Supplements and Other Changes to Approved New Animal Drug Applications, 74766-74785 [E6-21133]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 71, Number 239 (Wednesday, December 13, 2006)]
[Rules and Regulations]
[Pages 74766-74785]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: E6-21133]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 25, 500, 514, and 558

[Docket No. 1999N-1415] (formerly Docket No. 99N-1415)
RIN 0910-AF59


Supplements and Other Changes to Approved New Animal Drug 
Applications

AGENCY:  Food and Drug Administration, HHS.

ACTION:  Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending its 
regulations on supplements and other changes to approved new animal 
drug applications (NADAs) or abbreviated new animal drug applications 
(ANADAs) to implement the manufacturing changes provision of the Food 
and Drug Administration Modernization Act of 1997 (the Modernization 
Act). The final rule requires manufacturers to assess the effect of a 
manufacturing change on the identity, strength, quality, purity, and 
potency of a drug as those factors relate to the safety or 
effectiveness of the drug. The final rule sets forth requirements for 
changes requiring submission and approval of a supplement before the 
distribution of the drug made using the change, changes requiring the 
submission of a supplement at least 30 days prior to the distribution 
of the drug, changes requiring the submission of a supplement at the 
time of distribution of the drug, and changes to be described in an 
annual report.

DATES: The final rule is effective February 12, 2007.

FOR FURTHER INFORMATION CONTACT: Dennis M. Bensley, Jr., Center for 
Veterinary Medicine (HFV-140), Food and Drug Administration, 7500 
Standish Pl., Rockville, MD 20855, 301-827-6956, E-mail: 
dennis.bensley@fda.hhs.gov.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background
    A. Development of the Regulation
    B. Risk-Based Approach
II. Harmonization and Highlights of Revisions to the Proposed Rule
    A. Section 514.8(a)--Definitions
    B. Section 514.8(b)--Manufacturing Changes to an Approved 
Application Manufacturing Changes Requiring Preapproval of a Supplement 
(Proposed Sec.  514.8(b)(1)(ii))
    C. Labeling and Other Changes to an Approved Application
III. Responses to Comments on the Propose Rule
    A. Section 514.8(a)--Definitions
    B. Section 514.8(b)--Manufacturing Changes to an Approved 
Application
    C. Changes Requiring Submission and Approval of a Supplement Prior 
to Distribution of the Drug Made Using the Change (Major Changes)
    D. Changes Requiring Submission of a Supplement at Least 30 Days 
Prior to Distribution of the Drug Made Using the Change (Moderate 
Changes)
    E. Changes and Updated Stability Data to be Described and Submitted 
in and Annual Report (Minor Changes)
    F. Labeling and Other Changes to an Approved Application
    G. Implementation of the Final Rule and Guidance
    H. General Comments
IV. Unrelated Referenced Comments to the Proposed Rule
V. Conforming Amendments
VI. Environmental Impact
VII. Analysis of Impacts
VIII. Paperwork Reduction Act of 1995
IX. Federalism
X. References

I. Background

    Section 116 of the Modernization Act (Public Law 105-115) amended 
the Federal Food, Drug, and Cosmetic Act (the act) by adding section 
506A (21 U.S.C. 356a). That section describes requirements and 
procedures for making and reporting manufacturing changes to approved 
new drug and abbreviated new drug applications, to approved new animal 
drug and abbreviated new animal drug applications, and to license 
applications for biological products under section 351 of the Public 
Health Service (PHS) Act. Section 506A of the act revises current 
procedures for approving manufacturing changes. Major manufacturing 
changes, as defined in section 506A, are of a type determined by FDA to 
have a substantial potential to adversely affect the identity, 
strength, quality, purity, and potency as they may relate to the safety 
and effectiveness of a drug and require prior approval of a 
supplemental application. Under section 506A, FDA may require 
submission of a supplemental application for drugs made with 
manufacturing changes that are not major and may establish categories 
of manufacturing changes for which a supplemental application is 
required. In such a case, the applicant may begin distribution of a 
drug 30 days after FDA receives a supplemental application unless the 
agency notifies the applicant within the 30-day period that prior 
approval of the application is required. Under the statute, FDA may 
also designate a category of manufacturing changes that permit the 
applicant to begin distributing a drug made with such changes upon 
receipt by the agency of a supplemental application for the change. 
Finally, FDA may also authorize applicants to distribute drugs 
manufactured with a change without submitting a supplemental 
application. The law provides that FDA may establish categories of 
manufacturing changes that may be made without submitting a 
supplemental application.

[[Page 74767]]

A. Development of the Regulation

    In the Federal Register of October 1, 1999 (64 FR 53281), FDA 
published a proposed rule to implement section 506A of the act for 
NADAs and ANADAs. In that same issue of the Federal Register (64 FR 
53393), FDA announced the availability of a draft guidance for industry 
entitled ``Chemistry, Manufacturing and Control Changes to an Approved 
NADA or ANADA'' (GFI 83). The guidance assists applicants in 
determining how they should report changes to an approved NADA or ANADA 
under section 506A of the act and under the proposed revisions to the 
new animal drug regulations pertaining to supplements and other changes 
to an approved application. With the issuance of this final rule, we 
are announcing we will issue a revised final guidance to assist 
applicants in determining how they should report changes to an approved 
NADA or ANADA under both section 506A of the act and these final 
regulations. The guidance has been revised to conform to the final rule 
and, as appropriate, to comments received. It will be issued upon 
approval of information collection requirements that are subject to 
review by the Office of Management and Budget (OMB) under the Paperwork 
Reduction Act.

