[Federal Register Volume 62, Number 142 (Thursday, July 24, 1997)]
[Rules and Regulations]
[Pages 39890-39903]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-19427]



[[Page 39889]]

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Part II





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



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21 CFR Part 314, et al.



Changes to an Approved Application;



Guidance for Industry: Changes to an Approved Application For Specified 
Biotechnology and Specified Synthetic Biological Products and 
Biological Products; Final Rule and Notices

  Federal Register / Vol. 62, No. 142 / Thursday, July 24, 1997 / Rules 
and Regulations  

[[Page 39890]]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 314, 600, 601, 610, and 640

[Docket No. 95N-0329]
RIN 0910-AA57


Changes to an Approved Application

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending the 
biologics regulations for reporting changes to an approved application 
in order to reduce unnecessary reporting burdens on applicants holding 
licenses approved by the Center for Biologics Evaluation and Research 
(CBER) under the Public Health Service Act (the PHS Act) to manufacture 
biological products. In addition, FDA is amending the corresponding 
drug regulations for submitting supplements and reporting changes to an 
application approved under the Federal Food, Drug, and Cosmetic Act 
(the act) for specified biotechnology products reviewed in the Center 
for Drug Evaluation and Research (CDER) to harmonize the drugs and 
biologics regulations. This final rule is part of FDA's continuing 
effort to achieve the objectives of the President's ``Reinventing 
Government'' initiatives.

DATES: Effective Date: The regulation is effective October 7, 1997.
    Compliance Date: Submit initial annual reports required by 
Secs. 314.70(g)(3) and 601.12(d) and (f)(3) within 60 days of the first 
anniversary date of the approval of the application of the product 
occurring on or after January 20, 1998.
FOR FURTHER INFORMATION CONTACT:
    Steven F. Falter, Center for Biologics Evaluation and Research 
(HFM-630), Food and Drug Administration, 1401 Rockville Pike, suite 
200N, Rockville, MD 20852-1448, 301-594-3074,
    or
    Yuan Yuan Chiu, Center for Drug Evaluation and Research (HFD-800), 
Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 
301-443-0260.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of January 29, 1996 (61 FR 2739), FDA 
proposed to amend the biologics regulations in Sec. 601.12 (21 CFR 
601.12) for reporting to FDA changes to an approved application in 
order to reduce unnecessary reporting burdens on applicants holding 
licenses approved by CBER under the PHS Act to manufacture biological 
products. Similarly, FDA also proposed to amend the corresponding 
regulations applicable to drugs in Sec. 314.70 (21 CFR 314.70) for 
reporting changes to an approved application for certain biotechnology 
products (identified in the proposed rule as ``well-characterized 
biotechnology products'') to reduce unnecessary reporting burdens and 
to harmonize the regulations applicable to biotechnology products. FDA 
issued the proposed rule as part of its response to several mandates to 
reduce the burdens associated with government regulation. These 
mandates include, the President's memorandum of March 4, 1995, 
announcing the ``Regulatory Reinvention Initiative;'' the President's 
memorandum of April 21, 1995, ``Regulatory Reform--Waiver of Penalties 
and Reduction of Reports;'' the April 1995 publication, ``Reinventing 
Drug and Medical Device Regulations;'' and the November 1995, 
Presidential National Performance Review report, ``Reinventing the 
Regulation of Drugs Made From Biotechnology.'' Each included elements 
intended to reduce regulatory burdens while assuring the continued 
safety and effectiveness of regulated products.
    This final rule is part of FDA's continuing effort to achieve the 
objectives of the President's ``Reinventing Government'' initiative to 
harmonize regulations administered by CDER and CBER in FDA, to reduce 
unnecessary burdens, and to improve the consistency in the processes 
for complying with FDA's regulations without diminishing public health 
protection.

