[Federal Register Volume 64, Number 190 (Friday, October 1, 1999)]
[Proposed Rules]
[Pages 53281-53294]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-25493]
[[Page 53281]]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 5, 25, 500, 510, 514, and 558
[Docket No. 99N-1415]
RIN 0910-AB49
Supplements and Other Changes to Approved New Animal Drug
Applications
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
its regulations on supplements and other changes to an approved new
animal drug application (NADA) or abbreviated new animal drug
application (ANADA) to implement the manufacturing changes provision of
the Food and Drug Administration Modernization Act of 1997 (the
Modernization Act). This proposed rule would require manufacturers to
validate the effect of any manufacturing change on the identity,
strength, quality, purity, and potency of a new animal drug as those
factors relate to the safety or effectiveness of the product. The
proposal identifies changes requiring submission and approval of a
supplement prior to the distribution of the new animal drug made using
the change, changes requiring the submission of a supplement at least
30 days prior to the distribution of the new animal drug, changes
requiring the submission of a supplement at the time of distribution,
and changes to be described in an annual report.
DATES: Written comments by December 15, 1999.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852. Submit written comments on the information
collection requirements to the Office of Information and Regulatory
Affairs, Office of Management and Budget (OMB), New Executive Office
Bldg., 725 17th St. NW., rm. 10235, Washington, DC 20503, Attn.: Wendy
Taylor, Desk Officer for FDA.
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.
SUPPLEMENTARY INFORMATION:
I. Introduction
On November 21, 1997, the President signed the Modernization Act
into law (Public Law 105-115). Section 116 of the Modernization Act
amended the Federal Food, Drug, and Cosmetic Act (the act) by adding
section 506A (21 U.S.C. 356a), which describes requirements and
procedures for making and reporting manufacturing changes to approved
NADA's and ANADA's, new drug applications (NDA's) and abbreviated new
drug applications (ANDA's), and to license applications for biological
products. This proposed rule sets forth regulations to implement
section 506A of the act for NADA's and ANADA's. The Center for Drug
Evaluation and Research (CDER) and the Center for Biologics Evaluation
and Research (CBER) are issuing separate proposed regulations regarding
manufacturing changes for NDA's and ANDA's and for licensed biological
products.
Section 506A of the act makes no distinction between the
requirements for reporting manufacturing changes for human drug and
biological products regulated by CDER and CBER and for new animal drug
products regulated by the Center for Veterinary Medicine (CVM). CVM is
proposing this rule to harmonize the reporting requirements of
manufacturing changes for new animal drug products with those reporting
requirements for human drug and biological products.
The Modernization Act, section 116, becomes effective on the
effective date of these final regulations or 24 months after the
enactment of the Modernization Act (November 21, 1999), whichever
occurs first. This proposed rule updates and will replace Sec. 514.8
(21 CFR 514.8), which provides the current requirements for
manufacturing changes for NADA's.
II. Background
A. CVM's Current Rule
CVM currently evaluates all manufacturing changes to approved
NADA's under the regulations found in Sec. 514.8. Manufacturing changes
are currently submitted as permitted changes (Sec. 514.8(a)(5)),
changes being effected (CBE's) (Sec. 514.8(d), or changes requiring
approval prior to implementation (Sec. 514.8(a)(4)).
Under current Sec. 514.8(a)(5), permitted changes may be put into
effect without the approval of a supplemental application but must be
reported in the next annual drug experience report (DER). Section
514.8(a)(5) lists the types of manufacturing changes that are
considered permitted changes.
CBE's under current Sec. 514.8(d) include manufacturing changes
that would ``give increased assurance that the drug will have the
characteristics of identity, strength, quality, and purity which it
purports or is represented to possess.'' Such changes are to be placed
into effect at the earliest possible time with concurrent submission of
a supplemental application; hence such changes do not require CVM
approval before implementation.
Changes requiring approval of a supplemental application prior to
implementation are set out in current Sec. 514.8(a)(4) of the
regulations. Most manufacturing changes are currently reported in
preapproval supplemental applications under Sec. 514.8(a)(4).
B. Section 116 of The Modernization Act
Many of the concepts included in the Modernization Act were
incorporated from earlier rulemaking and guidance documents issued by
CDER and CBER. A discussion of CDER's earlier rulemaking, guidance
documents, and their underlying rationale can be found in the preamble
to CDER's proposed rulemaking to comply with section 506A of the act.
CDER had issued a series of guidance documents to ease preapproval
requirements for certain manufacturing changes that are unlikely to
have a detectable impact on a drug product's quality and performance as
distinguished from those that could have a significant impact. These
guidance documents were issued under a provision in current 21 CFR
314.70(a) that permits holders of an approved application to make
changes to the application in accordance with a guideline, notice, or
regulation published in the Federal Register that provides a less
burdensome notification of the change.
As of this date, CDER has issued several guidances addressing the
requirements relating to postapproval changes in manufacturing and
controls. These are known as the SUPAC (Scale-Up and Postapproval
Changes) documents. The first of these guidance documents was published
in November 1995 and is entitled ``Immediate Release Solid Oral Dosage
Forms; Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and
Controls; In Vitro Dissolution Testing; In Vivo Bioequivalence
Documentation'' (SUPAC-IR). This guidance provides recommendations to
holders of approved drug applications who intend, during the
postapproval period, to change: (1) The components or composition, (2)
the site of manufacture, (3) the scale of manufacture, and/or (4)
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the manufacturing (process and/or equipment) of an immediate release
solid oral dosage form.
In May 1997 and August 1997, CDER issued two related guidances
entitled ``Semisolid Dosage Forms Scale-Up and Postapproval Changes:
Chemistry, Manufacturing, and Controls; In Vitro Release Testing; In
Vivo Bioequivalence Documentation'' (SUPAC-SS) and ``Modified Release
Solid Oral Dosage Forms Scale-Up and Postapproval Changes: In Vitro
Dissolution Testing; In Vivo Bioequivalence Documentation'' (SUPAC-MR).
These two guidances cover the same general topics and use the same
general approaches as SUPAC-IR. The current series of guidance
documents relating to scale-up and postapproval changes focuses on
changes to manufacturing and controls for drug products. Future
guidances will consider changes in manufacturing and controls for the
drug substance, product containers and closures, and other topics as
well.
The underlying rationale of these guidances already completed or in
preparation is that the identity, strength, quality, purity, and
potency of an approved drug should remain unchanged in any important
aspect as a result of any postapproval change in manufacturing and
controls. This unchanged performance extends to changes that might
affect in vivo bioavailability and relative bioavailability
(bioequivalence).
CDER's guidance documents, described previously, originally applied
only to drug products approved under sections 505 (new and abbreviated
new drug applications) and 507 (antibiotic applications; revoked by the
Modernization Act) of the act (21 U.S.C. 355 and 357). However, CVM
adopted many of the concepts described in these guidance documents by
permitting the reporting of minor manufacturing changes in a biennial
supplement instead of in a preapproval supplement submitted in
accordance with the current regulation (Sec. 514.8). The biennial
supplement does not require CVM approval prior to the distribution of
the drug product made using the changes.
CDER's and CBER's proposed rulemaking and supporting guidance
documents allow for many moderate manufacturing changes to be reported
as CBE's that are not provided for in CVM's current regulations
(Sec. 514.8). CVM is proposing regulations that harmonize the reporting
of manufacturing changes for new animal drug products with the
reporting of manufacturing changes for human drug products, because:
(1) The act makes no distinction between the requirements for the
reporting of manufacturing changes for human drug products and for new
animal drug products, (2) the act does not provide for the reporting of
minor manufacturing changes in biennial supplements, (3) the proposed
rulemaking allows for flexibility in reporting many moderate changes as
CBE's, and (4) CVM and the animal drug industry can benefit from CDER's
expertise and resources to issue specific guidances on manufacturing
and controls changes used for drugs, generally.
CVM is currently collaborating with CDER on a number of guidance
documents addressing manufacturing and controls changes, including the
draft guidance document entitled ``Chemistry, Manufacturing and Control
Changes to an Approved NADA or ANADA'' to be made available for comment
along with this proposed rulemaking. On the effective date of these
final regulations or on November 21, 1999, whichever occurs first,
CVM's previous practices will be superseded by section 506A of the act
and/or the final regulations and the reporting of minor manufacturing
changes in biennial supplements will no longer be permitted. CVM
proposes to adopt CDER's current guidance documents for manufacturing
changes (SUPAC-IR, SUPAC-SS and SUPAC-MR). These documents will be
updated to reflect changes resulting from the proposed rulemaking, and
CVM intends to participate with CDER in the drafting of any guidance
documents covering manufacturing changes. In addition, CVM will also
issue guidance documents for specific new animal drug products such as
Type A medicated articles.