B. Risk-Based Approach

    The publication of this final rule is an important step in the 
process of adopting a risk-based approach to the regulation of drugs. 
In the 1990s, FDA sponsored research at the University of Maryland and 
other universities on the types of chemistry and manufacturing changes 
to immediate release solid oral drug products that could affect drug 
performance (i.e., identity, strength, quality, purity, and potency) 
and, therefore, safety and effectiveness. Using that research, FDA's 
Center for Drug Evaluation and Research (CDER) began to develop a risk-
based approach to the implementation of manufacturing changes. 
Following CDER's example, FDA's Center for Veterinary Medicine (CVM) 
also employed a similar risk-based approach to the implementation of 
manufacturing changes for animal drugs. This approach provided for a 
continued high level of scrutiny by FDA of changes that were most 
likely to affect the performance of a drug and decreased scrutiny of 
changes that were not likely to affect the performance of a drug.
    The risk-based approach was first explained in a series of guidance 
documents (the Scale-up and Postapproval Changes (SUPAC) guidances) 
that reduced the regulatory burden of obtaining FDA authorization to 
make certain changes. The work continued in regulations issued by the 
Center for Biologics Evaluation and Research (CBER) in 1997 (21 CFR 
601.12). In November 1997, this risk-based approach was codified in 
section 116 of the Modernization Act.
    This final rule implements section 116 of the Modernization Act by 
incorporating the statutory standards for characterizing proposed 
changes as having substantial, moderate, or minimal potential to 
adversely affect the identity, strength, quality, purity, and potency 
of a drug as they may relate to its safety and effectiveness and 
determining submission requirements based on the potential risks 
associated with the changes. For changes with a substantial potential 
to affect the designated characteristics of a drug, FDA must review and 
approve a supplement that contains information showing that the 
proposed change will not adversely affect the drug's characteristics 
(i.e., information developed by the holder of the application to 
validate the effect of the proposed change) before distribution of the 
product made using the change.
    It was anticipated when section 116 of the Modernization Act was 
written that the science of manufacturing would evolve over time and 
affect whether changes would be considered major or nonmajor. To 
accommodate future technological advancements, section 116 of the 
Modernization Act and this final implementing regulation both provide 
that FDA may, by regulation or guidance, change the designation of a 
particular category of change from major to nonmajor or vice versa. 
This concept of an evolving risk-based approach to manufacturing 
changes also is consistent with the agency's Good Manufacturing 
Practices Initiative launched in August 2002. The goals of this 
initiative include:
     Ensuring that state-of-the-art pharmaceutical science is 
utilized in the regulatory review and inspection policies;
     Encouraging the adoption of new technological advances in 
high quality and efficient manufacturing by the pharmaceutical 
industry;
     Assessing the applicable current good manufacturing 
practice (CGMP) requirements relative to the best quality management 
practices;
     Strengthening public health protection by implementing 
risk-based approaches that focus both industry and FDA attention on 
critical areas for improving product safety and quality; and
     Enhancing the consistency and coordination of FDA's drug 
quality oversight activities.
    Specifically, one of the efforts of the CGMP initiative is to 
facilitate continuous improvement and innovation in manufacturing by 
allowing manufacturers to make certain types of changes in their 
processes without prior FDA approval. This rule, in keeping with that 
initiative, provides for a mechanism of continuous improvement through 
the guidance process (21 CFR 10.115) that may provide for less 
burdensome documentation of certain changes as manufacturing processes 
and pharmaceutical science develop.

II. Harmonization and Highlights of Revisions to the Proposed Rule

    In the proposed rule to implement section 506A of the act for 
supplements and other changes to approved NADAs and ANADAs (64 FR 
53281), CVM stated its intent to harmonize the reporting requirements 
for manufacturing changes for animal drugs with those requirements 
applicable to human drugs, 21 CFR 314.70. CDER published their final 
rule in the Federal Register of April 8, 2004 (69 FR 18727). CDER 
modified their proposed rule in response to comments received. CVM has 
not received similar comments to its aforementioned proposed rule. 
However, as a result of its harmonization effort with CDER's proposed 
21 CFR 314.70, CVM has incorporated, as appropriate, many of the 
changes to CDER's proposed rule. This section describes the changes 
resulting from harmonization with CDER's final rule and other comments 
specific to 21 CFR 514.8. Other changes initiated by CVM are also 
described. Minor editorial changes are not described.

A. Section 514.8(a)--Definitions

1. Definition of ``Specification'' (Proposed Sec.  514.8(a)(2)(iii))
    FDA has revised the proposed definition of ``specification'' in 
Sec.  514.8(a)(2)(iii) for consistency with CDER's regulations and has 
renumbered Sec.  514.8(a)(2)(iii) through (a)(2)(v). The proposed 
definition included the phrase ``* * *other components including 
container closure systems, and in-process controls.'' This phrase has 
been revised to state ``components, in-process materials, container 
closure systems, and other materials used in the production of a 
drug.'' Thus, the revised definition is as follows: ``Specification 
means the quality standard (i.e., tests, analytical procedures, and 
acceptance

[[Page 74768]]

criteria) provided in an approved application to confirm the quality of 
drugs including, for example, drug substances, Type A medicated 
articles, drug products, intermediates, raw materials, reagents, 
components, in-process materials, container closure systems, and other 
materials used in the production of a drug. For the purpose of this 
definition, the term 'acceptance criteria' means numerical limits, 
ranges, or other criteria for the tests described.'' See the response 
to comment 4 regarding the use of the terms ``drug(s),'' ``drug 
substance(s),'' and ``drug product(s).''
2. Definition of ``validate the effects of the change'' (Proposed Sec.  
514.8(a)(2)(iv))
    FDA has revised the proposed definition of ``validate the effects 
of change'' in Sec.  514.8(a)(2)(iv) for consistency with CDER's 
regulations. The revised definition is as follows: ``Assess the effects 
of the change means to evaluate the effects of a manufacturing change 
on the identity, strength, quality, purity, and potency of a drug as 
these factors may relate to the safety or effectiveness of the drug.'' 
See the response to comment 3 regarding the use of the term ``assess'' 
instead of ``validate.''
3. Definitions of ``Listed drug'' and ``The list'' (Proposed Sec.  
514.8(a)(2)(i) and (v))
    FDA has deleted the definitions of ``Listed drug'' (proposed Sec.  
514.8(a)(2)(i)) and ``The list'' (proposed Sec.  514.8(a)(2)(v)). The 
definitions were originally proposed to clarify the meaning of 
``reference listed drug'' identified under proposed Sec.  
514.8(b)(2)(ii)(B). Since the term ``reference listed drug'' has been 
deleted from proposed Sec.  514.8(b)(2)(ii)(B), the definitions are 
currently not needed. See the discussion under Section B of the 
preamble regarding the changes to proposed section 514.8(b)(2)(ii)(B).

B. Section 514.8(b)--Manufacturing Changes to an Approved Application 
Manufacturing Changes Requiring Preapproval of a Supplement (Proposed 
Sec.  514.8(b)(1)(ii))