II. Proposed Rule

    In the proposed rule of January 29, 1996, FDA proposed that for 
reporting purposes changes to an approved application be divided into 
three categories. In Sec. 601.12(b), FDA proposed for a change that has 
a substantial potential to have an adverse effect on the safety, 
purity, potency, or effectiveness of the product, that a supplement to 
the approved application be submitted and that the product manufactured 
after the change not be distributed until the supplement is approved. 
In Sec. 601.12(c), FDA proposed for a change that has a moderate 
potential to have an adverse effect on the safety, purity, potency, or 
effectiveness of the product, that FDA be notified in writing of a 
change not less than 30 days before distribution of the product made 
using the change. Proposed Sec. 601.12(c)(2) provided that if any 
specified information in the notification is missing or if the type of 
change requires submission of a supplement and approval by FDA before 
implementation, the product may not be distributed until compliance 
with the requirements is achieved. In proposed Sec. 601.12(d), changes 
that have a minimal potential to have an adverse effect on the safety, 
purity, potency, or effectiveness of the product would be reported in 
an annual report, submitted each year within 60 days of the anniversary 
date of the approval of the application. The information that would be 
included in the annual report was specified in proposed 
Sec. 601.12(d)(1). In Sec. 601.12(e), FDA proposed regulations similar 
to those discussed above applicable to changes in labeling. For 
clarity, FDA proposed in 21 CFR 600.3 to add definitions for 
``amendment'' and ``supplement'' as the terms apply to license 
applications for biological products.
    For consistency, FDA also proposed to amend the corresponding 
regulations applicable to drugs in Sec. 314.70 for submitting 
supplements and reporting changes to an application approved under the 
act for certain biotechnology products reviewed in CDER (identified in 
the proposed rule as ``well-characterized biotechnology products'').
    In the same issue of the Federal Register of January 29, 1996, (61 
FR 2748 and 2749), FDA made available and invited public comment on two 
draft guidance documents entitled, ``Changes to an Approved Application 
for Well-Characterized Therapeutic Recombinant DNA-Derived and 
Monoclonal Antibody Biotechnology Products'' and ``Changes to an 
Approved Application.'' The draft guidance documents were intended to 
assist applicants in determining how they should report changes to an 
approved application under the revised regulations. Elsewhere in this 
issue of the Federal Register, FDA is announcing the availability of 
final guidance documents, revised from those proposed as a result of 
public comment, which are intended to aid applicants in complying with 
the requirements of this final rule.
    In the Federal Register of March 28, 1996 (61 FR 13793), FDA 
announced a public meeting, held on April 19, 1996, to discuss and 
gather information and views on the proposed rule and draft guidance 
documents. A transcript of the public meeting is on file in the public 
docket identified in the heading of this

[[Page 39891]]

document at Dockets Management Branch (HFA-305), Food and Drug 
Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857.

