[Federal Register Volume 71, Number 239 (Wednesday, December 13, 2006)]
[Rules and Regulations]
[Pages 74766-74785]
From the Federal Register Online via the Government Publishing 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: 
[email protected].

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 provisions of sections 501 or 502 of the act, 
even if it complies with USP/NF standards.
    Thus, while the standards in the USP/NF are legally enforceable 
standards for determining whether a drug is considered adulterated 
under section 501 of the act, these standards are not considered the 
complete regulatory specifications. FDA is responsible for establishing 
regulatory specifications as part of the approval of an application. 
Under section 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, an application must include a full 
description of the methods used in, and the facilities and controls 
used for, the manufacture, processing and packing of the drug. If the 
specifications included in the application are considered inadequate to 
ensure and preserve the identity, strength, quality, purity or potency 
of the drug, FDA will refuse to approve the application. Standards 
established by an official compendium may be inadequate for the 
purposes of approving an application under sections 512(d)(1) and 
512(c)(2)(A) (21 U.S.C. 360b(d)(1) and 360b(c)(2)(A)) of the act. The 
USP acknowledges that ``[w]hile one of the primary objectives of the 
Pharmacopoeia is to assure the user of official articles of their 
identity, strength, quality, and purity, it is manifestly impossible to 
include in each monograph a test for every impurity, contaminant, or 
adulterant that might be present, including microbial contamination. 
These may arise from a change in the sources of the material or from a 
change in the processing, or may be introduced from extraneous sources. 
Tests suitable for detecting such occurrences, the presence of which is 
inconsistent with applicable good manufacturing practice or good 
pharmaceutical practice, should be employed in addition to the tests 
provided in the individual monograph.'' (U.S.P. 29, General Notices, 
Foreign Substances and Impurities).
    Not all compendial standards or changes in existing compendial 
standards are adequate to ensure and preserve the identity, strength, 
quality, purity, or potency of the drug, or are consistent with other 
requirements of the act. For example, a deletion of an impurity test 
may result in an inadequate standard for ensuring the purity of the 
drug. Therefore, FDA does not believe that all changes made to comply 
with an official compendium are of a type that should be reported in an 
annual report.
    Analytical procedures: For compendial drugs, the determination of 
whether the drug is adulterated under section 501(b) of the act must be 
made in accordance with the analytical procedures set forth in the 
compendium, except when there is no analytical procedure prescribed in 
the compendium or if the tests prescribed in the official compendium 
are insufficient. In these situations, FDA can follow the process 
outlined in the statute and issue a regulation to provide an 
appropriate analytical procedure. Because of the legal status of 
compendial analytical procedures in the act and other requirements 
relating to analytical procedures in the statute, FDA concurs that 
changes in analytical procedures to comply with an official compendium 
may be filed in an annual report except for changes to comply with an 
official compendium that result in the deletion of a test or the 
relaxation of an acceptance criterion and has revised the regulation 
accordingly. FDA wishes to emphasize that under FDA's CGMP regulations, 
the suitability of all analytical procedures, including compendial 
procedures, must be verified under actual conditions of use. For 
example, an assay analytical procedure where degradation products, 
impurities, or excipients interfere with the analysis is not considered 
an acceptable analytical procedure. The use of unacceptable analytical 
procedures, even if specified in an official compendium, can be 
considered a violation of the act. FDA also wishes to emphasize that a 
change from an approved analytical procedure that is capable of 
quantifying impurities to a compendial analytical procedure that cannot 
quantify impurities is in essence a deletion of an impurities test. 
This change of procedure should not be reported in an annual report, 
but should be reported as any other request for deletion of an approved 
test.
    Tests and acceptance criteria: Under sections 512(b)(1)(D) and 
512(n)(1)(G) of the act, an application must include a full description 
of the methods used in, and the facilities and controls used for, the 
manufacture, processing and packing of the drug. If the specifications 
included in the application are considered inadequate to ensure and 
preserve the identity, strength, quality, purity, or potency of the 
drug, the agency will refuse to approve the application. As previously 
discussed, the standards established by an official compendium may be 
inadequate for the purposes of approving an application under sections 
512(d)(1) and 512(c)(2)(A) (21 U.S.C. 360b(d)(1)(C) and 
360b(c)(2)(A)(i)) of the act.
    As part of the detailed application review process and in 
accordance with section 512 of the act, FDA requires tests and 
acceptance criteria that the agency believes are necessary to ensure 
and preserve the identity, strength, quality, purity, and potency of 
the product. The specifications included in the approved application 
are legally binding upon the applicant, and a product that fails to 
comply with the specifications included in the approved application can 
be considered an unsafe new animal drug under section 512(a)(1) of the 
act. Compendial standards are often used in evaluating the 
specifications proposed in the application. However, compendial 
standards often must be supplemented with additional tests, such as a 
specific test for impurities, to ensure the identity, strength, 
quality, purity, and potency of the drug. Also, the tests and 
acceptance criteria in an application are often approved without the 
benefit of a compendial standard for a drug because no compendial 
standard has been established. Situations could arise where, for 
example, FDA requires tests and acceptance criteria for specific 
impurities as part of approval of an application. These impurities are 
not specified in an existing monograph or are not included in a 
monograph published subsequent to the approval of the drug. If FDA 
allowed all changes that comply with an official compendium to be 
included in an annual report, the applicant could interpret this 
provision as allowing it to delete the tests that are required as a 
condition of approving the application.
    A change to relax an acceptance criterion or delete a test is 
considered a major change. FDA needs to review a request for this type 
of change in the

[[Page 74776]]