    FDA has revised Sec.  514.8(b)(1)(ii) by replacing ``effect'' with 
``effects'' and deleting the phrase ``* * *on the identity, strength, 
quality, purity, or potency of the new animal drug as these factors may 
relate to the safety or effectiveness of the new animal drug* * *'' 
because ``assess the effects of the change'' already is defined under 
Sec.  514.8(a)(2)(i). Thus, proposed Sec.  514.8(b)(1)(ii) is revised 
as follows: ``The holder of an approved application under section 512 
of the act must assess the effects of the change before distributing a 
drug made with a manufacturing change.''
1. Provision of Supplemental Application to FDA District Office 
(Proposed Sec.  514.8(b)(1)(iv))
    FDA has revised proposed Sec.  514.8(b)(1)(iv) to apply to both 
supplements and amendments as provided in CDER's regulations, Sec.  
314.70. In addition, this section also includes clarification with 
regard to providing a field copy for supplemental changes to drugs 
manufactured outside of the United States, see the response to comment 
6. The section now provides that: ``In each supplement and amendment to 
a supplement providing for a change under paragraph (b)(2) or (b)(3) of 
this section, the applicant must include a statement certifying that a 
field copy has been provided to the appropriate FDA district office. No 
field copy is required for a supplement providing for a change made to 
a drug manufactured outside of the United States''
2. Changes That May Affect Drug Equivalence (Proposed Sec.  
514.8(b)(2)(ii)(B))
    FDA has revised Sec.  514.8(b)(2)(ii)(B) by: (1) Specifically 
identifying the drug as approved under section 512(b) of the act, (2) 
replacing ``animal'' in ``* * *appropriate animal studies'' with 
``clinical'' to be more consistent with the language of section 506A of 
the act, and (3) deleting ``or to the reference listed drug.'' Though 
Sec.  514.8 applies to supplements to abbreviated new animal drug 
applications, FDA intends to address the term ``reference listed drug'' 
in future regulations for drugs approved under section 512(c)(2)(A) (21 
U.S.C. 360b(c)(2)(A) of the act.
3. Container Closure Changes That May Affect Drug Impurity Profile 
(Proposed Sec.  514.8(b)(2)(ii)(E))
    FDA has limited the requirement for a prior approval supplement for 
drug product container closure systems to include only changes in the 
type or composition of a packaging component. FDA has revised Sec.  
514.8(b)(2)(ii)(E) to be similar to CDER's regulations, Sec.  314.70, 
and it now states: ``Changes in a drug product container closure system 
that controls the drug delivered to the animal or changes in the type 
or composition of a packaging component that may affect the impurity 
profile of the drug product.'' Unlike CDER's Sec.  314.70(b)(vi), CVM 
has not included specific examples of the container closure changes and 
believes that these examples are best addressed through guidance.
4. Supplement Approval Prior to Product Distribution (Proposed Sec.  
514.8(b)(2)(iii))
    FDA has added the sentence, ``The supplement must be labeled 
``Prior Approval Supplement'' after the first sentence in Sec.  
514.8(b)(2)(iii) to be consistent with the submission identification 
requirements described in Sec.  514.8(b)(3)(iii), (b)(3)(vi), and 
(b)(4).
5. Evaluate the Effects of the Change (Proposed Sec.  
514.8(b)(2)(iii)(E))
    FDA has revised Sec.  514.8(b)(2)(iii)(E) to state: ``A description 
of the methods used and studies performed to assess the effects of the 
change.'' See the response to comment 3.
6. Validation Protocols (Proposed Sec.  514.8(b)(2)(iii)(I))
    FDA has revised proposed Sec.  514.8(b)(2)(iii)(I) to be consistent 
with CDERs regulations by replacing ``test methodologies'' with ``test 
methodologies related to sterilization process validation.''
    FDA has deleted proposed Sec.  514.8(b)(2)(iii)(K) because 
submissions related to environmental considerations are addressed 
elsewhere in the regulations (see part 25 (21 CFR part 25)).
    FDA has included Sec.  514.8(b)(2)(iii)(J) to be consistent with 
section 506A(c)(1) of the act. The new section states: ``Any other 
information as directed by FDA.''
7. Protocol Submission as a Supplement (Proposed Sec.  514.8(b)(2)(v))
    FDA has revised the proposed rule to clarify that a protocol must 
be submitted as a prior approval supplement if the protocol was not 
already included in an approved application or when changing an 
approved protocol. These changes are consistent with CDER's 
regulations, Sec.  314.70.
8. Thirty-Day Changes-Being-Effected Supplement--Container Closure 
System (Proposed Sec.  514.8(b)(3)(ii)(A))
    To be consistent with CDER's regulations, FDA has revised proposed 
Sec.  514.8(b)(3)(ii)(A) to clarify the wording in sections 514.8(b)(2) 
and 514.8(b)(4) of the proposed regulations. Revised Sec.  
514.8(b)(3)(ii)(A) states: ``A change in the container closure system 
that does not affect the quality of the drug except as otherwise 
described in paragraphs (b)(2) and (b)(4) of this section.''
9. Thirty-Day Changes-Being-Effected Supplement (Proposed Sec.  
514.8(b)(3)(iii))
    FDA has revised proposed Sec.  514.8(b)(3)(iii) to incorporate

[[Page 74769]]

additional reference to Sec.  514.8(b)(3)(vi) since ``Supplements-
Changes Being Effected'' described under Sec.  514.8(b)(3)(vi) must 
also give a full explanation of the basis of the change and identify 
the date on which the change is made.
10. Thirty-Day Changes-Being-Effected Supplement (Proposed Sec.  
514.8(b)(3)(v)(B))
    FDA has revised proposed Sec.  514.8(b)(3)(v)(B) to be consistent 
with CDER's regulations, Sec.  314.70 and to clarify compliance with 
this section by allowing applicants the opportunity to amend a 
supplement by providing any missing information.
11. Minor Changes--Expiration Dating Period (Proposed Sec.  
514.8(b)(4)(ii)(F))
    The term ``full production batches'' is redundant and may 
incorrectly imply that only the largest production batches can be used 
to extend an expiration dating period. Therefore, FDA has revised Sec.  
514.8(b)(4)(ii)(F) by deleting the second ``full'' before ``production 
batches.''
12. Minor Changes--Alternate Analytical Procedure (Proposed Sec.  
514.8(b)(4)(ii)(G))
    FDA has revised Sec.  514.8(b)(4)(ii)(G) by adding ``* * *or 
deletion of an alternative analytical procedure'' to be consistent with 
CDER's regulations, Sec.  314.70.
13. Annual Report (Proposed Sec.  514.8(b)(4)(iii))
    FDA has revised Sec.  514.8(b)(4)(iii) by deleting from the first 
sentence ``a list of all products involved;'' and adding ``(A) A 
completed Form FDA 356V;'' to be consistent with Sec.  
514.8(b)(2)(iii)(A). FDA is also adding Sec.  514.8(b)(4)(iii)(J), 
``Any other information as directed by FDA'' to be consistent with 
section 506A(d)(2)(A) of the act and making additional revisions to 
Sec.  514.8(b)(4)(iii)(B) through (b)(4)(iii)(I) to be consistent with 
CDER's regulations, Sec.  314.70. Most of the changes in this section 
are either editorial or were made to maintain consistency with other 
sections under Sec.  514.8 or with CDER's regulations, Sec.  314.70. 
Revisions to Sec.  514.8(b)(4)(iii)(G) are made in response to comment 
25.

C. Labeling and Other Changes to an Approved Application

1. Preapproval Supplement--Required Information (Proposed Sec.  
514.8(c)(2))
    FDA has revised proposed Sec.  514.8(c)(2)(ii)(E) by adding ``* * 
*in support of the change'' in order to clarify the scope of the 
derived data used to support a change. FDA has deleted proposed Sec.  
514.8(b)(2)(iii)(D) and proposed Sec.  514.8(b)(2)(iii)(K), because 
submissions related to environmental considerations are addressed 
elsewhere in the regulations (see part 25). Additional changes are made 
to Sec.  514.8(c)(2)(i) by deleting the term ``prescription new animal 
drug mailing/promotional pieces,'' and to Sec.  514.8(c)(2)(i)(A) and 
Sec.  514.8(c)(3)(A) by replacing the term ``side effect'' with the 
term ``adverse reaction.''
2. Labeling Changes to be Placed Into Effect Prior to Receipt of a 
Written Notice of Approval of a Supplemental Application (Proposed 
Sec.  514.8(c)(3)(iv))
    FDA has revised proposed Sec.  514.8(c)(3)(iv) to read ``If the 
supplemental application is not approved, FDA may initiate an 
enforcement action because the drug is misbranded under section 502 of 
the act and/or adulterated under section 501 the act. In addition, 
under section 512(e) of the act, FDA may issue a notice of opportunity 
for hearing to withdraw the approval of the application.'' Section 
514.8(c)(3)(iv) is being revised to clarify potential legal options.