III. Highlights and Summary of Changes in the Final Rule

    Under the proposed rule, an applicant would be required to report a 
change by one of three mechanisms, depending on the potential for the 
change to have an adverse effect on the safety, purity, potency, or 
effectiveness of the product. Similarly, the final rule will require 
reporting of changes under one of three mechanisms, depending on the 
potential for the change to have an adverse effect on the ``identity, 
strength, quality, purity, or potency of the product, as they may 
relate to the safety or effectiveness of the product'' (hereinafter 
referred to in the document as ``the safety or effectiveness of the 
product'').
    The scope of applicability of the changes to Sec. 314.70 is being 
revised to identify the specific products, i.e., recombinant 
deoxyribonucleic acid (DNA)-derived protein/polypeptide products and 
complexes or conjugates of drugs with monoclonal antibodies regulated 
under the act, to which new Sec. 314.70(g) applies. Monoclonal 
antibodies for in vivo use complexed or conjugated with 
radiopharmaceuticals or toxins would be covered by Sec. 601.12 of the 
final rule.
    Some changes in each category are identified in the final rule. 
Several of these changes differ from those changes identified in the 
proposed rule. Some of these changes were previously discussed in the 
draft guidance documents as FDA's interpretation of the types of 
changes FDA believed would fall into each category. Based on comments 
received, they are now included in the final rule to provide added 
clarity as to the types of changes which have a substantial, moderate, 
or minimal potential to have an adverse effect on the safety or 
effectiveness of a product.
    The final rule provides for the use of a protocol, sometimes called 
a ``comparability protocol,'' which would describe the specific tests 
and validation studies and acceptable limits to be achieved to 
demonstrate the lack of adverse effect for specified types of changes 
on the safety or effectiveness of the product. Upon approval of the 
protocol, FDA may determine that certain changes evaluated in 
accordance with the protocol may be reported by a less burdensome 
means; for example, a change generally requiring preapproval by FDA 
could be made and the product distributed 30 days after receipt by FDA 
of the supplement reporting the change. For a change normally requiring 
a 30-day wait, use of the approved protocol could justify distribution 
at the time of receipt of the supplement by FDA. An approved 
comparability protocol may also be used, in some cases, to reduce the 
reporting category from requiring a 30-day supplement submission to an 
annual report submission.
    For those changes that have a moderate potential to have an adverse 
effect on the safety or effectiveness of the product, the final rule 
will require the submission of a supplement subject to FDA approval, 
and the product made using the change may be distributed not less than 
30 days after receipt of the supplement by FDA; or, in some cases, the 
product made using the change may be distributed immediately upon 
receipt of the supplement by FDA.
    Similar to the proposed rule, changes that have a minimal potential 
to have an adverse effect on the safety or effectiveness of the product 
will be reported in an annual report, submitted within 60 days of the 
first year of date of approval of the application. The final rule also 
allows an applicant holding a license under section 351 of the PHS Act 
to request FDA approval to submit an annual report on a date other than 
the first year so that annual reports for multiple products may be 
combined in a single annual report submission.
    The requirements for reporting changes to the labeling for 
biological products are basically unchanged from the proposed rule. One 
clarification is the form to be used for submission of advertisements 
and promotional labeling for biological products. Form FDA-2253 
(Transmittal of Advertisements and Promotional Labeling for Drugs for 
Human Use), the form specified in Sec. 314.81(b)(3) (21 CFR 
314.81(b)(3)), is currently under revision by the agency. When final, 
it will be used for both drug and biological products for submission of 
advertisements and promotional labeling. The final rule now states that 
``Form FDA-2567 (Transmittal of Labels and Circulars) or an equivalent 
form shall be used.'' In the future, FDA intends that a revised Form 
FDA-2253 will be used instead of Form FDA-2567. A future Federal 
Register notice will announce the availability of the revised Form FDA-
2253.
    The final rule includes a conforming amendment to Sec. 610.9 (21 
CFR 610.9) for biological products subject to licensing, so that 
changes to methods and processes equivalent to those specified in the 
regulations may be submitted in accordance with Sec. 601.12 in the 
final rule. Similarly, FDA is revising Sec. 640.120 (21 CFR 640.120) so 
that an exception or alternative to the regulations applicable to 
blood, blood components, or blood products may be submitted, for 
licensed products, in accordance with Sec. 601.12.
    Other minor changes to improve the clarity and consistency of the 
regulations are also included throughout the final rule.

IV. Responses to Comments

    FDA provided 90 days for the submission of written comments on the 
proposed rule. FDA also invited the submission of written comments at 
the public meeting of April 19, 1996. To ensure that there was adequate 
time for the submission of written comments resulting from the public 
meeting, as announced in the notice of the public meeting, FDA extended 
the comment period an additional 8 days, providing 98 days for public 
comment.
    The transcript of the public meeting, written comments to the 
proposed rule, and comments submitted at or after the public meeting 
are on file in the Dockets Management Branch (address above).
    FDA received eleven letters of comment in response to the proposed 
rule, including one letter filed in response to one of the guidance 
documents but which includes comments pertaining to the proposed rule. 
Comments received and FDA's responses to the comments are discussed 
below.
    1. Two comments on proposed Sec. 314.70(g) recommended that the 
term ``well-characterized biotechnology product'' be broadened to 
include additional products, consistent with the definition proposed by 
the Pharmaceutical Research and Manufacturers of America.
    FDA has determined that it is more appropriate to clearly specify 
products covered by the final rule than to use a general term such as 
``well-characterized biotechnology products.'' As proposed, 
Sec. 314.70(g) would have applied only to those ``well-characterized 
biotechnology products'' which are regulated as new drugs, rather than 
as biologics. FDA has determined that defining such products is 
difficult and no longer uses the term in this or other regulations (see 
the final rule, Elimination of Establishment License Application for 
Specified Biotechnology and Specified Synthetic Biological Products (61 
FR 24227, May 14, 1996), concerning appropriate terminology for these 
products). To clarify the regulation, FDA is amending Sec. 314.70(g) in 
the final rule to identify the specific products to which paragraph (g) 
applies; i.e., recombinant DNA-derived protein/

