[Federal Register: December 13, 2006 (Volume 71, Number 239)]
[Rules and Regulations]
[Page 74766-74785]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr13de06-6]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 25, 500, 514, and 558
[Docket No. 1999N-1415] (formerly Docket No. 99N-1415)
RIN 0910-AF59
Supplements and Other Changes to Approved New Animal Drug
Applications
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is amending its
regulations on supplements and other changes to approved new animal
drug applications (NADAs) or abbreviated new animal drug applications
(ANADAs) to implement the manufacturing changes provision of the Food
and Drug Administration Modernization Act of 1997 (the Modernization
Act). The final rule requires manufacturers to assess the effect of a
manufacturing change on the identity, strength, quality, purity, and
potency of a drug as those factors relate to the safety or
effectiveness of the drug. The final rule sets forth requirements for
changes requiring submission and approval of a supplement before the
distribution of the drug made using the change, changes requiring the
submission of a supplement at least 30 days prior to the distribution
of the drug, changes requiring the submission of a supplement at the
time of distribution of the drug, and changes to be described in an
annual report.
DATES: The final rule is effective February 12, 2007.
FOR FURTHER INFORMATION CONTACT: Dennis M. Bensley, Jr., Center for
Veterinary Medicine (HFV-140), Food and Drug Administration, 7500
Standish Pl., Rockville, MD 20855, 301-827-6956, E-mail:
dennis.bensley@fda.hhs.gov.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Background
A. Development of the Regulation
B. Risk-Based Approach
II. Harmonization and Highlights of Revisions to the Proposed Rule
A. Section 514.8(a)--Definitions
B. Section 514.8(b)--Manufacturing Changes to an Approved
Application Manufacturing Changes Requiring Preapproval of a Supplement
(Proposed Sec. 514.8(b)(1)(ii))
C. Labeling and Other Changes to an Approved Application
III. Responses to Comments on the Propose Rule
A. Section 514.8(a)--Definitions
B. Section 514.8(b)--Manufacturing Changes to an Approved
Application
C. Changes Requiring Submission and Approval of a Supplement Prior
to Distribution of the Drug Made Using the Change (Major Changes)
D. Changes Requiring Submission of a Supplement at Least 30 Days
Prior to Distribution of the Drug Made Using the Change (Moderate
Changes)
E. Changes and Updated Stability Data to be Described and Submitted
in and Annual Report (Minor Changes)
F. Labeling and Other Changes to an Approved Application
G. Implementation of the Final Rule and Guidance
H. General Comments
IV. Unrelated Referenced Comments to the Proposed Rule
V. Conforming Amendments
VI. Environmental Impact
VII. Analysis of Impacts
VIII. Paperwork Reduction Act of 1995
IX. Federalism
X. References
I. Background
Section 116 of the Modernization Act (Public Law 105-115) amended
the Federal Food, Drug, and Cosmetic Act (the act) by adding section
506A (21 U.S.C. 356a). That section describes requirements and
procedures for making and reporting manufacturing changes to approved
new drug and abbreviated new drug applications, to approved new animal
drug and abbreviated new animal drug applications, and to license
applications for biological products under section 351 of the Public
Health Service (PHS) Act. Section 506A of the act revises current
procedures for approving manufacturing changes. Major manufacturing
changes, as defined in section 506A, are of a type determined by FDA to
have a substantial potential to adversely affect the identity,
strength, quality, purity, and potency as they may relate to the safety
and effectiveness of a drug and require prior approval of a
supplemental application. Under section 506A, FDA may require
submission of a supplemental application for drugs made with
manufacturing changes that are not major and may establish categories
of manufacturing changes for which a supplemental application is
required. In such a case, the applicant may begin distribution of a
drug 30 days after FDA receives a supplemental application unless the
agency notifies the applicant within the 30-day period that prior
approval of the application is required. Under the statute, FDA may
also designate a category of manufacturing changes that permit the
applicant to begin distributing a drug made with such changes upon
receipt by the agency of a supplemental application for the change.
Finally, FDA may also authorize applicants to distribute drugs
manufactured with a change without submitting a supplemental
application. The law provides that FDA may establish categories of
manufacturing changes that may be made without submitting a
supplemental application.
[[Page 74767]]
A. Development of the Regulation
In the Federal Register of October 1, 1999 (64 FR 53281), FDA
published a proposed rule to implement section 506A of the act for
NADAs and ANADAs. In that same issue of the Federal Register (64 FR
53393), FDA announced the availability of a draft guidance for industry
entitled ``Chemistry, Manufacturing and Control Changes to an Approved
NADA or ANADA'' (GFI 83). The guidance assists applicants in
determining how they should report changes to an approved NADA or ANADA
under section 506A of the act and under the proposed revisions to the
new animal drug regulations pertaining to supplements and other changes
to an approved application. With the issuance of this final rule, we
are announcing we will issue a revised final guidance to assist
applicants in determining how they should report changes to an approved
NADA or ANADA under both section 506A of the act and these final
regulations. The guidance has been revised to conform to the final rule
and, as appropriate, to comments received. It will be issued upon
approval of information collection requirements that are subject to
review by the Office of Management and Budget (OMB) under the Paperwork
Reduction Act.
B. Risk-Based Approach
The publication of this final rule is an important step in the
process of adopting a risk-based approach to the regulation of drugs.
In the 1990s, FDA sponsored research at the University of Maryland and
other universities on the types of chemistry and manufacturing changes
to immediate release solid oral drug products that could affect drug
performance (i.e., identity, strength, quality, purity, and potency)
and, therefore, safety and effectiveness. Using that research, FDA's
Center for Drug Evaluation and Research (CDER) began to develop a risk-
based approach to the implementation of manufacturing changes.
Following CDER's example, FDA's Center for Veterinary Medicine (CVM)
also employed a similar risk-based approach to the implementation of
manufacturing changes for animal drugs. This approach provided for a
continued high level of scrutiny by FDA of changes that were most
likely to affect the performance of a drug and decreased scrutiny of
changes that were not likely to affect the performance of a drug.
The risk-based approach was first explained in a series of guidance
documents (the Scale-up and Postapproval Changes (SUPAC) guidances)
that reduced the regulatory burden of obtaining FDA authorization to
make certain changes. The work continued in regulations issued by the
Center for Biologics Evaluation and Research (CBER) in 1997 (21 CFR
601.12). In November 1997, this risk-based approach was codified in
section 116 of the Modernization Act.
This final rule implements section 116 of the Modernization Act by
incorporating the statutory standards for characterizing proposed
changes as having substantial, moderate, or minimal potential to
adversely affect the identity, strength, quality, purity, and potency
of a drug as they may relate to its safety and effectiveness and
determining submission requirements based on the potential risks
associated with the changes. For changes with a substantial potential
to affect the designated characteristics of a drug, FDA must review and
approve a supplement that contains information showing that the
proposed change will not adversely affect the drug's characteristics
(i.e., information developed by the holder of the application to
validate the effect of the proposed change) before distribution of the
product made using the change.
