sample of almost 3,000 dietary
supplement labels (Ref. E7). Although
some ingredients may be missing from
the labels and some listed ingredients
may be missing from the products, the
ingredient list represents the best
evidence we have on what ingredients
are used in dietary supplements.
Although comments claimed that we
underestimated the number of
ingredients, they offered no evidence
that would persuade us to change our
estimates, which are based on a sample
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representing at least 10 percent of the
products in the market.
According to the sample of listed
ingredients, vitamin and mineral
products contain about 13 listed dietary
ingredients. Other dietary supplements,
mainly herbals, contain about four listed
dietary ingredients (Ref. E7).
Number of unlisted components.
Dietary supplements are manufactured
using solvents, binders, and lubricants
that may not show up in the final
product. An industry source (Ref. E21)
says that four to six unlisted
components are typical per product,
although fewer are certainly possible.
The minimum number is zero. Based on
industry data, we assume that the
number of unlisted components would
be zero to six for vitamins and minerals,
and zero to four for herbal and other
products.
Number of shipments (i.e., shipment
lots) of ingredients and unlisted
components. We have no direct
information on the number of shipment
lots of dietary ingredients and other
components. We also have no
information on the number of shipments
per lot or on the number of shipments
per batch. It is costly to store
components, so some establishments
may buy many small lots of dietary
ingredients and other components
rather than a few large lots. Crude
botanical and other ingredients are
inherently unstable and may lose their
stability in even a short time unless
costly temperature, humidity, and light
controls are in place. We also know,
however, that some dietary ingredient
suppliers produce and ship ingredients
in large lots. For dietary supplements
produced using part of a large
production run of a dietary ingredient,
the number of batches per shipment lot
could be large. Also, some producers
buy a single large shipment lot of a raw
material and use it in many batches. We
assume that as many as 12 batches per
shipment lot of dietary ingredient is a
plausible maximum. Based on
consultation with industry (Ref. E21),
we assumed, in the cost calculation, that
1 was the minimum and 12 the
maximum number of batches produced
per lot, with 6.5 the average. We
received no comments on our use of the
assumption in the analysis of the
proposed rule and continue to use it in
our analysis of the final rule. In the
sensitivity analysis, we show how costs
change when we change the
assumption.
Number of batches produced. We
have survey results on the number of
batches produced per establishment
(Ref. E2). Several comments stated that
we underestimated the number of
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batches produced, which we found to be
the case because of an erroneous
calculation in the contractor’s report. In
the revised contract survey results, very
small establishments produce an
average of 444 (revised from 223)
batches per year, small establishments
produce an average of 2,436 (revised
from 554) batches per year, and large
establishments produce an average of
1,164 (revised from 309) batches per
year.
Number of final product tests per
batch. We have reduced the number of
tests required for final products. We
assume that establishments will test a
representative sample of batches to
ensure that the final products meet
specifications. We do not specify any
particular statistical sampling plan.
Costs per test. We estimate the costs
per test partly with published prices of
independent laboratories as posted on
the Internet (Refs. E22 and E23), and
partly from our conversations with FDA
and industry experts on testing. Testing
costs vary according to frequency and
complexity. The more frequently
technicians perform tests, the lower are
the costs per test. Many tests require
sophisticated equipment, such as gas
chromatography, high pressure liquid
chromatography, distillation, extraction,
various spectrophotometers, and other
types of equipment. Using sophisticated
equipment requires trained personnel.
Even simple physical or organoleptic
testing requires training or experienced
personnel. The type of ingredient,
compound, or product can also affect
the cost because some are easily
identified using routine or single step
techniques and others require multiple
steps or complex techniques, especially
if there are similar products that can be
mistaken for the products being
identified. The type of defect tested for
affects the cost; some defects can be
found visually if they are found on the
surface, but others are latent. Some tests
require multiple samples or multiple
steps. In addition, tests require taking
and preparing samples, whose cost can
vary. By assuming a single distribution
for testing costs, we may overestimate
testing costs for sectors or products with
below-average costs and underestimate
testing cost for sectors with aboveaverage costs. In the cost model, for
example, we distinguish between
botanical ingredients and nonbotanical
ingredients in the number of tests, but
not in average testing costs. If the
average cost of testing botanical
products is higher than the average cost
for vitamins and minerals, the
distribution of costs may underestimate
total testing costs for botanical products.
We do not have sufficient information
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on the range of testing costs for
botanical ingredients to determine if the
average cost of testing is higher or lower
than for other ingredients.
The average cost per test is about $60,
based on a range of costs we found on
the Internet. This cost represents the full
cost of carrying out a test, including
collecting and storing the sample, the
time for training the personnel who
carry out the test, and any associated
records. We assume that $20 per test
represents a lower bound. Although
some Internet prices for tests are as high
as $300, we assumed that, with frequent
testing, $150 would be a more plausible
upper bound average cost. The majority
of listed prices fell into the $20 to $80
range, so we selected $50 (the midpoint)
as most likely.
The number and cost of tests:
Summary. We estimate the number of
tests required of the representative
manufacturer as a weighted average of
the number of tests required for
vitamins and minerals and the number
of tests required for all other
supplements (which were mainly herbal
products). The weights, shown as
follows, differ by size of manufacturer:
• 24 percent of very small
manufacturers produce vitamins and
minerals; 76 percent produce other
dietary supplements.
• 42 percent of small manufacturers
produce vitamins and minerals; 58
percent produce other dietary
supplements.
• 69 percent of large manufacturers
produce vitamins and minerals; 31
percent produce other dietary
supplements.
Most establishments already conduct
some tests, or send samples out for
testing. We therefore adjusted the
estimated testing costs of the final rule
to include only required tests and to
account for the testing costs currently
borne voluntarily by manufacturers. The
survey results showed how many
respondents were conducting various
types of tests.
TABLE 27.—VALUES USED TO ESTIMATE TESTING COSTS
Name
Value or Distribution Used
Source
Vitamins and minerals—13
All other categories—4
Sample from 3,000 dietary supplement labels (Ref. E7)
Number of identity tests per dietary ingredient
lot
1 identity test per ingredient lot
Based on requirements of final rule
Number of identity tests per other component
lot
1 identity test per subset of component lots
Assumption based on use of certificates of analysis for ingredients
Number of tests for specifications per ingredient lot
1 to 5 tests per subset of ingredient lots
Assumption based on use of certificates of analysis for ingredients
Number of unlisted components
0 to 6 components for vitamins and minerals, 0 to 4
for herbal and other products
Ref. E21
Number of shipments (lots) of ingredients and
unlisted components
1 to 12 batches per shipment lot of dietary ingredients
Assumption based on discussions
with industry
Number of batches produced per year
Very small establishments–444
Small establishments–2,436
Large–1,164
Ref. E2
Number of final product tests per batch
1 test per subset
Based on requirements of the final
rule
Costs per test
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Number of dietary ingredients per product
batch
Beta pert distribution skewed rightward between $20
and $150; $50 most likely; $60 average
Refs. E22 and E23
(Comment 356) We received
comments on labor costs that would be
incurred as a result of the 2003 CGMP
Proposal. All comments state that
personnel costs will increase
significantly. One comment states that
the average manufacturing wage we
used to estimate labor costs, $15.65,
does not reflect the true cost of
additional labor, since higher skilled
employees, such as quality control
engineers and, as one comment asserts,
Ph.D.-level employees, will need to be
hired to comply with the rule. This
comment states that, including benefits,
the wage actually ranges between $23.28
and $72.00 per hour, depending on
skill. Other comments estimate
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additional annual labor costs ranging
between $25,000 and $350,000.
(Response) We used more recent
estimates to the average manufacturing
wage cost of $26 per hour to estimate
the cost of labor (Ref. E24). The
comment that asserted Ph.D.-level
employees are needed to comply with
the rule, provided no basis for this
assertion. We disagree that Ph.D.-level
workers are needed for the tasks
required by this final rule because most
of the costs estimated as labor costs all
involved ordinary labor tasks such as
sanitation, monitoring, and
recordkeeping. For more difficult or
complicated tasks, more skilled workers
may be required, but the overall average
labor cost represents the best overall
estimate for valuing the average cost of
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labor in the industry. We assume that
various tasks required by the final rule
would take some number of hours per
year, per batch of product, or per square
foot of physical plant.
Estimating costs. We initially gathered
information and made assumptions
about the full cost of a provision. We
then adjusted these estimates to account
for the many activities already being
carried out, as well other activities that
would not have to be carried out by all
establishments. We used the survey to
estimate the likelihood that an
establishment will incur a cost. To get
an estimate of the average cost of a
provision (adjusted for baseline
activities) for each category, we
multiply the average cost per
establishment by the probability that the
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establishment will need to undertake
the expense (one minus the probability
that the establishment is already doing
it). For each provision of the final rule,
the simulation carried out the following
calculation:
Cost per unit of analysis for each
provision =
number of units of analysis per
establishment x
probability that establishment incurs
cost x
cost per provision per establishment.
We estimate both a setup cost (a onetime fixed cost) of the provision and an
annual recurring cost. To get the total
costs of the rule, we multiply the
number of establishments in each size
category (from the survey) by the
average costs per establishment in that
category. We then adjust for the
establishments that did not respond to
the survey but are believed to be in the
industry. Two hundred thirty-eight
establishments responded to the survey;
we estimate that 1,566 firms are in the
industry, including ingredient
suppliers. The number of firms covered
by most of the provisions will therefore
be about 1,460.
We estimate total costs with the
following calculation:
(Number of very small establishments x
costs per very small establishment) +
34933
(number of small establishments x costs
per small establishment) +
(number of large establishments x costs
per large establishment) +
(number of warehouses x costs per
warehouse).
The rule is complex and the industry
is made up of very different kinds of
firms, so cost estimates are averages
with, in some cases, large variances. The
cost per unit, number of batches and
employees, and probability that the
establishment would incur the cost all
contain uncertainty. The values in table
28 of this document are used in the cost
estimates, and are generated from
multiple sources.
TABLE 28.—ADDITIONAL VALUES USED IN COST CALCULATIONS
Name
Value or Distribution Used
Source
$26
Employment Index, Bureau of Labor Statistics
(Ref. E24)
Average size of establishments in square feet
very small = 24,674
small = 71,354
large = 596,000
Ref. E2
Average number of employees
very small = 7.6
small = 95
large = 1,005
Ref. E2
Procedures
8 to 16 hours setup time for small firms; 30 to
40 hours for large firms; annual cost is 10
percent of setup time per provision
Ref. E25
Personnel sanitation
1 hour per week per worker
Assumption, based on requirements of final
rule
Sanitation time for physical plant
1 hour per week for very small establishments; costs per small and large plants
scaled in proportion to size of plant
Assumption, based on difference in average
physical plant size
Sanitation supervisor
1 hour per week
Assumption, based on requirements of final
rule
Pest control setup costs
$1,500 to $2,000 for very small establishments; $1,800 to $2,400 for small establishments; $2,600 to $3,400 for large establishments. Average for each size establishment was midpoint ($1,750, $2,100,
$3,000)
Ref. E26
Pest control annual costs
$400 to $600 per month for very small establishments; $480 to $720 for small establishments; $700 to $1,000 for large establishments. Average for each size establishment was the midpoint ($500, $600, $850)
Ref. E26
Renovation cost
$50 per square foot; with 0 to 20 percent of
physical plant to be renovated, with 10 percent most likely
Based on construction costs and square feet
(Ref. E2)
Equipment replacement
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Average wage per hour
For very small establishments, 0 to $1,000;
costs per small and large plants scaled in
proportion to size of plant
Assumption, based on size of establishments
(Ref. E2)
Setup costs for automatic equipment
$500 for hardware, 16 hours
Software costs and assumptions about labor
hours
Annual costs for automatic equipment
10 percent of setup costs
Assumption based on requirements of the
final rule
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TABLE 28.—ADDITIONAL VALUES USED IN COST CALCULATIONS—Continued
Name
Value or Distribution Used
Source
Sanitation of equipment and surfaces
5 hours per week for very small establishments; costs per small and large plants
scaled in proportion to size of plant
Assumption based on average sizes of establishments (Ref. E2)
Holding products and dietary ingredients: Capital requirements
Same as costs of equipment upgrades
Based on average sizes of establishments
(Ref. E2)
Default probabilities that establishments are
not currently acting in accordance with a
provision
For very small establishments, 0.2; for small
establishments, 0.05, for large establishments, 0.01
Based on results of survey for other practices
(Ref. E2)
The total setup costs for this final rule
will be $41 million, spread out over the
36 months following the publication
date of the final rule. The annual costs,
once the final rule is fully implemented,
will be $164 million, with the two
largest costs being $52 million for
testing and $24 million for records. The
estimated total cost is the mean of a
range of estimates based on the data and
assumptions described in tables 27 and
28 of this document. In the uncertainty
and sensitivity analyses in section
XXIV.B.11 of this document, we show
how uncertainty and different
assumptions generate higher or lower
$322 million, with a mean estimate of
$164 million. The rule will not be fully
effective until 36 months after the
publication date. Table 29 of this
document shows how the phase-in of
the final rule will generate the costs and
quantifiable benefits for the first 4 years.
Table 30 of this document shows the
present and annualized values of costs
and quantifiable benefits over 20 years,
calculated at discount rates of 3 percent
and 7 percent. We have determined,
based in part on the analysis presented
here, that the benefits, quantified and
unquantified, of this final rule justify
the costs.
estimated costs. Using plausible
assumptions about the uncertain
variables, we estimate that total
quantified costs most likely will fall
within a range of $104 million to $322
million per year.
8. Summary of Benefits and Costs
We estimate that, once it is fully
implemented, the annual quantified
benefits from the final rule will be $8
million to $64 million, with a mean
estimate of $44 million. However, there
are potentially large benefits of the rule
that we were not able to quantify. The
annual costs will be $104 million to
TABLE 29.—COSTS AND QUANTIFIABLE BENEFITS BY YEAR
1st year
Costs (in millions)
2nd year
3rd year
4th year
$16
$120
$190
$164
$3
$29
$44
$44
Benefits (in millions)
TABLE 30. PRESENT AND ANNUALIZED VALUES OF COSTS AND QUANTIFIABLE BENEFITS
Present value at 3 percent
(in billions)
Present value at 7 percent
(in billions)
Annualized Value over 20
years at 3 percent (in millions)
Annualized Value over 20
years at 7 percent (in millions)
Costs
$2.3
$1.6
$153
$149
Benefits
$0.6
$0.4
$40
$39
In table 31 of this document we show
the annual costs for each subpart of the
regulation. We identify selected costs
for particular activities for some of the
subparts. We are unable to estimate
benefits by subpart, because we estimate
the benefits by type of benefit rather
than by provision of the final rule.
TABLE 31.—COSTS BY SUBPART
Subpart
Setup Cost (in millions)
A. General provisions
not applicable
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$2.3
$0.5
negligible
$0.3
E. Establish production and process control system
Subtotal for identity testing
Subtotal for all other testing
$17.4
$0.9
D. Equipment and utensils
$15.7
$34.0
C. Physical plant and grounds
not applicable
$1.5
B. Personnel
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Annual Cost (in millions)
$66.1
$45.0
$ 6.8
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TABLE 31.—COSTS BY SUBPART—Continued
Subpart
Setup Cost (in millions)
Annual Cost (in millions)
F. Quality control
negligible
$2.1
G. Components, packaging, labels, and dietary supplements received
negligible
$31.6
$0.1
negligible
negligible
$5.4
$0.2
negligible
negligible
$2.2
L. Packaging and labeling operations
$0.1
$10.8
M. Holding and distributing
$2.7
$0.5
negligible
$0.2
$0.1
$4.5
P. Records and recordkeeping
not applicable
not applicable
Paperwork cost for all subparts
$3.7
$24.2
H. Master manufacturing record
I. Batch production record
J. Laboratory operations
K. Manufacturing operations
N. Returned dietary supplements
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O. Product complaints
(Comment 357) We received several
comments on the summary of the costs
and benefits. In general, the comments
state that we overestimated the benefits
of the 2003 CGMP Proposal and
underestimated the costs. Other
comments assert that total estimated
benefits of the 2003 CGMP Proposal
would not be $216.6 million, as
estimated by us, but as low as $13.9
million. Comments also estimate firstyear costs as high as $629 million, with
annual costs estimated as high as $860
million. Other comments predict
product prices will increase, and
consumers will decrease consumption
of dietary supplements.
(Response) We agree with the
comments stating that we
underestimated the costs and
overestimated the quantified benefits of
the 2003 CGMP Proposal. We have
increased our estimate of costs in this
final rule compared with the estimate in
the 2003 CGMP Proposal. We have
decreased our estimate of quantified
benefits of the final rule compared with
the estimate in the 2003 CGMP
Proposal. As explained previously, we
are unable to quantify all of the benefits
of the final rule. These changes in the
estimated benefits and costs of this final
rule reflect both the changes in the 2003
CGMP Proposal and the changes in our
analysis in response to comments.
We agree with the comment that part
of the costs of this final rule will be
passed on to consumers as higher prices
for dietary supplements. The annual
costs of this final rule are less than 1
percent of total spending on dietary
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supplements. We expect that the
majority of these costs will be borne by
consumers of dietary supplements, who
will likely respond to the increase in
prices by reducing consumption.
The comments suggesting very high
costs and very low benefits did not
persuade us that those extreme values
were more likely than our estimates. We
recognize, however, that the
uncertainties in our analysis make a
broad range of benefits and costs
possible. In the analysis of uncertainty,
we will show the range of predicted
benefits and costs. We also will show
the sensitivity of costs and benefits to
certain key assumptions used in the
analysis, and how changes in those
assumptions can generate the extreme
values cited in some comments.
9. Benefits and Costs of Regulatory
Options
We considered several regulatory
options, including: (1) No new
regulatory action, (2) fewer
requirements for vitamins and minerals,
(3) more restrictive regulations than the
final rule, (4) HACCP without the other
elements of the final rule, (5) final
product testing only, (6) a final rule for
high-risk products or hazards only, and
(7) the 2003 CGMP Proposal. Although
we received no comments on our
analysis of the benefits and costs of
options 2 through 6, we received many
comments on the estimated benefits and
costs of the 2003 CGMP Proposal. We
have now revised the estimated
quantifiable benefits and costs of the
2003 CGMP Proposal. The revised
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estimates are based on the comments
received and the corrections made to the
data.
Using the same method as used in this
final rule to determine benefits, we
estimate that the quantifiable benefits of
the 2003 CGMP Proposal would be
approximately the same as the
quantifiable benefits of the final rule,
$44 million per year.
With the corrected estimated number
of batches produced, we estimate that
the setup costs of the 2003 CGMP
Proposal would be $51 million. If the
2003 CGMP Proposal had been
finalized, the annual costs of complying
with the requirements would be $282
million, or about $118 million more
than this final rule. The 2003 CGMP
Proposal relied more on testing final
products and other controls closer to the
end-product. Under the 2003 CGMP
Proposal, for example, annual testing
costs would be about $97 million.
10. Cost Effectiveness Analysis
Both benefit-cost analysis and costeffectiveness analysis provide a
systematic framework for identifying
and evaluating the likely outcomes of
alternative regulatory choices. OMB
Circular A–4 requires that major
rulemakings be supported by both types
of analysis wherever possible. A costeffectiveness analysis is particularly
useful when the primary benefits of the
rulemaking are improved public health
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and safety.18 The main advantage of
measures of effectiveness are that they
account for a rule’s impact on morbidity
(nonfatal illness, injury, impairment,
and quality of life) as well as premature
death. The inclusion of morbidity
effects is important because some
illnesses (e.g., asthma) cause more
instances of pain and suffering than
they do premature death.
The primary benefits expected to
result from this rulemaking are reduced
numbers of acute and chronic illnesses
and reduced number of recalls involving
dietary supplement products. We were
not able to quantify chronic illnesses
that could be avoided as a result of this
rulemaking. We were able to determine
that we could avoid about $40 million
annually in costs of acute illnesses and
$4 million in avoided recalls as a result
of improved dietary supplement
manufacturing.
We can use the $40 million annually
in avoided acute illnesses costs to
calculate a cost-effectiveness measure
for this rule; $40 million in reduced
illness costs translates into 48,662
QALDs saved on an annual basis. Given
that the annual costs of this final rule
are expected to be $164 million, the cost
of each QALD saved is $3,370. This is
an overestimate of the cost of a QALD
saved because we were unable to
quantify the benefits of reduced chronic
illness as a result of this rulemaking.
11. Uncertainties in the Analysis
We used indirect measures of the
benefits of this final rule which required
several key assumptions that are critical
for our estimates. With the exception of
the recall benefit, which is based
directly on our recall records, each
component of the estimated benefits
involves assumptions that reflect our
uncertainty. The estimated costs also
embody key assumptions that reflect our
uncertainty.
One assumption that affects both
estimated costs and estimated benefits is
that manufacturing practices in the
industry will persist in the absence of
additional regulation. If the trend in the
market is toward the adoption of more
manufacturing controls than we are
proposing here, then both the costs and
benefits of the rule will be less than we
estimate. If the market trend is toward
fewer voluntary controls, then both the
costs and benefits of the regulation will
be greater than we estimate.
In addition to the general assumption
about the effects of the rule, we rely on
several key assumptions.
We assume there is an average of one
reported illness for each class 1 and 2
recall.
The frequency of actual illnesses is
100 times the frequency of reported
illnesses. We recognize that there is
considerable uncertainty about the
factor of 100.
For the baseline estimates, we assume
$5 million is the value of a statistical
life and $300,000 is the value of a
quality-adjusted life year. The estimated
health benefits change with changes in
those valuations.
Finally, we assume that the reported
recalls that occurred from 1990 through
1999 represent the number and type of
recalls that would have occurred but for
the implementation of this regulation.
The cost model also relies on several
key assumptions. We assume that single
shipment lots of ingredients and
unlisted components will be used for
many batches of final dietary
supplement products. We assume that
all testing other than identity testing of
incoming ingredients will be done on
representative samples. The number of
batches or lots tested will be the square
root of n + 1, with n equal to the total
number of batches or lots.
We also assume that the costs per test,
which include the labor costs of
selecting the samples and arranging for
the tests, will be between $20 and $150,
with $50 most likely.