[[Page 39892]]

 polypeptide products or complexes and conjugates of drugs with 
monoclonal antibodies (where the primary mode of action is due to the 
drug). For all other drug products, including synthetic peptides and 
antisense nucleotides, the applicant will continue to report changes as 
provided in Sec. 314.70(a) through (f). For monoclonal antibodies 
complexed or conjugated with radiopharmaceuticals or toxins, changes to 
approved applications will be reported under Sec. 601.12.
    2. Three comments requested additional clarification of what 
constitutes a ``substantial,'' ``moderate,'' and ``minimal'' potential 
to have an adverse effect on the product. The comments stated that 
further definition of the risks that are of concern to FDA are 
necessary to understand the regulation and that such clarification was 
preferable to providing exhaustive lists of examples of changes in 
agency guidance.
    The regulations in the final rule apply to many types of changes 
for a broad spectrum of products, including many biotechnology 
products, vaccines, blood and blood components, and other biological 
products. The regulations will apply to products that are currently 
experimental or in the conceptual stages of development, which may have 
special concerns that FDA cannot, at this time, anticipate. The 
regulations are written to accommodate the many types of changes for 
such a broad range of products.
    In addition, there is a need to preserve flexibility in the 
regulations to ensure that the least burdensome means for reporting 
changes are made available. FDA believes that this flexibility will 
ensure the continued improvement 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 an 
adverse effect on the safety or effectiveness of the product. 
Conversely, a change now considered, for example, to have a moderate 
potential to have an adverse effect on the safety or effectiveness of 
the product may, based on information not available at this time, be 
later determined by the agency to have a substantial potential to have 
an adverse effect on a product.
    FDA agrees there is a need to clarify the regulations to help 
identify those changes which have a substantial, moderate, or minimal 
potential to have an adverse effect on the safety or effectiveness of 
the product. In this regard, FDA has included examples of specific 
changes in the final rule in order to further clarify the types of 
changes that fall into each category and to provide further 
predictability about the application of the rule.
    Many factors should be considered in determining whether a change 
has a substantial, moderate, or minimal potential to have an adverse 
effect on the safety or effectiveness of the product. For example, the 
level of knowledge about the product and its active components may 
affect the ability to assess the effect of a change. The type of change 
being made will also contribute to the risk of the change having an 
adverse effect. Some manufacturing changes have a greater potential to 
cause unwanted or unexpected changes to the product which may be 
difficult to assess by merely testing to specifications. The type of 
product is also a factor to consider in determining the potential risk 
of an adverse effect on the product. Some products can be adversely 
affected by small changes which may cause larger effects even though 
the changes may seem to be low risk. For example, a change in passage 
number for a live virus vaccine could affect the safety of the vaccine 
and this type of change may be difficult to assess.
    Therefore, defining ``substantial,'' ``moderate,'' and ``minimal'' 
in the regulations with such specificity that they exhaustively 
