Amendments to the Current Good Manufacturing Practice Regulations for Finished Pharmaceuticals, 51919-51933 [E8-20709]
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10. Order dated June 11, 2003, signed by
Julie Louise Gerberding, Director, Centers for
Disease Control and Prevention, and Mark B.
McClellan, Commissioner of Food and Drugs,
titled ‘‘Joint Order of the Centers for Disease
Control and Prevention and the Food and
Drug Administration, Department of Health
and Human Services.’’
11. 68 FR 36566 (June 18, 2003).
12. Fleischauer, A. T., et al., ‘‘Evaluation of
Human-to-Human Transmission of
Monkeypox from Infected Patients to Health
Care Workers,’’ Clinical Infectious Diseases,
40: 689–694 (2004).
13. Xiao, S.Y., et al., ‘‘Experimental
Infection of Prairie Dogs with Monkeypox
Virus,’’ Emerging Infectious Diseases 11(4):
539–545 (2005).
14. Likos, A.M., et al., ‘‘A Tale of Two
Clades: Monkeypox Viruses,’’ Journal of
General Virology 86: 2661–2672 (2005).
15. Nalca, A., Rimoin, A.W., Bavari, S. and
Whitehouse, C.A., ‘‘Reemergence of
Monkeypox: Prevalence, Diagnostics, and
Countermeasures,’’ Clinical Infectious
Diseases 41: 1765–1771 (2005).
16. Kile, J.C., et al., ‘‘Transmission of
Monkeypox Among Persons Exposed to
Infected Prairie Dogs in Indiana in 2003,’’
Archives of Pediatric Adolescent Medicine
159: 1022–1025 (2005).
17. Guarner, J. et al., ‘‘Monkeypox
Transmission and Pathogenesis in Prairie
Dogs,’’ Emerging Infectious Diseases, 10:
426–431 (March 2004).
18. Bernard, S., and Anderson, S.,
‘‘Qualitative Risk Assessment: Monkeypox in
the United States Associated with Domestic
Trade in Certain Animal Species,’’ Emerging
Infectious Diseases, 12: 1827–1833 (2006).
19. Anderson, M.G., et al., ‘‘A Case of
Severe Monkeypox Virus Disease in an
American Child: Emerging Infections and
Changing Professional Values,’’ Pediatric
Infectious Disease, 22: 1093–1096 (2003).
20. Croft, D.R., et al., ‘‘Occupational Risks
during a Monkeypox Outbreak, Wisconsin,
2003,’’ Emerging Infectious Diseases, 13:
1150–1157 (2007).
21. Reynolds, M.G., et al., ‘‘Spectrum of
Infection and Risk Factors for Human
Monkeypox, United States, 2003,’’ Emerging
Infectious Diseases, 13: 1332–1339 (2007).
22. Reed, K. D., Davis, J. P., and Damon,
I. K., ‘‘Monkeypox in the Western
Hemisphere,’’ (Response to a Letter to the
Editor), New England Journal of Medicine,
350: 1791 (April 22, 2004).
23. Hutson, C.L., et al., ‘‘Monkeypox
Zoonotic Associations: Insights from
Laboratory Evaluation of Animals Associated
with the Multi-State US Outbreak,’’
American Journal of Tropical Medicine and
Hygiene, 76: 757–767 (2007).
24. Centers for Disease Control and
Prevention, ‘‘Multistate Outbreak of
Monkeypox - Illinois, Indiana, and
Wisconsin, 2003,’’ Morbidity and Mortality
Weekly Report, 52: 537–540 (June 13, 2003).
VIII. Federalism
FDA has analyzed this rule in
accordance with the principles set forth
in Executive Order 13132. We have
determined that the rule does not
contain policies that have substantial
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direct effects on 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. Accordingly, we
have concluded that the 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.
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
List of Subjects
AGENCY:
21 CFR Part 16
ACTION:
Administrative practice and
procedure.
SUMMARY: The Food and Drug
Administration (FDA) is amending
certain of its regulations on current good
manufacturing practice (CGMP)
requirements for finished
pharmaceuticals as the culmination of
the first phase of an incremental
approach to modifying the CGMP
regulations for these products. This rule
revises CGMP requirements primarily
concerning aseptic processing,
verification of performance of
operations by a second individual, and
the use of asbestos filters. We are
amending the regulations to modernize
or clarify some of the requirements as
well as to harmonize them with other
FDA regulations and international
CGMP standards.
DATES: This rule is effective December 8,
2008.
FOR FURTHER INFORMATION CONTACT:
Mary Malarkey, Center for Biologics
Evaluation and Research (HFM–600),
Food and Drug Administration, 1401
Rockville Pike, Rockville, MD 20852–
1448, 301–827–6190; or
Dennis Bensley, Center for Veterinary
Medicine (HFV–140), Food and Drug
Administration, 7500 Standish Pl.,
Rockville, MD 20855, 240–276–8268; or
Brian Hasselbalch, Center for Drug
Evaluation and Research, Food and
Drug Administration, 10903 New
Hampshire Ave., rm. 4364, Silver
Spring, MD 20993, 301–796–3279.
SUPPLEMENTARY INFORMATION:
Communicable diseases, Public
health, Travel restrictions, Water
supply.
Therefore, under the Public Health
Service Act and under authority
delegated to the Commissioner of Food
and Drugs, 21 CFR 16 and 1240 are
amended as follows:
I
PART 16—REGULATORY HEARING
BEFORE THE FOOD AND DRUG
ADMINISTRATION
1. The authority citation for 21 CFR
part 16 continues to read as follows:
I
Authority: 15 U.S.C. 1451–1461; 21 U.S.C.
141–149, 321–394, 467f, 679, 821, 1034; 28
U.S.C. 2112; 42 U.S.C. 201–262, 263b, 364.
§ 16.1 [Amended]
2. Section 16.1 is amended in
paragraph (b)(2) by removing the entry
for ‘‘§ 1240.63(c)(3) ’’.
I
PART 1240—CONTROL OF
COMMUNICABLE DISEASES
3. The authority citation for 21 CFR
part 1240 continues to read as follows:
I
Authority: 42 U.S.C. 216, 243, 264, 271.
§ 1240.63 [Removed]
Dated: August 27, 2008.
Jeffrey Shuren,
Associate Commissioner for Policy and
Planning.
[FR Doc. E8–20779 Filed 9–5–08; 8:45 am]
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Amendments to the Current Good
Manufacturing Practice Regulations for
Finished Pharmaceuticals
Food and Drug Administration,
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Final rule.
Table of Contents
4. Remove § 1240.63.
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21 CFR Parts 210 and 211
HHS.
21 CFR Part 1240
I
Food and Drug Administration
I. Background
II. Summary of the Final Rule
A. Aseptic Processing
B. Asbestos Filters
C. Verification by a Second Individual
D. Other Minor Changes
III. Comments on the Proposed Rule and
FDA’s Response
A. General Comments
B. Plumbing
C. Aseptic Processing
D. Asbestos Filters
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E. Verification by a Second Individual
F. Miscellaneous Minor Changes
Based on 1996 Proposal
IV. Analysis of Impacts
V. Environmental Impact
VI. Federalism
VII. Paperwork Reduction Act of 1995
I. Background
Since the development of the CGMP
regulations for drug products in 1962,
FDA has balanced the need for easily
understood minimum standards with
the need to encourage innovation and
the development of improved
manufacturing technologies. We strive
to give manufacturers latitude to
determine how to achieve the level of
control necessary for CGMP compliance,
recognizing that, in some instances,
more direction from FDA is necessary to
provide a uniform standard to the entire
industry, minimize the potential for
harm, or achieve some other CGMP
objective. We periodically reassess and
revise the CGMP regulations to
accommodate advances in technology
and other scientific knowledge that
further safeguard the drug
manufacturing process and the public
health.
In 1996, as part of this reassessment
process, we proposed to: (1) Amend
certain requirements of the CGMP
regulations for finished pharmaceuticals
to clarify certain manufacturing, quality
control, and documentation
requirements and (2) ensure that the
regulations more accurately
encompassed current industry practice
(61 FR 20104, May 3, 1996) (1996
proposed rule). Subsequently, as a part
of the risk-based Pharmaceutical CGMPs
for the 21st Century initiative, we
created a CGMP Harmonization
Analysis Working Group (CGMP
Working Group) to analyze related
CGMP requirements in effect in the
United States and internationally,
including those related to quality
systems. The CGMP Working Group
compared parts 210 and 211 (21 CFR
parts 210 and 211) with the CGMPs of
the European Union (EU), as well as
other FDA regulations (e.g., the Quality
Systems Regulation, 21 CFR part 820) to
identify the differences and consider the
value of supplementing or changing the
current regulations. Based on the CGMP
Working Group’s analysis, we decided
to take an incremental approach to
modifying parts 210 and 211.
Because of this change in approach,
we decided not to finalize the 1996
proposed rule. On December 4, 2007, we
published a document withdrawing the
1996 proposed rule (72 FR 68111) (the
December 2007 proposed rule). On the
same date, we published a direct final
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rule (72 FR 68064) and companion
proposed rule (72 FR 68113) to clarify
and modernize certain provisions of the
CGMP regulations. The comment period
for the direct final rule closed on
February 19, 2008. On April 4, 2008, we
published a document withdrawing the
direct final rule because we received
significant adverse comments (73 FR
18440). In the document withdrawing
the direct final rule, we explained that
the comments received would be
considered under our usual procedures
for notice and comment in connection
with the notice of proposed rulemaking
that was published as a companion to
the direct final rule.
After careful consideration of all
comments received, we are now
publishing this final rule. The final rule
represents the culmination of the first
increment of modifications to parts 210
and 211.
II. Summary of the Final Rule
The final rule revises the drug CGMP
regulations primarily in three areas:
Aseptic processing, use of asbestos
filters, and verification of operations by
a second individual.
A. Aseptic Processing
The final rule revises § 211.113(b) to
clarify that required written procedures
designed to prevent microbiological
contamination of sterile drug products
must include procedures on the
validation of all aseptic processes in
addition to sterilization processes. Other
changes related to aseptic processing
include the following:
• Revised § 211.67(a) requires that
equipment and utensils be cleaned,
maintained, and, as appropriate for the
nature of the drug, sanitized ‘‘and/or
sterilized’’ at appropriate intervals to
prevent malfunction or contamination.
This change recognizes that for sterile
drug products, sterilization (sometimes
in addition to sanitization) is
appropriate.
• Revised § 211.84(d)(6) requires
microbiological tests before use of each
lot of a component, drug product
container, or closure ‘‘with potential for
microbiological contamination’’ that is
objectionable in view of its intended
use, consistent with longstanding
agency interpretation of this regulation.
• Revised § 211.94(c) requires
validation of depyrogenation processes
for drug product containers and
closures, consistent with longstanding
industry practice and agency
interpretation of this regulation.
• Revised § 211.110(a) adds
bioburden testing to the list (which is
not all-inclusive) of in-process control
procedures relating to the sampling and
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testing of in-process materials, which
again is consistent with industry
practice.
B. Asbestos Filters
We revised §§ 210.3(b)(6) and 211.72
to eliminate provisions permitting
limited use of asbestos-containing filters
used in processing injectable drug
products. We had proposed to simply
delete references to asbestos filters in
these provisions. However, in response
to comments, we also added to § 211.72
the statement ‘‘The use of an asbestoscontaining filter is prohibited.’’ Also in
response to comments, we revised
§ 211.72 to reflect appropriate technical
standards for nonfiber-releasing filters.
C. Verification by a Second Individual
The final rule makes several changes
to the regulations to acknowledge,
consistent with our longstanding
interpretation, that certain operations
may be performed by automated
equipment and verified by a person,
rather than one person performing an
operation and another person verifying
that the operation was correctly
performed. In particular, we added new
paragraph (c) to § 211.68 stating that
automated equipment used to perform
operations addressed in §§ 211.101(c) or
(d), 211.103, 211.182, or 211.188(b)(11)
can satisfy the requirements in those
sections for the performance of an
operation by one person and checking
by another person if the equipment is
used in conformity with § 211.68 and
one person checks that the operations
are properly performed. In response to
comments, we revised the paragraph to
minimize the possibility that the
provision might be misinterpreted as
requiring a person to repeat by hand all
calculations performed by automated
equipment.
In accordance with the addition of
§ 211.68(c), we are adopting
corresponding changes to the following
provisions:
• Section 211.101(c) and (d)
(concerning charge-in of components
and containers),
• Section 211.103 (calculation of
yields),
• Section 211.182 (equipment
cleaning and maintenance), and
• Section 211.188(b)(11) (batch
production and control records).
D. Other Minor Changes
In addition to the revisions to the
regulations previously noted, we have
made minor revisions to the following
provisions to provide greater clarity
without changing meaning or intent:
• Section 211.82(b) (storage of
components, containers, and closures),
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• Section 211.84(c)(1) and (d)(3)
(collection and testing of samples of
components, containers, and closures),
and
• Section 211.160(b)(1) (laboratory
controls for determining conformity to
specifications).
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III. Comments on the Proposed Rule
and FDA’s Response
We received comments on the
proposed rule from drug and biologic
manufacturers, industry associations,
consultants, and other interested
persons. A summary of the comments
received and our responses follow. We
first respond to comments of a general
nature and then to comments on the five
topics set forth in the preamble of the
direct final rule.
To make it easier to identify
comments and our responses, the word
‘‘Comment,’’ in parentheses, appears
before the comment’s description, and
the word ‘‘Response,’’ in parentheses,
appears before our response. We have
numbered each comment to help
distinguish between different
comments. Similar comments are
grouped together under the same
number if the same response would be
given for each. The number assigned to
each comment is purely for
organizational purposes and does not
signify the comment’s value or
importance or the order in which it was
received.
A. General Comments
(Comment 1) One comment stated
that it will be very important for FDA
to ensure clarity and consistency in the
understanding of the final rule among
agency staff, including both product
reviewers and CGMP inspectors, to
minimize different interpretations and
applications of these regulations.
(Response) We agree that it is
important that FDA employees who
perform application reviews, as well as
conduct CGMP inspections and other
compliance activities, understand these
regulations and apply them in a
consistent manner in the performance of
their duties. Therefore, we will take
appropriate steps to ensure that agency
staff receive adequate training regarding
the new regulations.
(Comment 2) One comment stated
that we should not withdraw the 1996
proposed rule because it contained
many good features with respect to test
method validation and the out-ofspecification test result problem. The
comment maintained that the guidance
for industry entitled ‘‘Investigating Outof-Specification (OOS) Test Results for
Pharmaceutical Production’’ (71 FR
60158, October 12, 2006) is not helpful
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to people working with biological drugs
and other products. Another comment
stated that the December 2007 proposed
rule should have incorporated many of
the changes in the 1996 proposed rule
regarding such matters as validation,
quality control unit responsibilities,
batch failure investigations, and
stability samples because they involve
some of the most common CGMP
deficiencies.
(Response) As we stated in the
December 4, 2007, document, we
withdrew the 1996 proposed rule
because we concluded that, given our
new approach to CGMP under the 21st
century initiative, it would be preferable
to revise the CGMP regulations
incrementally rather than in a one-time,
comprehensive fashion. Furthermore,
we believe that it is appropriate to
reevaluate some of the matters
considered in the 1996 proposed rule in
light of recent scientific and
technological advances. We appreciate
the comments’ interest in the specified
CGMP issues, and we will consider
these issues in future phases of our
CGMP modernization efforts.
(Comment 3) One comment
encouraged FDA to consider other
CGMP regulations that need
modernization or clarification, or are no
longer necessary due to technological
advances, such as aspects of 21 CFR
610.12 concerning the requirements for
bulk sterility testing and allowance for
sterility retesting for biological
products.
(Response) We appreciate the
comment’s interest in modernizing
CGMP regulations. As previously stated,
this final rule represents only our first
step in updating the drug CGMP
regulations to reflect current industry
practice and harmonize the regulations
with international CGMP requirements.
We will consider other aspects of CGMP
in future rulemaking proceedings.
B. Plumbing
Section 211.48(a) requires that potable
water be supplied under continuous
positive pressure in a plumbing system
free of defects that could contribute
contamination to any drug product. It
further requires that potable water meet
the standards established by the U.S.
Environmental Protection Agency (EPA)
for primary drinking water in 40 CFR
part 141. Proposed § 211.48(a) would
have deleted the requirement that the
potable water used in a plumbing
system meet EPA’s standards for
primary drinking water, and instead
required that the water be ‘‘safe for
human consumption.’’ This proposed
revision was intended to improve
harmonization with foreign regulations
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(particularly those of the EU and Japan)
and to make the U.S. regulation more
consistent with the United States
Pharmacopeia standard. In the preamble
of the direct final rule, we stated that
the revised requirement could be met by
compliance with the standards in the
EPA regulations or in the current
regulations of the EU or Japan for
potable water used to prepare water for
pharmaceutical purposes.
(Comment 4) Four comments objected
to the proposed change. Among other
things, the comments stated that the
standard of ‘‘safe for human
consumption’’ is not sufficiently
prescriptive.
