[Federal Register Volume 64, Number 123 (Monday, June 28, 1999)]
[Proposed Rules]
[Pages 34608-34625]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-16191]



[[Page 34608]]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 5, 206, 250, 314, 600, and 601

[Docket No. 99N-0193]
RIN 0910-AB61


Supplements and Other Changes to an Approved Application

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 
application to implement the manufacturing changes provision of the 
Food and Drug Administration Modernization Act of 1997 (the 
Modernization Act). The proposed rule would require manufacturers to 
validate the effect of any manufacturing change on the identity, 
strength, quality, purity, and potency of a drug or biological product 
as those factors relate to the safety or effectiveness of the product. 
The proposal sets forth requirements for changes requiring supplement 
submission and approval prior to the distribution of the product made 
using the change, changes requiring supplement submission at least 30 
days prior to the distribution of the product, changes requiring 
supplement submission at the time of distribution, and changes to be 
described in an annual report.

DATES: Written comments by September 13, 1999. Comments on the 
collection of information by July 28, 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: Desk 
Officer for FDA.
FOR FURTHER INFORMATION CONTACT:
    Eric B. Sheinin, Center for Drug Evaluation and Research (HFD-800), 
Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 
301-827-5918, or
    Robert A. Yetter, Center for Biologics Evaluation and Research 
(HFM-10), Food and Drug Administration, 1401 Rockville Pike, Rockville, 
MD 20852, 301-827-0373.

SUPPLEMENTARY INFORMATION:

I. Introduction

    On November 21, 1997, the President signed the Modernization Act 
(Pub. L. 105-115) into law. 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 
new drug and abbreviated new drug applications, to new and abbreviated 
animal drug applications, and to license applications for biological 
products. This proposed rule sets forth regulations to implement 
section 506A of the act for human new drug and abbreviated new drug 
applications and for licensed biological products. The Center for 
Veterinary Medicine is developing separate regulations regarding 
manufacturing changes for new and abbreviated animal drug applications.
    This proposed rule will update and replace current Sec. 314.70 (21 
CFR 314.70), which provides the requirements for manufacturing changes 
for human drug applications. This proposal also proposes changes to 
Sec. 601.12 (21 CFR 601.12), which provides the requirements for 
manufacturing changes for licensed biological products. Although the 
current Sec. 601.12 for licensed biological products is in full 
compliance with the new provisions in the Modernization Act, FDA is 
making the proposed changes in order to maintain harmonization with 
proposed Sec. 314.70 for human drug applications.

II. Background

    The requirements for reporting manufacturing changes under current 
Sec. 314.70 were developed originally as part of a comprehensive effort 
to improve the investigational new drug application (IND) and the new 
drug application (NDA) processes. This effort began in October 1982 (47 
FR 46622, October 19, 1982) and consisted of three phases. The first 
phase, termed the NDA rewrite (50 FR 7452, February 22, 1985), 
finalized procedures in part 314 (21 CFR part 314), including 
Sec. 314.70, for FDA review of new drug and antibiotic applications. 
The NDA rewrite of Sec. 314.70 created three mechanisms for reporting 
manufacturing changes: Supplements requiring prior approval, 
supplements not requiring prior approval, and annual reports. The 
rationale behind the need for three mechanisms to report manufacturing 
and controls changes is that some changes have a significant potential 
to affect the safety or effectiveness of a final drug product and 
should be reviewed and approved by FDA prior to distribution of the 
product made with the change. Other changes have a lesser potential to 
affect safety or effectiveness and could be implemented by a firm with 
notification to FDA concurrently (changes being effected supplement). A 
third category of changes has a minimal potential to affect safety or 
effectiveness and could, therefore, be submitted in the next annual 
report without compromising drug safety or effectiveness.
    The second phase of the effort to improve the IND and NDA process, 
termed the IND rewrite (52 FR 8831, March 19, 1987), finalized FDA 
procedures in 21 CFR part 312 for reviewing IND's. The third phase 
involved preparation of a series of agency guidances that elaborated on 
the concepts contained in the IND and NDA regulations and provided more 
detail concerning application formats and how to fulfill testing and 
other regulatory requirements.
    In implementing Sec. 314.70, the agency recognized both the need 
for greater consistency in the approaches FDA recommended for 
application holders making postapproval manufacturing and controls 
changes as well as a need to reduce regulatory burden consistent with 
the public health. Accordingly, FDA formed the Scale-up and 
Postapproval Changes (SUPAC) Task Force. This SUPAC Task Force, which 
was established by the Center for Drug Evaluation and Research (CDER) 
Chemistry, Manufacturing, and Controls Coordinating Committee, oversaw 
the acquisition of data on the effects of postapproval changes on the 
quality and performance of drugs. Based on the data and CDER's 
experience reviewing thousands of manufacturing change supplements, 
CDER developed guidance documents designed to ease preapproval 
requirements by categorizing certain manufacturing changes according to 
whether they had a minor, moderate, or major potential to affect 
product quality and performance. The SUPAC guidance documents were 
issued under Sec. 314.70(a), which stated that holders of an approved 
application shall make changes to the application in accordance with a 
guideline, notice, or regulation published in the Federal Register that 
provides for a less burdensome notification of the change.
    The existing postapproval change guidances are based on the concept 
that the identity, strength, quality, purity, and potency of an 
approved drug should

[[Page 34609]]

remain unchanged in any important aspect as a result of any 
postapproval change in manufacturing and controls. A change in any 
important aspect may thus require redemonstration of pharmaceutical 
equivalence and/or bioequivalence as defined in 21 CFR 320.1.
    Regulations governing manufacturing changes to licensed biological 
products were similar to Sec. 314.70, although they did not include the 
three categories of changes provided in Sec. 314.70. In 1997, as part 
of an agency initiative to reduce regulatory burden, FDA revised 
Sec. 601.12 to add three categories of manufacturing changes for 
licensed biological products with different reporting requirements for 
each category. In addition, because certain biotechnology products were 
regulated as drugs under section 505 of the act (21 U.S.C. 355), FDA 
sought to harmonize regulatory approaches for those biotechnology 
products that were regulated as drugs by adding new Sec. 314.70(g) that 
addressed reporting changes to an approved application for certain 
biotechnology products (see 61 FR 2739, January 29, 1996, and 62 FR 
39890, July 24, 1997). Revised Sec. Sec. 601.12 and 314.70(g), like the 
original Sec. 314.70, provided for three risk-based filing categories: 
(1) Those having a substantial potential to have an adverse effect on 
the identity, strength, quality, purity, and potency of a drug as those 
factors relate to the safety or effectiveness of the product; (2) those 
having a moderate potential to have these types of effects; and (3) 
those with minimal potential to have such effects. In addition, 
Sec. Sec. 601.12 and 314.70(g) provided for four different reporting 
categories instead of the three originally provided in Sec. 314.70. 
These categories were: (1) Prior approval supplement; (2) 30-day wait 
changes being effected supplement; (3) no-wait changes being effected 
supplement; and (4) annual report.
    Sections 601.12 and 314.70(g) also provided that applicants could 
submit as a preapproval supplement a comparability protocol that 
described 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 a product as they may relate to the 
safety or effectiveness of the product. If approved, such a protocol 
could justify a reduced reporting category for the particular change 
described because the use of the protocol for the change could reduce 
the potential risk of an adverse effect associated with the change.

III. Summary of the Legislation

    Section 116 of the Modernization Act amended the act by adding 
section 506A, which built upon the concepts embodied in the IND/NDA 
rewrite, the SUPAC program, and the changes to Sec. Sec. 601.12 and 
314.70(g). 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 or effectiveness of the drug (sections 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 determined to be appropriate by FDA 
and include the information developed by the applicant when 
``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 (parts 210 and 
211 (21 CFR parts 210 and 211)). Unless otherwise specified by FDA, 
some CGMP validation (e.g., process, equipment) data need not be filed 
in an NDA, abbreviated new drug application (ANDA), or license 
application for a biological product but should be retained at the 
facility and be available for review by FDA at its discretion. Some 
other CGMP validation information, in addition to the information 
validating the effects of the change specified in section 506A(c)(1) of 
the act, should be submitted in an NDA, ANDA, or license application 
for a biological product (e.g., sterilization and advantageous agent 
removal process validation).
    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 FDA by regulation or 
guidance; (2) a change determined by FDA by regulation or guidance to 
require completion of an appropriate clinical study demonstrating 
equivalence of the drug to the drug manufactured without the change; 
and (3) other changes determined by FDA 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 require submission of a supplemental application for 
drugs made with manufacturing changes that are not major (section 
506A(d)(1)(B) of the act) and establish categories of manufacturing 
changes for which a supplemental application is required (section 
506A(d)(1)(C) of the act). In such a case the applicant may begin 
distribution of the drug 30 days after FDA receives a supplemental 
application unless the agency notifies the applicant within the 30-day 
period that prior approval of the application is required (section 
506A(d)(3)(B)(i) of the act). FDA may also designate a category of 
manufacturing changes that permit the applicant to begin distributing a 
drug made with such changes upon receipt by the agency of a 
supplemental application for the change (section 506A(d)(3)(B)(ii) of 
the act). If FDA disapproves 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 an annual 
reporting requirement, FDA may authorize the applicant to submit a 
single report containing the required information for all the changes 
made during the year

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(annual report) (section 506A(d)(2)(B) of the act).
    Section 506A of the act provides FDA with considerable flexibility 
to determine the information and filing mechanism required for the 
agency to assess the effect of manufacturing changes in the safety and 
effectiveness of the product. 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 will allow it 
to be responsive to increasing knowledge of and experience with certain 
types of changes and help ensure the efficacy 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 minimal or 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, further research and data collection, 
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, help reduce the number of manufacturing changes specifically 
identified as requiring supplements.
    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. Section 506A of the act 
explicitly provides FDA the authority to use guidance documents to 
determine the type of changes that do or do not have a substantial 
potential to adversely affect the safety or effectiveness of the drug 
product. The use of guidance documents will allow FDA to more easily 
and quickly modify and update important information. (FDA's use of 
guidance documents under current Sec. Sec. 314.70(a) and 601.12 has 
proven effective in accomplishing this goal.) Guidance documents will 
be developed according to the procedures set out in FDA's ``Good 
Guidance Practices'' published in the Federal Register of February 27, 
1997 (62 FR 8961 at 8967 through 8972). A notice of availability of a 
draft guidance entitled ``Guidance for Industry: Changes to an Approved 
NDA or ANDA'' is published elsewhere in this issue of the Federal 
Register. This draft guidance covers recommended reporting categories 
for various postapproval manufacturing changes. Previously published 
guidances, including the SUPAC guidances, provide recommendations on 
reporting categories as well as 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 they 
may relate to the safety or effectiveness of the product. To the extent 
that the recommendations on reporting categories in this guidance, when 
finalized, are inconsistent with previously published guidance, such as 
the SUPAC guidances, the recommended reporting categories in such prior 
guidance will be superseded by this new guidance upon its publication 
in final form. CDER intends to update the previously published 
guidances to make them consistent with this guidance.
    FDA has also published a guidance entitled ``Changes to an Approved 
Application for Specified Biotechnology and Specified Synthetic 
Biological Products'' (62 FR 39904, July 24, 1997). FDA intends to 
update this guidance as appropriate based on any final rule that may 
issue as a result of this proposal.