It was anticipated when section 116 of the Modernization Act was
written that the science of manufacturing would evolve over time and
affect whether changes would be considered major or nonmajor. To
accommodate future technological advancements, section 116 of the
Modernization Act and this final implementing regulation both provide
that FDA may, by regulation or guidance, change the designation of a
particular category of change from major to nonmajor or vice versa.
This concept of an evolving risk-based approach to manufacturing
changes also is consistent with the agency's Good Manufacturing
Practices Initiative launched in August 2002. The goals of this
initiative include:
Ensuring that state-of-the-art pharmaceutical science is
utilized in the regulatory review and inspection policies;
Encouraging the adoption of new technological advances in
high quality and efficient manufacturing by the pharmaceutical
industry;
Assessing the applicable current good manufacturing
practice (CGMP) requirements relative to the best quality management
practices;
Strengthening public health protection by implementing
risk-based approaches that focus both industry and FDA attention on
critical areas for improving product safety and quality; and
Enhancing the consistency and coordination of FDA's drug
quality oversight activities.
Specifically, one of the efforts of the CGMP initiative is to
facilitate continuous improvement and innovation in manufacturing by
allowing manufacturers to make certain types of changes in their
processes without prior FDA approval. This rule, in keeping with that
initiative, provides for a mechanism of continuous improvement through
the guidance process (21 CFR 10.115) that may provide for less
burdensome documentation of certain changes as manufacturing processes
and pharmaceutical science develop.
II. Harmonization and Highlights of Revisions to the Proposed Rule
In the proposed rule to implement section 506A of the act for
supplements and other changes to approved NADAs and ANADAs (64 FR
53281), CVM stated its intent to harmonize the reporting requirements
for manufacturing changes for animal drugs with those requirements
applicable to human drugs, 21 CFR 314.70. CDER published their final
rule in the Federal Register of April 8, 2004 (69 FR 18727). CDER
modified their proposed rule in response to comments received. CVM has
not received similar comments to its aforementioned proposed rule.
However, as a result of its harmonization effort with CDER's proposed
21 CFR 314.70, CVM has incorporated, as appropriate, many of the
changes to CDER's proposed rule. This section describes the changes
resulting from harmonization with CDER's final rule and other comments
specific to 21 CFR 514.8. Other changes initiated by CVM are also
described. Minor editorial changes are not described.
A. Section 514.8(a)--Definitions
1. Definition of ``Specification'' (Proposed Sec. 514.8(a)(2)(iii))
FDA has revised the proposed definition of ``specification'' in
Sec. 514.8(a)(2)(iii) for consistency with CDER's regulations and has
renumbered Sec. 514.8(a)(2)(iii) through (a)(2)(v). The proposed
definition included the phrase ``* * *other components including
container closure systems, and in-process controls.'' This phrase has
been revised to state ``components, in-process materials, container
closure systems, and other materials used in the production of a
drug.'' Thus, the revised definition is as follows: ``Specification
means the quality standard (i.e., tests, analytical procedures, and
acceptance
[[Page 74768]]
criteria) provided in an approved application to confirm the quality of
drugs including, for example, drug substances, Type A medicated
articles, drug products, intermediates, raw materials, reagents,
components, in-process materials, container closure systems, and other
materials used in the production of a drug. For the purpose of this
definition, the term 'acceptance criteria' means numerical limits,
ranges, or other criteria for the tests described.'' See the response
to comment 4 regarding the use of the terms ``drug(s),'' ``drug
substance(s),'' and ``drug product(s).''
2. Definition of ``validate the effects of the change'' (Proposed Sec.
514.8(a)(2)(iv))
FDA has revised the proposed definition of ``validate the effects
of change'' in Sec. 514.8(a)(2)(iv) for consistency with CDER's
regulations. The revised definition is as follows: ``Assess the effects
of the change means to evaluate the effects of a manufacturing change
on the identity, strength, quality, purity, and potency of a drug as
these factors may relate to the safety or effectiveness of the drug.''
See the response to comment 3 regarding the use of the term ``assess''
instead of ``validate.''
3. Definitions of ``Listed drug'' and ``The list'' (Proposed Sec.
514.8(a)(2)(i) and (v))
FDA has deleted the definitions of ``Listed drug'' (proposed Sec.
514.8(a)(2)(i)) and ``The list'' (proposed Sec. 514.8(a)(2)(v)). The
definitions were originally proposed to clarify the meaning of
``reference listed drug'' identified under proposed Sec.
514.8(b)(2)(ii)(B). Since the term ``reference listed drug'' has been
deleted from proposed Sec. 514.8(b)(2)(ii)(B), the definitions are
currently not needed. See the discussion under Section B of the
preamble regarding the changes to proposed section 514.8(b)(2)(ii)(B).
B. Section 514.8(b)--Manufacturing Changes to an Approved Application
Manufacturing Changes Requiring Preapproval of a Supplement (Proposed
Sec. 514.8(b)(1)(ii))
FDA has revised Sec. 514.8(b)(1)(ii) by replacing ``effect'' with
``effects'' and deleting the phrase ``* * *on the identity, strength,
quality, purity, or potency of the new animal drug as these factors may
relate to the safety or effectiveness of the new animal drug* * *''
because ``assess the effects of the change'' already is defined under
Sec. 514.8(a)(2)(i). Thus, proposed Sec. 514.8(b)(1)(ii) is revised
as follows: ``The holder of an approved application under section 512
of the act must assess the effects of the change before distributing a
drug made with a manufacturing change.''
1. Provision of Supplemental Application to FDA District Office
(Proposed Sec. 514.8(b)(1)(iv))
FDA has revised proposed Sec. 514.8(b)(1)(iv) to apply to both
supplements and amendments as provided in CDER's regulations, Sec.
314.70. In addition, this section also includes clarification with
regard to providing a field copy for supplemental changes to drugs
manufactured outside of the United States, see the response to comment
6. The section now provides that: ``In each supplement and amendment to
a supplement providing for a change under paragraph (b)(2) or (b)(3) of
this section, the applicant must include a statement certifying that a
field copy has been provided to the appropriate FDA district office. No
field copy is required for a supplement providing for a change made to
a drug manufactured outside of the United States''
2. Changes That May Affect Drug Equivalence (Proposed Sec.
514.8(b)(2)(ii)(B))
FDA has revised Sec. 514.8(b)(2)(ii)(B) by: (1) Specifically
identifying the drug as approved under section 512(b) of the act, (2)
replacing ``animal'' in ``* * *appropriate animal studies'' with
``clinical'' to be more consistent with the language of section 506A of
the act, and (3) deleting ``or to the reference listed drug.'' Though
Sec. 514.8 applies to supplements to abbreviated new animal drug
applications, FDA intends to address the term ``reference listed drug''
in future regulations for drugs approved under section 512(c)(2)(A) (21
U.S.C. 360b(c)(2)(A) of the act.