III. Summary of the Legislation
Section 116 of the Modernization Act amended the act by adding
section 506A, which provides requirements for making and reporting
manufacturing changes to an approved application and for distributing a
drug made with such changes. Section 506A of the act includes the
following provisions:
1. A drug made with a manufacturing change, whether a major
manufacturing change or otherwise, may be distributed only after the
applicant validates the effects of the change on the identity,
strength, quality, purity, and potency of the drug as these factors may
relate to the safety and effectiveness of the drug (section 506A(a)(1)
and (b) of the act). This section recognizes that additional testing,
beyond testing to ensure that an approved specification is met, is
required to ensure unchanged identity, strength, quality, purity, or
potency as these factors may relate to the safety or effectiveness of
the drug.
2. A drug made with a major manufacturing change may be distributed
only after the applicant submits a supplemental application to FDA and
the supplemental application is approved by the agency. The application
is required to contain information that FDA deems appropriate and
include the information developed by the applicant validating the
effects of the change (section 506A(c)(1) of the act). The phrase
``validating the effects of the change,'' as used in this proposed
rule, is not the same as ``validation'' required in FDA's current good
manufacturing practice (CGMP) regulations (21 CFR parts 210 and 211).
3. A major manufacturing change is a manufacturing change
determined by FDA to have substantial potential to adversely affect the
identity, strength, quality, purity, or potency of the drug as these
factors may relate to the safety or effectiveness of the drug. Such
changes include: (1) A change made in the qualitative or quantitative
formulation of the drug involved or in the specifications in the
approved application or license unless exempted by regulation or
guidance, (2) a change determined by FDA through regulation or guidance
to require completion of an appropriate clinical study demonstrating
equivalence of the drug to the drug manufactured without the change or
a reference listed drug, and (3) other changes determined by regulation
or guidance to have a substantial potential to adversely affect the
safety or effectiveness of the drug (section 506A(c)(2) of the act).
4. FDA may establish categories of manufacturing changes, other
than major manufacturing changes, and require submission of a
supplemental application for drugs made with such manufacturing changes
(section 506A(d)(1)(B) and (d)(1)(C) of the act). For changes, other
than major changes, that require submission of a supplemental
application, the applicant may begin distribution of the drug 30 days
after FDA receives the supplemental application unless the agency
notifies the applicant within the 30-day period that FDA review and
prior approval of the application is required (section 506A(d)(3)(B)(i)
of the act). FDA may also designate a category of manufacturing changes
for which the applicant may begin distributing a drug made with such
changes upon receipt by the agency of the supplemental application for
the change (section 506A(d)(3)(B)(ii) of the act). If FDA fails
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to approve a supplemental application, the agency may order the
manufacturer to cease the distribution of drugs that have been made
with the disapproved change (section 506A(d)(3)(B)(iii) of the act).
5. FDA may authorize applicants to distribute drugs without
submitting a supplemental application (section 506A(d)(1)(A) of the
act) and may establish categories of manufacturing changes that may be
made without submitting a supplemental application (section
506A(d)(1)(C) of the act). The applicant is required to submit a report
to FDA on such a change, and the report is required to contain
information the agency deems to be appropriate and information
developed by the applicant when validating the effects of the change.
FDA may also specify the date on which the report is to be submitted
(section 506A(d)(2)(A) of the act). If during a single year an
applicant makes more than one manufacturing change subject to a
reporting requirement, the act permits FDA to authorize the applicant
to submit a single annual report containing the required information
for all the changes made during the year (section 506A(d)(2)(B) of the
act).
Section 506A of the act recognizes that the amount of testing and
the data to be included in a submission and the appropriate method for
reporting the data are related to the scope and the type of change
being made. Four methods of reporting changes (i.e., supplements that
require FDA review and prior approval, CBE's supplements with a 30-day
wait, CBE's supplements with no wait, and annual reports) are discussed
in section 506A of the act and in this proposal. The appropriate method
for reporting any specific change depends on the potential for that
change to impact the fundamental safety or effectiveness of the product
by adversely affecting the basic aspects of the drug product--its
identity, strength, quality, purity, and potency.
The main objective of a review of a supplemental application that
documents postapproval changes to an NADA or ANADA is to ensure
``sameness'' or ``equivalence'' between the pre- and post-change
product. ``Sameness or equivalence'' do not mean ``identical'' since
certain manufacturing changes lead to differences. Such differences
should not, however, affect the safety or effectiveness of the drug
product. Also, a proposed manufacturing change should not be so
extensive that a new drug product is created. If a manufacturing change
does produce a fundamental alteration (i.e., a pharmaceutically
inequivalent dose form), a new application may be required for the
resulting product.
Generally, in the case of NADA products, the pre- and post-change
drug product should be compared. In the case of ANADA products, the
pre- and post-change drug products should be compared to the reference
listed drug, typically the pioneer drug product. Confirmation of
``sameness'' or ``equivalence'' is particularly important when changes
are made that involve the active pharmaceutical ingredient or affect
critical manufacturing steps. Examples of such changes include, but are
not limited to, components and overall composition of the formulation;
manufacturing site, scale, equipment, process, or specifications; and
analytical procedures.
Many factors should be considered in determining whether a change
has a substantial, moderate, or minimal potential to have an adverse
effect on the identity, strength, quality, purity, or potency of the
product as they may relate to the safety or effectiveness of the
product. Some types of manufacturing changes have a greater potential
to cause unwanted or unexpected changes to the product that may be
difficult to assess by merely testing to specifications. The type of
product is also a factor to consider in determining the potential risk
of a manufacturing change having an adverse effect on the product. Some
products may be substantially affected by what appear to be small
manufacturing changes.
Therefore, defining ``substantial,'' ``moderate,'' and ``minimal''
in the regulations with such specificity that they exhaustively
describe all of the many individual changes that may occur is not
feasible. FDA is planning, however, to provide greater detail in
guidance about the types or categories of changes that the agency
believes should be considered ``substantial,'' ``moderate,'' or
``minimal.''
Section 506A of the act provides FDA with considerable flexibility
to establish required information and filing requirements for
manufacturing changes. There is a corresponding need to retain such
flexibility in the proposed regulations implementing section 506A of
the act to ensure that the least burdensome means for reporting changes
are available. FDA believes that such flexibility is necessary to be
responsive to increasing knowledge of and experience with certain types
of changes and to help ensure the effectiveness and safety of the
products involved. For example, a change that may currently be
considered to have a substantial potential to have an adverse effect on
the safety or effectiveness of the product may, at a later date, based
on new information or advances in technology, be determined to have a
lesser potential to have such an adverse effect. Conversely, a change
originally considered to have a moderate potential to have an adverse
effect on the safety or effectiveness of the product may later, as a
result of new information, be found to have an increased, substantial
potential to adversely affect the product.
The agency believes it can more readily respond to knowledge gained
from manufacturing experience, and advances in technology by issuing
regulations that set out broad, general categories of manufacturing
changes and by using guidance documents to provide FDA's current
thinking on the specific changes that fall into those general
categories. The proposed rule would, therefore, reduce the number of
manufacturing changes specifically identified as being subject to
supplements requiring or not requiring review and approval. The agency
also understands that applicants expect some predictability on what
type of reporting will be expected for specific changes. FDA intends to
make available guidance documents to describe the agency's current
interpretation of specific changes falling into the four filing
categories and to modify the documents as needed to reflect changes
based on new information. The use of guidance documents as provided for
in section 506A of the act will allow FDA to more easily and quickly
modify and update important information. Guidance documents will be
developed according to the procedures set out in FDA's Good Guidance
Practices as published in the Federal Register of February 27, 1997 (62
FR 8961 at 8967 to 8972). A notice of availability for a draft guidance
entitled ``Chemistry, Manufacturing and Control Changes to an Approved
NADA or ANADA'' is published elsewhere in this issue of the Federal
Register. This guidance covers recommended reporting categories for
various postapproval manufacturing changes. FDA has published
guidances, including SUPAC guidances and CVM's ``Animal Drug
Manufacturing Guidelines,'' that provide recommendations on both
reporting categories and/or the type of information that should be
developed by the applicant to validate the effect of the change on the
identity, strength, quality, purity, or potency of a product as these
factors may relate to the safety or effectiveness of the product. To
the extent that the recommendations on reporting categories in this
proposed guidance, when finalized, are
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inconsistent with previously published guidances, such as the SUPAC's,
the recommended reporting categories in such prior guidances will be
superseded by this new guidance upon its publication in final form. FDA
intends to update the prior published guidances to make them consistent
with this guidance.
IV. Description of the Proposed Rule
A. Definitions
FDA has added a new paragraph to define terms and phrases as used
in proposed Sec. 514.8. Proposed Sec. 514.8(a) would add definitions of
``minor changes and stability report (MCSR),'' ``specification,''
``validate the effects of the change,'' `listed drug,'' and ``the
list.'' These definitions are necessary to implement the provisions of
section 506A of the act.