(Response) Because of the comments
received and other considerations, we
have decided not to revise § 211.48(a) at
this time. We will address the issue of
standards for water used in a facility’s
plumbing system when we consider
proposing regulations for water used as
a drug product component in the next
phase of our CGMP initiative.
C. Aseptic Processing
In the proposed rule, we sought to
amend several regulations on aseptic
processing to reflect current industry
standards and practices. Some of the
proposed revisions would also affect
other types of processes and operations.
We noted that the proposed changes
would not affect the applicability of the
guidance for industry entitled ‘‘Sterile
Drug Products Produced by Aseptic
Processing—Current Good
Manufacturing Practice’’ (Aseptic
Processing Guidance), issued on
October 4, 2004 (69 FR 59258).
1. Equipment Cleaning and
Maintenance (§ 211.67(a))
The version of § 211.67(a) amended
by this final rule stated: ‘‘Equipment
and utensils shall be cleaned,
maintained, and sanitized at appropriate
intervals to prevent malfunctions or
contamination that would alter the
safety, identity, strength, quality, or
purity of the drug product beyond the
official or other established
requirements.’’ We proposed to add the
phrase ‘‘and/or sterilized’’ after the
word ‘‘sanitized’’ in § 211.67(a) to
reflect the fact that sterilization is
appropriate for sterile drug products.
On our own initiative, we have
revised § 211.67(a) to state that
equipment and utensils shall be
cleaned, maintained, ‘‘and, as
appropriate for the nature of the drug,
sanitized and/or sterilized at
appropriate intervals * * *.’’ This
revision does not alter the meaning of
the proposed rule change, but clarifies
that for some equipment and utensils
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used in the production of certain drug
products, sanitization is appropriate; for
other equipment and utensils,
sterilization is appropriate; and for still
others, both sanitization and
sterilization are appropriate.
(Comment 5) One comment stated
that it is not appropriate to address
sterilization in § 211.67(a). Instead, the
comment recommended that a reference
to sterilization of equipment and
utensils be added to § 211.113(b), which
requires the adoption of written
procedures designed to prevent
microbiological contamination of drug
products purporting to be sterile.
(Response) We do not agree with the
comment because, as previously noted,
equipment and utensils used in the
production of sterile drug products must
be sterilized, not merely sanitized. In
addition, we have revised § 211.113(b)
as discussed in section III.C.5 of this
final rule.
(Comment 6) One comment suggested
that we could simplify the language in
this regulation by changing the phrase
‘‘beyond the official or other established
requirements’’ to ‘‘beyond the
established (or other official)
requirements.’’
(Response) We do not believe that the
suggested change simplifies the current
phrase, which we believe is clear.
Therefore, we do not believe that the
suggested change is necessary.
(Comment 7) One comment stated
that § 211.67(a) should not apply to the
production of medical gases because
most medical gas manufacturing lines
are product-specific, closed systems that
are not subject to cleaning or sanitation
as part of an established periodic cycle,
but instead are specially cleaned to be
‘‘oxygen ready’’ and carefully handled
in accordance with established
procedures. The comment maintained
that additional cleaning efforts beyond
the initial cleaning regimen
substantially increase the risk of
introducing contaminants into the
system. Therefore, the comment stated,
it is not necessary to require cleaning of
equipment at ‘‘appropriate intervals’’ for
medical gas manufacturing. The
comment suggested that, alternatively, it
might be appropriate for the agency to
state that medical gases may represent
unique circumstances that will be
reflected in a separate guidance.
(Response) We decline to exempt
medical gases from the requirements of
§ 211.67(a) as recommended because
this would exceed the scope of our
proposed change to clarify that
sterilization is appropriate for sterile
drug products and would instead focus
on whether there is any need for
periodic cleaning of medical gas
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systems. We might consider in a future
CGMP rulemaking whether it is
appropriate to revise § 211.67(a) to
address its application to medical gases.
2. Microbiological Testing of
Objectionable Lots of Components, Drug
Product Containers, and Closures
(§ 211.84(d)(6))
The version of § 211.84(d)(6) amended
by this final rule stated: ‘‘Each lot of a
component, drug product container, or
closure that is liable to microbiological
contamination that is objectionable in
view of its intended use shall be
subjected to microbiological tests before
use.’’ We proposed to change the phrase
‘‘that is liable to microbiological
contamination’’ to ‘‘with potential for
microbiological contamination.’’
(Comment 8) One comment stated
that the proposed change was
unnecessarily restrictive and might lead
to testing every lot when the risk of
microbial contamination is low and the
impact on the intended use is
insignificant. This comment suggested
replacing ‘‘that is liable to microbial
contamination’’ with ‘‘prone to
microbial contamination.’’ One
comment stated that the proposed
change could make it more difficult for
drug manufacturers to replace a less
effective, quality control-based
inspection and test method with a more
modern and effective quality audit
method. The comment stated that
because the bioburden of dry items such
as vials and stoppers is often
heterogeneous, improved assurance of
this quality attribute is better achieved
through the audit, selection, and control
by the manufacturers of these items.
This comment maintained that
knowledge of and control over the
manufacturing processes for containers
and closures might fall short of
justifying that those products do not
have a ‘‘potential for contamination.’’
(Response) We decline to adopt the
recommended change to § 211.84(d)(6)
from ‘‘that is liable to microbial
contamination’’ to ‘‘prone to
microbiological contamination.’’ We
believe that our proposed change to
‘‘with potential for microbiological
contamination’’ clarifies our
longstanding interpretation of the
regulation that each lot of component,
drug product container, or closure that
is susceptible to contamination must
undergo microbiological testing before
use. Therefore, we have revised
§ 211.84(d)(6) to refer to components,
containers, or closures ‘‘with potential
for microbiological contamination’’ as
proposed.
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3. Validation of Depyrogenation of Drug
Product Containers and Closures
(§ 211.94(c))
The version of § 211.94(c) amended
by this final rule stated: ‘‘Drug product
containers and closures shall be clean
and, where indicated by the nature of
the drug, sterilized and processed to
remove pyrogenic properties to assure
that they are suitable for their intended
use.’’ In the preamble to the direct final
rule, we stated that it has been
longstanding industry practice to
validate the sterilization and
depyrogenation processes used for drug
product containers and closures to
ensure consistent removal of microbial
contamination and pyrogens or
endotoxins. Therefore, we proposed to
add a provision to § 211.94(c) requiring
the validation of these depyrogenation
processes.
(Comment 9) One comment suggested
that we require validation of
‘‘sterilization’’ as well as
depyrogenation processes.
(Response) We do not believe that the
suggested change is needed because
§ 211.113(b) already requires validation
of sterilization processes for the
prevention of microbiological
contamination of drug products
purporting to be sterile.
(Comment 10) Four comments
objected to the requirement in existing
§ 211.94(c) because it requires
depyrogenation of components based on
the nature of the drug and does not take
into account the fact that some
containers and closures are inherently
nonpyrogenic, have been qualified not
to require active depyrogenation, or do
not require depyrogenation because of
handling procedures. Three of the
comments proposed that in addition to
the nature of the drug, the drug’s
manufacturing process be included as a
factor in determining when containers
and closures must be sterilized and
processed to remove pyrogenic
properties. Two of the comments
recommended that the requirement to
validate depyrogenation processes be
limited to containers and closures that
are made nonpyrogenic by a designated
depyrogenation process (thus excluding
inherently nonpyrogenic containers and
closures from the regulation).
(Response) We decline to adopt the
suggested revisions because they go
beyond the scope of our proposed
change to require validation of
depyrogenation processes and instead
focus on the need for depyrogenation
itself.
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4. Inclusion of Bioburden Testing in InProcess Testing (§ 211.110(a))
Section 211.110(a) requires that
written procedures be established and
followed that describe in-process
controls and tests or examinations to be
conducted on samples of in-process
materials of each batch of a drug
product. The regulation specifies five
control procedures that must be
established, where appropriate, to
monitor the output and to validate the
performance of manufacturing processes
that may be responsible for causing
variation in the characteristics of inprocess material and the drug product.
We proposed to add bioburden testing
to this list (which is not all-inclusive)
because testing for bioburden is
standard industry practice for in-process
materials and drug products that are
produced by aseptic processing.
(Comment 11) Three comments
objected to the addition of bioburden
testing to § 211.110(a). One comment
objected to the inclusion of any specific
test and suggested that specific tests be
addressed in agency guidance. One
comment stated that bioburden testing
is not conducted at the same time as
other tests specified in § 211.110(a) and
is not an in-process test or control
because it does not yield immediate
results that allow for process
adjustment. The comment stated that it
would be more appropriate to address
bioburden testing in § 211.84. One
comment suggested that because
§ 211.110 covers the sampling and
testing of all in-process materials and
drug products, adding bioburden testing
as a mandatory control procedure could
expand current industry validation
procedure and produce diversity among
the industry and regulators on the
circumstances in which validation of
bioburden testing is appropriate.
(Response) We do not agree with the
comments. As stated in the direct final
rule, testing for bioburden is an
important in-process control,
particularly for drug products that are
produced through aseptic processing.
Section 211.110(a) provides flexibility
to manufacturers so that they need only
conduct bioburden testing where the
testing is appropriate to assure batch
uniformity and drug product integrity.
We believe that manufacturers
understand for which types of drug
products, and at what point in the
manufacturing process for these drugs,
bioburden testing is appropriate.
Accordingly, we have added bioburden
testing to § 211.110(a).
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5. Control of Microbiological
Contamination (§ 211.113(b))
Section 211.113(b) states that
appropriate written procedures,
designed to prevent microbiological
contamination of drug products
purporting to be sterile, must be
established and followed. The version of
§ 211.113(b) amended by this final rule
further stated: ‘‘Such procedures shall
include validation of any sterilization
process.’’ We proposed to substitute ‘‘all
aseptic and sterilization processes’’ for
‘‘any sterilization process.’’ As noted in
the preamble of the direct final rule,
even before we issued the now-replaced
guidance on ‘‘Sterile Drug Products
Produced by Aseptic Processing’’ in
1987, industry routinely conducted
validation studies (often referred to as
media fills) that substituted
microbiological media for the actual
product to demonstrate that its aseptic
processes were validated (72 FR 68064
at 68066). The proposed change was
intended to clarify existing practice and
to harmonize § 211.113 with Annex 1 of
the EU CGMPs.
(Comment 12) Several comments
objected to the proposed change to
§ 211.113(b) on the basis that aseptic
processing cannot be validated. One
comment stated that validation of
aseptic processing technically cannot be
done, although the manufacturer can
ensure tight control over the process.
One comment stated that aseptic
processing simulations demonstrate the
capability of a facility, equipment, and
operational controls to provide a
minimal microbial contamination rate
in a single event, but they cannot
predict the outcome of a similar process
performed at a different time. The
comment maintained that to consider
aseptic processing to be validated
overstates the ability to measure and
control the process and could be
interpreted as approval to relax the
controls necessary for its success. The
comment recommended that
§ 211.113(b) be revised to require
validation of ‘‘all sterilization/
depyrogenation processes’’ and to direct
that aseptic processes ‘‘be subjected to
periodic assessment to demonstrate the
capability of the control strategy to
adequately support end product
sterility.’’
One comment stated that there is
currently no means to comply with the
proposed requirement to validate
aseptic processes. The comment
maintained that the microbiological and
decontamination methods used in
aseptic processing lack the sensitivity,
recoverability, and accuracy of the
physical and chemical measurement
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systems normally associated with
process validation. The comment
further claimed that media fills do not
validate aseptic processing because they
measure only detectable microorganisms and do not verify that no
micro-organisms exist. The comment
stated that although aseptic processing
cannot be validated, a state of control
can be established, ensuring that the
aseptically produced drug consistently
meets its specifications and quality
attributes. The comment recommended
that rather than validation of aseptic
processes, § 211.113(b) require ‘‘a
formalized quality risk management and
control strategy for aseptic processes to
provide assurance of requisite and
continued process capability and
product quality.’’
One comment stated that although
media fills can evaluate an aseptic
process, they cannot be considered to
validate the process. The comment
recommended that we either not adopt
the proposed requirement to validate
aseptic processes or provide more
clarity on what is expected for
validation of aseptic processes.
Similarly, another comment
recommended that we not revise
§ 211.113(b) as proposed unless we
clarify that more than media fills are
required to validate an aseptic process.
The comment stated that a wellcontrolled, robust process is required for
aseptic processes and that once a state
of control has been established for the
process, media fills can be useful in
confirming the state of control.
(Response) Although we acknowledge
that aseptic process validation does not
provide absolute assurance of product
sterility, we do not agree that aseptic
processes cannot be validated.
Validation of aseptic processes, which is
a common practice throughout the
pharmaceutical industry, means
establishing documented evidence that
provides a high degree of assurance that
a particular process will consistently
produce a product meeting its
predetermined specifications and
quality attributes. Media fills, together
with operational controls,
environmental controls, and product
sterility testing, provide a sufficient
level of assurance that drugs purported
to be sterile are in fact sterile.
(Comment 13) One comment
suggested adding a definition of aseptic
processing to part 210.
(Response) We do not believe that it
is necessary to define aseptic processing
in the regulation. The Aseptic
Processing Guidance makes it clear to
manufacturers what aseptic processing
entails.
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(Comment 14) One comment
requested confirmation that it is
acceptable to follow the current FDA
guidance and use media fills to meet the
requirement to validate aseptic
processes.
(Response) As stated in the preamble
to the direct final rule and reiterated
previously in this document,
manufacturers can follow the
recommendations in the Aseptic
Processing Guidance to comply with
CGMP requirements for aseptic
processing, including validation.
However, as with any guidance, the
Aseptic Processing Guidance is not
binding on industry or the agency, and
manufacturers may use an alternative
approach to achieve compliance if the
approach meets the requirements of the
act and FDA regulations.
(Comment 15) One comment sought
clarification that the requirement to
validate aseptic processing would not
inhibit implementation of novel
technologies recommended by the
International Conference on
Harmonisation of Technical
Requirements for Registration of
Pharmaceuticals for Human Use (ICH)
in the ICH Q8, Q9, and Q10 guidances,
or other innovative approaches in these
areas.
(Response) We do not believe that the
requirement to validate aseptic
processing will interfere with the
implementation of new technologies
either as part of following ICH
recommendations or as part of other
efforts to meet CGMP requirements. As
stated in section I of this document, we
have always attempted to balance the
need for easily understood minimum
CGMP standards with the desire to
encourage innovation and the
development of improved
manufacturing technologies. We are
confident that industry can meet the
requirement to validate aseptic
processing with no adverse impact on
technological innovation in drug
product manufacturing.
D. Asbestos Filters
As stated in the preamble to the direct
final rule, we need to update our
regulations on filters used in processing
liquid injectable products. The version
of § 211.72 amended by this final rule
required manufacturers, before using an
asbestos-containing filter, to submit
proof to FDA that an alternative
nonfiber-releasing filter will, or is likely
to, compromise the safety or
effectiveness of the product. However,
we are not aware that asbestos filters are
currently commercially manufactured
for pharmaceutical use or are used in
drug production, and their use is not
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considered a good manufacturing
practice. Therefore, we proposed to
delete the reference to the use of
asbestos-containing filters from § 211.72
and to delete the reference to asbestos
filters from the definition of ‘‘nonfiberreleasing filter’’ in § 210.3(b)(6).
(Comment 16) Two comments stated
that the regulations should state that the
use of asbestos filters is prohibited. One
comment stated that if asbestoscontaining filters are in fact available
and the proposed changes were
interpreted as permitting their use, this
might pose a risk to patients.
(Response) We agree with the
comments. Therefore, in addition to
deleting the reference to asbestoscontaining filters in § 210.3(b)(6), we
have revised the last sentence of
§ 211.72 to state that the use of an
asbestos-containing filter is prohibited.
(Comment 17) One comment
recommended that we clarify the second
sentence in proposed § 211.72, which
stated: ‘‘Fiber-releasing filters may not
be used in the manufacture, processing,
or packing of these injectable drug
products unless it is not possible to
manufacture such drug products
without the use of such filters.’’ The
comment recommended that this
sentence be revised to state as follows:
‘‘Fiber-releasing filters may be used
when/where it is not possible to
manufacture such drug products
without the use of such filters.’’
(Response) We agree with this
proposed change and have revised
§ 211.72 accordingly.
(Comment 18) Four comments
recommended revising the following
provision in proposed § 211.72: ‘‘If use
of a fiber-releasing filter is necessary, an
additional nonfiber-releasing filter of
0.22 micron maximum mean porosity
(0.45 micron if the manufacturing
conditions so dictate) shall
subsequently be used to reduce the
content of particles in the injectable
drug product.’’ Each of these comments
stated that it is technically more
accurate to describe a filter in terms of
its nominal pore size rating than its
mean porosity. One comment stated that
the filter pore size standard of 0.22
micron is outdated and should be
changed to 0.2 micron.
(Response) These suggested technical
changes are consistent with statements
in our guidances for industry (e.g., the
Aseptic Processing Guidance)
concerning filters. Therefore, we have
revised § 211.72 to require that if use of
a fiber-releasing filter is necessary, an
additional nonfiber-releasing filter
having a maximum nominal pore size
rating of 0.2 micron be used.