We first characterized the
uncertainties as a probability
distribution. We ran 5,000 computer
simulations to estimate both benefits
and costs. The simulations used
distributions (given in the tables and the
text) in place of point estimates.
TABLE 32.—DISTRIBUTION OF SIMULATION RESULTS FOR ANNUAL BENEFITS AND COSTS
5th Percentile
Annual costs (in millions)
95th Percentile
$109
The Monte Carlo computer
simulations give the distributions of
estimated benefits and costs. If the
underlying distributions fully capture
the uncertainty of the estimates, then
the simulation results give a full picture
of the uncertainty. With uncertain
distributions used in the simulations,
however, the ranges reported in the
tables may not fully capture the
uncertainties of the analysis. An
alternative way to show the uncertainty
is to see how sensitive the results are to
plausible changes in certain key
assumptions. We start with benefits.
For our baseline estimated benefits of
this final rule, we use a $5 million value
for a statistical life (VSL) and a $300,000
value for a quality-adjusted life year. In
$164
$260
$36
Annual quantified benefits (in millions)
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Mean
$44
$54
the sensitivity analysis, we use values of
$3 million for a statistical life and
$100,000 for a quality-adjusted life year
to generate a ‘‘low’’ estimate of health
benefits and values of $7 million and
$500,000 to generate a ‘‘high’’ estimate.
The reporting rate of illnesses
associated with dietary supplements is
unknown, which makes our estimate of
the total number of illnesses highly
uncertain. We use 1 percent as the
average reporting rate, which implies
that total illness are 100 times our
estimate of reported illnesses. Although
we assume this reporting rate is the
most plausible for illnesses associated
with dietary supplements, the evidence
supporting it is not strong. We show the
effects of reporting rates of 2.5 percent
and 10 percent.
(Comment 358) Several comments
questioned our assumption that the final
rule will eliminate the recalls used to
estimate benefits.
(Response) We do not assume that all
recalls will be eliminated; we only
assume that the recalls caused by
manufacturing problems identified
previously will be eliminated if the rule
is fully effective. If the rule is not fully
effective, then the quantified benefits
will be less than we have estimated. In
the following discussion we show the
effects of different assumptions about
the effectiveness of the final rule.
The quantified benefits depend on the
hazards found in recalled products
18It should be noted that many of the benefits of
this rule are quality benefits that are not quantified
and will not be part of this analysis.
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between 1990 and 1999. The 69 recalls
in 1998 dominate the estimate,
accounting for 58 percent of class 1 and
class 2 recalls, and 35 percent of all
recalls for the decade. In this sensitivity
analysis we estimate the effect of
excluding 1998 from the data used to
estimate average annual benefits. We
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also consider the effects of using the
annual average number of recalls from
2000 through 2005 to estimate benefits.
TABLE 33.—SENSITIVITY OF BENEFITS
Estimated Annual Benefits
(after 3 years) (in millions)
Description
Final rule
$44
VSL = $3 million and $/QALY = $100,000 (baselines are $5 million and $300,000)
$24
VSL = $7 million and $/QALY = $500,000 (baselines are $5 million and $300,000)
$64
Each recall represents one illness, with reporting rate of 10 percent (baseline is 1 percent)
$8
Each recall represents one illness, with reporting rate of 2.5 percent (baseline is 1 percent)
$20
Final rule reduces manufacturing recalls by 80 percent (baseline is 100 percent)
$35
Exclude 1998 recalls from estimate, so average annual number of manufacturing recalls is 14 (baseline is
19.5)
$27
Average annual number of manufacturing recalls = 2000–2005 average, so average per year is 10 (baseline
is 19.5)
$26
In the sensitivity analysis of annual
costs, we change assumptions about the
numbers covered by the rule, the
number of batches produced per
establishment, the number of lots per
batch, the average costs per test, and the
rate of verification testing.
The number of establishments
covered is uncertain because we based
it on voluntary survey responses and
other evidence from the 1990s. If the
number of establishments has increased
or decreased, or if our original data
overstated or understated the correct
number, then the estimated costs will be
either too low or too high. We show the
effects of different numbers for one
arbitrarily lower number covered and
one arbitrarily higher number covered.
The number of batches produced is
our basic measure of output. Annual
costs therefore vary directly with this
measure and its components. We show
how the costs depend on the number of
batches by estimating costs for 50
percent less and 50 percent more
batches than estimated from the survey.
The number of shipment lots and the
cost per test determine identity testing
costs, the single largest contributor to
annual costs. We show how the costs
vary if the average number of batches
per lot is 1 or 12. We vary the average
cost per test from $20 to $100.
TABLE 34.—SENSITIVITY OF COSTS
Estimated Annual Cost
(after 3 years) (in millions)
Description
$164
Number of covered establishments is 1,300 (baseline is 1,460)
$148
Number of covered establishments is 1,600 (baseline is 1,460)
$178
Number of batches are 50 percent of baseline (baseline is 444, 2,436, and 1,164)
$104
Number of batches are 150 percent of baseline (baseline is 444, 2,436, and 1,164)
$224
1 batch of dietary supplements per shipment lot of a dietary ingredient (baseline is 6.5)
$322
12 batches of dietary supplements per shipment lot of a dietary ingredient (baseline is 6.5)
$136
Average cost per test is $20 (baseline is $60)
$129
Average cost per test is $100 (baseline is $60)
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Final rule
$197
We combine the results of the
sensitivity analyses to generate overall
ranges for benefits and costs. We
estimate that, once it is fully
implemented, the annual benefits, able
to be quantified, from the final rule will
be $8 million to $64 million; the annual
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costs will be $104 million to $322
million.
C. Final Regulatory Flexibility Analysis
1. Introduction
We have examined the economic
implications of this final rule as
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required by the Regulatory Flexibility
Act (5 U.S.C. 601–612). If a rule has a
significant economic impact on a
substantial number of small entities, the
Regulatory Flexibility Act requires
agencies to analyze regulatory options
that would lessen the economic effect of
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the rule on small entities. We find that
this final rule will have a significant
economic impact on a substantial
number of small entities.
2. Economic Effects on Small Entities
a. Number of small entities affected.
The final rule will affect many small
entities. A small business in this
industry is any establishment with
fewer than 500 employees. For purposes
of the cost-benefit analysis, we also
looked at the category we call very small
establishments: Establishments with
fewer than 20 employees. Based on the
survey (Ref. E2), we estimated that 774
establishments, 53 percent of the total
establishments, could be classified as
very small (under 20 employees) and
526 as small (20 to 499 employees),
which is 36 percent of the total
establishments. Based on the results of
the survey (Ref. E2), we estimated the
total number of warehouses,
wholesalers, and other holders likely to
be covered by this regulation to be
15,689, of which 15,421 are small
businesses.
The small establishments that will be
affected by the final rule are those
establishments that will have to perform
the various required activities, and
would not have done so without the
rule. We determined estimated baseline
(pre-CGMP requirements)
manufacturing practices with the survey
of the industry (Ref. E2). The survey
asked representative respondents to
answer a series of questions, including
how many employees they had and
what their existing practices were. From
the survey, we determined that small
establishments do not now follow all of
the provisions of the final rule. Those
that do not follow all the applicable
provisions will incur a cost to do so.
b. Costs to small entities.
Implementation costs vary across
establishments depending on current
practices and the types of products
manufactured, packaged, labeled, or
held. We estimated the range of current
practices using the survey of the
industry. The cost model, which we
describe in detail in section XXIV.B.7 of
this document, divided establishments
by size, which allowed us to estimate
the distribution of costs per
establishment for each size and product
class. Table 35 of this document shows
the cost per establishment for very small
and small establishments. For
comparison, we include the estimated
average cost per large establishment and
the median revenues for each size
category. As table 35 of this document
shows, costs per establishment are
proportionally higher for very small
than for large establishments. The
table’s most striking result is that annual
costs are highest for small (20 to 499
employees) establishments.
TABLE 35.—COSTS PER ESTABLISHMENT, BY SIZE
Setup Costs per
Establishment
Annual Costs per
Establishment
Median Annual Revenue per
Establishment
Very small establishments
$26,000
$46,000
Under $1 million
Small establishments
$20,000
$184,000
$5 to $10 million
Large establishments
$31,000
$69,000
$10 to $50 million
$360
$1,000
Not applicable
Warehouses, wholesalers, and other holders
TABLE 36.—TOTAL COSTS BY ESTABLISHMENT SIZE
Setup Costs
Percent of Total Setup
Costs
Annual Costs
Percent of Total Annual
Costs
$20 million
49 percent
$38 million
23 percent
Small establishments
$10 million
24 percent
$98 million
60 percent
Large establishments
$5 million
12 percent
$11 million
7 percent
Warehouses, wholesalers, and other holders
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Very small establishments
$6 million
15 percent
$17 million
10 percent
Small establishments that do not
perform a substantial number of the
actions required by the final rule will
bear relatively high costs for compliance
with the provisions of this final rule.
Although the final rule will raise
product prices, the price increase
(which would largely be determined by
changes made by large establishments)
may be much smaller than the increase
in the average costs of very small
producers. The average burden to very
small establishments will be about 4
percent of annual revenue. The average
burden to small establishments will be
1.5 to 3 percent of annual revenue.
Establishments with above average
costs, and even establishments with
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average costs, could be hard pressed to
continue to operate. Some of these may
decide it is too costly and either change
product lines or go out of business.
We use a model developed under
contract by Eastern Research Group to
estimate the effects of FDA regulations
on small businesses (Ref. E27). The
model is designed to assess the effects
of a wide range of potential regulatory
activities, ranging from HACCP to
product labeling. CGMP regulations are
included as a potential regulatory
activity. The model allows us to predict
the probability and frequency of small
business failure as a result of our
regulations.
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We ran the model for the final rule.
The model predicts that, as a result of
the final rule, 140 very small and 32
small dietary supplement manufacturers
will be at risk of going out of business.
The model estimates the number of
workers in those firms to be about 2,250.
The regulatory costs of this final rule
will also discourage new small
businesses from entering the industry.
The dietary supplement has been
characterized by substantial entry of
small businesses. Although we cannot
quantify how much that will change, we
expect that the rate of entry of very
small and small businesses will
decrease.
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3. Regulatory Options
a. Exemptions for small entities. The
burden on small establishments would
be reduced if they were exempt from
some provisions of the final rule. Most
entities (we estimate close to 90 percent)
affected by this final rule, however, are
small. Exempting small establishments
from some or all of its provisions would
substantially reduce benefits.
b. Longer compliance periods.
Lengthening the compliance period
provides some regulatory relief for
businesses with fewer than 500
employees. The longer compliance
period will allow additional time for
setting up recordkeeping, making
capital improvements to the physical
plant, purchasing new or replacement
equipment, and other one-time
expenditures. It will also delay the
impact of the annual costs of
compliance. We have given businesses
with fewer than 20 employees an
additional 24 months and businesses
with fewer than 500 but 20 or more
employees an additional 12 months for
compliance. The final rule, then, will be
phased-in over 36 months, with firms
with 500 or more employees complying
after 12 months, firms with under 500
but 20 or more employees after 24
months, and firms with fewer than 20
employees after 36 months. The cost
savings of delay may well be larger than
simply the present value of the delay
because the firms with fewer than 500
employees may also be able to reduce
their compliance costs by taking
advantage of increases in industry
knowledge and experience in
implementing these regulations.
c. Reduced requirements in the final
rule. The modification of requirements
in this final rule, compared with the
2003 CGMP Proposal, significantly
reduce the costs borne by small
businesses. We estimate the average
setup costs under the 2003 CGMP
Proposal to be $25,000 for very small
establishments and $40,000 for small
establishments. We estimate that the
annual costs of the 2003 CGMP Proposal
would be $90,000 for very small
establishments and $300,000 for small
establishments. The final rule therefore
reduces annual costs for very small
establishments to about half of the
estimated costs of the proposed rule and
reduces costs for very small
establishments to about 60 percent of
the estimated costs of the 2003 CGMP
Proposal. Under the 2003 CGMP
Proposal, 216 very small and 50 small
businesses would be at risk of going out
of business, over 50 percent more than
under the final rule.
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4. Description of Recordkeeping and
Reporting
The Regulatory Flexibility Act
requires a description of the
recordkeeping and reporting required
for compliance with this final rule. This
final rule will require the preparation of
records. As described in the 2003 CGMP
Proposal, Preliminary Regulatory Impact
Analysis, written records or electronic
documents must be kept that
demonstrate that specific actions
occurred in the manufacturing process
in compliance with the final rule.
Records that will be required in this
final rule will demonstrate that
corrective actions were taken; that
equipment, instruments, and controls
used in laboratory operations and
quality control were installed and
calibrated properly; that maintenance
programs were followed; and that the
results of any testing show that
components or dietary supplements
meet the established specifications.
The compliance cost of recordkeeping
is the sum of both the initial design and
printing of the recordkeeping
documents and the recurring costs of
maintaining the records. The cost of
training personnel to use the new
documents is a recurring cost depending
on how frequently documents are
modified, how often personnel turn
over, and how complicated the tasks are
that are being recorded. The recurring
costs are measured by the workers’ wage
rate multiplied by the expected labor
hours necessary for a written or
electronic record and the time necessary
for management to review the records to
see that actions are documented
accurately. In addition, electronic
records necessitate recurring time spent
ensuring that the equipment is serviced
and maintained properly.
5. Summary
The final rule will have a significant
economic impact on a substantial
number of small entities.
(Comment 359) We received many
comments on the 2003 CGMP Proposal
Preliminary Regulatory Flexibility
Analysis. Nearly all of the comments
addressing small business state that the
requirements of the 2003 CGMP
Proposal, the testing requirements in
particular, would be an enormous
burden on small business. Other
comments assert that, because of this
burden, the rule is in violation of the
Regulatory Flexibility Act. In addition,
comments assert small business will be
particularly burdened by the rule and
that consumers will see little
improvement in product safety as a
result.
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34939
Some small firms estimate annual
testing costs for the 2003 CGMP
Proposal as high as $600,000, as
opposed to the $60,000 per year
estimated by us. Another firm estimates
setup costs in the range of 4 to 7 times
our estimate and annual costs 8 to 30
times our estimate. Comments also
express concern that we have
underestimated the number of
businesses forced to close if this rule is
made final as proposed; one comment
states that the rule would cause 50
percent of small businesses to shut
down. Some comments assert that this
rule is anti-competitive: That is, the
comments claim that this rule will make
dietary supplement manufacturing so
expensive that only large companies
will survive. In addition, a few
comments note the loss of product
choice, innovation, and domestic
employment that accompany firm
closures, in addition to the increase in
prices of products made by remaining
firms. In addition, another comment
suggests that foreign manufacturers will
be at an advantage because they will not
have to comply with the rule’s
requirements.
Some comments reiterate the points
made earlier that the use of statistical
sampling and supplier certificates of
analysis could help reduce the burden
on small business.
One comment states that it would be
extremely costly for small firms to come
into compliance with the 2003 CGMP
Proposal, especially because, as several
firms pointed out, small firms often
produce batches that are small in size.
A few comments, however, say that
small firms should be made to comply
with the new rule at the same time as
large firms.
We received many comments on the
compliance period of this rule. Some of
these comments favor the extended
compliance periods granted to small
and very small firms. Other comments
do not support the compliance periods,
stating that they are not long enough for
firms to set up recordkeeping systems,
make capital improvements, and so on.
Other comments do not favor granting
small firms more time to comply. Three
comments state that granting small firms
a longer compliance period defeats the
purpose of the rule, by making it
difficult for consumers to determine
which dietary supplements comply with
the CGMPs and which do not yet
comply. Another comment suggests that
products made by firms not in
compliance 1 year after the rule’s
effective date be labeled to say, ‘‘This
product may not conform to government
standards for purity and potency.’’
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Other comments propose a single
compliance period for all firms.
(Response) We disagree with
comments that the burden of this final
rule violates the Regulatory Flexibility
Act. The act requires agencies to
consider the burden of their regulatory
proposals on small entities, analyze and
consider effective alternatives that
reduce the burden on small entities, and
make their analyses available for public
comment. We have considered the
burden of this final rule on all covered
firms, including small businesses, and
as a result have modified certain
requirements to reduce the costs of the
final rule as compared with the 2003
CGMP Proposal. In addition, small
businesses are allowed more time to
comply with the rule. The burden on
small businesses remains large, but the
Regulatory Flexibility Act does not
require agencies to adopt regulations
that impose the least burden on small
entities. In addition, the Data Quality
Act has been fulfilled by using the most
objective data available. In this analysis,
we used data from surveys and from
other Federal agencies. Although more
data are desirable, we consider the
quality of the data used in this analysis
and in the references to be the best
available and sufficient to fulfill the
requirements of the Regulatory
Flexibility and Data Quality Acts.
We have reduced the amount of
testing required in this final rule in
response to comments on the burden of
testing costs on the 2003 CGMP
Proposal. As explained in Section
XXIV.B.7 of this document, we
underestimated costs in the proposed
rule because of an error in a contractor’s
report. We have corrected the cost
calculations, including estimated testing
costs, for this final regulatory flexibility
analysis.
We note that foreign firms that sell
dietary supplements in the United
States are required to be in compliance
with the final rule.
In response to comments on the
number of firms likely to go out of
business, we have used our small
business model to estimate that 172
small and very small firms will be at
risk of going out of business. Many other
small firms—some of them already
experiencing financial difficulties–may
see their financial condition worsen as
a result of this final rule.
We disagree with the comments that
oppose longer compliance periods for
small businesses. The additional time
will only slightly delay the full
implementation (and full benefits) of
this final rule, and may provide the
margin of survival for some small
businesses.
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D. Unfunded Mandates
The Unfunded Mandates Reform Act
of 1995 (Public Law 104–4) requires
cost-benefit and other analyses for rules
that would cost more than $100 million
in a single year. The current (2005)
inflation-adjusted statutory threshold is
$122 million. This final rule qualifies as
a significant rule under the statute. Most
of the requirements of the Unfunded
Mandates are fulfilled in the Executive
Order 12866 analysis. The requirements
under the Unfunded Mandates Reform
Act of 1995 include assessing the rule’s
effects on future costs; productivity;
particular regions, communities, or
industrial sectors; economic growth; full
employment; job creation; and exports.
The future costs from the rule are the
recurring costs, which reach their longterm value in the third year after the
effective date of this rule. These costs
would be incurred, directly or
indirectly, by the establishments that
manufacture, process, pack, label,
transport, distribute, receive, hold, or
import dietary supplements or
ingredients. Recurring costs from the
regulatory requirements will be incurred
in each future year. Table 29 of this
document summarizes the annual future
recurring costs.
The costs, direct and indirect, of the
rule will be shared among
manufacturers, processors, packagers,
transporters, receivers, holders, and
importers of dietary supplements or
ingredients, as well as domestic
consumers. Much of the higher costs
incurred by domestic suppliers of
dietary supplement products as a result
of these regulations will be passed on to
consumers as higher prices. The higher
prices will be offset by the benefits from
these regulations.
Although this final regulation is
significant, we do not expect it to
substantially affect national
productivity, growth, jobs, or full
employment. The dietary supplement
industry is too small a part of the
domestic economy to influence overall
economic activity.
This final rule will require additional
controls throughout the production and
distribution chain for the manufacture
of dietary supplements. The additional
costs will increase the total costs of
production and distribution for all of
the regulated products, including
products sold within the United States
and across national borders. These
increased costs will be partly passed on
to consumers in the form of higher
prices, which will tend to reduce the
quantity demanded of the regulated
products. The increased prices of U.S.
exports could reduce the quantity of
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U.S. exports demanded, particularly in
comparison with exports from countries
that do not implement similar
regulations. We expect this effect to be
insignificant, because under the final
rule the increases in the price of U.S.
exports (and resulting decreases in
quantity demanded) will be quite small.
XXV. Analysis of Environmental
Impact
We have carefully considered the
potential environmental effects of this
action. We have concluded under 21
CFR 25.30(h) that this action is of a type
that does not individually or
cumulatively have a significant effect on
the human environment. Therefore,
neither an environmental assessment
nor an environmental impact statement
is required.
XXVI. Federalism
We have analyzed this final rule in
accordance with the principles set forth
in Executive Order 13132. We have
determined that the final rule does not
contain policies that have substantial
direct effects on the States, on the
relationship between the National
Government and the States, or on the
distribution of power and
responsibilities among the various
levels of government. Furthermore, we
did not receive any comments from
States or their representative
organizations regarding to our analysis
of the proposed rule regarding the
principles set forth in Executive Order
13132. Accordingly, we conclude that
the final rule does not contain policies
that have federalism implications as
defined in the Executive order and,
consequently, a federalism summary
impact statement is not required.
XXVII. References
The following references have been
placed on display in the Division of
Dockets Management (HFA–305), Food
and Drug Administration, 5630 Fishers
Lane, rm. 1061, Rockville, MD 20857,
and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday
through Friday. (FDA has verified the
Web site addresses, but FDA is not
responsible for any subsequent changes
to the Web sites after this document
publishes in the Federal Register.)
1. U.S. Food and Drug Administration,
Memorandum of Site Visit, August 10, 1999,
to General Nutrition Products, Inc.,
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for Food Safety and Applied Nutrition.
2. U.S. Food and Drug Administration,
Memorandum of Site Visit, August 11, 1999,
to Perrigo Company of South Carolina, Inc.,
Greenville, SC. Memorandum dated October
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25, 1999 by Roslyn F. Powers, Ph.D., Center
for Food Safety and Applied Nutrition.
3. U.S. Food and Drug Administration,
Memorandum of Site Visit, August 17, 1999,
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Wilmington, NC. Memorandum dated
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Center for Food Safety and Applied
Nutrition.
4. U.S. Food and Drug Administration,
Memorandum of Site Visit, September 21,
1999, to Pharmavite Corporation, San
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25, 1999 by Roslyn F. Powers, Ph.D., Center
for Food Safety and Applied Nutrition.
5. U.S. Food and Drug Administration,
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1999, to Shaklee Manufacturing Center,
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for Food Safety and Applied Nutrition.