FDA is proposing to define ``specification'' as the quality
standard (i.e., tests, analytical procedures, and acceptance criteria)
provided in an approved application to confirm the quality of drug
substances, drug products, intermediates, raw materials, reagents, and
other components including container closure systems, and in-process
controls. FDA is proposing to define ``specification'' because section
506A of the act includes a change ``in the specifications in the
approved application or license'' as a major change. To clarify the
meaning of the term ``acceptance criteria'' as used in the definition
of ``specification,'' FDA is including in the proposed definition of
``specification'' the statement that ``acceptance criteria'' refers to
numerical limits, ranges, or other criteria for the tests described. To
determine if a material being tested complies with a specification,
there must be predetermined criteria. These criteria may include
numerical limits or ranges (e.g., not more than 1 percent) or other
criteria (e.g., white to off-white in color).
FDA is proposing to define the phrase ``validate the effects of the
change'' as an assessment of the effect of a manufacturing change on
the identity, strength, quality, purity, or potency of a drug as these
factors relate to the safety or effectiveness of the drug. FDA is
proposing to define this phrase because section 506A of the act
includes a requirement that a drug made with a manufacturing change may
only be distributed after the applicant validates the effects of the
change. Validating the effects of the change is important in
determining whether manufacturing changes alter the identity, strength,
quality, purity, or potency of a drug product as these factors may
relate to drug safety or effectiveness, and includes testing beyond
that in an approved specification, such as redocumentation of the
pharmaceutical equivalence or bioequivalence.
``Minor changes and stability report'' would mean a report that is
submitted once each year within 60 days of the anniversary of the
application's original approval or a mutually agreed upon date for
minor manufacturing changes made according to proposed Sec. 514.8(b)(4)
or a statement that no changes were made, and updated stability data
generated on commercial or production batches according to an approved
stability protocol.
The MCSR is the annual report described in section 506A(d)(2)(B) of
the act, and it is different and distinct from the annual report
described and submitted in accordance with current Sec. 510.300 (21 CFR
510.300) (i.e., periodic DER's). The MCSR is a type of ``annual''
report for manufacturing changes only. The MCSR would be submitted to
and reviewed by CVM's Office of New Animal Drug Evaluation (ONADE)
rather than by CVM's Office of Surveillance and Compliance (OSC). The
MCSR must include minor manufacturing changes implemented over the past
year and an update of ongoing stability data generated on production
lots. Currently, ongoing stability data are submitted as part of DER's
to OSC. CVM has decided that it is more efficient to allow the
administrative review of information relating to manufacturing changes
and stability to reside in one group. Information regarding labeling
changes and product defects would continue to be submitted to CVM's
OSC.
FDA is proposing to define ``listed drug'' and ``the list'' to
clarify ``reference listed drug'' cited in proposed
Sec. 514.8(b)(2)(ii)(B).
B. Manufacturing Changes to an Approved Application
Proposed Sec. 514.8(b) sets forth general requirements under which
an applicant must notify FDA when making a change to an approved
application and replaces current Sec. 514.8(a). This paragraph states
that an applicant must notify FDA about each change in each condition
established in an approved application beyond the variations already
provided for in the application, and that the notice is required to
describe the change fully. It also states that the applicant must,
depending on the type of change, notify FDA of the change in a
supplement under proposed Sec. 514.8(b)(2) or (b)(3) or by the
inclusion of the information in an annual report (the MCSR) under
proposed Sec. 514.8(b)(4). Reference in current Sec. 514.8(a)(1) to
current regulations, Sec. 510.300, has been deleted and, instead,
proposed Sec. 514.8(b)(1)(i) makes reference to annual reports
described under proposed Sec. 514.8(b)(4). Manufacturing changes and/or
updated stability data generated according to an approved stability
commitment would no longer be reported in periodic DER's (i.e., annual
reports under current Sec. 510.300) but be reported under proposed
Sec. 514.8(b)(4) in an MCSR. CVM intends to publish a final rule
revising Sec. 510.300, which will be renumbered as Sec. 514.80. Since
CVM expects to publish the final rule for Sec. 514.80 (Records and
reports concerning experience with new animal drugs for which an
approved application is in effect. (56 FR 65581, December 17, 1991))
before the final rule for Sec. 514.8, CVM will, if necessary, amend the
rule for Records and reports concerning experience with new animal
drugs for which an approved application is in effect. after the final
rule for Sec. 514.8 publishes.
Proposed Sec. 514.8(b)(1)(ii) would require the holder of an
approved application under section 512 of the act (21 U.S.C. 360b) to
validate the effects of manufacturing changes on the identity, strength
(e.g., assay and content uniformity), quality (e.g., physical,
chemical, and biological properties), purity (e.g., impurities and
degradation products) and potency (e.g., biological activity,
bioavailability, and bioequivalence) of a drug as these factors may
relate to the safety or effectiveness of the drug. These validation
requirements must be met before a product made with a manufacturing
change may be distributed. This amendment implements section 506A(a)(1)
and (b) of the act.
Proposed Sec. 514.8(b)(1)(iii) states that notwithstanding the
requirements of Sec. 514.8(b)(2) and (b)(3), an applicant must report 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, a type of manufacturing change subject to review
and approval by FDA under proposed Sec. 514.8(b)(2) might be identified
in regulation or guidance as a change that could be reported in a
supplement not requiring review and approval or in an annual report.
CDER used this provision to reduce the regulatory burden for submission
of supplements for manufacturing changes that were not likely to
adversely affect drug product quality or performance in the SUPAC
guidance documents.
[[Page 53285]]
Proposed Sec. 514.8(b)(1)(iv) requires the applicant to include in
each supplemental application providing for a change under proposed
Sec. 514.8(b)(2) or (b)(3), a statement that a copy of the supplement
has been provided to the appropriate FDA district office whose
jurisdiction includes the facility where the manufacturing change is
implemented.
Proposed Sec. 514.8(b)(1)(v) would add a requirement that a list of
all changes contained in the supplement or annual report must be
included in the cover letter for the supplement or annual report. For
many years, most supplements and annual reports have routinely included
such cover letters. Including a list of all changes in the cover
letters will enable FDA to more efficiently locate and evaluate changes
in what are often substantial documents, thus facilitating FDA review
of supplements and annual reports.
Proposed Sec. 514.8(b)(2)(iii) describes the information that must
be included in a supplement. References to regulations for categorical
exclusion or an environmental assessment have been updated and included
in Sec. 514.8(b)(2)(iii)(K).
C. Changes Requiring Supplement Submission and Approval Prior to
Distribution of the Product Made Using the Change (Major Change)
Certain drug manufacturing steps are so critical that changes in
these steps must be subject to the submission of a supplement to FDA
that is approved by FDA prior to distribution of the drug product made
using the change. Current Sec. 514.8(a)(4) sets forth changes for which
such review and approval are required.
Proposed Sec. 514.8(b)(2) would revise the current sections to
implement section 506A of the act. Proposed Sec. 514.8(b)(2)(i)
implements section 506A(c)(2) of the act and would require a
preapproval supplement to be submitted for any major change, i.e., any
change in the product, 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
product as these factors may relate to the safety or effectiveness of
the product.
Also, there are times when manufacturing changes are demonstrated
to have an adverse effect on the identity, strength, quality, purity,
or potency of the drug product. In many cases the applicant chooses not
to implement these manufacturing changes, but in other cases the
applicant may still wish to do so. If an assessment by the sponsor
shows that a manufacturing change has adversely affected the identity,
strength, quality, purity, or potency of the drug product and the
sponsor wants to make the change, the change should be filed in a
supplement that requires review and approval by FDA before distribution
of the product, regardless of whether the change is listed as an
example of one that normally does not need FDA approval prior to
distribution of the product made with the change. The applicant should
submit this change in a supplement that requires review and approval
with appropriate information to demonstrate that the manufacturing
change has not altered the continued safety and effectiveness of the
product. The agency will assess the effect of any adverse change in a
drug product, as the change may relate to the safety or effectiveness
of the product, during the review of the supplement that requires
approval prior to distribution of the product.
Proposed Sec. 514.8(b)(2)(ii) lists examples of those changes
requiring submission and approval of a supplement prior to
distribution, including those designated as major manufacturing changes
in section 506A(c)(2) of the act, and changes to certain biotechnology
products. These changes have a substantial potential to have an adverse
effect on the identity, strength, quality, purity, or potency of the
product as these factors may relate to the safety or effectiveness of
the product. The agency's continued review and approval of these
changes prior to product distribution is necessary to protect the
animals and the public from products for which safety or effectiveness
may have been compromised.