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E. Verification by a Second Individual
The current CGMP regulations
include several provisions requiring that
certain activities be performed by one
person and checked as specified by a
second person.
• Section 211.101(c) requires that: (1)
Each container of component dispensed
for use in manufacturing be examined
by a second person to assure that it was
released by the quality control unit, (2)
the weight or measure is correct as
stated in the batch production records,
and (3) the containers are properly
identified.
• Section 211.101(d) requires that
each component be added to the batch
by one person and verified by a second
person.
• Section 211.103 requires that
specified yield calculations be
performed by one person and
independently verified by a second
person.
• Section 211.182 requires the
persons performing and doublechecking the cleaning and maintenance
of major equipment to date and sign or
initial equipment logs indicating that
the work was performed.
• Section 211.188(b)(11) requires that
batch production and control records
include identification of the persons
performing and directly supervising or
checking each significant step in the
operation.
When we amended the CGMP
regulations in 1978, we established
§ 211.68, which provides that automatic,
mechanical, or electronic equipment or
other types of equipment, including
computers, or related systems that will
perform a function satisfactorily, may be
used in the manufacture, processing,
packing, and holding of a drug product,
subject to the following requirements:
• Equipment is routinely checked
according to a program designed to
assure proper performance,
• Changes to records are made only
by authorized personnel,
• Input and output are checked for
accuracy, and
• Appropriate backup of data is
maintained.
In the preamble to the 1978 final rule,
we stated that the verification
requirements in § 211.101 for charge-in
of components when automated systems
are used would be met if a person
verified that the automated system was
working properly (43 FR 45014 at
45051, September 29, 1978). Thus, in
this situation, the first individual is
replaced by a machine or other
automated process, and only one person
is necessary to verify that the automated
system is functioning as intended.
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Because we have received questions
about the performance and checking
requirements in §§ 211.101(c) or (d),
211.103, 211.182, or 211.188(b)(11)
when the operations are performed by
automated equipment, such as the
widespread and increasing use of
computer-controlled operations, we
proposed to revise these sections. We
proposed to amend these regulations to
indicate that when automated
equipment is used to perform certain
operations, only one person is needed to
verify that the automated equipment is
functioning adequately.
Correspondingly, proposed § 211.68(c)
stated that automated equipment used
for performance of operations addressed
by §§ 211.101(c) or (d), 211.103,
211.182, or 211.188(b)(11) can satisfy
the requirements included in those
sections for the performance of an
operation by one person and checking
by another person if such equipment is
used in conformity with § 211.68 and
one person verifies that the operations
addressed in those sections are
performed accurately by such
equipment. We stated in the preamble of
the direct final rule that these revisions
would clarify our longstanding policy
that verification by a second individual
may not be necessary when automatic
equipment is used under § 211.68.
1. General Comments on Verification
(Comment 19) One comment stated
that validated, automated systems
equipped with real time alarms that do
not require any human intervention
should not require human verification.
Another comment stated that such
systems should not require human
verification with each use and, when
human verification is needed, the level
of verification required should be
consistent with the level of automation
used. Both of these comments
maintained that requiring operator
verification of automated, validated
equipment under §§ 211.68(c),
211.101(c)(3) and (d), 211.103, and
211.188(b)(11) might hinder the
implementation of process analytical
technology (PAT) in the drug industry.
(Response) In the Federal Register of
February 12, 1991 (56 FR 5671) (the
1991 proposal), we issued a proposed
rule in part to amend § 211.68 to add
what is now the third sentence of
§ 211.68(b): ‘‘The degree and frequency
of input/output verification shall be
based on the complexity and reliability
of the computer or related system.’’ This
revision was adopted as part of the final
rule issued on January 20, 1995 (60 FR
4087) (the 1995 final rule).
In the 1995 final rule, we responded
to several comments on the proposed
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revision. Two comments suggested that
the revised regulation did not
accommodate the accepted use of
validated computerized drug production
and control systems. We declined to
change the revision as proposed, stating
our belief that the wording in the
revised rule adequately encompasses
the use of these systems (60 FR 4087 at
4089).
Two comments on the 1991 proposal
questioned the need for human
verification of operations that are
performed by validated computer
systems. The comments listed other
regulations that were not the subject of
the proposed rule that required more
than one person to verify certain
manufacturing operations, apparently to
show that additional personnel would
be needed to comply with proposed
§ 211.68. We noted in the 1995 final rule
that the revisions to § 211.68 do not
impose any specific personnel
requirements. We also noted that the
agency is aware that computers are
subject to malfunctions, some of which
could possibly result in the loss of
critical information regarding the
manufacturing process or a serious
production error and the possible
distribution of an adulterated product.
Therefore, we stated that while
increasingly sophisticated system
safeguards and computerized
monitoring of essential equipment and
programs help protect data, no
automated system exists that can
completely substitute for human
oversight and supervision. We further
indicated that while the degree of
verification is left to the manufacturer’s
discretion, the exercise of such
discretion under § 211.68 requires the
use of routine accuracy checks to
provide a high degree of assurance that
input to and output from a computer or
related system are reliable and accurate.
We stated our intent that each
manufacturer exercise reasonable
judgment based on a variety of factors,
including, but not limited to, the
complexity of the computer or related
system, in developing a method to
prevent inaccurate data input and
output (60 FR 4087 at 4089).
The December 4, 2007, direct final
rule and companion proposed rule were
intended to amend the regulations
involving second-person checks only to
clarify our longstanding policy that
verification by a second individual may
not be necessary when automatic
equipment is used under § 211.68, and
that in such situations only one person
is needed to verify that the automated
equipment is functioning adequately.
The amendments were not intended to
either add to or detract from any
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51925
existing requirements in this regard, but
only to clarify our longstanding
interpretation and policy for these
requirements. We note that the same
basic considerations apply in this regard
today as we expressed in the 1995 final
rule. Although increasingly
sophisticated controls and safeguards
have been implemented for some
automated systems, our policy has been
that some degree of human oversight,
supervision, verification, monitoring, or
checking is still necessary to verify
proper performance as part of assuring
the identity, strength, quality, and
purity of drug products. For suitably
validated automated systems, even with
real time alarms, it is still necessary for
a human to verify that the systems are
operating as planned and to monitor for
abnormalities. We agree that the level,
nature, and frequency of such human
verification will vary depending on the
level of automation used as well as the
nature of the system and controls, and
the manufacturer has the flexibility and
responsibility to determine what is
suitable and necessary. Contrary to the
comments, we believe that
manufacturers can conduct human
verification of automated operations in
conjunction with the use of PAT in drug
production.
For these reasons, we continue to
believe that human verification is
necessary to ensure that automated
systems are functioning properly.
(Comment 20) One comment stated
that many current biotech processes
include component additions and
deletions in a continuous or periodic
manner over long periods of time. The
comment stated that there would be no
added value in requiring a manual
verification of this component
management scheme in a fully
automated scenario.
(Response) For the reasons stated in
our response to comment 19, we believe
that some degree of human oversight,
supervision, verification, monitoring, or
checking is a necessary part of CGMP
for such processes and that there is
added value in having greater assurance
that the automated systems are
operating properly as intended. We do
not expect that each individual
component change must be witnessed in
person, but rather that a suitable system
of human oversight be established and
followed to effectively verify that the
automated processes are indeed
operating correctly in the performance
of these operations.
(Comment 21) One comment
maintained that our statement in the
preamble of the direct final rule that the
verifying individual may be, but is not
required to be, the operator is a
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contradiction of the CGMP regulations,
which require (in § 211.25(a)) that all
individuals have the education,
training, and experience to enable them
to perform their assigned functions. The
comment asked why the agency would
allow an untrained operator to perform
a sole verification of a critical step if an
automated system is used and
recommended that we retract the noted
preamble statement.
(Response) The comment incorrectly
concluded that allowing the verifying
individual to be a person other than the
operator would thereby allow an
untrained individual to perform the
function of verifying a critical step.
Section 211.25(a) requires each person
performing an assigned function to have
the education, training, and experience,
or any combination thereof, to enable
that person to perform the function.
Thus, any person, whether the operator
or not, who performs such a verification
step would necessarily be required to
have the knowledge, training, and
experience needed to perform that
function. Therefore, our preamble
statement does not conflict with the
regulations.
(Comment 22) One comment stated
that the proposed changes regarding
second person verification should be
extended to include § 211.188(a), which
requires the preparation of batch
production and control records that
include an accurate reproduction of the
appropriate master production or
control record, checked for accuracy,
dated, and signed. The comment stated
that when there is only one signature
needed, but the system is automated, it
would also follow that no human
signature or signature equivalent would
be necessary, such as in issuance of a
batch record under § 211.188(a), when
the record is electronic. The comment
also stated that in this case, it is
impossible to check the pages for a true
and accurate copy. The comment
recommended revising § 211.68(c) to
include § 211.188(a) in the listing of
sections affected and to state that there
could be single performance verification
under § 211.188(a).
(Response) We do not agree with the
recommended changes to § 211.188(a),
which would eliminate any human
verification of the records. As
previously stated, we are clarifying in
this rule that the checking of automated
equipment by one person can satisfy the
requirements of those regulations that
address the performance of a step by
one person and the verification of the
step by a second person. Our proposal
regarding verification of operations was
intended to make clear that only one
person is needed to verify that
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automated equipment for a processing
step is functioning properly; we did not
propose deleting all human verification
of the step. In addition, we disagree
with the comment’s apparent contention
that no human signature would be
needed for issuance of electronic batch
production and control records. If such
records are generated and issued
electronically as part of an automated
system, a person must verify that the
correct records were issued and that
they are still accurate and complete. We
believe it is clear that § 211.188(a)
requires only one check for accuracy,
with date and signature (which could be
electronic), and that it does not require
a separate second check of this step.
Therefore, no changes to § 211.188(a)
are necessary or appropriate.
(Comment 23) Three comments
addressed second-person verification in
§ 211.194. Section 211.194(a) requires
that laboratory records include complete
data derived from all tests necessary to
assure compliance with established
specifications and standards as
specified in that subsection. Section
211.194(a)(7) requires that laboratory
records include the initials or signature
of the person who performs each test
and the date(s) the tests were performed.
Section 211.194(a)(8) requires the
initials or signature of a second person
showing that the original records have
been reviewed for accuracy,
completeness, and compliance with
established standards. Two of the
comments stated that the principle
behind the proposed second-person
verification revisions should be
extended to § 211.194 to include
checking laboratory records involving
automated laboratory equipment. The
first comment recommended revising
§ 211.194 generally. The second
comment specifically recommended
that § 211.194(a)(8) be revised to add
that if laboratory tests have been
performed by automated equipment
under § 211.68, the laboratory record
need only include the identification of
one person conducting the review of the
tests performed by the automated
system. The comment also asked that
§ 211.194(a)(8) be added to the list of
sections affected in § 211.68(c). The
third comment stated that the failure to
include § 211.194(a)(7) and (a)(8) in the
proposed revisions implies that the use
of automated systems to perform or
check testing is not allowed.
(Response) We decline to include
§ 211.194 among the sections
enumerated in § 211.68(c) concerning
second-person verification of operations
performed by automated equipment. We
acknowledge that automated equipment
may be used to conduct certain
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laboratory testing operations. However,
when automated equipment is used to
perform a laboratory test, typically a
person initiates the test and ensures that
the correct equipment is used and that
it operates properly. In this situation,
one person assists in or oversees the
performance of the laboratory test and a
second person reviews the records for
accuracy, completeness, and
compliance with established standards.
Thus, the use of equipment to perform
laboratory tests, though permissible, is
not a situation in which automated
equipment (rather than a person)
performs an operation and a person
verifies that performance, which is the
situation addressed in revised
§ 211.68(c). Therefore, it would not be
appropriate to include a reference to
§ 211.194 (or to § 211.194(a)(8)
specifically) in revised § 211.68(c).
2. Automatic, Mechanical, and
Electronic Equipment (§ 211.68)
(Comment 24) One comment stated
that § 211.68 is no longer in line with
the technological improvements of the
past 30 years and with the increasing
knowledge of computer validation by
industry and regulators. The comment
recommended that § 211.68 be aligned
with 21 CFR 820.70(i), section 5.4 of the
ICH Q7A guidance entitled ‘‘Good
Manufacturing Practice Guidance for
Active Pharmaceutical Ingredients,’’ and
the Pharmaceutical Inspection
Cooperation Scheme’s Annex 11 on
computerized systems.
(Response) We decline to adopt the
suggested revisions because they exceed
the scope of our proposed revision of
§ 211.68, which only addressed secondperson verification of operations
performed by automated equipment. We
might consider revising other provisions
of § 211.68 as part of a future
rulemaking to update the CGMP
regulations and make them consistent
with international CGMP provisions.
(Comment 25) One comment
recommended that instead of our
proposed changes to § 211.68(c) and
other regulations concerning secondperson verification, we revise
§ 211.68(a), which permits the use of
automatic, mechanical, or electronic
equipment in the manufacture,
processing, packing, and holding of
drug products. The comment stated that
the wording of our proposed changes
only allows for actions to be performed
by automated equipment and checked
by a person, which would prevent the
introduction of automated systems to
check operations performed by a person.
The comment also stated that our
proposed changes would still require
the involvement of at least one person
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in each of these circumstances and
prevent the use of a controlled system
or systems that both perform and
independently verify the relevant
operations. One comment suggested that
rather than our proposed revisions, the
desired clarification concerning
automated equipment and secondperson checks would be better achieved
by adding to § 211.68(a) the following
sentence: ‘‘Automated equipment can
satisfy the requirements for the
performance of an operation by one
person and/or checking by another
person.’’
(Response) We do not agree with the
recommended change. The proposed
rule simply clarified our longstanding
position that only one human check is
necessary to verify a processing step
performed by automated equipment.
The suggested revision of § 211.68(a),
however, would allow manufacturers to
rely solely on automated equipment to
verify the human performance of certain
processing steps and allow automated
equipment to both perform and check
operational steps, which would
constitute a significant change from the
current regulations. As stated in our
response to comment 19, we believe that
human verification of certain processing
steps, even when those steps are
performed by automated equipment, is
still necessary.
(Comment 26) One comment stated
that although proposed § 211.68(c)
implies that the automated equipment is
doing the work and a person can verify
that the work is done, there are cases in
which a person does the work and
automated equipment might be able to
verify the person’s work. The comment
cited as an example the case in which
an automated system scans the bar
codes of ingredients and equipment to
ensure that the ingredient is correct for
use with the equipment for that step in
the process, but the physical addition of
the ingredient is by the human operator
(followed by the automated system
scanning). The comment recommended,
therefore, that § 211.68(c) be modified to
allow both the automated system and
the person to do either the performance
or the verification tasks for the
operations addressed by §§ 211.101(c) or
(d), 211.103, 211.182, 211.188(b)(11), or
211.194(a)(8), or a single performance
verification in the case of § 211.188(a).
(Response) We acknowledge that it
might be possible to design an
automated system to verify operations
performed by humans, but as stated in
our response to comment 19, we
continue to believe that some human
verification of the processing steps
performed by an automated system is
necessary.
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(Comment 27) One comment
suggested revising § 211.68(c) to state
that automated equipment can satisfy
the requirements for verification of
operations addressed by the listed
sections as follows: (1) If such unit
operation is fully automated, no manual
verification is necessary and (2) if there
is an operator for the automated
equipment, the verifying individual may
be, but is not required to be, the
operator. The comment gave several
reasons for this change:
• Automated, validated systems
equipped with real-time alarms that do
not require any human intervention
should not require human verification
because § 211.68(a) adequately
addresses the maintenance and
verification of performance of these
systems.
• The need and type of verification
required should be consistent with the
level of automation used. For example,
operations that are not fully automated
and require operator participation may
serve as verification of the operator’s
activities, while fully manual operations
would require a second human
verification.
• As proposed, § 211.68(c) might
hinder the adoption of PAT (e.g., there
would be no value added by manual
verification when components are
charged in a fully automated manner
according to a validated algorithm).
(Response) As stated in our response
to comment 19, we do not agree with
the contention that no human
verification is necessary when fully
automated systems are used, and we
therefore decline to make these
requested changes to § 211.68(c). We
also do not believe that § 211.68(c) will
hinder the adoption of PAT. As stated
in the preamble to the direct final rule,
we agree that if there is an operator for
the automated equipment, the verifying
individual may be, but is not required
to be, the operator. However, § 211.68(c)
does not require that the verifying
individual be the operator, and we do
not believe that it is necessary that the
provision explicitly state that the
verifying individual need not be the
operator.
(Comment 28) One comment stated
that the proposed revision of
§ 211.68(c), when applied to
§ 211.188(b), might be more restrictive
than FDA’s position in Compliance
Policy Guide (CPG) Sec. 425.500,
Computerized Drug Processing;
Identification of ‘‘Persons’’ on Batch
Production and Control Records
(formerly CPG 7132a.08). CPG 425.500
states that when significant steps in the
manufacturing, processing, packing, or
holding of a batch are performed,
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supervised, or checked by a
computerized system, an acceptable
means of complying with the
identification requirements in
§ 211.188(b)(11) would consist of
conformance to certain requirements.