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Company Recalls Solgar’s Digestive Aid 100’s
Dietary Supplements Because of Possible
Salmonella Contamination, April 26, 2001;
Karuna Corporation, Karuna Corporation
Recalls HCl Nutritional Product Because of
Possible Health Risk, May 17, 2001; Licata
Enterprises, Licata Enterprises Recalls
Digestive Aid Products Because of Possible
Health Risk, May 18, 2001; Natural Organics,
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Recall of Digestive Aid Dietary Supplements
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Contaminated Raw Material Supplied by
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(Press releases available at https://
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27. ‘‘Sanitizing Rinses (for previously
cleaned food-contact surfaces), DIS/TSS–4
Efficacy Data Requirements’’ Disinfectant
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Environmental Protection Agency, Jan 30,
1979. Available on the Internet at https://
www.epa.gov/oppad001/dis_tss_docs/dis04.htm.
28. ‘‘Guide to Minimize Microbial Food
Safety Hazards for Fresh Fruits and
Vegetables,’’ U.S. Food and Drug
Administration, October 26, 1998. Available
on the Internet at https://www.cfsan.fda.gov/
~dms/prodguid.html.
29. Human Drug CGMP Notes, Volume 5,
Number 4, Division of Manufacturing and
Product Quality, Office of Compliance,
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S. Food and Drug Administration, December
1997. Available on the Internet at https://
www.fda.gov/cder/hdn/cnotesd7.pdf.
30. ‘‘Action Levels For Poisonous Or
Deleterious Substances In Human Food And
Animal Feed,’’ Industry Activities Staff,
Center for Food Safety and Applied
Nutrition, U.S. Food and Drug
Administration, August 2000. Available on
the Internet at https://www.cfsan.fda.gov/
~lrd/fdaact.html.
31. ‘‘Hazard Analysis and Critical Control
Point Principles and Application
Guidelines,’’ National Advisory Committee
on Microbiological Criteria for Foods, August
14, 1997.
32. ‘‘Draft Report of the Food Advisory
Committee Dietary Supplement Working
Group on Ingredient Identity Testing and
Records and Retention,’’ FDA Food Advisory
Committee Dietary Supplement Working
Group, Center for Food Safety and Applied
Nutrition, FDA, June 25, 1999.
33. ‘‘Guidance for Industry Part 11,
Electronic Records; Electronic signatures—
Scope and Application’’, available at https://
www.fda.gov/cder/guidance/5667fnl.htm.
34. ‘‘Dietary Supplement Labels: Key
Elements,’’ U.S. Department of Health and
Human Services (HHS). Office of the
Inspector General (OIG), Publication No.
OEI–01–01–00120. Available on the Internet
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00120.pdf.
35. NSF International Standard/American
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Economic Characterization of the Dietary
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2290: Task Order 3, March 1999.
E2. Research Triangle Institute (RTI).
Survey of Manufacturing Practices in the
Dietary Supplement Industry. Contract No.
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Revised, March 2004.
E3. ‘‘Herbal Rx: The Promises and Pitfalls.’’
1999. Consumer Reports (March): 44–48.
E4. ConsumerLab. 2000. Independent tests
of herbal, vitamin, and mineral supplements.
Accessed on March 16, 2005 at https://
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E5. Rothman, G. ‘‘Herbal Remedy Ripoffs.’’ Dallas/Fort Worth Magazine (April):
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E6. Saper, Robert B., Stefanos N. Kales,
Janet Parquin, Michael J. Burns, David M.
Eisenberg, Roger B. Davis, and Russell S.
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E7. Research Triangle Institute (RTI).
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Association. Facts about the Nutrition
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Nutrition, Report of Adverse Health
Outcomes Associated With the Consumption
of Dietary Supplements Which Were
Prepared Using Poor Manufacturing
Practices, June 11, 2001.
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Klein-Schwartz, G. C. Rodgers, Jr., J. Youniss,
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Borys. ‘‘2003 Annual report of the American
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ENF00875.html; Slifman NR, Obermeyer WR,
Aloi BK, Musser SM, Correll WA, Cichowicz
SM, Betz JM, Love LA. Contamination of
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Kelley S. Scanlon, Charles G. Helmick, and
Joseph Mulinare, ‘‘Cost-Effectiveness of
Strategies to Prevent Neural Tube Defects.’’
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edited by Marthe R. Gold, Joanna A. Siegel,
Louise B. Russell, and Milton C. Weinstein.
(New York: Oxford University Press, 1996),
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List of Subjects in 21 CFR Part 111
Dietary foods, Drugs, Foods,
Packaging and containers.
Therefore, under the Federal Food,
Drug, and Cosmetic Act and under
authority delegated to the Commissioner
of Food and Drugs, FDA is amending 21
CFR chapter I by adding part 111 to read
as follows:
I
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PART 111—CURRENT GOOD
MANUFACTURING PRACTICE IN
MANUFACTURING, PACKAGING,
LABELING, OR HOLDING
OPERATIONS FOR DIETARY
SUPPLEMENTS
Subpart A—General Provisions
Sec.
111.1 Who is subject to this part?
111.3 What definitions apply to this part?
111.5 Do other statutory provisions and
regulations apply?
Subpart B—Personnel
111.8 What are the requirements under this
subpart B for written procedures?
111.10 What requirements apply for
preventing microbial contamination from
sick or infected personnel and for
hygienic practices?
111.12 What personnel qualification
requirements apply?
111.13 What supervisor requirements
apply?
111.14 Under this subpart B, what records
must you make and keep?
Subpart C—Physical Plant and Grounds
111.15 What sanitation requirements apply
to your physical plant and grounds?
111.16 What are the requirements under
this subpart C for written procedures?
111.20 What design and construction
requirements apply to your physical
plant?
111.23 Under this subpart C, what records
must you make and keep?
Subpart D—Equipment and Utensils
111.25 What are the requirements under
this subpart D for written procedures?
111.27 What requirements apply to the
equipment and utensils that you use?
111.30 What requirements apply to
automated, mechanical, or electronic
equipment?
111.35 Under this subpart D, what records
must you make and keep?
Subpart E—Requirement to Establish a
Production and Process Control System
111.55 What are the requirements to
implement a production and process
control system?
111.60 What are the design requirements
for the production and process control
system?
111.65 What are the requirements for
quality control operations?
111.70 What specifications must you
establish?
111.73 What is your responsibility for
determining whether established
specifications are met?
111.75 What must you do to determine
whether specifications are met?
111.77 What must you do if established
specifications are not met?
111.80 What representative samples must
you collect?
111.83 What are the requirements for
reserve samples?
111.87 Who conducts a material review and
makes a disposition decision?
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111.90 What requirements apply to
treatments, in-process adjustments, and
reprocessing when there is a deviation or
unanticipated occurrence or when a
specification established in accordance
with § 111.70 is not met?
111.95 Under this subpart E, what records
must you make and keep?
Subpart F—Production and Process Control
System: Requirements for Quality Control
111.103 What are the requirements under
this subpart F for written procedures?
111.105 What must quality control
personnel do?
111.110 What quality control operations are
required for laboratory operations
associated with the production and
process control system?
111.113 What quality control operations are
required for a material review and
disposition decision?
111.117 What quality control operations are
required for equipment, instruments, and
controls?
111.120 What quality control operations are
required for components, packaging, and
labels before use in the manufacture of
a dietary supplement?
111.123 What quality control operations are
required for the master manufacturing
record, the batch production record, and
manufacturing operations?
111.127 What quality control operations are
required for packaging and labeling
operations?
111.130 What quality control operations are
required for returned dietary
supplements?
111.135 What quality control operations are
required for product complaints?
111.140 Under this subpart F, what records
must you make and keep?
Subpart G—Production and Process
Control System: Requirements for
Components, Packaging, and Labels and
for Product That You Receive for Packaging
or Labeling as a Dietary Supplement
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111.153 What are the requirements under
this subpart G for written procedures?
111.155 What requirements apply to
components of dietary supplements?
111.160 What requirements apply to
packaging and labels received?
111.165 What requirements apply to a
product received for packaging or
labeling as a dietary supplement (and for
distribution rather than for return to the
supplier)?
111.170 What requirements apply to
rejected components, packaging, and
labels, and to rejected products that are
received for packaging or labeling as a
dietary supplement?
111.180 Under this subpart G, what records
must you make and keep?
Subpart H—Production and Process
Control System: Requirements for the
Master Manufacturing Record
111.205 What is the requirement to
establish a master manufacturing record?
111.210 What must the master
manufacturing record include?
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Subpart I—Production and Process Control
System: Requirements for the Batch
Production Record
111.255 What is the requirement to
establish a batch production record?
111.260 What must the batch record
include?
Subpart J—Production and Process Control
System: Requirements for Laboratory
Operations
111.303 What are the requirements under
this subpart J for written procedures?
111.310 What are the requirements for the
laboratory facilities that you use?
111.315 What are the requirements for
laboratory control processes?
111.320 What requirements apply to
laboratory methods for testing and
examination?
111.325 Under this subpart J, what records
must you make and keep?
Subpart K—Production and Process
Control System: Requirements for
Manufacturing Operations
111.353 What are the requirements under
this subpart K for written procedures?
111.355 What are the design requirements
for manufacturing operations?
111.360 What are the requirements for
sanitation?
111.365 What precautions must you take to
prevent contamination?
111.370 What requirements apply to
rejected dietary supplements?
111.375 Under this subpart K, what records
must you make and keep?
Subpart L—Production and Process Control
System: Requirements for Packaging and
Labeling Operations
111.403 What are the requirements under
this subpart L for written procedures?
111.410 What requirements apply to
packaging and labels?
111.415 What requirements apply to filling,
assembling, packaging, labeling, and
related operations?
111.420 What requirements apply to
repackaging and relabeling?
111.425 What requirements apply to a
packaged and labeled dietary
supplement that is rejected for
distribution?
111.430 Under this subpart L, what records
must you make and keep?
Subpart M—Holding and Distributing
111.453 What are the requirements under
this subpart M for written procedures?
111.455 What requirements apply to
holding components, dietary
supplements, packaging, and labels?
111.460 What requirements apply to
holding in-process material?
111.465 What requirements apply to
holding reserve samples of dietary
supplements?
111.470 What requirements apply to
distributing dietary supplements?
111.475 Under this subpart M, what records
must you make and keep?
Subpart N—Returned Dietary Supplements
111.503 What are the requirements under
this subpart N for written procedures?
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111.510 What requirements apply when a
returned dietary supplement is received?
111.515 When must a returned dietary
supplement be destroyed, or otherwise
suitably disposed of?
111.520 When may a returned dietary
supplement be salvaged?
111.525 What requirements apply to a
returned dietary supplement that quality
control personnel approve for
reprocessing?
111.530 When must an investigation be
conducted of your manufacturing
processes and other batches?
111.535 Under this subpart N, what records
must you make and keep?
Subpart O—Product Complaints
111.553 What are the requirements under
this subpart O for written procedures?
111.560 What requirements apply to the
review and investigation of a product
complaint?
111.570 Under this subpart O, what records
must you make and keep?
Subpart P—Records and Recordkeeping
111.605 What requirements apply to the
records that you make and keep?
111.610 What records must be made
available to FDA?
Authority: 21 U.S.C. 321, 342, 343, 371,
374, 381, 393; 42 U.S.C. 264.
Subpart A—General Provisions
§ 111.1
Who is subject to this part?
(a) Except as provided by paragraph
(b) of this section, you are subject to this
part if you manufacture, package, label,
or hold a dietary supplement, including:
(1) A dietary supplement you
manufacture but that is packaged or
labeled by another person; and
(2) A dietary supplement imported or
offered for import in any State or
territory of the United States, the
District of Columbia, or the
Commonwealth of Puerto Rico.
(b) The requirements pertaining to
holding dietary supplements do not
apply to you if you are holding those
dietary supplements at a retail
establishment for the sole purpose of
direct retail sale to individual
consumers. A retail establishment does
not include a warehouse or other storage
facility for a retailer or a warehouse or
other storage facility that sells directly
to individual consumers.
§ 111.3
What definitions apply to this part?
The definitions and interpretations of
terms in section 201 of the Federal
Food, Drug, and Cosmetic Act (the act)
apply to such terms when used in this
part. For the purpose of this part, the
following definitions also apply:
Actual yield means the quantity that
is actually produced at any appropriate
step of manufacture or packaging of a
particular dietary supplement.
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Batch means a specific quantity of a
dietary supplement that is uniform, that
is intended to meet specifications for
identity, purity, strength, and
composition, and that is produced
during a specified time period according
to a single manufacturing record during
the same cycle of manufacture.
Batch number, lot number, or control
number means any distinctive group of
letters, numbers, or symbols, or any
combination of them, from which the
complete history of the manufacturing,
packaging, labeling, and/or holding of a
batch or lot of dietary supplements can
be determined.
Component means any substance
intended for use in the manufacture of
a dietary supplement, including those
that may not appear in the finished
batch of the dietary supplement.
Component includes dietary ingredients
(as described in section 201(ff) of the
act) and other ingredients.
Contact surface means any surface
that contacts a component or dietary
supplement, and those surfaces from
which drainage onto the component or
dietary supplement, or onto surfaces
that contact the component or dietary
supplement, occurs during the normal
course of operations. Examples of
contact surfaces include containers,
utensils, tables, contact surfaces of
equipment, and packaging.
Ingredient means any substance that
is used in the manufacture of a dietary
supplement and that is intended to be
present in the finished batch of the
dietary supplement. An ingredient
includes, but is not necessarily limited
to, a dietary ingredient as defined in
section 201(ff) of the act.
In-process material means any
material that is fabricated, compounded,
blended, ground, extracted, sifted,
sterilized, derived by chemical reaction,
or processed in any other way for use
in the manufacture of a dietary
supplement.
Lot means a batch, or a specific
identified portion of a batch, that is
uniform and that is intended to meet
specifications for identity, purity,
strength, and composition; or, in the
case of a dietary supplement produced
by continuous process, a specific
identified amount produced in a
specified unit of time or quantity in a
manner that is uniform and that is
intended to meet specifications for
identity, purity, strength, and
composition.
Microorganisms means yeasts, molds,
bacteria, viruses, and other similar
microscopic organisms having public
health or sanitary concern. This
definition includes species that:
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(1) May have public health
significance;
(2) May cause a component or dietary
supplement to decompose;
(3) Indicate that the component or
dietary supplement is contaminated
with filth; or
(4) Otherwise may cause the
component or dietary supplement to be
adulterated.
Must is used to state a requirement.
Pest means any objectionable insect or
other animal including birds, rodents,
flies, mites, and larvae.
Physical plant means all or any part
of a building or facility used for or in
connection with manufacturing,
packaging, labeling, or holding a dietary
supplement.
Product complaint means any
communication that contains any
allegation, written, electronic, or oral,
expressing concern, for any reason, with
the quality of a dietary supplement, that
could be related to current good
manufacturing practice. Examples of
product complaints are: Foul odor, off
taste, illness or injury, disintegration
time, color variation, tablet size or size
variation, under-filled container, foreign
material in a dietary supplement
container, improper packaging,
mislabeling, or dietary supplements that
are superpotent, subpotent, or contain
the wrong ingredient, or contain a drug
or other contaminant (e.g., bacteria,
pesticide, mycotoxin, glass, lead).
Quality means that the dietary
supplement consistently meets the
established specifications for identity,
purity, strength, and composition, and
limits on contaminants, and has been
manufactured, packaged, labeled, and
held under conditions to prevent
adulteration under section 402(a)(1),
(a)(2), (a)(3), and (a)(4) of the act.
Quality control means a planned and
systematic operation or procedure for
ensuring the quality of a dietary
supplement.
Quality control personnel means any
person, persons, or group, within or
outside of your organization, who you
designate to be responsible for your
quality control operations.
Representative sample means a
sample that consists of an adequate
number of units that are drawn based on
rational criteria, such as random
sampling, and that are intended to
ensure that the sample accurately
portrays the material being sampled.
Reprocessing means using, in the
manufacture of a dietary supplement,
clean, uncontaminated components or
dietary supplements that have been
previously removed from manufacturing
and that have been made suitable for
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use in the manufacture of a dietary
supplement.
Reserve sample means a
representative sample of product that is
held for a designated period of time.
Sanitize means to adequately treat
cleaned equipment, containers, utensils,
or any other cleaned contact surface by
a process that is effective in destroying
vegetative cells of microorganisms of
public health significance, and in
substantially reducing numbers of other
microorganisms, but without adversely
affecting the product or its safety for the
consumer.
Theoretical yield means the quantity
that would be produced at any
appropriate step of manufacture or
packaging of a particular dietary
supplement, based upon the quantity of
components or packaging to be used, in
the absence of any loss or error in actual
production.
Water activity (aw) is a measure of the
free moisture in a component or dietary
supplement and is the quotient of the
water vapor pressure of the substance
divided by the vapor pressure of pure
water at the same temperature.
We means the U.S. Food and Drug
Administration (FDA).
You means a person who
manufactures, packages, labels, or holds
dietary supplements.
§ 111.5 Do other statutory provisions and
regulations apply?
In addition to this part, you must
comply with other applicable statutory
provisions and regulations under the act
related to dietary supplements.
Subpart B—Personnel
§ 111.8 What are the requirements under
this subpart B for written procedures?
You must establish and follow written
procedures for fulfilling the
requirements of this subpart.
§ 111.10 What requirements apply for
preventing microbial contamination from
sick or infected personnel and for hygienic
practices?
(a) Preventing microbial
contamination. You must take measures
to exclude from any operations any
person who might be a source of
microbial contamination, due to a
health condition, where such
contamination may occur, of any
material, including components, dietary
supplements, and contact surfaces used
in the manufacture, packaging, labeling,
or holding of a dietary supplement.
Such measures include the following:
(1) Excluding from working in any
operations that may result in
contamination any person who, by
medical examination, the person’s
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acknowledgement, or supervisory
observation, is shown to have, or
appears to have, an illness, infection,
open lesion, or any other abnormal
source of microbial contamination, that
could result in microbial contamination
of components, dietary supplements, or
contact surfaces, until the health
condition no longer exists; and
(2) Instructing your employees to
notify their supervisor(s) if they have or
if there is a reasonable possibility that
they have a health condition described
in paragraph (a)(1) of this section that
could result in microbial contamination
of any components, dietary
supplements, or any contact surface.
(b) Hygienic practices. If you work in
an operation during which adulteration
of the component, dietary supplement,
or contact surface could occur, you must
use hygienic practices to the extent
necessary to protect against such
contamination of components, dietary
supplements, or contact surfaces. These
hygienic practices include the
following:
(1) Wearing outer garments in a
manner that protects against the
contamination of components, dietary
supplements, or any contact surface;
(2) Maintaining adequate personal
cleanliness;
(3) Washing hands thoroughly (and
sanitizing if necessary to protect against
contamination with microorganisms) in
an adequate hand-washing facility:
(i) Before starting work; and
(ii) At any time when the hands may
have become soiled or contaminated;
(4) Removing all unsecured jewelry
and other objects that might fall into
components, dietary supplements,
equipment, or packaging, and removing
hand jewelry that cannot be adequately
sanitized during periods in which
components or dietary supplements are
manipulated by hand. If hand jewelry
cannot be removed, it must be covered
by material that is maintained in an
intact, clean, and sanitary condition and
that effectively protects against
contamination of components, dietary
supplements, or contact surfaces;
(5) Maintaining gloves used in
handling components or dietary
supplements in an intact, clean, and
sanitary condition. The gloves must be
of an impermeable material;
(6) Wearing, where appropriate, in an
effective manner, hair nets, caps, beard
covers, or other effective hair restraints;
(7) Not storing clothing or other
personal belongings in areas where
components, dietary supplements, or
any contact surfaces are exposed or
where contact surfaces are washed;
(8) Not eating food, chewing gum,
drinking beverages, or using tobacco
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products in areas where components,
dietary supplements, or any contact
surfaces are exposed, or where contact
surfaces are washed; and
(9) Taking any other precautions
necessary to protect against the
contamination of components, dietary
supplements, or contact surfaces with
microorganisms, filth, or any other
extraneous materials, including
perspiration, hair, cosmetics, tobacco,
chemicals, and medicines applied to the
skin.
§ 111.12 What personnel qualification
requirements apply?
(a) You must have qualified
employees who manufacture, package,
label, or hold dietary supplements.
(b) You must identify who is
responsible for your quality control
operations. Each person who is
identified to perform quality control
operations must be qualified to do so
and have distinct and separate
responsibilities related to performing
such operations from those
responsibilities that the person
otherwise has when not performing
such operations.
(c) Each person engaged in
manufacturing, packaging, labeling, or
holding, or in performing any quality
control operations, must have the
education, training, or experience to
perform the person’s assigned functions.
§ 111.13
apply?
What supervisor requirements
(a) You must assign qualified
personnel to supervise the
manufacturing, packaging, labeling, or
holding of dietary supplements.
(b) Each supervisor whom you use
must be qualified by education, training,
or experience to supervise.
§ 111.14 Under this subpart B, what
records must you make and keep?
(a) You must make and keep records
required under this subpart B in
accordance with subpart P of this part.
(b) You must make and keep the
following records:
(1) Written procedures for fulfilling
the requirements of this subpart B; and
(2) Documentation of training,
including the date of the training, the
type of training, and the person(s)
trained.
Subpart C—Physical Plant and
Grounds
§ 111.15 What sanitation requirements
apply to your physical plant and grounds?
(a) Grounds. You must keep the
grounds of your physical plant in a
condition that protects against the
contamination of components, dietary
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supplements, or contact surfaces. The
methods for adequate ground
maintenance include:
(1) Properly storing equipment,
removing litter and waste, and cutting
weeds or grass within the immediate
vicinity of the physical plant so that it
does not attract pests, harbor pests, or
provide pests a place for breeding;
(2) Maintaining roads, yards, and
parking lots so that they do not
constitute a source of contamination in
areas where components, dietary
supplements, or contact surfaces are
exposed;
(3) Adequately draining areas that
may contribute to the contamination of
components, dietary supplements, or
contact surfaces by seepage, filth or any
other extraneous materials, or by
providing a breeding place for pests;
(4) Adequately operating systems for
waste treatment and disposal so that
they do not constitute a source of
contamination in areas where
components, dietary supplements, or
contact surfaces are exposed; and
(5) If your plant grounds are bordered
by grounds not under your control, and
if those other grounds are not
maintained in the manner described in
this section, you must exercise care in
the plant by inspection, extermination,
or other means to exclude pests, dirt,
and filth or any other extraneous
materials that may be a source of
contamination.