FDA is proposing to describe additional specific examples of
changes that have substantial, moderate, and minimal potential to
adversely affect a product in guidance documents rather than enumerate
them in the proposed regulations. As discussed previously, section 506A
of the act expressly states that the agency, through guidance, may
categorize the manufacturing changes. FDA anticipates that scientific
advances and future experience may reduce the need for approval of
supplements providing for certain changes, and the agency will respond
to changed circumstances by revising the guidance documents. A notice
of availability of a draft guidance document entitled ``Guidance for
Industry: Chemistry, Manufacturing and Controls Changes to an Approved
NADA or ANADA,'' that provides more detailed recommendations on how to
report proposed changes, is being published elsewhere in this issue of
the Federal Register, and the agency is soliciting comments on the
draft guidance in addition to the proposed rule.
In regard to proposed Sec. 514.8(b)(2)(ii)(B), section 506A of the
act also states in part that ``* * * equivalence of the drug to the
drug as manufactured without the change'' should be demonstrated. For
those generic drug products for which, at the time of approval, a
generic drug applicant was required to show equivalence between the
proposed generic drug and a reference listed drug (typically the
referenced pioneer drug product), a proposed manufacturing change
should not significantly change the equivalence demonstrated at the
time of approval. In addition, for the more significant manufacturing
changes for generic drugs the approval of which relied on a
demonstration of bioequivalence to a reference listed drug, the
applicant is required to conduct a bioequivalence study comparing the
drug product made with the change to the reference listed drug,
typically the pioneer drug product.
Under proposed Sec. 514.8 (b)(2)(ii)(G) changes to a product under
an application that is subject to a validity assessment because of
significant questions regarding the integrity of the data supporting
the application require approval prior to distribution. Until questions
about the integrity of the data in the application have been resolved,
there are inadequate assurances that any change will not adversely
affect the safety or effectiveness of the product. Moreover, a change
to a product cannot be validated, as required under 506A(b) of the act,
until the integrity of the underlying data in such an application is
validated. Consequently, there is a significant potential that the
change will have an adverse effect on the identity, strength, quality,
purity, or potency of the product. After a validity assessment has been
completed, and data integrity questions resolved, the holder of an
approved application may submit supplements for manufacturing changes
as otherwise provided in Sec. 514.8.
Current Sec. 514.8(a)(4)(iii), (a)(4)(iv), and (a)(4)(v) regarding
general manufacturing and control changes requiring approval prior to
distribution are not included in proposed Sec. 514.8(b)(2), because
some of these changes would fall into the proposed major manufacturing
change category while others would fall into other proposed categories
depending on whether the change is considered to have a substantial,
moderate, or minimal potential to adversely affect the
[[Page 53286]]
identity, strength, quality, purity, or potency of the drug as they may
relate to the safety or effectiveness of the drug. FDA plans to provide
recommendations on how to submit the supplements in guidance documents,
including the draft guidance document mentioned previously. Current
Sec. 514.8(a)(4)(v) relating to identification of distributors has been
updated and reproposed as Sec. 514.8(c)(4).
Proposed Sec. 514.8(b)(2)(iii) states that the applicant must
obtain approval of a supplement from FDA before distributing a product
using a change under Sec. 514.8(b)(2), and it specifies information to
be included in the supplement.
Proposed Sec. 514.8(b)(2)(iv) permits a request for an expedited
review of a supplement for public health reasons or if a delay in
making the change described in the supplement would impose an
extraordinary hardship on the applicant. FDA is including this
provision for expedited review for extraordinary hardship reasons but
wishes to clarify that these requests should focus on manufacturing
changes made necessary by catastrophic events (e.g., fire) or by events
that could not be reasonably foreseen and for which the applicant could
not plan. Requests for expedited review will be assessed on a case-by-
case basis. All requests may not be granted.
Under proposed Sec. 514.8(b)(2)(v), an applicant may submit one or
more protocols describing specific tests, validation studies, and
acceptable limits to be achieved to demonstrate the lack of an adverse
effect for specified types of manufacturing changes on the identity,
strength, quality, purity, or potency of the drug as these factors may
relate to the safety or effectiveness of the drug. Such protocols, or
changes to a protocol, would be submitted as a supplement requiring
approval from FDA prior to distribution. If approved, the use of such a
protocol in making the specified changes may justify a reduced
reporting category for the change because of the reduced risk of an
adverse effect.
Generally, when considering a change in the manufacture of a
product, the manufacturer will prepare a protocol, often called a
``comparability protocol,'' identifying tests to be performed in
evaluating the change and its effect on the product and defining the
criteria against which the impact of the change will be evaluated. By
providing FDA an opportunity to review and approve the comparability
protocol before it is used by the applicant to evaluate a change, FDA
can have a greater assurance that the change is being properly
evaluated and there is, therefore, less potential for the change to
have an adverse effect on the safety or effectiveness of the product.
D. Changes Requiring Supplement Submission at Least 30 Days Prior to
Distribution of the Drug Product Made Using the Change (Moderate
Changes)
Current Sec. 514.8(d)(3) provides for manufacturing changes that
give an increased assurance that the drug will have the characteristics
of identity, strength, quality, and purity that it purports or is
represented to possess to be placed into effect at the earliest
possible time. Proposed Sec. 514.8(b)(3) implements section
506A(d)(1)(B) and (d)(3) of the act and provides that products made
using the changes listed under this section may only be distributed not
sooner than 30 days after receipt of a supplement by FDA. FDA
recognizes that animal and the public health can be adequately
protected without requiring approval of certain manufacturing changes
prior to distribution of the product made with the change. FDA
continues to believe that it is important that such changes be
documented and validated so that there is a mechanism for assessing the
consequences of the change and that the agency approve such changes.
The requirement to submit a supplement 30 days before distribution of
the product balances FDA's need to review applications to protect
against the distribution of unsafe or ineffective products and the need
to make improved products available.
Proposed Sec. 514.8(b)(3)(i) would require that a supplement be
submitted for any change in the product, production process, quality
controls, equipment, or facilities that has a moderate potential to
have an adverse effect on the identity, strength, quality, purity, or
potency of the product as these factors may relate to the safety or
effectiveness of the product. Proposed Sec. 514.8(b)(3)(iii) states
that a supplement submitted under Sec. 514.8(b)(3)(i) is required to
give a full explanation of the basis for the change and identify the
date on which the change is to be made, and that the supplement must be
labeled ``Supplement--Changes Being Effected in 30 Days.''
Proposed Sec. 514.8(b)(3)(ii) describes the types of changes that
require submission of a supplement 30 days before distribution.
Proposed Sec. 514.8(b)(3)(iv) states that distribution of a product
made using a change listed under this section may not begin until 30
days after receipt of a supplement by FDA. This section would also
require that the same information listed in proposed
Sec. 514.8(b)(2)(iii), discussed previously, must be contained in the
supplement required under proposed Sec. 514.8(b)(3).
According to proposed Sec. 514.8(b)(3)(v), during the 30-day period
following receipt of the supplement, FDA would perform a preliminary
review to determine whether the supplement is complete and whether the
type of change is appropriate for review as a supplement under proposed
Sec. 514.8(b)(3). If the proposed change is determined to be a major
change that should appropriately be submitted under proposed
Sec. 514.8(b)(2), the agency would inform the applicant and the
applicant would be required to receive FDA's approval before a product
produced with the change could be distributed. If FDA determines that
the change is properly submitted as a supplement under
Sec. 514.8(b)(3)(i), but the required information is incomplete, the
applicant would be required to supply the missing information and wait
until FDA has determined that the supplement is in compliance before
distributing the product.
Under proposed Sec. 514.8(b)(3)(vii), if FDA disapproves a
supplemental application under this section, the agency may order the
manufacturer to cease distribution of the drug products made with the
manufacturing change. This amendment would implement section
506A(d)(3)(B)(iii) of the act.
E. Changes That May Be Implemented When FDA Receives a Supplement
(Moderate Changes)
Section 506A(d)(3)(B)(ii) of the act gives FDA authority to
designate a category of changes for which the holder of an approved
application making such change may begin distribution of the drug upon
receipt by FDA of a supplemental application for the change. FDA
recognizes that animals and the public can be adequately protected
without requiring approval of certain manufacturing changes prior to
distribution of the product made with the change. FDA continues to
believe that it is important that such changes be documented and
validated so that there is a mechanism for assessing the consequences
of the change and that the agency approve such changes. However, based
on FDA's experience, certain changes may be implemented when FDA
receives the supplement, rather than delaying distribution for 30 days
because, in general, these changes provide the same or increased
assurance that the product will have the characteristics of identity,
strength,
[[Page 53287]]
quality, purity, or potency that it purports or is represented to have.