context of a particular NADA or ANADA to determine if the change will 
adversely affect the identity, strength, quality, purity, or potency of 
the drug. Changes such as these, when requested solely at the 
discretion of the applicant, must be filed in a prior approval 
supplement. Reporting these changes in an annual report is not 
appropriate. However, when a change to relax an acceptance criterion or 
delete a test is made to comply with a change to an official 
compendium, the change is considered to have a moderate potential to 
have an adverse effect on the identity, strength, quality, purity, or 
potency of the drug as these factors may relate to the safety or 
effectiveness of the drug. The change is considered to be moderate 
because: (1) The change has been reviewed by an independent, impartial 
group that has the goal of promoting public health, and (2) FDA has had 
the opportunity through the USP process of reviewing the proposed 
change in general, but not necessarily in the context of each 
individual application affected by the change. Therefore, FDA will 
require a changes-being-effected-in-30-days supplement for a change to 
relax an acceptance criterion or delete a test to comply with a change 
to an official compendium. A change made to comply with an official 
compendium that results in a tightening of an approved acceptance 
criterion or an addition of a test may be filed in an annual report.
    The provisions in the final rule for changes to comply with an 
official compendium might be viewed by some as an increase in burden 
over how FDA has been interpreting its regulations regarding 
supplements in the past. However, FDA believes that the provisions are 
necessary and consistent with the requirements of section 506A for the 
establishment of the reporting category for a change based on the 
change's 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 the drug.
    For the reasons discussed previously, the agency is adding Sec.  
514.8(b)(3)(ii)(C) as follows: ``Relaxation of an acceptance criterion 
or deletion of a test to comply with an official compendium that is 
consistent with FDA statutory and regulatory requirements.'' The agency 
also is revising Sec.  514.8(b)(4)(ii)(A) as follows: ``Any change made 
to comply with an official compendium, except a change in paragraph 
(b)(3)(ii)(C) of this section, that is consistent with FDA statutory 
and regulatory requirements.''
2. Minor Changes--Replacement of Equipment (Proposed Sec.  
514.8(b)(4)(ii)(C))
    Under proposed Sec.  514.8(b)(4)(ii)(C), the following minor change 
must be documented in the next annual report: Replacement of equipment 
with that of the same design and operating principles except for 
equipment used with a natural product, a recombinant DNA-derived 
protein/polypeptide product, or a complex or conjugate of a new animal 
drug with a monoclonal antibody.
    (22) One comment requested deleting the words ``except for 
equipment used with a natural product, a recombinant DNA-derived 
protein/polypeptide product.'' According to the comment, singling out 
these products by requiring a higher classification for these changes 
is inappropriate, as there is no scientific basis for a blanket 
application of this distinction and all changes should be assessed on 
their potential for adverse affects on the safety or effectiveness of 
the product. The comment further stated that equipment for natural 
products (as defined in this rule) should be evaluated on the same 
basis as that for all other products.
    Agency Response: FDA declines to revise the regulation as 
requested, but has revised it to provide clarity by referencing section 
(b)(3) in regard to exceptions for equipment replacement. As discussed 
in the response to comment 15, there are specific issues and concerns 
for these drugs as a result of scale and/or equipment changes not 
routinely associated with other classes of drugs. Changes to identical 
equipment used in the production of proteins could be reported in an 
annual report. However, a change to equipment of the same design and 
operating principle, but not identical equipment (e.g., capacity), is 
not considered a minor change for protein products.
3. Minor Changes--Container Changes (Proposed Sec.  514.8(b)(4)(ii)(D))
    Under proposed Sec.  514.8(b)(4)(ii)(D), the following minor change 
is documented in the next annual report: A change in the size and/or 
shape of a container containing the same number of dosage units for a 
nonsterile solid dosage form, without a change from one container 
closure system to another.
    (23) Several comments recommended deleting ``containing the same 
number of dosage units.'' According to the comments, for nonsterile 
dosage forms, the fill count of the bottle should be allowed to be 
changed along with the size/shape. The current language would allow 
size of the bottle to increase (resulting in more headspace) but the 
fill count to not equivalently change.
    Agency Response: FDA declines to revise the regulation as 
requested. Due to the differences and complexities of labeling issues 
for animal drug products versus human drug products, regulation of 
labeling changes is not being harmonized with human drug product 
regulations. However, information regarding the reporting of labeling 
and other types of changes to animal drug products has been updated and 
consolidated under Sec.  514.8(c). Labeling changes related to 
manufacturing changes, e.g., changes to the labeled storage conditions, 
will be identified in the final guidance.
4. Minor Changes--Code Imprints (Proposed Sec.  514.8(b)(4)(ii)(H))
    Under proposed Sec.  514.8(b)(4)(ii)(H), the following minor change 
is documented in the next annual report: The addition by embossing, 
debossing, or engraving of a code imprint to a solid oral dosage form 
drug product other than a modified release dosage form, or a minor 
change in an existing code imprint.
    (24) A few comments requested that FDA revise this provision to 
allow the addition of an ink imprint. Another comment said it is not 
clear whether the provision includes ink printing, and a cross-
reference to part 206, Imprinting of Solid Oral Dosage Form Drug 
Products for Human Use, may also be helpful. One comment requested that 
wording should be added to allow for ink printing on modified dosage 
forms, as this should not impact drug release.
    Agency Response: FDA declines to revise the regulation as requested 
and is clarifying that inks are not included in this provision. FDA 
believes that any recommendations on how to report the addition of inks 
is best handled in guidance documents so that the issues and conditions 
associated with such changes can be fully explained. For example, FDA 
would expect that any colors used in ink imprint would be listed for 
use in or on a drug in FDA regulations (see 21 CFR parts 73, 74, 81, 
and 82).
5. Annual Report--Required Information (Proposed Sec.  
514.8(b)(4)(iii))
    Proposed Sec.  514.8(b)(4)(iii) requires the applicant to submit in 
the annual report a list of all products affected by a change in this 
category, and: (1) A statement by the holder of the approved 
application that the effects of the change have been validated; (2) a 
full description of the manufacturing and control changes, including 
the manufacturing site(s) or area(s)

[[Page 74777]]

involved; (3) the date each change was made; (4) cross reference to 
relevant validation protocols and/or SOP's; (5) relevant data from 
studies and tests performed to evaluate the effect of the change on the 
identity, strength, quality, purity, or potency of the product as these 
factors may relate to the safety or effectiveness of the product 
(validation); (6) appropriate documentation (for example, updated 
master batch records, specification sheets, etc.) including previously 
approved documentation (with the change highlighted) or references to 
previously approved documentation; and (7) updated stability data 
generated on commercial or production batches according to an approved 
stability protocol.
    (25) Several comments recommended that the reference to SOPs and 
the term ``validation'' be deleted, and that the agency also eliminate 
the requirements that the applicant submit the date each change was 
made and cross reference to relevant validation protocols and/or SOPs, 
as the data represent compliance information and are better suited for 
field inspections. The comments asserted that the addition of this 
proposed information to existing practice would result in increased 
regulatory burden.
    Agency Response: FDA is revising the provision to clarify when 
validation protocols and SOPs are needed. The agency's response to 
comment 26 addresses the recommended deletion of providing the date 
each change was made. As discussed with regard to comment 11, 
validation protocols and data need not be filed in the application, 
unless otherwise specified by FDA, but should be retained at the 
facility and be available for review by FDA at the agency's discretion. 
For most drugs, FDA does not require the submission of validation 
protocols and data. However, for a natural protein, a recombinant DNA-
derived protein/polypeptide, a complex or conjugate of a drug substance 
with a monoclonal antibody, or sterilization process, FDA does require 
the submission of validation protocols for certain critical 
manufacturing processes unique to these drugs. In addition, an 
applicant is required to submit a full description of controls used for 
the manufacture, processing, and packing of a drug (sections 
512(b)(1)(d) and 512(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 drug 
substance with a monoclonal antibody, or a sterilization process, 
information contained in SOPs is often relevant to the review of 
certain aspects of an application.
6. Annual Report--Provision of Date(s) of Changes (Proposed Sec.  
514.8(b)(4)(iii)(C))
    (26) One comment recommended that Sec.  514.8(b)(4)(iii)(C), which 
provides that the date each minor change is made be submitted in an 
annual report, be modified to state ``Either the date each change was 
made or the first lot produced using the change.'' The comment suggests 
that for processes that take several days, the first lot number is more 
appropriate than the date. The lot number allows traceability through 
the entire process to better determine the effect of the change.
    Agency Response: FDA declines to revise the regulation as 
requested. The date when a change is made is important to identify the 
production batches that may be affected by the change. This is 
important for various reasons; for instance, it allows reviewers to 
easily compare data generated at different times to determine if there 
are any changes or trends in product quality over time. The reporting 
of a lot number may not readily indicate to the reviewer the date the 
change was made.
7. Annual Report--Appropriate Documentation (Proposed Sec.  
514.8(b)(4)(iii)(F))
    (27) One comment stated that requiring the submission of batch 
records with changes highlighted is an unnecessary additional burden 
that will not increase the assurance of the safety, purity, or 
effectiveness of products, and is in contravention of the goals of the 
proposed rule and the intent of the Modernization Act. Batch records 
may be issued or reissued to correct minor typographical errors or to 
clarify instructions. Several versions may be issued in 1 year. 
Requiring the highlighting of all of these changes in the annual update 
is unnecessary, as batch records and their history are maintained at 
the manufacturing site and are available for review during inspections.
    Agency Response: FDA declines to revise the regulation as 
requested. Under Sec.  514.8(b)(1)(v), FDA is requiring that a list of 
changes be provided in both supplemental applications and annual 
reports. FDA proposed this requirement as a means to more efficiently 
locate and identify changes in what are often substantial documents. It 
is expected that any change to an approved document (e.g., master batch 
record, raw material specification sheet, analytical method procedure, 
etc.), other than a minor editorial or format change, results in an 
updated document that must be included as part of the supplemental 
application or annual report. Highlighting the proposed or implemented 
change(s), other than editorial or format change(s), will allow the 
reviewer to easily review and assess the impact of these change(s), if 
any, on the identity, strength, quality, purity or potency of a drug as 
these factors may relate to the safety or effectiveness of the drug. 
For changes reported in the annual report, it is expected only the most 
recently revised document at the time of preparation be submitted with 
the minor changes highlighted and with a copy of the previously 
approved document (or reference to where this document can be found in 
the new animal drug file).
    Section 506A(d)(2)(A) also states in part that a holder making a 
certain type of manufacturing change shall submit a report on the 
change ``which shall contain such information as the Secretary 
determines to be appropriate* * *.'' Therefore, for new animal drugs, 
FDA determines that this requirement is appropriate for ease of review 
and assessment of the impact of a minor change(s).