describe all of the many individual changes that may occur is not 
feasible. However, as FDA gains experience in the use of this rule, it 
will consider whether to propose additional revisions to further 
clarify how to determine the appropriate submission for a change to an 
approved application.
    At this time, FDA is clarifying the final regulations in several 
ways while providing adequate flexibility. The revisions are as 
follows:
    a. Clarification of wording. FDA is amending the final rule by 
specifying a change in quality controls as a type of change within the 
scope of reporting provisions of the final rule. Similarly, for 
purposes of clarity and consistency, FDA is including in 
Sec. 601.12(a), (b)(1), (c)(1), and (d)(1) a change in responsible 
personnel as subject to the requirements of the final rule. 
``Responsible personnel'' was inadvertently included in only some, but 
not all, of the appropriate parts of the proposed rule.
    FDA is further amending the final rule to specify that the 
mechanism for reporting a change is based on the degree of potential of 
the change ``to have an adverse effect on the identity, strength, 
quality, purity, or potency of the product as they may relate to the 
safety or effectiveness of the product.'' ``Identity, strength, 
quality, purity, and potency'' are all elements that are assessed in 
determining the safety or effectiveness of the product. In addition, 
FDA is adding the term ``major changes'' to the headings of 
Secs. 314.70(g)(1) and 601.12(b), and ``minor changes'' to the headings 
of Secs. 314.70(g)(3) and 601.12(d), in order to further clarify the 
types of changes which would fall into each category.
    b. Inclusion of examples of changes falling under each reporting 
category. In proposed Secs. 314.70(g)(1)(i)(A), (g)(1)(i)(B), and 
(g)(1)(i)(C) and 601.12(b)(1)(i), (b)(1)(ii), and (b)(1)(iii), FDA 
specifically identified changes that would be among those subject to 
supplement submission and approval prior to distribution of the product 
made using the change. FDA has reevaluated the proposed regulations and 
has determined that, for purposes of clarification, more types of 
changes should be specifically identified in the regulations as being 
subject to supplement submission and approval prior to distribution of 
the product made using the change. Accordingly, the final rule provides 
in Secs. 314.70(g)(1)(ii)(A) through (g)(1)(ii)(F) and 601.12(b)(2)(i) 
through (b)(2)(vi) more types of changes that FDA has determined are 
subject to submission of a supplement and approval by FDA prior to 
distribution of the product made using the change.
    Similarly, FDA is including examples of changes that have a 
moderate potential or a minimal potential to have an adverse effect on 
the safety or effectiveness of a product in Secs. 314.70(g)(2)(ii) and 
601.12(c)(2), and Secs. 314.70(g)(3)(ii) and 601.12(d)(2), 
respectively. These lists are not intended to be all inclusive but are 
examples of the types of changes that fall into each category
    3. One comment recommended that proposed Sec. 314.70(g) not be 
added to part 314 (21 CFR part 314). Instead, the comment suggested 
that changes related to any well-characterized biotechnology product, 
whether regulated as a drug or as a biologic, should be reported in 
accordance with existing Sec. 314.70(a) through (f).
    FDA disagrees in part with the comment. FDA agrees that 
biotechnology products should be regulated consistently but believes 
the regulations in the final rule are necessary to ensure the continued 
safety and effectiveness of recombinant DNA-derived protein/polypeptide 
products and complexes or conjugates of drugs with monoclonal 
antibodies. Products