3. Container Closure Changes That May Affect Drug Impurity Profile
(Proposed Sec. 514.8(b)(2)(ii)(E))
FDA has limited the requirement for a prior approval supplement for
drug product container closure systems to include only changes in the
type or composition of a packaging component. FDA has revised Sec.
514.8(b)(2)(ii)(E) to be similar to CDER's regulations, Sec. 314.70,
and it now states: ``Changes in a drug product container closure system
that controls the drug delivered to the animal or changes in the type
or composition of a packaging component that may affect the impurity
profile of the drug product.'' Unlike CDER's Sec. 314.70(b)(vi), CVM
has not included specific examples of the container closure changes and
believes that these examples are best addressed through guidance.
4. Supplement Approval Prior to Product Distribution (Proposed Sec.
514.8(b)(2)(iii))
FDA has added the sentence, ``The supplement must be labeled
``Prior Approval Supplement'' after the first sentence in Sec.
514.8(b)(2)(iii) to be consistent with the submission identification
requirements described in Sec. 514.8(b)(3)(iii), (b)(3)(vi), and
(b)(4).
5. Evaluate the Effects of the Change (Proposed Sec.
514.8(b)(2)(iii)(E))
FDA has revised Sec. 514.8(b)(2)(iii)(E) to state: ``A description
of the methods used and studies performed to assess the effects of the
change.'' See the response to comment 3.
6. Validation Protocols (Proposed Sec. 514.8(b)(2)(iii)(I))
FDA has revised proposed Sec. 514.8(b)(2)(iii)(I) to be consistent
with CDERs regulations by replacing ``test methodologies'' with ``test
methodologies related to sterilization process validation.''
FDA has deleted proposed Sec. 514.8(b)(2)(iii)(K) because
submissions related to environmental considerations are addressed
elsewhere in the regulations (see part 25 (21 CFR part 25)).
FDA has included Sec. 514.8(b)(2)(iii)(J) to be consistent with
section 506A(c)(1) of the act. The new section states: ``Any other
information as directed by FDA.''
7. Protocol Submission as a Supplement (Proposed Sec. 514.8(b)(2)(v))
FDA has revised the proposed rule to clarify that a protocol must
be submitted as a prior approval supplement if the protocol was not
already included in an approved application or when changing an
approved protocol. These changes are consistent with CDER's
regulations, Sec. 314.70.
8. Thirty-Day Changes-Being-Effected Supplement--Container Closure
System (Proposed Sec. 514.8(b)(3)(ii)(A))
To be consistent with CDER's regulations, FDA has revised proposed
Sec. 514.8(b)(3)(ii)(A) to clarify the wording in sections 514.8(b)(2)
and 514.8(b)(4) of the proposed regulations. Revised Sec.
514.8(b)(3)(ii)(A) states: ``A change in the container closure system
that does not affect the quality of the drug except as otherwise
described in paragraphs (b)(2) and (b)(4) of this section.''
9. Thirty-Day Changes-Being-Effected Supplement (Proposed Sec.
514.8(b)(3)(iii))
FDA has revised proposed Sec. 514.8(b)(3)(iii) to incorporate
[[Page 74769]]
additional reference to Sec. 514.8(b)(3)(vi) since ``Supplements-
Changes Being Effected'' described under Sec. 514.8(b)(3)(vi) must
also give a full explanation of the basis of the change and identify
the date on which the change is made.
10. Thirty-Day Changes-Being-Effected Supplement (Proposed Sec.
514.8(b)(3)(v)(B))
FDA has revised proposed Sec. 514.8(b)(3)(v)(B) to be consistent
with CDER's regulations, Sec. 314.70 and to clarify compliance with
this section by allowing applicants the opportunity to amend a
supplement by providing any missing information.
11. Minor Changes--Expiration Dating Period (Proposed Sec.
514.8(b)(4)(ii)(F))
The term ``full production batches'' is redundant and may
incorrectly imply that only the largest production batches can be used
to extend an expiration dating period. Therefore, FDA has revised Sec.
514.8(b)(4)(ii)(F) by deleting the second ``full'' before ``production
batches.''
12. Minor Changes--Alternate Analytical Procedure (Proposed Sec.
514.8(b)(4)(ii)(G))
FDA has revised Sec. 514.8(b)(4)(ii)(G) by adding ``* * *or
deletion of an alternative analytical procedure'' to be consistent with
CDER's regulations, Sec. 314.70.
13. Annual Report (Proposed Sec. 514.8(b)(4)(iii))
FDA has revised Sec. 514.8(b)(4)(iii) by deleting from the first
sentence ``a list of all products involved;'' and adding ``(A) A
completed Form FDA 356V;'' to be consistent with Sec.
514.8(b)(2)(iii)(A). FDA is also adding Sec. 514.8(b)(4)(iii)(J),
``Any other information as directed by FDA'' to be consistent with
section 506A(d)(2)(A) of the act and making additional revisions to
Sec. 514.8(b)(4)(iii)(B) through (b)(4)(iii)(I) to be consistent with
CDER's regulations, Sec. 314.70. Most of the changes in this section
are either editorial or were made to maintain consistency with other
sections under Sec. 514.8 or with CDER's regulations, Sec. 314.70.
Revisions to Sec. 514.8(b)(4)(iii)(G) are made in response to comment
25.
C. Labeling and Other Changes to an Approved Application
1. Preapproval Supplement--Required Information (Proposed Sec.
514.8(c)(2))
FDA has revised proposed Sec. 514.8(c)(2)(ii)(E) by adding ``* *
*in support of the change'' in order to clarify the scope of the
derived data used to support a change. FDA has deleted proposed Sec.
514.8(b)(2)(iii)(D) and proposed Sec. 514.8(b)(2)(iii)(K), because
submissions related to environmental considerations are addressed
elsewhere in the regulations (see part 25). Additional changes are made
to Sec. 514.8(c)(2)(i) by deleting the term ``prescription new animal
drug mailing/promotional pieces,'' and to Sec. 514.8(c)(2)(i)(A) and
Sec. 514.8(c)(3)(A) by replacing the term ``side effect'' with the
term ``adverse reaction.''
2. Labeling Changes to be Placed Into Effect Prior to Receipt of a
Written Notice of Approval of a Supplemental Application (Proposed
Sec. 514.8(c)(3)(iv))
FDA has revised proposed Sec. 514.8(c)(3)(iv) to read ``If the
supplemental application is not approved, FDA may initiate an
enforcement action because the drug is misbranded under section 502 of
the act and/or adulterated under section 501 the act. In addition,
under section 512(e) of the act, FDA may issue a notice of opportunity
for hearing to withdraw the approval of the application.'' Section
514.8(c)(3)(iv) is being revised to clarify potential legal options.