F. Labeling and Other Changes to an Approved Application

1. Approved Application--Labeling and Other Changes (Proposed Sec.  
514.8(c))
    Proposed Sec.  514.8(c) describes labeling and other changes to an 
approved application.
    (28) One comment stated that this section appears to eliminate the 
ability to report minor changes to labeling in an annual update. 
According to the comment, label changes are classified as major changes 
(Sec.  514.8(c)(2)) or requiring a written notice of a supplemental 
application--Changes Being Effected (Sec.  514.8(c)(3)). It is 
requested that this section be clarified and the opportunity to submit 
minor changes in an annual update be added. Labeling changes unrelated 
to product effectiveness or safety should be permitted as minor changes 
and included in annual reporting. The accompanying guidance document 
should be expanded to address labeling changes.
    Agency Response: FDA declines to revise the provision as requested. 
However, FDA agrees that a few labeling changes (e.g., changes to the 
labeled storage condition to be submitted in a

[[Page 74778]]

prior approval supplement) are more appropriately reported to and 
reviewed by FDA/CVM's Division of Manufacturing Technologies in either 
a prior approval supplement, changes-being-effected supplement, or 
annual report, i.e., minor changes and stability reports. Labeling 
changes more appropriately submitted to the Division of Manufacturing 
Technologies, including those labeling changes that can be reported in 
an annual report, will be described in the final version of the 
companion guidance document. Labeling changes (for example, design and 
style) that do not decrease safety of drug use and that are proposed in 
supplemental applications may be placed into effect prior to written 
notice of approval from FDA of a supplemental application (Sec.  
514.8(c)(3)(ii)).
2. Approved Applications--General Provisions for Labeling and Other 
Changes (Proposed Sec.  514.8(c)(1))
    Proposed Sec.  514.8(c)(1) states that the applicant must notify 
FDA about each change in each condition established in an approved 
application beyond the variations already provided for in the 
application. The notice is required to describe the change fully.
    (29) One comment recommended that the statement ``Any change made 
in labeling to comply with an official compendium may be submitted in 
the annual report'' be included in proposed Sec.  514.8(c)(1) as 
follows: ``(1) General Provisions. The applicant must notify FDA about 
each change in each condition established in an approved application 
beyond the variations already provided for in the application. The 
notice is required to describe the change fully. Any change made in 
labeling to comply with an official compendium may be submitted in the 
annual report.''
    Agency Response: FDA declines to revise the provision as requested. 
While the labeling requirements in the USP/NF are legally enforceable 
standards for determining whether a product is misbranded under section 
502 of the act, use of these standards alone does not ensure compliance 
with the act. Moreover, the USP states that ``Articles in this 
Pharmacopoeia are subject to compliance with such labeling requirements 
as may be promulgated by governmental bodies in addition to the 
Pharmacopoeial requirements set forth for the articles.'' (U.S.P. 29, 
General Notices, Labeling).
3. Labeling Changes and Sec.  514.80 (Proposed Sec.  514.8(c)(2)(C)(3))
    Proposed Sec.  514.8(c)(2)(C)(3) provides that the prescription 
drug labeling not requiring an approved supplemental application is 
submitted in accordance with Sec.  514.80(b)(3)(ii). Proposed Sec.  
514.8(c)(4) describes ``Changes providing for additional distributors 
to be reported under Records and reports concerning experience with new 
animal drugs for which an approved application is in effect'' (Sec.  
514.80). According to Sec.  514.8(c)(4), supplemental applications as 
described under Sec.  514.8(c)(2) will not be required for an 
additional distributor to distribute a drug that is the subject of an 
approved new animal drug application if the conditions described under 
Sec.  514.80(a)(2), (b)(3), and (b)(5)(iii) are met.
    (30) One comment recommended that the reference to Sec.  514.80 be 
removed since it refers to a non-existent rule.
    Agency Response: The final rule for Sec.  514.80 was published on 
March 31, 2003 (68 FR 15365). Therefore, the agency is retaining the 
reference to Sec.  514.80.

G. Implementation of the Final Rule and Guidance

    (31) One comment recommended that the proposed rule and draft 
guidance be withdrawn in order to allow development of a revised 
proposed rule and associated industry guidance that clearly reflect the 
intent of Congress, as required by the Modernization Act. The comment 
also encouraged FDA to work in collaboration with the industry in 
crafting improved versions of these important regulations. The comment 
contends that the proposal and guidance fails to address and fulfill 
the intent of the Modernization Act, a substantial number of individual 
issues in the proposed rule and guidance require revision, there was a 
lack of industry and public involvement in drafting the documents, and 
the time provided by FDA for the evaluation, comment, and considered 
revisions was too short.
    Agency Response: FDA declines to withdraw the proposed rule and 
guidance. FDA's procedures for rulemaking are governed by the 
Administrative Procedure Act (5 U.S.C. 553) and set forth in FDA 
regulations at 21 CFR 10.40 and 10.80. Guidances are developed in 
accordance with FDA's good guidance practices (GGPs) (see the Federal 
Register of September 19, 2000 (65 FR 56468) and 21 CFR 10.115). As 
discussed previously in this document, the use of guidance documents 
will allow FDA to more easily and quickly modify and update important 
information. Moreover, section 506A of the act explicitly provides FDA 
the authority to use guidance documents to determine the type of 
changes that do or do not have a substantial potential to adversely 
affect the safety or effectiveness of the drug. In the October 1, 1999 
proposal, FDA proposed to implement section 506A of the act for NADAs 
and ANADAs. In that same issue of the Federal Register, FDA announced 
the availability of a draft guidance for industry entitled ``Chemistry, 
Manufacturing and Control Changes to an Approved NADA or ANADA'' to 
assist applicants in determining how they should report changes to an 
approved application. FDA allowed for public participation in the 
development of the regulation and guidance consistent with FDA 
regulations and policy and to the extent practicable. The time period 
to provide public comment was consistent with FDA's regulations and 
statutory requirements. FDA also held a public meeting on August 19, 
1999, to hear comments on the guidance and the proposed rule. FDA has 
carefully considered the public comments and believes that the final 
regulation and guidance provide for significant reduction in regulatory 
burden and comply fully with section 506A of the act.
    (32) One comment noted that the animal drug industry has been very 
pleased with the successful 1996 CVM initiative, ``Alternate 
Administrative Process for the Implementation and Submission of 
Supplemental Chemistry, Manufacturing and Control Changes (AAP),'' and 
their support of the Modernization Act was given based on their legal 
interpretation that the Modernization Act did not preclude the 
continuation of the AAP program. The comment further stated that the 
AAP program very succinctly provided a process for determining minor 
supplemental chemistry, manufacturing, and control changes that are 
reported on a biennial basis; as such, the concepts embodied in the AAP 
are strongly supported. There is concern that implementation of the 
proposed rule will be more burdensome than the AAP on both FDA and 
industry. Therefore, the proposed rule will be a significant step 
backwards.
    Agency Response: The AAP program has been superseded by section 
506A of the act and the revised Sec.  514.8 regulations. Section 506A 
of the act does not allow for the reporting of minor manufacturing 
changes in biennial supplements (as allowed in the AAP program) rather 
than annual reports. FDA disagrees that the proposed rule will be a 
significant step backwards from the AAP program since the proposed rule 
and supporting guidance will allow more flexibility in