Submission of a supplement gives FDA ready access to information
regarding such changes. The requirement for approval of such
supplements allows FDA to protect against the distribution of unsafe or
ineffective products while allowing products that are likely to be
improved to be available more quickly. Examples of such changes are
listed in proposed Sec. 514.8(b)(3)(vi). The supplement submitted under
this paragraph is required to give a full explanation of the basis for
the change and the supplement must be labeled ``Supplement--Changes
Being Effected.''
Under proposed Sec. 514.8(b)(3)(vii), if FDA disapproves a
supplemental application under this section, the agency may order the
manufacturer to cease distribution of the drug products made with the
manufacturing change.
Current Sec. 514.8(d) describes the types of changes that can be
placed into effect at the earliest possible time. Such changes are
being described in proposed Sec. 514.8(b)(3)(vi) and (c)(3).
F. Changes and Updated Stability Data to Be Described and Submitted in
an Annual Report (Minor Changes)
Minor manufacturing changes are currently submitted in an annual
report under Sec. 510.300(b)(6) as referenced in current
Sec. 514.8(a)(5) or in a biennial supplement. Proposed Sec. 514.8(b)(4)
would provide that changes to the product, production process, quality
controls, equipment, or facilities that have a minimal potential to
have an adverse effect on the identity, strength, quality, purity, or
potency as these factors may relate to the safety or effectiveness of
the product be documented by the applicant in the next annual report,
i.e., ``Minor Changes and Stability Report,'' as described under
proposed Sec. 514.8(b)(4). FDA recognizes that there are manufacturing
changes that have a minimal potential to have an adverse affect on a
product's safety or effectiveness. FDA believes that agency approval of
these changes prior to product distribution is unnecessary and is
proposing in Sec. 514.8(b)(4) that such changes would not be required
to be approved by the agency. FDA continues to believe that it is
important that such changes be documented and validated so that FDA can
assess the consequences of the change. FDA can effectively assess
compliance with this section and CGMP requirements for changes that
have a minimal potential to adversely affect the product's safety or
effectiveness by having ready access to information regarding such
changes through submission of an annual report and by inspection.
Section 506A(d)(1)(C) of the act authorizes FDA to establish
reporting categories (i.e., annual report) of manufacturing changes
(i.e., minor changes) that may be made without submitting a
supplemental application. Section 506A(d)(2)(A) of the act permits
minor changes to be reported separately or in an annual report. Section
506A of the act has no provisions for reporting minor manufacturing
changes in biennial supplements as permitted by CVM's pilot program.
Therefore, all minor manufacturing changes described in regulations or
guidance should be submitted in an MCSR to the application annually.
The MCSR will be reviewed by the appropriate CVM office that reviews
manufacturing supplements. No manufacturing changes or updated
stability data are to be reported in the periodic DER that is submitted
to CVM's OSC. But reports of manufacturing defects must continue to be
submitted to OSC. The MCSR must be submitted each year within 60 days
of the anniversary of approval of the application or mutually agreed
upon date. Proposed Sec. 514.8(b)(4)(ii) lists examples of changes that
can be reported in the MCSR.
Proposed Sec. 514.8(b)(4)(iii) states that the MCSR must list all
products to which minor changes were made.
Proposed Sec. 514.8(b)(4) replaces current Sec. 514.8(a)(5).
G. Labeling and Other Changes Requiring Submission and Approval of a
Supplement Prior to Distribution of the Product Made Using the Change
(Major Changes)
Labeling changes addressed in current Sec. 514.8(a) and (b) are
newly addressed by proposed Sec. 514.8(c). Proposed Sec. 514.8(c)(1)
describes when an applicant must notify FDA that the applicant is
making such a change to an approved application. This section states
that an applicant must notify FDA about each change in each condition
established in an approved application beyond the variations already
provided for in the application, and that the notice is required to
describe the change fully.
Proposed Sec. 514.8(c)(2) updates current Sec. 514.8(a)(3),
(a)(4)(i) and (a)(4)(ii) regarding labeling changes and addition of
intended use requiring preapproval supplements. Labeling and other
changes requiring submission of a supplemental application are
described in proposed Sec. 514.8(c)(2)(i).
Proposed Sec. 514.8(c)(2)(ii) requires an applicant to obtain
approval of a supplement by FDA before distributing a product subject
to a change listed under Sec. 514.8(c)(2)(i), and specifies information
to be included in the supplement.
Current Sec. 514.8(a)(3) regarding mailing or promotional pieces
for a prescription drug has been updated and is included under proposed
Sec. 514.8(c)(2). Current Sec. 514.8(a)(4)(i) and (a)(4)(ii) regarding
revisions in labeling and addition of claim, respectively, have been
updated and included under proposed Sec. 514.8(c)(2)(i)(A) and
(c)(2)(i)(B).
H. 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) updates and redesignates current
Sec. 514.8(d) regarding 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)(i) requires labeling changes that
increase the assurance of product safety, such as additional warnings,
contraindications, or side effects or deletions of false, misleading,
or unsupportive statements; and any other changes as directed by FDA to
be placed into effect immediately. These changes, proposed
Sec. 514.8(c)(3)(i)(A) and (c)(3)(i)(B), are listed in current
Sec. 514.8(d)(1) and (d)(2).
Proposed Sec. 514.8(c)(3)(ii) permits labeling changes to the style
and format that do not decrease the safety of product approved in
supplemental applications to be placed into effect prior to written
notice of approval from FDA of a supplemental application.
Proposed Sec. 514.8(c)(3)(iii) updates current Sec. 514.8(e) and
describes what must be included in a supplement submitted under
Sec. 514.8(c)(3). FDA will not take action against products or sponsors
solely because a change in labeling described in Sec. 514.8(c)(3) is
implemented prior to FDA receipt and approval of a supplement if the
information listed in Sec. 514.8(c)(3)(iii) has been submitted to the
agency.
Proposed Sec. 514.8(c)(4) would require applicants to notify CVM of
additional designated distributors under proposed Sec. 514.80(a)(2),
(b)(3), and (b)(5)(iii) (Records and reports concerning experience with
new animal drugs for which an approved application is in effect.--as
noted in section IV.B of this document, CVM expects to publish the
final rule for Sec. 514.80 before the final rule for this document).
This notification will be accompanied by a Form FDA 2301, submitted to
DER, and reported at the time of initial product distribution by the
new distributor. This type of change is not considered a
[[Page 53288]]
manufacturing change, rather a type of labeling change to be reported
to the Division of Epidemiology and Surveillance in the OSC, CVM.
In addition to section 506A of the act, other sections of the act
authorize FDA to propose Sec. 514.8. Section 501 of the act (21 U.S.C.
351) prohibits the manufacture, processing, packing, or holding of
drugs that do not conform to CGMP; the use of an unsafe new animal drug
under the meaning of section 512 of the act; the use of unsafe color
additives in or on a drug under section 721 of the act (21 U.S.C.
379e); and the distribution of a drug that differs in the strength,
purity, or quality that it purports or is represented to possess.
Section 502 of the act (21 U.S.C. 352) prohibits false or misleading
labeling of drugs, drugs that lack adequate directions for use and
adequate warnings, and the distribution of drugs that are dangerous to
health when used in the manner suggested in the labeling. Under section
512 of the act, FDA will approve an application for a new intended use
of a new animal drug if, among other things, the methods used in, and
the facilities and controls used for, the manufacture, processing, and
packing of such drug are adequate to preserve its identity, strength,
quality, and purity. Section 701 of the act (21 U.S.C. 371) authorizes
FDA to issue regulations for the efficient enforcement of the act.
I. Other Information.
Proposed Sec. 514.8(d) regarding patent information is included to
comply with section 512(c)(3) of the act. Proposed Sec. 514.8(e)
regarding claimed exclusivity is included to comply with section
512(c)(2)(F) of the act. Proposed Sec. 514.8(f) regarding good
laboratory practice for nonclinical laboratory studies is redesignated
as current Sec. 514.8(l).
J. Sections Proposed for Removal
The agency is proposing that a number of paragraphs be removed
after reevaluation of the regulations covering changes to an approved
application because the agency has determined that these paragraphs are
no longer relevant to current practices. These regulations are
described in the next two paragraphs.
FDA has determined that the regulations covering special
circumstances of NADA's effective prior to October 10, 1962, are no
longer needed. Thus FDA is proposing to eliminate current
Sec. 514.8(g), (k), and (j).
Current Sec. 514.8(h) stating that nothing in Sec. 514.8 limits the
Secretary of Health and Human Services's authority to suspend or
withdraw approval of a new animal drug application is adequately
addressed in section 512(c)(1)(F) of the act and need not be addressed
in the proposed regulations. Similarly, FDA is removing current
Sec. 514.8(i) that provides for a deferral of final action on
supplemental applications as described under current Sec. 514.8(d),
(e), and (g).