IV. Description of the Proposed Rule

A. Definitions

    FDA is proposing to amend the ``Definitions'' sections of the 
regulations on applications for FDA approval to market a new drug 
(Sec. 314.3) and a biological product (21 CFR 600.3) by adding 
definitions for ``specification'' and ``validate the effects of the 
change.'' 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 
materials. FDA is proposing to define ``specification'' because under 
section 506A of the act a ``major change'' includes a change ``in the 
specifications in the approved application or license.''
    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 ``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 they relate to drug 
safety or effectiveness, and may require testing beyond that in an 
approved specification, such as testing to ensure pharmaceutical 
equivalence and/or bioequivalence.

B. Changes to an Approved Application

    Current Sec. 314.70(a) sets forth general requirements under which 
an applicant must notify FDA when making 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. It also states that, depending on the type of change, the 
applicant must notify FDA of it in a supplement under current 
Sec. 314.70(b) or (c) or by inclusion of the information in an annual 
report under current Sec. 314.70(d). FDA is proposing to retain these 
general requirements under proposed Sec. 314.70(a)(1). A similar 
provision is included in the regulations on changes to an approved 
application for biological products under current Sec. 601.12(a). FDA 
is proposing to

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redesignate this requirement as Sec. 601.12(a)(1).
    Proposed Sec. 314.70(a)(2) would require the holder of an approved 
application under section 505 of the act 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) or 
potency (e.g., biological activity, bioavailability, and 
bioequivalence) of a drug as these factors may relate to the safety and 
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. A 
similar provision is included in the regulations on changes to an 
approved application for biological products under current 
Sec. 601.12(a). FDA is proposing to add minor wording changes for 
consistency with revised Sec. 314.70 and to redesignate this 
requirement as Sec. 601.12(a)(2). In addition, applicants continue to 
be subject to the validation requirements of parts 210 and 211 as 
mentioned previously.
    Current Sec. 314.70(a) states that notwithstanding the supplement 
submission requirements of current Sec. 314.70(b) and (c), an applicant 
shall make a manufacturing change in accordance with ``a guideline, 
notice, or regulation published in the Federal Register that provides 
for a less burdensome notification of the change.'' For example, a type 
of manufacturing change subject to prior approval by FDA under current 
Sec. 314.70(b) might be identified in a ``guideline, notice, or 
regulation'' as a change that could be reported in a supplement not 
requiring prior approval or in an annual report. In the SUPAC guidance 
documents, 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.
    FDA is proposing to retain this requirement under proposed 
Sec. 314.70(a)(3) and to add it to the regulations on changes to an 
approved application for biological products as proposed 
Sec. 601.12(a)(3). This exception may be used as pharmaceutical science 
evolves for those changes that FDA no longer considers to have a 
substantial potential to have an adverse effect on the product. 
However, to ensure consistency with the principles of FDA's good 
guidance practices, proposed Sec. Sec. 314.70(a)(3) and 601.12(a)(3) 
would eliminate the reference to a Federal Register ``notice'' and 
change the word ``guideline'' to ``guidance.'' Proposed 
Sec. 314.70(a)(3) is expressly sanctioned in section 506A(c)(2)(A), 
(c)(2)(B), and (c)(2)(C) of the act which permit FDA to categorize 
manufacturing changes ``by regulation or guidance.''
    Current Sec. 314.70(c) states, in the introductory paragraph, that 
the applicant who submits a change being effected supplement to FDA 
must promptly revise all promotional labeling and drug advertising to 
make it consistent with any change in the labeling. FDA is proposing to 
retain this provision as proposed Sec. 314.70(a)(4) and to add it to 
the regulations on changes to an approved application for biological 
products as proposed Sec. 601.12(a)(4). Because the prompt revision of 
all promotional labeling and product advertising applies equally to all 
labeling changes (see Sec. 314.81(b)(3)), FDA is proposing that this 
provision expressly apply to labeling changes requiring approval prior 
to the distribution of the product, labeling changes that may be 
submitted in a changes being effected supplement, and those changes 
that may be filed in an annual report.
    Current Sec. 314.70(a) also requires that, except for a 
supplemental application providing for a change in the labeling, the 
applicant, other than a foreign applicant, shall include in each 
supplemental application providing for a change under paragraph (b) or 
(c) of current Sec. 314.70, a statement certifying that a field copy of 
the supplement has been provided to the applicant's home FDA district 
office. FDA is proposing to retain this requirement as proposed 
Sec. 314.70(a)(5). However, as proposed, this section would omit the 
phrase ``other than a foreign applicant'' because foreign applicants 
now routinely supply field copies of supplements to the agency.
    Proposed Sec. Sec. 314.70(a)(6) and 601.12(a)(5) 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.

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

    Certain drug or biological product manufacturing steps are so 
critical that changes in these steps must be submitted in a supplement 
to FDA and approved by FDA prior to distribution of the product made 
using the change. Similarly, certain labeling changes must be approved 
prior to distribution of the product with the new labeling. Current 
regulations at Sec. Sec. 314.70(b) and (g)(1) and 601.12(b) set forth 
prior approval requirements. FDA is proposing to revise these 
regulations to implement section 506A of the act. Proposed 
Sec. 314.70(b)(1) would implement section 506A(c)(1) and (c)(2) of the 
act and would require that a preapproval 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.
    Sometimes, during assessment of a change, an applicant will find 
that the manufacturing change will have an adverse effect on the 
identity, strength, quality, purity, or potency of the drug product. In 
many cases, the applicant will not implement this manufacturing change, 
but in some cases may still wish to do so. If an assessment concludes 
that a manufacturing change has adversely affected the identity, 
strength, quality, purity, or potency of the drug product, the change 
should be filed in a prior approval supplement, regardless of whether 
the change is one that normally does not need FDA approval prior to 
distribution of the product made with the change. The applicant could 
submit this change in a prior approval supplement with appropriate 
information to support 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 prior approval supplement.
    Proposed Sec. 314.70(b)(4) would retain the provision in current 
Sec. 314.70(b) that provides that an applicant may request an expedited 
review of a supplement if a delay in making the change would impose an 
extraordinary hardship. Proposed Sec. 314.70(b)(4) would also permit a 
request for an expedited review of a supplement for public health 
reasons. FDA is retaining the provision

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for expedited review for extraordinary hardship reasons but wishes to 
clarify that these requests should be reserved for 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. FDA is also proposing to add this provision for expedited 
review, as proposed in Sec. 314.70(b)(4), to the regulations on changes 
to an approved application for biological products as proposed 
Sec. 601.12(b)(4). Requests for expedited review will be assessed on a 
case-by-case basis. All requests may not be granted.
    Proposed Sec. 314.70(b)(2) lists changes requiring supplement 
submission and FDA approval prior to distribution, including changes 
designated as major manufacturing changes in section 506A(c)(2) of the 
act and changes to certain biotechnology products that are currently 
subject to prior approval requirements under current Sec. 314.70(g)(1). 
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 believes that the filing mechanism for these significant 
changes is unlikely to vary with technological advances or due to 
differences among products, and that these changes should be enumerated 
in the proposed regulations. The agency's continued prior review and 
approval of such changes is necessary to protect the public from 
products for which safety or effectiveness may have been compromised. 
The changes in proposed Sec. 314.70(b)(2) would include but are not 
limited to the following changes.
    1. Changes in the qualitative or quantitative formulation of the 
drug, including inactive ingredients, or in the specifications in the 
approved application or license, except as provided in proposed 
Sec. 314.70(c) and (d) (proposed Sec. 314.70(b)(2)(i)). Section 
506A(c)(2)(A) of the act specifically requires that this change be 
submitted in a supplement requiring FDA approval prior to distribution. 
These types of changes are included under current Sec. 314.70(b) and 
(g) as requiring a prior approval supplement. FDA is also proposing to 
revise current Sec. 601.12(b)(2)(i) in the regulations on changes to an 
approved application for biological products to be consistent with 
proposed Sec. 314.70(b)(2)(i).
    2. Changes requiring completion of studies in accordance with part 
320 (21 CFR part 320) to demonstrate the equivalence of the drug to the 
drug as manufactured without the change or to the reference listed drug 
(proposed Sec. 314.70(b)(2)(ii)). A similar change is included under 
current Sec. 314.70(g)(1) as requiring a prior approval supplement. FDA 
is proposing that these changes be submitted in a supplement requiring 
prior approval because section 506A of the act provides that a major 
manufacturing change shall include a change ``determined by the 
Secretary by regulation or guidance to require completion of an 
appropriate clinical study demonstrating equivalence of the drug to the 
drug as manufactured without the change''(section 506A(c)(2)(B) of the 
act). The studies most likely to be conducted to support a 
manufacturing change would be bioavailability or bioequivalence studies 
conducted in humans in accordance with FDA regulations at part 320. 
Well-controlled clinical trials or nonclinical tests may also be used 
to establish bioavailability or bioequivalence (Sec. 320.24). These are 
the types of studies the statute refers to as demonstrating the 
equivalence of one drug to another. FDA proposes interpreting 
``Appropriate clinical stud[ies],'' referenced in section 506A(c)(2)(B) 
of the act for NDA products, to be ``studies in accordance with part 
320 of this chapter'' to clarify the types of studies triggering a 
prior approval supplement. This phrase is used in the proposed 
regulation at Sec. 314.70(b)(2)(ii).
    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. FDA is including in proposed Sec. 314.70(b)(2)(ii) the 
statement that the equivalence of the drug may sometimes be 
demonstrated by comparison to a reference listed drug. This is 
consistent with the drug approval requirements for generic drugs 
because, at the time of approval, a generic drug applicant is required 
to show equivalence between the proposed generic drug and a reference 
listed drug, and a proposed manufacturing change should not 
significantly change the equivalence demonstrated at the time of 
approval (Sec. 320.21(b)). For the more significant manufacturing 
changes for generic drugs, the applicant is required to conduct a 
bioequivalence study comparing the drug product made with the change to 
the reference listed drug. FDA is not proposing the same changes to 
Sec. 601.12 because biological products are not subject to part 320 and 
have unique properties. Therefore, the agency will retain the wording 
in current Sec. 601.12(b)(2)(ii).
    3. 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 
(proposed Sec. 314.70(b)(2)(iii)). Current Sec. Sec. 314.70(g)(1) and 
601.12(b)(2)(vi) require a prior approval supplement for this change.
    4. Changes in the synthesis or manufacture of the drug substance 
that may affect the impurity profile and/or the physical, chemical, or 
biological properties of the drug substance (proposed 
Sec. 314.70(b)(2)(iv)). A similar change in current Sec. 314.70(b)(1) 
requires a prior approval supplement.
    5. Changes in labeling, except those described in proposed 
Sec. 314.70(c)(6)(iii) (changes to add or strengthen certain warnings 
or statements), Sec. 314.70(d)(2)(ix) (certain changes in the 
description or information about a drug), and Sec. 314.70(d)(2)(x) 
(certain editorial or minor changes) (proposed Sec. 314.70(b)(2)(v)). 
This change requires a prior approval supplement under current 
Sec. 314.70(b)(3).
    6. Changes in a container closure system that controls drug 
delivery or that may affect the impurity profile of the drug product 
(proposed Sec. 314.70(b)(2)(vi)). Significant changes in container 
closure systems require a prior approval supplement under current 
Sec. 314.70(b)(2).
    7. Changes solely affecting a natural product, a recombinant 
deoxyribonucleic acid (DNA)-derived protein/polypeptide product, or a 
complex or conjugate of a drug with a monoclonal antibody for: (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 (proposed 
Sec. 314.70(b)(2)(vii)). This change requires a prior approval 
supplement under current Sec. 314.70(g)(1).
    8. Changes to a product under an application subject to a validity 
assessment because of significant questions regarding the integrity of 
the data supporting that application (proposed 
Sec. 314.70(b)(2)(viii)). 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 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