[[Page 39893]]

manufactured using biotechnology can present somewhat different 
scientific issues than products manufactured using more traditional 
techniques. In new Secs. 314.70(g) and 601.12, the agency is 
promulgating requirements appropriate for this category of product, 
whether regulated as a drug or biologic.
    4. One comment on proposed Secs. 314.70(g)(3) and 601.12(d) 
recommended that the requirements be amended to be consistent with 
current Sec. 314.70(d)(1) so that changes made by an applicant to 
comply with an official compendium would be among those for which only 
notification in an annual report would be necessary.
    FDA agrees with the comment and is including this change in 
Secs. 314.70(g)(3)(ii) and 601.12(d)(2) of the final rule as one that 
may be reported in the annual report.
    5. One comment on proposed Sec. 601.12 suggested that the term 
``effectiveness'' should not be used in reference to blood and plasma 
establishments. The comment stated that the effectiveness of a blood 
component can be greatly affected by circumstances of its use, which is 
entirely out of the control of the manufacturer and that Source Plasma, 
being a source material for the manufacture of other products, has no 
``effectiveness'' in and of itself.
    FDA disagrees with the comment. There are many examples of types of 
changes in manufacturing a blood or blood component product which may 
have an adverse effect on the effectiveness of the product. For 
example, any change that may affect the viability of Red Blood Cells, 
such as a change in dating period, anticoagulant, or processing 
methods, may directly affect the effectiveness of the product and the 
impact of the change should be evaluated accordingly. The comment is 
correct that Source Plasma is only used in the manufacture of other 
products and the ``effectiveness'' of Source Plasma is not by itself a 
consideration. However, inclusion of the ``effectiveness'' in the 
regulations has no effect upon the burdens associated with the 
regulations for Source Plasma or other intermediate products where 
effectiveness of the product is not directly a factor. FDA believes it 
is unnecessary to clarify further the regulations in this respect.
    6. One comment disagreed with the examples of changes given in 
proposed Sec. 601.12(b)(1), which would require submission of a 
supplement and approval by FDA before distribution of the product made 
using the change. The comment stated that most of the examples of 
changes should be reported as notifications to FDA rather than 
requiring preapproval.
    FDA disagrees with the comment. The types of changes identified in 
Sec. 601.12(b)(1) of the proposed rule and those in the final rule are 
based on FDA's experience of reviewing supplements and are those for 
which FDA believes there is a substantial potential to have an adverse 
effect on the safety or effectiveness of the product. Listing examples 
of the types of changes with such potential provides useful information 
to applicants for assessing the appropriate category of reporting.
    However, FDA also recognizes there may be instances when the agency 
may determine that a reduced reporting category for a specific 
manufacturing change is justified for a type of change that is 
ordinarily subject to submission of a supplement and approval by FDA 
prior to distribution of the product made using the change.
    If the agency can be assured that when a manufacturing change is 
implemented appropriate procedures have been followed by the applicant 
to evaluate the effect of the change on the safety or effectiveness of 
the product, FDA believes that in certain cases the potential for an 
adverse effect may be lessened.
    Generally, when considering a change in the manufacture of a 
product, the manufacturer will prepare a protocol, often called a 
``comparability protocol,'' identifying and describing the 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 an opportunity for FDA 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, therefore, that there is less potential 
for the change to have an adverse effect on the safety or effectiveness 
of the product.
    Accordingly, FDA is adding Secs. 314.70(g)(4) and 601.12(e) in the 
final rule to provide that an applicant may submit to FDA as a 
supplement a protocol 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 
safety or effectiveness of the product. Upon approval of the protocol, 
FDA may determine that the use of the approved protocol for the 
particular change justifies the use of a reduced reporting category for 
that change because the use of the protocol reduces the potential risk 
of adverse effect.
    The guidance documents being made available with this final rule 
provide examples of how, consistent with FDA's current interpretation 
of the rule, a comparability protocol approved by FDA may be used to 
justify a reduction in the reporting category. For example, use of an 
approved protocol for a particular change may result in a determination 
by FDA that a change usually subject to supplement submission and 
approval by FDA prior to distribution of the product made using the 
change may be submitted as a change subject to supplement submission at 
least 30 days prior to distribution of the product made using the 
change. Similarly, FDA is including in Secs. 314.70(g)(2)(v) and 
601.12(c)(5) in the final rule that use of a previously approved 
protocol is one means by which FDA may determine that a product made 
using a specified change may be distributed immediately upon receipt of 
the supplement by FDA (see also, FDA's response to comment 10 of this 
document for additional discussion of the means for permitting the 
immediate distribution of a product made using a change).
    However, use of a comparability protocol approved by FDA may not 
justify a reduction in the reporting category for every type of change. 
Some steps in manufacturing a biological product are so critical to the 
safety and effectiveness of the product that a change in that 
manufacturing step would always be subject to the submission of a 
supplement to FDA and approval by FDA prior to distribution of the 
product made using the change.
    7. Two comments related to proposed Sec. 601.12(c), which would 
provide for notification to FDA of certain changes not less than 30 
days before distribution of the product made using the change. The 
comments recommended that Sec. 601.12(c) be deleted and that there be 
only two tiers of changes: Those requiring submission of a supplement 
and preapproval by FDA, and those which may be reported in an annual 
report. One of the comments recommended that, when other safety issues 
have been addressed, changes which result in a product meeting 
currently approved release criteria should be reported in an annual 
report. One of the comments noted that, in effect, the submission of a 
notification was equivalent in reporting burden to the submission of a 
supplement.
    FDA disagrees with the comment that there should be only two 
categories of changes but recognizes that the regulations should be 
revised to allow