K. Section 514.106 Approval of Supplemental Applications
This proposal would modify Sec. 514.106(b) regarding the
administrative categorization of supplemental applications to provide
for proper references to proposed Sec. 514.8.
V. Conforming Amendments
A number of sections in the regulations covering new animal drugs
are affected by these proposed changes. Conforming changes are being
proposed in Secs. 5.83, 25.33, 500.25, 510.300, 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 25.24(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 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). Executive
Order 12866 directs agencies to assess all costs and benefits of
available regulatory alternatives and, when regulation is necessary, to
select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). Executive Order 12866
classifies a rule as significant if it meets any one of a number of
specified conditions, including having an annual effect on the economy
of $100 million or adversely affecting in a material way a sector of
the economy, competition, or jobs. The agency believes that this
proposed rule is consistent with the regulatory philosophy and
principles identified in the Executive Order. The Office of Management
and Budget (OMB) has determinied that this proposed rule is a
significant regulatory action subject to review under the Executive
Order.
The agency is proposing to amend current Sec. 514.8 to implement
section 116 of the Modernization Act. 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 and this proposed rule is to permit sponsors to
use a less burdensome notification procedure for some types of changes,
while also clarifying the regulations and harmonizing them, where
possible, with CDER's and CBER's regulations. Downgrading the level of
agency review for some of these supplements will lead to compliance
cost savings due to the resulting improvement in manufacturing
efficiencies.
The agency has not estimated the value of the expected improvements
in manufacturing efficiencies due to the myriad of factors affecting
the production schedules of new animal drugs. FDA believes, however,
that these changes will result in shorter average lag times between the
decision to make certain minor changes to the manufacturing process for
a new animal drug and the time at which that change can be implemented.
A report by the Eastern Research Group, an FDA contractor, on the
effects of the human drug scale-up and postapproval change guidance for
immediate release solid oral dosage form (SUPAC-IR), concluded that
this type of supplement change can result 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 (CBE's) or
annual reports.''
The proposed 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 is included in 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
[[Page 53289]]
as it will no longer require agency approval before implementation.
The third category concerns those supplement changes that can be
effected upon the agency's receipt of submission 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 act specifically dictates 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 an MCSR. This annual MCSR replaces the current
regulation that also requires an annual report of these changes.
Nevertheless, those firms currently reporting these CMC changes in the
biennial supplement described previously in this document, will incur
the additional burden of an extra report every other year.
Based on prior years' submissions, the agency estimates that it
will receive about 906 CMC supplements. According to estimates from
agency reviewers, about 755 of these would have required preapproval
under the current regulation. Under the proposed rule, the number
requiring preapproval is estimated at 154. The difference of 601
supplements represents the approximate number of additional changes
that can be made without 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
proposed rule would lower this requirement to two copies, providing
further small savings for industry. Although the proposal 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 MCSR may provide additional opportunity for
savings because it may include minor manufacturing changes that were
previously submitted as CBE's or other supplement types that require a
higher level of review. Under the proposal, each firm will be able to
accumulate and submit them together each year, rather than
individually.
A. Regulatory Flexibility Analysis
The Regulatory Flexibility Act requires agencies to analyze
regulatory options to minimize any significant impact on small
entities. The proposed rule implements section 506A of the act. The
intent of the rule is to clarify the regulations for submitting
supplemental applications for new animal drugs, harmonize the
regulations with those for CDER and CBER, and lessen the compliance
burden for some supplements by reducing the level of agency review
necessary before implementation of certain changes. The effects of the
proposed rule will be spread across all firms that submit supplements,
regardless of their size. The Small Business Administration defines
small businesses as businesses with fewer than 750 employees. Because
these are the firms that are most likely to be submitting reports of
minor changes as prior approval supplements, even though not required
to do so by current regulations, rather than as biennial supplements as
allowed under CVM's pilot project, they are even more likely to realize
a benefit from this regulation than the larger industry members that
participated in CVM's pilot project. At worst, a few small firms
participating in CVM's pilot project may have to submit an annual
report rather than a biennial supplement. Because the burden of
submitting one additional report every other year will not impose a
significant cost on small businesses, the agency certifies that the
rule will not have a significant effect on a substantial number of
small entities.
B. Unfunded Mandates Reform Act
Section 202 of the Unfunded Mandates Reform Act requires that
agencies prepare an assessment of anticipated costs and benefits before
proposing any rule that may result in expenditure by State, local, and
tribal governments, in the aggregate, or by the private sector of $100
million or more (adjusted annually for inflation) in any one year.
Because the agency estimates that the proposed rule will not result in
expenditures of funds by State, local, and tribal governments or the
private sector in excess of $100 million or more in any one year, but
will result in only insignificant expenditures by the industry, and in
fact should provide a net savings, it is not required to perform a
cost/benefit analysis according to the Unfunded Mandates Reform Act.
VIII. Paperwork Reduction Act of 1995
This proposed rule contains information collection provisions that
are subject to review by the 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.
FDA invites comments on: (1) Whether the proposed collection of
information is necessary for the proper performance of FDA's functions,
including whether the information will have practical utility; (2) the
accuracy of FDA's estimate of the burden of the proposed collection of
information, including the validity of the methodology and assumptions
used; (3) ways to enhance the quality, utility, and clarity of the
information to be collected; and (4) ways to minimize the burden of the
collection of information on respondents, including through the use of
automated collection techniques, when appropriate, and other forms of
information technology.
Title: Supplements and Other Changes to Approved New Animal Drug
Applications.
Description: As directed by the Modernization Act, FDA is proposing
regulations to describe reporting procedures and requirements for
making major and other manufacturing changes to an approved NADA. The
proposed regulations also describe reporting procedures and
requirements for making labeling changes to an approved NADA. Under
proposed Sec. 514.8(b)(2) and (c)(2), the agency will continue to
require an approved supplemental application prior to distribution of a
product made with a major manufacturing or labeling change to an
approved NADA. Major manufacturing changes are those determined to have
substantial potential to adversely affect the identity, strength,
quality, purity, or potency of the drug. For moderate manufacturing
changes, as defined in proposed Sec. 514.8(b)(3), sponsors would be
required to submit a supplemental application at least 30 days prior to
distribution of the product made using the change. Under proposed
Sec. 514.8(b)(4), sponsors would not be required to submit supplemental
applications for minor manufacturing changes, but would describe these
changes in annual reports. Additionally, under proposed
Sec. 514.8(c)(3), certain labeling changes would require supplemental
applications, but would be placed into effect immediately.
Under current regulations, CVM evaluates all manufacturing and
labeling changes to approved NADA's whether they are submitted as
permitted changes, CBE's, or those requiring approval prior to
implementation. CVM provided greater flexibility to the
[[Page 53290]]
current regulations by permitting the reporting of minor manufacturing
changes in a biennial supplement, as discussed earlier in this
document. Changes mandated by the Modernization Act will supersede this
practice, replacing the biennial supplement with an annual report, the
MCSR.
The proposed rule is expected to lessen paperwork burden by
requiring: (1) Fewer copies of labels for labeling changes, (2) fewer
submissions because certain changes that are submitted under the
current rule as individual CBE's or other supplement types may now be
accumulated and submitted together once a year in the MCSR, and (3)
agency approval of fewer types of changes.
Listed in Table 1 of this document is an estimate of the burden
placed on industry for the various types of submissions discussed in
the proposed regulation. FDA based the number of respondents upon the
total number of potential sponsors. The number of total annual
responses was derived from agency reviewers' estimates based upon prior
years' submissions. The number of responses per respondent is an
estimate that the agency arrived at by dividing the number of total
responses the agency expects to receive by the total number of
potential responses. Changes under Sec. 514.8(b)(2) through (b)(4) and
(c)(2) through (c)(3) are submitted on FDA Form 356V (OMB approval
number 0910-0032). Labeling changes under Sec. 514.8(c)(4) are made on
FDA Form 2301 (OMB approval number 0910-0019).
Description of Respondents: Sponsors of new animal drug
applications.
In compliance with section 3507(d) of the Paperwork Reduction Act
of 1995 (44 U.S.C. 3507(d)), the agency has submitted the information
collection provisions of this proposed rule to OMB for review.
Interested persons are requested to send comments regarding this
information collection by November 1, 1999, to the Office of
Information and Regulatory Affairs, OMB, New Executive Office Bldg.,
725 17th St. NW., rm. 10235, Washington, DC 20503, Attn: Wendy Taylor,
Desk Officer for FDA.