[[Page 34613]]

questions resolved, the holder of an approved application may submit 
supplements for manufacturing changes as otherwise provided in 
Sec. 314.70.
    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 this proposed regulation. As discussed previously, section 116 
of the Modernization Act expressly states that the agency may through 
guidance categorize the manufacturing changes. FDA anticipates that 
scientific advances and future experience may reduce the need for 
premarket approval of 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: Changes to an Approved NDA or ANDA'' 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 guidance as well as on the 
proposed rule.
    Current Sec. 314.70(b)(1) requires that supplements requiring prior 
approval be submitted for the following changes in a drug substance: 
(1) Relaxing the limits for a specification (Sec. 314.70(b)(1)(i)); (2) 
establishing a new regulatory analytical method 
(Sec. 314.70(b)(1)(ii)); (3) deleting a specification or regulatory 
analytical method (Sec. 314.70(b)(1)(iii)); (4) changing the synthesis 
of the drug substance, including a change in solvents and a change in 
the route of synthesis (Sec. 314.70(b)(1)(iv)); and (5) using a 
different facility or establishment to manufacture the drug substance 
(Sec. 314.70(b)(1)(v)). FDA is proposing to revoke current 
Sec. 314.70(b)(1)(i), (b)(1)(ii), and (b)(1)(iii) because these relate 
to a change in a specification which is already covered under proposed 
Sec. 314.70(b)(1). FDA is proposing to revoke current 
Sec. 314.70(b)(1)(iv) and (b)(1)(v) 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 identity, strength, quality, purity, 
or potency of the drug as they may relate to the safety or 
effectiveness of the drug. FDA has decided not to include these changes 
in this proposed rule, but plans to provide recommendations on the 
filing mechanisms for these types of changes in the guidance documents 
discussed previously.
    Current Sec. 314.70(b)(2) requires that supplements requiring prior 
approval be submitted for the following changes in a drug product: (1) 
Adding or deleting an ingredient, or otherwise changing the composition 
of the drug product, other than deletion of an ingredient intended only 
to affect the color of the drug product (Sec. 314.70(b)(2)(i)); (2) 
relaxing the limits for a specification (Sec. 314.70(b)(2)(ii)); (3) 
establishing a new regulatory analytical method 
(Sec. 314.70(b)(2)(iii)); (4) deleting a specification or regulatory 
analytical method (Sec. 314.70(b)(2)(iv)); (5) changing the method of 
manufacture of the drug product, including changing or relaxing an in-
process control (Sec. 314.70(b)(2)(v)); (6) using a different facility 
or establishment, including a different contract laboratory or labeler, 
to manufacture, process, or pack the drug product 
(Sec. 314.70(b)(2)(vi)); (7) changing the container and closure system 
for the drug product or changing a specification or regulatory 
analytical method for the container and closure system 
(Sec. 314.70(b)(2)(vii)); (8) changing the size of the container, 
except for solid dosage forms, without a change in the container and 
closure system (Sec. 314.70(b)(2)(viii)); (9) extending the expiration 
date of the drug product based on data obtained under a new or revised 
stability testing protocol that has not been approved in the 
application (Sec. 314.70(b)(2)(ix)); (10) establishing a new procedure 
for reprocessing a batch of the drug product that fails to meet 
specifications (Sec. 314.70(b)(2)(x)); (11) adding a code imprint by 
printing with ink on a solid oral dosage form drug product 
(Sec. 314.70(b)(2)(xi)); (12) adding a code imprint by embossing, 
debossing, or engraving on a modified release solid oral dosage form 
drug product (Sec. 314.70(b)(2)(xii)). FDA is proposing to revoke 
Sec. 314.70(b)(2)(i) through (b)(2)(iv) because these provisions relate 
to a change in qualitative or quantitative formulation or a 
specification that is already covered under proposed Sec. 314.70(b)(1). 
FDA is proposing to revoke current Sec. 314.70(b)(2)(v) through 
(b)(2)(xii) because some changes would fall into the proposed major 
manufacturing changes category while others would fall into other 
proposed categories. FDA plans to provide recommendations on the filing 
mechanism for these changes in the guidance documents discussed 
previously.
    Proposed Sec. 314.70(b)(3) states that the applicant must obtain 
approval of a supplement from FDA before distributing a product using a 
change under Sec. 314.70(b), and specifies information to be included 
in the supplement. The supplement must include: (1) A detailed 
description of the proposed change; (2) the product(s) involved; (3) 
the manufacturing site(s) or area(s) affected; (4) 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 (validating the effects of the change); (5) data derived from 
such studies; (6) 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 under Sec. 314.70(b)(3)(iv) and (b)(3)(v); 
(7) for sterilization process and test methodologies, relevant 
validation protocols must be provided in addition to the requirements 
under Sec. 314.70(b)(3)(iv) and (b)(3)(v); and (8) if applicable, a 
reference list of relevant standard operating procedures (SOP's). These 
supplement content requirements are already required under current 
Sec. Sec. 314.70(g)(1)(iii) and 601.12(b)(3), and FDA is proposing to 
retain the requirements in this rule, except that the proposal 
specifies that relevant validation protocols and data apply to a 
natural product, a recombinant DNA-derived protein/polypeptide product, 
or a complex or conjugate of a drug with a monoclonal antibody, as well 
as protocols and data for sterilization processes and test 
methodologies.
    Current Sec. 314.70(g)(1)(iii) only applies to recombinant DNA-
derived protein/polypeptide products or complexes or conjugates of a 
drug with a monoclonal antibody. Some information requirements listed 
under current Sec. 314.70(g)(1)(iii) are not applicable to all CDER 
drug products. FDA is proposing to clarify the requirements in current 
Sec. 314.70(g)(1)(iii) to describe the limited circumstances under 
which certain information would be required.

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

    Current Sec. 314.70(c) describes changes that may be made before 
FDA approval of a supplement. These include changes to enhance the safe 
use of a drug by adding specifications to strengthen warnings, or to 
delete false, misleading, or unsupported indications for use. Current 
Sec. 314.70(g)(2) describes changes requiring supplement submission at 
least 30 days prior to distribution of the

[[Page 34614]]

product made using the change. These include changes in the site of 
testing from one facility to another, an increase or decrease in 
production scale during finishing steps that involves new or different 
equipment, and 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. FDA recognizes 
that 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 there is a 
mechanism for assessing the consequences of the change and that the 
agency approve such changes. Ready access to information regarding such 
changes through submission of a supplement 30 days before distribution 
of the product would protect against the distribution of unsafe or 
ineffective products while speeding the availability of improved 
products.
    Proposed Sec. 314.70(c) implements section 506A(d)(1)(B) and 
(d)(3)(B)(i) of the act and provides that products made using changes 
listed under this section may be distributed not sooner than 30 days 
after receipt of a supplement by FDA. Proposed Sec. 314.70(c)(1) 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. 314.70(c)(3) states that a supplement submitted under paragraph 
(c)(1) 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'' or, if applicable under paragraph (c)(6) of this 
section, ``Supplement--Changes Being Effected.''
    Proposed Sec. 314.70(c)(2) describes the types of changes that 
would be included under this section:
    1. A change in the container closure system that does not affect 
the quality of the final drug product (proposed Sec. 314.70(c)(2)(i)).
    2. Changes solely affecting a natural protein product, a 
recombinant DNA-derived protein/polypeptide product or a complex or 
conjugate of a 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 (proposed Sec. 314.70(c)(2)(ii)). These changes are listed 
in current Sec. 314.70(g)(2) as requiring the submission of a 
supplement at least 30 days prior to distribution.
    Current Sec. 314.70(g)(2) lists a change in the site of testing 
from one facility to another as a change that must be filed in a 
supplement submitted at least 30 days prior to distribution. FDA has 
decided not to include a similar change in proposed Sec. 314.70(c) and 
is proposing to delete this change from current Sec. 601.12(c)(2)(i). 
FDA plans to provide recommendations on the filing mechanism for this 
change in the guidance documents discussed previously.
    Proposed Sec. 314.70(c)(4) states that distribution of a product 
made using a change under this section may begin not less than 30 days 
after receipt of a supplement by FDA. This section would also require 
that the same information listed in paragraph (b)(3), discussed 
previously, must be contained in the supplement required under proposed 
Sec. 314.70(c).
    Proposed Sec. 314.70(c)(5) states that 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. 314.70(c). If the proposed change is determined to be a major 
change that should be submitted under proposed Sec. 314.70(b), the 
agency would inform the applicant and the applicant would be required 
to receive FDA 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. 314.70(c), 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. These provisions are 
provided in section 506A(d)(3) of the act. These requirements are 
included under current Sec. Sec. 314.70(g)(2)(iv) and 601.12(c)(4) and 
FDA is retaining and expanding this requirement to cover all drugs.
    Under proposed Sec. 314.70(c)(7), 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. FDA is also proposing to add this provision to the regulations 
on changes to an approved application for biological products as 
proposed Sec. 601.12(c)(6).