III. Responses to Comments on the Proposed Rule
CVM received comments on many aspects of the proposed rule from
five parties, including pharmaceutical industry associations and other
interested persons. One comment to the proposed rule also fully
endorsed comments by a pharmaceutical trade organization to the
analogous proposed rule for human new and abbreviated new drug
applications by CDER, which was published in the Federal Register of
June 28, 1999 (64 FR 34608). These endorsed comments also are addressed
in this final rule. All comments and the agency's responses are
summarized below.
A. Section 514.8(a)--Definitions
1. Definition of ``Minor Changes and Stability Report'' (Proposed Sec.
514.8(a)(2)(ii))
Proposed Sec. 514.8(a)(2)(ii) states that the ``Minor changes and
stability report'' is a report that is submitted to the new animal drug
application or abbreviated new animal drug application once each year
within 60 days of the anniversary date of the application's original
approval or mutually agreed upon date.
(1) One comment requested clarification of the requirement of
submitting the minor changes and stability report noting that the time
frame in the proposed provision extends before and after this agreed
upon date. The commenter suggested that the requirement be revised to
require submission of the report ``within 60 days of the anniversary
date of the application's original approval or mutually agreed upon
date.''
Agency Response: FDA agrees to revise the definition as requested
with some modification. The definition is revised to state, in part,
``* * *within 60 days before or after the anniversary of the
application's original approval or mutually agreed upon date.''
2. Definition of ``Specification'' (Proposed Sec. 514.8(a)(2)(iii))
``Specification'' is defined in proposed Sec. 514.8(a)(2)(iii) as
the quality standard (i.e., tests, analytical procedures, and
acceptance criteria) provided in an approved NADA or ANADA to confirm
the quality of drug substances, drug products, intermediates, raw
materials, reagents, and other components including container closure
systems and in-process controls. The proposed regulation states that
the term ``acceptance criteria'' refers to numerical limits, ranges, or
other criteria for the tests described.
(2) One comment stated that ``* * *intermediates, raw materials,
reagents, and other components including container closure systems and
in-process materials'' should be deleted from the definition of
specification, with changes for these materials handled separately from
the final rule and final guidance. The comment stated that the
definition is not consistent with the International Conference on
Harmonization (ICH) guidance on specifications entitled ``Test
Procedures and Acceptance Criteria for New Drug Substances and New Drug
Products: Chemical Substances'' (ICH Q6A), which includes only drug
substance and drug product. Additionally, the comment indicated that
inclusion of items beyond the drug substance and drug product
represents a level of complexity that would be better dealt with in
guidances that can adequately evaluate the significance of changes to
specific items.
Agency Response: FDA declines to revise the definition as
requested. Section 512(b)(1)(D) (for NADAs) and section 512(n)(1)(G)
(for ANADAs) of the act (21 U.S.C. 360b(b)(1)(D) and 360b(n)(1)(G))
require that a full description of the methods used in, and the
facilities and controls used for, the manufacture, processing, and
packing of a drug be provided in an application. The regulation for the
establishment of
[[Page 74770]]
a performance standard at 21 CFR 514.1(b)(5)(v) also requires
information to ensure proper identity, strength, quality, and purity of
the raw materials, whether active or not, including the specifications
for acceptance and methods of testing for each lot of raw material.
Intermediates, raw materials, reagents, container closure systems,
in-process materials and other materials that are used in the
manufacture of drug substances, Type A medicated articles, or drug
products are considered part of the manufacturing method and can have a
direct effect on the identity, strength, quality, purity, or potency of
the drug. While the extent of a specification (e.g., number or type of
tests, strictness of acceptance criteria) for these materials may vary
depending on the materials' use in a given manufacturing process, FDA
has required specifications for these materials to be included in
applications as part of the description of the manufacturing method and
will continue to do so. Similar to the ICH Q6A guidance, the scope of
the Veterinary International Conference on Harmonization (VICH)
guidance entitled ``Test Procedures and Acceptance Criteria for New
Veterinary Drug Substances and New Medicinal Products: Chemical
Substances'' (GL39) is limited to only drug substances and drug
products, whereas in this regulation the definition of
``Specification'' (see Sec. 514.8(a)(2)(iii)), is intended to cover
all drug materials including drug substances, drug products, raw
materials, reagents, etc.
3. Definition of ``Validate the Effects of the Change'' (Proposed Sec.
514.8(a)(2)(iv))
Proposed Sec. 514.8(a)(2)(iv) defines ``validate the effects of
the change'' to mean to assess the effect of a manufacturing change on
the identity, strength, quality, purity, or potency of a new animal
drug as these factors relate to the safety or effectiveness of the new
animal drug.
(3) Several comments recommended that FDA replace the terms
``validate'' or ``validation'' with ``assess'' or ``assessment.'' One
comment stated that although FDA is using the terms consistently with
Congress' use of the terms in section 506A of the act, the term
``validate'' is likely to cause confusion because this term has long
been associated with, and has specific meaning under, FDA's current
good manufacturing practices (CGMPs) regulations.
Agency Response: FDA agrees to revise the definition as requested,
as the revision makes the definition more clear without changing its
meaning. FDA, on its own initiative, is also revising the phrase ``* *
*purity, or potency'' to ``* * *purity, and potency* * *'' to be
consistent with section 506A(b) of the act. In addition, FDA is
replacing the term ``assess'' with ``evaluate'' and the ``effect'' with
``effects.'' FDA notes that while the effect of a manufacturing change
on the identity, strength, quality, purity and potency of a drug is to
be assessed, this assessment could involve testing of materials
directly affected by a change (e.g., drug substance) in addition to or
instead of drug testing. FDA has also revised Sec. 514.8(b)(2)(iii)(E)
accordingly to state: ``A description of the methods used and studies
performed to assess the effects of the change.''
Other Changes to ``Definitions'' Section (Proposed Sec. 514.8(a))
(4) Several comments requested clarification and standardization of
the terms ``drug product,'' ``drug,'' and ``product.'' They further
suggested that ``drug substance'' be changed to ``active pharmaceutical
ingredient'' (API) to be consistent with other guidances. Also,
clarification of whether ``product'' refers to API was requested.