(b) Physical plant facilities. (1) You
must maintain your physical plant in a
clean and sanitary condition; and
(2) You must maintain your physical
plant in repair sufficient to prevent
components, dietary supplements, or
contact surfaces from becoming
contaminated.
(c) Cleaning compounds, sanitizing
agents, pesticides, and other toxic
materials. (1) You must use cleaning
compounds and sanitizing agents that
are free from microorganisms of public
health significance and that are safe and
adequate under the conditions of use.
(2) You must not use or hold toxic
materials in a physical plant in which
components, dietary supplements, or
contact surfaces are manufactured or
exposed, unless those materials are
necessary as follows:
(i) To maintain clean and sanitary
conditions;
(ii) For use in laboratory testing
procedures;
(iii) For maintaining or operating the
physical plant or equipment; or
(iv) For use in the plant’s operations.
(3) You must identify and hold
cleaning compounds, sanitizing agents,
pesticides, pesticide chemicals, and
other toxic materials in a manner that
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protects against contamination of
components, dietary supplements, or
contact surfaces.
(d) Pest control. (1) You must not
allow animals or pests in any area of
your physical plant. Guard or guide
dogs are allowed in some areas of your
physical plant if the presence of the
dogs will not result in contamination of
components, dietary supplements, or
contact surfaces;
(2) You must take effective measures
to exclude pests from the physical plant
and to protect against contamination of
components, dietary supplements, and
contact surfaces on the premises by
pests; and
(3) You must not use insecticides,
fumigants, fungicides, or rodenticides,
unless you take precautions to protect
against the contamination of
components, dietary supplements, or
contact surfaces.
(e) Water supply. (1) You must
provide water that is safe and sanitary,
at suitable temperatures, and under
pressure as needed, for all uses where
water does not become a component of
the dietary supplement.
(2) Water that is used in a manner
such that the water may become a
component of the dietary supplement,
e.g., when such water contacts
components, dietary supplements, or
any contact surface, must, at a
minimum, comply with applicable
Federal, State, and local requirements
and not contaminate the dietary
supplement.
(f) Plumbing. The plumbing in your
physical plant must be of an adequate
size and design and be adequately
installed and maintained to:
(1) Carry sufficient amounts of water
to required locations throughout the
physical plant;
(2) Properly convey sewage and liquid
disposable waste from your physical
plant;
(3) Avoid being a source of
contamination to components, dietary
supplements, water supplies, or any
contact surface, or creating an
unsanitary condition;
(4) Provide adequate floor drainage in
all areas where floors are subject to
flooding-type cleaning or where normal
operations release or discharge water or
other liquid waste on the floor; and
(5) Not allow backflow from, or cross
connection between, piping systems
that discharge waste water or sewage
and piping systems that carry water
used for manufacturing dietary
supplements, for cleaning contact
surfaces, or for use in bathrooms or
hand-washing facilities.
(g) Sewage disposal. You must
dispose of sewage into an adequate
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sewage system or through other
adequate means.
(h) Bathrooms. You must provide
your employees with adequate, readily
accessible bathrooms. The bathrooms
must be kept clean and must not be a
potential source of contamination to
components, dietary supplements, or
contact surfaces.
(i) Hand-washing facilities. You must
provide hand-washing facilities that are
designed to ensure that an employee’s
hands are not a source of contamination
of components, dietary supplements, or
any contact surface, by providing
facilities that are adequate, convenient,
and furnish running water at a suitable
temperature.
(j) Trash disposal. You must convey,
store, and dispose of trash to:
(1) Minimize the development of
odors;
(2) Minimize the potential for the
trash to attract, harbor, or become a
breeding place for pests;
(3) Protect against contamination of
components, dietary supplements, any
contact surface, water supplies, and
grounds surrounding your physical
plant; and
(4) Control hazardous waste to
prevent contamination of components,
dietary supplements, and contact
surfaces.
(k) Sanitation supervisors. You must
assign one or more employees to
supervise overall sanitation. Each of
these supervisors must be qualified by
education, training, or experience to
develop and supervise sanitation
procedures.
§ 111.16 What are the requirements under
this subpart C for written procedures?
You must establish and follow written
procedures for cleaning the physical
plant and for pest control.
§ 111.20 What design and construction
requirements apply to your physical plant?
Any physical plant you use in the
manufacture, packaging, labeling, or
holding of dietary supplements must:
(a) Be suitable in size, construction,
and design to facilitate maintenance,
cleaning, and sanitizing operations;
(b) Have adequate space for the
orderly placement of equipment and
holding of materials as is necessary for
maintenance, cleaning, and sanitizing
operations and to prevent
contamination and mixups of
components and dietary supplements
during manufacturing, packaging,
labeling, or holding;
(c) Permit the use of proper
precautions to reduce the potential for
mixups or contamination of
components, dietary supplements, or
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contact surfaces, with microorganisms,
chemicals, filth, or other extraneous
material. Your physical plant must
have, and you must use, separate or
defined areas of adequate size or other
control systems, such as computerized
inventory controls or automated systems
of separation, to prevent contamination
and mixups of components and dietary
supplements during the following
operations:
(1) Receiving, identifying, holding,
and withholding from use, components,
dietary supplements, packaging, and
labels that will be used in or during the
manufacturing, packaging, labeling, or
holding of dietary supplements;
(2) Separating, as necessary,
components, dietary supplements,
packaging, and labels that are to be used
in manufacturing from components,
dietary supplements, packaging, or
labels that are awaiting material review
and disposition decision, reprocessing,
or are awaiting disposal after rejection;
(3) Separating the manufacturing,
packaging, labeling, and holding of
different product types including
different types of dietary supplements
and other foods, cosmetics, and
pharmaceutical products;
(4) Performing laboratory analyses
and holding laboratory supplies and
samples;
(5) Cleaning and sanitizing contact
surfaces;
(6) Packaging and label operations;
and
(7) Holding components or dietary
supplements.
(d) Be designed and constructed in a
manner that prevents contamination of
components, dietary supplements, or
contact surfaces.
(1) The design and construction must
include:
(i) Floors, walls, and ceilings that can
be adequately cleaned and kept clean
and in good repair;
(ii) Fixtures, ducts, and pipes that do
not contaminate components, dietary
supplements, or contact surfaces by
dripping or other leakage, or
condensate;
(iii) Adequate ventilation or
environmental control equipment such
as airflow systems, including filters,
fans, and other air-blowing equipment,
that minimize odors and vapors
(including steam and noxious fumes) in
areas where they may contaminate
components, dietary supplements, or
contact surfaces;
(iv) Equipment that controls
temperature and humidity, when such
equipment is necessary to ensure the
quality of the dietary supplement; and
(v) Aisles or working spaces between
equipment and walls that are adequately
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unobstructed and of adequate width to
permit all persons to perform their
duties and to protect against
contamination of components, dietary
supplements, or contact surfaces with
clothing or personal contact.
(2) When fans and other air-blowing
equipment are used, such fans and
equipment must be located and
operated in a manner that minimizes the
potential for microorganisms and
particulate matter to contaminate
components, dietary supplements, or
contact surfaces;
(e) Provide adequate light in:
(1) All areas where components or
dietary supplements are examined,
processed, or held;
(2) All areas where contact surfaces
are cleaned; and
(3) Hand-washing areas, dressing and
locker rooms, and bathrooms.
(f) Use safety-type light bulbs,
fixtures, skylights, or other glass or
glass-like materials when the light
bulbs, fixtures, skylights or other glass
or glass-like materials are suspended
over exposed components or dietary
supplements in any step of preparation,
unless your physical plant is otherwise
constructed in a manner that will
protect against contamination of
components or dietary supplements in
case of breakage of glass or glass-like
materials.
(g) Provide effective protection against
contamination of components and
dietary supplements in bulk
fermentation vessels, by, for example:
(1) Use of protective coverings;
(2) Placement in areas where you can
eliminate harborages for pests over and
around the vessels;
(3) Placement in areas where you can
check regularly for pests, pest
infestation, filth or any other extraneous
materials; and
(4) Use of skimming equipment.
(h) Use adequate screening or other
protection against pests, where
necessary.
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§ 111.23 Under this subpart C, what
records must you make and keep?
(a) You must make and keep records
required under this subpart C in
accordance with subpart P of this part.
(b) You must make and keep records
of the written procedures for cleaning
the physical plant and for pest control.
(c) You must make and keep records
that show that water, when used in a
manner such that the water may become
a component of the dietary supplement,
meets the requirements of § 111.15(e)(2).
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Subpart D—Equipment and Utensils
§ 111.25 What are the requirements under
this subpart D for written procedures?
You must establish and follow written
procedures for fulfilling the
requirements of this subpart D,
including written procedures for:
(a) Calibrating instruments and
controls that you use in manufacturing
or testing a component or dietary
supplement;
(b) Calibrating, inspecting, and
checking automated, mechanical, and
electronic equipment; and
(c) Maintaining, cleaning, and
sanitizing, as necessary, all equipment,
utensils, and any other contact surfaces
that are used to manufacture, package,
label, or hold components or dietary
supplements.
§ 111.27 What requirements apply to the
equipment and utensils that you use?
(a) You must use equipment and
utensils that are of appropriate design,
construction, and workmanship to
enable them to be suitable for their
intended use and to be adequately
cleaned and properly maintained.
(1) Equipment and utensils include
the following:
(i) Equipment used to hold or convey;
(ii) Equipment used to measure;
(iii) Equipment using compressed air
or gas;
(iv) Equipment used to carry out
processes in closed pipes and vessels;
and
(v) Equipment used in automated,
mechanical, or electronic systems.
(2) You must use equipment and
utensils of appropriate design and
construction so that use will not result
in the contamination of components or
dietary supplements with:
(i) Lubricants;
(ii) Fuel;
(iii) Coolants;
(iv) Metal or glass fragments;
(v) Filth or any other extraneous
material;
(vi) Contaminated water; or
(vii) Any other contaminants.
(3) All equipment and utensils you
use must be:
(i) Installed and maintained to
facilitate cleaning the equipment,
utensils, and all adjacent spaces;
(ii) Corrosion-resistant if the
equipment or utensils contact
components or dietary supplements;
(iii) Made of nontoxic materials;
(iv) Designed and constructed to
withstand the environment in which
they are used, the action of components
or dietary supplements, and, if
applicable, cleaning compounds and
sanitizing agents; and
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(v) Maintained to protect components
and dietary supplements from being
contaminated by any source.
(4) Equipment and utensils you use
must have seams that are smoothly
bonded or maintained to minimize
accumulation of dirt, filth, organic
material, particles of components or
dietary supplements, or any other
extraneous materials or contaminants.
(5) Each freezer, refrigerator, and
other cold storage compartment you use
to hold components or dietary
supplements:
(i) Must be fitted with an indicating
thermometer, temperature-measuring
device, or temperature-recording device
that indicates and records, or allows for
recording by hand, the temperature
accurately within the compartment; and
(ii) Must have an automated device
for regulating temperature or an
automated alarm system to indicate a
significant temperature change in a
manual operation.
(6) Instruments or controls used in the
manufacturing, packaging, labeling, or
holding of a dietary supplement, and
instruments or controls that you use to
measure, regulate, or record
temperatures, hydrogen-ion
concentration (pH), water activity, or
other conditions, to control or prevent
the growth of microorganisms or other
contamination must be:
(i) Accurate and precise;
(ii) Adequately maintained; and
(iii) Adequate in number for their
designated uses.
(7) Compressed air or other gases you
introduce mechanically into or onto a
component, dietary supplement, or
contact surface or that you use to clean
any contact surface must be treated in
such a way that the component, dietary
supplement, or contact surface is not
contaminated.
(b) You must calibrate instruments
and controls you use in manufacturing
or testing a component or dietary
supplement. You must calibrate:
(1) Before first use;
(2) At the frequency specified in
writing by the manufacturer of the
instrument and control; or
(3) At routine intervals or as
otherwise necessary to ensure the
accuracy and precision of the
instrument and control.
(c) You must repair or replace
instruments or controls that cannot be
adjusted to agree with the reference
standard.
(d) You must maintain, clean, and
sanitize, as necessary, all equipment,
utensils, and any other contact surfaces
used to manufacture, package, label, or
hold components or dietary
supplements.
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(1) Equipment and utensils must be
taken apart as necessary for thorough
maintenance, cleaning, and sanitizing.
(2) You must ensure that all contact
surfaces, used for manufacturing or
holding low-moisture components or
dietary supplements, are in a dry and
sanitary condition when in use. When
the surfaces are wet-cleaned, they must
be sanitized, when necessary, and
thoroughly dried before subsequent use.
(3) If you use wet processing during
manufacturing, you must clean and
sanitize all contact surfaces, as
necessary, to protect against the
introduction of microorganisms into
components or dietary supplements.
When cleaning and sanitizing is
necessary, you must clean and sanitize
all contact surfaces before use and after
any interruption during which the
contact surface may have become
contaminated. If you use contact
surfaces in a continuous production
operation or in consecutive operations
involving different batches of the same
dietary supplement, you must
adequately clean and sanitize the
contact surfaces, as necessary.
(4) You must clean surfaces that do
not come into direct contact with
components or dietary supplements as
frequently as necessary to protect
against contaminating components or
dietary supplements.
(5) Single-service articles (such as
utensils intended for one-time use,
paper cups, and paper towels) must be:
(i) Stored in appropriate containers;
and
(ii) Handled, dispensed, used, and
disposed of in a manner that protects
against contamination of components,
dietary supplements, or any contact
surface.
(6) Cleaning compounds and
sanitizing agents must be adequate for
their intended use and safe under their
conditions of use;
(7) You must store cleaned and
sanitized portable equipment and
utensils that have contact surfaces in a
location and manner that protects them
from contamination.
sroberts on PROD1PC70 with RULES
§ 111.30 What requirements apply to
automated, mechanical, or electronic
equipment?
For any automated, mechanical, or
electronic equipment that you use to
manufacture, package, label, or hold a
dietary supplement, you must:
(a) Design or select equipment to
ensure that dietary supplement
specifications are consistently met;
(b) Determine the suitability of the
equipment by ensuring that your
equipment is capable of operating
satisfactorily within the operating limits
required by the process;
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(c) Routinely calibrate, inspect, or
check the equipment to ensure proper
performance. Your quality control
personnel must periodically review
these calibrations, inspections, or
checks;
(d) Establish and use appropriate
controls for automated, mechanical, and
electronic equipment (including
software for a computer controlled
process) to ensure that any changes to
the manufacturing, packaging, labeling,
holding, or other operations are
approved by quality control personnel
and instituted only by authorized
personnel; and
(e) Establish and use appropriate
controls to ensure that the equipment
functions in accordance with its
intended use. These controls must be
approved by quality control personnel.
§ 111.35 Under this subpart D, what
records must you make and keep?
(a) You must make and keep records
required under this subpart D in
accordance with subpart P of this part.
(b) You must make and keep the
following records:
(1) Written procedures for fulfilling
the requirements of this subpart,
including written procedures for:
(i) Calibrating instruments and
controls that you use in manufacturing
or testing a component or dietary
supplement;
(ii) Calibrating, inspecting, and
checking automated, mechanical, and
electronic equipment; and
(iii) Maintaining, cleaning, and
sanitizing, as necessary, all equipment,
utensils, and any other contact surfaces
that are used to manufacture, package,
label, or hold components or dietary
supplements;
(2) Documentation, in individual
equipment logs, of the date of the use,
maintenance, cleaning, and sanitizing of
equipment, unless such documentation
is kept with the batch record;
(3) Documentation of any calibration,
each time the calibration is performed,
for instruments and controls that you
use in manufacturing or testing a
component or dietary supplement. In
your documentation, you must:
(i) Identify the instrument or control
calibrated;
(ii) Provide the date of calibration;
(iii) Identify the reference standard
used including the certification of
accuracy of the known reference
standard and a history of recertification
of accuracy;
(iv) Identify the calibration method
used, including appropriate limits for
accuracy and precision of instruments
and controls when calibrating;
(v) Provide the calibration reading or
readings found;
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(vi) Identify the recalibration method
used, and reading or readings found, if
accuracy or precision or both accuracy
and precision limits for instruments and
controls were not met; and
(vii) Include the initials of the person
who performed the calibration and any
recalibration.
(4) Written records of calibrations,
inspections, and checks of automated,
mechanical, and electronic equipment;
(5) Backup file(s) of current software
programs (and of outdated software that
is necessary to retrieve records that you
are required to keep in accordance with
subpart P of this part, when current
software is not able to retrieve such
records) and of data entered into
computer systems that you use to
manufacture, package, label, or hold
dietary supplements.
(i) Your backup file (e.g., a hard copy
of data you have entered, diskettes,
tapes, microfilm, or compact disks)
must be an exact and complete record
of the data you entered.
(ii) You must keep your backup
software programs and data secure from
alterations, inadvertent erasures, or loss;
and
(6) Documentation of the controls that
you use to ensure that equipment
functions in accordance with its
intended use.
Subpart E—Requirement to Establish a
Production and Process Control
System
§ 111.55 What are the requirements to
implement a production and process
control system?
You must implement a system of
production and process controls that
covers all stages of manufacturing,
packaging, labeling, and holding of the
dietary supplement to ensure the quality
of the dietary supplement and that the
dietary supplement is packaged and
labeled as specified in the master
manufacturing record.
§ 111.60 What are the design requirements
for the production and process control
system?
(a) Your production and in-process
control system must be designed to
ensure that the dietary supplement is
manufactured, packaged, labeled, and
held in a manner that will ensure the
quality of the dietary supplement and
that the dietary supplement is packaged
and labeled as specified in the master
manufacturing record; and
(b) The production and in-process
control system must include all
requirements of subparts E through L of
this part and must be reviewed and
approved by quality control personnel.
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§ 111.65 What are the requirements for
quality control operations?
You must implement quality control
operations in your manufacturing,
packaging, labeling, and holding
operations for producing the dietary
supplement to ensure the quality of the
dietary supplement and that the dietary
supplement is packaged and labeled as
specified in the master manufacturing
record.
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§ 111.70 What specifications must you
establish?
(a) You must establish a specification
for any point, step, or stage in the
manufacturing process where control is
necessary to ensure the quality of the
dietary supplement and that the dietary
supplement is packaged and labeled as
specified in the master manufacturing
record.
(b) For each component that you use
in the manufacture of a dietary
supplement, you must establish
component specifications as follows:
(1) You must establish an identity
specification;
(2) You must establish component
specifications that are necessary to
ensure that specifications for the purity,
strength and composition of dietary
supplements manufactured using the
components are met; and
(3) You must establish limits on those
types of contamination that may
adulterate or may lead to adulteration of
the finished batch of the dietary
supplement to ensure the quality of the
dietary supplement.
(c) For the in-process production:
(1) You must establish in-process
specifications for any point, step, or
stage in the master manufacturing
record where control is necessary to
help ensure that specifications are met
for the identity, purity, strength, and
composition of the dietary supplements
and, as necessary, for limits on those
types of contamination that may
adulterate or may lead to adulteration of
the finished batch of the dietary
supplement;
(2) You must provide adequate
documentation of your basis for why
meeting the in-process specifications, in
combination with meeting component
specifications, will help ensure that the
specifications are met for the identity,
purity, strength, and composition of the
dietary supplements and for limits on
those types of contamination that may
adulterate or may lead to adulteration of
the finished batch of the dietary
supplement; and
(3) Quality control personnel must
review and approve the documentation
that you provide under paragraph (c)(2)
of this section.
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(d) You must establish specifications
for dietary supplement labels (label
specifications) and for packaging that
may come in contact with dietary
supplements (packaging specifications).
Packaging that may come into contact
with dietary supplements must be safe
and suitable for its intended use and
must not be reactive or absorptive or
otherwise affect the safety or quality of
the dietary supplement.
(e) For each dietary supplement that
you manufacture you must establish
product specifications for the identity,
purity, strength, and composition of the
finished batch of the dietary
supplement, and for limits on those
types of contamination that may
adulterate, or that may lead to
adulteration of, the finished batch of the
dietary supplement to ensure the quality
of the dietary supplement.
(f) If you receive a product from a
supplier for packaging or labeling as a
dietary supplement (and for distribution
rather than for return to the supplier),
you must establish specifications to
provide sufficient assurance that the
product you receive is adequately
identified and is consistent with your
purchase order.
(g) You must establish specifications
for the packaging and labeling of the
finished packaged and labeled dietary
supplements, including specifications
that ensure that you used the specified
packaging and that you applied the
specified label.
§ 111.73 What is your responsibility for
determining whether established
specifications are met?
You must determine whether the
specifications you establish under
§ 111.70 are met.
§ 111.75 What must you do to determine
whether specifications are met?
(a) Before you use a component, you
must:
(1) Conduct at least one appropriate
test or examination to verify the identity
of any component that is a dietary
ingredient; and
(2) Confirm the identity of other
components and determine whether
other applicable component
specifications established in accordance
with § 111.70(b) are met. To do so, you
must either:
(i) Conduct appropriate tests or
examinations; or
(ii) Rely on a certificate of analysis
from the supplier of the component that
you receive, provided that:
(A) You first qualify the supplier by
establishing the reliability of the
supplier’s certificate of analysis through
confirmation of the results of the
supplier’s tests or examinations;
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(B) The certificate of analysis includes
a description of the test or examination
method(s) used, limits of the test or
examinations, and actual results of the
tests or examinations;
(C) You maintain documentation of
how you qualified the supplier;
(D) You periodically re-confirm the
supplier’s certificate of analysis; and
(E) Your quality control personnel
review and approve the documentation
setting forth the basis for qualification
(and re-qualification) of any supplier.
(b) You must monitor the in-process
points, steps, or stages where control is
necessary to ensure the quality of the
finished batch of dietary supplement to:
(1) Determine whether the in-process
specifications are met; and
(2) Detect any deviation or
unanticipated occurrence that may
result in a failure to meet specifications.