E. Changes That May Be Implemented When FDA Receives a Supplement 
(Moderate Changes)

    Under proposed Sec. 314.70(c)(6), FDA may designate a category of 
changes for which the holder of an approved application making such a 
change may begin distribution of the drug upon receipt by FDA of a 
supplemental application for the change. This provision implements 
section 506A(d)(3)(B)(ii) of the act. FDA recognizes that 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 there is a mechanism for 
assessing the consequences of the changes and for the agency to 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. In general, these changes provide the same or 
increased assurance that the product will have the characteristics of 
identity, strength, quality, purity, or potency that it purports or is 
represented to have. Ready access to information by FDA regarding such 
changes, through the submission of a supplement, would protect against 
the distribution of unsafe or ineffective products while speeding the 
availability of improved products.
    These changes include, but are not limited to:
    1. The addition to a specification or changes in the methods or 
controls to provide increased assurance that the drug will have the 
characteristics of identity, strength, quality, purity, or potency that 
it purports or is represented to possess (proposed 
Sec. 314.70(c)(6)(i)). A similar change is listed under current 
Sec. 314.70(c). Proposed Sec. 314.70(c)(6)(i) revises current 
Sec. 314.70(c) to provide clarification based on the proposed 
definition of specification and to delete the reference to facilities. 
FDA plans to provide recommendations on the filing mechanism for 
facility changes in the guidance documents discussed previously.
    2. A change in the size and/or shape of a container (containing the 
same

[[Page 34615]]

labeled amount of product) for a nonsterile drug product, except for 
solid dosage forms, without a change from one container closure system 
to another (proposed Sec. 314.70(c)(6)(ii)). A similar change is listed 
under current Sec. 314.70(b) as requiring prior approval. The proposal 
differs from the existing rule in that it only applies to nonsterile 
drug products, thereby reducing the potential risks and eliminating the 
need for a prior approval requirement. FDA is also clarifying that 
changes in container size relate to changes in the physical size of the 
container and do not include changes in the labeled amount of the drug.
    3. Changes in the labeling to add or strengthen a contraindication, 
warning, precaution, or adverse reaction, or to add or strengthen a 
statement about drug abuse, dependence, psychological effect, or 
overdosage, or to add or strengthen an instruction about dosage and 
administration that is intended to increase the safe use of the product 
(proposed Sec. 314.70(c)(6)(iii)(A), (c)(6)(iii)(B), and 
(c)(6)(iii)(C)). These changes are required under current 
Sec. 314.70(c)(2), except that FDA is proposing to include labeling 
changes relating to adding or strengthening a statement about 
psychological effects to maintain consistency with current 
Sec. 601.12(f)(2)(B).
    4. The deletion of false, misleading, or unsupported indications 
for use or claims for effectiveness (proposed 
Sec. 314.70(c)(6)(iii)(D)). This change is required under current 
Sec. 314.70(c)(2).
    5. Any other labeling changes specifically requested by FDA 
(proposed Sec. 314.70(c)(6)(iii)(E)). FDA is proposing to include this 
change under this section to enable the agency to allow for labeling 
changes that normally require prior approval to be submitted in a 
changes being effected supplement when FDA specifically requests the 
change. FDA is also proposing to add this requirement to the 
regulations on changes to an approved application for biological 
products as proposed Sec. 601.12(f)(2)(i)(E).
    Current Sec. 314.70(c)(3) lists the following changes to use a 
different facility or establishment to manufacture the drug substance 
that may be made before FDA approval: (1) Where the manufacturing 
process in the new facility or establishment does not differ materially 
from that in the former facility or establishment, and (2) where the 
new facility or establishment has received a satisfactory CGMP 
inspection within the previous 2 years covering that manufacturing 
process. FDA is proposing not to include these changes in this proposed 
rule but plans to provide recommendations on the filing mechanism for 
these changes in the guidance documents discussed previously.

F. Changes To Be Described in the Next Annual Report (Minor Changes)

    Proposed Sec. 314.70(d) 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 of the product as these factors 
may relate to the safety or effectiveness of the product would be 
documented by the applicant in the next annual report in accordance 
with current Sec. 314.81(b)(2). This provision is provided in section 
506A(d)(2) of the act. FDA recognizes that there are manufacturing 
changes that have minimal potential to have an adverse effect on a 
product's safety or effectiveness. FDA believes that prior agency 
approval of these changes is unnecessary and is proposing in 
Sec. 314.70(d) 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 there is a mechanism for 
assessing the consequences of the change. FDA can effectively assess 
compliance with Sec. 314.70(d) 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.
    Under proposed Sec. 314.70(d)(2), these changes would include, but 
are not limited to:
    1. Any change made to comply with an official compendium that is 
consistent with FDA requirements and provides increased assurance that 
the drug will have the characteristics of identity, strength, quality, 
purity, or potency that it purports or is represented to possess 
(proposed Sec. 314.70(d)(2)(i)). Similar changes are listed in current 
Sec. 314.70(d) and (g) as changes to be described in the next annual 
report. FDA is limiting the situations in which these changes can be 
submitted in an annual report because certain changes in a 
specification (e.g., deleting a test, relaxing acceptance criteria) are 
not considered to have minimal potential to effect a product's safety 
or effectiveness. FDA is also proposing to revise current 
Sec. 601.12(d)(2)(i) in the regulations on changes to an approved 
application for biological products to be consistent with proposed 
Sec. 314.70(d)(2)(i).
    2. The deletion or reduction of an ingredient intended only to 
affect the color of the product (proposed Sec. 314.70(d)(2)(ii)). A 
similar change is listed in current Sec. 314.70(d) and (g)(3) which 
states that the deletion of an ingredient intended only to affect the 
color of the drug product should be submitted in an annual report. FDA 
is proposing to broaden this provision to include changes that reduce 
the quantity of an ingredient intended only to affect the color of the 
product. FDA is also proposing to revise current Sec. 601.12(d)(2)(ii) 
in the regulations on changes to an approved application for biological 
products to be consistent with proposed Sec. 314.70(d)(2)(ii).
    3. The replacement of equipment with that of the same design and 
operating principles except for equipment used with a natural protein 
product, a recombinant DNA-derived protein/polypeptide product, or a 
complex or conjugate of a drug with a monoclonal antibody (proposed 
Sec. 314.70(d)(2)(iii)). FDA is proposing to add this change to clarify 
when certain changes in equipment could be reported in an annual 
report. In general, under current regulations (e.g., 
Sec. 314.70(b)(2)(v)), changes in process, which may include changes in 
equipment, require a prior approval supplement and this proposal would 
reduce the regulatory burden without adversely affecting the quality of 
the drug product.
    4. A change in the size and/or shape of a container containing the 
same number of dose units for a nonsterile solid dosage form, without a 
change from one container closure system to another (proposed 
Sec. 314.70(d)(2)(iv)). A similar change is listed in current 
Sec. 314.70(d) and (g)(3) which states that a change in the size of a 
container for a solid dosage form without a change from one container 
and closure system to another must be filed in an annual report. FDA is 
proposing to broaden this provision to include a change in the shape of 
the container. FDA is also clarifying that a change in container size 
relates to a change in the physical size of the container and does not 
include a change involving the number of dosage units. FDA is also 
proposing to revise current Sec. 601.12(d)(2)(v) in the regulations on 
changes to an approved application for biological products to be 
consistent with proposed Sec. 314.70(d)(2)(iv).
    5. A change within the container closure system for a nonsterile 
drug product, based upon a showing of equivalency to the approved 
system under a protocol approved in the application or published in an 
official

[[Page 34616]]

compendium (proposed Sec. 314.70(d)(2)(v)). A similar change is listed 
in current Sec. 314.70(d) and (g)(3) which states that a change within 
the container and closure system for the drug product (for example, a 
change from one high density polyethylene (HDPE) to another HDPE), 
except a change in container size for nonsolid dosage forms, based upon 
a showing of equivalency to the approved system under a protocol 
approved in the application or published in an official compendium, 
should be submitted in an annual report. The current regulations limit 
this provision by excluding a change in container size for nonsolid 
dosage forms. FDA is proposing to broaden this provision to allow such 
changes for all nonsterile drug products. FDA is also proposing to 
revise current Sec. 601.12(d)(2)(iv) in the regulations on changes to 
an approved application for biological products to be consistent with 
proposed Sec. 314.70(d)(2)(v).
    6. 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 (proposed Sec. 314.70(d)(2)(vi)). A similar 
change is listed under current Sec. 314.70(d) and (g)(3) as one to be 
filed in an annual report. FDA is clarifying that the extension of an 
expiration date in an annual report should be based on data from full 
production batches. FDA is also proposing to revise current 
Sec. 601.12(d)(2)(iii) regarding changes to an approved application for 
biological products to be consistent with proposed 
Sec. 314.70(d)(2)(vi).
    7. 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 (proposed Sec. 314.70(d)(2)(vii)). A similar change is 
listed in current Sec. 314.70(d) and (g)(3) which state that the 
addition or deletion of an alternate analytical method should be filed 
in an annual report. FDA is proposing to broaden this provision to 
include revisions of alternate analytical procedures. FDA is also 
clarifying that any changes in alternate analytical procedures should 
provide 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. FDA is also 
proposing to revise current Sec. 601.12(d)(2)(vii) in the regulations 
on changes to an approved application for biological products to be 
consistent with proposed Sec. 314.70(d)(2)(vii).
    8. 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 
(proposed Sec. 314.70(d)(2)(viii)). These changes are listed in current 
Sec. 314.70(d) and (g)(3) as changes to be described in the next annual 
report.
    9. A change in the labeling concerning the description of the drug 
product or in the information about how the drug is supplied, that does 
not involve a change in the dosage strength or dosage form (proposed 
Sec. 314.70(d)(2)(ix)). These changes are listed in current 
Sec. 314.70(d) as changes to be described in the next annual report.
    10. An editorial or similar minor change in labeling (proposed 
Sec. 314.70(d)(2)(x)). These changes are listed in current 
Sec. 314.70(d) as changes to be described in the next annual report.
    Under proposed Sec. 314.70(d)(3), an applicant must submit in the 
annual report a list of all products involved and: (1) A statement by 
the holder of the approved application that the effects of the change 
have been validated; (2) a full description of the manufacturing and 
controls changes, including the manufacturing site(s) or area(s) 
involved; and (3) the date each change was made, a cross-reference to 
relevant validation protocol(s) and/or SOP's, and 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 
(validating the effects of the change). FDA is also proposing to revise 
current Sec. 601.12(d)(3) in the regulations on changes to an approved 
application for biological products to add, as proposed 
Sec. 601.12(d)(3)(iii), the requirement that the applicant must submit 
a statement that the effects of the change have been validated.