[[Page 39894]]

more types of changes to be implemented in 30 days. An important 
objective of this rulemaking is to provide for the prompt 
implementation of changes while allowing FDA to ensure that the changes 
do not have an adverse effect on the safety or effectiveness of the 
product. As proposed, Secs. 314.70(g)(2) and 601.12(c) would have 
provided for the distribution of a product made using certain changes 
30 days after notification to FDA but they did not provide for the full 
evaluation and approval by FDA of information gathered by the applicant 
in validating the change. As a consequence, under the proposed rule, 
FDA would have been unable to determine, because of the absence of 
data, that many changes could be considered to have a moderate, rather 
than a substantial, potential to have an adverse effect on the safety 
or effectiveness of the product.
    Accordingly, FDA is revising proposed Secs. 314.70(g)(2) and 
601.12(c) to require, for changes which have a moderate potential to 
have an adverse effect on the safety or effectiveness of the product, 
the submission of a supplement, rather than a notification, 30 days 
before distribution of the product made using the change. FDA is taking 
this initiative so that significantly more types of changes may be 
moved from the prior approval category, thereby allowing distribution 
of the product at or near the time of submission.
    In this regard, in preparing this final rule, FDA reviewed those 
changes that were identified in the proposed rule (and discussed in the 
draft guidance documents) as subject to supplement submission and FDA 
approval prior to distribution of the product made using the change. 
The agency determined that for many of these changes, agency review of 
the data is necessary to assess any potential long-term effect on the 
continued safety or effectiveness of the product, but that it is 
unnecessary to require that FDA approval of the supplement be obtained 
before the product made using the change is initially distributed. In 
addition, as discussed previously in this document, FDA has decided to 
permit the use of a ``comparability protocol'' for certain changes in 
lieu of requiring supplement submission and approval prior to 
distribution of the particular product made using the change. Thus, as 
described in the guidance documents being made available with this 
final rule, a change that is usually considered to have a substantial 
potential to have an adverse effect on the safety or effectiveness of 
the product may, in certain circumstances, be implemented and the 
product distributed not less than 30 days after FDA's receipt of the 
supplement or, in some cases, immediately upon submission of the 
supplement notifying the agency of the change, provided the change has 
been evaluated by the applicant in accordance with an FDA approved 
comparability protocol. The supplement is then reviewed by FDA to 
assure that there is adequate evidence that the change will 
consistently result in a safe and effective product. As provided in 
Secs. 314.70(g)(2)(iii) and 601.12(c)(3) of the final rule, the 
information to be submitted would be the same type of information as is 
required for a supplement subject to approval by FDA prior to 
distributing the product made using the change.
    In the guidance documents being made available elsewhere in this 
issue of the Federal Register, FDA identifies a number of additional 
types of changes which, under its current interpretation of the rule, 
may be implemented 30 days after receipt by FDA of the supplement, but 
for which FDA approval before implementation would have been required 
under the proposed rule. In addition, the final rule provides that, for 
some other types of changes, implementation can occur immediately upon 
submission of the supplement to FDA. The reduction in delays gained by 
reducing the number of types of changes subject to supplement 
submission and prior approval by FDA before distribution of the product 
made using the change, and from the use of comparability protocols, can 
only be achieved if FDA has the opportunity to evaluate the information 
in the form of a supplement to assure that there is no long-term 
potential that the change or many sequential changes made over time may 
have an adverse effect on the product.
    Potential applicants should be aware that complete review and 
approval of a supplement will take longer than 30 days. There may be 
instances where FDA determines, after the product made using the change 
has been distributed, that the information submitted in the supplement 
fails to adequately demonstrate the continued safety or effectiveness 
of the product made using the change. In such cases, FDA will make all 
possible efforts to resolve problems with the applicant concerning the 
supplement submission without requiring removal of the product from the 
marketplace. In assessing an applicant's plans to correct a problem, 
the agency intends to consider the applicant's reasons for making the 
change and the available alternatives to the change. In cases where FDA 
determines that there may be a danger to public health due to the 
continued marketing of the product, or when FDA determines that the 
issues may not otherwise be resolved, the agency may require that the 
applicant cease distribution of the product made using the change or 
that the product be removed from distribution pending resolution of the 
issues related to the change.
    8. One comment on proposed Sec. 601.12(b)(2)(vi) 
(Sec. 601.12(b)(3)(vi) in the final rule) recommended that an applicant 
have the option of providing a detailed summary of the validation 
protocol and data, and the agency could request copies of the entire 
protocol and all data, if needed.
    FDA disagrees with the comment. FDA believes that submission of the 
complete validation protocol and data is necessary to assure that FDA 
may fully evaluate any variability in test results that might not be 
apparent in a summary of test results. The agency has frequently 
encountered instances in which the average of the test results was 
within acceptable limits but variability in test results indicated a 
problem with the reproducibility of the test or demonstrated 
variability in product quality. In order to understand the implications 
of any such variability, it is necessary to review all data and the 
complete validation protocol specifying the test methodology used.
    9. One comment recommended that only one supplement to a product 
license application should be necessary to implement a change by all 
facilities under a single establishment license.
    This rulemaking does not address the overall licensing policies of 
the agency. In a related initiative, FDA is reviewing licensing 
policies and regulations. FDA will consider the comment in its general 
review of licensing policies and intends to publish additional 
documents in the Federal Register regarding licensing policies.
    10. One comment on proposed Sec. 601.12(c) suggested that the 
requirement for notification to FDA not less than 30 days prior to 
distributing the product be expanded to include a subcategory for 
permitting the notification of FDA concurrent with the distribution of 
the product made using the change.
    FDA agrees with the comment. FDA believes 30 days is often 
necessary to assure that the supplement is complete and that the change 
qualifies for the moderate potential category. However, in other cases, 
such as when the change has been evaluated in accordance with an 
approved comparability protocol, or

