[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]



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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