The comment maintained that CPG
425.500 gives companies the flexibility
to automate not only the performance of
critical actions but also the supervision
and checking of these actions if it is
shown that the efficacy of these controls
would be at least equivalent to the level
of efficacy if the verification were done
by a second person. The comment stated
that this flexibility should be extended
to all CGMP sections in which a
verification is requested. The comment
therefore asked that § 211.68(c) be
revised to state that automated
equipment used for performance of
operations addressed by §§ 211.101(c) or
(d), 211.103, 211.182, or 211.188(b)(11)
can satisfy the requirements included in
those sections for the performance of an
operation by one person and checking
by another person if such equipment is
used in conformity with § 211.68 and
one person either performs the
operations addressed in those sections
under the control of the automated
equipment or verifies that these
operations are performed accurately by
such equipment.
(Response) We do not agree with the
comment’s apparent interpretation of
CPG 425.500 that the CPG allows for
elimination of human oversight. The
purpose of the CPG is to explain what
constitutes ‘‘identification’’ of persons
in batch records under § 211.188(b)(11)
when automated systems are used for
various functions. The CPG states that
when an automated system is used to
perform, directly supervise, or check
significant steps in the production of a
drug, the identification requirements in
§ 211.188(b)(11) are met if there is
documentation that the system contains
adequate checks (and documentation of
the performance of the system itself),
validation of the system’s performance,
and recording of specific checks in
batch records (including initial,
branching, and final steps). These
conditions for applying the
identification requirements to steps
using automated equipment involve the
responsibilities of persons. For example,
a person, rather than automated
equipment, is needed to record these
checks of production steps in batch
records. Therefore, contrary to the
comment’s implication, the CPG does
not state that human oversight is
unnecessary when an automated system
is involved in the performance,
supervision, or checking of production
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steps. All automated systems require
some level (commensurate with the
complexity and risk inherent in the
system) of human oversight or checking
for expected performance at appropriate
intervals. Therefore, we decline to
revise § 211.68(c) as recommended.
(Comment 29) One comment,
although supportive of the proposal to
allow initial activities to be performed
by automated equipment, objected to
requiring that the output of an
automated and adequately validated
activity be checked for accuracy by a
person. The comment maintained that
the act of having validated software and
its related processes itself constitutes an
independent check that operations are
being performed accurately and argued
that this is more reliable than any
contemporaneous check by a person.
The comment therefore asked that
§ 211.68(c) be changed to state that
independent checks may consist of
contemporaneous analysis and
verification by a second person
following completion of the activity; or,
where the automated process has been
validated to a high degree of confidence,
the prior validation can satisfy this
requirement and a second person’s
check may then consist of verifying the
validated status of the equipment and
processes.
(Response) We do not agree with the
suggested change. Although we agree
that it is an important part of process
controls to ensure the validated status of
equipment and processes even before
they are used, we do not believe that
verifying this validated status can
satisfy the requirement for checking the
actual performance of automated
equipment. However, we believe that
the requirement in proposed § 211.68(c)
that one person ‘‘verifies that the
operations * * * are performed
accurately’’ by automated equipment
may have led some comments to believe
that we were requiring a more specific
and detailed repetitive type of check
than we intended. When automated
equipment is used for operations
addressed by revised § 211.68(c) in
conformance with § 211.68, the person
doing the checking must verify that the
automated equipment is functioning
properly and that the operations are
reliably performed in the intended
manner. As discussed in the response to
comment 19, the nature and frequency
necessary for such verification will vary
depending on the level of automation
used as well as the nature of the system
and controls. We do not expect that it
will normally be necessary, under
§ 211.68(c), for a person to repeat all of
the automatic calculations by hand to
ensure their accuracy. Therefore, we
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have revised § 211.68(c) to clarify that
automated equipment can be used to
perform an operation when the
performance is checked by a person
provided that ‘‘such equipment is used
in conformity with this section
[§ 211.68] and one person checks that
the equipment properly performed the
operation.’’
3. Verification of Weighing, Measuring,
or Subdividing Operations (§ 211.101(c))
Section 211.101 concerns charge-in of
components. Proposed § 211.101(c)
stated, in part, that if the weighing,
measuring, or subdividing operations
for components are performed by
automated equipment under § 211.68,
only one person is needed to ensure that
the requirements in § 211.101(c)(1),
(c)(2), and (c)(3) are met.
(Comment 30) One comment
proposed broadening § 211.101(c) to
clarify that the weighing, measuring,
and subdividing operations could be
either performed by automated
equipment or checked by automated
equipment after being performed
manually.
(Response) We decline to make this
suggested change for the reasons
provided in response to comments 19
and 25. Revised § 211.101(c) only
permits human checking of weighing,
measuring, and subdividing operations
performed by automated equipment; we
did not propose to allow automated
checking of these operations. We
continue to believe that human
verification of these processing steps is
necessary.
(Comment 31) One comment stated
that with respect to medical gases, there
is no measurement of components to be
dispensed for manufacturing that needs
to be double-checked to ensure that the
right quantity of the right component
was added, because transfers of pure
gases are within product-specific
systems. However, the comment stated,
with respect to gas mixtures, it is
appropriate to have a verification of
hook-ups as different components are
added unless there is subsequent purity
testing for each component.
(Response) We decline to exempt
single gas filling operations from certain
requirements of § 211.101(c) as
recommended because such a change
would exceed the scope of our proposed
change to § 211.101(c), which only
addressed human checking of weighing,
measuring, and subdividing operations
performed by automated equipment. We
might consider in a future rulemaking
whether it is appropriate to exempt
medical gases from certain requirements
of § 211.101(c).
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4. Verification of Components Added to
the Batch (§ 211.101(d))
Proposed § 211.101(d) would have
required that each component be either
added to the batch by one person and
verified by a second person or, if the
components are added by automated
equipment under § 211.68, only verified
by one person.
(Comment 32) One comment stated
that eliminating a double check for
adding materials to a batch is
problematic because an error in those
operations would be difficult to detect
and might not be discovered before the
product is distributed, which could
result in patient injury and product
recall. The comment recommended
deleting or modifying the ability to use
a sole verifier for operations involving
addition of materials.
(Response) The comment appears to
suggest that we proposed to eliminate
the requirements concerning
verification that appropriate
components were added to a batch. The
revisions we are adopting do not
eliminate the requirement to verify
performance in § 211.101(d); they
simply codify our longstanding policy
that components may be added either by
a person or by suitable automated
equipment. The addition of components
still must be checked by a person.
(Comment 33) One comment stated
that under the proposed change to
§ 211.101(d), if a validated system
performs a function, it is acceptable for
one person to verify that action, but if
an automated system prompts an
operator to perform a function, a second
person would be required to confirm the
proper execution of the action. The
comment recommended changing
§ 211.101(d) to state that each
component must be added to the batch
by one person and verified by a second
person, ‘‘unless the components are
added by automated equipment under
§ 211.68, in which case verification can
be performed by one person.’’
(Response) We decline to accept the
suggested change because we do not
believe that it constitutes a substantive
difference from the language of
proposed § 211.101(d). It is irrelevant
whether use of a particular automated
system for component charge-in
requires an operator to perform a related
function; in either case, verification of
the charge-in operation(s) must be
performed by a person.
(Comment 34) One comment
recommended changing § 211.101(d) to
specify that the weighing, measuring, or
subdividing operations might be
performed by automated equipment or
checked by automated equipment after
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being performed manually. The
comment also stated that in many
instances, the verification by a person of
actions performed by automated
equipment can only be done on the
basis of outputs from the equipment. As
an example, the comment stated, when
the introduction of components in a
liquid production line is fully
automated, there is no possibility for the
operator to check that the correct
amount of materials was incorporated
into the batch other than by relying on
information given by the same
automated equipment. The comment
stated that in that case, the verification
would consist of confirming that the
component’s incorporation process was
completed without errors or alarms.
(Response) We decline to make this
suggested change for the reasons stated
in response to comments 19 and 25.
Revised § 211.101(d) only permits
human checking of component
additions performed by automated
equipment; we did not propose to allow
automated checking of component
additions performed by humans. In the
example given in the comment, human
verification that components were
properly added to the liquid production
line by the automated equipment would
be needed to ensure that the equipment
performed properly. We continue to
believe that human verification of this
processing step is necessary.
5. Calculation of Yield (§ 211.103)
We proposed, in § 211.103, to require
that calculations of actual yields and
percentages of theoretical yields be
performed by one person and
independently verified by a second
person or, if the yield is calculated by
automated equipment under § 211.68,
be independently verified by one
person.
(Comment 35) One comment stated
that it is not necessary to have a person
recalculate a yield manually after a
validated system does it automatically.
The comment asked that § 211.103 be
revised to limit the human interaction to
data entry and data verification, but not
recalculation of yields if yields are
calculated by a validated, automated
system. A similar comment stated that
§ 211.103 should be changed to state
that if the yield is calculated by
automated equipment, a person must
verify the data entries, rather than
regenerate the calculations.
(Response) We do not believe that the
recommended changes are needed or
appropriate. Revised § 211.103 does not
require that all yield calculations be
repeated manually. Manual
recalculation might be a suitable
approach to verifying yield calculations,
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but § 211.103 also permits the use of
other approaches, including verification
that automated equipment functioned
properly while performing yield
calculations.
(Comment 36) One comment
reiterated the views expressed in its
comments on the CGMP for medical
gases draft guidance. Thus, the
comment requested that the
requirements for yield calculation in
§ 211.103 not be applied to medical
gases because of the atmospheric-gasseparation and cylinder-filling processes
associated with medical gases. In further
support of its position, the comment
referred to an FDA publication (Human
Drug CGMP Notes, vol. 5, no. 2, June
1997) in which the agency stated that it
would propose to revise the CGMP
regulations to exempt medical gases
from the requirements for yield
reconciliation.
(Response) We decline to exempt
medical gases from the requirements for
yield calculation in § 211.103 as
recommended because this would
exceed the scope of our proposed
change to § 211.103, which addressed
only human checking of yield
calculations performed by automated
equipment. We might consider in a
future CGMP rulemaking whether it is
appropriate to exempt medical gases
from certain requirements of § 211.103.
In addition, we might consider
providing specific recommendations to
medical gas manufacturers to help them
comply with the requirements for
calculating yields in the course of
finalizing the draft guidance on CGMP
for medical gases.
6. Equipment Cleaning and Use Log
(§ 211.182)
We proposed, in § 211.182, to require
the persons performing and doublechecking equipment cleaning and
maintenance (or, if the cleaning and
maintenance is performed using
automated equipment under § 211.68,
only the person verifying the cleaning
and maintenance done by the automated
equipment) to date and sign or initial
the log indicating that the work was
performed.
(Comment 37) One comment stated
that eliminating a double check for
cleaning equipment is problematic
because an error in those operations
would be difficult to detect and might
not be discovered before the product is
distributed, which could result in
patient injury and product recall. The
comment recommended deleting or
modifying the ability to use a sole
verifier for operations involving
equipment cleaning.
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(Response) The comment appears to
suggest that we proposed to eliminate
the requirements concerning
verification that equipment was
appropriately cleaned and maintained.
The revisions we are adopting do not
eliminate the requirement to verify
performance in § 211.182; they simply
codify our longstanding policy that
equipment may be cleaned and
maintained either by a person or by
suitable automated equipment. Cleaning
and maintenance of equipment must
still be checked by a person.
(Comment 38) One comment stated
that operations addressed by §§ 211.182
and 211.188(b)(11) are often performed
using semi-automated equipment that
requires an operator to select the correct
menu. The comment stated that major
pieces of equipment such as ‘‘Clean in
Place’’ (CIP) skids and vial washers
often require the operator to select the
appropriate process menu before the
execution of the actual automated cycle
by the equipment’s controller. The
comment asked whether, when operator
input is necessary to select but not
perform an operation, the signature of
the operator selecting the menu is
required in cases when there is a second
signature that verifies the performance
of the cycle. One comment requested
that we verify in § 211.182 or the
preamble of the final rule that a single
verification remains sufficient when
automated but portable cleaning skids
are used.
(Response) We do not believe that
initiation of the automated cleaning
cycle by a human operator constitutes
performance of the cleaning process for
purposes of revised § 211.182. The
revised regulation requires that after an
automated cleaning process (such as
CIP) is completed, the human operator
must date and sign or initial the log
verifying that the equipment performed
the automated cleaning process
properly. The regulation does not
require the operator to date and sign or
initial the log simply for the initiation
of the automated cleaning cycle. This
approach applies to both portable
equipment skids and fixed equipment.
(Comment 39) One comment stated
that in many instances, the human
verification of an action performed by
automated equipment can only be done
on the basis of outputs from the
equipment. As an example, the
comment stated, when equipment is
cleaned through CIP, the verification
should consist of confirming that the
system reports the cleaning as
successfully completed without alarms.
(Response) What constitutes adequate
verification that equipment has been
properly cleaned or maintained using
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automated equipment in accordance
with revised § 211.182 depends on the
particular circumstances. The outputs
from the automated equipment will
normally be key factors, but not
necessarily the only ones. The
manufacturer should determine the
reliability of the outputs and
periodically check them. For example, it
might be appropriate to verify that an
alarm is working properly and is
successfully monitoring the equipment’s
critical functions. There might be other
ways of verifying the adequate
performance of cleaning and
maintenance by automated equipment,
such as by monitoring the usage of
cleaning supplies in a cleaning cycle or
conducting an independent check of the
rinse.
(Comment 40) One comment stated
that for most medical gas systems,
routine or periodic cleaning is not
performed because the industry is
characterized by product-specific closed
systems that undergo an appropriate
cleaning process before initial use. The
comment stated that because of the high
number of batches produced on a
weekly/monthly basis in the medical
gas industry, it is more appropriate to
keep cleaning and maintenance records
separate from batch records. The
comment maintained that although
requiring documentation of equipment
cleaning, maintenance, and use in
individual equipment logs may be
appropriate for traditional
pharmaceuticals (where key processing
equipment may be used for multiple
products and lot numbers), applying
this requirement to medical gases would
make retrieval and management of
cleaning and maintenance records much
more difficult. The comment added that
use logs are not appropriate for medical
gases because batch record
documentation provides a consecutive
listing of products manufactured on
each system.
(Response) We decline to exempt
medical gases from certain requirements
of § 211.182 as recommended because
this would exceed the scope of our
proposed change to § 211.182, which
addressed human verification of
cleaning steps performed by automated
equipment. We might consider in a
future CGMP rulemaking whether it is
appropriate to exempt medical gases
from certain requirements of § 211.182.
7. Batch Production and Control
Records (§ 211.188(b)(11))
Section 211.188 concerns batch
production and control records.
Proposed 211.188(b)(11) specified that
when a significant step in the operation
is performed by automated equipment
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under § 211.68, the record would need
to identify the person checking the
significant step performed by the
automated equipment.
(Comment 41) One comment stated
that § 211.188(b)(11) should be changed
to state that a significant manufacturing
step could be either performed or
checked by automated equipment. The
comment stated that this approach is
permitted by CPG 425.500.
(Response) We decline to make this
suggested change. As stated in our
response to comment 28, CPG 425.500
does not, as the comment implies, state
that human oversight is unnecessary
when an automated system is involved
in the performance, supervision, or
checking of production steps. To revise
§ 211.188(b)(11) as recommended by the
comment might be interpreted as
permitting manufacturers to rely solely
on automated equipment to verify the
human performance of certain
production steps. As stated in our
response to comments 19 and 25, we
believe that human verification of
processing steps is still necessary.
F. Miscellaneous Minor Changes Based
on 1996 Proposal
We proposed to make miscellaneous
minor changes to CGMP regulations to
clarify certain manufacturing, quality
control, and documentation
requirements and to align the
regulations with industry practice.
1. Storage of Untested Components,
Drug Product Containers, and Closures
(§ 211.82(b))
The version of § 211.82(b) amended
by this final rule stated: ‘‘Components,
drug product containers, and closures
shall be stored under quarantine until
they have been tested or examined, as
appropriate, and released.’’ We
proposed to replace the phrase ‘‘as
appropriate’’ with the phrase
‘‘whichever is appropriate’’ to eliminate
any ambiguity in § 211.82(b) and to
emphasize that it is accepted industry
practice to conduct some testing or
examination before components, drug
product containers, or closures are
released from quarantine.
(Comment 42) One comment
requested that medical gas containerclosure assemblies returned from
customers and reused be exempted from
§ 211.82(b). The comment stated that
assembled cylinder/valve medical gas
combinations are reused and handled
differently than they would be at the
time of initial receipt. The comment
stated that returned assemblies are
individually inspected for all critical
quality issues immediately before
filling; those assemblies that do not
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meet the inspection criteria are moved
to a quarantine area. The comment
stated that this practice satisfies the
intention that components, containers,
and closures be inspected to ensure that
unacceptable assemblies are not used in
the manufacturing process.