Agency Response: FDA agrees that terminology should be standardized
throughout the proposed 21 CFR 514.8 regulations. Therefore, FDA has
replaced the terms ``product'' and ``new animal drug'' with ``drug''
where applicable throughout 21 CFR 514.8. This change differs from the
human drug regulations where the terms ``product'' and ``drug'' are
replaced by the terms ``drug substance'' or ``drug product'' throughout
21 CFR 314.70. The reason for the difference is that animal drugs such
as free-choice feeds (21 CFR 510.455), Type A medicated articles (21
CFR 558.3(b)(2)) and Type B or Type C medicated feed manufactured from
a drug component (21 CFR 558.3(b)(5)) are not considered ``drug
products'' as defined under 21 CFR 210.3(b)(4). However these products
require approved new animal drug applications and therefore are also
covered by 21 CFR 514.8. Using the term ``drug product'' instead of
``drug'' in 21 CFR 514.8 may incorrectly imply that reporting of
manufacturing changes for the previously mentioned approved products is
not required. The term ``drug'' as defined under section 201(g)(1) of
the act (21 U.S.C. 321(g)(1)) encompasses drug substances, drug
products, Type A medicated articles, etc. The terms ``drug substance''
and ``drug products'' are included in certain parts of 21 CFR 514.8,
specifically in the description of changes that do not apply to free-
choice medicated feeds, Type A medicated articles or Type B and Type C
medicated feed manufactured from a drug component, see 21 CFR
514.8(b)(2)(ii), (b)(3)(ii), (b)(3)(vi) and (b)(4)(ii).
FDA declines to change ``drug substance'' to ``active
pharmaceutical ingredient,'' as requested. ``Drug substance'' is the
commonly accepted term for filing purposes whereas the term ``active
pharmaceutical ingredient'' is more commonly used for compliance
purposes. Both terms are often used interchangeably. Since Sec. 514.8
deals with filing issues, FDA prefers to use the term ``drug
substance.'' FDA has included a definition of ``drug substance'' under
Sec. 514.8(a)(2)(ii) to read ``Drug substance means an active
ingredient as defined under Sec. 210.3(b)(7).''
B. Section 514.8(b)--Manufacturing Changes to an Approved Application
1. Manufacturing Changes Requiring Prior Approval of a Supplement
(Proposed Sec. 514.8(b)(1)(ii))
Proposed Sec. 514.8(b)(1)(ii) requires the holder of an approved
application to validate the effect of the manufacturing change on the
identity, strength, quality, purity, or potency of the new animal drug
as these factors may relate to the safety or effectiveness of the new
animal drug before distributing a drug made with a manufacturing
change.
(5) One comment recommended that FDA replace the term ``validate''
with ``assess'' in proposed Sec. 514.8(b)(1)(ii).
Agency Response: FDA agrees to revise the definition as requested.
2. Provision of Supplemental Application to FDA District Office
(Proposed Sec. 514.8(b)(1)(iv))
Proposed Sec. 514.8(b)(1)(iv) states that an applicant must
include in each supplemental application providing for a change under
paragraph (b)(2) or (b)(3) of this section, a statement certifying that
a copy of the supplement has been provided to the appropriate FDA
district office.
(6) One comment requested deletion of this requirement since many
district offices have neither the space to store these documents nor
the need for all submission documents. Any submission documents desired
or required by the district office are available either from the
Document Control Unit, by request from the manufacturing site, or at
the manufacturing site during an inspection. Requiring copies to be
sent to the district offices is a non-productive use of both industry
and agency resources and effectively circumvents the goal of this rule
and the intent of the Modernization Act.
[[Page 74771]]
Another comment requested clarification as to whether the field
copy should be sent to the applicant's home district office, to the FDA
office where the change is being made, or to the FDA office in the
district of the company's corporate headquarters. FDA also was asked to
clarify to what FDA office the copy should be sent for changes outside
of the United States.
Agency Response: FDA declines to revise the regulations as
suggested.
FDA disagrees that sending copies to the district offices is a non-
productive use of both industry and agency resources. Instead, this
requirement may reduce the burden on FDA resources (for example,
searching and copying documents in the Document Control Unit by the CVM
review staff), increase the awareness and interaction of district
offices with FDA headquarters regarding manufacturing changes placed
into effect for animal drugs, and improve the timeliness of CGMP
inspections for certain types of changes for animal drugs, if needed.
FDA also believes that this requirement is in accord with the
intent of the Modernization Act, specifically section 506A of the act.
That section describes requirements and procedures for making and
reporting manufacturing changes. One of the requirements specified in
section 506A of the act is that the holder must ``validate'' or assess
the effects of a change before distributing a drug made with the
change. In order for FDA to determine whether an applicant has made a
change according to section 506A of the act, the FDA's district offices
also must be informed of the effected change or change to be effected
concurrently with the change being reported to FDA headquarters in a
supplemental application.
Field copies should be sent to the FDA district office where the
changes are being made. No field copy is required for changes made
outside of the United States. Proposed Sec. 514.8(b)(1)(iv) is amended
by adding the statement ``No field copy is required for a supplement
providing for a change made to a drug manufactured outside of the
United States''
3. Changes Listed in the Cover Letter (Proposed Sec. 514.8(b)(1)(v))
Proposed Sec. 514.8(b)(1)(v) adds a requirement that a list of all
changes contained in a supplement or annual report described in Sec.
514.8(b)(4) must be included in the cover letter for the supplement or
annual report.
(7) Several comments requested that ``cover letter'' be replaced by
``introduction to the document'' since cover letters are not considered
confidential.
Agency Response: FDA declines to revise the regulation as
suggested. The standards for disclosing specific information from a
cover letter or application do not differ depending on where this
information is provided or what the document is titled. Information
that is exempt from disclosure (e.g., trade secret or confidential
commercial information) is not disclosed whether it is in a cover
letter or an application (see also 21 CFR 514.11). FDA has revised
proposed Sec. 514.8(b)(1)(v) to harmonize with the reporting
requirements in CDER's regulations Sec. 314.70(a)(6) to only require
supplements to provide a list of all the changes in the cover letter.
For annual reports, the list of changes may be provided in the cover
letter or in the submission's summary section.
C. Changes Requiring Submission and Approval of a Supplement Prior to
Distribution of the Drug Made Using the Change (Major Changes)
1. Changes That May Affect Product Sterility Assurance (Proposed Sec.
514.8(b)(2)(ii)(C))
Proposed Sec. 514.8(b)(2)(ii)(C) requires prior approval for
changes that may affect product sterility assurance, such as changes in
product or component sterilization method(s) or an addition, deletion,
or substitution of steps in an aseptic processing operation.
(8) Several comments suggested that the language be modified to
state ``changes that reduce the sterility assurance level'' since the
impact on the sterility assurance level should be the guiding factor
and the language, as proposed, is too burdensome in terms of regulatory
reporting.
Agency Response: FDA declines to revise the provision as requested.
The assessment as to whether a change reduces the sterility assurance
is a complex and multidimensional analysis. For example, a change to a
more stringent terminal sterilization process, while in theory
providing a lower probability of non-sterile units, may damage the
container closure system so that sterility of individual units could
not be maintained. FDA also disagrees that the proposed language is too
burdensome with regard to regulatory reporting. Under the previous
regulations in Sec. 514.8(a)(2), most manufacturing and control
changes, including manufacturing and control changes for sterile drug
substance or drug products, required prior approval supplements. The
proposed regulations allow the opportunity for applicants to report
more manufacturing changes in changes-being-effected supplements or
annual reports, including those manufacturing changes that will not
negatively impact sterility assurance levels.