III. Responses to Comments on the Proposed Rule

    CVM received comments on many aspects of the proposed rule from 
five parties, including pharmaceutical industry associations and other 
interested persons. One comment to the proposed rule also fully 
endorsed comments by a pharmaceutical trade organization to the 
analogous proposed rule for human new and abbreviated new drug 
applications by CDER, which was published in the Federal Register of 
June 28, 1999 (64 FR 34608). These endorsed comments also are addressed 
in this final rule. All comments and the agency's responses are 
summarized below.

A. Section 514.8(a)--Definitions

1. Definition of ``Minor Changes and Stability Report'' (Proposed Sec.  
514.8(a)(2)(ii))
    Proposed Sec.  514.8(a)(2)(ii) states that the ``Minor changes and 
stability report'' is a report that is submitted to the new animal drug 
application or abbreviated new animal drug application once each year 
within 60 days of the anniversary date of the application's original 
approval or mutually agreed upon date.
    (1) One comment requested clarification of the requirement of 
submitting the minor changes and stability report noting that the time 
frame in the proposed provision extends before and after this agreed 
upon date. The commenter suggested that the requirement be revised to 
require submission of the report ``within 60 days of the anniversary 
date of the application's original approval or mutually agreed upon 
date.''
    Agency Response: FDA agrees to revise the definition as requested 
with some modification. The definition is revised to state, in part, 
``* * *within 60 days before or after the anniversary of the 
application's original approval or mutually agreed upon date.''
2. Definition of ``Specification'' (Proposed Sec.  514.8(a)(2)(iii))
    ``Specification'' is defined in proposed Sec.  514.8(a)(2)(iii) as 
the quality standard (i.e., tests, analytical procedures, and 
acceptance criteria) provided in an approved NADA or ANADA to confirm 
the quality of drug substances, drug products, intermediates, raw 
materials, reagents, and other components including container closure 
systems and in-process controls. The proposed regulation states that 
the term ``acceptance criteria'' refers to numerical limits, ranges, or 
other criteria for the tests described.
    (2) One comment stated that ``* * *intermediates, raw materials, 
reagents, and other components including container closure systems and 
in-process materials'' should be deleted from the definition of 
specification, with changes for these materials handled separately from 
the final rule and final guidance. The comment stated that the 
definition is not consistent with the International Conference on 
Harmonization (ICH) guidance on specifications entitled ``Test 
Procedures and Acceptance Criteria for New Drug Substances and New Drug 
Products: Chemical Substances'' (ICH Q6A), which includes only drug 
substance and drug product. Additionally, the comment indicated that 
inclusion of items beyond the drug substance and drug product 
represents a level of complexity that would be better dealt with in 
guidances that can adequately evaluate the significance of changes to 
specific items.
    Agency Response: FDA declines to revise the definition as 
requested. Section 512(b)(1)(D) (for NADAs) and section 512(n)(1)(G) 
(for ANADAs) of the act (21 U.S.C. 360b(b)(1)(D) and 360b(n)(1)(G)) 
require that a full description of the methods used in, and the 
facilities and controls used for, the manufacture, processing, and 
packing of a drug be provided in an application. The regulation for the 
establishment of

[[Page 74770]]

a performance standard at 21 CFR 514.1(b)(5)(v) also requires 
information to ensure proper identity, strength, quality, and purity of 
the raw materials, whether active or not, including the specifications 
for acceptance and methods of testing for each lot of raw material.
    Intermediates, raw materials, reagents, container closure systems, 
in-process materials and other materials that are used in the 
manufacture of drug substances, Type A medicated articles, or drug 
products are considered part of the manufacturing method and can have a 
direct effect on the identity, strength, quality, purity, or potency of 
the drug. While the extent of a specification (e.g., number or type of 
tests, strictness of acceptance criteria) for these materials may vary 
depending on the materials' use in a given manufacturing process, FDA 
has required specifications for these materials to be included in 
applications as part of the description of the manufacturing method and 
will continue to do so. Similar to the ICH Q6A guidance, the scope of 
the Veterinary International Conference on Harmonization (VICH) 
guidance entitled ``Test Procedures and Acceptance Criteria for New 
Veterinary Drug Substances and New Medicinal Products: Chemical 
Substances'' (GL39) is limited to only drug substances and drug 
products, whereas in this regulation the definition of 
``Specification'' (see Sec.  514.8(a)(2)(iii)), is intended to cover 
all drug materials including drug substances, drug products, raw 
materials, reagents, etc.
3. Definition of ``Validate the Effects of the Change'' (Proposed Sec.  
514.8(a)(2)(iv))
    Proposed Sec.  514.8(a)(2)(iv) defines ``validate the effects of 
the change'' to mean to assess the effect of a manufacturing change on 
the identity, strength, quality, purity, or potency of a new animal 
drug as these factors relate to the safety or effectiveness of the new 
animal drug.
    (3) Several comments recommended that FDA replace the terms 
``validate'' or ``validation'' with ``assess'' or ``assessment.'' One 
comment stated that although FDA is using the terms consistently with 
Congress' use of the terms in section 506A of the act, the term 
``validate'' is likely to cause confusion because this term has long 
been associated with, and has specific meaning under, FDA's current 
good manufacturing practices (CGMPs) regulations.
    Agency Response: FDA agrees to revise the definition as requested, 
as the revision makes the definition more clear without changing its 
meaning. FDA, on its own initiative, is also revising the phrase ``* * 
*purity, or potency'' to ``* * *purity, and potency* * *'' to be 
consistent with section 506A(b) of the act. In addition, FDA is 
replacing the term ``assess'' with ``evaluate'' and the ``effect'' with 
``effects.'' FDA notes that while the effect of a manufacturing change 
on the identity, strength, quality, purity and potency of a drug is to 
be assessed, this assessment could involve testing of materials 
directly affected by a change (e.g., drug substance) in addition to or 
instead of drug testing. FDA has also revised Sec.  514.8(b)(2)(iii)(E) 
accordingly to state: ``A description of the methods used and studies 
performed to assess the effects of the change.''
Other Changes to ``Definitions'' Section (Proposed Sec.  514.8(a))
    (4) Several comments requested clarification and standardization of 
the terms ``drug product,'' ``drug,'' and ``product.'' They further 
suggested that ``drug substance'' be changed to ``active pharmaceutical 
ingredient'' (API) to be consistent with other guidances. Also, 
clarification of whether ``product'' refers to API was requested.
    Agency Response: FDA agrees that terminology should be standardized 
throughout the proposed 21 CFR 514.8 regulations. Therefore, FDA has 
replaced the terms ``product'' and ``new animal drug'' with ``drug'' 
where applicable throughout 21 CFR 514.8. This change differs from the 
human drug regulations where the terms ``product'' and ``drug'' are 
replaced by the terms ``drug substance'' or ``drug product'' throughout 
21 CFR 314.70. The reason for the difference is that animal drugs such 
as free-choice feeds (21 CFR 510.455), Type A medicated articles (21 
CFR 558.3(b)(2)) and Type B or Type C medicated feed manufactured from 
a drug component (21 CFR 558.3(b)(5)) are not considered ``drug 
products'' as defined under 21 CFR 210.3(b)(4). However these products 
require approved new animal drug applications and therefore are also 
covered by 21 CFR 514.8. Using the term ``drug product'' instead of 
``drug'' in 21 CFR 514.8 may incorrectly imply that reporting of 
manufacturing changes for the previously mentioned approved products is 
not required. The term ``drug'' as defined under section 201(g)(1) of 
the act (21 U.S.C. 321(g)(1)) encompasses drug substances, drug 
products, Type A medicated articles, etc. The terms ``drug substance'' 
and ``drug products'' are included in certain parts of 21 CFR 514.8, 
specifically in the description of changes that do not apply to free-
choice medicated feeds, Type A medicated articles or Type B and Type C 
medicated feed manufactured from a drug component, see 21 CFR 
514.8(b)(2)(ii), (b)(3)(ii), (b)(3)(vi) and (b)(4)(ii).
    FDA declines to change ``drug substance'' to ``active 
pharmaceutical ingredient,'' as requested. ``Drug substance'' is the 
commonly accepted term for filing purposes whereas the term ``active 
pharmaceutical ingredient'' is more commonly used for compliance 
purposes. Both terms are often used interchangeably. Since Sec.  514.8 
deals with filing issues, FDA prefers to use the term ``drug 
substance.'' FDA has included a definition of ``drug substance'' under 
Sec.  514.8(a)(2)(ii) to read ``Drug substance means an active 
ingredient as defined under Sec.  210.3(b)(7).''