(Response) Under revised § 211.82(b),
manufacturers of medical gases would
retain the ability to sequester and
inspect returned valve/cylinder
assemblies before refilling in accordance
with the industry practice described by
the comment. The practice described by
the comment is to have the assembled
valve/cylinders placed in a segregated
area (apparently not identified using the
word ‘‘quarantine’’), examined for
conformance to quality standards, and,
if the criteria are met, immediately
made available for refilling. This
practice would meet the requirement for
a quarantine status if goods in such
areas or under such a status are not
acceptable for use as-is unless and until
they are qualified to be suitable for use.
Therefore, we do not believe that the
practice as described violates revised
§ 211.82(b), and there is no need to
exempt medical gas manufacturers from
this requirement.
2. Cleaning of Component Container
Samples (§ 211.84(c)(1))
The version of § 211.84(c)(1) amended
by this final rule stated: ‘‘The containers
of components selected [for sampling]
shall be cleaned where necessary, by
appropriate means.’’ We proposed to
replace the phrase ‘‘where necessary, by
appropriate means’’ with the phrase
‘‘when necessary in a manner to prevent
introduction of contaminants into the
component.’’ This change was intended
to clarify that the act of cleaning is done
for a particular purpose—to prevent the
introduction of contaminants—and
must be done unless cleaning is not
necessary to prevent contamination.
(Comment 43) One comment
expressed concern that the proposed
change might be interpreted to require
validation of this prevention of
contamination during sampling. The
comment requested that we confirm that
our intent is to place the contamination
concern into the controls and
procedures for sampling and into the
training of staff who perform these
activities, rather than to require
validation of the absence of
contamination.
(Response) Revised § 211.84(c)(1)
does not require manufacturers to
conduct validation studies to prove that
the method of sampling prevents
contamination. When properly designed
and followed, the cleaning procedures,
training, and facility and equipment
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controls, along with supervisory and
quality unit oversight, should ensure
compliance with § 211.84(c)(1).
3. Editorial Changes (§§ 211.84(d)(3) and
211.160(b)(1))
We proposed minor editorial changes
to two regulations, §§ 211.84(d)(3) and
211.160(b)(1). The version of
§ 211.84(d)(3) amended by this final rule
stated: ‘‘Containers and closures shall be
tested for conformance with all
appropriate written procedures.’’ We
proposed to replace the word
‘‘conformance’’ with ‘‘conformity’’ and
the word ‘‘procedures’’ with
‘‘specifications.’’ The first sentence of
the version of § 211.160(b)(1) amended
by this final rule stated: ‘‘Determination
of conformance to appropriate written
specifications for the acceptance of each
lot within each shipment of
components, drug product containers,
closures, and labeling used in the
manufacture, processing, packing, or
holding of drug products.’’ We proposed
to replace the word ‘‘conformance’’ with
‘‘conformity’’ and the word
‘‘appropriate’’ with ‘‘applicable.’’ We
stated in the preamble to the direct final
rule that these revisions would provide
clarity without changing the meaning or
intent of these regulations. We received
no comments on these proposed
changes, and we have revised these
provisions as proposed.
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IV. Analysis of Impacts
FDA has examined the impacts of this
final rule under Executive Order 12866
and the Regulatory Flexibility Act (5
U.S.C. 601–612), and the Unfunded
Mandates Reform Act of 1995 (Public
Law 104–4). 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). The agency
believes that this final rule is not a
significant regulatory action as defined
by the Executive order, because the rule
either clarifies the agency’s
longstanding interpretation of, or
increases latitude for manufacturers in
complying with, existing CGMP
requirements.
The Regulatory Flexibility Act
requires agencies to analyze regulatory
options that would minimize any
significant impact of a rule on small
entities. Because this final rule does not
impose any new regulatory obligations,
the agency believes that the rule will not
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have a significant economic impact on
a substantial number of small entities.
Section 202(a) of the Unfunded
Mandates Reform Act of 1995 requires
that agencies prepare a written
statement, which includes an
assessment of anticipated costs and
benefits, before proposing ‘‘any rule that
includes any Federal mandate that may
result in the expenditure by State, local,
and tribal governments, in the aggregate,
or by the private sector, of $100,000,000
or more (adjusted annually for inflation)
in any one year.’’ The current threshold
after adjustment for inflation is $127
million, using the most current (2006)
Implicit Price Deflator for the Gross
Domestic Product. This rule does not
result in any 1-year expenditure that
would meet or exceed this amount.
The purpose of this final rule is to
update the codified language to reflect
current practice and to harmonize
requirements in the CGMP regulations
with requirements in other regulations
and with international CGMP standards.
It does not impose any additional
requirements; therefore, industry will
not incur incremental compliance costs
for these proposed changes.
V. Environmental Impact
FDA concludes that issuing these
clarifying amendments to the CGMP
regulations will not have a significant
impact on the human environment.
Therefore, an environmental impact
statement is not required.
VI. Federalism
FDA has analyzed this final rule in
accordance with the principles set forth
in Executive Order 13132. We have
determined that the 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. Accordingly, we
have concluded that the 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.
VII. Paperwork Reduction Act of 1995
This final rule contains collections of
information 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
PRA). The collections of information
(recordkeeping requirements) in part
211 have already been approved by
OMB under control number 0910–0139.
The final rule amends certain sections
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51931
of part 211 as well as § 210.3 (§ 210.3
does not contain information collection
requirements). As concluded in section
IV of this document, ‘‘Analysis of
Impacts,’’ the purpose of the final rule
is to update the regulations to reflect
current practice and to harmonize
requirements in the CGMP regulations
with requirements in other regulations
and with international CGMP standards.
The final rule does not impose any
additional requirements. Thus, because
the final rule does not substantively
revise the information collection
requirements in part 211 or add new
information collection requirements,
there is no need to conduct an analysis
under the PRA.
List of Subjects
21 CFR Part 210
Drugs, Packaging and containers.
21 CFR Part 211
Drugs, Labeling, Laboratories,
Packaging and containers, Prescription
drugs, Reporting and recordkeeping
requirements, Warehouses.
I Therefore, under the Federal Food,
Drug, and Cosmetic Act and under
authority delegated to the Commissioner
of Food and Drugs, 21 CFR parts 210
and 211 are amended as follows:
PART 210—CURRENT GOOD
MANUFACTURING PRACTICE IN
MANUFACTURING, PROCESSING,
PACKING, OR HOLDING OF DRUGS;
GENERAL
1. The authority citation for 21 CFR
part 210 continues to read as follows:
I
Authority: 21 U.S.C. 321, 351, 352, 355,
360b, 371, 374; 42 U.S.C. 216, 262, 263a, 264.
2. Section 210.3 is amended by
revising paragraph (b)(6) to read as
follows:
I
§ 210.3
Definitions.
(b) * * *
(6) Nonfiber releasing filter means any
filter, which after appropriate
pretreatment such as washing or
flushing, will not release fibers into the
component or drug product that is being
filtered.
*
*
*
*
*
PART 211—CURRENT GOOD
MANUFACTURING PRACTICE FOR
FINISHED PHARMACEUTICALS
3. The authority citation for 21 CFR
part 211 continues to read as follows:
I
Authority: 21 U.S.C. 321, 351, 352, 355,
360b, 371, 374; 42 U.S.C. 216, 262, 263a, 264.
4. Section 211.67 is amended by
revising paragraph (a) to read as follows:
I
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Federal Register / Vol. 73, No. 174 / Monday, September 8, 2008 / Rules and Regulations
§ 211.67 Equipment cleaning and
maintenance.
(a) Equipment and utensils shall be
cleaned, maintained, and, as
appropriate for the nature of the drug,
sanitized and/or sterilized at
appropriate intervals to prevent
malfunctions or contamination that
would alter the safety, identity, strength,
quality, or purity of the drug product
beyond the official or other established
requirements.
*
*
*
*
*
I 5. Section 211.68 is amended by
adding paragraph (c) to read as follows:
§ 211.68 Automatic, mechanical, and
electronic equipment.
*
*
*
*
*
(c) Such automated equipment used
for performance of operations addressed
by §§ 211.101(c) or (d), 211.103,
211.182, or 211.188(b)(11) can satisfy
the requirements included in those
sections relating to the performance of
an operation by one person and
checking by another person if such
equipment is used in conformity with
this section, and one person checks that
the equipment properly performed the
operation.
I 6. Section 211.72 is revised to read as
follows:
§ 211.72
Filters.
Filters for liquid filtration used in the
manufacture, processing, or packing of
injectable drug products intended for
human use shall not release fibers into
such products. Fiber-releasing filters
may be used when it is not possible to
manufacture such products without the
use of these filters. If use of a fiberreleasing filter is necessary, an
additional nonfiber-releasing filter
having a maximum nominal pore size
rating of 0.2 micron (0.45 micron if the
manufacturing conditions so dictate)
shall subsequently be used to reduce the
content of particles in the injectable
drug product. The use of an asbestoscontaining filter is prohibited.
I 7. Section 211.82 is amended by
revising paragraph (b) to read as follows:
§ 211.82 Receipt and storage of untested
components, drug product containers, and
closures.
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*
*
*
*
*
(b) Components, drug product
containers, and closures shall be stored
under quarantine until they have been
tested or examined, whichever is
appropriate, and released. Storage
within the area shall conform to the
requirements of § 211.80.
I 8. Section 211.84 is amended by
revising paragraphs (c)(1), (d)(3), and
(d)(6) to read as follows:
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17:07 Sep 05, 2008
Jkt 214001
§ 211.84 Testing and approval or rejection
of components, drug product containers,
and closures.
*
*
*
*
*
(c) * * *
(1) The containers of components
selected shall be cleaned when
necessary in a manner to prevent
introduction of contaminants into the
component.
*
*
*
*
*
(d) * * *
(3) Containers and closures shall be
tested for conformity with all
appropriate written specifications. In
lieu of such testing by the manufacturer,
a certificate of testing may be accepted
from the supplier, provided that at least
a visual identification is conducted on
such containers/closures by the
manufacturer and provided that the
manufacturer establishes the reliability
of the supplier’s test results through
appropriate validation of the supplier’s
test results at appropriate intervals.
*
*
*
*
*
(6) Each lot of a component, drug
product container, or closure with
potential for microbiological
contamination that is objectionable in
view of its intended use shall be
subjected to microbiological tests before
use.
*
*
*
*
*
I 9. Section 211.94 is amended by
revising paragraph (c) as follows:
§ 211.94 Drug product containers and
closures.
*
*
*
*
*
(c) Drug product containers and
closures shall be clean and, where
indicated by the nature of the drug,
sterilized and processed to remove
pyrogenic properties to assure that they
are suitable for their intended use. Such
depyrogenation processes shall be
validated.
*
*
*
*
*
I 10. Section 211.101 is amended by
revising paragraphs (c) and (d) to read
as follows:
§ 211.101
Charge-in of components.
*
*
*
*
*
(c) Weighing, measuring, or
subdividing operations for components
shall be adequately supervised. Each
container of component dispensed to
manufacturing shall be examined by a
second person to assure that:
(1) The component was released by
the quality control unit;
(2) The weight or measure is correct
as stated in the batch production
records;
(3) The containers are properly
identified. If the weighing, measuring,
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Fmt 4700
Sfmt 4700
or subdividing operations are performed
by automated equipment under
§ 211.68, only one person is needed to
assure paragraphs (c)(1), (c)(2), and
(c)(3) of this section.
(d) Each component shall either be
added to the batch by one person and
verified by a second person or, if the
components are added by automated
equipment under § 211.68, only verified
by one person.
I 11. Section 211.103 is revised to read
as follows:
§ 211.103
Calculation of yield.
Actual yields and percentages of
theoretical yield shall be determined at
the conclusion of each appropriate
phase of manufacturing, processing,
packaging, or holding of the drug
product. Such calculations shall either
be performed by one person and
independently verified by a second
person, or, if the yield is calculated by
automated equipment under § 211.68,
be independently verified by one
person.
I 12. Section 211.110 is amended by
revising paragraph (a) introductory text
and by adding paragraph (a)(6) to read
as follows:
§ 211.110 Sampling and testing of inprocess materials and drug products.
(a) To assure batch uniformity and
integrity of drug products, written
procedures shall be established and
followed that describe the in-process
controls, and tests, or examinations to
be conducted on appropriate samples of
in-process materials of each batch. Such
control procedures shall be established
to monitor the output and to validate
the performance of those manufacturing
processes that may be responsible for
causing variability in the characteristics
of in-process material and the drug
product. Such control procedures shall
include, but are not limited to, the
following, where appropriate:
*
*
*
*
*
(6) Bioburden testing.
*
*
*
*
*
I 13. Section 211.113 is amended by
revising paragraph (b) to read as follows:
§ 211.113 Control of microbiological
contamination.
*
*
*
*
*
(b) Appropriate written procedures,
designed to prevent microbiological
contamination of drug products
purporting to be sterile, shall be
established and followed. Such
procedures shall include validation of
all aseptic and sterilization processes.
I 14. Section 211.160 is amended by
revising paragraph (b)(1) to read as
follows:
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08SER1
Federal Register / Vol. 73, No. 174 / Monday, September 8, 2008 / Rules and Regulations
§ 211.160
General requirements.
*
*
*
*
*
(b) * * *
(1) Determination of conformity to
applicable written specifications for the
acceptance of each lot within each
shipment of components, drug product
containers, closures, and labeling used
in the manufacture, processing, packing,
or holding of drug products. The
specifications shall include a
description of the sampling and testing
procedures used. Samples shall be
representative and adequately
identified. Such procedures shall also
require appropriate retesting of any
component, drug product container, or
closure that is subject to deterioration.
*
*
*
*
*
I 15. Section 211.182 is revised to read
as follows:
§ 211.182
Equipment cleaning and use log.
A written record of major equipment
cleaning, maintenance (except routine
maintenance such as lubrication and
adjustments), and use shall be included
in individual equipment logs that show
the date, time, product, and lot number
of each batch processed. If equipment is
dedicated to manufacture of one
product, then individual equipment logs
are not required, provided that lots or
batches of such product follow in
numerical order and are manufactured
in numerical sequence. In cases where
dedicated equipment is employed, the
records of cleaning, maintenance, and
use shall be part of the batch record.
The persons performing and doublechecking the cleaning and maintenance
(or, if the cleaning and maintenance is
performed using automated equipment
under § 211.68, just the person verifying
the cleaning and maintenance done by
the automated equipment) shall date
and sign or initial the log indicating that
the work was performed. Entries in the
log shall be in chronological order.
I 16. Section 211.188 is amended by
revising paragraph (b)(11) to read as
follows:
§ 211.188
records.
Batch production and control
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*
*
*
*
*
(b) * * *
(11) Identification of the persons
performing and directly supervising or
checking each significant step in the
operation, or if a significant step in the
operation is performed by automated
equipment under § 211.68, the
identification of the person checking the
significant step performed by the
automated equipment.
*
*
*
*
*
VerDate Aug<31>2005
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Jkt 214001
Dated: August 22, 2008.
Jeffrey Shuren,
Associate Commissioner for Policy and
Planning.
[FR Doc. E8–20709 Filed 9–5–08; 8:45 am]
51933
Office of Foreign Assets Control
appears at the end of this document.
Comments received will be made
available to the public via
regulations.gov or upon request, without
change and including any personal
information provided.
FOR FURTHER INFORMATION CONTACT:
Elton Ellison, Assistant Director, Civil
Penalties, (202) 622–6140 (not a toll-free
call).
SUPPLEMENTARY INFORMATION:
31 CFR Part 501
Electronic Availability
BILLING CODE 4160–01–S
DEPARTMENT OF THE TREASURY
Economic Sanctions Enforcement
Guidelines
Office of Foreign Assets
Control, Treasury.
ACTION: Interim final rule with request
for comments.
AGENCY:
The Office of Foreign Assets
Control (OFAC) of the U.S. Department
of the Treasury is issuing this interim
final rule, ‘‘Economic Sanctions
Enforcement Guidelines,’’ as
enforcement guidance for persons
subject to the requirements of U.S.
sanctions statutes, Executive orders and
regulations. This interim final rule
supersedes the Economic Sanctions
Enforcement Guidelines set forth in
OFAC’s proposed rule of January 29,
2003 1 (with the exception of the
proposed Appendix to the Cuban Assets
Control Regulations, 31 CFR Part 515,
set forth therein) and the Economic
Sanctions Enforcement Procedures for
Banking Institutions set forth in OFAC’s
interim final rule of January 12, 2006.2
These Enforcement Guidelines are
published as an appendix to the
Reporting, Procedures and Penalties
Regulations, 31 CFR Part 501.
DATES: The interim final rule is effective
September 8, 2008. Written comments
may be submitted on or before
November 7, 2008.
ADDRESSES: You may submit comments
by any of the following methods:
Federal eRulemaking Portal: https://
www.regulations.gov.
Follow the instructions for submitting
comments.
Fax: Attn: Request for Comments
(Enforcement Guidelines) (202) 622–
1657.