G. Other Information

    Under proposed Sec. 314.70(e), 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 prior approval 
from FDA prior to distribution of the drug. If the supplement is 
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. This proposed requirement is 
provided for in current Sec. Sec. 314.70(g)(4) and 601.12(e).
    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 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.
    Under proposed Sec. 314.70(f), an applicant would be required to 
comply with the patent information requirements under section 505(c)(2) 
of the act. This proposed requirement is identical to the current 
requirement at Sec. 314.70(e).
    Proposed Sec. 314.70(g) would require an applicant claiming 
exclusivity under Sec. 314.108 to include, with the supplemental 
application, information required under Sec. 314.50(j). This proposed 
requirement is identical to the current requirement at Sec. 314.70(f).
    In addition to section 506A of the act, other sections of the act 
authorize FDA to revise Sec. Sec. 314.70 and 601.12. Sections 301 and 
501 of the act (21 U.S.C. 331 and 351) prohibit the manufacture, 
processing, packing, or holding of drugs that do not conform to CGMP; 
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. Sections 301 and 502 of the act (21 U.S.C. 352) prohibit 
false or misleading labeling of drugs, including, under section 201(n) 
of the act (21 U.S.C. 321(n)), failure to reveal material facts 
relating to potential consequences under customary conditions of use; 
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 their labeling. Under section 505 of the act, FDA 
will approve an NDA if the drug is shown to be safe and effective for 
its intended use and if, among other things, the methods used

[[Page 34617]]

in, and the facilities and controls used for, the manufacture, 
processing and packing of the 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.
    The Public Health Service Act (the PHS Act) provides additional 
authority for FDA to revise Sec. 601.12. Section 351(a) of the PHS Act 
(42 U.S.C. 262(a)) provides that license applications for biological 
products may be approved upon a showing that the product is safe, pure, 
and potent and that the manufacturing facility meets standards designed 
to ensure continued safety, purity, and potency of the product. In 
addition, under section 351(b) of the PHS Act, biological products and 
their containers or packages may not be falsely labeled or marked.

V. Conforming Amendments

    The regulations on supplements and changes to an approved 
application or license are cited throughout FDA's regulations. Because 
FDA is proposing to revise these regulations, the agency is taking this 
opportunity to make conforming amendments to 21 CFR parts 5, 206, 250, 
314, 600, and 601 to reflect these proposed regulations. These 
conforming amendments will ensure the accuracy and consistency of the 
regulations.

VI. 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 (Pub. L. 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. Under the Regulatory Flexibility 
Act, if a rule has a significant economic impact on a substantial 
number of small entities, an agency must analyze regulatory options 
that would minimize any significant impact of the rule on small 
entities. Title II of the Unfunded Mandates Reform Act (in section 202) 
requires that agencies prepare a written assessment of anticipated 
costs and benefits before proposing any rule that may result in an 
expenditure in any one year by State, local, and tribal governments, in 
the aggregate, or by the private sector of $100 million (adjusted 
annually for inflation).
    The agency believes that this proposed rule is consistent with the 
regulatory philosophy and principles identified in Executive Order 
12866 and in these two statutes. As shown in the following paragraphs, 
the rule will not be significant as defined by the Executive Order and 
the Unfunded Mandates Reform Act, and the agency certifies that the 
proposed rule will not have a significant economic impact on a 
substantial number of small entities.
    The purpose of the proposed rule is to implement section 506A of 
the act and to reduce the number of manufacturing changes subject to 
supplements requiring FDA approval prior to product distribution. The 
proposed rule would affect all drug manufacturers that submit 
manufacturing supplements and would result in a substantial reduction 
in burdens to applicants making manufacturing changes subject to the 
proposed regulation. The proposed rule would permit earlier 
implementation of the changes and quicker marketing of products 
improved by manufacturing or labeling modifications. Faster 
implementation can result in marked gains in production efficiency, and 
generally reduces the paperwork burden associated with reporting the 
changes to the agency. For example, a report by the Eastern Research 
Group (ERG), an FDA contractor, on the effects of the SUPAC guidance 
for immediate release solid oral dosage forms (SUPAC-IR) found that 
reducing the number of changes that require preapproval gives companies 
greater control over their production resources, which could lead to 
significant net savings to industry (Eastern Research Group, 
Pharmaceutical Industry Cost Savings Through Use of the Scale-Up and 
Post-Approval Guidance for Immediate Release Solid Oral Dosage Forms 
(SUPAC-IR), January 7, 1998, Contract No. 223-94-8301). Such economic 
incentives may encourage manufacturers to improve their products, 
product labeling, and methods of manufacture.
     Due to the multiplicity of products and manufacturing changes, the 
agency has not estimated the total savings to industry as a result of 
this rule, but anticipates that they would increase over time. New 
information and technology will allow a greater number of changes to be 
reported in supplements that do not require prior approval or in annual 
reports. ERG estimated that companies may already have saved $71 
million in 1997 due to the agency's implementation of more flexible 
reporting procedures for chemistry, manufacturing, and control changes. 
This proposed rule would broaden the potential scope of such savings. 
Because the proposal would benefit manufacturers regardless of size and 
impose no additional costs, the agency certifies that this rule will 
not have a significant adverse economic impact on a substantial number 
of small entities.

VII. Paperwork Reduction Act of 1995

    This proposed rule contains collections of information that are 
subject to review by OMB under the Paperwork Reduction Act of 1995 (the 
PRA) (44 U.S.C. 3501-3520). ``Collection of information'' includes any 
request or requirement that persons obtain, maintain, retain, or report 
information to the agency, or disclose information to a third party or 
to the public (44 U.S.C. 3502(3) and 5 CFR 1320.3(c)). The title, 
description, and respondent description of the information collection 
are shown under this section VII with an estimate of the annual 
reporting burden. Included in the estimate is the time for reviewing 
instructions, gathering and maintaining the data needed, and completing 
and reviewing the collection of information.
    FDA invites comments on: (1) Whether the proposed collection of 
information is necessary for 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 an Approved Application.
    Description: The proposed rule would implement the manufacturing 
changes provision of section 116 of the Modernization Act and require 
manufacturers to validate the effect of any manufacturing change on the 
identity, strength, quality, purity, and potency of a drug or 
biological product as those factors relate to the safety or 
effectiveness of the product. The respondent would report the change to

[[Page 34618]]

FDA in one of the following ways depending on the potential for the 
change to have an adverse effect on the safety or effectiveness of the 
product: (1) Changes that have a substantial potential to have an 
adverse effect on a product would be submitted in a supplement 
requiring prior approval by FDA before distribution of the product made 
using the change; (2) changes that have a moderate potential to have an 
adverse effect on a product would be submitted to FDA in a supplement 
not less than 30 days prior to distribution of the product made using 
the change; (3) changes that have a moderate potential to have an 
adverse effect on a product would be submitted to FDA in a supplement 
at the time of distribution of the product made using the change ; and 
(4) changes that have a minimal potential to have an adverse effect on 
a product would be documented by the respondent in the next annual 
report.
    Proposed Sec. Sec. 314.70(a)(2) and 601.12(a)(2) would require the 
holder of an approved application to validate the effects of a 
manufacturing change on the identity, strength, quality, purity, or 
potency of the drug as these factors may relate to the safety or 
effectiveness of the drug before distributing a drug made with the 
change. This proposed requirement implements the statutory requirement 
for information collection under section 506A(a) and (b) of the act 
and, therefore, no burden estimate has been calculated for this 
regulation.
    Proposed Sec. Sec. 314.70(a)(4) and 601.12(a)(4) would require the 
applicant to promptly revise all promotional labeling and advertising 
to make it consistent with any labeling change implemented. The 
transmittal to FDA of advertisements and promotional labeling for drugs 
and biologics is accompanied by Form FDA 2253 and regulated by 
Sec. Sec. 314.81(b)(3)(i) and 601.12(f)(4). This information collection 
is approved by OMB until August 31, 2001, under OMB control number 
0910-0376. Therefore, this requirement is not estimated in Table 1 of 
this document.
    Proposed Sec. 314.70(a)(5) would require that the applicant include 
in each supplement (except for a supplement providing for a change in 
the labeling) a statement certifying that a field copy of the 
supplement has been provided to the applicant's home FDA district 
office. Based on data concerning the number of supplements received by 
the agency, FDA estimates that approximately 4,278 certifications and 
field copies will be submitted annually as required by proposed 
Sec. 314.70(a)(5). FDA estimates that approximately 594 applicants will 
submit these certifications and field copies. Preparation of a field 
copy would involve copying material already prepared for the 
supplement, and FDA estimates that it will take an average of 1 hour 
for applicants to include an additional field copy for FDA.
    Proposed Sec. Sec. 314.70(a)(6) and 601.12(a)(5) would require the 
applicant to include in the cover letter a list of all changes 
contained in the supplement or annual report. Based on data concerning 
the number of supplements and annual reports received by the agency, 
FDA estimates that approximately 11,913 lists of all changes in the 
supplement or annual report will be submitted annually as required by 
proposed Sec. 314.70(a)(6). FDA estimates that approximately 704 
applicants will submit these lists. Because the information required 
would be generated in preparing the supplement or annual report, the 
agency estimates that, under proposed Sec. 314.70(a)(6), it will take 
approximately 1 hour to include a list of changes in a cover letter for 
a supplement or an annual report. FDA estimates that approximately 
2,983 lists of all changes in the supplement or annual report will be 
submitted annually as required by proposed Sec. 601.12(a)(5). FDA 
estimates that approximately 190 applicants will submit these lists. 
Because the information required would be generated in preparing the 
supplement or annual report, the agency estimates that, under proposed 
Sec. 601.12(a)(5), it will take approximately 1 hour to include a list 
of changes in a cover letter for a supplement or an annual report.
    Proposed Sec. 314.70(b) and current Sec. 601.12(b) set forth 
requirements for changes requiring supplement submission and approval 
prior to distribution of the product made using the change (major 
changes). Proposed Sec. 314.70(b)(1) and current Sec. 601.12(b)(1) 
state that 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.
    Under proposed Sec. 314.70(b)(3) and current Sec. 601.12(b)(3), the 
applicant must obtain approval of a supplement from FDA prior to 
distribution of a product made using the change, and the following must 
be contained in the supplement: (i) A detailed description of the 
proposed change; (ii) The product(s) involved; (iii) The manufacturing 
site(s) or area(s) affected; (iv) 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 (validating 
the effects of the change); (v) The data derived from such studies; 
(vi) 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; 
(vii) For sterilization process and test methodologies, relevant 
validation protocols must be provided; and (viii) A reference list of 
relevant standard operating procedures when applicable.
    The changes requiring supplement submission and approval prior to 
distribution of the product made using the change (major changes) are 
listed in proposed Sec. 314.70(b)(2) and current Sec. 601.12(b)(2) 
(including proposed Sec. 601.12(b)(2)(i)): (i) Changes in the 
qualitative or quantitative formulation of the drug, including inactive 
ingredients, or in the specifications provided in the approved 
application; (ii) Changes requiring completion of studies in accordance 
with 21 CFR part 320 to demonstrate the equivalence of the drug to the 
drug as manufactured without the change or to the reference listed 
drug; (iii) 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; (iv) Changes in the synthesis or manufacture of the drug 
substance that may affect the impurity profile and/or the physical, 
chemical, or biological properties of the drug substance; (v) Certain 
changes in labeling; (vi) Changes in a container closure system that 
controls drug delivery or that may affect the impurity profile of the 
drug product; (vii) Changes solely affecting a natural product, a 
recombinant DNA-derived protein/polypeptide product, or a complex or 
conjugate of a drug with a monoclonal antibody for the following: (A) 
Changes in the virus or adventitious agent removal or inactivation 
method(s); (B) Changes in the source material or cell line; and (C) 
Establishment of a new master cell bank or seed; (viii) 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 that application.
    Under proposed Sec. Sec. 314.70(b)(4) and 601.12(b)(4), 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