2. Changes Affecting Natural Products (Proposed Sec.
514.8(b)(2)(ii)(F))
Proposed Sec. 514.8(b)(2)(ii)(F) requires prior approval for
changes solely affecting a natural product, a recombinant DNA-derived
protein/polypeptide product, or a complex or conjugate of a new animal
drug with a monoclonal antibody for the following: (1) Changes in the
virus or adventitious agent removal or inactivation method(s), (2)
changes in the source material or cell line, and (3) establishment of a
new master cell bank or seed.
(9) Several comments requested that FDA delete the reference to
``natural products'' since the definition of natural products is not
clear and having special requirements for this additional category of
products represents additional regulatory reporting requirements beyond
current practice.
Agency Response: FDA declines to delete the phrase ``natural
products'' from this provision. The changes identified in this
provision are major changes and apply equally to a natural product, a
recombinant DNA-derived protein/polypeptide, or a complex or conjugate
of a drug substance with a monoclonal antibody. FDA will provide a
definition of natural product in the final guidance that will be
published shortly, but declines to provide the definition in the
regulation because advancements in technology may require that the
definition be revised.
FDA also disagrees that having special requirements for this
additional category of products imposes additional regulatory reporting
requirements beyond current practice. Under the previous regulations at
Sec. 514.8(a)(2), most manufacturing and control changes, including
those for a natural product, DNA-derived protein/polypeptide, or a
complex or conjugate of a new animal drug with a monoclonal antibody,
required prior approval supplements. In the final guidance, FDA will
identify changes related to these products that may now be filed in
changes-being-effected supplements or annual reports. However, the
three changes specified in this provision, which are unique to the
identified types of drug products, are considered to have a substantial
potential to adversely affect the identity, strength, quality, purity,
or potency of a drug as these factors may relate to the safety or
effectiveness of a drug. Virus or adventitious agent removal or
[[Page 74772]]
inactivation processes are the means by which FDA ensures that these
types of agents are removed. Failure to remove such agents has a
significant potential to adversely affect public safety. Changes in
source material or cell line, or establishment of a new master cell
bank or seed, have a substantial potential to affect the quality of a
drug substance. For example, a change in source material (e.g.,
species, geographic region of harvesting) could result in different
impurities or contaminants (e.g., pesticides) than were previously seen
or cause a change in potency.
3. Supplement Approval Prior to Product Distribution (Proposed Sec.
514.8(b)(2)(iii))
Proposed Sec. 514.8(b)(2)(iii) specifies the information to be
included in the supplement.
(10) Several comments requested adding ``as appropriate'' as
follows: ``Except for submissions under paragraph (e) of this section,
the following shall be contained in the supplement, as appropriate.''
The comments said that not all listed material is relevant for every
submission.
Agency Response: FDA declines to revise the provision as requested.
FDA expects that the information specified in Sec. 514.8(b)(2)(iii)(A)
through (I) will be needed for many supplemental applications. FDA
believes that the addition of ``as appropriate'' may incorrectly give
the impression that this information is not routinely needed and would
result in supplemental applications being submitted with insufficient
information.
4. Validation Protocols for Natural Products (Proposed Sec.
514.8(b)(2)(iii)(H))
Proposed Sec. 514.8(b)(2)(iii)(H) states that for a natural
product, a recombinant DNA-derived protein/polypeptide product, or a
complex or conjugate of a drug with a monoclonal antibody, relevant
validation protocols must be provided in addition to the requirements
in Sec. 514.8(b)(2)(iii)(E) and (b)(2)(iii)(F).
(11) One comment requested that FDA delete the requirement for the
submission of validation protocols for ``natural products, et. al.''
because: (1) Validation protocols are maintained at the manufacturing
site and are more appropriately reviewed on site, and (2) requiring
submission of validation protocols only for natural products is a new
and additional requirement that provides no greater assurance of safety
or effectiveness of these products. The comment further stated that the
additional regulatory burden is in opposition to the goals of the
proposed rule and to the intent of the Modernization Act, and that
there is no scientific rationale for singling out natural products
under this requirement. In addition, there is no clear definition of
these products, although the accompanying guidance states that natural
products include products derived from microorganisms. Many products,
including antibiotics, are derived from microorganisms and have been
produced and used for many years, some for decades, with adequate
controls on manufacturing changes and no adverse effects. Requiring
submission of validation protocols for only this single class of
products is excessive.
Agency Response: FDA declines to revise the provision as requested.
Unless otherwise specified by FDA, validation protocols and data need
not be filed in the application but should be retained at the facility
and be available for review by FDA at the agency's discretion. For most
products, FDA does not require the submission of validation protocols
and data. However, for a natural product, a recombinant DNA-derived
protein/polypeptide, or a complex or conjugate of a drug substance with
a monoclonal antibody, FDA does require the submission of validation
protocols for certain critical manufacturing processes unique to these
drug substances or drug products. For example, FDA would expect the
validation protocol for the virus or adventitious agent removal or
inactivation process to be submitted in an application. FDA currently
requires this type of information to be submitted in an application.
Under Sec. 514.8(b)(1)(iii), FDA may publish future guidances to
address specific filing requirements for these types of drug substances
or drug products, including drug substances derived from
microorganisms.
FDA also disagrees that this requirement is an additional
regulatory burden and contravenes the intent of the Modernization Act.
Under the previous regulations at Sec. 514.8(a)(2), most manufacturing
and control changes, including those for a natural product, required
prior approval supplements. In the final guidance, FDA will identify
many changes related to these products that may be filed in changes-
being-effected supplements or annual reports. As discussed previously,
FDA will provide a definition of a natural product in the final
guidance.
5. Validation Protocols and SOP's (Proposed Sec. 514.8(b)(2)(iii)(I)
and (J))
Proposed Sec. 514.8(b)(2)(iii)(I) states that for sterilization
process and test methodologies, relevant validation protocols must be
provided in addition to the requirements in paragraphs (b)(2)(iii)(E)
and (b)(2)(iii)(F) of this section. Proposed Sec. 514.8(b)(2)(iii)(J)
states that a reference list of relevant standard operating procedures
(SOPs), when applicable, must be contained in the supplement.
(12) Several comments recommended that reference to SOPs be deleted
because: (1) The data represent compliance information and are better
suited for field inspections, and (2) the addition of this information
to existing practice would result in increased regulatory burden.