B. Section 514.8(b)--Manufacturing Changes to an Approved Application

1. Manufacturing Changes Requiring Prior Approval of a Supplement 
(Proposed Sec.  514.8(b)(1)(ii))
    Proposed Sec.  514.8(b)(1)(ii) requires the holder of an approved 
application to validate the effect of the manufacturing change on the 
identity, strength, quality, purity, or potency of the new animal drug 
as these factors may relate to the safety or effectiveness of the new 
animal drug before distributing a drug made with a manufacturing 
change.
    (5) One comment recommended that FDA replace the term ``validate'' 
with ``assess'' in proposed Sec.  514.8(b)(1)(ii).
    Agency Response: FDA agrees to revise the definition as requested.
2. Provision of Supplemental Application to FDA District Office 
(Proposed Sec.  514.8(b)(1)(iv))
    Proposed Sec.  514.8(b)(1)(iv) states that an applicant must 
include in each supplemental application providing for a change under 
paragraph (b)(2) or (b)(3) of this section, a statement certifying that 
a copy of the supplement has been provided to the appropriate FDA 
district office.
    (6) One comment requested deletion of this requirement since many 
district offices have neither the space to store these documents nor 
the need for all submission documents. Any submission documents desired 
or required by the district office are available either from the 
Document Control Unit, by request from the manufacturing site, or at 
the manufacturing site during an inspection. Requiring copies to be 
sent to the district offices is a non-productive use of both industry 
and agency resources and effectively circumvents the goal of this rule 
and the intent of the Modernization Act.

[[Page 74771]]

    Another comment requested clarification as to whether the field 
copy should be sent to the applicant's home district office, to the FDA 
office where the change is being made, or to the FDA office in the 
district of the company's corporate headquarters. FDA also was asked to 
clarify to what FDA office the copy should be sent for changes outside 
of the United States.
    Agency Response: FDA declines to revise the regulations as 
suggested.
    FDA disagrees that sending copies to the district offices is a non-
productive use of both industry and agency resources. Instead, this 
requirement may reduce the burden on FDA resources (for example, 
searching and copying documents in the Document Control Unit by the CVM 
review staff), increase the awareness and interaction of district 
offices with FDA headquarters regarding manufacturing changes placed 
into effect for animal drugs, and improve the timeliness of CGMP 
inspections for certain types of changes for animal drugs, if needed.
    FDA also believes that this requirement is in accord with the 
intent of the Modernization Act, specifically section 506A of the act. 
That section describes requirements and procedures for making and 
reporting manufacturing changes. One of the requirements specified in 
section 506A of the act is that the holder must ``validate'' or assess 
the effects of a change before distributing a drug made with the 
change. In order for FDA to determine whether an applicant has made a 
change according to section 506A of the act, the FDA's district offices 
also must be informed of the effected change or change to be effected 
concurrently with the change being reported to FDA headquarters in a 
supplemental application.
    Field copies should be sent to the FDA district office where the 
changes are being made. No field copy is required for changes made 
outside of the United States. Proposed Sec.  514.8(b)(1)(iv) is amended 
by adding the statement ``No field copy is required for a supplement 
providing for a change made to a drug manufactured outside of the 
United States''
3. Changes Listed in the Cover Letter (Proposed Sec.  514.8(b)(1)(v))
    Proposed Sec.  514.8(b)(1)(v) adds a requirement that a list of all 
changes contained in a supplement or annual report described in Sec.  
514.8(b)(4) must be included in the cover letter for the supplement or 
annual report.
    (7) Several comments requested that ``cover letter'' be replaced by 
``introduction to the document'' since cover letters are not considered 
confidential.
    Agency Response: FDA declines to revise the regulation as 
suggested. The standards for disclosing specific information from a 
cover letter or application do not differ depending on where this 
information is provided or what the document is titled. Information 
that is exempt from disclosure (e.g., trade secret or confidential 
commercial information) is not disclosed whether it is in a cover 
letter or an application (see also 21 CFR 514.11). FDA has revised 
proposed Sec.  514.8(b)(1)(v) to harmonize with the reporting 
requirements in CDER's regulations Sec.  314.70(a)(6) to only require 
supplements to provide a list of all the changes in the cover letter. 
For annual reports, the list of changes may be provided in the cover 
letter or in the submission's summary section.

C. Changes Requiring Submission and Approval of a Supplement Prior to 
Distribution of the Drug Made Using the Change (Major Changes)