(c) For a subset of finished dietary
supplement batches that you identify
through a sound statistical sampling
plan (or for every finished batch), you
must verify that your finished batch of
the dietary supplement meets product
specifications for identity, purity,
strength, composition, and for limits on
those types of contamination that may
adulterate or that may lead to
adulteration of the finished batch of the
dietary supplement. To do so:
(1) You must select one or more
established specifications for identity,
purity, strength, composition, and the
limits on those types of contamination
that may adulterate or that may lead to
adulteration of the dietary supplement
that, if tested or examined on the
finished batches of the dietary
supplement, would verify that the
production and process control system
is producing a dietary supplement that
meets all product specifications (or only
those product specifications not
otherwise exempted from this provision
by quality control personnel under
paragraph (d) of this section);
(2) You must conduct appropriate
tests or examinations to determine
compliance with the specifications
selected in paragraph (c)(1) of this
section;
(3) You must provide adequate
documentation of your basis for
determining compliance with the
specification(s) selected under
paragraph (c)(1) of this section, through
the use of appropriate tests or
examinations conducted under
paragraph (c)(2) of this section, will
ensure that your finished batch of the
dietary supplement meets all product
specifications for identity, purity,
strength, and composition, and the
limits on those types of contamination
that may adulterate, or that may lead to
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the adulteration of, the dietary
supplement; and
(4) Your quality control personnel
must review and approve the
documentation that you provide under
paragraph (c)(3) of this section.
(d)(1) You may exempt one or more
product specifications from verification
requirements in paragraph (c)(1) of this
section if you determine and document
that the specifications you select under
paragraph (c)(1) of this section for
determination of compliance with
specifications are not able to verify that
the production and process control
system is producing a dietary
supplement that meets the exempted
product specification and there is no
scientifically valid method for testing or
examining such exempted product
specification at the finished batch stage.
In such a case, you must document why,
for example, any component and inprocess testing, examination, or
monitoring, and any other information,
will ensure that such exempted product
specification is met without verification
through periodic testing of the finished
batch; and
(2) Your quality control personnel
must review and approve the
documentation that you provide under
paragraph (d)(1) of this section.
(e) Before you package or label a
product that you receive for packaging
or labeling as a dietary supplement (and
for distribution rather than for return to
the supplier), you must visually
examine the product and have
documentation to determine whether
the specifications that you established
under § 111.70 (f) are met.
(f)(1) Before you use packaging, you
must, at a minimum, conduct a visual
identification of the containers and
closures and review the supplier’s
invoice, guarantee, or certification to
determine whether the packaging
specifications are met; and
(2) Before you use labels, you must, at
a minimum, conduct a visual
examination of the label and review the
supplier’s invoice, guarantee, or
certification to determine whether label
specifications are met.
(g) You must, at a minimum, conduct
a visual examination of the packaging
and labeling of the finished packaged
and labeled dietary supplements to
determine whether you used the
specified packaging and applied the
specified label.
(h)(1) You must ensure that the tests
and examinations that you use to
determine whether the specifications
are met are appropriate, scientifically
valid methods.
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(2) The tests and examinations that
you use must include at least one of the
following:
(i) Gross organoleptic analysis;
(ii) Macroscopic analysis;
(iii) Microscopic analysis;
(iv) Chemical analysis; or
(v) Other scientifically valid methods.
(i) You must establish corrective
action plans for use when an established
specification is not met.
§ 111.77 What must you do if established
specifications are not met?
(a) For specifications established
under § 111.70(a), (b)(2), (b)(3), (c), (d),
(e), and (g) that you do not meet, quality
control personnel, in accordance with
the requirements in subpart F of this
part, must reject the component, dietary
supplement, package or label unless
such personnel approve a treatment, an
in-process adjustment, or reprocessing
that will ensure the quality of the
finished dietary supplement and that
the dietary supplement is packaged and
labeled as specified in the master
manufacturing record. No finished batch
of dietary supplements may be released
for distribution unless it complies with
§ 111.123(b).
(b) For specifications established
under § 111.70(b)(1) that you do not
meet, quality control personnel must
reject the component and the
component must not be used in
manufacturing the dietary supplement.
(c) For specifications established
under § 111.70(f) that you do not meet,
quality control personnel must reject the
product and the product may not be
packaged or labeled for distribution as
a dietary supplement.
§ 111.80 What representative samples
must you collect?
The representative samples that you
must collect include:
(a) Representative samples of each
unique lot of components, packaging,
and labels that you use to determine
whether the components, packaging,
and labels meet specifications
established in accordance with
§ 111.70(b) and (d), and as applicable,
§ 111.70(a) (and, when you receive
components, packaging, or labels from a
supplier, representative samples of each
unique shipment, and of each unique lot
within each unique shipment);
(b) Representative samples of inprocess materials for each manufactured
batch at points, steps, or stages, in the
manufacturing process as specified in
the master manufacturing record where
control is necessary to ensure the
identity, purity, strength, and
composition of dietary supplements to
determine whether the in-process
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materials meet specifications
established in accordance with
§ 111.70(c), and as applicable,
§ 111.70(a);
(c) Representative samples of a subset
of finished batches of each dietary
supplement that you manufacture,
which you identify through a sound
statistical sampling plan (or otherwise
every finished batch), before releasing
for distribution to verify that the
finished batch of dietary supplement
meets product specifications established
in accordance with § 111.70(e), and as
applicable, § 111.70(a);
(d) Representative samples of each
unique shipment, and of each unique lot
within each unique shipment, of
product that you receive for packaging
or labeling as a dietary supplement (and
for distribution rather than for return to
the supplier) to determine whether the
received product meets specifications
established in accordance with
§ 111.70(f), and as applicable,
§ 111.70(a); and
(e) Representative samples of each lot
of packaged and labeled dietary
supplements to determine whether the
packaging and labeling of the finished
packaged and labeled dietary
supplements meet specifications
established in accordance with
§ 111.70(g), and as applicable,
§ 111.70(a).
§ 111.83 What are the requirements for
reserve samples?
(a) You must collect and hold reserve
samples of each lot of packaged and
labeled dietary supplements that you
distribute.
(b) The reserve samples must:
(1) Be held using the same containerclosure system in which the packaged
and labeled dietary supplement is
distributed, or if distributing dietary
supplements to be packaged and
labeled, using a container-closure
system that provides essentially the
same characteristics to protect against
contamination or deterioration as the
one in which it is distributed for
packaging and labeling elsewhere;
(2) Be identified with the batch, lot,
or control number;
(3) Be retained for 1 year past the
shelf life date (if shelf life dating is
used), or for 2 years from the date of
distribution of the last batch of dietary
supplements associated with the reserve
sample, for use in appropriate
investigations; and
(4) Consist of at least twice the
quantity necessary for all tests or
examinations to determine whether or
not the dietary supplement meets
product specifications.
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§ 111.87 Who conducts a material review
and makes a disposition decision?
Quality control personnel must
conduct all required material reviews
and make all required disposition
decisions.
§ 111.90 What requirements apply to
treatments, in-process adjustments, and
reprocessing when there is a deviation or
unanticipated occurrence or when a
specification established in accordance
with § 111.70 is not met?
(a) You must not reprocess a rejected
dietary supplement or treat or provide
an in-process adjustment to a
component, packaging, or label to make
it suitable for use in the manufacture of
a dietary supplement unless:
(1) Quality control personnel conduct
a material review and make a
disposition decision to approve the
reprocessing, treatment, or in-process
adjustment; and
(2) The reprocessing, treatment, or inprocess adjustment is permitted by
§ 111.77;
(b) You must not reprocess any
dietary supplement or treat or provide
an in-process adjustment to a
component to make it suitable for use in
the manufacture of a dietary
supplement, unless:
(1) Quality control personnel conduct
a material review and make a
disposition decision that is based on a
scientifically valid reason and approves
the reprocessing, treatment, or inprocess adjustment; and
(2) The reprocessing, treatment or inprocess adjustment is permitted by
§ 111.77;
(c) Any batch of dietary supplement
that is reprocessed, that contains
components that you have treated, or to
which you have made in-process
adjustments to make them suitable for
use in the manufacture of the dietary
supplement must be approved by
quality control personnel and comply
with § 111.123(b) before releasing for
distribution.
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§ 111.95 Under this subpart E, what
records must you make and keep?
(a) You must make and keep records
required under this subpart E in
accordance with subpart P of this part.
(b) Under this subpart E, you must
make and keep the following records:
(1) The specifications established;
(2) Documentation of your
qualification of a supplier for the
purpose of relying on the supplier’s
certificate of analysis;
(3) Documentation for why meeting
in-process specifications, in
combination with meeting component
specifications, helps ensure that the
dietary supplement meets the
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specifications for identity, purity,
strength, and composition; and for
limits on those types of contamination
that may adulterate or may lead to
adulteration of the finished batch of the
dietary supplement; and
(4) Documentation for why the results
of appropriate tests or examinations for
the product specifications selected
under § 111.75(c)(1) ensure that the
dietary supplement meets all product
specifications;
(5) Documentation for why any
component and in-process testing,
examination, or monitoring, and any
other information, will ensure that a
product specification that is exempted
under § 111.75(d) is met without
verification through periodic testing of
the finished batch, including
documentation that the selected
specifications tested or examined under
§ 111.75 (c)(1) are not able to verify that
the production and process control
system is producing a dietary
supplement that meets the exempted
product specification and there is no
scientifically valid method for testing or
examining such exempted product
specification at the finished batch stage.
Subpart F—Production and Process
Control System: Requirements for
Quality Control
§ 111.103 What are the requirements under
this subpart F for written procedures?
You must establish and follow written
procedures for the responsibilities of the
quality control operations, including
written procedures for conducting a
material review and making a
disposition decision, and for approving
or rejecting any reprocessing.
§ 111.105 What must quality control
personnel do?
Quality control personnel must
ensure that your manufacturing,
packaging, labeling, and holding
operations ensure the quality of the
dietary supplement and that the dietary
supplement is packaged and labeled as
specified in the master manufacturing
record. To do so, quality control
personnel must perform operations that
include:
(a) Approving or rejecting all
processes, specifications, written
procedures, controls, tests, and
examinations, and deviations from or
modifications to them, that may affect
the identity, purity, strength, or
composition of a dietary supplement;
(b) Reviewing and approving the
documentation setting forth the basis for
qualification of any supplier;
(c) Reviewing and approving the
documentation setting forth the basis for
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34951
why meeting in-process specifications,
in combination with meeting
component specifications, will help
ensure that the identity, purity, strength,
and composition of the dietary
supplement are met;
(d) Reviewing and approving the
documentation setting forth the basis for
why the results of appropriate tests or
examinations for each product
specification selected under
§ 111.75(c)(1) will ensure that the
finished batch of the dietary supplement
meets product specifications;
(e) Reviewing and approving the basis
and the documentation for why any
product specification is exempted from
the verification requirements in
§ 111.75(c)(1), and for why any
component and in-process testing,
examination, or monitoring, or other
methods will ensure that such exempted
product specification is met without
verification through periodic testing of
the finished batch;
(f) Ensuring that required
representative samples are collected;
(g) Ensuring that required reserve
samples are collected and held;
(h) Determining whether all
specifications established under
§ 111.70(a) are met; and
(i) Performing other operations
required under this subpart.
§ 111.110 What quality control operations
are required for laboratory operations
associated with the production and process
control system?
Quality control operations for
laboratory operations associated with
the production and process control
system must include:
(a) Reviewing and approving all
laboratory control processes associated
with the production and process control
system;
(b) Ensuring that all tests and
examinations required under § 111.75
are conducted; and
(c) Reviewing and approving the
results of all tests and examinations
required under § 111.75.
§ 111.113 What quality control operations
are required for a material review and
disposition decision?
(a) Quality control personnel must
conduct a material review and make a
disposition decision if:
(1) A specification established in
accordance with § 111.70 is not met;
(2) A batch deviates from the master
manufacturing record, including when
any step established in the master
manufacturing record is not completed
and including any deviation from
specifications;
(3) There is any unanticipated
occurrence during the manufacturing
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operations that adulterates or may lead
to adulteration of the component,
dietary supplement, or packaging, or
could lead to the use of a label not
specified in the master manufacturing
record;
(4) Calibration of an instrument or
control suggests a problem that may
have resulted in a failure to ensure the
quality of a batch or batches of a dietary
supplement; or
(5) A dietary supplement is returned.
(b)(1) When there is a deviation or
unanticipated occurrence during the
production and in-process control
system that results in or could lead to
adulteration of a component, dietary
supplement, or packaging, or could lead
to the use of a label not specified in the
master manufacturing record, quality
control personnel must reject the
component, dietary supplement,
packaging, or label unless it approves a
treatment, an in-process adjustment, or
reprocessing to correct the applicable
deviation or occurrence.
(2) When a specification established
in accordance with § 111.70 is not met,
quality control personnel must reject the
component, dietary supplement,
package or label, unless quality control
personnel approve a treatment, an inprocess adjustment, or reprocessing, as
permitted in § 111.77.
(c) The person who conducts a
material review and makes the
disposition decision must, at the time of
performance, document that material
review and disposition decision.
§ 111.117 What quality control operations
are required for equipment, instruments,
and controls?
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Quality control operations for
equipment, instruments, and controls
must include:
(a) Reviewing and approving all
processes for calibrating instruments
and controls;
(b) Periodically reviewing all records
for calibration of instruments and
controls;
(c) Periodically reviewing all records
for calibrations, inspections, and checks
of automated, mechanical, or electronic
equipment; and
(d) Reviewing and approving controls
to ensure that automated, mechanical,
or electronic equipment functions in
accordance with its intended use.
§ 111.120 What quality control operations
are required for components, packaging,
and labels before use in the manufacture of
a dietary supplement?
Quality control operations for
components, packaging, and labels
before use in the manufacture of a
dietary supplement must include:
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(a) Reviewing all receiving records for
components, packaging, and labels;
(b) Determining whether all
components, packaging, and labels
conform to specifications established
under § 111.70 (b) and (d);
(c) Conducting any required material
review and making any required
disposition decision;
(d) Approving or rejecting any
treatment and in-process adjustments of
components, packaging, or labels to
make them suitable for use in the
manufacture of a dietary supplement;
and
(e) Approving, and releasing from
quarantine, all components, packaging,
and labels before they are used.
§ 111.123 What quality control operations
are required for the master manufacturing
record, the batch production record, and
manufacturing operations?
(a) Quality control operations for the
master manufacturing record, the batch
production record, and manufacturing
operations must include:
(1) Reviewing and approving all
master manufacturing records and all
modifications to the master
manufacturing records;
(2) Reviewing and approving all batch
production-related records;
(3) Reviewing all monitoring required
under subpart E;
(4) Conducting any required material
review and making any required
disposition decision;
(5) Approving or rejecting any
reprocessing;
(6) Determining whether all inprocess specifications established in
accordance with § 111.70(c) are met;
(7) Determining whether each
finished batch conforms to product
specifications established in accordance
with § 111.70(e); and
(8) Approving and releasing, or
rejecting, each finished batch for
distribution, including any reprocessed
finished batch.
(b) Quality control personnel must not
approve and release for distribution:
(1) Any batch of dietary supplement
for which any component in the batch
does not meet its identity specification;
(2) Any batch of dietary supplement,
including any reprocessed batch, that
does not meet all product specifications
established in accordance with
§ 111.70(e);
(3) Any batch of dietary supplement,
including any reprocessed batch, that
has not been manufactured, packaged,
labeled, and held under conditions to
prevent adulteration under section
402(a)(1), (a)(2), (a)(3), and (a)(4) of the
act; and
(4) Any product received from a
supplier for packaging or labeling as a
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dietary supplement (and for distribution
rather than for return to the supplier) for
which sufficient assurance is not
provided to adequately identify the
product and to determine that the
product is consistent with your
purchase order.
§ 111.127 What quality control operations
are required for packaging and labeling
operations?
Quality control operations for
packaging and labeling operations must
include:
(a) Reviewing the results of any visual
examination and documentation to
ensure that specifications established
under § 111.70(f) are met for all
products that you receive for packaging
and labeling as a dietary supplement
(and for distribution rather than for
return to the supplier);
(b) Approving, and releasing from
quarantine, all products that you receive
for packaging or labeling as a dietary
supplement (and for distribution rather
than for return to the supplier) before
they are used for packaging or labeling;
(c) Reviewing and approving all
records for packaging and label
operations;
(d) Determining whether the finished
packaged and labeled dietary
supplement conforms to specifications
established in accordance with
§ 111.70(g);
(e) Conducting any required material
review and making any required
disposition decision;
(f) Approving or rejecting any
repackaging of a packaged dietary
supplement;
(g) Approving or rejecting any
relabeling of a packaged and labeled
dietary supplement; and
(h) Approving for release, or rejecting,
any packaged and labeled dietary
supplement (including a repackaged or
relabeled dietary supplement) for
distribution.
§ 111.130 What quality control operations
are required for returned dietary
supplements?
Quality control operations for
returned dietary supplements must
include:
(a) Conducting any required material
review and making any required
disposition decision; including:
(1) Determining whether tests or
examination are necessary to determine
compliance with product specifications
established in accordance with
§ 111.70(e); and
(2) Reviewing the results of any tests
or examinations that are conducted to
determine compliance with product
specifications established in accordance
with § 111.70(e);
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(b) Approving or rejecting any salvage
and redistribution of any returned
dietary supplement;
(c) Approving or rejecting any
reprocessing of any returned dietary
supplement; and
(d) Determining whether the
reprocessed dietary supplement meets
product specifications and either
approving for release, or rejecting, any
returned dietary supplement that is
reprocessed.
§ 111.135 What quality control operations
are required for product complaints?
Quality control operations for product
complaints must include reviewing and
approving decisions about whether to
investigate a product complaint and
reviewing and approving the findings
and followup action of any investigation
performed.
sroberts on PROD1PC70 with RULES
§ 111.140 Under this subpart F, what
records must you make and keep?
(a) You must make and keep the
records required under this subpart F in
accordance with subpart P of this part.
(b) You must make and keep the
following records:
(1) Written procedures for the
responsibilities of the quality control
operations, including written
procedures for conducting a material
review and making a disposition
decision and written procedures for
approving or rejecting any reprocessing;
(2) Written documentation, at the time
of performance, that quality control
personnel performed the review,
approval, or rejection requirements by
recording the following:
(i) Date that the review, approval, or
rejection was performed; and
(ii) Signature of the person performing
the review, approval, or rejection; and
(3) Documentation of any material
review and disposition decision and
followup. Such documentation must be
included in the appropriate batch
production record and must include:
(i) Identification of the specific
deviation or the unanticipated
occurrence;
(ii) Description of your investigation
into the cause of the deviation from the
specification or the unanticipated
occurrence;
(iii) Evaluation of whether or not the
deviation or unanticipated occurrence
has resulted in or could lead to a failure
to ensure the quality of the dietary
supplement or a failure to package and
label the dietary supplement as
specified in the master manufacturing
record;
(iv) Identification of the action(s)
taken to correct, and prevent a
recurrence of, the deviation or the
unanticipated occurrence;
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(v) Explanation of what you did with
the component, dietary supplement,
packaging, or label;
(vi) A scientifically valid reason for
any reprocessing of a dietary
supplement that is rejected or any
treatment or in-process adjustment of a
component that is rejected; and
(vii) The signature of the individual(s)
designated to perform the quality
control operation, who conducted the
material review and made the
disposition decision, and of each
qualified individual who provides
information relevant to that material
review and disposition decision.
Subpart G—Production and Process
Control System: Requirements for
Components, Packaging, and Labels
and for Product That You Receive for
Packaging or Labeling as a Dietary
Supplement
§ 111.153 What are the requirements under
this subpart G for written procedures?
You must establish and follow written
procedures for fulfilling the
requirements of this subpart G.
§ 111.155 What requirements apply to
components of dietary supplements?
(a) You must visually examine each
immediate container or grouping of
immediate containers in a shipment that
you receive for appropriate content
label, container damage, or broken seals
to determine whether the container
condition may have resulted in
contamination or deterioration of the
components;
(b) You must visually examine the
supplier’s invoice, guarantee, or
certification in a shipment you receive
to ensure the components are consistent
with your purchase order;
(c) You must quarantine components
before you use them in the manufacture
of a dietary supplement until:
(1) You collect representative samples
of each unique lot of components (and,
for components that you receive, of each
unique shipment, and of each unique lot
within each unique shipment);
(2) Quality control personnel review
and approve the results of any tests or
examinations conducted on
components; and
(3) Quality control personnel approve
the components for use in the
manufacture of a dietary supplement,
including approval of any treatment
(including in-process adjustments) of
components to make them suitable for
use in the manufacture of a dietary
supplement, and releases them from
quarantine.
(d)(1) You must identify each unique
lot within each unique shipment of
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components that you receive and any lot
of components that you produce in a
manner that allows you to trace the lot
to the supplier, the date received, the
name of the component, the status of the
component (e.g., quarantined, approved,
or rejected); and to the dietary
supplement that you manufactured and
distributed.
(2) You must use this unique
identifier whenever you record the
disposition of each unique lot within
each unique shipment of components
that you receive and any lot of
components that you produce.
(e) You must hold components under
conditions that will protect against
contamination and deterioration, and
avoid mixups.
§ 111.160 What requirements apply to
packaging and labels received?
(a) You must visually examine each
immediate container or grouping of
immediate containers in a shipment for
appropriate content label, container
damage, or broken seals to determine
whether the container condition may
have resulted in contamination or
deterioration of the packaging and
labels.
(b) You must visually examine the
supplier’s invoice, guarantee, or
certification in a shipment to ensure
that the packaging or labels are
consistent with your purchase order.
(c) You must quarantine packaging
and labels before you use them in the
manufacture of a dietary supplement
until:
(1) You collect representative samples
of each unique shipment, and of each
unique lot within each unique
shipment, of packaging and labels and,
at a minimum, conduct a visual
identification of the immediate
containers and closures;
(2) Quality control personnel review
and approve the results of any tests or
examinations conducted on the
packaging and labels; and
(3) Quality control personnel approve
the packaging and labels for use in the
manufacture of a dietary supplement
and release them from quarantine.
(d)(1) You must identify each unique
lot within each unique shipment of
packaging and labels in a manner that
allows you to trace the lot to the
supplier, the date received, the name of
the packaging and label, the status of the
packaging and label (e.g., quarantined,
approved, or rejected); and to the
dietary supplement that you distributed;
and
(2) You must use this unique
identifier whenever you record the
disposition of each unique lot within
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each unique shipment of packaging and
labels.