[[Page 34619]]

hardship on the applicant. Such a supplement and its mailing cover 
should be marked: ``Prior Approval Supplement-Expedited Review 
Requested.''
    Based on data concerning the number of supplements received by the 
agency, FDA estimates that approximately 1,744 supplements will be 
submitted annually under proposed Sec. 314.70(b)(1) and (b)(3). FDA 
estimates that approximately 594 applicants will submit such 
supplements, and that it will take approximately 80 hours to prepare 
and submit to FDA each supplement. FDA estimates that approximately 903 
supplements are submitted annually under Sec. 601.12(b)(1) and (b)(3). 
FDA estimates that approximately 190 applicants submit such 
supplements, and that it takes approximately 80 hours to prepare and 
submit to FDA each supplement. The burden for an applicant's request, 
under proposed Sec. Sec. 314.70(b)(4) and 601.12(b)(4), for FDA to 
expedite its review of a supplement is negligible and has not been 
estimated in Table 1 of this document.
    Proposed Sec. 314.70(c) and current Sec. 601.12(c) set forth 
requirements for changes requiring supplement submission at least 30 
days prior to distribution of the product made using the change 
(moderate changes). Proposed Sec. 314.70(c)(1) and current 
Sec. 601.12(c)(1) state that 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. Under proposed Sec. 314.70(c)(1), the applicant must submit 12 
copies of final printed labeling for all labeling changes.
    Under proposed Sec. 314.70(c)(3) and current Sec. 601.12(c)(1), the 
supplement must set forth 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.'' Under proposed Sec. 314.70(c)(4) and current Sec. 601.12(c)(3), 
distribution of the product made using the change may begin not less 
than 30 days after receipt of the supplement by FDA. The information 
listed previously for proposed Sec. 314.70(b)(3) and current 
Sec. 601.12(b)(3) must be contained in the supplement.
    The changes requiring supplement submission at least 30 days prior 
to distribution of the product made using the change (moderate changes) 
are listed in proposed Sec. 314.70(c)(2) (the changes in 
Sec. 314.70(c)(2)(ii)(A) and (c)(2)(ii)(B) are also listed in current 
Sec. 601.12(c)(2)): (i) A change in the container closure system that 
does not affect the quality of the final drug product; and (ii) Changes 
solely affecting a natural protein product, a recombinant DNA-derived 
protein/polypeptide product or a complex or conjugate of a drug with a 
monoclonal antibody, including: (A) An increase or decrease in 
production scale during finishing steps that involves new or different 
equipment; and (B) 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.
    Based on data concerning the number of supplements received by the 
agency, FDA estimates that approximately 2,754 supplements will be 
submitted annually under proposed Sec. 314.70(c)(1), (c)(3), and 
(c)(4). FDA estimates that approximately 594 applicants will submit 
such supplements, and that it will take approximately 50 hours to 
prepare and submit to FDA each supplement. FDA estimates that 
approximately 255 supplements are submitted annually under 
Sec. 601.12(c)(1) and (c)(3). FDA estimates that approximately 98 
applicants submit such supplements, and that it takes approximately 50 
hours to prepare and submit to FDA each supplement.
    Under proposed Sec. 314.70(c)(6) and current Sec. 601.12(c)(5), FDA 
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 upon receipt by the 
agency of a supplement for the change. These changes include: (i) 
Addition to a specification or changes in the methods or controls to 
provide increased assurance that the drug will have the characteristics 
of identity, strength, quality, purity, or potency that it purports or 
is represented to possess; (ii) 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 or from one container 
closure system to another; (iii) Changes in the labeling to accomplish 
any of the following: (A) To add or strengthen a contraindication, 
warning, precaution, or adverse reaction; (B) To add or strengthen a 
statement about drug abuse, dependence, psychological effect, or 
overdosage; (C) To add or strengthen an instruction about dosage and 
administration that is intended to increase the safe use of the 
product; (D) To delete false, misleading, or unsupported indications 
for use or claims for effectiveness; or (E) Any other changes 
specifically requested by FDA. Under proposed Sec. 314.70(c)(3) and 
current Sec. 601.12(c)(1), the supplement must be labeled 
``Supplement--Changes Being Effected.''
    Based on data concerning the number of supplements received by the 
agency, FDA estimates that approximately 486 supplements will be 
submitted annually under proposed Sec. 314.70(c)(6). FDA estimates that 
approximately 486 applicants will submit such supplements, and that it 
will take approximately 50 hours to prepare and submit to FDA each 
supplement. FDA estimates that approximately 47 supplements are 
submitted annually under Sec. 601.12(c)(5). FDA estimates that 
approximately 34 applicants submit such supplements, and that it takes 
approximately 50 hours to prepare and submit to FDA each supplement.
    Proposed Sec. 314.70(d) and current Sec. 601.12(d) set forth 
requirements for changes to be described in an annual report (minor 
changes). Proposed Sec. 314.70(d)(1) and current Sec. 601.12(d)(1) 
state that 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 
next annual report.
    Under proposed Sec. 314.70(d)(3) and current Sec. 601.12(d)(3) 
(including proposed Sec. 601.12(d)(3)(iii)), the applicant must submit 
in the annual report a list of all products involved; and (i) A 
statement by the holder of the approved application that the effects of 
the change have been validated; (ii) A full description of the 
manufacturing and controls changes, including the manufacturing site(s) 
or area(s) involved; and (iii) The date each change was made, a cross-
reference to relevant validation protocols and/or SOP's, and 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).
     The changes to be described in an annual report (minor changes) 
are listed in proposed Sec. 314.70(d)(2) and current Sec. 601.12(d)(2) 
(including proposed Sec. 601.12(d)(2)(i) through (d)(2)(v) and 
(d)(2)(vii)): (i) Any change made to comply with an official compendium 
that is consistent with FDA requirements and provides increased 
assurance that the drug will have the

[[Page 34620]]

characteristics of identity, strength, quality, purity, or potency that 
it purports or is represented to possess; (ii) The deletion or 
reduction of an ingredient intended to affect only the color of the 
product; (iii) Replacement of equipment with that of the same design 
and operating principles except for equipment used with a natural 
protein product, a recombinant DNA-derived protein/polypeptide product, 
or a complex or conjugate of a drug with a monoclonal antibody; (iv) 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; (v) A change 
within the container closure system for a nonsterile drug product, 
based upon a showing of equivalency to the approved system under a 
protocol approved in the application or published in an official 
compendium; (vi) An extension of an expiration dating period based upon 
full shelf-life data obtained from a protocol approved in the 
application; (vii) 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; (viii) 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; (ix) A change in the labeling concerning the description of 
the drug product or in the information about how the drug is supplied, 
that does not involve a change in the dosage strength or dosage form; 
and (x) An editorial or similar minor change in labeling.
    Based on data concerning the number of supplements and annual 
reports received by the agency, FDA estimates that approximately 6,929 
annual reports will include documentation of certain manufacturing 
changes as required under proposed Sec. 314.70(d)(1) and (d)(3). FDA 
estimates that approximately 704 applicants will submit such 
information, and that it will take approximately 10 hours to prepare 
and submit to FDA the information for each annual report. FDA estimates 
that approximately 227 annual reports include documentation of certain 
manufacturing changes as required under current Sec. 601.12(d)(1) and 
(d)(3). FDA estimates that approximately 166 applicants submit such 
information, and that it takes approximately 10 hours to prepare and 
submit to FDA the information for each annual report. Proposed 
Sec. 314.70(d)(3) and current Sec. 601.12(d)(3) require a statement by 
the applicant that the effects of the change have been validated. This 
information is developed by the applicant to validate the effects of 
the change regarding identity, strength, quality, purity, and potency, 
and is expressly required to be submitted under section 506A(d)(3)(A) 
of the act. Therefore, the burden associated with such collection of 
information is not included in the estimates of Table 1 of this 
document.
    The proposed regulation would reduce the overall number of 
manufacturing changes subject to supplements, particularly those 
requiring FDA approval prior to product distribution. Many changes that 
are currently reported in supplements would be reported in annual 
reports. Supplement submissions contain more burdensome reporting 
requirements than a submission through an annual report. The proposed 
regulation would not increase the number of annual reports but would 
allow applicants to include in an annual report information currently 
required to be reported to the agency in a supplemental application. 
The number of manufacturing changes currently reported in supplements 
that would be reported in annual reports is approximately 1,283.
    Proposed Sec. 314.70(e) and current Sec. 601.12(e) state that an 
applicant may submit one or more protocols describing the specific 
tests and validation studies and acceptable limits to be achieved to 
demonstrate the lack of adverse effect for specified types of 
manufacturing changes on the identity, strength, quality, purity, or 
potency of the drug as these factors may relate to the safety or 
effectiveness of the drug. Any such protocols, or changes to a 
protocol, must be submitted as a supplement requiring approval from FDA 
prior to distribution of a drug produced with the manufacturing change. 
The supplement, if approved, may subsequently justify a reduced 
reporting category for the particular change because the use of the 
protocol for that type of change reduces the potential risk of an 
adverse effect.
    Based on data concerning the number of supplements received by the 
agency, FDA estimates that approximately 50 protocols will be submitted 
annually under proposed Sec. 314.70(e). FDA estimates that 
approximately 50 applicants will submit such protocols, and that it 
will take approximately 20 hours to prepare and submit to FDA each 
protocol. FDA estimates that approximately 20 protocols are submitted 
annually under Sec. 601.12(e). FDA estimates that approximately 14 
applicants submit such protocols, and that it takes approximately 20 
hours to prepare and submit to FDA each protocol.
    Current Sec. 601.12(f) sets forth the requirements for supplement 
submission for labeling changes for biological products. Current 
Sec. 601.12(f)(2)(i)(A) through (f)(2)(i)(D) specify those labeling 
changes for which an applicant must submit a supplement to FDA at the 
time the change is made. Proposed Sec. 601.12(f)(2)(i)(E) would add 
``any other changes specifically requested by FDA'' to these types of 
changes. FDA estimates that approximately 12 labeling supplements are 
submitted annually under current Sec. 601.12(f)(1). FDA estimates that 
approximately 12 applicants submit these supplements, and that it takes 
approximately 40 hours to prepare and submit to FDA each supplement. 
FDA estimates that approximately 10 labeling supplements are submitted 
annually under current Sec. 601.12(f)(2), including those that would be 
submitted under proposed Sec. 601.12(f)(2)(i)(E). FDA estimates that 
approximately 10 applicants submit these supplements, and that it takes 
approximately 20 hours to prepare and submit to FDA each supplement. 
FDA estimates that approximately 100 annual reports for labeling 
changes are submitted under current Sec. 601.12(f)(3). FDA estimates 
that approximately 70 applicants submit these reports, and that it 
takes approximately 10 hours to prepare and submit to FDA each report. 
FDA estimates that approximately 1,495 labeling supplements are 
submitted annually under current Sec. 601.12(f)(4). FDA estimates that 
approximately 61 applicants submit these supplements, and that it takes 
approximately 10 hours to prepare and submit to FDA each supplement.
    Proposed Sec. 314.70(f) states that an applicant must comply with 
the patent information requirements under section 505(c)(2) of the act. 
Proposed Sec. 314.70(g) states that an applicant must include any 
applicable exclusivity information with a supplement as required under 
Sec. 314.50(j). Patent and exclusivity information collection 
requirements are approved by OMB until May 31, 2001, under OMB control 
number 0910-0305. Therefore, this requirement is not estimated in Table 
1 of this document.
    Description of Respondents: Business or other for-profit 
organizations.
    In compliance with section 3507(d) of the PRA (44 U.S.C. 3507(d)), 
the agency has submitted a copy of this proposed rule to OMB for its 
review and approval of these information collections.