[[Page 74779]]

the reporting of moderate changes in immediate changes-being-effected 
or 30-day-changes-being-effected supplemental applications. 
Implementation of moderate changes under the past regulations or under 
the AAP program would have required a prior approval supplement and 
would not have been considered appropriate for filing under the AAP 
program.

H. General Comments

    (33) Several comments argued that the proposal does not meet the 
intent of Congress or Section 116 of the Modernization Act. The 
comments stated that Congress expected substantial improvement in the 
management of technical supplements for manufacturing changes, but 
that: (1) The proposed rule does not provide significant regulatory 
relief, (2) significant numbers of additional new categories of 
manufacturing changes requiring prior approval supplements have been 
added without evidence of the need or a scientific rationale for such 
additional requirements, (3) there are no new approaches to the 
regulations and guidances for manufacturing changes, and (4) the 
reporting burden would be substantially increased.
    Agency Response: FDA believes that these regulations are consistent 
with the intent of Congress and the regulatory requirements and 
reporting categories are consistent with section 506A of the act. The 
regulations provide a new approach to regulating post-approval 
manufacturing changes. The approach is based on the potential for a 
change to adversely affect the identity, strength, quality, purity, or 
potency of the drug as these factors relate to the safety or 
effectiveness of the drug. The regulations and its companion guidance 
will provide significant regulatory relief by allowing post-approval 
manufacturing changes to be implemented more rapidly, while still 
ensuring the identity, strength, quality, purity, and potency of the 
drug. Under this final rule, many of these same changes can now be 
reported in changes-being-effected supplements or annual reports. In 
contrast, under the previous regulations, almost all manufacturing 
changes required FDA approval prior to implementation. As an example, 
the previous regulations required prior approval for all manufacturing 
site changes for drug products. Now, fewer types of animal drug 
manufacturing site changes will require submission in prior approval 
supplements. Many will be submitted in a changes-being-effected-in-30-
days supplement or in the annual report.
    (34) Several comments stated that if appropriate studies comparing 
pre- and post-change material are performed (as required) and no 
evidence of an adverse effect is found, then a reduced reporting 
structure for the evaluated change is appropriate. One comment added 
that the FDA should adopt a ``decision tree'' or ``key questions'' 
approach in implementing Section 116 of the Modernization Act. The 
decision tree approach would base regulatory reporting requirements on 
the results of scientific comparison of the quality of a drug product 
both pre- and post-change. Thus, the decision tree would focus on 
answering key questions rather than producing an exhaustive 
categorization of potential types of changes.
    Agency Response: FDA agrees that decision trees are a viable 
approach to post-approval manufacturing changes. However, a decision or 
decision tree that does not consider the potential for a change to have 
an adverse effect is not consistent with section 506A of the act. The 
act bases the reporting category for a change on the potential for that 
change to have an adverse effect, not on the outcome of the assessment 
studies. In some cases, based on the potential for an adverse effect, 
FDA would expect to review a change prior to distribution of the drug 
made with the change, even if the applicant concludes that its studies 
and data demonstrate that the change has no significant adverse effect. 
FDA must evaluate whether the studies performed by the applicant are 
sufficient to assess the effects of the change, and that the data 
support the applicant's claim that the change has not adversely 
affected the identity, strength, quality, purity, or potency of the 
drug as these factors may relate to the safety and effectiveness of the 
drug.
    FDA regulates a wide range of products, and a decision tree should 
address the fact that the potential for an adverse effect will vary 
depending on such factors as the dosage form and route of 
administration. For example, in general, a packaging change that 
involves a parenteral drug product is viewed by FDA to have a higher 
potential to cause an adverse effect on the quality of the drug product 
as it relates to the drug's safety and effectiveness than a packaging 
change for a solid oral dosage form product. One rationale for FDA's 
increased concern is that leaching from packaging for parenteral drug 
products is more likely to occur than for solid oral dosage forms; 
therefore, a higher potential for adverse reactions due to the route of 
administration may occur. A safety determination by FDA must be made. A 
decision tree that does not address these differences in the potential 
for a change to adversely affect the identity, strength, quality, 
purity, or potency of a drug as these factors relate to the safety or 
effectiveness of the drug would not be consistent with section 506A of 
the act.
    (35) Several comments stated that FDA has not presented evidence of 
the substantial adverse impact of the proposed rule and the 
accompanying draft guidance. The requirement for FDA to present such 
evidence was a clearly stated expectation during the development and 
enactment of the manufacturing provisions of the Modernization Act.
    Agency Response: FDA has examined the impact of the proposed rule 
under Executive Order 12866, the Regulatory Flexibility Act (5 U.S.C. 
601-612), and the Unfunded Mandates Reform Act of 1995 (Public Law 104-
4). The discussion of the analysis of impacts is in section VII of the 
preamble to the final rule.
    (36) Several comments resubmitted comments previously provided to 
the agency on the draft guidances entitled ``BACPAC I,'' ``Changes to 
an Approved NDA or ANDA,'' and ``Chemistry, Manufacturing and Control 
Changes to an Approved NADA or ANADA,'' requesting that FDA consider 
these comments in finalizing the proposed regulation.
    Agency Response: FDA has considered the resubmitted comments to the 
extent that they were applicable to the proposed regulation.
    (37) Another comment stated that FDA should provide for realistic 
and workable filing mechanisms and requirements with regard to changes 
in the manufacture of drug substances where the relevant information 
already is included in drug master files.
    Agency Response: The regulations and companion guidance for 
industry provide recommendations on reporting changes in the conditions 
established in an approved application, including changes in the drug 
substance covered by master files. Issues relating to master files and 
how these are used in the application review process are outside the 
scope of this regulation.

IV. Unrelated Referenced Comments to the Proposed Rule

    (Comments (38) through (40)). One comment recommended for the human 
drug regulations under Sec.  314.70(b)(2)(v) that ``labeling'' be 
clarified to ``drug product labeling'' Another comment suggested that 
the final sentence in Sec.  314.70(c)(1) be changed to ``If the change 
concerns labeling only, include.'' Yet another comment recommended that 
the phrase ``* * *a

[[Page 74780]]

distributor's name or editorial changes to comply with an official 
compendium'' be added to Sec.  314.70(d)(2)(x).
    Agency Response: These comments are outside the scope of this final 
rule. Therefore, the agency declines to address them at this time.

V. Conforming Amendments

    FDA has made conforming changes in Sec. Sec.  25.33, 500.25, 
514.106, and 558.5 because of the reorganization of the existing 
information or introduction of new requirements.