(e) You must hold packaging and
labels under conditions that will protect
against contamination and deterioration,
and avoid mixups.
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§ 111.165 What requirements apply to a
product received for packaging or labeling
as a dietary supplement (and for
distribution rather than for return to the
supplier)?
(a) You must visually examine each
immediate container or grouping of
immediate containers in a shipment of
product that you receive for packaging
or labeling as a dietary supplement (and
for distribution rather than for return to
the supplier) for appropriate content
label, container damage, or broken seals
to determine whether the container
condition may have resulted in
contamination or deterioration of the
received product.
(b) You must visually examine the
supplier’s invoice, guarantee, or
certification in a shipment of the
received product to ensure that the
received product is consistent with your
purchase order.
(c) You must quarantine the received
product until:
(1) You collect representative samples
of each unique shipment, and of each
unique lot within each unique
shipment, of received product;
(2) Quality control personnel review
and approve the documentation to
determine whether the received product
meets the specifications that you
established under § 111.70(f); and
(3) Quality control personnel approve
the received product for packaging or
labeling as a dietary supplement and
release the received product from
quarantine.
(d)(1) You must identify each unique
lot within each unique shipment of
received product in a manner that
allows you to trace the lot to the
supplier, the date received, the name of
the received product, the status of the
received product (e.g., quarantined,
approved, or rejected), and to the
product that you packaged or labeled
and distributed as a dietary supplement.
(2) You must use this unique
identifier whenever you record the
disposition of each unique lot within
each unique shipment of the received
product.
(e) You must hold the received
product under conditions that will
protect against contamination and
deterioration, and avoid mixups.
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§ 111.170 What requirements apply to
rejected components, packaging, and
labels, and to rejected products that are
received for packaging or labeling as a
dietary supplement?
You must clearly identify, hold, and
control under a quarantine system for
appropriate disposition any component,
packaging, and label, and any product
that you receive for packaging or
labeling as a dietary supplement (and
for distribution rather than for return to
the supplier), that is rejected and
unsuitable for use in manufacturing,
packaging, or labeling operations.
§ 111.180 Under this subpart G, what
records must you make and keep?
(a) You must make and keep records
required under this subpart G in
accordance with subpart P of this part.
(b) You must make and keep the
following records:
(1) Written procedures for fulfilling
the requirements of this subpart.
(2) Receiving records (including
records such as certificates of analysis,
suppliers’ invoices, and suppliers’
guarantees) for components, packaging,
and labels and for products that you
receive for packaging or labeling as a
dietary supplement (and for distribution
rather than for return to the supplier);
and
(3) Documentation that the
requirements of this subpart were met.
(i) The person who performs the
required operation must document, at
the time of performance, that the
required operation was performed.
(ii) The documentation must include:
(A) The date that the components,
packaging, labels, or products that you
receive for packaging or labeling as a
dietary supplement were received;
(B) The initials of the person
performing the required operation;
(C) The results of any tests or
examinations conducted on
components, packaging, or labels, and of
any visual examination of product that
you receive for packaging or labeling as
a dietary supplement; and
(D) Any material review and
disposition decision conducted on
components, packaging, labels, or
products that you receive for packaging
or labeling as a dietary supplement.
Subpart H—Production and Process
Control System: Requirements for the
Master Manufacturing Record
§ 111.205 What is the requirement to
establish a master manufacturing record?
(a) You must prepare and follow a
written master manufacturing record for
each unique formulation of dietary
supplement that you manufacture, and
for each batch size, to ensure uniformity
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in the finished batch from batch to
batch.
(b) The master manufacturing record
must:
(1) Identify specifications for the
points, steps, or stages in the
manufacturing process where control is
necessary to ensure the quality of the
dietary supplement and that the dietary
supplement is packaged and labeled as
specified in the master manufacturing
record; and
(2) Establish controls and procedures
to ensure that each batch of dietary
supplement that you manufacture meets
the specifications identified in
accordance with paragraph (b)(1) of this
section.
(c) You must make and keep master
manufacturing records in accordance
with subpart P of this part.
§ 111.210 What must the master
manufacturing record include?
The master manufacturing record
must include:
(a) The name of the dietary
supplement to be manufactured and the
strength, concentration, weight, or
measure of each dietary ingredient for
each batch size;
(b) A complete list of components to
be used;
(c) An accurate statement of the
weight or measure of each component to
be used;
(d) The identity and weight or
measure of each dietary ingredient that
will be declared on the Supplement
Facts label and the identity of each
ingredient that will be declared on the
ingredients list of the dietary
supplement;
(e) A statement of any intentional
overage amount of a dietary ingredient;
(f) A statement of theoretical yield of
a manufactured dietary supplement
expected at each point, step, or stage of
the manufacturing process where
control is needed to ensure the quality
of the dietary supplement, and the
expected yield when you finish
manufacturing the dietary supplement,
including the maximum and minimum
percentages of theoretical yield beyond
which a deviation investigation of a
batch is necessary and material review
is conducted and disposition decision is
made;
(g) A description of packaging and a
representative label, or a cross-reference
to the physical location of the actual or
representative label;
(h) Written instructions, including the
following:
(1) Specifications for each point, step,
or stage in the manufacturing process
where control is necessary to ensure the
quality of the dietary supplement and
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that the dietary supplement is packaged
and labeled as specified in the master
manufacturing record;
(2) Procedures for sampling and a
cross-reference to procedures for tests or
examinations;
(3) Specific actions necessary to
perform and verify points, steps, or
stages in the manufacturing process
where control is necessary to ensure the
quality of the dietary supplement and
that the dietary supplement is packaged
and labeled as specified in the master
manufacturing record.
(i) Such specific actions must include
verifying the weight or measure of any
component and verifying the addition of
any component; and
(ii) For manual operations, such
specific actions must include:
(A) One person weighing or
measuring a component and another
person verifying the weight or measure;
and
(B) One person adding the component
and another person verifying the
addition.
(4) Special notations and precautions
to be followed; and
(5) Corrective action plans for use
when a specification is not met.
Subpart I—Production and Process
Control System: Requirements for the
Batch Production Record
§ 111.255 What is the requirement to
establish a batch production record?
(a) You must prepare a batch
production record every time you
manufacture a batch of a dietary
supplement;
(b) Your batch production record
must include complete information
relating to the production and control of
each batch;
(c) Your batch production record must
accurately follow the appropriate master
manufacturing record and you must
perform each step in the production of
the batch; and
(d) You must make and keep batch
production records in accordance with
subpart P of this part.
sroberts on PROD1PC70 with RULES
§ 111.260
include?
What must the batch record
The batch production record must
include the following:
(a) The batch, lot, or control number:
(1) Of the finished batch of dietary
supplement; and
(2) That you assign in accordance
with § 111.415(f) for the following:
(i) Each lot of packaged and labeled
dietary supplement from the finished
batch of dietary supplement;
(ii) Each lot of dietary supplement,
from the finished batch of dietary
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supplement, that you distribute to
another person for packaging or
labeling;
(b) The identity of equipment and
processing lines used in producing the
batch;
(c) The date and time of the
maintenance, cleaning, and sanitizing of
the equipment and processing lines
used in producing the batch, or a crossreference to records, such as individual
equipment logs, where this information
is retained;
(d) The unique identifier that you
assigned to each component (or, when
applicable, to a product that you receive
from a supplier for packaging or labeling
as a dietary supplement), packaging,
and label used;
(e) The identity and weight or
measure of each component used;
(f) A statement of the actual yield and
a statement of the percentage of
theoretical yield at appropriate phases
of processing;
(g) The actual results obtained during
any monitoring operation;
(h) The results of any testing or
examination performed during the batch
production, or a cross-reference to such
results;
(i) Documentation that the finished
dietary supplement meets specifications
established in accordance with
§ 111.70(e) and (g);
(j) Documentation, at the time of
performance, of the manufacture of the
batch, including:
(1) The date on which each step of the
master manufacturing record was
performed; and
(2) The initials of the persons
performing each step, including:
(i) The initials of the person
responsible for weighing or measuring
each component used in the batch;
(ii) The initials of the person
responsible for verifying the weight or
measure of each component used in the
batch;
(iii) The initials of the person
responsible for adding the component to
the batch; and
(iv) The initials of the person
responsible for verifying the addition of
components to the batch;
(k) Documentation, at the time of
performance, of packaging and labeling
operations, including:
(1) The unique identifier that you
assigned to packaging and labels used,
the quantity of the packaging and labels
used, and, when label reconciliation is
required, reconciliation of any
discrepancies between issuance and use
of labels;
(2) An actual or representative label,
or a cross-reference to the physical
location of the actual or representative
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label specified in the master
manufacturing record; and
(3) The results of any tests or
examinations conducted on packaged
and labeled dietary supplements
(including repackaged or relabeled
dietary supplements), or a crossreference to the physical location of
such results;
(l) Documentation at the time of
performance that quality control
personnel:
(1) Reviewed the batch production
record, including:
(i) Review of any monitoring
operation required under subpart E of
this part; and
(ii) Review of the results of any tests
and examinations, including tests and
examinations conducted on
components, in-process materials,
finished batches of dietary supplements,
and packaged and labeled dietary
supplements;
(2) Approved or rejected any
reprocessing or repackaging; and
(3) Approved and released, or
rejected, the batch for distribution,
including any reprocessed batch; and
(4) Approved and released, or
rejected, the packaged and labeled
dietary supplement, including any
repackaged or relabeled dietary
supplement.
(m) Documentation at the time of
performance of any required material
review and disposition decision.
(n) Documentation at the time of
performance of any reprocessing.
Subpart J—Production and Process
Control System: Requirements for
Laboratory Operations
§ 111.303 What are the requirements under
this subpart J for written procedures?
You must establish and follow written
procedures for laboratory operations,
including written procedures for the
tests and examinations that you conduct
to determine whether specifications are
met.
§ 111.310 What are the requirements for
the laboratory facilities that you use?
You must use adequate laboratory
facilities to perform whatever testing
and examinations are necessary to
determine whether:
(a) Components that you use meet
specifications;
(b) In-process specifications are met
as specified in the master manufacturing
record; and
(c) Dietary supplements that you
manufacture meet specifications.
§ 111.315 What are the requirements for
laboratory control processes?
You must establish and follow
laboratory control processes that are
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reviewed and approved by quality
control personnel, including the
following:
(a) Use of criteria for establishing
appropriate specifications;
(b) Use of sampling plans for
obtaining representative samples, in
accordance with subpart E of this part,
of:
(1) Components, packaging, and
labels;
(2) In-process materials;
(3) Finished batches of dietary
supplements;
(4) Product that you receive for
packaging or labeling as a dietary
supplement (and for distribution rather
than for return to the supplier); and
(5) Packaged and labeled dietary
supplements.
(c) Use of criteria for selecting
appropriate examination and testing
methods;
(d) Use of criteria for selecting
standard reference materials used in
performing tests and examinations; and
(e) Use of test methods and
examinations in accordance with
established criteria.
§ 111.320 What requirements apply to
laboratory methods for testing and
examination?
(a) You must verify that the laboratory
examination and testing methodologies
are appropriate for their intended use.
(b) You must identify and use an
appropriate scientifically valid method
for each established specification for
which testing or examination is required
to determine whether the specification
is met.
sroberts on PROD1PC70 with RULES
§ 111.325 Under this subpart J, what
records must you make and keep?
(a) You must make and keep records
required under this subpart J in
accordance with subpart P of this part.
(b) You must make and keep the
following records:
(1) Written procedures for laboratory
operations, including written
procedures for the tests and
examinations that you conduct to
determine whether specifications are
met;
(2) Documentation that laboratory
methodology established in accordance
with this subpart J is followed.
(i) The person who conducts the
testing and examination must
document, at the time of performance,
that laboratory methodology established
in accordance with this subpart J is
followed.
(ii) The documentation for laboratory
tests and examinations must include the
results of the testing and examination.
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Subpart K—Production and Process
Control System: Requirements for
Manufacturing Operations
§ 111.353 What are the requirements under
this subpart K for written procedures?
You must establish and follow written
procedures for manufacturing
operations.
§ 111.355 What are the design
requirements for manufacturing
operations?
You must design or select
manufacturing processes to ensure that
product specifications are consistently
met.
§ 111.360 What are the requirements for
sanitation?
You must conduct all manufacturing
operations in accordance with adequate
sanitation principles.
§ 111.365 What precautions must you take
to prevent contamination?
You must take all the necessary
precautions during the manufacture of a
dietary supplement to prevent
contamination of components or dietary
supplements. These precautions
include:
(a) Performing manufacturing
operations under conditions and
controls that protect against the
potential for growth of microorganisms
and the potential for contamination;
(b) Washing or cleaning components
that contain soil or other contaminants;
(c) Using water that, at a minimum,
complies with the applicable Federal,
State, and local requirements and does
not contaminate the dietary supplement
when the water may become a
component of the finished batch of
dietary supplement;
(d) Performing chemical,
microbiological, or other testing, as
necessary to prevent the use of
contaminated components;
(e) Sterilizing, pasteurizing, freezing,
refrigerating, controlling hydrogen-ion
concentration (pH), controlling
humidity, controlling water activity
(aw), or using any other effective means
to remove, destroy, or prevent the
growth of microorganisms and prevent
decomposition;
(f) Holding components and dietary
supplements that can support the rapid
growth of microorganisms of public
health significance in a manner that
prevents the components and dietary
supplements from becoming
adulterated;
(g) Identifying and holding any
components or dietary supplements, for
which a material review and disposition
decision is required, in a manner that
protects components or dietary
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supplements that are not under a
material review against contamination
and mixups with those that are under a
material review;
(h) Performing mechanical
manufacturing steps (such as cutting,
sorting, inspecting, shredding, drying,
grinding, blending, and sifting) by any
effective means to protect the dietary
supplements against contamination, by,
for example:
(1) Cleaning and sanitizing contact
surfaces;
(2) Using temperature controls; and
(3) Using time controls.
(i) Using effective measures to protect
against the inclusion of metal or other
foreign material in components or
dietary supplements, by, for example:
(1) Filters or strainers,
(2) Traps,
(3) Magnets, or
(4) Electronic metal detectors.
(j) Segregating and identifying all
containers for a specific batch of dietary
supplements to identify their contents
and, when necessary, the phase of
manufacturing; and
(k) Identifying all processing lines and
major equipment used during
manufacturing to indicate their
contents, including the name of the
dietary supplement and the specific
batch or lot number and, when
necessary, the phase of manufacturing.
§ 111.370 What requirements apply to
rejected dietary supplements?
You must clearly identify, hold, and
control under a quarantine system for
appropriate disposition any dietary
supplement that is rejected and
unsuitable for use in manufacturing,
packaging, or labeling operations.
§ 111.375 Under this subpart K, what
records must you make and keep?
(a) You must make and keep records
required under this subpart K in
accordance with subpart P of this part.
(b) You must make and keep records
of the written procedures for
manufacturing operations.
Subpart L—Production and Process
Control System: Requirements for
Packaging and Labeling Operations
§ 111.403 What are the requirements under
this subpart L for written procedures?
You must establish and follow written
procedures for packaging and labeling
operations.
§ 111.410 What requirements apply to
packaging and labels?
(a) You must take necessary actions to
determine whether packaging for dietary
supplements meets specifications so
that the condition of the packaging will
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ensure the quality of your dietary
supplements;
(b) You must control the issuance and
use of packaging and labels and
reconciliation of any issuance and use
discrepancies. Label reconciliation is
not required for cut or rolled labels if a
100-percent examination for correct
labels is performed by appropriate
electronic or electromechanical
equipment during or after completion of
finishing operations; and
(c) You must examine, before
packaging and labeling operations,
packaging and labels for each batch of
dietary supplement to determine
whether the packaging and labels
conform to the master manufacturing
record; and
(d) You must be able to determine the
complete manufacturing history and
control of the packaged and labeled
dietary supplement through
distribution.
sroberts on PROD1PC70 with RULES
§ 111.415 What requirements apply to
filling, assembling, packaging, labeling, and
related operations?
You must fill, assemble, package,
label, and perform other related
operations in a way that ensures the
quality of the dietary supplement and
that the dietary supplement is packaged
and labeled as specified in the master
manufacturing record. You must do this
using any effective means, including the
following:
(a) Cleaning and sanitizing all filling
and packaging equipment, utensils, and
dietary supplement packaging, as
appropriate;
(b) Protecting manufactured dietary
supplements from contamination,
particularly airborne contamination;
(c) Using sanitary handling
procedures;
(d) Establishing physical or spatial
separation of packaging and label
operations from operations on other
components and dietary supplements to
prevent mixups;
(e) Identifying, by any effective
means, filled dietary supplement
containers that are set aside and held in
unlabeled condition for future label
operations, to prevent mixups;
(f) Assigning a batch, lot, or control
number to:
(1) Each lot of packaged and labeled
dietary supplement from a finished
batch of dietary supplement; and,
(2) Each lot of dietary supplement,
from a finished batch of dietary
supplement, that you distribute to
another person for packaging or
labeling.
(g) Examining a representative sample
of each batch of the packaged and
labeled dietary supplement to determine
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whether the dietary supplement meets
specifications established in accordance
with § 111.70(g); and
(h) Suitably disposing of labels and
packaging for dietary supplements that
are obsolete or incorrect to ensure that
they are not used in any future
packaging and label operations.
§ 111.420 What requirements apply to
repackaging and relabeling?
(a) You may repackage or relabel
dietary supplements only after quality
control personnel have approved such
repackaging or relabeling.
(b) You must examine a representative
sample of each batch of repackaged or
relabeled dietary supplements to
determine whether the repackaged or
relabeled dietary supplements meet all
specifications established in accordance
with § 111.70(g).
(c) Quality control personnel must
approve or reject each batch of
repackaged or relabeled dietary
supplement prior to its release for
distribution.
§ 111.425 What requirements apply to a
packaged and labeled dietary supplement
that is rejected for distribution?
You must clearly identify, hold, and
control under a quarantine system for
appropriate disposition any packaged
and labeled dietary supplement that is
rejected for distribution.
§ 111.430 Under this subpart L, what
records must you make and keep?
(a) You must make and keep records
required under this subpart L in
accordance with subpart P of this part.
(b) You must make and keep records
of the written procedures for packaging
and labeling operations.
Subpart M—Holding and Distributing
§ 111.453 What are the requirements under
this subpart for M written procedures?
34957
to the mixup, contamination, or
deterioration of components, dietary
supplements, packaging, and labels.
§ 111.460 What requirements apply to
holding in-process material?
(a) You must identify and hold inprocess material under conditions that
protect against mixup, contamination,
and deterioration.
(b) You must hold in-process material
under appropriate conditions of
temperature, humidity, and light.
§ 111.465 What requirements apply to
holding reserve samples of dietary
supplements?
(a) You must hold reserve samples of
dietary supplements in a manner that
protects against contamination and
deterioration. This includes:
(1) Holding the reserve samples under
conditions consistent with product
labels or, if no storage conditions are
recommended on the label, under
ordinary storage conditions; and
(2) Using the same container-closure
system in which the packaged and
labeled dietary supplement is
distributed, or if distributing dietary
supplements to be packaged and
labeled, using a container-closure
system that provides essentially the
same characteristics to protect against
contamination or deterioration as the
one in which you distribute the dietary
supplement for packaging and labeling
elsewhere.
(b) You must retain reserve samples
for 1 year past the shelf life date (if shelf
life dating is used), or for 2 years from
the date of distribution of the last batch
of dietary supplements associated with
the reserve samples, for use in
appropriate investigations.
You must establish and follow written
procedures for holding and distributing
operations.
§ 111.470 What requirements apply to
distributing dietary supplements?
§ 111.455 What requirements apply to
holding components, dietary supplements,
packaging, and labels?
You must distribute dietary
supplements under conditions that will
protect the dietary supplements against
contamination and deterioration.
(a) You must hold components and
dietary supplements under appropriate
conditions of temperature, humidity,
and light so that the identity, purity,
strength, and composition of the
components and dietary supplements
are not affected.
(b) You must hold packaging and
labels under appropriate conditions so
that the packaging and labels are not
adversely affected.
(c) You must hold components,
dietary supplements, packaging, and
labels under conditions that do not lead
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§ 111.475 Under this subpart M, what
records must you make and keep?
(a) You must make and keep records
required under this subpart M in
accordance with subpart P of this part.
(b) You must make and keep the
following records:
(1) Written procedures for holding
and distributing operations; and
(2) Records of product distribution.
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Federal Register / Vol. 72, No. 121 / Monday, June 25, 2007 / Rules and Regulations
Subpart N—Returned Dietary
Supplements
§ 111.503 What are the requirements under
this subpart N for written procedures?
You must establish and follow written
procedures to fulfill the requirements of
this subpart.
§ 111.510 What requirements apply when a
returned dietary supplement is received?
You must identify and quarantine
returned dietary supplements until
quality control personnel conduct a
material review and make a disposition
decision.
§ 111.515 When must a returned dietary
supplement be destroyed, or otherwise
suitably disposed of?
(1) Written procedures for fulfilling
the requirements of this subpart N.
(2) Any material review and
disposition decision on a returned
dietary supplement;
(3) The results of any testing or
examination conducted to determine
compliance with product specifications
established under § 111.70(e); and,
(4) Documentation of the reevaluation
by quality control personnel of any
dietary supplement that is reprocessed
and the determination by quality control
personnel of whether the reprocessed
dietary supplement meets product
specifications established in accordance
with § 111.70(e).
Subpart O—Product Complaints
You must destroy, or otherwise
suitably dispose of, any returned dietary
supplement unless the outcome of a
material review and disposition
decision is that quality control
personnel do the following:
(a) Approve the salvage of the
returned dietary supplement for
redistribution or
(b) Approve the returned dietary
supplement for reprocessing.
§ 111.553 What are the requirements under
this subpart O for written procedures?
You must establish and follow written
procedures to fulfill the requirements of
this subpart O.
§ 111.560 What requirements apply to the
review and investigation of a product
complaint?