1. Changes That May Affect Product Sterility Assurance (Proposed Sec.  
514.8(b)(2)(ii)(C))
    Proposed Sec.  514.8(b)(2)(ii)(C) requires prior approval for 
changes that may affect product sterility assurance, such as changes in 
product or component sterilization method(s) or an addition, deletion, 
or substitution of steps in an aseptic processing operation.
    (8) Several comments suggested that the language be modified to 
state ``changes that reduce the sterility assurance level'' since the 
impact on the sterility assurance level should be the guiding factor 
and the language, as proposed, is too burdensome in terms of regulatory 
reporting.
    Agency Response: FDA declines to revise the provision as requested. 
The assessment as to whether a change reduces the sterility assurance 
is a complex and multidimensional analysis. For example, a change to a 
more stringent terminal sterilization process, while in theory 
providing a lower probability of non-sterile units, may damage the 
container closure system so that sterility of individual units could 
not be maintained. FDA also disagrees that the proposed language is too 
burdensome with regard to regulatory reporting. Under the previous 
regulations in Sec.  514.8(a)(2), most manufacturing and control 
changes, including manufacturing and control changes for sterile drug 
substance or drug products, required prior approval supplements. The 
proposed regulations allow the opportunity for applicants to report 
more manufacturing changes in changes-being-effected supplements or 
annual reports, including those manufacturing changes that will not 
negatively impact sterility assurance levels.
2. Changes Affecting Natural Products (Proposed Sec.  
514.8(b)(2)(ii)(F))
    Proposed Sec.  514.8(b)(2)(ii)(F) requires prior approval for 
changes solely affecting a natural product, a recombinant DNA-derived 
protein/polypeptide product, or a complex or conjugate of a new animal 
drug with a monoclonal antibody for the following: (1) Changes in the 
virus or adventitious agent removal or inactivation method(s), (2) 
changes in the source material or cell line, and (3) establishment of a 
new master cell bank or seed.
    (9) Several comments requested that FDA delete the reference to 
``natural products'' since the definition of natural products is not 
clear and having special requirements for this additional category of 
products represents additional regulatory reporting requirements beyond 
current practice.
    Agency Response: FDA declines to delete the phrase ``natural 
products'' from this provision. The changes identified in this 
provision are major changes and apply equally to a natural product, a 
recombinant DNA-derived protein/polypeptide, or a complex or conjugate 
of a drug substance with a monoclonal antibody. FDA will provide a 
definition of natural product in the final guidance that will be 
published shortly, but declines to provide the definition in the 
regulation because advancements in technology may require that the 
definition be revised.
    FDA also disagrees that having special requirements for this 
additional category of products imposes additional regulatory reporting 
requirements beyond current practice. Under the previous regulations at 
Sec.  514.8(a)(2), most manufacturing and control changes, including 
those for a natural product, DNA-derived protein/polypeptide, or a 
complex or conjugate of a new animal drug with a monoclonal antibody, 
required prior approval supplements. In the final guidance, FDA will 
identify changes related to these products that may now be filed in 
changes-being-effected supplements or annual reports. However, the 
three changes specified in this provision, which are unique to the 
identified types of drug products, are considered to have a substantial 
potential to adversely affect the identity, strength, quality, purity, 
or potency of a drug as these factors may relate to the safety or 
effectiveness of a drug. Virus or adventitious agent removal or

[[Page 74772]]

inactivation processes are the means by which FDA ensures that these 
types of agents are removed. Failure to remove such agents has a 
significant potential to adversely affect public safety. Changes in 
source material or cell line, or establishment of a new master cell 
bank or seed, have a substantial potential to affect the quality of a 
drug substance. For example, a change in source material (e.g., 
species, geographic region of harvesting) could result in different 
impurities or contaminants (e.g., pesticides) than were previously seen 
or cause a change in potency.
3. Supplement Approval Prior to Product Distribution (Proposed Sec.  
514.8(b)(2)(iii))
    Proposed Sec.  514.8(b)(2)(iii) specifies the information to be 
included in the supplement.
    (10) Several comments requested adding ``as appropriate'' as 
follows: ``Except for submissions under paragraph (e) of this section, 
the following shall be contained in the supplement, as appropriate.'' 
The comments said that not all listed material is relevant for every 
submission.
    Agency Response: FDA declines to revise the provision as requested. 
FDA expects that the information specified in Sec.  514.8(b)(2)(iii)(A) 
through (I) will be needed for many supplemental applications. FDA 
believes that the addition of ``as appropriate'' may incorrectly give 
the impression that this information is not routinely needed and would 
result in supplemental applications being submitted with insufficient 
information.
4. Validation Protocols for Natural Products (Proposed Sec.  
514.8(b)(2)(iii)(H))
    Proposed Sec.  514.8(b)(2)(iii)(H) states that for a natural 
product, a recombinant DNA-derived protein/polypeptide product, or a 
complex or conjugate of a drug with a monoclonal antibody, relevant 
validation protocols must be provided in addition to the requirements 
in Sec.  514.8(b)(2)(iii)(E) and (b)(2)(iii)(F).
    (11) One comment requested that FDA delete the requirement for the 
submission of validation protocols for ``natural products, et. al.'' 
because: (1) Validation protocols are maintained at the manufacturing 
site and are more appropriately reviewed on site, and (2) requiring 
submission of validation protocols only for natural products is a new 
and additional requirement that provides no greater assurance of safety 
or effectiveness of these products. The comment further stated that the 
additional regulatory burden is in opposition to the goals of the 
proposed rule and to the intent of the Modernization Act, and that 
there is no scientific rationale for singling out natural products 
under this requirement. In addition, there is no clear definition of 
these products, although the accompanying guidance states that natural 
products include products derived from microorganisms. Many products, 
including antibiotics, are derived from microorganisms and have been 
produced and used for many years, some for decades, with adequate 
controls on manufacturing changes and no adverse effects. Requiring 
submission of validation protocols for only this single class of 
products is excessive.
    Agency Response: FDA declines to revise the provision as requested. 
Unless otherwise specified by FDA, validation protocols and data need 
not be filed in the application but should be retained at the facility 
and be available for review by FDA at the agency's discretion. For most 
products, FDA does not require the submission of validation protocols 
and data. However, for a natural product, a recombinant DNA-derived 
protein/polypeptide, or a complex or conjugate of a drug substance with 
a monoclonal antibody, FDA does require the submission of validation 
protocols for certain critical manufacturing processes unique to these 
drug substances or drug products. For example, FDA would expect the 
validation protocol for the virus or adventitious agent removal or 
inactivation process to be submitted in an application. FDA currently 
requires this type of information to be submitted in an application. 
Under Sec.  514.8(b)(1)(iii), FDA may publish future guidances to 
address specific filing requirements for these types of drug substances 
or drug products, including drug substances derived from 
microorganisms.
    FDA also disagrees that this requirement is an additional 
regulatory burden and contravenes the intent of the Modernization Act. 
Under the previous regulations at Sec.  514.8(a)(2), most manufacturing 
and control changes, including those for a natural product, required 
prior approval supplements. In the final guidance, FDA will identify 
many changes related to these products that may be filed in changes-
being-effected supplements or annual reports. As discussed previously, 
FDA will provide a definition of a natural product in the final 
guidance.
5. Validation Protocols and SOP's (Proposed Sec.  514.8(b)(2)(iii)(I) 
and (J))
    Proposed Sec.  514.8(b)(2)(iii)(I) states that for sterilization 
process and test methodologies, relevant validation protocols must be 
provided in addition to the requirements in paragraphs (b)(2)(iii)(E) 
and (b)(2)(iii)(F) of this section. Proposed Sec.  514.8(b)(2)(iii)(J) 
states that a reference list of relevant standard operating procedures 
(SOPs), when applicable, must be contained in the supplement.
    (12) Several comments recommended that reference to SOPs be deleted 
because: (1) The data represent compliance information and are better 
suited for field inspections, and (2) the addition of this information 
to existing practice would result in increased regulatory burden.
    Agency Response: FDA has revised the regulation in response to the 
comment. An applicant is required to submit a ``full description of the 
methods used in, and the facilities and controls used for, the 
manufacture, processing, and packing of such drug'' (sections 
512(b)(1)(D) and 512(n)(1)(G) (21 U.S.C. 360b(b)(1)(D) and 
360b(n)(1)(G)) of the act). This information may be submitted in 
different forms, including SOPs. In most cases, SOPs do not include 
information relevant to the NADA or ANADA review, but rather 
information relevant to determining an applicant's compliance with 
CGMPs. However, in the case of a natural product, a recombinant DNA-
derived protein/polypeptide, or a complex or conjugate of a new animal 
drug with a monoclonal antibody, or a sterilization process, 
information contained in SOPs is often relevant to the review of 
certain aspects of an application.
    FDA is deleting proposed Sec.  514.8(b)(2)(iii)(J) and is revising 
proposed Sec. Sec.  514.8(b)(2)(iii)(H) and (I) to limit the need for 
information on SOPs to these situations. As discussed previously, 
information regarding SOPs is needed in some cases. FDA wishes to 
emphasize that while the information is needed for the application 
review, it is not always necessary to submit the actual SOP as long as 
the required information is provided in sufficient detail as part of 
the application.
6. Expedited Review of Supplement (Proposed Sec.  514.8(b)(2)(iv))
    Proposed Sec.  514.8(b)(2)(iv) states that an applicant may request 
an expedited review of a supplement for public health reasons or if a 
delay in making the change described in the supplement