VI. Environmental Impact

    The agency has determined under 21 CFR 25.30(h) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

VII. Analysis of Impacts

    FDA has examined the impacts of the 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 under the 
Executive order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because small businesses will likely incur a net 
benefit while only incurring negligible costs, the agency certifies 
that the final rule will not 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 $122 million, using the most current (2005) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
final rule to result in any 1-year expenditure that would meet or 
exceed this amount.
    FDA proposed amendments to 21 CFR 514.8 that would implement 
section 506A of the act (64 FR 53281). This section establishes 
reporting procedures and requirements for making major and other 
manufacturing changes to an approved NADA or ANADA. The intent of 
section 506A of the act is to permit sponsors to use a less burdensome 
notification procedure for some types of manufacturing changes. 
Downgrading the level of agency review for some of these supplements is 
expected to lead to compliance cost savings due to the resulting 
improvement in manufacturing efficiencies. This final rule makes some 
minor changes to the proposed rule but does not alter the basic 
reporting structure as outlined in the proposal.
    Although the proposed rule would have increased manufacturing 
efficiencies, we did not estimate the value of the expected 
improvements due to the myriad of factors affecting the production 
schedules of animal drugs. Comments to the proposed rule have not 
provided any more data or arguments that add to, or refute, this 
position. Therefore, we retain it for this final rule. The final rule 
will result in shorter average lag times between the decision to make 
certain changes to the manufacturing process for an animal drug and the 
time at which that change can be implemented. A report by the Eastern 
Research Group (ERG), an FDA contractor, on the effects of the human 
drug Scale-Up and Post-Approval Change Guidance for Immediate Release 
Solid Oral Dosage Form (SUPAC-IR), concluded that this type of 
supplement change often results in significant net savings to industry. 
In particular, the report found that companies gain greater control 
over their production resources and ``shorter waiting times for changes 
that can now be filed as Changes Being Effected (CBEs) or annual 
reports'' (Ref. 1).
    We received many comments to the proposed rule that stated that the 
new supplement reporting structure would impose new reporting burdens 
on industry. Those comments have been addressed previously in this 
preamble. Our interpretation of the current regulations leads us to 
conclude that this final rule would not impose more than minimal 
additional reporting burdens, as described in the proposed rule and 
this section. Further, the final rule retains and reiterates our 
initial estimate of the number of manufacturing changes that could be 
made more quickly as a result of the lower level of agency review of 
certain manufacturing supplements.
    The final rule contains four reporting categories for supplemental 
chemistry, manufacturing and control (CMC) changes, whereas the current 
regulation Sec.  514.8 contains three. The first category concerns 
those changes requiring approval prior to implementation and defines 
what constitutes a ``major'' change. These requirements are very 
similar to those in the existing regulation, but clarify some of the 
existing language. The second category is a new ``30-day changes being 
effected,'' or 30-day CBE category. The purpose of this new category is 
to provide for a less burdensome method of reporting some ``moderate'' 
CMC changes that previously were reported as major changes requiring 
approval before implementation. The firm submitting the supplement will 
be able to implement the change more quickly as it will no longer 
require agency approval before implementation.
    The third category concerns those supplemental changes that can be 
effected upon receipt by FDA of the supplemental application. The 
current regulation concerning this reporting category contained 
language that allowed for the change ``at the earliest possible time,'' 
while the Modernization Act specifically dictates that the change be 
allowed at the time of agency receipt of the supplement. The fourth 
category concerns the minor manufacturing changes and updated stability 
data to be submitted in a periodic minor changes and stability report 
(MCSR). This annual MCSR replaces the current regulation that also 
requires an annual report of these changes.
    Based on prior year submissions, the agency estimates that CVM will 
receive about 1,188 CMC supplements annually. According to estimates 
from agency reviewers, about 755 of these would have required 
preapproval under the current regulation. Under the final rule, the 
number requiring preapproval is estimated at 234. The difference of 521 
supplements represents the approximate number of additional changes 
that can be made without prior agency approval. Companies submitting 
these supplements will have the opportunity to make quicker changes and 
realize increased manufacturing efficiencies.
    Further savings are expected from another provision of the rule 
that concerns labeling supplements. Currently, labeling supplements are 
required to include nine copies of the labeling in the submission. The 
final rule would lower this requirement to

[[Page 74781]]

two copies, providing further savings for industry. Although this rule 
also reorganizes the rules for labeling supplements, the agency does 
not expect these changes to alter the number of labeling supplements 
submitted annually.
    The creation of the annual MCSR may provide additional opportunity 
for savings because it may include minor manufacturing changes that 
were previously submitted as CBEs or other supplement types that 
require a higher level of review. Under the final rule, each firm will 
be able to accumulate and submit them together each year, rather than 
individually.
Regulatory Flexibility Analysis
    The Regulatory Flexibility Act (as amended by the Small Business 
Regulatory Enforcement Fairness Act) requires agencies to analyze 
regulatory options to minimize any significant impact on small 
entities. The final rule implements section 506A of the act. The intent 
of the rule is to clarify the regulations for submitting supplements to 
new animal drugs applications, harmonize the regulations with those for 
human drugs, and lessen the compliance burden for some supplements by 
reducing the level of agency review necessary before implementation of 
the change. The effects of these changes will be spread across all 
firms that submit supplements, regardless of their size. The Small 
Business Administration limits small businesses affected by this final 
rule to those manufacturers with fewer than 750 employees. In the 
proposed rule, the agency certified that the rule will not have a 
significant effect on a substantial number of small entities. This 
certification was based in part on the agency's belief that small 
businesses are more likely to realize a benefit from this regulation 
because they are more likely to submit reports of minor changes as 
prior approval supplements. While we recognized that a few small firms 
may have to start submitting an annual report rather than a biennial 
supplement, we did not believe that this would impose a significant 
cost on small businesses. We received no comments on small business 
impacts that lead us to change this position. Therefore, the agency 
certifies that the rule will not have a significant effect on a 
substantial number of small entities.

VIII. Paperwork Reduction Act of 1995

    This final rule contains information collection provisions that are 
subject to review by the Office of Management and Budget (OMB) under 
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The title, 
description, and respondent description of the information collection 
provisions are shown below with an estimate of the annual reporting 
burden. Included in the estimate is the time for reviewing 
instructions, searching existing data sources, gathering and 
maintaining the data needed, and completing and reviewing each 
collection of information.
    Title: Supplements and Other Changes to Approved New Animal Drug 
Applications
    Description: The FDA with this final rule is amending its 
regulations on supplements and other changes to an approved NADA or 
ANADA to implement the manufacturing changes provisions of section 506A 
of the act. Under Sec.  514.8(b)(2), the regulation describes reporting 
requirements for submission and approval of a supplement prior to 
distribution of the drug made using the change (major change). Section 
514.8(b)(3)(i) describes reporting requirements for submission of a 
supplement at least 30 days prior to distribution of the drug made 
using the change (moderate change). Section 514.8(b)(3)(vi) describes 
reporting requirements for a category of supplemental changes 
designated by the agency which allows the holder of an approved 
application to commence distribution of the drug involved upon receipt 
by the agency of a supplement for the change. Section 514.8(b)(4)(iii) 
provides requirements for changes and updated stability data to be 
submitted in an annual report (minor changes). Section 514.8(c)(2)(ii) 
describes reporting requirements for labeling and other changes 
requiring submission and approval of a supplement prior to distribution 
of the drug made using the change (major change). Section 514.8 
(c)(3)(iii) provides reporting requirements for labeling changes to be 
placed in effect prior to receipt of written notice of approval of a 
supplemental application, and Sec.  514.8(c)(4) describes reporting 
requirements for changes providing for additional distributors to be 
reported under Sec.  514.80, records and reports concerning experience 
with approved new animal drugs.
    Description of Respondents: Sponsors of new animal drug 
applications.
    FDA estimates the burden of this collection of information as 
follows.