If the reason for a dietary supplement
being returned implicates other batches,
you must conduct an investigation of
your manufacturing processes and each
of those other batches to determine
compliance with specifications.
(a) A qualified person must:
(1) Review all product complaints to
determine whether the product
complaint involves a possible failure of
a dietary supplement to meet any of its
specifications, or any other
requirements of this part 111, including
those specifications and other
requirements that, if not met, may result
in a risk of illness or injury; and
(2) Investigate any product complaint
that involves a possible failure of a
dietary supplement to meet any of its
specifications, or any other
requirements of this part, including
those specifications and other
requirements that, if not met, may result
in a risk of illness or injury.
(b) Quality control personnel must
review and approve decisions about
whether to investigate a product
complaint and review and approve the
findings and followup action of any
investigation performed.
(c) The review and investigation of
the product complaint by a qualified
person, and the review by quality
control personnel about whether to
investigate a product complaint, and the
findings and followup action of any
investigation performed, must extend to
all relevant batches and records.
§ 111.535 Under this subpart N, what
records must you make and keep?
§ 111.570 Under this subpart O, what
records must you make and keep?
(a) You must make and keep records
required under this subpart N in
accordance with subpart P of this part.
(b) You must make and keep the
following records:
(a) You must make and keep the
records required under this subpart O in
accordance with subpart P of this part.
(b) You must make and keep the
following records:
§ 111.520 When may a returned dietary
supplement be salvaged?
You may salvage a returned dietary
supplement only if quality control
personnel conduct a material review
and make a disposition decision to
allow the salvage.
§ 111.525 What requirements apply to a
returned dietary supplement that quality
control personnel approve for
reprocessing?
(a) You must ensure that any returned
dietary supplements that are
reprocessed meet all product
specifications established in accordance
with § 111.70(e); and
(b) Quality control personnel must
approve or reject the release for
distribution of any returned dietary
supplement that is reprocessed.
sroberts on PROD1PC70 with RULES
§ 111.530 When must an investigation be
conducted of your manufacturing
processes and other batches?
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(1) Written procedures for fulfilling
the requirements of this subpart,
(2) A written record of every product
complaint that is related to good
manufacturing practice,
(i) The person who performs the
requirements of this subpart must
document, at the time of performance,
that the requirement was performed.
(ii) The written record of the product
complaint must include the following:
(A) The name and description of the
dietary supplement;
(B) The batch, lot, or control number
of the dietary supplement, if available;
(C) The date the complaint was
received and the name, address, or
telephone number of the complainant, if
available;
(D) The nature of the complaint
including, if known, how the product
was used;
(E) The reply to the complainant, if
any; and
(F) Findings of the investigation and
followup action taken when an
investigation is performed.
Subpart P—Records and
Recordkeeping
§ 111.605 What requirements apply to the
records that you make and keep?
(a) You must keep written records
required by this part for 1 year past the
shelf life date, if shelf life dating is used,
or 2 years beyond the date of
distribution of the last batch of dietary
supplements associated with those
records.
(b) Records must be kept as original
records, as true copies (such as
photocopies, microfilm, microfiche, or
other accurate reproductions of the
original records), or as electronic
records.
(c) All electronic records must comply
with part 11 of this chapter.
§ 111.610 What records must be made
available to FDA?
(a) You must have all records required
under this part, or copies of such
records, readily available during the
retention period for inspection and
copying by FDA when requested.
(b) If you use reduction techniques,
such as microfilming, you must make
suitable reader and photocopying
equipment readily available to FDA.
Dated: May 8, 2007.
Andrew C. von Eschenbach,
Commissioner of Food and Drugs.
Dated: May 8, 2007.
Michael O. Leavitt,
Secretary of Health and Human Services.
[FR Doc. 07–3039 Filed 6–22–07; 8:45 am]
BILLING CODE 4160–01–S
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]]>Agencies
[Federal Register Volume 72, Number 121 (Monday, June 25, 2007)]
[Rules and Regulations]
[Pages 34752-34958]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 07-3039]
[[Page 34751]]
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Part II
Department of Health and Human Services
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Food and Drug Administration
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21 CFR Part 111
Current Good Manufacturing Practice in Manufacturing, Packaging,
Labeling, or Holding Operations for Dietary Supplements; Final Rule
Petition To Request an Exemption From 100 Percent Identity Testing of
Dietary Ingredients; Interim Final Rule
Federal Register / Vol. 72, No. 121 / Monday, June 25, 2007 / Rules
and Regulations
[[Page 34752]]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 111
[Docket No. 1996N-0417] (formerly Docket No. 96N-0417)
RIN 0910-AB88
Current Good Manufacturing Practice in Manufacturing, Packaging,
Labeling, or Holding Operations for Dietary Supplements
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule
regarding current good manufacturing practice (CGMP) for dietary
supplements. The final rule establishes the minimum CGMPs necessary for
activities related to manufacturing, packaging, labeling, or holding
dietary supplements to ensure the quality of the dietary supplement.
The final rule is one of many actions related to dietary supplements
that we are taking to promote and protect the public health.
DATES: This rule is effective August 24, 2007.
Compliance Dates: The compliance date is June 25, 2008; except that
for businesses employing fewer than 500, but 20 or more full-time
equivalent employees, the compliance date is June 25, 2009; and except
that for businesses that employ fewer than 20 full-time equivalent
employees, the compliance date is June 25, 2010.
FOR FURTHER INFORMATION CONTACT: Vasilios H. Frankos, Center for Food
Safety and Applied Nutrition (HFS-810), Food and Drug Administration,
5100 Paint Branch Pkwy., College Park, MD 20740, 301-436-1696.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Background and Related Information
II. How is the Final Rule Organized?
III. What Does the Final Rule Do?
A. Overview of CGMP
B. Highlights of the Final Rule
IV. What General Comments Did We Receive?
A. What Comments Did We Receive on the Structure and Organization
of the Rule?
B. What Comments Did We Receive on the Need for Dietary Supplement
CGMP Requirements?
C. What Comments Did We Receive on Written Procedures?
1. Overview
2. Written Procedures That Are Required by This Final Rule
3. Written Procedures That Are Not Required by This Final Rule
D. Other Comments on Written Procedures
E. What Other General Comments Did We Receive?
V. What Legal Authority Comments Did We Receive?
A. Modeled After CGMP for Food
B. Records Authority
C. Public Health Service Act Authority
1. The Communicable Disease Risk Posed by Dietary Supplements
2. Activities For Which We Are Asserting Legal Authority Under the
PHS Act
D. The Interstate Commerce Nexus for the Final Rule
1. The PHS Act
2. The Act
3. Commerce Clause
E. Fifth Amendment
F. Miscellaneous
VI. What Comments Did We Receive on the General Provisions? (Subpart A)
A. Organization of Final Subpart A
B. Who Is Subject to This Part? (Final Sec. 111.1)
C. What Definitions Apply to This Part? (Final Sec. 111.3)
1. Actual Yield
2. Batch
3. Batch Number, Lot Number, or Control Number
4. Component
5. Contact Surface
6. Ingredient
7. In-Process Material
8. Lot
9. Microorganisms
10. Must
11. Pest
12. Physical Plant
13. Product Complaint
14. Quality
15. Quality Control
16. Quality Control Personnel
17. Representative Sample
18. Reprocessing
19. Reserve Sample
20. Sanitize
21. Theoretical Yield
22. Water Activity
23. We
24. You
25. What Other Terms Did the Comments Want Defined?
26. What Definitions Did the Comments Want Us to Delete?
D. Do Other Statutory Provisions and Regulations Apply? (Final
Sec. 111.5)
E. What Sections Did We Remove From the Rule, and Why?
1. ``What Are These Regulations Intended to Accomplish?'' (Proposed
Sec. 111.2)
2. ``Exclusions'' (Proposed Sec. 111.6)
VII. Comments on Personnel (Final Subpart B)
A. Organization of Final Subpart B
B. Highlights of Changes to the Proposed Requirements for Personnel
1. Revisions
2. Changes After Considering Comments
C. General Comments on Proposed Subpart B
D. What Are the Requirements Under This Subpart for Written
Procedures? (Final Sec. 111.8)
E. What Requirements Apply for Preventing Microbial Contamination
From Sick or Infected Personnel and for Hygienic Practices? (Final
Sec. 111.10)
1. Final Sec. 111.10(a)
2. Final Sec. 111.10(b)
F. What Personnel Qualification Requirements Apply? (Final Sec.
111.12)
G. What Supervisor Requirements Apply? (Final Sec. 111.13)
H. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.14)
VIII. Comments on Physical Plant and Grounds (Final Subpart C)
A. Organization of Final Subpart C
B. Highlights of Changes to the Proposed Requirements for Physical
Plant and Grounds
1. Revisions
2. Changes After Considering Comments
C. General Comments on Proposed Subpart C
D. What Sanitation Requirements Apply to Your Physical Plant and
Grounds? (Final Sec. 111.15)
1. Final Sec. 111.15(a)
2. Final Sec. 111.15(b)(1)
3. Final Sec. 111.15(c)
4. Final Sec. 111.15(d)
5. Final Sec. 111.15(e)
6. Final Sec. 111.15(f)
7. Final Sec. 111.15(g)
8. Final Sec. 111.15(h)
9. Final Sec. 111.15(i)
10. Final Sec. 111.15(j)
11. Final Sec. 111.15(k)
E. What Are the Requirements Under This Subpart for Written
Procedures? (Final Sec. 111.16)
F. What Design and Construction Requirements Apply to Your Physical
Plant? (Final Sec. 111.20)
1. Final Sec. 111.20(a) and (b)
2. Final Sec. 111.20(c)
3. Final Sec. 111.20(d)
4. Final Sec. 111.20(e)
5. Final Sec. 111.20(f)
6. Final Sec. 111.20(g)
7. Final Sec. 111.20(h)
[[Page 34753]]
G. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.23)
IX. Comments on Requirements Related to Equipment and Utensils (Subpart
D)
A. Organization of Final Subpart D
B. Highlights of Changes to the Proposed Requirements for Equipment
and Utensils
1. Revisions
2. Revisions Associated With the Reorganization
3. Changes After Considering Comments
C. General Comments on Proposed Subpart D
D. What Are the Requirements Under This Subpart for Written
Procedures? (Final Sec. 111.25)
E. What Requirements Apply to the Equipment and Utensils That You
Use? (Final Sec. 111.27)
1. Final 111.27(a)
2. Final Sec. 111.27(b)
3. Final Sec. 111.27(c)
4. Final Sec. 111.27(d)
F. Reorganization of Certain Paragraphs in Proposed Sec. 111.25
G. What Requirements Apply to Automated, Mechanical, or Electronic
Equipment? (Final Sec. 111.30)
1. Comments on the Organization and Framework of Proposed Sec.
111.30
2. Comments Specific to Proposed Sec. 111.30
3. Reorganization of Certain Paragraphs in Proposed Sec. 111.30
H. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.35)
1. Final Sec. 111.35(a)
2. Final Sec. 111.35(b)(1) and (b)(2)
3. Final Sec. 111.35(b)(3)
4. Final Sec. 111.35(b)(4)
5. Final Sec. 111.35(b)(5)
6. Final Sec. 111.35(b)(6)
X. Comments on Requirement to Establish a Production and Process
Control System (Final Subpart E)
A. Reorganization of Proposed Sec. 111.35 Into Final Subpart E
B. General Comments on Proposed Sec. 111.35
C. Final Subpart E and Highlights of Changes to the Proposed
Regulations
D. What Are the Requirements to Implement a Production and Process
Control System? (Final Sec. 111.55)
E. What Are the Design Requirements for the Production and Process
Control System? (Final Sec. 111.60)
F. What Are the Requirements for Quality Control Operations? (Final
Sec. 111.65)
G. What Specifications Must You Establish? (Final Sec. 111.70)
1. Final Sec. 111.70(a)
2. Final Sec. 111.70(b)
3. Final Sec. 111.70(c)
4. Final Sec. 111.70(d)
5. Final Sec. 111.70(e)
6. Final Sec. 111.70(f)
7. Final Sec. 111.70(g)
H. What is Your Responsibility for Determining Whether Established
Specifications Are Met? (Final Sec. 111.73)
I. What Must You Do to Determine Whether Specifications Are Met?
(Final Sec. 111.75)
1. Final Sec. 111.75(a)
2. Final Sec. 111.75(b)
3. Final Sec. 111.75(c) and (d)
4. Final Sec. 111.75(e)
5. Final Sec. 111.75(f)
6. Final Sec. 111.75(g)
7. Final Sec. 111.75(h)
8. Final Sec. 111.75(i)
J. What Must You Do if Established Specifications Are Not Met?
(Final Sec. 111.77)
1. Final Sec. 111.77
2. Final Sec. 111.77(a)
3. Final Sec. 111.77(b)
4. Final Sec. 111.77(c)
K. Comments on Shelf Life
L. What Representative Samples Must You Collect? (Final Sec.
111.80)
1. Final Sec. 111.80(a)
2. Final Sec. 111.80(b)
3. Final Sec. 111.80(c)
4. Final Sec. 111.80(d)
5. Final Sec. 111.80(e)
M. What Are the Requirements for Reserve Samples? (Final Sec.
111.83)
1. Final Sec. 111.83(a)
2. Final Sec. 111.83(b)(1)
3. Final Sec. 111.83(b)(2)
4. Final Sec. 111.83(b)(3)
5. Final Sec. 111.83(b)(4)
N. Who Conducts a Material Review and Makes a Disposition Decision?
(Final Sec. 111.87)
O. What Requirements Apply to Treatments, In-Process Adjustments,
and Reprocessing When There is a Deviation or Unanticipated Occurrence
or When a Specification Established in Accordance With Sec. 111.70 Is
Not Met? (Final Sec. 111.90)
1. Final Sec. 111.90
2. Final Sec. 111.90(a)
3. Final Sec. 111.90(b)
4. Final Sec. 111.90(c)
P. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.95)
1. Final Sec. 111.95(a)
2. Final Sec. 111.95(b)
XI. Comments on Requirements for Quality Control (Final Subpart F)
A. Organization of Final Subpart F
B. Highlights of Changes to the Proposed Requirements for Quality
Control Operations
1. Revisions
2. Changes Associated With the Reorganization
3. Changes After Considering Comments
C. General Comments on Proposed Sec. 111.37 (Final Subpart F)
D. What Are the Requirements Under This Subpart for Written
Procedures? (Final Sec. 111.103)
E. What Must Quality Control Personnel Do? (Final Sec. 111.105)
1. Final Sec. 111.105(a)
2. Final Sec. 111.105(b), (c), (d), and (e)
3. Final Sec. 111.105(f)
4. Final Sec. 111.105(g)
5. Final Sec. 111.105(h)
6. Final Sec. 111.105(i)
F. What Quality Control Operations Are Required for Laboratory
Operations Associated With the Production and Process Control System?
(Final Sec. 111.110)
1. Final Sec. 111.110(a)
2. Final Sec. 111.110(b)
3. Final Sec. 111.110(c)
G. What Quality Control Operations Are Required for a Material
Review and Disposition Decision? (Final Sec. 111.113)
1. Final Sec. 111.113(a)
2. Final Sec. 111.113(b)
3. Final Sec. 111.113(c)
H. What Quality Control Operations Are Required for Equipment,
Instruments, and Controls? (Final Sec. 111.117)
1. Final Sec. 111.117(a) through (c)
2. Final Sec. 111.117(d)
I. What Quality Control Operations Are Required for Components,
Packaging, and Labels Before Use in the Manufacture of a Dietary
Supplement? (Final Sec. 111.120)
1. Final Sec. 111.120(a)
2. Final Sec. 111.120(b)
3. Final Sec. 111.120(c)
4. Final Sec. 111.120(d)
5. Final Sec. 111.120(e)
J. What Quality Control Operations Are Required for the Master
Manufacturing Record, the Batch Production Record, and Manufacturing
Operations? (Final Sec. 111.123)
1. Final Sec. 111.123(a)(1)
2. Final Sec. 111.123(a)(2)
3. Final Sec. 111.123(a)(3)
4. Final Sec. 111.123(a)(4)
5. Final Sec. 111.123(a)(5)
6. Final Sec. 111.123(a)(6)
7. Final Sec. 111.123(a)(7)
8. Final Sec. 111.123(a)(8)
9. Final Sec. 111.123(b)
K. What Quality Control Operations Are Required for Packaging and
Labeling Operations? (Final Sec. 111.127)
[[Page 34754]]
1. Final Sec. 111.127(a) and (b)
2. Final Sec. 111.127(c)
3. Final Sec. 111.127(d)
4. Final Sec. 111.127(e)
5. Final Sec. 111.127(f) and (g)
6. Final Sec. 111.127(h)
L. What Quality Control Operations Are Required for Returned
Dietary Supplements? (Final Sec. 111.130)
1. Final Sec. 111.130(a)
2. Final Sec. 111.130(a)(1) and (a)(2)
3. Final Sec. 111.130(b)
4. Final Sec. 111.130(c)
5. Final Sec. 111.130(d)
M. What Quality Control Operations Are Required for Product
Complaints? (Final Sec. 111.135)
N. What Records Must You Make and Keep? (Final Sec. 111.140)
1. Final Sec. 111.140(a)
2. Final Sec. 111.140(b)(1)
3. Final Sec. 111.140(b)(2)
4. Final Sec. 111.140(b)(3)
XII. Comments on the Production and Process Control System:
Requirements for Components, Packaging, and Labels, and for Product
That You Receive for Packaging or Labeling as a Dietary Supplement
(Final Subpart G)
A. Organization of Final Subpart G
B. Highlights of Changes to the Proposed Requirements for
Components, Packaging, and Labels, and Product That You Receive for
Packaging or Labeling as a Dietary Supplement
1. Revisions
2. Changes After Considering Comments
C. General Comments on Proposed Sec. 111.40 (Final Subpart G)
D. What Are the Requirements Under This Subpart for Written
Procedures? (Final Sec. 111.153)
E. What Requirements Apply to Components of Dietary Supplements?
(Final Sec. 111.155)
1. Proposed Sec. 111.35(d)
2. Final Sec. 111.155(a)
3. Final Sec. 111.155(b)
4. Final Sec. 111.155(c)
5. Final Sec. 111.155(d)
6. Final Sec. 111.155(e)
F. What Requirements Apply to Packaging and Labels Received? (Final
Sec. 111.160)
1. Final Sec. 111.160(a)
2. Final Sec. 111.160(b)
3. Final Sec. 111.160(c)
4. Final Sec. 111.160(d)
5. Final Sec. 111.160(e)
G. What Requirements Apply to a Product Received for Packaging or
Labeling as a Dietary Supplement (and for distribution rather than for
return to the supplier)? (Final Sec. 111.165)
1. Final Sec. 111.165(a)
2. Final Sec. 111.165(b)
3. Final Sec. 111.165(c)
4. Final Sec. 111.165(d)
5. Final Sec. 111.165(e)
H. What Requirements Apply to Rejected Components, Packaging, and
Labels, and to Rejected Products That Are Received for Packaging or
Labeling as a Dietary Supplement? (Final Sec. 111.170)
I. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.180)
1. Final Sec. 111.180(a)
2. Final Sec. 111.180(b)(1)
3. Final Sec. 111.180(b)(2)
4. Final Sec. 111.180(b)(3)
XIII. Comments on the Production and Process Control System:
Requirements for the Master Manufacturing Record (Final Subpart H)
A. Organization of Final Subpart H
B. Highlights of Changes to the Proposed Requirements for the
Master Manufacturing Record
1. Revisions
2. Changes Associated With the Reorganization
3. Changes After Considering Comments
C. General Comments on Proposed Sec. 111.45 (Final Subpart H)
1. Comments on Written Procedures
2. Comments That Support Proposed Sec. 111.45
D. What Is the Requirement to Establish a Master Manufacturing
Record? (Final Sec. 111.205)
1. Final Sec. 111.205(a)
2. Final Sec. 111.205(b)(1)
3. Final Sec. 111.205(b)(2)
4. Final Sec. 111.205(c)
E. What Must the Master Manufacturing Record Include? (Final Sec.
111.210)
1. Final Sec. 111.210(a)
2. Final Sec. 111.210(b)
3. Final Sec. 111.210(c)
4. Final Sec. 111.210(d)
5. Final Sec. 111.210(e)
6. Final Sec. 111.210(f)
7. Final Sec. 111.210(g)
8. Final Sec. 111.210(h)(1)
9. Final Sec. 111.210(h)(2)
10. Final Sec. 111.210(h)(3)
11. Final Sec. 111.210(h)(4)
12. Final Sec. 111.210(h)(5)
F. Quality Control Responsibility (Proposed Sec. 111.45(c))
XIV. Comments on the Production and Process Control System:
Requirements for the Batch Production Record (Final Subpart I)
A. Organization of Final Subpart I
B. Highlights of Changes to the Proposed Requirements for the Batch
Production Record
1. Revisions
2. Changes Associated With the Reorganization
3. Changes After Considering Comments
C. What Is the Requirement to Establish a Batch Production Record?
(Final Sec. 111.255)
D. What Must the Batch Record Include? (Final Sec. 111.260)
1. Final Sec. 111.260(a)
2. Final Sec. 111.260(b)
3. Final Sec. 111.260(c)
4. Final Sec. 111.260(d)
5. Final Sec. 111.260(e) and (f)
6. Final Sec. 111.260(g)
7. Final Sec. 111.260(h)
8. Final Sec. 111.260(i)
9. Final Sec. 111.260(j)
10. Final Sec. 111.260(k)
11. Final Sec. 111.260(l)
12. Final Sec. 111.260(m)
13. Final Sec. 111.260(n)
E. Review of Batch Production Record Deviations (Proposed Sec.
111.50(d)(1), (e)(2), (e)(3), and (e)(4))
XV. Comments on Production and Process Control System: Requirements for
Laboratory Operations (Final Subpart J)
A. Organization of Final Subpart J
B. Highlights of the Changes to the Proposed Requirements for
Laboratory Operations
1. Revisions
2. Changes Associated With the Reorganization
3. Changes After Considering Comments
C. What Are the Requirements Under This Subpart for Written
Procedures? (Final Sec. 111.303)
D. What Are the Requirements for the Laboratory Facilities That You
Use? (Final Sec. 111.310)