Mail: Attn: Request for Comments
(Enforcement Guidelines), Office of
Foreign Assets Control, Department of
the Treasury, 1500 Pennsylvania
Avenue, NW., Washington, DC 20220.
Instructions: All submissions received
must include the agency name and the
Federal Register Doc. number that
SUMMARY:
1 68
2 71
PO 00000
FR 4422–4429 (January 29, 2003).
FR 1971–1976 (January 12, 2006).
Frm 00035
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This document and additional
information concerning OFAC are
available from OFAC’s Web site
(https://www.treas.gov/ofac) or via
facsimile through a 24-hour fax-ondemand service, tel.: (202) 622–0077.
Procedural Requirements
Because this interim final rule
imposes no obligations on any person,
but only explains OFAC’s enforcement
policy and procedures based on existing
substantive rules, prior notice and
public comment are not required
pursuant to 5 U.S.C. 553(b)(A). Because
no notice of proposed rulemaking is
required, the provisions of the
Regulatory Flexibility Act (5 U.S.C.
chapter 6) do not apply. This interim
final rule is not a significant regulatory
action for purposes of Executive Order
12866.
Although a prior notice of proposed
rulemaking is not required, as discussed
in more detail below, OFAC is soliciting
comments on this interim final rule in
order to consider how it might make
improvements to these Guidelines.
Comments must be submitted in
writing. The addresses and deadline for
submitting comments appear near the
beginning of this notice. OFAC will not
accept comments accompanied by a
request that all or part of the submission
be treated confidentially because of its
business proprietary nature or for any
other reason. All comments received by
the deadline will be a matter of public
record and will be made available to the
public via regulations.gov.
The collections of information related
to the Reporting, Procedures and
Penalties Regulations have been
previously approved by the Office of
Management and Budget (OMB) under
control number 1505–0164. A small
adjustment to that collection has been
submitted to OMB in order to take into
account the voluntary self-disclosure
process set forth in these Guidelines. An
agency may not conduct or sponsor, and
a person is not required to respond to,
a collection of information unless it
displays a valid control number
assigned by OMB. This collection of
E:\FR\FM\08SER1.SGM
08SER1
Agencies
[Federal Register Volume 73, Number 174 (Monday, September 8, 2008)]
[Rules and Regulations]
[Pages 51919-51933]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: E8-20709]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 210 and 211
[Docket No. FDA-2007-N-0379] (formerly Docket No. 2007N-0280)
Amendments to the Current Good Manufacturing Practice Regulations
for Finished Pharmaceuticals
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is amending certain of
its regulations on current good manufacturing practice (CGMP)
requirements for finished pharmaceuticals as the culmination of the
first phase of an incremental approach to modifying the CGMP
regulations for these products. This rule revises CGMP requirements
primarily concerning aseptic processing, verification of performance of
operations by a second individual, and the use of asbestos filters. We
are amending the regulations to modernize or clarify some of the
requirements as well as to harmonize them with other FDA regulations
and international CGMP standards.
DATES: This rule is effective December 8, 2008.
FOR FURTHER INFORMATION CONTACT: Mary Malarkey, Center for Biologics
Evaluation and Research (HFM-600), Food and Drug Administration, 1401
Rockville Pike, Rockville, MD 20852-1448, 301-827-6190; or
Dennis Bensley, Center for Veterinary Medicine (HFV-140), Food and
Drug Administration, 7500 Standish Pl., Rockville, MD 20855, 240-276-
8268; or
Brian Hasselbalch, Center for Drug Evaluation and Research, Food
and Drug Administration, 10903 New Hampshire Ave., rm. 4364, Silver
Spring, MD 20993, 301-796-3279.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Background
II. Summary of the Final Rule
A. Aseptic Processing
B. Asbestos Filters
C. Verification by a Second Individual
D. Other Minor Changes
III. Comments on the Proposed Rule and FDA's Response
A. General Comments
B. Plumbing
C. Aseptic Processing
D. Asbestos Filters
[[Page 51920]]
E. Verification by a Second Individual
F. Miscellaneous Minor Changes Based on 1996 Proposal
IV. Analysis of Impacts
V. Environmental Impact
VI. Federalism
VII. Paperwork Reduction Act of 1995
I. Background
Since the development of the CGMP regulations for drug products in
1962, FDA has balanced the need for easily understood minimum standards
with the need to encourage innovation and the development of improved
manufacturing technologies. We strive to give manufacturers latitude to
determine how to achieve the level of control necessary for CGMP
compliance, recognizing that, in some instances, more direction from
FDA is necessary to provide a uniform standard to the entire industry,
minimize the potential for harm, or achieve some other CGMP objective.
We periodically reassess and revise the CGMP regulations to accommodate
advances in technology and other scientific knowledge that further
safeguard the drug manufacturing process and the public health.
In 1996, as part of this reassessment process, we proposed to: (1)
Amend certain requirements of the CGMP regulations for finished
pharmaceuticals to clarify certain manufacturing, quality control, and
documentation requirements and (2) ensure that the regulations more
accurately encompassed current industry practice (61 FR 20104, May 3,
1996) (1996 proposed rule). Subsequently, as a part of the risk-based
Pharmaceutical CGMPs for the 21st Century initiative, we created a CGMP
Harmonization Analysis Working Group (CGMP Working Group) to analyze
related CGMP requirements in effect in the United States and
internationally, including those related to quality systems. The CGMP
Working Group compared parts 210 and 211 (21 CFR parts 210 and 211)
with the CGMPs of the European Union (EU), as well as other FDA
regulations (e.g., the Quality Systems Regulation, 21 CFR part 820) to
identify the differences and consider the value of supplementing or
changing the current regulations. Based on the CGMP Working Group's
analysis, we decided to take an incremental approach to modifying parts
210 and 211.
Because of this change in approach, we decided not to finalize the
1996 proposed rule. On December 4, 2007, we published a document
withdrawing the 1996 proposed rule (72 FR 68111) (the December 2007
proposed rule). On the same date, we published a direct final rule (72
FR 68064) and companion proposed rule (72 FR 68113) to clarify and
modernize certain provisions of the CGMP regulations. The comment
period for the direct final rule closed on February 19, 2008. On April
4, 2008, we published a document withdrawing the direct final rule
because we received significant adverse comments (73 FR 18440). In the
document withdrawing the direct final rule, we explained that the
comments received would be considered under our usual procedures for
notice and comment in connection with the notice of proposed rulemaking
that was published as a companion to the direct final rule.
After careful consideration of all comments received, we are now
publishing this final rule. The final rule represents the culmination
of the first increment of modifications to parts 210 and 211.
II. Summary of the Final Rule
The final rule revises the drug CGMP regulations primarily in three
areas: Aseptic processing, use of asbestos filters, and verification of
operations by a second individual.
A. Aseptic Processing
The final rule revises Sec. 211.113(b) to clarify that required
written procedures designed to prevent microbiological contamination of
sterile drug products must include procedures on the validation of all
aseptic processes in addition to sterilization processes. Other changes
related to aseptic processing include the following:
Revised Sec. 211.67(a) requires that equipment and
utensils be cleaned, maintained, and, as appropriate for the nature of
the drug, sanitized ``and/or sterilized'' at appropriate intervals to
prevent malfunction or contamination. This change recognizes that for
sterile drug products, sterilization (sometimes in addition to
sanitization) is appropriate.
Revised Sec. 211.84(d)(6) requires microbiological tests
before use of each lot of a component, drug product container, or
closure ``with potential for microbiological contamination'' that is
objectionable in view of its intended use, consistent with longstanding
agency interpretation of this regulation.
Revised Sec. 211.94(c) requires validation of
depyrogenation processes for drug product containers and closures,
consistent with longstanding industry practice and agency
interpretation of this regulation.
Revised Sec. 211.110(a) adds bioburden testing to the
list (which is not all-inclusive) of in-process control procedures
relating to the sampling and testing of in-process materials, which
again is consistent with industry practice.
B. Asbestos Filters
We revised Sec. Sec. 210.3(b)(6) and 211.72 to eliminate
provisions permitting limited use of asbestos-containing filters used
in processing injectable drug products. We had proposed to simply
delete references to asbestos filters in these provisions. However, in
response to comments, we also added to Sec. 211.72 the statement ``The
use of an asbestos-containing filter is prohibited.'' Also in response
to comments, we revised Sec. 211.72 to reflect appropriate technical
standards for nonfiber-releasing filters.
C. Verification by a Second Individual
The final rule makes several changes to the regulations to
acknowledge, consistent with our longstanding interpretation, that
certain operations may be performed by automated equipment and verified
by a person, rather than one person performing an operation and another
person verifying that the operation was correctly performed. In
particular, we added new paragraph (c) to Sec. 211.68 stating that
automated equipment used to perform operations addressed in Sec. Sec.
211.101(c) or (d), 211.103, 211.182, or 211.188(b)(11) can satisfy the
requirements in those sections for the performance of an operation by
one person and checking by another person if the equipment is used in
conformity with Sec. 211.68 and one person checks that the operations
are properly performed. In response to comments, we revised the
paragraph to minimize the possibility that the provision might be
misinterpreted as requiring a person to repeat by hand all calculations
performed by automated equipment.
In accordance with the addition of Sec. 211.68(c), we are adopting
corresponding changes to the following provisions:
Section 211.101(c) and (d) (concerning charge-in of
components and containers),
Section 211.103 (calculation of yields),
Section 211.182 (equipment cleaning and maintenance), and
Section 211.188(b)(11) (batch production and control
records).
D. Other Minor Changes
In addition to the revisions to the regulations previously noted,
we have made minor revisions to the following provisions to provide
greater clarity without changing meaning or intent:
Section 211.82(b) (storage of components, containers, and
closures),
[[Page 51921]]
Section 211.84(c)(1) and (d)(3) (collection and testing of
samples of components, containers, and closures), and
Section 211.160(b)(1) (laboratory controls for determining
conformity to specifications).
III. Comments on the Proposed Rule and FDA's Response
We received comments on the proposed rule from drug and biologic
manufacturers, industry associations, consultants, and other interested
persons. A summary of the comments received and our responses follow.
We first respond to comments of a general nature and then to comments
on the five topics set forth in the preamble of the direct final rule.
To make it easier to identify comments and our responses, the word
``Comment,'' in parentheses, appears before the comment's description,
and the word ``Response,'' in parentheses, appears before our response.
We have numbered each comment to help distinguish between different
comments. Similar comments are grouped together under the same number
if the same response would be given for each. The number assigned to
each comment is purely for organizational purposes and does not signify
the comment's value or importance or the order in which it was
received.
A. General Comments
(Comment 1) One comment stated that it will be very important for
FDA to ensure clarity and consistency in the understanding of the final
rule among agency staff, including both product reviewers and CGMP
inspectors, to minimize different interpretations and applications of
these regulations.
(Response) We agree that it is important that FDA employees who
perform application reviews, as well as conduct CGMP inspections and
other compliance activities, understand these regulations and apply
them in a consistent manner in the performance of their duties.
Therefore, we will take appropriate steps to ensure that agency staff
receive adequate training regarding the new regulations.
(Comment 2) One comment stated that we should not withdraw the 1996
proposed rule because it contained many good features with respect to
test method validation and the out-of-specification test result
problem. The comment maintained that the guidance for industry entitled
``Investigating Out-of-Specification (OOS) Test Results for
Pharmaceutical Production'' (71 FR 60158, October 12, 2006) is not
helpful to people working with biological drugs and other products.
Another comment stated that the December 2007 proposed rule should have
incorporated many of the changes in the 1996 proposed rule regarding
such matters as validation, quality control unit responsibilities,
batch failure investigations, and stability samples because they
involve some of the most common CGMP deficiencies.
(Response) As we stated in the December 4, 2007, document, we
withdrew the 1996 proposed rule because we concluded that, given our
new approach to CGMP under the 21st century initiative, it would be
preferable to revise the CGMP regulations incrementally rather than in
a one-time, comprehensive fashion. Furthermore, we believe that it is
appropriate to reevaluate some of the matters considered in the 1996
proposed rule in light of recent scientific and technological advances.
We appreciate the comments' interest in the specified CGMP issues, and
we will consider these issues in future phases of our CGMP
modernization efforts.
(Comment 3) One comment encouraged FDA to consider other CGMP
regulations that need modernization or clarification, or are no longer
necessary due to technological advances, such as aspects of 21 CFR
610.12 concerning the requirements for bulk sterility testing and
allowance for sterility retesting for biological products.
(Response) We appreciate the comment's interest in modernizing CGMP
regulations. As previously stated, this final rule represents only our
first step in updating the drug CGMP regulations to reflect current
industry practice and harmonize the regulations with international CGMP
requirements. We will consider other aspects of CGMP in future
rulemaking proceedings.
B. Plumbing
Section 211.48(a) requires that potable water be supplied under
continuous positive pressure in a plumbing system free of defects that
could contribute contamination to any drug product. It further requires
that potable water meet the standards established by the U.S.
Environmental Protection Agency (EPA) for primary drinking water in 40
CFR part 141. Proposed Sec. 211.48(a) would have deleted the
requirement that the potable water used in a plumbing system meet EPA's
standards for primary drinking water, and instead required that the
water be ``safe for human consumption.'' This proposed revision was
intended to improve harmonization with foreign regulations
(particularly those of the EU and Japan) and to make the U.S.
regulation more consistent with the United States Pharmacopeia
standard. In the preamble of the direct final rule, we stated that the
revised requirement could be met by compliance with the standards in
the EPA regulations or in the current regulations of the EU or Japan
for potable water used to prepare water for pharmaceutical purposes.
(Comment 4) Four comments objected to the proposed change. Among
other things, the comments stated that the standard of ``safe for human
consumption'' is not sufficiently prescriptive.
(Response) Because of the comments received and other
considerations, we have decided not to revise Sec. 211.48(a) at this
time. We will address the issue of standards for water used in a
facility's plumbing system when we consider proposing regulations for
water used as a drug product component in the next phase of our CGMP
initiative.
C. Aseptic Processing
In the proposed rule, we sought to amend several regulations on
aseptic processing to reflect current industry standards and practices.
Some of the proposed revisions would also affect other types of
processes and operations. We noted that the proposed changes would not
affect the applicability of the guidance for industry entitled
``Sterile Drug Products Produced by Aseptic Processing--Current Good
Manufacturing Practice'' (Aseptic Processing Guidance), issued on
October 4, 2004 (69 FR 59258).
1. Equipment Cleaning and Maintenance (Sec. 211.67(a))
The version of Sec. 211.67(a) amended by this final rule stated:
``Equipment and utensils shall be cleaned, maintained, and sanitized at
appropriate intervals to prevent malfunctions or contamination that
would alter the safety, identity, strength, quality, or purity of the
drug product beyond the official or other established requirements.''
We proposed to add the phrase ``and/or sterilized'' after the word
``sanitized'' in Sec. 211.67(a) to reflect the fact that sterilization
is appropriate for sterile drug products.
On our own initiative, we have revised Sec. 211.67(a) to state
that equipment and utensils shall be cleaned, maintained, ``and, as
appropriate for the nature of the drug, sanitized and/or sterilized at
appropriate intervals * * *.'' This revision does not alter the meaning
of the proposed rule change, but clarifies that for some equipment and
utensils
[[Page 51922]]
used in the production of certain drug products, sanitization is
appropriate; for other equipment and utensils, sterilization is
appropriate; and for still others, both sanitization and sterilization
are appropriate.
(Comment 5) One comment stated that it is not appropriate to
address sterilization in Sec. 211.67(a). Instead, the comment
recommended that a reference to sterilization of equipment and utensils
be added to Sec. 211.113(b), which requires the adoption of written
procedures designed to prevent microbiological contamination of drug
products purporting to be sterile.
(Response) We do not agree with the comment because, as previously
noted, equipment and utensils used in the production of sterile drug
products must be sterilized, not merely sanitized. In addition, we have
revised Sec. 211.113(b) as discussed in section III.C.5 of this final
rule.
(Comment 6) One comment suggested that we could simplify the
language in this regulation by changing the phrase ``beyond the
official or other established requirements'' to ``beyond the
established (or other official) requirements.''
(Response) We do not believe that the suggested change simplifies
the current phrase, which we believe is clear. Therefore, we do not
believe that the suggested change is necessary.
(Comment 7) One comment stated that Sec. 211.67(a) should not
apply to the production of medical gases because most medical gas
manufacturing lines are product-specific, closed systems that are not
subject to cleaning or sanitation as part of an established periodic
cycle, but instead are specially cleaned to be ``oxygen ready'' and
carefully handled in accordance with established procedures. The
comment maintained that additional cleaning efforts beyond the initial
cleaning regimen substantially increase the risk of introducing
contaminants into the system. Therefore, the comment stated, it is not
necessary to require cleaning of equipment at ``appropriate intervals''
for medical gas manufacturing. The comment suggested that,
alternatively, it might be appropriate for the agency to state that
medical gases may represent unique circumstances that will be reflected
in a separate guidance.