                                                     Table 1.--Estimated Annual Reporting Burden\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                              No. Of         No. Of Responses       Total Annual        Hours per
                    21 CFR Section                         Respondents        Per Respondent         Responses           Response         Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
514.8(b)(2)                                                            40                   5.9                234                100             23,400
--------------------------------------------------------------------------------------------------------------------------------------------------------
514.8(b)(3)(i)                                                         40                   5.0                200                 40              8,000
--------------------------------------------------------------------------------------------------------------------------------------------------------
514.8(b)(3)(vi)                                                        40                   3.6                145                 40              5,800
--------------------------------------------------------------------------------------------------------------------------------------------------------
514.8(b)(4)(iii)                                                       40                  15.2                609                 40             24,360
--------------------------------------------------------------------------------------------------------------------------------------------------------
514.8(c)(2)(ii)                                                        40                   0.3                 10                100              1,000
--------------------------------------------------------------------------------------------------------------------------------------------------------
514.8(c)(3)(iii)                                                       40                   0.5                 20                 40                800
--------------------------------------------------------------------------------------------------------------------------------------------------------
514.8(c)(4)                                                            40                   0.3                 10                 20                200
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total                                                                                                                                             63,560
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\There are no capital costs or operating and maintenance costs associated with this collection of information.

    FDA announced that the proposed rule contained information 
collection provisions that were subject to review by OMB under the 
Paperwork Reduction Act of 1995 and invited public comment (64 FR 
53281). In

[[Page 74782]]

response to that notice, FDA did not receive any comments regarding the 
information collection requirements contained in the final rule. 
However, with the use of improved technology, CVM performed a 
retrospective burden analysis resulting in an adjustment to the 
previous burden table that was published in the October 1, 1999, 
Federal Register. CVM examined fiscal year 2003 data for its analysis 
and using CVM's database, for tracking submissions including 
supplements to NADAs and ANDAs, was able to determine the number of 
respondents and the types and number of supplements submitted that 
year. The number of respondents (40) is the approximate number of 
sponsors of New Animal Drug Applications and Abbreviated New Animal 
Drug Applications that submitted supplemental applications. This number 
was determined by using a retrospective analysis of supplements 
actually received by CVM for fiscal year 2003. The number of responses 
per respondent was obtained by dividing the ``Total Annual Responses'' 
by the ``Number of Respondents.'' The ``Total Annual Responses'' are 
the actual manufacturing supplement numbers, i.e., completed 
submissions for the analysis year (fiscal year 2003).
    The information collection provisions of this final rule have been 
submitted to OMB for review. Prior to the effective date of this final 
rule, FDA will publish a notice in the Federal Register announcing 
OMB's decision to approve, modify, or disapprove the information 
collection provisions in this final rule. An agency may not conduct or 
sponsor, and a person is not required to respond to, a collection of 
information unless it displays a currently valid OMB control number.

IX. Federalism

    FDA has analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has 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, the agency has 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.

X. References

    The following reference has been placed on display in the Dockets 
Management Branch (see ADDRESSES) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.
    1. Eastern Research Group, Pharmaceutical Industry Cost Savings 
Through Use of the Scale-Up and Post-Approval Guidance for Immediate 
Release Solid Oral Dosage Forms (SUPAC-IR), January 7, 1998, 
Contract Number 223-94-8031, page 8.

List of Subjects

21 CFR Part 25

    Environmental impact statements, Foreign relations, Reporting and 
recordkeeping requirements.

21 CFR Part 500

    Animal drugs, Animal feeds, Cancer, Labeling, Packaging and 
containers, Polychlorinated biphenyls (PCB's).

21 CFR Part 514

    Administrative practice and procedure, Animal drugs, Confidential 
business information, Reporting and recordkeeping requirements.

21 CFR Part 558

    Animal drugs, Animal feeds.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR parts 
25, 500, 514, and 558 are amended as follows:

PART 25--ENVIRONMENTAL IMPACT CONSIDERATIONS

0
1. The authority citation for 21 CFR part 25 continues to read as 
follows:

    Authority: 21 U.S.C. 321-393; 42 U.S.C. 262, 263b-264; 42 U.S.C. 
4321, 4332; 40 CFR parts 1500-1508; E.O. 11514, 35 FR 4247, 3 CFR, 
1971 Comp., p. 531-533 as amended by E.O. 11991, 42 FR 26967, 3 CFR, 
1978 Comp., p. 123-124 and E.O. 12114, 44 FR 1957, 3 CFR, 1980 
Comp., p. 356-360.


Sec.  25.33  [Amended]

0
2. Section 25.33 is amended in paragraph (a)(4) by removing 
``514.8(a)(5), (a)(6), or (d)'' and by adding in its place 
``514.8(b)(3), (b)(4), or (c)(3).''

PART 500--GENERAL

0
3. The authority citation for 21 CFR part 500 continues to read as 
follows:

    Authority:  21 U.S.C. 321, 331, 342, 343, 348, 351, 352, 353, 
360b, 371.


Sec.  500.25  [Amended]

0
4. Section 500.25 is amended in the first sentence of paragraph (c) by 
removing ``514.8(d) and (e)'' and by adding in its place 
``514.8(c)(3).''

PART 514--NEW ANIMAL DRUG APPLICATIONS

0
5. The authority citation for 21 CFR part 514 is revised to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 356a, 360b, 371, 379e, 
381.

0
6. Section 514.8 is revised to read as follows:


Sec.  514.8  Supplements and other changes to an approved application.

    (a) Definitions. (1) The definitions and interpretations contained 
in section 201 of the Federal Food, Drug, and Cosmetic Act (the act) 
apply to those terms when used in this part.
    (2) The following definitions of terms apply to this part:
    (i) 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.
    (ii) Drug substance means an active ingredient as defined under 
Sec.  210.3(b)(7) of this chapter.
    (iii) Minor changes and stability report (MCSR) means an annual 
report that is submitted to the application once each year within 60 
days before or after the anniversary date of the application's original 
approval or on a mutually agreed upon date. The report must include 
minor manufacturing and control changes made according to Sec.  
514.8(b)(4) or state that no changes were made; and stability data 
generated on commercial or production batches according to an approved 
stability protocol or commitment.
     (iv) Specification means the quality standard (i.e., tests, 
analytical procedures, and acceptance 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.
    (b) Manufacturing changes to an approved application--(1) General 
provisions. (i) The applicant must notify FDA about each change in each 
condition established in an approved application beyond the variations 
already provided for in the application. The notice is required to 
describe the change fully. Depending on the type of