Agency Response: FDA has revised the regulation in response to the
comment. An applicant is required to submit a ``full description of the
methods used in, and the facilities and controls used for, the
manufacture, processing, and packing of such drug'' (sections
512(b)(1)(D) and 512(n)(1)(G) (21 U.S.C. 360b(b)(1)(D) and
360b(n)(1)(G)) of the act). This information may be submitted in
different forms, including SOPs. In most cases, SOPs do not include
information relevant to the NADA or ANADA review, but rather
information relevant to determining an applicant's compliance with
CGMPs. However, in the case of a natural product, a recombinant DNA-
derived protein/polypeptide, or a complex or conjugate of a new animal
drug with a monoclonal antibody, or a sterilization process,
information contained in SOPs is often relevant to the review of
certain aspects of an application.
FDA is deleting proposed Sec. 514.8(b)(2)(iii)(J) and is revising
proposed Sec. Sec. 514.8(b)(2)(iii)(H) and (I) to limit the need for
information on SOPs to these situations. As discussed previously,
information regarding SOPs is needed in some cases. FDA wishes to
emphasize that while the information is needed for the application
review, it is not always necessary to submit the actual SOP as long as
the required information is provided in sufficient detail as part of
the application.
6. Expedited Review of Supplement (Proposed Sec. 514.8(b)(2)(iv))
Proposed Sec. 514.8(b)(2)(iv) states that an applicant may request
an expedited review of a supplement for public health reasons or if a
delay in making the change described in the supplement
[[Page 74773]]
would impose an extraordinary hardship.
(13) Several comments requested that FDA provide feedback to the
applicant on the acceptance or refusal of an ``Expedited Review Request
within 30 days.''
Agency Response: FDA declines to revise the provision as requested.
FDA intends to issue future guidance on requesting expedited reviews of
supplemental manufacturing changes.
7. Protocol Submission as a Supplement (Proposed Sec. 514.8(b)(2)(v))
Proposed Sec. 514.8(b)(2)(v) states that an applicant may submit
one or more protocols describing the specific tests and validation
studies and acceptable limits to be achieved to demonstrate the lack of
adverse effect for specified types of manufacturing changes on the
identity, strength, quality, purity, or potency of the product as these
factors may relate to the safety or effectiveness of the product. Any
such protocols, or change to a protocol, must be submitted as a
supplement requiring FDA approval prior to distribution of the product.
The supplement, if approved, may result in the proposed change
subsequently falling within a reduced reporting category for the
specific product because the use of the protocol for that type of
change reduces the potential risk of an adverse effect.
(14) One comment recommended deleting or modifying the requirement
that protocols ``must be submitted as a supplement requiring approval
for FDA prior to distribution of the product'' because this requirement
will have an effect opposite of the intent of the Modernization Act.
Submission as a supplement subjects protocols to a 180-day review
timeframe. Currently, such protocols are reviewed in a 30-45 day
timeframe. Extending the review timeframe will delay implementation of
changes contrary to the stated purpose of this rule. The comment
suggested that the aforementioned requirement either should be deleted
or subject to a limited 30-day review timeframe.
Agency Response: FDA declines to revise the regulation as
requested. The protocols or ``comparability protocols'' described in
proposed Sec. 514.8(b)(2)(v) are new types of protocols for drugs and
differ from the types of protocols (e.g., stability protocols)
typically submitted to an investigational new animal drug file. It is
expected that applicants will use comparability protocols to justify a
reduced reporting category for the particular change, for example, by
requesting that they be allowed to implement a major change without
prior approval by FDA. These protocols, in effect, will reduce the
regulatory oversight of the specified changes, and FDA considers this
to have the potential to have an adverse effect on the identity,
strength, quality, purity, or potency of a drug as these factors may
relate to the safety or effectiveness of the drug. Also, where
previously allowed by regulations, these changes were specified as
requiring prior approval, and this rule just extends that option of
submitting protocols for animal drugs.
FDA has revised Sec. 514.8(b)(2)(v) by adding the title
``Comparability Protocol'' to differentiate this type of protocol from
other types of protocols; and has included other language to be
consistent with CDER's regulations.
D. Changes Requiring Submission of a Supplement at Least 30 Days Prior
to Distribution of the Drug Made Using the Change (Moderate Changes)
8. Thirty-Day Changes-Being-Effected Supplement (Proposed Sec.
514.8(b)(3)(ii)(B))
Proposed Sec. 514.8(b)(3)(ii)(B) provides for a 30-day changes-
being-effected supplement for changes solely affecting a natural
product, a recombinant DNA-derived protein/polypeptide product or a
complex or conjugate of a new animal drug with a monoclonal antibody,
including: (1) An increase or decrease in production scale during
finishing steps that involves new or different equipment; and (2)
replacement of equipment with that of a similar, but not identical,
design and operating principle that does not affect the process
methodology or process operating parameters.
(15) Several comments stated that having special requirements for
this category of products represents additional regulatory reporting
requirements and regulatory burden beyond current practice and the
intent of the Modernization Act. One comment requested that this
section be removed and these changes be reported in annual reports. One
comment stated that there is no scientific basis for singling out all
natural products under this requirement as, for instance,
microorganisms (from which some natural products are derived) form the
basis of many products such as antibiotics, which have been produced
and used for many years with adequate controls on manufacturing changes
and no adverse effects. Rather, this comment advocated that these types
of changes be evaluated on the potential for adverse impact on safety
or effectiveness of the drug product.
Agency Response: FDA declines to revise the regulation as
requested. However, FDA has revised Sec. 514.8(b)(3)(ii)(B) to specify
``natural protein'' rather than ``natural product'' to be consistent
with CDER's regulations. There are specific issues and concerns
relating to the production of natural protein products that are not
routinely associated with other classes of drugs and, therefore, FDA
has specified certain requirements for proteins. Proteins are
susceptible to denaturation. Denaturation can be caused by changes in
sheer force as a result of scale and/or equipment changes. Also,
proteins differentially adsorb to surfaces. The identity, strength,
quality, purity, or potency of the product could be affected by changes
in scale or equipment because of these characteristics.
(16) Several comments requested that FDA clarify whether this
section applies to drug products or drug substances.
Agency Response: FDA agrees to clarify the proposed language as
appropriate. This section applies to all animal drugs, including Type A
medicated articles. The terms ``drug substance'' and ``drug product''
are specifically identified if the changes do not apply to free-choice
medicated feeds, Type A medicated articles or Type B and Type C
medicated feed manufactured from a drug component (see response to
comment 4).
(17) Several comments requested clarification of ``finishing
steps.''
Agency Response: FDA declines to revise the regulations to provide
clarification of the term ``finishing steps.'' In general, finishing
steps are considered those steps in the manufacturing process where the
stability or the property and performance of a protein product is less
likely to be affected by changes in scale or equipment. The steps in a
manufacturing process that would be considered finishing steps depend
on the manufacturing process and the specific protein being
manufactured. A particular manufacturing step may be considered a
finishing step for one product but not for another. An applicant is
encouraged to discuss with FDA which steps would be considered
finishing steps for its particular product and process. This discussion
should occur as early in the process as possible, including during INAD
meetings.