[[Page 34621]]

Interested persons are requested to send comments regarding this 
collection of information, including suggestions for reducing this 
burden, to the Office of Information and Regulatory Affairs, OMB 
(address above), Attn: Wendy Taylor, Desk Officer for FDA. Submit 
written comments on the collection of information by July 28, 1999.

                                  Table 1.--Estimated Annual Reporting Burden1
----------------------------------------------------------------------------------------------------------------
                                                  No. of
       21 CFR Section             No. of       Responses per   Total Annual      Hours per        Total Hours
                                Respondents     Respondent       Responses       Response
----------------------------------------------------------------------------------------------------------------
314.70(a)(5)                      594               7           4,278               1               4,278
314.70(a)(6)                      704              17          11,913               1              11,913
314.70(b)(1) and (b)(3)           594               3           1,744              80             139,520
314.70(c)(1),(c)(3), and          594               5           2,754              50             137,700
 (c)(4)
314.70(c)(6)                      486               1             486              50              24,300
314.70(d)(1) and (d)(3)           704              10           6,929              10              69,290
314.70(e)                          50               1              50              20               1,000
601.12(a)(5)                      190              16           2,983               1               2,983
601.12(b)(1) and (b)(3)           190               5             903              80              72,240
601.12(c)(1) and (c)(3)            98               3             255              50              12,750
601.12(c)(5)                       34               1              47              50               2,350
601.12(d)(1) and (d)(3)6            1             227              10           2,270
601.12(e)                          14               1              20              20                 400
601.12(f)(1)                       12               1              12              40                 480
601.12(f)(2)                       10               1              10              20                 200
601.12(f)(3)                       70               1             100              10               1,000
601.12(f)(4)                       61              25           1,495              10              14,950
Total                                                                                             497,624
----------------------------------------------------------------------------------------------------------------
\1\There are no capital costs or operating and maintenance costs associated with this collection of information.

VIII. Environmental Impact

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

IX. Request for Comments

    Interested persons may, on or before September 13, 1999, submit to 
the Dockets Management Branch (address above) written comments 
regarding this proposal. 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. Submit written 
comments on the information collection requirements as described in 
paragraph VII of this document by July 28, 1999.

List of Subjects

 21 CFR Part 5

    Authority delegations (Government agencies), Imports, Organization 
and functions (Government agencies).

 21 CFR Parts 206 and 250

    Drugs.

21 CFR Part 314

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

21 CFR Part 600

    Biologics, Reporting and recordkeeping requirements.

21 CFR Part 601

    Administrative practice and procedure, Biologics, Confidential 
business information.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR parts 5, 206, 250, 314, 600, and 601 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-1; 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.


Sec. 5.80  [Amended]

    2. Section 5.80 Approval of new drug applications and their 
supplements is amended in the first sentence of paragraphs (d) and (f) 
by removing the phrase ``Sec. Sec. 314.70(b)(1), (b)(2)(ii) through 
(b)(2)(x), (c)(1), and (c)(3)'' and by adding in its place the phrase 
``Sec. 314.70(b)(1), (b)(2)(i) excluding changes in qualitative or 
quantitative formulation, (b)(2)(iii), (b)(2)(iv), (b)(2)(vi), 
(b)(2)(vii), (c)(2)(i), (c)(2)(ii), (c)(6)(i), and (c)(6)(ii)''; and in 
the first sentence of paragraph (e) by removing the phrase 
``Sec. Sec. 314.70(b)(3) and (c)(2)(i) through (c)(2)(iv)'' and by 
adding in its place the phrase ``Sec. 314.70(b)(2)(v) and 
(c)(6)(iii)''.

PART 206--IMPRINTING OF SOLID ORAL DOSAGE FORM DRUG PRODUCTS FOR 
HUMAN USE

    3. The authority citation for 21 CFR part 206 is revised to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 355, 371; 42 U.S.C. 
262.


Sec. 206.10  [Amended]

    4. Section 206.10 Code imprint required is amended in the first 
sentence of paragraph (b) by removing the phrase 
``Sec. 314.70(b)(2)(xi) or (b)(2)(xii)'' and by adding in its place the 
phrase ``Sec. 314.70(b)''.

PART 250--SPECIAL REQUIREMENTS FOR SPECIFIC HUMAN DRUGS

    5. The authority citation for 21 CFR part 250 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 336, 342, 352, 353, 355, 361(a), 
362(a) and (c), 371, 375(b).

[[Page 34622]]

Sec. 250.250  [Amended]

    6. Section 250.250 Hexachlorophene, as a component of drug and 
cosmetic products is amended in the last sentence of paragraph 
(c)(4)(ii) by removing the phrase ``Sec. 314.70(c)(2)'' and by adding 
in its place the phrase ``Sec. 314.70(c)(6)(iii)''.

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG

    7. The authority citation for 21 CFR part 314 is revised to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356a, 371, 
374, 379e.

    8. Section 314.3 is amended in paragraph (b) by alphabetically 
adding the definitions for ``Specification'' and ``Validate the effects 
of the change'' to read as follows:


Sec. 314.3  Definitions.


* * * * *
    (b) * * *
    Specification means 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 materials. For the purpose of 
this definition, acceptance criteria means numerical limits, ranges, or 
other criteria for the tests described.
* * * * *
    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 drug as these factors relate to the safety or 
effectiveness of the drug.
    9. Section 314.50 is amended in paragraph (d)(1)(ii)(b) by removing 
the phrase ``specifications and test procedures'' and by adding in its 
place the word ``specification''; in paragraph (d)(1)(v) by removing 
the phrase ``Except for a foreign applicant, the'' and by adding in its 
place the word ``The''; in paragraph (d)(3)(i) by adding the word 
``procedures'' after the word ``analytical''; in paragraph (d)(3)(ii) 
by removing the phrases ``specifications or analytical methods'' and 
``specification or analytical methods'' each time they appear and by 
adding in their places the phrase ``tests, analytical procedures, and 
acceptance criteria''; in paragraph (d)(4)(iv) by removing the word 
``methods'' and by adding in its place the word ``procedures''; in the 
last sentence of paragraph (e)(1) introductory text and in the first 
sentence of paragraph (e)(2)(i) by removing the word ``methods'' each 
time it appears and by adding in its place the word ``procedures''; and 
by revising the first two sentences of paragraphs (d)(1)(i) and 
(d)(1)(ii)(a) to read as follows:


Sec. 314.50  Content and format of an application.

* * * * *
    (d) * * *
    (1) * * *
    (i) Drug substance. A full description of the drug substance 
including its physical and chemical characteristics and stability; the 
name and address of its manufacturer; the method of synthesis (or 
isolation) and purification of the drug substance; the process controls 
used during manufacture and packaging; and the specifications necessary 
to ensure the identity, strength, quality, and purity of the drug 
substance and the bioavailability of the drug products made from the 
substance, including, for example, tests, analytical procedures, and 
acceptance criteria relating to stability, sterility, particle size, 
and crystalline form. The application may provide additionally for the 
use of alternatives to meet any of these requirements, including 
alternative sources, process controls, and analytical procedures. * * *
    (ii)(a) Drug product. A list of all components used in the 
manufacture of the drug product (regardless of whether they appear in 
the drug product) and a statement of the composition of the drug 
product; the specifications for each component; the name and address of 
each manufacturer of the drug product; a description of the 
manufacturing and packaging procedures and in-process controls for the 
drug product; the specifications necessary to ensure the identity, 
strength, quality, purity, potency, and bioavailability of the drug 
product, including, for example, tests, analytical procedures, and 
acceptance criteria relating to sterility, dissolution rate, containers 
and closure systems; and stability data with proposed expiration 
dating. The application may provide additionally for the use of 
alternatives to meet any of these requirements, including alternative 
components, manufacturing and packaging procedures, in-process 
controls, and analytical procedures. * * *
* * * * *


Sec. 314.60  [Amended]

    10. Section 314.60 Amendments to an unapproved application is 
amended in paragraph (c) by removing the phrase ``, other than a 
foreign applicant,''.
     11. Section 314.70 is revised to read as follows:


Sec. 314.70  Supplements and other changes to an approved application.

    (a) Changes to an approved application. (1) The applicant shall 
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 shall notify FDA about 
it in a supplement under paragraph (b) or (c) of this section or by 
inclusion of the information in the annual report to the application 
under paragraph (d) of this section.
    (2) The holder of an approved application under section 505 of the 
act shall validate the effects of the change on the identity, strength, 
quality, purity, or potency of the drug as these factors may relate to 
the safety or effectiveness of the drug before distributing a drug made 
with a manufacturing change.
    (3) Notwithstanding the requirements of paragraphs (b) and (c) of 
this section, an applicant shall 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 in an annual report).
    (4) The applicant shall promptly revise all promotional labeling 
and advertising to make it consistent with any labeling change 
implemented in accordance with this section.
    (5) Except for a supplement providing for a change in the labeling, 
the applicant shall include in each supplemental application providing 
for a change under paragraph (b) or (c) of this section a statement 
certifying that a field copy of the supplement has been provided to the 
applicant's home FDA district office.
    (6) A supplement or annual report shall include in the cover letter 
a list of all changes contained in the supplement or annual report.
    (b) Changes requiring supplement submission and approval prior to 
distribution of the product made using the change (major changes). (1) 
A supplement shall 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.