FDA estimates the burden of this collection of information as
follows:
Table 1.--Estimated Annual Reporting Burden\1\
----------------------------------------------------------------------------------------------------------------
No. of
21 CFR Section No. of Responses per Total Annual Hours per Total
Respondents Respondents Responses Response
----------------------------------------------------------------------------------------------------------------
514.8(b)(2)(iii) 190 0.81 154 100 15,400
514.8(b)(2)(v) 190 0.59 112 80 8,960
514.8(b)(3)(i) 190 2.64 502 60 30,120
514.8(b)(3)(vi) 190 1.32 250 60 15,000
514.8(b)(4) 190 5.17 982 24 23,568
514.8(c)(2) 190 0.26 50 20 1,000
514.8(c)(3) 190 0.26 50 60 3,000
514.8(c)(4) 190 0.39 74 3 222
Total 2,174 97,270
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
IX. Comments
Interested persons may, on or before December 15, 1999, submit to
the Dockets Management Branch (address above) written comments
regarding this proposed rule. Two copies of any comments are to be
submitted, except that individuals may submit one copy. Comments are to
be identified with the docket number found in brackets in the heading
of this document. Received comments may be seen in the office above
between 9 a.m. and 4 p.m., Monday through Friday.
List of Subjects
21 CFR Part 5
Authority delegations (Government agencies), Imports, Organization
and functions (Government agencies).
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, Polichlorinated biphenyls (PCB's).
21 CFR Part 510
Administrative practice and procedure, Animal drugs, Labeling,
Reporting and recordkeeping requirements.
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.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegate to the Commissioner of Food and Drugs, it is
proposed that 21 CFR parts 5, 25, 500, 510, 514, and 558 be amended as
follows:
PART 5--DELEGATIONS OF AUTHORITY AND ORGANIZATION
1. The authority citation for 21 CFR part 5 continues to read as
follows:
Authority: 5 U.S.C. 504, 552, App. 2; 7 U.S.C. 138a, 2271; 15
U.S.C. 638, 1261-1282, 3701-3711a; 15 U.S.C. 1451-1461; 21 U.S.C.
41-50, 61-63, 141-149, 321-394, 467f, 679(b), 801-886, 1031-1309; 35
U.S.C. 156; 42 U.S.C. 241, 242, 242a, 242l, 242n, 243, 262, 263,
264, 265, 300u-300u-5, 300aa-l; 1395y, 3246b, 4332, 4831(a), 10007-
10008; E.O. 11921, 41 FR 24294, 3 CFR, 1977 Comp., p. 124-131; E.O.
12591, 52 FR 13414, 3 CFR, 1988 Comp., p. 220-223.
2. Section 5.83 is amended by revising paragraph (c) to read as
follows:
Sec. 5.83 Approval of new animal drug applications, medicated feed
mill license applications and their supplements.
* * * * *
(c) The Director, Division of Manufacturing Technologies, Office of
New Animal Drug Evaluation, CVM, is authorized to perform all of the
functions of the Commissioner of Food and Drugs with regard to the
approval of supplemental applications that are described by
Sec. 514.8(b)(2) and (b)(3) of this chapter.
* * * * *
PART 25--ENVIRONMENTAL IMPACT CONSIDERATIONS
3. 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
[[Page 53291]]
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]
4. Section 25.33 Animal drugs 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
5. 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]
6. Section 500.25 Anthelmintic drugs for use in animals 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 510--NEW ANIMAL DRUGS
7. The authority citation for 21 CFR part 510 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 360b, 371, 379e.
Sec. 510.300 [Amended]
8. Section 510.300 Records and reports concerning experience with
new animal drugs for which an approved application is in effect is
amended by removing paragraph (a)(6).
PART 514--NEW ANIMAL DRUG APPLICATIONS
9. The authority citation for 21 CFR part 514 is revised to read as
follows:
Authority: 21 U.S.C. 351, 352, 356a, 360b, 371, 379e, 381.
10. 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) Listed drug means a new animal drug product that has an
effective approval under section 512 of the act, which has not been
withdrawn or suspended under section 512 of the act, and which has not
been withdrawn from sale for what the Food and Drug Administration
(FDA) has determined are reasons for safety or effectiveness. Listed
drug status is evidenced by the new animal drug product's
identification as a new animal drug with an effective approval in the
current edition of FDA's ``FDA Approved Animal Drug Products'' (the
list) or any current supplement thereto, as a new animal drug with an
effective approval. A new animal drug product is deemed to be a listed
drug on the date of effective approval of the application or
abbreviated application for that new animal drug product.
(ii) Minor changes and stability report means an annual 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 of the application's original approval or a mutually agreed
upon date. The report must include minor manufacturing and controls
changes made according to Sec. 514.8(b)(4) or state that no changes
were made; and update stability data generated on commercial or
production batches according to the approved stability protocol/
commitment.
(iii) Specification means the quality standard (i.e., tests,
analytical procedures, and acceptance criteria) provided in an approved
new animal drug application or abbreviated new animal drug application
to confirm the quality of drug substances, drug products,
intermediates, raw materials, reagents, and other components including
container closure systems, and in-process controls. For the purpose of
this definition, acceptance criteria means numerical limits, ranges, or
other criteria for the tests described.
(iv) Validate the effects of the change means 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.
(v) The list means the list of new animal drug products with
effective approvals published in the current edition of FDA's
publication ``FDA Approved Animal Drug Products'' and any current
supplement to the publication.
(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 change, the
applicant must notify FDA about it in a supplement under paragraph
(b)(2) or (b)(3) of this section or include the information in the
annual report to the application described in paragraph (b)(4) of this
section.
(ii) The holder of an approved application under section 512 of the
act must validate the effect of the 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.
(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 product or by notification in the next annual
report described in paragraph (b)(4) of this section).
(iv) The 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.
(v) The cover letter for 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.
(2) Changes requiring submission and approval of a supplement prior
to distribution of the product made using the change (major changes).
(i) A supplement must be submitted for any change in the product,
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 product as these factors
may relate to the safety or effectiveness of the product.
(ii) These changes include, but are not limited to:
(A) Except as provided in paragraphs (b)(3) and (b)(4) of this
section, changes in the qualitative or quantitative formulation of the
new animal drug, including inactive ingredients, or other
specifications as provided in the approved application;
(B) Changes requiring completion of appropriate animal studies to
demonstrate the equivalence of the drug to the new animal drug as
manufactured without the change or to the reference listed drug;
(C) 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;
(D) Changes in the synthesis or manufacture of the new animal drug
substance that may affect the impurity
[[Page 53292]]
profile and/or the physical, chemical, or biological properties of the
drug substance;
(E) Changes in a container closure system that controls drug
delivery or that may affect the impurity profile of the new animal drug
product;
(F) 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; and
(G) Changes to a product under an application that is subject to a
validity assessment because of significant questions regarding the
integrity of the data supporting the application.
(iii) The applicant must obtain approval of a supplement from FDA
prior to distribution of a product made using a change under paragraph
(b)(2) of this section. Except for submissions under paragraph
(b)(2)(v) of this section, the following must be contained in the
supplement:
(A) A completed Form FDA 356V;
(B) A detailed description of the proposed change;
(C) The product(s) involved;
(D) The manufacturing site(s) or area(s) affected;
(E) A description of the methods used and studies 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);
(F) The data derived from such studies;
(G) Appropriate documentation (for example, updated master batch
records, specification sheets) including previously approved
documentation (with the changes highlighted) or references to
previously approved documentation;
(H) For a natural product, a recombinant DNA-derived protein/
polypeptide 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 paragraphs (b)(2)(iii)(E) and
(b)(2)(iii)(F) of this section;
(I) 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;
(J) A reference list of relevant standard operating procedures
(SOP's) when applicable; and
(K) A claim for categorical exclusion under Sec. 25.30 or
Sec. 25.33 of this chapter or an environmental assessment under
Sec. 25.40 of this chapter.
(iv) An applicant may ask FDA to expedite its review of a
supplement for public health reasons or if a delay in making the change
described in it would impose an extraordinary hardship on the
applicant. Such a supplement and its mailing cover should be plainly
marked: ``Prior Approval Supplement--Expedited Review Requested.''
(v) 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 approval from FDA
prior to distribution of the product. The supplement, if approved, may
result in the proposed change subsequently falling within a reduced
reporting category because the use of the protocol for that type of
change reduces the potential risk of an adverse effect.
(3) Changes requiring submission of a supplement at least 30 days
prior to distribution of the product made using the change (moderate
changes). (i) A supplement must be submitted for any change in the
product, production process, quality controls, equipment, or facilities
that has a moderate potential to have an adverse effect on the
identity, strength, quality, purity, or potency of the product as these
factors may relate to the safety or effectiveness of the product.
(ii) These changes include, but are not limited to:
(A) A change in the container closure system that does not affect
the quality of the final new animal drug product; and
(B) 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 similar, but not
identical, design and operating principle that does not affect the
process methodology or process operating parameters.
(iii) A supplement submitted under paragraph (b)(3)(i) of this
section is required to give a full explanation of the basis for the
change and identify the date on which the change is to be made. The
supplement must be labeled ``Supplement--Changes Being Effected in 30
Days.''