(18) Several comments requested clarification of the difference
between equipment that is ``similar, but not identical,'' proposed as a
changes-being-effected-in-30-days supplement, and the SUPAC terminology
of equipment of the ``same design and operating principle,'' which
already is defined in the SUPAC guidance and the proposed rule as an
[[Page 74774]]
annual report change. The comments further suggested that for equipment
changes that are of different operating principle and design, FDA
should consider classification within the major change category, and
for equipment changes that are of the same operating principle but
different design, FDA should consider classification within the
moderate change category.
Agency Response: FDA agrees that replacement of equipment with that
of a different design that does not affect the process operating
parameters may be reported as a changes-being-effected-in-30-days
supplement. Therefore, FDA is clarifying the requirement by replacing
the phrase ``similar, but not identical, design and operating
principle'' with the phrase ``different design.'' Equipment of a
different design may or may not have a different operating principle.
FDA is also revising section 514.8(b)(3)(ii)(B)(2) by deleting
``new or'' since new equipment may not necessarily be different
equipment in regard to process methodology or process operating
parameters.
9. Supplement--Changes Being Effected (Proposed Sec. 514.8(b)(3)(vi))
Proposed Sec. 514.8(b)(3)(vi) states that the agency may designate
a category of changes for the purpose of providing that, in the case of
a change in such category, the holder of an approved application may
begin distribution of the drug involved upon receipt by the agency of a
supplement for the change. The information listed under paragraph
(b)(2)(iii) of this section must be contained in the supplement. The
supplement must be labeled ``Supplement--Changes Being Effected.''
These changes include, but are not limited to: (1) Addition to a
specification or changes in the methods or controls to provide
increased assurance that the new animal drug will have the
characteristics of identity, strength, quality, purity, or potency that
it purports or is represented to possess and (2) a change in the size
and/or shape of a container for a nonsterile drug product, except for
solid dosage forms, without a change in the labeled amount of product
from one container closure system to another.
(19) Several comments recommended that FDA add ``a sterile drug
product or a sterile drug substance'' to expand the type of drug
products for which the container changes allowed in this section would
apply, since size and shape changes for sterile API and drug products
have only moderate potential impact. This is especially true when the
size/shape changes are very minor in nature, as is often the case when
suppliers make minute adjustments in their packaging components.
Agency Response: FDA declines to revise the regulation as
requested. Sterility of drug products is a fundamental and essential
quality attribute of these drugs and is a critical aspect of the safety
assessment. Changes in the container closure system, even if minimal,
may affect the sterility assurance of the drug product and are
considered major changes. FDA acknowledges that the effects of changes
in the size and/or shape of the container closure system for sterile
drug substances are considered by FDA to be a lower risk than for
sterile drug products because of the differences in procedures for
sterilizing drug substances and finished drug products. However, they
are still of a higher risk than for nonsterile products. Therefore, FDA
declines to specify in the regulations that these changes can be
submitted in a changes-being-effected supplement. Additional
information on changing container closure systems for drug products is
included in the final guidance.
10. Disapproved Supplements and Drug Distribution Stoppage (Proposed
Sec. 514.8(b)(3)(vii))
Proposed Sec. 514.8(b)(3)(vii) provides that if the agency
disapproves the supplemental application submitted under paragraph
(b)(3) of this section, the agency may order the manufacturer to cease
distribution of the drug products made with the manufacturing change.
(20) Several comments recommend replacing the language in Sec.
514.8(b)(3)(vii) with ``If FDA later determines that the supplemental
application is not immediately approvable, the agency will work with
the applicant to resolve all issues and to assure the continued
availability of the drug,'' since this is the current practice and the
intent of the U.S. Senate as recorded in Senate Report 105-43.
Agency Response: FDA declines to revise the provision as requested.
The regulation is consistent with section 506A(d)(3)(B)(iii) of the
act, which allows FDA to disapprove a supplemental application and
order the manufacturer to cease distribution of the drug made with the
change.
E. Changes and Updated Stability Data to be Described and Submitted in
an Annual Report (Minor Changes)
1. Minor Changes Documented in an Annual Report (Proposed Sec.
514.8(b)(4)(ii)(A))
Under proposed Sec. 514.8(b)(4)(ii)(A), the following type of
change must be documented in the next annual report: Any change made to
comply with an official compendium that is consistent with FDA
requirements and provides increased assurance that the new animal drug
will have the characteristics of identity, strength, quality, purity,
or potency that it purports or is represented to possess.
(21) Several comments requested that FDA change this requirement to
read ``Any change to comply with an official compendium.'' One of these
comments added that: (1) Section 501(b) of the act requires the FDA to
resolve any differences with the compendial body, the United States
Pharmacopoeia (USP), (2) it is unfair to place the applicant in the
middle of these discussions, and the compendial review process should
be the mechanism by which the FDA has influence, and (3) it should be
permitted and appropriate that any USP-adopted changes, including
changes that may relax acceptance criteria and/or analytical
procedures, be updated via an annual report, with both the innovator as
well as any generic companies subject to this requirement. Another one
of these comments added that FDA's proposed regulations are
inconsistent with the statutory structure for drug approval and
quality, and that requiring supplements for labeling changes consistent
with compendial revisions would likely cause confusion and uncertainty
about a product's legal status and further impose unnecessary,
burdensome requirements on industry.
Agency Response: FDA declines to revise the provision as requested,
but is revising the regulations to provide further clarification. The
basis for this decision is set forth as follows.
Under section 501(b) of the act (21 U.S.C. 351(b)), a drug that is
recognized in an official compendium may be considered adulterated if
its strength differs from, or its quality or purity falls below, the
standards set in the compendium. Determinations of adulteration under
this provision of the act must be made in accordance with the
analytical procedures prescribed in the compendium, except when there
is no analytical procedure prescribed in the compendium or if the tests
prescribed in the compendium are insufficient and the agency has gone
through the process outlined in the
[[Page 74775]]
statute and has issued a regulation to provide an appropriate
analytical procedure. No drug defined in an official compendium will be
considered adulterated under section 501(b) of the act because its
strength differs from, or its quality or purity falls below, the
standards set in the compendium if the differences from the standard
are stated in its label. Under section 502(g) of the act (21 U.S.C.
352(g)), a drug that is recognized in an official compendium may be
considered misbranded if the drug is not packaged and labeled as
prescribed in the compendium.
FDA is aware of the legal status of the United States
Pharmacopoeia/National Formulary (USP/NF) under the act as a standard
for determining whether a drug may be considered adulterated or
misbranded. A compendial product that fails to comply with USP/NF
standards may be considered to be adulterated or misbranded under the
act. However, a compendial product can still be considered adulterated
or misbranded under other 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 paragr