(Response) We decline to exempt medical gases from the requirements
of Sec. 211.67(a) as recommended because this would exceed the scope
of our proposed change to clarify that sterilization is appropriate for
sterile drug products and would instead focus on whether there is any
need for periodic cleaning of medical gas systems. We might consider in
a future CGMP rulemaking whether it is appropriate to revise Sec.
211.67(a) to address its application to medical gases.
2. Microbiological Testing of Objectionable Lots of Components, Drug
Product Containers, and Closures (Sec. 211.84(d)(6))
The version of Sec. 211.84(d)(6) amended by this final rule
stated: ``Each lot of a component, drug product container, or closure
that is liable to microbiological contamination that is objectionable
in view of its intended use shall be subjected to microbiological tests
before use.'' We proposed to change the phrase ``that is liable to
microbiological contamination'' to ``with potential for microbiological
contamination.''
(Comment 8) One comment stated that the proposed change was
unnecessarily restrictive and might lead to testing every lot when the
risk of microbial contamination is low and the impact on the intended
use is insignificant. This comment suggested replacing ``that is liable
to microbial contamination'' with ``prone to microbial contamination.''
One comment stated that the proposed change could make it more
difficult for drug manufacturers to replace a less effective, quality
control-based inspection and test method with a more modern and
effective quality audit method. The comment stated that because the
bioburden of dry items such as vials and stoppers is often
heterogeneous, improved assurance of this quality attribute is better
achieved through the audit, selection, and control by the manufacturers
of these items. This comment maintained that knowledge of and control
over the manufacturing processes for containers and closures might fall
short of justifying that those products do not have a ``potential for
contamination.''
(Response) We decline to adopt the recommended change to Sec.
211.84(d)(6) from ``that is liable to microbial contamination'' to
``prone to microbiological contamination.'' We believe that our
proposed change to ``with potential for microbiological contamination''
clarifies our longstanding interpretation of the regulation that each
lot of component, drug product container, or closure that is
susceptible to contamination must undergo microbiological testing
before use. Therefore, we have revised Sec. 211.84(d)(6) to refer to
components, containers, or closures ``with potential for
microbiological contamination'' as proposed.
3. Validation of Depyrogenation of Drug Product Containers and Closures
(Sec. 211.94(c))
The version of Sec. 211.94(c) amended by this final rule stated:
``Drug product containers and closures shall be clean and, where
indicated by the nature of the drug, sterilized and processed to remove
pyrogenic properties to assure that they are suitable for their
intended use.'' In the preamble to the direct final rule, we stated
that it has been longstanding industry practice to validate the
sterilization and depyrogenation processes used for drug product
containers and closures to ensure consistent removal of microbial
contamination and pyrogens or endotoxins. Therefore, we proposed to add
a provision to Sec. 211.94(c) requiring the validation of these
depyrogenation processes.
(Comment 9) One comment suggested that we require validation of
``sterilization'' as well as depyrogenation processes.
(Response) We do not believe that the suggested change is needed
because Sec. 211.113(b) already requires validation of sterilization
processes for the prevention of microbiological contamination of drug
products purporting to be sterile.
(Comment 10) Four comments objected to the requirement in existing
Sec. 211.94(c) because it requires depyrogenation of components based
on the nature of the drug and does not take into account the fact that
some containers and closures are inherently nonpyrogenic, have been
qualified not to require active depyrogenation, or do not require
depyrogenation because of handling procedures. Three of the comments
proposed that in addition to the nature of the drug, the drug's
manufacturing process be included as a factor in determining when
containers and closures must be sterilized and processed to remove
pyrogenic properties. Two of the comments recommended that the
requirement to validate depyrogenation processes be limited to
containers and closures that are made nonpyrogenic by a designated
depyrogenation process (thus excluding inherently nonpyrogenic
containers and closures from the regulation).
(Response) We decline to adopt the suggested revisions because they
go beyond the scope of our proposed change to require validation of
depyrogenation processes and instead focus on the need for
depyrogenation itself.
[[Page 51923]]
4. Inclusion of Bioburden Testing in In-Process Testing (Sec.
211.110(a))
Section 211.110(a) requires that written procedures be established
and followed that describe in-process controls and tests or
examinations to be conducted on samples of in-process materials of each
batch of a drug product. The regulation specifies five control
procedures that must be established, where appropriate, to monitor the
output and to validate the performance of manufacturing processes that
may be responsible for causing variation in the characteristics of in-
process material and the drug product. We proposed to add bioburden
testing to this list (which is not all-inclusive) because testing for
bioburden is standard industry practice for in-process materials and
drug products that are produced by aseptic processing.
(Comment 11) Three comments objected to the addition of bioburden
testing to Sec. 211.110(a). One comment objected to the inclusion of
any specific test and suggested that specific tests be addressed in
agency guidance. One comment stated that bioburden testing is not
conducted at the same time as other tests specified in Sec. 211.110(a)
and is not an in-process test or control because it does not yield
immediate results that allow for process adjustment. The comment stated
that it would be more appropriate to address bioburden testing in Sec.
211.84. One comment suggested that because Sec. 211.110 covers the
sampling and testing of all in-process materials and drug products,
adding bioburden testing as a mandatory control procedure could expand
current industry validation procedure and produce diversity among the
industry and regulators on the circumstances in which validation of
bioburden testing is appropriate.
(Response) We do not agree with the comments. As stated in the
direct final rule, testing for bioburden is an important in-process
control, particularly for drug products that are produced through
aseptic processing. Section 211.110(a) provides flexibility to
manufacturers so that they need only conduct bioburden testing where
the testing is appropriate to assure batch uniformity and drug product
integrity. We believe that manufacturers understand for which types of
drug products, and at what point in the manufacturing process for these
drugs, bioburden testing is appropriate. Accordingly, we have added
bioburden testing to Sec. 211.110(a).
5. Control of Microbiological Contamination (Sec. 211.113(b))
Section 211.113(b) states that appropriate written procedures,
designed to prevent microbiological contamination of drug products
purporting to be sterile, must be established and followed. The version
of Sec. 211.113(b) amended by this final rule further stated: ``Such
procedures shall include validation of any sterilization process.'' We
proposed to substitute ``all aseptic and sterilization processes'' for
``any sterilization process.'' As noted in the preamble of the direct
final rule, even before we issued the now-replaced guidance on
``Sterile Drug Products Produced by Aseptic Processing'' in 1987,
industry routinely conducted validation studies (often referred to as
media fills) that substituted microbiological media for the actual
product to demonstrate that its aseptic processes were validated (72 FR
68064 at 68066). The proposed change was intended to clarify existing
practice and to harmonize Sec. 211.113 with Annex 1 of the EU CGMPs.
(Comment 12) Several comments objected to the proposed change to
Sec. 211.113(b) on the basis that aseptic processing cannot be
validated. One comment stated that validation of aseptic processing
technically cannot be done, although the manufacturer can ensure tight
control over the process. One comment stated that aseptic processing
simulations demonstrate the capability of a facility, equipment, and
operational controls to provide a minimal microbial contamination rate
in a single event, but they cannot predict the outcome of a similar
process performed at a different time. The comment maintained that to
consider aseptic processing to be validated overstates the ability to
measure and control the process and could be interpreted as approval to
relax the controls necessary for its success. The comment recommended
that Sec. 211.113(b) be revised to require validation of ``all
sterilization/depyrogenation processes'' and to direct that aseptic
processes ``be subjected to periodic assessment to demonstrate the
capability of the control strategy to adequately support end product
sterility.''
One comment stated that there is currently no means to comply with
the proposed requirement to validate aseptic processes. The comment
maintained that the microbiological and decontamination methods used in
aseptic processing lack the sensitivity, recoverability, and accuracy
of the physical and chemical measurement systems normally associated
with process validation. The comment further claimed that media fills
do not validate aseptic processing because they measure only detectable
micro-organisms and do not verify that no micro-organisms exist. The
comment stated that although aseptic processing cannot be validated, a
state of control can be established, ensuring that the aseptically
produced drug consistently meets its specifications and quality
attributes. The comment recommended that rather than validation of
aseptic processes, Sec. 211.113(b) require ``a formalized quality risk
management and control strategy for aseptic processes to provide
assurance of requisite and continued process capability and product
quality.''
One comment stated that although media fills can evaluate an
aseptic process, they cannot be considered to validate the process. The
comment recommended that we either not adopt the proposed requirement
to validate aseptic processes or provide more clarity on what is
expected for validation of aseptic processes. Similarly, another
comment recommended that we not revise Sec. 211.113(b) as proposed
unless we clarify that more than media fills are required to validate
an aseptic process. The comment stated that a well-controlled, robust
process is required for aseptic processes and that once a state of
control has been established for the process, media fills can be useful
in confirming the state of control.
(Response) Although we acknowledge that aseptic process validation
does not provide absolute assurance of product sterility, we do not
agree that aseptic processes cannot be validated. Validation of aseptic
processes, which is a common practice throughout the pharmaceutical
industry, means establishing documented evidence that provides a high
degree of assurance that a particular process will consistently produce
a product meeting its predetermined specifications and quality
attributes. Media fills, together with operational controls,
environmental controls, and product sterility testing, provide a
sufficient level of assurance that drugs purported to be sterile are in
fact sterile.
(Comment 13) One comment suggested adding a definition of aseptic
processing to part 210.
(Response) We do not believe that it is necessary to define aseptic
processing in the regulation. The Aseptic Processing Guidance makes it
clear to manufacturers what aseptic processing entails.
[[Page 51924]]
(Comment 14) One comment requested confirmation that it is
acceptable to follow the current FDA guidance and use media fills to
meet the requirement to validate aseptic processes.
(Response) As stated in the preamble to the direct final rule and
reiterated previously in this document, manufacturers can follow the
recommendations in the Aseptic Processing Guidance to comply with CGMP
requirements for aseptic processing, including validation. However, as
with any guidance, the Aseptic Processing Guidance is not binding on
industry or the agency, and manufacturers may use an alternative
approach to achieve compliance if the approach meets the requirements
of the act and FDA regulations.
(Comment 15) One comment sought clarification that the requirement
to validate aseptic processing would not inhibit implementation of
novel technologies recommended by the International Conference on
Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH) in the ICH Q8, Q9, and Q10
guidances, or other innovative approaches in these areas.
(Response) We do not believe that the requirement to validate
aseptic processing will interfere with the implementation of new
technologies either as part of following ICH recommendations or as part
of other efforts to meet CGMP requirements. As stated in section I of
this document, we have always attempted to balance the need for easily
understood minimum CGMP standards with the desire to encourage
innovation and the development of improved manufacturing technologies.
We are confident that industry can meet the requirement to validate
aseptic processing with no adverse impact on technological innovation
in drug product manufacturing.
D. Asbestos Filters
As stated in the preamble to the direct final rule, we need to
update our regulations on filters used in processing liquid injectable
products. The version of Sec. 211.72 amended by this final rule
required manufacturers, before using an asbestos-containing filter, to
submit proof to FDA that an alternative nonfiber-releasing filter will,
or is likely to, compromise the safety or effectiveness of the product.
However, we are not aware that asbestos filters are currently
commercially manufactured for pharmaceutical use or are used in drug
production, and their use is not considered a good manufacturing
practice. Therefore, we proposed to delete the reference to the use of
asbestos-containing filters from Sec. 211.72 and to delete the
reference to asbestos filters from the definition of ``nonfiber-
releasing filter'' in Sec. 210.3(b)(6).
(Comment 16) Two comments stated that the regulations should state
that the use of asbestos filters is prohibited. One comment stated that
if asbestos-containing filters are in fact available and the proposed
changes were interpreted as permitting their use, this might pose a
risk to patients.
(Response) We agree with the comments. Therefore, in addition to
deleting the reference to asbestos-containing filters in Sec.
210.3(b)(6), we have revised the last sentence of Sec. 211.72 to state
that the use of an asbestos-containing filter is prohibited.
(Comment 17) One comment recommended that we clarify the second
sentence in proposed Sec. 211.72, which stated: ``Fiber-releasing
filters may not be used in the manufacture, processing, or packing of
these injectable drug products unless it is not possible to manufacture
such drug products without the use of such filters.'' The comment
recommended that this sentence be revised to state as follows: ``Fiber-
releasing filters may be used when/where it is not possible to
manufacture such drug products without the use of such filters.''
(Response) We agree with this proposed change and have revised
Sec. 211.72 accordingly.
(Comment 18) Four comments recommended revising the following
provision in proposed Sec. 211.72: ``If use of a fiber-releasing
filter is necessary, an additional nonfiber-releasing filter of 0.22
micron maximum mean porosity (0.45 micron if the manufacturing
conditions so dictate) shall subsequently be used to reduce the content
of particles in the injectable drug product.'' Each of these comments
stated that it is technically more accurate to describe a filter in
terms of its nominal pore size rating than its mean porosity. One
comment stated that the filter pore size standard of 0.22 micron is
outdated and should be changed to 0.2 micron.
(Response) These suggested technical changes are consistent with
statements in our guidances for industry (e.g., the Aseptic Processing
Guidance) concerning filters. Therefore, we have revised Sec. 211.72
to require that if use of a fiber-releasing filter is necessary, an
additional nonfiber-releasing filter having a maximum nominal pore size
rating of 0.2 micron be used.
E. Verification by a Second Individual
The current CGMP regulations include several provisions requiring
that certain activities be performed by one person and checked as
specified by a second person.
Section 211.101(c) requires that: (1) Each container of
component dispensed for use in manufacturing be examined by a second
person to assure that it was released by the quality control unit, (2)
the weight or measure is correct as stated in the batch production
records, and (3) the containers are properly identified.
Section 211.101(d) requires that each component be added
to the batch by one person and verified by a second person.
Section 211.103 requires that specified yield calculations
be performed by one person and independently verified by a second
person.
Section 211.182 requires the persons performing and
double-checking the cleaning and maintenance of major equipment to date
and sign or initial equipment logs indicating that the work was
performed.
Section 211.188(b)(11) requires that batch production and
control records include identification of the persons performing and
directly supervising or checking each significant step in the
operation.
When we amended the CGMP regulations in 1978, we established Sec.
211.68, which provides that automatic, mechanical, or electronic
equipment or other types of equipment, including computers, or related
systems that will perform a function satisfactorily, may be used in the
manufacture, processing, packing, and holding of a drug product,
subject to the following requirements:
Equipment is routinely checked according to a program
designed to assure proper performance,
Changes to records are made only by authorized personnel,
Input and output are checked for accuracy, and
Appropriate backup of data is maintained.
In the preamble to the 1978 final rule, we stated that the
verification requirements in Sec. 211.101 for charge-in of components
when automated systems are used would be met if a person verified that
the automated system was working properly (43 FR 45014 at 45051,
September 29, 1978). Thus, in this situation, the first individual is
replaced by a machine or other automated process, and only one person
is necessary to verify that the automated system is functioning as
intended.
[[Page 51925]]
Because we have received questions about the performance and
checking requirements in Sec. Sec. 211.101(c) or (d), 211.103,
211.182, or 211.188(b)(11) when the operations are performed by
automated equipment, such as the widespread and increasing use of
computer-controlled operations, we proposed to revise these sections.
We proposed to amend these regulations to indicate that when automated
equipment is used to perform certain operations, only one person is
needed to verify that the automated equipment is functioning
adequately. Correspondingly, proposed Sec. 211.68(c) stated that
automated equipment used for performance of operations addressed by
Sec. Sec. 211.101(c) or (d), 211.103, 211.182, or 211.188(b)(11) can
satisfy the requirements included in those sections for the performance
of an operation by one person and checking by another person if such
equipment is used in conformity with Sec. 211.68 and one person
verifies that the operations addressed in those sections are performed
accurately by such equipment. We stated in the preamble of the direct
final rule that these revisions would clarify our longstanding policy
that verification by a second individual may not be necessary when
automatic equipment is used under Sec. 211.68.
1. General Comments on Verification
(Comment 19) One comment stated that validated, automated systems
equipped with real time alarms that do not require any human
intervention should not require human verification. Another comment
stated that such systems should not require human verification with
each use and, when human verification is needed, the level of
verification required should be consistent with the level of automation
used. Both of these comments maintained that requiring operator
verification of automated, validated equipment under Sec. Sec.
211.68(c), 211.101(c)(3) and (d), 211.103, and 211.188(b)(11) might
hinder the implementation of process analytical technology (PAT) in the
drug industry.
(Response) In the Federal Register of February 12, 1991 (56 FR
5671) (the 1991 proposal), we issued a proposed rule in part to amend
Sec. 211.68 to add what is now the third sentence of Sec. 211.68(b):
``The degree and frequency of input/output verification shall be based
on the complexity and reliability of the computer or related system.''
This revision was adopted as part of the final rule issued on January
20, 1995 (60 FR 4087) (the 1995 final rule).
In the 1995 final rule, we responded to several comments on the
proposed revision. Two comments suggested that the revised regulation
did not accommodate the accepted use of validated computerized drug
production and control systems. We declined to change the revision as
proposed, stating our belief that the wording in the revised rule
adequately encompasses the use of these systems (60 FR 4087 at 4089).