E. What Are the Requirements for Laboratory Control Processes?
(Final Sec. 111.315)
1. Final Sec. 111.315(a)
2. Final Sec. 111.315(b)
3. Final Sec. 111.315(c)
4. Final Sec. 111.315(d)
5. Final Sec. 111.315(e)
F. What Requirements Apply to Laboratory Methods for Testing and
Examination? (Final Sec. 111.320)
1. Final Sec. 111.320(a)
2. Final Sec. 111.320(b)
G. Appropriate Test Method Validation (Proposed Sec.
111.60(b)(1)(v))
H. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.325)
1. Final Sec. 111.325(a)
2. Final Sec. 111.325(b)(1)
3. Final Sec. 111.325(b)(2)
XVI. Comments on the Production and Process Control System:
Requirements for Manufacturing Operations (Final Subpart K)
A. Organization of Final Subpart K
[[Page 34755]]
B. Highlights of Changes to the Proposed Requirements for
Manufacturing Operations
1. Revisions
2. Changes Made After Considering Comments
3. Revisions Associated With the Reorganization
C. General Comments on Manufacturing Operations
D. What Are the Requirements Under This Subpart for Written
Procedures? (Final Sec. 111.353)
E. What Are the Design Requirements for Manufacturing Operations?
(Final Sec. 111.355)
F. What Are the Requirements for Sanitation? (Final Sec. 111.360)
G. What Precautions Must You Take to Prevent Contamination? (Final
Sec. 111.365)
1. Final Sec. 111.365(a)
2. Final Sec. 111.365(b)
3. Final Sec. 111.365(c)
4. Final Sec. 111.365(d)
5. Final Sec. 111.365(e)
6. Final Sec. 111.365(f)
7. Final Sec. 111.365(g)
8. Final Sec. 111.365(h)
9. Final Sec. 111.365(i)
10. Final Sec. 111.365(j)
11. Final Sec. 111.365(k)
H. What Requirements Apply to Rejected Dietary Supplements? (Final
Sec. 111.370)
I. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.375)
XVII. Comments on the Production and Process Control System:
Requirements for Packaging and Labeling Operations (Final Subpart L)
A. Organization of Final Subpart L
B. Highlights of Changes to the Proposed Requirements for Packaging
and Labeling Operations
1. Revisions
2. Changes Associated With the Reorganization
3. Changes After Considering Comments
C. General Comments on Proposed Requirements for Packaging and
Labeling Operations
D. General Comments on Requirements for What Must Be on the Product
Label Rather Than for Labeling Operations
E. What Are the Requirements Under This Subpart for Written
Procedures? (Final Sec. 111.403)
F. What Requirements Apply to Packaging and Labels? (Final Sec.
111.410)
1. Final Sec. 111.410(a)
2. Final Sec. 111.410(b)
3. Final Sec. 111.410(c)
4. Final Sec. 111.410(d)
G. What Requirements Apply to Filling, Assembling, Packaging,
Labeling, and Related Operations? (Final Sec. 111.415)
H. What Requirements Apply to Repackaging and Relabeling? (Final
Sec. 111.420)
1. Final Sec. 111.420(a)
2. Final Sec. 111.420(b) and (c)
I. What Requirements Apply to a Packaged and Labeled Dietary
Supplement That Is Rejected for Distribution? (Final Sec. 111.425)
J. Under this Subpart, What Records Must You Make and Keep? (Final
Sec. 111.430)
1. Final Sec. 111.430(a)
2. Final Sec. 111.430(b)
XVIII. Comments on Holding and Distributing (Final Subpart M)
A. Organization of Final Subpart M
B. Highlights of Changes to the Proposed Requirements for Holding
and Distributing
1. Revisions
2. Changes Associated With the Reorganization
3. Changes After Considering Comments
C. General Comments on Proposed Sec. Sec. 111.80, 111.82, 111.83,
and 111.85
D. What Are the Requirements Under This Subpart for Written
Procedures? (Final Sec. 111.453)
E. What Requirements Apply to Holding Components, Dietary
Supplements, Packaging, and Labels? (Final Sec. 111.455)
1. Final Sec. 111.455(a)
2. Final Sec. 111.455(b)
3. Final Sec. 111.455(c)
F. What Requirements Apply to Holding In-Process Material? (Final
Sec. 111.460)
1. Final Sec. 111.460(a)
2. Final Sec. 111.460(b)
G. Proposed Requirement for Holding Reserve Samples of Components
(Proposed Sec. 111.83(a))
H. What Requirements Apply to Holding Reserve Samples of Dietary
Supplements? (Final Sec. 111.465)
1. Final Sec. 111.465(a)
2. Final Sec. 111.465(b)
I. What Requirements Apply to Distributing Dietary Supplements?
(Final Sec. 111.470)
J. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.475)
XIX. Comments on Returned Dietary Supplements (Final Subpart N)
A. Organization of Final Subpart N
B. Highlights of Changes to the Proposed Requirements for Returned
Dietary Supplements
1. Revisions
2. Changes After Considering Comments
C. General Comments on Proposed Sec. 111.85
D. What Are the Requirements Under This Subpart for Written
Procedures? (Final Sec. 111.503)
E. What Requirements Apply When a Returned Dietary Supplement is
Received? (Final Sec. 111.510)
F. When Must a Returned Dietary Supplement be Destroyed, or
Otherwise Suitably Disposed Of? (Final Sec. 111.515)
G. When May a Returned Dietary Supplement Be Salvaged? (Final Sec.
111.520)
H. What Requirements Apply to a Returned Dietary Supplement That
Quality Control Personnel Approve for Reprocessing? (Final Sec.
111.525)
I. When Must an Investigation Be Conducted of Your Manufacturing
Processes and Other Batches? (Final Sec. 111.530)
J. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.535)
1. Final Sec. 111.535(a)
2. Final Sec. 111.535(b)(1)
3. Final Sec. 111.535(b)(2)
4. Final Sec. 111.535(b)(3)
5. Final Sec. 111.535(b)(4)
XX. Comments on Product Complaints (Final Subpart O)
A. Organization of Final Subpart O
B. Highlights of Changes to the Proposed Requirements for Product
Complaints
1. Revisions
2. Changes After Considering Comments
C. General Comments on Proposed Sec. 111.95 (Final Subpart O)
D. What Are the Requirements Under This Subpart for Written
Procedures? (Final Sec. 111.553)
E. What Requirements Apply to the Review and Investigation of a
Product Complaint? (Final Sec. 111.560)
1. Final Sec. 111.560(a)(1)
2. Final Sec. 111.560(a)(2), (b), and (c)
F. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.570)
1. Final Sec. 111.570(a)
2. Final Sec. 111.570(b)(1)
3. Final Sec. 111.570(b)(2)
4. Final Sec. 111.570(b)(2)(i)
5. Final Sec. 111.570(b)(2)(ii)
XXI. Comments on Records and Recordkeeping (Final Subpart P)
A. Organization of Final Subpart P
B. Highlights of Changes to the Proposed Requirements for Records
and Recordkeeping
1. Revisions
2. Changes After Considering Comments
C. General Comments on Proposed
[[Page 34756]]
Sec. 111.125
D. What Requirements Apply to the Records That You Make and Keep?
(Final Sec. 111.605)
1. Final Sec. 111.605(a)
2. Final Sec. 111.605(b)
3. Final Sec. 111.605(c)
E. What Records Must Be Made Available to FDA? (Final Sec.
111.610)
1. Final Sec. 111.610(a)
2. Final Sec. 111.610(b)
XXII. Other Comments and Miscellaneous
A. Comments on Guidance Documents To Be Used With the Final Rule
B. Comments on Consideration for Other CGMP Programs
C. Comments on Public Involvement
D. Comments on Implementation and Enforcement
E. Removal of References to Part 112
XXIII. Paperwork Reduction Act of 1995
XXIV. Analysis of Impacts
A. Introduction
1. Summary of the Economic Analysis
2. Summary of Comments on the Economic Analysis
B. Final Regulatory Impact Analysis
1. The Need for the Final Current Good Manufacturing Practice Rule
2. Regulatory Options
3. Coverage of the Final Rule
4. Baseline Practices
5. Baseline Risk
6. Benefits
7. Costs
8. Summary of Benefits and Costs
9. Benefits and Costs of Regulatory Options
10. Cost Effectiveness Analysis
11. Uncertainties in the Analysis
C. Final Regulatory Flexibility Analysis
1. Introduction
2. Economic Effects on Small Entities
3. Regulatory Options
4. Description of Recordkeeping and Reporting
5. Summary
D. Unfunded Mandates
XXV. Analysis of Environmental Impact
XXVI. Federalism
XXVII. References
I. Background and Related Information
On October 25, 1994, the Dietary Supplement Health and Education
Act (DSHEA) (Public Law 103-417) was signed into law. DSHEA, among
other things, amended the Federal Food, Drug, and Cosmetic Act (the
act) by adding section 402(g) of the act (21 U.S.C. 342(g)). Section
402(g)(2) of the act provides, in part, that the Secretary of Health
and Human Services (the Secretary) may, by regulation, prescribe good
manufacturing practices for dietary supplements. Section 402(g) of the
act also stipulates that such regulations shall be modeled after CGMP
regulations for food and may not impose standards for which there are
no current and generally available analytical methodology. The final
rule establishes, in part 111 (21 CFR part 111), the minimum CGMPs
necessary for activities related to manufacturing, packaging, labeling,
or holding dietary supplements to ensure the quality of the dietary
supplement. The final rule is one of many actions related to dietary
supplements that we are taking to promote and protect the public
health.
In response to DSHEA, we issued an Advance Notice of Proposed
Rulemaking (the 1997 ANPRM) in the Federal Register of February 6, 1997
(62 FR 5700). The 1997 ANPRM contained a CGMP outline submitted to us
on November 20, 1995, by representatives of the dietary supplement
industry. The 1997 ANPRM also asked nine questions that addressed
issues that the industry outline did not. For example, we asked if
there is a need to develop specific defect action levels (DALs) for
dietary ingredients. We also asked whether a CGMP rule should require
manufacturers to establish procedures to document, on a continuing or
daily basis, that they followed pre-established procedures for making
dietary supplements.
We received more than 100 comments in response to the 1997 ANPRM.
We evaluated these comments before we drafted and ultimately issued a
proposed rule on CGMPs for dietary ingredients and dietary supplements
(which we discuss later in this section of this document).
Additionally, during 1999, we conducted a number of outreach
activities related to dietary supplements. We held several public
meetings to develop our overall strategy for achieving effective
regulation of dietary supplements, which could include establishing
CGMP regulations. We also held public meetings focused specifically on
CGMPs and the economic impact that any CGMP rule for dietary
ingredients and dietary supplements might have on small businesses.
Further, we toured several dietary supplement manufacturing facilities
to better understand the manufacturing processes and practices that
potentially would be subject to CGMP requirements for dietary
ingredients and dietary supplements (Refs. 1 through 6). These
activities contributed to our knowledge about the industry.
In the Federal Register of March 13, 2003 (68 FR 12157), we
published a proposed rule to establish CGMP requirements for dietary
ingredients and dietary supplements (the 2003 CGMP Proposal). The
preamble to the 2003 CGMP Proposal addressed the comments we had
received regarding the nine questions in the 1997 ANPRM, discussed our
legal authority to issue a CGMP rule, and described the basis for each
proposed requirement.
The 2003 CGMP Proposal specifically requested comment on a variety
of areas, including the need for written procedures and recordkeeping
requirements. Although the proposed rule's comment period was scheduled
to end on June 11, 2003, in the Federal Register of May 19, 2003 (68 FR
27008), we extended the comment period to August 11, 2003.
After we published the proposed rule, we conducted and/or
participated in outreach activities related to dietary supplements and
dietary ingredients. We held public stakeholder meetings on April 29,
2003, in College Park, MD, and on May 6, 2003, in Oakland, CA. We also
held a public meeting, via satellite downlink, on May 9, 2003, with
viewing sites at our district and regional offices throughout the
country. These public meetings gave an overview of the proposed rule,
and clarified specific points in the proposed rule. Since the public
stakeholder meetings held as part of our outreach efforts, we also have
participated in several meetings with industry and other interested
parties which are reflected in the public docket.
We received approximately 400 comments in response to the proposal.
The comments came from trade associations, government organizations and
officials, manufacturers of dietary supplements and dietary
ingredients, health care practitioners, consumer groups, and
individuals. In general, the comments supported the idea of CGMPs,
although many comments disagreed with specific aspects of the proposal.
Published elsewhere in this issue of the Federal Register we are
also issuing an interim final rule that sets forth a procedure for
requesting an exception to a CGMP requirement in this final rule. The
interim final rule allows for submission to, and review by, FDA of an
alternative to the required 100-percent identity testing of components
that are dietary ingredients (as discussed in section X of this
document (subpart E)), provided certain conditions are met. The interim
final rule also includes a requirement for retention of records related
to the FDA grant of an exception request.
[[Page 34757]]
II. How is the Final Rule Organized?
The 2003 CGMP Proposal was divided into eight subparts, with each
subpart devoted to a particular topic. For example, proposed subpart A
was titled ``General Provisions'' and contained sections describing the
rule's scope, purpose, definitions, applicability of other statutory
and regulatory provisions, and exclusions. As another example, proposed
subpart B was titled ``Personnel'' and described microbial
contamination and hygiene requirements, personnel qualification
requirements, and supervisor requirements.
In response to comments seeking a simpler, more ``user-friendly''
final rule or seeking clarification of the rule's applicability to
certain persons, items, or activities, and to reduce redundant
provisions or combine similar provisions, we have reorganized the final
rule into 16 subparts, with new subparts focusing on specific aspects
of the manufacturing process or addressing specific issues. For
example, the proposed rule placed all production and process control
requirements for manufacturing, packaging, labeling, and laboratory
operations in a single subpart (proposed subpart E). The final rule
creates separate subparts for the specific operations to make it easier
to find the relevant production and process control requirements for a
particular activity.
Table 1 of this document summarizes how we reorganized the rule. We
are providing this information to help readers understand the
structural changes we made between the proposed and final rules.
Table 1.--Reorganization and Revisions: 2003 CGMP Proposal and Final
Rule
------------------------------------------------------------------------
Final Final
Proposed Subpart Proposed Sections in Subpart and Sections in
and Title the Subpart Title the Subpart
------------------------------------------------------------------------
A--General 111.1 A--General 111.1
Provisions 111.2 Provisions 111.3
111.3 111.5
111.5
111.6
------------------------------------------------------------------------
B--Personnel 111.10 B--Personnel 111.8 (new)
111.12 111.10
111.13 111.12
111.13
111.14 (new)
------------------------------------------------------------------------
C--Physical Plant 111.15 C--Physical 111.15
111.20 Plant and 111.16 (new)
Grounds 111.20
111.23
(formerly
proposed
Sec.
111.15(d)(3)
and (e)(2))
------------------------------------------------------------------------
D--Equipment and 111.25 D--Equipment 111.25
Utensils 111.30 and (formerly
Utensils proposed
Sec.
111.25(c)(1)
and (e)(1))
111.27
(formerly
proposed
Sec.
111.25 (a),
(b), (d)\1\,
and (e))
111.30
111.35
(formerly
proposed
Sec. Sec.
111.25
(c)(1),
(c)(2), (d),
(f),
111.30(b)(2)
, (b)(5),
and (c),
111.50(c)(4)
)
------------------------------------------------------------------------
[[Page 34758]]
E--Production and 111.35 E--Requireme 111.55
Process Controls 111.37 nt to (formerly
111.40 Establish a proposed
111.45 Production Sec.
111.50 and Process 111.35(a))
111.60 Control 111.60
111.65 System (formerly
111.70 proposed
111.74 Sec.
111.35(b))
111.65
(formerly
proposed
Sec.
111.35(c))
111.70
(formerly
proposed
Sec.
111.35(e),
(f), (g),
and (k))
111.73
(formerly
proposed
Sec.
111.35(f),
(g), and (h)
111.75
(formerly
proposed
Sec.
111.35(e)
through (i),
(k), and
(l)), Sec.
111.37(b)(11
(iv), and
Sec.
111.40(a)(2)
111.77 (new)
111.80
(formerly
proposed
Sec.
111.37(b)(11
))
111.83
(formerly
proposed
Sec. Sec.
111.37(b)(12
),
111.50(h),
and
111.83(b)(2)
)
111.87
(formerly
proposed
Sec. Sec.
111.35(i)
and (n),
111.37(b)(5)
and (b)(14),
111.40(a)(3)
,
111.50(d)(1)
, and
111.85(a)
and (c))
111.90
(formerly
proposed
Sec. Sec.
111.35(i)(4)
,
111.50(d)(1)
, (f), and
(g), and
111.65(d))
111.95
(formerly
proposed
Sec.
111.35(o))
------------------------------------------------------------------------
[[Page 34759]]
....................... F--Productio 111.103 (new)
n and 111.105
Process (formerly
Control proposed
System: Sec.
Requirement 111.37(a),
s for (b)(1),
Quality (b)(11), and
Control (b)(12))
111.110
(formerly
proposed
Sec.
111.37(b)(9)
and (b)(13))
111.113
(formerly
proposed
Sec. Sec.
111.35(i)(2)
, (i)(3),
(i)(4)(i),
(i)(4)(ii),
(j), and
(n),
111.37(b)(3)
and (c),
111.40(a)(3)
and (b)(2),
111.50(d)(1)
, 111.65(d),
and
111.70(c))
111.117
(formerly
proposed
Sec. Sec.
111.30(b)(4)
and
111.37(b)(6)
through
(b)(8))
111.120
(formerly
proposed
Sec. Sec.
111.35(i)(4)
(i) and
(i)(4)(ii),
111.37(b)(2)
and (b)(10),
111.40(a)(3)
and (b)(2),
and
111.50(e)(1)
)
111.123
(formerly
proposed
Sec. Sec.
111.35(e)(2)
, (f),
(i)(2), and
(o)(2)
111.37(a),
(b)(2),
(b)(4),
(b)(5), and
(b)(11),
111.45(c),
and
111.50(d)(1)
, (d)(2),
and (g))
111.127
(formerly
proposed
Sec. Sec.
111.37(b)(2)
, (b)(10),
and (b)(11),
111.40(a)(2)
and (a)(3),
and
111.70(c),
(d) and (e))
111.130
(formerly
proposed
Sec. Sec.
111.37(b)(2)
and (b)(15),
and
111.85(a))
111.135 (new)
111.140
(formerly
proposed
Sec. Sec.
111.35(j)
and
111.37(c)
and (d)
------------------------------------------------------------------------
....................... G--Productio 111.153 (new)
n and 111.155
Process (formerly
Control proposed
System: Sec. Sec.
Requirement 111.35(d)(1)
s for through
Components, (d)(5) and
Packaging, 111.40(a)(1)
and Labels through
and for (a)(5))
Product 111.160
That You (formerly
Receive for proposed
Packaging Sec. Sec.
or Labeling 111.35(e)(4)
a Dietary , and
Supplement 111.40(a)(2)
and (b)(1)
through
(b)(4))
111.165
(formerly
proposed
Sec.
111.40(a)(1)
through
(a)(5))
111.170
(formerly
proposed
Sec.
111.74)
111.180
(formerly
proposed
Sec. Sec.
111.35(d)(4)
, and
111.40(c)(1)
(i) through
(c)(1)(iv)
and (c)(2))
------------------------------------------------------------------------
....................... H--Productio 111.205
n and (formerly
Process proposed
Control Sec.
System: 111.45(a)(1)
Requirement , (a)(2),
s for the and (d))
Master 111.210
Manufacturi (formerly
ng Record proposed
Sec.
111.45(b))
------------------------------------------------------------------------
[[Page 34760]]
....................... I--Productio 111.255
n and (formerly
Process proposed
Control Sec.
System: 111.50(a),
Requirement (b), and
s for the (i))
Batch 111.260
Production (formerly
Record proposed
Sec. Sec.
111.35(i)(2)
, (j), (m),
and (o)(2),
111.37(b)(3)
, (b)(5),
(b)(9) and
111.50(c)(1)
through
(c)(11),
(c)(13),
(c)(14),
(d)(2), (e),
and (g), and
111.70(b)(6)
and (g))
------------------------------------------------------------------------
....................... J--Productio 111.303 (new)
n and 111.310
Process (formerly
Control proposed
System: Sec.
Requirement 111.60(a))
s for 111.315
Laboratory (formerly
Operations proposed
Sec.
111.60(b)(1)
)
111.320
(formerly
proposed
Sec.
111.60(c)
and (d))
111.325
(formerly
proposed
Sec.
111.60(b)(2)
and (b)(3))
------------------------------------------------------------------------
....................... K--Productio 111.353 (new)
n and 111.355
Process (formerly
Control proposed
System: Sec.
Requirement 111.65(a))
s for 111.360
Manufacturi (formerly
ng proposed
Operations Sec.
111.65(b))
111.365
(formerly
proposed
Sec.
111.65(c))
111.370
(formerly
proposed
Sec.
111.74)
111.375 (new)
------------------------------------------------------------------------
....................... L--Productio 111.403 (new)
n and 111.410
Process (formerly
Control proposed
System: Sec.
Requirement 111.70(a),
s for (b)(6), and
Packaging (f))
and 111.415
Labeling (formerly
Operations proposed
Sec.
111.70(b))
111.420
(formerly
proposed
Sec.
111.70(d)
and (e))
111.425
(formerly
proposed
Sec.
111.74)
111.430
(formerly
proposed
Sec.
111.70(g)
and (h))
------------------------------------------------------------------------
F--Holding and 111.80 M--Holding 111.453 (new)
Distributing 111.82 and 111.455
111.83 Distributin (formerly
111.85 g proposed
111.90 Sec.
111.80)
111.460
(formerly
proposed
Sec.
111.82)
111.465
(formerly
proposed
Sec.
111.83(b)(1)
and (b)(2))
111.470
(formerly
proposed
Sec.
111.90)
111.475 (new)
------------------------------------------------------------------------
[[Page 34761]]
....................... N--Returned 111.503 (new)
Dietary 111.510
Supplements (formerly
proposed
Sec.
111.85(a))
111.515
(formerly
proposed
Sec.
111.85(b)
and (c))
111.520
(formerly
proposed
Sec.