(iv) Pending approval of the supplement by FDA and except as
provided in paragraph (b)(3)(vi) of this section, distribution of the
product made using the moderate change under paragraph (b)(3) of this
section may begin not less than 30 days after receipt of the supplement
by FDA. The supplement must contain the information listed in
paragraphs (b)(2)(iii)(A) through (b)(2)(iii)(K) of this section.
(v) The applicant must not distribute the product made using the
change if within 30 days following FDA's receipt of the supplement, FDA
informs the applicant that either:
(A) The change requires approval prior to distribution of the
product in accordance with paragraph (b)(2) of this section; or
(B) Any of the information required under paragraph (b)(3)(iv) of
this section is missing. The applicant shall not distribute the product
until FDA determines that compliance with this section is achieved.
(vi) The agency may designate a category of changes for the purpose
of providing that, in the case of a change in such category, the holder
of an approved application may commence distribution of the drug
product 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:
(A) 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
(B) A change in the size and/or shape of a container for a
nonsterile drug product, except for solid dosage forms, without a
change in the labeled amount of product from one container closure
system to another;
(vii) If the agency disapproves the supplemental application
submitted under paragraph (b)(3) of this section, it
[[Page 53293]]
may order the manufacturer to cease distribution of the drug products
made with the manufacturing change.
(4) Changes and updated stability data to be described and
submitted in an annual report (minor changes). (i) Changes in the
product, production process, quality controls, equipment, or facilities
that have a minimal potential to have an adverse effect on the
identity, strength, quality, purity, or potency of the product as these
factors may relate to the safety or effectiveness of the product must
be documented by the applicant in the annual report to the application
in accordance with paragraph (a)(2)(ii) of this section. The report
shall be labeled ``Minor Changes and Stability Report.''
(ii) These changes include but are not limited to:
(A) 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;
(B) The deletion or reduction of an ingredient intended to affect
only the color of the product;
(C) 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;
(D) A change in the size and/or shape of a container containing the
same number of dosage units for a nonsterile solid dosage form, without
a change from one container closure system to another;
(E) A change within the container closure system for a nonsterile
new animal drug product, based upon showing of equivalency to the
approved system under a protocol approved in the application or
published in an official compendium;
(F) An extension of an expiration dating period based upon full
shelf-life data on full production batches obtained from a protocol
approved in the application;
(G) The addition, deletion, or revision of an alternate analytical
procedure that provides the same or increased assurance of the
identity, strength, quality, purity, or potency of the material being
tested as the analytical procedure described in the approved
application; and
(H) The addition by embossing, debossing, or engraving of a code
imprint to a solid oral dosage form drug product other than a modified
release dosage form, or a minor change in an existing code imprint.
(iii) For changes under this category, the applicant is required to
submit in the annual report a list of all products involved; and
(A) A statement by the holder of the approved application that the
effects of the change have been validated;
(B) A full description of the manufacturing and controls changes,
including the manufacturing site(s) or area(s) involved;
(C) The date each change was made;
(D) Cross reference to relevant validation protocols and/or SOP's;
(E) 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);
(F) Appropriate documentation (for example, updated master batch
records, specification sheets, etc.) including previously approved
documentation (with the changes highlighted) or references to
previously approved documentation; and
(G) Updated stability data generated on commercial or production
batches according to an approved stability protocol.
(c) Labeling and other changes to an approved application--(1)
General provisions. The applicant must notify FDA about each change in
each condition established in an approved application beyond the
variations already provided for in the application. The notice is
required to describe the change fully.
(2) Labeling changes requiring the submission and approval of a
supplement prior to distribution of the product made using the change
(major changes). (i) Addition of intended uses, changes to labeling,
and prescription new animal drug mailing/promotional pieces require a
supplement. These changes include, but are not limited to:
(A) Revision in labeling, such as updating information pertaining
to effects, dosages, side effects, contraindications, which includes
information headed ``side effects,'' ``warnings,'' ``precautions,'' and
``contraindications,'' except ones described in (c)(3) of this section;
(B) Addition of intended use;
(C) If it is a prescription new animal drug, any mailing or
promotional piece used after the drug is placed on the market is
labeling requiring a supplemental application, unless:
(1) Such labeling furnishing directions, warnings, and information
for use of the new animal drug are the same in language and emphasis as
labeling approved or permitted; and
(2) Any other such labeling are consistent with and not contrary to
such approved or permitted labeling.
(3) Prescription drug labeling not requiring an approved
supplemental application is submitted in accordance with
Sec. 514.80(b)(3)(ii).\1\
---------------------------------------------------------------------------
\1\ Sec. 514.80 was proposed at 56 FR 65581, December 17, 1991.
---------------------------------------------------------------------------
(D) Any other changes in labeling, except ones described in
paragraph (c)(3) of this section.
(ii) The applicant must obtain approval of the supplement from FDA
prior to distribution of the product. The supplement must contain the
following:
(A) A completed Form FDA 356V;
(B) A detailed description of the proposed change;
(C) The product(s) involved;
(D) The manufacturing site(s) or area(s) affected;
(E) The data derived from studies;
(F) A claim for categorical exclusion under Sec. 25.30 or
Sec. 25.33 of this chapter or an environmental assessment under
Sec. 25.40 of this chapter; and
(G) Any other information as directed by FDA.
(3) Labeling changes to be placed into effect prior to receipt of a
written notice of approval of a supplemental application. (i) Labeling
changes of the following kinds that increase the assurance of product
safety proposed in supplemental applications must be placed into effect
immediately:
(A) The addition to package labeling, promotional labeling, or
prescription new animal drug advertising of additional warning,
contraindication, side effect, and precaution information;
(B) The deletion from package labeling, promotional labeling, or
drug advertising of false, misleading, or unsupported intended uses or
claims for effectiveness; and
(C) Any other changes as directed by FDA.
(ii) Labeling changes (for example, design and style) that do not
decrease safety of product use proposed in supplemental applications
may be placed into effect prior to written notice of approval from FDA
of a supplemental application.
(iii) A supplement submitted under paragraph (c)(3) of this section
must include the following information:
(A) A full explanation of the basis for the changes, the date on
which such changes are being effected, and plainly marked on the
mailing cover and on the supplement, ``Supplement--Changes Being
Effected'';
[[Page 53294]]
(B) Two sets of printed copies of any revised labeling to be placed
in use, identified with the new animal drug application number; and
(C) A statement by the applicant that all promotional labeling and
all new animal drug advertising will promptly be revised consistent
with the changes made in the labeling on or within the new animal drug
package no later than upon approval of the supplemental application.
(iv) If the supplemental application is not approved, FDA may order
the manufacturer to cease distribution of the drug under the proposed
labeling.
(4) 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)\2\.
Supplemental applications as described under paragraph (c)(2) of this
section will not be required for an additional distributor to
distribute a drug that is the subject of an approved new animal drug
application if the conditions described under Sec. 514.80(a)(2),
(b)(3), and (b)(5)(iii) are met.
---------------------------------------------------------------------------
\2\ See footnote 1.
---------------------------------------------------------------------------
(d) Patent information. The applicant shall comply with the patent
information requirements under section 512(c)(3) of the act.
(e) Claimed exclusivity. If an applicant claims exclusivity under
section 512(c)(2)(F) of the act upon approval of a supplemental
application for a change in its previously approved new animal drug
product, the applicant shall include such a statement.
(f) Good laboratory practice for nonclinical laboratory studies. A
supplemental application that contains nonclinical laboratory studies
shall include, with respect to each nonclinical study, either a
statement that the study was conducted in compliance with the
requirements set forth in part 58 of this chapter, or, if the study was
not conducted in compliance with such regulations, a brief statement of
the reason for the noncompliance.
11. Section 514.106 is amended by removing paragraph (b)(1)(xiv)
and by revising paragraphs (b)(1)(vi) and (b)(1)(xiii) to read as
follows:
Sec. 514.106 Approval of supplemental applications.
* * * * *
(b) * * *
(1) * * *
(vi) A change in promotional material for a prescription new animal
drug not exempted by Sec. 514.8(c)(2)(i)(C)(3).
* * * * *
(xiii) A change permitted in advance of approval as described under
Sec. 514.8(b)(3).
* * * * *
PART 558--NEW ANIMAL DRUGS FOR USE IN ANIMAL FEEDS
12. The authority citation for 21 CFR part 558 continues to read as
follows:
Authority: 21 U.S.C. 360b, 371.
Sec. 558.5 [Amended]
13. Section 558.5 New animal drug requirements for liquid Type B
feeds is amended in paragraph (e) by removing ``514.8(d) and (e)'' and
by adding in its place ``514.8(c)(3)''.
Dated: June 23, 1999.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 99-25493 Filed 9-30-99; 8:45 am]
BILLING CODE 4160-01-F