[[Page 74773]]

would impose an extraordinary hardship.
    (13) Several comments requested that FDA provide feedback to the 
applicant on the acceptance or refusal of an ``Expedited Review Request 
within 30 days.''
    Agency Response: FDA declines to revise the provision as requested. 
FDA intends to issue future guidance on requesting expedited reviews of 
supplemental manufacturing changes.
7. Protocol Submission as a Supplement (Proposed Sec.  514.8(b)(2)(v))
    Proposed Sec.  514.8(b)(2)(v) states that an applicant may submit 
one or more protocols describing the specific tests and validation 
studies and acceptable limits to be achieved to demonstrate the lack of 
adverse effect for specified types of manufacturing changes on the 
identity, strength, quality, purity, or potency of the product as these 
factors may relate to the safety or effectiveness of the product. Any 
such protocols, or change to a protocol, must be submitted as a 
supplement requiring FDA approval prior to distribution of the product. 
The supplement, if approved, may result in the proposed change 
subsequently falling within a reduced reporting category for the 
specific product because the use of the protocol for that type of 
change reduces the potential risk of an adverse effect.
    (14) One comment recommended deleting or modifying the requirement 
that protocols ``must be submitted as a supplement requiring approval 
for FDA prior to distribution of the product'' because this requirement 
will have an effect opposite of the intent of the Modernization Act. 
Submission as a supplement subjects protocols to a 180-day review 
timeframe. Currently, such protocols are reviewed in a 30-45 day 
timeframe. Extending the review timeframe will delay implementation of 
changes contrary to the stated purpose of this rule. The comment 
suggested that the aforementioned requirement either should be deleted 
or subject to a limited 30-day review timeframe.
    Agency Response: FDA declines to revise the regulation as 
requested. The protocols or ``comparability protocols'' described in 
proposed Sec.  514.8(b)(2)(v) are new types of protocols for drugs and 
differ from the types of protocols (e.g., stability protocols) 
typically submitted to an investigational new animal drug file. It is 
expected that applicants will use comparability protocols to justify a 
reduced reporting category for the particular change, for example, by 
requesting that they be allowed to implement a major change without 
prior approval by FDA. These protocols, in effect, will reduce the 
regulatory oversight of the specified changes, and FDA considers this 
to have the potential to have an adverse effect on the identity, 
strength, quality, purity, or potency of a drug as these factors may 
relate to the safety or effectiveness of the drug. Also, where 
previously allowed by regulations, these changes were specified as 
requiring prior approval, and this rule just extends that option of 
submitting protocols for animal drugs.
    FDA has revised Sec.  514.8(b)(2)(v) by adding the title 
``Comparability Protocol'' to differentiate this type of protocol from 
other types of protocols; and has included other language to be 
consistent with CDER's regulations.

D. Changes Requiring Submission of a Supplement at Least 30 Days Prior 
to Distribution of the Drug Made Using the Change (Moderate Changes)

8. Thirty-Day Changes-Being-Effected Supplement (Proposed Sec.  
514.8(b)(3)(ii)(B))
    Proposed Sec.  514.8(b)(3)(ii)(B) provides for a 30-day changes-
being-effected supplement for changes solely affecting a natural 
product, a recombinant DNA-derived protein/polypeptide product or a 
complex or conjugate of a new animal drug with a monoclonal antibody, 
including: (1) An increase or decrease in production scale during 
finishing steps that involves new or different equipment; and (2) 
replacement of equipment with that of a similar, but not identical, 
design and operating principle that does not affect the process 
methodology or process operating parameters.
    (15) Several comments stated that having special requirements for 
this category of products represents additional regulatory reporting 
requirements and regulatory burden beyond current practice and the 
intent of the Modernization Act. One comment requested that this 
section be removed and these changes be reported in annual reports. One 
comment stated that there is no scientific basis for singling out all 
natural products under this requirement as, for instance, 
microorganisms (from which some natural products are derived) form the 
basis of many products such as antibiotics, which have been produced 
and used for many years with adequate controls on manufacturing changes 
and no adverse effects. Rather, this comment advocated that these types 
of changes be evaluated on the potential for adverse impact on safety 
or effectiveness of the drug product.
    Agency Response: FDA declines to revise the regulation as 
requested. However, FDA has revised Sec.  514.8(b)(3)(ii)(B) to specify 
``natural protein'' rather than ``natural product'' to be consistent 
with CDER's regulations. There are specific issues and concerns 
relating to the production of natural protein products that are not 
routinely associated with other classes of drugs and, therefore, FDA 
has specified certain requirements for proteins. Proteins are 
susceptible to denaturation. Denaturation can be caused by changes in 
sheer force as a result of scale and/or equipment changes. Also, 
proteins differentially adsorb to surfaces. The identity, strength, 
quality, purity, or potency of the product could be affected by changes 
in scale or equipment because of these characteristics.
    (16) Several comments requested that FDA clarify whether this 
section applies to drug products or drug substances.
    Agency Response: FDA agrees to clarify the proposed language as 
appropriate. This section applies to all animal drugs, including Type A 
medicated articles. The terms ``drug substance'' and ``drug product'' 
are specifically identified if the changes do not apply to free-choice 
medicated feeds, Type A medicated articles or Type B and Type C 
medicated feed manufactured from a drug component (see response to 
comment 4).
    (17) Several comments requested clarification of ``finishing 
steps.''
    Agency Response: FDA declines to revise the regulations to provide 
clarification of the term ``finishing steps.'' In general, finishing 
steps are considered those steps in the manufacturing process where the 
stability or the property and performance of a protein product is less 
likely to be affected by changes in scale or equipment. The steps in a 
manufacturing process that would be considered finishing steps depend 
on the manufacturing process and the specific protein being 
manufactured. A particular manufacturing step may be considered a 
finishing step for one product but not for another. An applicant is 
encouraged to discuss with FDA which steps would be considered 
finishing steps for its particular product and process. This discussion 
should occur as early in the process as possible, including during INAD 
meetings.
    (18) Several comments requested clarification of the difference 
between equipment that is ``similar, but not identical,'' proposed as a 
changes-being-effected-in-30-days supplement, and the SUPAC terminology 
of equipment of the ``same design and operating principle,'' which 
already is defined in the SUPAC guidance and the proposed rule as an