[[Page 74783]]

change, the applicant must notify FDA about it in a supplement under 
paragraph (b)(2) or (b)(3) of this section or by inclusion of the 
information in the annual report to the application under paragraph 
(b)(4) of this section.
    (ii) 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.
    (iii) Notwithstanding the requirements of paragraphs (b)(2) and 
(b)(3) of this section, an applicant must make a change provided for in 
those paragraphs in accordance with a regulation or guidance that 
provides for a less burdensome notification of the change (for example, 
by submission of a supplement that does not require approval prior to 
distribution of the drug, or by notification in the next annual report 
described in paragraph (b)(4) of this section).
    (iv) 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.
    (v) A supplement or annual report described in paragraph (b)(4) of 
this section must include a list of all changes contained in the 
supplement or annual report. For supplements, this list must be 
provided in the cover letter.
    (2) Changes requiring submission and approval of a supplement prior 
to distribution of the drug made using the change (major changes). (i) 
A supplement must be submitted for any change in the drug, production 
process, quality controls, equipment, or facilities that has a 
substantial potential to have an adverse effect on the identity, 
strength, quality, purity, or potency of the drug as these factors may 
relate to the safety or effectiveness of the drug.
    (ii) These changes include, but are not limited to:
    (A) Except those described in paragraphs (b)(3) and (b)(4) of this 
section, changes in the qualitative or quantitative formulation of the 
drug, including inactive ingredients, or in the specifications provided 
in the approved application;
    (B) Changes requiring completion of appropriate clinical studies to 
demonstrate the equivalence of the drug to the drug as manufactured 
without the change;
    (C) Changes that may affect drug substance or drug product 
sterility assurance, such as changes in drug substance, drug product or 
component sterilization method(s) or an addition, deletion, or 
substitution of steps in an aseptic processing operation;
    (D) Changes in the synthesis or manufacture of the drug substance 
that may affect the impurity profile and/or the physical, chemical, or 
biological properties of the drug substance;
    (E) 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;
    (F) Changes solely affecting a natural product, a recombinant DNA-
derived protein/polypeptide, or a complex or conjugate of a drug 
substance 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;
    (G) Changes to a drug under an application that is subject to a 
validity assessment because of significant questions regarding the 
integrity of the data supporting that application.
    (iii) The applicant must obtain approval of a supplement from FDA 
prior to distribution of a drug made using a change under paragraph 
(b)(2) of this section. The supplement must be labeled ``Prior Approval 
Supplement.'' Except for submissions under paragraph (b)(2)(v) of this 
section, the following information must be contained in the supplement:
    (A) A completed Form FDA 356V;
    (B) A detailed description of the proposed change;
    (C) The drug(s) involved;
    (D) The manufacturing site(s) or area(s) affected;
    (E) A description of the methods used and studies performed to 
assess the effects of the change;
    (F) The data derived from such studies;
    (G) Appropriate documentation (for example, updated master batch 
records, specification sheets) including previously approved 
documentation (with the changes highlighted) or references to 
previously approved documentation;
    (H) For a natural product, a recombinant DNA-derived protein/
polypeptide, or a complex or conjugate of a drug substance with a 
monoclonal antibody, relevant validation protocols and standard 
operating procedures must be provided in addition to the requirements 
in paragraphs (b)(2)(iii)(E) and (b)(2)(iii)(F) of this section;
    (I) For sterilization process and test methodologies related to 
sterilization process validation, relevant validation protocols and a 
list of relevant standard operating procedures must be provided in 
addition to the requirements in paragraphs (b)(2)(iii)(E) and 
(b)(2)(iii)(F) of this section; and
    (J) Any other information as directed by FDA.
    (iv) An applicant may ask FDA to expedite its review of a 
supplement for public health reasons or if a delay in making the change 
described in it would impose an extraordinary hardship on the 
applicant. Such a supplement and its mailing cover must be plainly 
marked: ``Prior Approval Supplement-Expedited Review Requested.''
    (v) Comparability Protocols. An applicant may submit one or more 
protocols describing the specific tests and studies and acceptance 
criteria to be achieved to demonstrate the lack of adverse effect for 
specified types of manufacturing changes on the identity, strength, 
quality, purity, and potency of the drug as these factors may relate to 
the safety or effectiveness of the drug. Any such protocols, if not 
included in the approved application, or changes to an approved 
protocol, must be submitted as a supplement requiring approval from FDA 
prior to distribution of the drug produced with the manufacturing 
change. The supplement, if approved, may subsequently justify a reduced 
reporting category for the particular change because the use of the 
protocol for that type of change reduces the potential risk of an 
adverse effect. A comparability protocol supplement must be labeled 
``Prior Approval Supplement--Comparability Protocol.''
    (3) Changes requiring submission of a supplement at least 30 days 
prior to distribution of the drug made using the change (moderate 
changes). (i) A supplement must be submitted for any change in the 
drug, production process, quality controls, equipment, or facilities 
that has a moderate potential to have an adverse effect on the 
identity, strength, quality, purity, or potency of the drug as these 
factors may relate to the safety or effectiveness of the drug.
    (ii) These changes include, but are not limited to:
    (A) 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;
    (B) Changes solely affecting a natural protein, a recombinant DNA-
derived protein/polypeptide or a complex or conjugate of a drug 
substance with a monoclonal antibody, including:

[[Page 74784]]

    (1) An increase or decrease in production scale during finishing 
steps that involves different equipment, and
    (2) Replacement of equipment with that of a different design that 
does not affect the process methodology or process operating 
parameters.
    (C) Relaxation of an acceptance criterion or deletion of a test to 
comply with an official compendium that is consistent with FDA 
statutory and regulatory requirements.
    (iii) A supplement submitted under paragraph (b)(3)(i) or 
(b)(3)(vi) of this section is required to give a full explanation of 
the basis for the change and identify the date on which the change is 
made. The supplement submitted under paragraph (b)(3)(i) must be 
labeled ``Supplement-Changes Being Effected in 30 Days.''
    (iv) Pending approval of the supplement by FDA and except as 
provided in paragraph (b)(3)(vi) of this section, distribution of the 
drug made using the change may begin not less than 30 days after 
receipt of the supplement by FDA. The information listed in paragraphs 
(b)(2)(iii)(A) through (b)(2)(iii)(J) of this section must be contained 
in the supplement.
    (v) The applicant must not distribute the drug made using the 
change if within 30 days following FDA's receipt of the supplement, FDA 
informs the applicant that either:
    (A) The change requires approval prior to distribution of the drug 
in accordance with paragraph (b)(2) of this section; or
    (B) Any of the information required under paragraph (b)(3)(iv) of 
this section is missing. In this case, the applicant must not 
distribute the drug made using the change until the supplement has been 
amended to provide the missing information.
    (vi) 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 commence distribution of the drug 
involved upon receipt by the agency of a supplement for the change. The 
information listed in paragraphs (b)(2)(iii)(A) through (b)(2)(iii)(J) 
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:
    (A) Addition to a specification or changes in the methods or 
controls to provide increased assurance that the drug will have the 
characteristics of identity, strength, quality, purity, or potency that 
it purports or is represented to possess; and
    (B) 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 drug product or from one container 
closure system to another.
    (vii) If the agency disapproves the supplemental application, it 
may order the manufacturer to cease distribution of the drug(s) made 
with the manufacturing change.
    (4) Changes and updated stability data to be described and 
submitted in an annual report (minor changes). (i) Changes in the drug, 
production process, quality controls, equipment, or facilities that 
have a minimal potential to have an adverse effect on the identity, 
strength, quality, purity, or potency of the drug as these factors may 
relate to the safety or effectiveness of the drug must be documented by 
the applicant in an annual report to the application as described under 
paragraph (a)(2)(iii) of this section. The report must be labeled 
``Minor Changes and Stability Report.''
    (ii) These changes include but are not limited to:
    (A) Any change made to comply with a change to an official 
compendium, except a change in paragraph (b)(3)(ii)(C) of this section, 
that is consistent with FDA statutory and regulatory requirements;
    (B) The deletion or reduction of an ingredient intended to affect 
only the color of the drug product;
    (C) Replacement of equipment with that of the same design and 
operating principles except for those equipment changes described in 
paragraph (b)(3)(ii)(B)(2) of this section;
    (D) A change in the size and/or shape of a container containing the 
same number of dosage units for a nonsterile solid dosage form drug 
product, without a change from one container closure system to another;
    (E) A change within the container closure system for a nonsterile 
drug product, based upon a showing of equivalency to the approved 
system under a protocol approved in the application or published in an 
official compendium;
    (F) An extension of an expiration dating period based upon full 
shelf-life data on production batches obtained from a protocol approved 
in the application;
    (G) The addition or revision of an alternative analytical procedure 
that provides the same or increased assurance of the identity, 
strength, quality, purity, or potency of the drug being tested as the 
analytical procedure described in the approved application, or deletion 
of an alternative analytical procedure; and
    (H) The addition by embossing, debossing, or engraving of a code 
imprint to a solid oral dosage form drug product other than a modified 
release dosage form, or a minor change in an existing code imprint.
    (iii) For changes under this category, the applicant is required to 
submit in the annual report:
    (A) A completed Form FDA 356V;
    (B) A statement by the holder of the approved application that the 
effects of the change have been assessed;
    (C) A detailed description of the change(s);
    (D) The manufacturing site(s) or area(s) involved;
    (E) The date each change was implemented;
    (F) Data from studies and tests performed to assess the effects of 
the change;
    (G) For a natural product, recombinant DNA-derived protein/
polypeptide, complex or conjugate of a drug substance with a monoclonal 
antibody, sterilization process or test methodology related to 
sterilization process validation, relevant validation protocols and/or 
standard operating procedures;
    (H) Appropriate documentation (for example, updated master batch 
records, specification sheets, etc.) including previously approved 
documentation (with the changes highlighted) or references to 
previously approved documentation;
    (I) Updated stability data generated on commercial or production 
batches according to an approved stability protocol or commitment; and
    (J) Any other information as directed by FDA.
    (c) Labeling and other changes to an approved application--(1) 
General provisions. The applicant must notify FDA about each change in 
each condition established in an approved application beyond the 
variations already provided for in the application. The notice is 
required to describe the change fully.
    (2) Labeling changes requiring the submission and approval of a 
supplement prior to distribution of the drug made using the change 
(major changes). (i) Addition of intended uses and changes to package 
labeling require a supplement. These changes include, but are not 
limited to:
    (A) Revision in labeling, such as updating information pertaining 
to effects, dosages, adverse reactions, contraindications, which 
includes information headed ``adverse reactions,'' ``warnings,'' 
``precautions,'' and ``contraindications,'' except ones described in 
(c)(3) of this section;