Two comments on the 1991 proposal questioned the need for human
verification of operations that are performed by validated computer
systems. The comments listed other regulations that were not the
subject of the proposed rule that required more than one person to
verify certain manufacturing operations, apparently to show that
additional personnel would be needed to comply with proposed Sec.
211.68. We noted in the 1995 final rule that the revisions to Sec.
211.68 do not impose any specific personnel requirements. We also noted
that the agency is aware that computers are subject to malfunctions,
some of which could possibly result in the loss of critical information
regarding the manufacturing process or a serious production error and
the possible distribution of an adulterated product. Therefore, we
stated that while increasingly sophisticated system safeguards and
computerized monitoring of essential equipment and programs help
protect data, no automated system exists that can completely substitute
for human oversight and supervision. We further indicated that while
the degree of verification is left to the manufacturer's discretion,
the exercise of such discretion under Sec. 211.68 requires the use of
routine accuracy checks to provide a high degree of assurance that
input to and output from a computer or related system are reliable and
accurate. We stated our intent that each manufacturer exercise
reasonable judgment based on a variety of factors, including, but not
limited to, the complexity of the computer or related system, in
developing a method to prevent inaccurate data input and output (60 FR
4087 at 4089).
The December 4, 2007, direct final rule and companion proposed rule
were intended to amend the regulations involving second-person checks
only to clarify our longstanding policy that verification by a second
individual may not be necessary when automatic equipment is used under
Sec. 211.68, and that in such situations only one person is needed to
verify that the automated equipment is functioning adequately. The
amendments were not intended to either add to or detract from any
existing requirements in this regard, but only to clarify our
longstanding interpretation and policy for these requirements. We note
that the same basic considerations apply in this regard today as we
expressed in the 1995 final rule. Although increasingly sophisticated
controls and safeguards have been implemented for some automated
systems, our policy has been that some degree of human oversight,
supervision, verification, monitoring, or checking is still necessary
to verify proper performance as part of assuring the identity,
strength, quality, and purity of drug products. For suitably validated
automated systems, even with real time alarms, it is still necessary
for a human to verify that the systems are operating as planned and to
monitor for abnormalities. We agree that the level, nature, and
frequency of such human verification will vary depending on the level
of automation used as well as the nature of the system and controls,
and the manufacturer has the flexibility and responsibility to
determine what is suitable and necessary. Contrary to the comments, we
believe that manufacturers can conduct human verification of automated
operations in conjunction with the use of PAT in drug production.
For these reasons, we continue to believe that human verification
is necessary to ensure that automated systems are functioning properly.
(Comment 20) One comment stated that many current biotech processes
include component additions and deletions in a continuous or periodic
manner over long periods of time. The comment stated that there would
be no added value in requiring a manual verification of this component
management scheme in a fully automated scenario.
(Response) For the reasons stated in our response to comment 19, we
believe that some degree of human oversight, supervision, verification,
monitoring, or checking is a necessary part of CGMP for such processes
and that there is added value in having greater assurance that the
automated systems are operating properly as intended. We do not expect
that each individual component change must be witnessed in person, but
rather that a suitable system of human oversight be established and
followed to effectively verify that the automated processes are indeed
operating correctly in the performance of these operations.
(Comment 21) One comment maintained that our statement in the
preamble of the direct final rule that the verifying individual may be,
but is not required to be, the operator is a
[[Page 51926]]
contradiction of the CGMP regulations, which require (in Sec.
211.25(a)) that all individuals have the education, training, and
experience to enable them to perform their assigned functions. The
comment asked why the agency would allow an untrained operator to
perform a sole verification of a critical step if an automated system
is used and recommended that we retract the noted preamble statement.
(Response) The comment incorrectly concluded that allowing the
verifying individual to be a person other than the operator would
thereby allow an untrained individual to perform the function of
verifying a critical step. Section 211.25(a) requires each person
performing an assigned function to have the education, training, and
experience, or any combination thereof, to enable that person to
perform the function. Thus, any person, whether the operator or not,
who performs such a verification step would necessarily be required to
have the knowledge, training, and experience needed to perform that
function. Therefore, our preamble statement does not conflict with the
regulations.
(Comment 22) One comment stated that the proposed changes regarding
second person verification should be extended to include Sec.
211.188(a), which requires the preparation of batch production and
control records that include an accurate reproduction of the
appropriate master production or control record, checked for accuracy,
dated, and signed. The comment stated that when there is only one
signature needed, but the system is automated, it would also follow
that no human signature or signature equivalent would be necessary,
such as in issuance of a batch record under Sec. 211.188(a), when the
record is electronic. The comment also stated that in this case, it is
impossible to check the pages for a true and accurate copy. The comment
recommended revising Sec. 211.68(c) to include Sec. 211.188(a) in the
listing of sections affected and to state that there could be single
performance verification under Sec. 211.188(a).
(Response) We do not agree with the recommended changes to Sec.
211.188(a), which would eliminate any human verification of the
records. As previously stated, we are clarifying in this rule that the
checking of automated equipment by one person can satisfy the
requirements of those regulations that address the performance of a
step by one person and the verification of the step by a second person.
Our proposal regarding verification of operations was intended to make
clear that only one person is needed to verify that automated equipment
for a processing step is functioning properly; we did not propose
deleting all human verification of the step. In addition, we disagree
with the comment's apparent contention that no human signature would be
needed for issuance of electronic batch production and control records.
If such records are generated and issued electronically as part of an
automated system, a person must verify that the correct records were
issued and that they are still accurate and complete. We believe it is
clear that Sec. 211.188(a) requires only one check for accuracy, with
date and signature (which could be electronic), and that it does not
require a separate second check of this step. Therefore, no changes to
Sec. 211.188(a) are necessary or appropriate.
(Comment 23) Three comments addressed second-person verification in
Sec. 211.194. Section 211.194(a) requires that laboratory records
include complete data derived from all tests necessary to assure
compliance with established specifications and standards as specified
in that subsection. Section 211.194(a)(7) requires that laboratory
records include the initials or signature of the person who performs
each test and the date(s) the tests were performed. Section
211.194(a)(8) requires the initials or signature of a second person
showing that the original records have been reviewed for accuracy,
completeness, and compliance with established standards. Two of the
comments stated that the principle behind the proposed second-person
verification revisions should be extended to Sec. 211.194 to include
checking laboratory records involving automated laboratory equipment.
The first comment recommended revising Sec. 211.194 generally. The
second comment specifically recommended that Sec. 211.194(a)(8) be
revised to add that if laboratory tests have been performed by
automated equipment under Sec. 211.68, the laboratory record need only
include the identification of one person conducting the review of the
tests performed by the automated system. The comment also asked that
Sec. 211.194(a)(8) be added to the list of sections affected in Sec.
211.68(c). The third comment stated that the failure to include Sec.
211.194(a)(7) and (a)(8) in the proposed revisions implies that the use
of automated systems to perform or check testing is not allowed.
(Response) We decline to include Sec. 211.194 among the sections
enumerated in Sec. 211.68(c) concerning second-person verification of
operations performed by automated equipment. We acknowledge that
automated equipment may be used to conduct certain laboratory testing
operations. However, when automated equipment is used to perform a
laboratory test, typically a person initiates the test and ensures that
the correct equipment is used and that it operates properly. In this
situation, one person assists in or oversees the performance of the
laboratory test and a second person reviews the records for accuracy,
completeness, and compliance with established standards. Thus, the use
of equipment to perform laboratory tests, though permissible, is not a
situation in which automated equipment (rather than a person) performs
an operation and a person verifies that performance, which is the
situation addressed in revised Sec. 211.68(c). Therefore, it would not
be appropriate to include a reference to Sec. 211.194 (or to Sec.
211.194(a)(8) specifically) in revised Sec. 211.68(c).
2. Automatic, Mechanical, and Electronic Equipment (Sec. 211.68)
(Comment 24) One comment stated that Sec. 211.68 is no longer in
line with the technological improvements of the past 30 years and with
the increasing knowledge of computer validation by industry and
regulators. The comment recommended that Sec. 211.68 be aligned with
21 CFR 820.70(i), section 5.4 of the ICH Q7A guidance entitled ``Good
Manufacturing Practice Guidance for Active Pharmaceutical
Ingredients,'' and the Pharmaceutical Inspection Cooperation Scheme's
Annex 11 on computerized systems.
(Response) We decline to adopt the suggested revisions because they
exceed the scope of our proposed revision of Sec. 211.68, which only
addressed second-person verification of operations performed by
automated equipment. We might consider revising other provisions of
Sec. 211.68 as part of a future rulemaking to update the CGMP
regulations and make them consistent with international CGMP
provisions.
(Comment 25) One comment recommended that instead of our proposed
changes to Sec. 211.68(c) and other regulations concerning second-
person verification, we revise Sec. 211.68(a), which permits the use
of automatic, mechanical, or electronic equipment in the manufacture,
processing, packing, and holding of drug products. The comment stated
that the wording of our proposed changes only allows for actions to be
performed by automated equipment and checked by a person, which would
prevent the introduction of automated systems to check operations
performed by a person. The comment also stated that our proposed
changes would still require the involvement of at least one person
[[Page 51927]]
in each of these circumstances and prevent the use of a controlled
system or systems that both perform and independently verify the
relevant operations. One comment suggested that rather than our
proposed revisions, the desired clarification concerning automated
equipment and second-person checks would be better achieved by adding
to Sec. 211.68(a) the following sentence: ``Automated equipment can
satisfy the requirements for the performance of an operation by one
person and/or checking by another person.''
(Response) We do not agree with the recommended change. The
proposed rule simply clarified our longstanding position that only one
human check is necessary to verify a processing step performed by
automated equipment. The suggested revision of Sec. 211.68(a),
however, would allow manufacturers to rely solely on automated
equipment to verify the human performance of certain processing steps
and allow automated equipment to both perform and check operational
steps, which would constitute a significant change from the current
regulations. As stated in our response to comment 19, we believe that
human verification of certain processing steps, even when those steps
are performed by automated equipment, is still necessary.
(Comment 26) One comment stated that although proposed Sec.
211.68(c) implies that the automated equipment is doing the work and a
person can verify that the work is done, there are cases in which a
person does the work and automated equipment might be able to verify
the person's work. The comment cited as an example the case in which an
automated system scans the bar codes of ingredients and equipment to
ensure that the ingredient is correct for use with the equipment for
that step in the process, but the physical addition of the ingredient
is by the human operator (followed by the automated system scanning).
The comment recommended, therefore, that Sec. 211.68(c) be modified to
allow both the automated system and the person to do either the
performance or the verification tasks for the operations addressed by
Sec. Sec. 211.101(c) or (d), 211.103, 211.182, 211.188(b)(11), or
211.194(a)(8), or a single performance verification in the case of
Sec. 211.188(a).
(Response) We acknowledge that it might be possible to design an
automated system to verify operations performed by humans, but as
stated in our response to comment 19, we continue to believe that some
human verification of the processing steps performed by an automated
system is necessary.
(Comment 27) One comment suggested revising Sec. 211.68(c) to
state that automated equipment can satisfy the requirements for
verification of operations addressed by the listed sections as follows:
(1) If such unit operation is fully automated, no manual verification
is necessary and (2) if there is an operator for the automated
equipment, the verifying individual may be, but is not required to be,
the operator. The comment gave several reasons for this change:
Automated, validated systems equipped with real-time
alarms that do not require any human intervention should not require
human verification because Sec. 211.68(a) adequately addresses the
maintenance and verification of performance of these systems.
The need and type of verification required should be
consistent with the level of automation used. For example, operations
that are not fully automated and require operator participation may
serve as verification of the operator's activities, while fully manual
operations would require a second human verification.
As proposed, Sec. 211.68(c) might hinder the adoption of
PAT (e.g., there would be no value added by manual verification when
components are charged in a fully automated manner according to a
validated algorithm).
(Response) As stated in our response to comment 19, we do not agree
with the contention that no human verification is necessary when fully
automated systems are used, and we therefore decline to make these
requested changes to Sec. 211.68(c). We also do not believe that Sec.
211.68(c) will hinder the adoption of PAT. As stated in the preamble to
the direct final rule, we agree that if there is an operator for the
automated equipment, the verifying individual may be, but is not
required to be, the operator. However, Sec. 211.68(c) does not require
that the verifying individual be the operator, and we do not believe
that it is necessary that the provision explicitly state that the
verifying individual need not be the operator.
(Comment 28) One comment stated that the proposed revision of Sec.
211.68(c), when applied to Sec. 211.188(b), might be more restrictive
than FDA's position in Compliance Policy Guide (CPG) Sec. 425.500,
Computerized Drug Processing; Identification of ``Persons'' on Batch
Production and Control Records (formerly CPG 7132a.08). CPG 425.500
states that when significant steps in the manufacturing, processing,
packing, or holding of a batch are performed, supervised, or checked by
a computerized system, an acceptable means of complying with the
identification requirements in Sec. 211.188(b)(11) would consist of
conformance to certain requirements. The comment maintained that CPG
425.500 gives companies the flexibility to automate not only the
performance of critical actions but also the supervision and checking
of these actions if it is shown that the efficacy of these controls
would be at least equivalent to the level of efficacy if the
verification were done by a second person. The comment stated that this
flexibility should be extended to all CGMP sections in which a
verification is requested. The comment therefore asked that Sec.
211.68(c) be revised to state that automated equipment used for
performance of operations addressed by Sec. Sec. 211.101(c) or (d),
211.103, 211.182, or 211.188(b)(11) can satisfy the requirements
included in those sections for the performance of an operation by one
person and checking by another person if such equipment is used in
conformity with Sec. 211.68 and one person either performs the
operations addressed in those sections under the control of the
automated equipment or verifies that these operations are performed
accurately by such equipment.
(Response) We do not agree with the comment's apparent
interpretation of CPG 425.500 that the CPG allows for elimination of
human oversight. The purpose of the CPG is to explain what constitutes
``identification'' of persons in batch records under Sec.
211.188(b)(11) when automated systems are used for various functions.
The CPG states that when an automated system is used to perform,
directly supervise, or check significant steps in the production of a
drug, the identification requirements in Sec. 211.188(b)(11) are met
if there is documentation that the system contains adequate checks (and
documentation of the performance of the system itself), validation of
the system's performance, and recording of specific checks in batch
records (including initial, branching, and final steps). These
conditions for applying the identification requirements to steps using
automated equipment involve the responsibilities of persons. For
example, a person, rather than automated equipment, is needed to record
these checks of production steps in batch records. Therefore, contrary
to the comment's implication, the CPG does not state that human
oversight is unnecessary when an automated system is involved in the
performance, supervision, or checking of production
[[Page 51928]]
steps. All automated systems require some level (commensurate with the
complexity and risk inherent in the system) of human oversight or
checking for expected performance at appropriate intervals. Therefore,
we decline to revise Sec. 211.68(c) as recommended.
(Comment 29) One comment, although supportive of the proposal to
allow initial activities to be performed by automated equipment,
objected to requiring that the output of an automated and adequately
validated activity be checked for accuracy by a person. The comment
maintained that the act of having validated software and its related
processes itself constitutes an independent check that operations are
being performed accurately and argued that this is more reliable than
any contemporaneous check by a person. The comment therefore asked that
Sec. 211.68(c) be changed to state that independent checks may consist
of contemporaneous analysis and verification by a second person
following completion of the activity; or, where the automated process
has been validated to a high degree of confidence, the prior validation
can satisfy this requirement and a second person's check may then
consist of verifying the validated status of the equipment and
processes.
(Response) We do not agree with the suggested change. Although we
agree that it is an important part of process controls to ensure the
validated status of equipment and processes even before they are used,
we do not believe that verifying this validated status can satisfy the
requirement for checking the actual performance of automated equipment.
However, we believe that the requirement in proposed Sec. 211.68(c)
that one person ``verifies that the operations * * * are performed
accurately'' by automated equipment may have led some comments to
believe that we were requiring a more specific and detailed repetitive
type of check than we intended. When automated equipment is used for
operations addressed by revised Sec. 211.68(c) in conformance with
Sec. 211.68, the person doing the checking must verify that the
automated equipment is functioning properly and that the operations are
reliably performed in the intended manner. As discussed in the response
to comment 19, the nature and frequency necessary for such verification
will vary depending on the level of automation used as well as the
nature of the system and controls. We do not expect that it will
normally be necessary, under Sec. 211.68(c), for a person to repeat
all of the automatic calculations by hand to ensure their accuracy.
Therefore, we have revised Sec. 211.68(c) to clarify that automated
equipment can be used to perform an operation when the performance is
checked by a person provided that ``such equipment is used in
conformity with this section [Sec. 211.68] and one person checks that
the equipment properly performed the operation.''
3. Verification of Weighing, Measuring, or Subdividing Operations
(Sec. 211.101(c))
Section 211.101 concerns charge-in of components. Proposed Sec.
211.101(c) stated, in part, that if the weighing, measuring, or
subdividing operations for components are performed by automated
equipment under Sec. 211.68, only one person is needed to ensure that
the requirements in Sec. 211.101(c)(1), (c)(2), and (c)(3) are met.
(Comment 30) One comme