[[Page 74774]]

annual report change. The comments further suggested that for equipment 
changes that are of different operating principle and design, FDA 
should consider classification within the major change category, and 
for equipment changes that are of the same operating principle but 
different design, FDA should consider classification within the 
moderate change category.
    Agency Response: FDA agrees that replacement of equipment with that 
of a different design that does not affect the process operating 
parameters may be reported as a changes-being-effected-in-30-days 
supplement. Therefore, FDA is clarifying the requirement by replacing 
the phrase ``similar, but not identical, design and operating 
principle'' with the phrase ``different design.'' Equipment of a 
different design may or may not have a different operating principle.
    FDA is also revising section 514.8(b)(3)(ii)(B)(2) by deleting 
``new or'' since new equipment may not necessarily be different 
equipment in regard to process methodology or process operating 
parameters.
9. Supplement--Changes Being Effected (Proposed Sec.  514.8(b)(3)(vi))
    Proposed Sec.  514.8(b)(3)(vi) states that the agency may designate 
a category of changes for the purpose of providing that, in the case of 
a change in such category, the holder of an approved application may 
begin distribution of the drug involved upon receipt by the agency of a 
supplement for the change. The information listed under paragraph 
(b)(2)(iii) of this section must be contained in the supplement. The 
supplement must be labeled ``Supplement--Changes Being Effected.'' 
These changes include, but are not limited to: (1) Addition to a 
specification or changes in the methods or controls to provide 
increased assurance that the new animal drug will have the 
characteristics of identity, strength, quality, purity, or potency that 
it purports or is represented to possess and (2) a change in the size 
and/or shape of a container for a nonsterile drug product, except for 
solid dosage forms, without a change in the labeled amount of product 
from one container closure system to another.
    (19) Several comments recommended that FDA add ``a sterile drug 
product or a sterile drug substance'' to expand the type of drug 
products for which the container changes allowed in this section would 
apply, since size and shape changes for sterile API and drug products 
have only moderate potential impact. This is especially true when the 
size/shape changes are very minor in nature, as is often the case when 
suppliers make minute adjustments in their packaging components.
    Agency Response: FDA declines to revise the regulation as 
requested. Sterility of drug products is a fundamental and essential 
quality attribute of these drugs and is a critical aspect of the safety 
assessment. Changes in the container closure system, even if minimal, 
may affect the sterility assurance of the drug product and are 
considered major changes. FDA acknowledges that the effects of changes 
in the size and/or shape of the container closure system for sterile 
drug substances are considered by FDA to be a lower risk than for 
sterile drug products because of the differences in procedures for 
sterilizing drug substances and finished drug products. However, they 
are still of a higher risk than for nonsterile products. Therefore, FDA 
declines to specify in the regulations that these changes can be 
submitted in a changes-being-effected supplement. Additional 
information on changing container closure systems for drug products is 
included in the final guidance.
10. Disapproved Supplements and Drug Distribution Stoppage (Proposed 
Sec.  514.8(b)(3)(vii))
    Proposed Sec.  514.8(b)(3)(vii) provides that if the agency 
disapproves the supplemental application submitted under paragraph 
(b)(3) of this section, the agency may order the manufacturer to cease 
distribution of the drug products made with the manufacturing change.
    (20) Several comments recommend replacing the language in Sec.  
514.8(b)(3)(vii) with ``If FDA later determines that the supplemental 
application is not immediately approvable, the agency will work with 
the applicant to resolve all issues and to assure the continued 
availability of the drug,'' since this is the current practice and the 
intent of the U.S. Senate as recorded in Senate Report 105-43.
    Agency Response: FDA declines to revise the provision as requested. 
The regulation is consistent with section 506A(d)(3)(B)(iii) of the 
act, which allows FDA to disapprove a supplemental application and 
order the manufacturer to cease distribution of the drug made with the 
change.

E. Changes and Updated Stability Data to be Described and Submitted in 
an Annual Report (Minor Changes)

1. Minor Changes Documented in an Annual Report (Proposed Sec.  
514.8(b)(4)(ii)(A))
    Under proposed Sec.  514.8(b)(4)(ii)(A), the following type of 
change must be documented in the next annual report: Any change made to 
comply with an official compendium that is consistent with FDA 
requirements and provides increased assurance that the new animal drug 
will have the characteristics of identity, strength, quality, purity, 
or potency that it purports or is represented to possess.
    (21) Several comments requested that FDA change this requirement to 
read ``Any change to comply with an official compendium.'' One of these 
comments added that: (1) Section 501(b) of the act requires the FDA to 
resolve any differences with the compendial body, the United States 
Pharmacopoeia (USP), (2) it is unfair to place the applicant in the 
middle of these discussions, and the compendial review process should 
be the mechanism by which the FDA has influence, and (3) it should be 
permitted and appropriate that any USP-adopted changes, including 
changes that may relax acceptance criteria and/or analytical 
procedures, be updated via an annual report, with both the innovator as 
well as any generic companies subject to this requirement. Another one 
of these comments added that FDA's proposed regulations are 
inconsistent with the statutory structure for drug approval and 
quality, and that requiring supplements for labeling changes consistent 
with compendial revisions would likely cause confusion and uncertainty 
about a product's legal status and further impose unnecessary, 
burdensome requirements on industry.
    Agency Response: FDA declines to revise the provision as requested, 
but is revising the regulations to provide further clarification. The 
basis for this decision is set forth as follows.
    Under section 501(b) of the act (21 U.S.C. 351(b)), a drug that is 
recognized in an official compendium may be considered adulterated if 
its strength differs from, or its quality or purity falls below, the 
standards set in the compendium. Determinations of adulteration under 
this provision of the act must be made in accordance with the 
analytical procedures prescribed in the compendium, except when there 
is no analytical procedure prescribed in the compendium or if the tests 
prescribed in the compendium are insufficient and the agency has gone 
through the process outlined in the

[[Page 74775]]

statute and has issued a regulation to provide an appropriate 
analytical procedure. No drug defined in an official compendium will be 
considered adulterated under section 501(b) of the act because its 
strength differs from, or its quality or purity falls below, the 
standards set in the compendium if the differences from the standard 
are stated in its label. Under section 502(g) of the act (21 U.S.C. 
352(g)), a drug that is recognized in an official compendium may be 
considered misbranded if the drug is not packaged and labeled as 
prescribed in the compendium.
    FDA is aware of the legal status of the United States 
Pharmacopoeia/National Formulary (USP/NF) under the act as a standard 
for determining whether a drug may be considered adulterated or 
misbranded. A compendial product that fails to comply with USP/NF 
standards may be considered to be adulterated or misbranded under the 
act. However, a compendial product can still be considered adulterated 
or misbranded under other provisi