[[Page 74785]]

    (B) Addition of an intended use;
    (C) If it is a prescription drug, any mailing or promotional piece 
used after the drug is placed on the market is labeling requiring a 
supplemental application, unless:
    (1) The parts of the labeling furnishing directions, warnings, and 
information for use of the drug are the same in language and emphasis 
as labeling approved or permitted; and
    (2) Any other parts of the labeling are consistent with and not 
contrary to such approved or permitted labeling.
    (3) Prescription drug labeling not requiring an approved 
supplemental application is submitted in accordance with Sec.  
514.80(b)(5)(ii).
    (D) Any other changes in labeling, except ones described in 
paragraph (c)(3) of this section.
    (ii) The applicant must obtain approval of the supplement from FDA 
prior to distribution of the drug. The supplement must contain the 
following:
    (A) A completed Form FDA 356V;
    (B) A detailed description of the proposed change;
    (C) The drug(s) involved;
    (D) The data derived from studies in support of the change; and
    (E) Any other information as directed by FDA.
    (3) Labeling changes to be placed into effect prior to receipt of a 
written notice of approval of a supplemental application. (i) Labeling 
changes of the following kinds that increase the assurance of drug 
safety proposed in supplemental applications must be placed into effect 
immediately:
    (A) The addition to package labeling, promotional labeling, or 
prescription drug advertising of additional warning, contraindication, 
adverse reaction, and precaution information;
    (B) The deletion from package labeling, promotional labeling, or 
drug advertising of false, misleading, or unsupported intended uses or 
claims for effectiveness; and
    (C) Any other changes as directed by FDA.
    (ii) Labeling changes (for example, design and style) that do not 
decrease safety of drug use proposed in supplemental applications may 
be placed into effect prior to written notice of approval from FDA of a 
supplemental application.
    (iii) A supplement submitted under paragraph (c)(3) of this section 
must include the following information:
    (A) A full explanation of the basis for the changes, the date on 
which such changes are being effected, and plainly marked on the 
mailing cover and on the supplement, ``Supplement--Labeling Changes 
Being Effected'';
    (B) Two sets of printed copies of any revised labeling to be placed 
in use, identified with the new animal drug application number; and
    (C) A statement by the applicant that all promotional labeling and 
all drug advertising will promptly be revised consistent with the 
changes made in the labeling on or within the new animal drug package 
no later than upon approval of the supplemental application.
    (iv) If the supplemental application is not approved and the drug 
is being distributed with the proposed labeling, FDA may initiate an 
enforcement action because the drug is misbranded under section 502 of 
the act and/or adulterated under section 501 of the act. In addition, 
under section 512(e) of the act, FDA may, after due notice and 
opportunity for a hearing, issue an order withdrawing approval of the 
application.
    (4) Changes providing for additional distributors to be reported 
under Records and reports concerning experience with approved new 
animal drugs (Sec.  514.80). Supplemental applications as described 
under paragraph (c)(2) of this section will not be required for an 
additional distributor to distribute a drug that is the subject of an 
approved new animal drug application or abbreviated new animal drug 
application if the conditions described under Sec.  514.80(b)(5)(iii) 
are met.
    (d) Patent information. The applicant must comply with the patent 
information requirements under section 512(c)(3) of the act.
    (e) Claimed exclusivity. If an applicant claims exclusivity under 
section 512(c)(2)(F) of the act upon approval of a supplemental 
application for a change in its previously approved drug, the applicant 
must include such a statement.
    (f) Good laboratory practice for nonclinical laboratory studies. A 
supplemental application that contains nonclinical laboratory studies 
must include, with respect to each nonclinical study, either a 
statement that the study was conducted in compliance with the 
requirements set forth in part 58 of this chapter, or, if the study was 
not conducted in compliance with such regulations, a brief statement of 
the reason for the noncompliance.

0
7. Section 514.106 is amended by removing paragraphs (b)(1)(xiv), and 
revising paragraphs (b)(1)(vi) and (b)(1)(xiii) to read as follows:


Sec.  514.106  Approval of supplemental applications.

* * * * *
    (b) * * *
    (1) * * *
    (vi) A change in promotional material for a prescription new animal 
drug not exempted by Sec.  514.8(c)(2)(i)(C)(1) through 
(c)(2)(i)(C)(3).
* * * * *
    (xiii) A change permitted in advance of approval as described under 
Sec.  514.8(b)(3).
* * * * *

PART 558--NEW ANIMAL DRUGS FOR USE IN ANIMAL FEEDS

0
8. The authority citation for 21 CFR part 558 continues to read as 
follows:

    Authority: 21 U.S.C. 360b, 371.


Sec.  558.5  [Amended]

0
9. Section 558.5 is amended in paragraph (j) by removing ``514.8(d) and 
(e)'' and by adding in its place ``514.8(c)(3)''.

    Dated: September 1, 2006.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. E6-21133 Filed 12-12-06; 8:45 am]
BILLING CODE 4160-01-S