[[Page 34623]]

    (2) These changes include, but are not limited to:
    (i) Except as provided in paragraphs (c) and (d) of this section, 
changes in the qualitative or quantitative formulation of the drug, 
including inactive ingredients, or in the specifications provided in 
the approved application;
    (ii) Changes requiring completion of studies in accordance with 
part 320 of this chapter to demonstrate the equivalence of the drug to 
the drug as manufactured without the change or to the reference listed 
drug;
    (iii) 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;
    (iv) Changes in the synthesis or manufacture of the drug substance 
that may affect the impurity profile and/or the physical, chemical, or 
biological properties of the drug substance;
    (v) Changes in labeling, except those described in paragraphs 
(c)(6)(iii), (d)(2)(ix), or (d)(2)(x) of this section;
    (vi) Changes in a container closure system that controls drug 
delivery or that may affect the impurity profile of the drug product;
    (vii) Changes solely affecting a natural product, a recombinant 
DNA-derived protein/polypeptide product, or a complex or conjugate of a 
drug with a monoclonal antibody for the following:
    (A) Changes in the virus or adventitious agent removal or 
inactivation method(s);
    (B) Changes in the source material or cell line; and
    (C) Establishment of a new master cell bank or seed.
    (viii) 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 that application.
    (3) The applicant must obtain approval of a supplement from FDA 
prior to distribution of a product made using a change under paragraph 
(b) of this section. Except for submissions under paragraph (e) of this 
section, the following shall be contained in the supplement:
    (i) A detailed description of the proposed change;
    (ii) The product(s) involved;
    (iii) The manufacturing site(s) or area(s) affected;
    (iv) 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 (validating the effects of the 
change);
    (v) The data derived from such studies;
    (vi) 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 shall be provided in 
addition to the requirements in paragraphs (b)(3)(iv) and (b)(3)(v) of 
this section; and
    (vii) For sterilization process and test methodologies, relevant 
validation protocols shall be provided in addition to the requirements 
in paragraphs (b)(3)(iv) and (b)(3)(v) of this section; and
    (viii) A reference list of relevant standard operating procedures 
(SOP's) when applicable.
    (4) 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.''
    (c) Changes requiring supplement submission at least 30 days prior 
to distribution of the drug product made using the change (moderate 
changes). (1) A supplement shall 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. If 
the change concerns labeling, include 12 copies of final printed 
labeling.
    (2) These changes include, but are not limited to:
    (i) A change in the container closure system that does not affect 
the quality of the final drug product; and
    (ii) Changes solely affecting a natural protein product, a 
recombinant DNA-derived protein/polypeptide product or a complex or 
conjugate of a drug with a monoclonal antibody, including:
    (A) An increase or decrease in production scale during finishing 
steps that involves new or different equipment; and
    (B) 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.
    (3) A supplement submitted under paragraph (c)(1) 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 
shall be labeled ``Supplement--Changes Being Effected in 30 Days'' or, 
if applicable under paragraph (c)(6) of this section, ``Supplement--
Changes Being Effected.''
    (4) Pending approval of the supplement by FDA, except as provided 
in paragraph (c)(6) of this section, distribution of the product made 
using the change may begin not less than 30 days after receipt of the 
supplement by FDA. The information listed in paragraphs (b)(3)(i) 
through (b)(3)(viii) of this section shall be contained in the 
supplement.
    (5) The applicant shall 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:
    (i) The change requires approval prior to distribution of the 
product in accordance with paragraph (b) of this section; or
    (ii) Any of the information required under paragraph (c)(4) of this 
section is missing; the applicant shall not distribute the product made 
using the change until FDA determines that compliance with this section 
is achieved.
    (6) The agency may designate a category of changes for the purpose 
of providing that, in the case of a change in such category, the holder 
of an approved application may commence distribution of the drug 
involved upon receipt by the agency of a supplement for the change. 
These changes include, but are not limited to:
    (i) Addition to a specification or changes in the methods or 
controls to provide increased assurance that the drug will have the 
characteristics of identity, strength, quality, purity, or potency that 
it purports or is represented to possess;
    (ii) 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 or from one container closure 
system to another;
    (iii) Changes in the labeling to accomplish any of the following:
    (A) To add or strengthen a contraindication, warning, precaution, 
or adverse reaction;
    (B) To add or strengthen a statement about drug abuse, dependence, 
psychological effect, or overdosage;
    (C) To add or strengthen an instruction about dosage and 
administration that is intended to increase the safe use of the 
product;
    (D) To delete false, misleading, or unsupported indications for use 
or claims for effectiveness; or

[[Page 34624]]

    (E) Any other changes specifically requested by FDA.
    (7) If the agency disapproves the supplemental application, it may 
order the manufacturer to cease distribution of the drug products made 
with the manufacturing change.
    (d) Changes to be described in an annual report (minor changes). 
(1) 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 shall be documented by the applicant in 
the next annual report in accordance with Sec. 314.81(b)(2).
    (2) These changes include, but are not limited to:
    (i) Any change made to comply with an official compendium that is 
consistent with FDA requirements and provides increased assurance that 
the drug will have the characteristics of identity, strength, quality, 
purity, or potency that it purports or is represented to possess;
    (ii) The deletion or reduction of an ingredient intended to affect 
only the color of the product;
    (iii) Replacement of equipment with that of the same design and 
operating principles except for equipment used with a natural protein 
product, a recombinant DNA-derived protein/polypeptide product, or a 
complex or conjugate of a drug with a monoclonal antibody;
    (iv) 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;
    (v) A change within the container closure system for a nonsterile 
drug product, based upon a showing of equivalency to the approved 
system under a protocol approved in the application or published in an 
official compendium;
    (vi) 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;
    (vii) 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;
    (viii) 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;
    (ix) A change in the labeling concerning the description of the 
drug product or in the information about how the drug is supplied, that 
does not involve a change in the dosage strength or dosage form; and
    (x) An editorial or similar minor change in labeling.
    (3) For changes under this category, the applicant is required to 
submit in the annual report a list of all products involved; and
    (i) A statement by the holder of the approved application that the 
effects of the change have been validated;
    (ii) A full description of the manufacturing and controls changes, 
including the manufacturing site(s) or area(s) involved; and
    (iii) The date each change was made, a cross-reference to relevant 
validation protocols and/or SOP's, and 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).
    (e) Protocols. 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 drug as these factors may relate to 
the safety or effectiveness of the drug. Any such protocols, or changes 
to a protocol, shall be submitted as a supplement requiring approval 
from FDA prior to distribution of a drug produced with the 
manufacturing change. The supplement, if approved, may subsequently 
justify a reduced reporting category for the particular change because 
the use of the protocol for that type of change reduces the potential 
risk of an adverse effect.
    (f) Patent information. The applicant shall comply with the patent 
information requirements under section 505(c)(2) of the act.
    (g) Claimed exclusivity. If an applicant claims exclusivity under 
Sec. 314.108 upon approval of a supplement for change to its previously 
approved drug product, the applicant shall include with its supplement 
the information required under Sec. 314.50(j).


Sec. 314.81  [Amended]

    12. Section 314.81 Other postmarketing reports is amended in 
paragraph (b)(1)(ii) by removing the word ``specifications'' and by 
adding in its place the word ``specification''.


Sec. 314.94  [Amended]

    13. Section 314.94 Content and format of an abbreviated application 
is amended in the second sentence of paragraph (d)(2) by removing the 
word ``methods'' each time it appears and by adding in its place the 
word ``procedures''.


Sec. 314.410  [Amended]

    14. Section 314.410 Imports and exports of new drugs is amended in 
paragraph (b)(2) by removing the word ``specifications'' and by adding 
in its place the word ``specification''.


Sec. 314.430  [Amended]

    15. Section 314.430 Availability for public disclosure of data and 
information in an application or abbreviated application is amended in 
paragraph (e)(6) by removing the word ``method'' and by adding in its 
place the word ``procedure''.

PART 600--BIOLOGICAL PRODUCTS: GENERAL

    16. The authority citation for 21 CFR part 600 is revised to read 
as follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 356a, 360, 360i, 
371, 374; 42 U.S.C. 216, 262, 263, 263a, 264, 300aa-25.

    17. Section 600.3 is amended by adding paragraphs (hh) and (ii) to 
read as follows:


Sec. 600.3  Definitions.

* * * * *
    (hh) Specification, as used in Sec. 601.12 of this chapter, means 
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 materials. For the purpose of this definition, 
acceptance criteria means numerical limits, ranges, or other criteria 
for the tests described.
    (ii) Validate the effects of the change, as used in Sec. 601.12 of 
this chapter, means to assess 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.

PART 601--LICENSING

    18. The authority citation for 21 CFR part 601 is revised to read 
as follows:

    Authority: 15 U.S.C. 1451-1561; 21 U.S.C. 321, 351, 352, 353, 
355, 356a, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C. 216, 
241, 262, 263.


[[Page 34625]]


    19. Section 601.12 is amended by revising paragraphs (a), 
(b)(2)(i), (d)(2)(i) through (d)(2)(v), and (d)(2)(vii); by adding 
paragraph (b)(4), (c)(6), (d)(3)(iii), and (f)(2)(i)(E); and by 
removing and reserving paragraph (c)(2)(i) to read as follows:


Sec. 601.12  Changes to an approved application.

    (a) General. (1) As provided by this section, an applicant shall 
inform the Food and Drug Administration (FDA) about each change in the 
product, production process, quality controls, equipment, facilities, 
responsible personnel, or labeling established in the approved license 
application(s).
    (2) Before distributing a product made using a change, an applicant 
shall validate the effects of the change and demonstrate through 
appropriate validation and/or other clinical and/or nonclinical 
laboratory studies the lack of adverse effect of the change on the 
identity, strength, quality, purity, or potency of the product as they 
may relate to the safety or effectiveness of the product.
    (3) Notwithstanding the requirements of paragraphs (b), (c), and 
(f) of this section, an applicant shall 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 in an annual report).
    (4) The applicant shall promptly revise all promotional labeling 
and advertising to make it consistent with any labeling change 
implemented in accordance with this section.
    (5) A supplement or annual report shall include in the cover letter 
a list of all changes contained in the supplement or annual report.
    (b) * * *
    (2) * * *
    (i) Except as provided in paragraphs (c) and (d) of this section, 
changes in the qualitative or quantitative formulation, including 
inactive ingredients, or in the specifications provided in the approved 
application;
* * * * *
    (4) 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.''
    (c) * * *
    (2) * * *
    (i) [Reserved]
* * * * *
    (6) If the agency disapproves the supplemental application, it may 
order the manufacturer to cease distribution of the products made with 
the manufacturing change.
    (d) * * *
    (2) * * *
    (i) Any change made to comply with an official compendium that is 
consistent with FDA requirements and provides increased assurance that 
the drug will have the characteristics of identity, strength, quality, 
purity, or potency that it purports or is represented to possess;
    (ii) The deletion or reduction of an ingredient intended only to 
affect the color of the product, except that a change intended only to 
affect Blood Grouping Reagents requires supplement submission and 
approval prior to distribution of the product made using the change in 
accordance with the requirements set forth in paragraph (b) of this 
section;
    (iii) 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;
    (iv) A change within the container closure system for a nonsterile 
drug product, based upon a showing of equivalency to the approved 
system under a protocol approved in the application or published in an 
official compendium;
    (v) 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;
* * * * *
    (vii) 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.
    (3) * * *
    (iii) A statement by the holder of the approved application or 
license that the effects of the change have been validated.
* * * * *
    (f) * * *
    (2) * * *
    (i) * * *
    (E) Any other changes specifically requested by FDA.
* * * * *

    Dated: June 18, 1999.
William K. Hubbard,
Acting Deputy Commissioner for Policy.
[FR Doc. 99-16191 Filed 6-25-99; 8:45 am]
BILLING CODE 4160-01-F