[[Page 39895]]

where a change is one which in the agency's experience has always been 
reported by applicants in the correct category, and with the proper 
documentation, a change may be implemented immediately upon submission 
of the supplement. Accordingly, FDA is adding Secs. 314.70(g)(2)(v) and 
601.12(c)(5) in the final rule to provide that FDA may, for certain 
changes otherwise requiring submission of a supplement at least 30 days 
prior to distribution of the product made using the change, permit the 
distribution of the product to begin immediately upon receipt of the 
supplement by the agency. Such types of changes may be made in 
connection with approved comparability protocols or may be discussed in 
guidance documents.
    11. One comment on proposed Sec. 601.12(c) noted that the proposed 
rule did not specify the manner by which FDA would notify an applicant 
of its determination of whether the notification was accepted or if 
additional information was needed. The comment recommended that FDA 
establish a maximum time period, such as 21 days, after which the 
applicant can be assured that no request for significant information is 
forthcoming, thus allowing the applicant to begin marketing the product 
30 days after submission with confidence that FDA has no objection.
    As discussed earlier in this document, the final rule has replaced 
the ``notification'' with a supplement which may be implemented in 30 
days. During the 30-day period from the date of receipt of a 
supplement, FDA will perform a preliminary review of the supplement to 
determine whether it is complete and whether the type of change 
qualifies under Secs. 314.70(g)(2)(iv) or 601.12(c)(4) for distribution 
of the product made using the change 30 days after receipt of the 
supplement. The means of notifying the applicant of whether the 
supplement has been accepted as a ``30-day supplement'' depends on the 
individual circumstances surrounding the supplement. FDA recognizes 
that when there are problems with the supplement that may delay product 
distribution, the applicant should be notified as quickly as possible. 
Official notification will be by letter. To notify the applicant that 
the supplement has been received, FDA will send an acknowledgment 
letter assigning a reference number to the supplement.
    Although FDA intends to perform this preliminary review as 
expeditiously as possible, there may be some cases where the entire 30-
day period is necessary to determine if the supplement is complete and 
qualifies for implementation 30 days after submission. It is the 
responsibility of the applicant to determine whether it should prepare 
to release the product 30 days after submission of the supplement, 
recognizing that the release may be delayed because of deficiencies in 
the supplement, or make other arrangements to better accommodate such a 
possibility.
    12. In the preamble to the proposed rule, FDA requested comments as 
to whether the information to be included in an annual report under 
existing Sec. 314.81(b)(2), currently applicable to nonbiological new 
drugs, should be applied to licensed biological products. One comment 
expressed the opinion that the information required under 
Sec. 314.81(b)(2) is more onerous than the proposed requirements in 
Sec. 601.12(d) and should not be applied. Another comment stated that 
the information required by Sec. 314.81(b)(2) has little relevance to 
blood and plasma establishments.
    FDA requested comment to determine if applicants who manufacture 
both drugs and biological products preferred that the required content 
of the annual reports for drugs and biologics be identical. Only two 
comments were received in response to the agency request and both 
opposed complete harmonization. The agency is committed to harmonizing 
reporting requirements for drugs and biologics as much as possible and 
will continue to evaluate the need for identical content in annual 
reports. However, based on comments received, FDA has determined that 
it would be appropriate to harmonize the requirements for the annual 
report as they relate only to manufacturing changes at this time. The 
final rule at Sec. 314.70(g)(3) references the annual report 
requirements for drugs approved under a new drug application (NDA) for 
products subject to Sec. 314.70(g). For biological products, the 
language in Sec. 601.12(d)(2)(i) through (d)(2)(vii) will require the 
same type and amount of information for manufacturing changes as is 
required under Sec. 314.81(b)(iv)(b). This harmonizes the reporting 
requirements as they relate to postapproval changes for drugs and 
biologics without adding, for biological products, the additional 
requirements for other information required in an annual report for a 
drug approved under an NDA. The full description of the changes would 
include pertinent data from studies and tests performed to evaluate the 
effect of the change on the safety and effectiveness of the product. 
This differs from the proposed rule and is now appropriate because more 
changes that previously required submission of a supplement to FDA 
under the proposed rule will now require only the submission of an 
annual report. These data will allow the agency to help assess the 
impact of numerous changes that may occur to a product over time.
    13. One comment on proposed Sec. 601.12(d) asked whether the annual 
report should include a description of all changes or only those not 
otherwise reported to FDA under the proposed regulations.
    The annual report should include information concerning only those 
changes that have not previously been reported to FDA in a supplement.
    FDA recognizes the need to avoid redundant reporting of changes. 
Some products, particularly blood and blood components, are closely 
related and a single change may affect multiple products. Under the 
proposed rule, a minor change, which has a minimal potential to have an 
adverse effect on the safety or effectiveness of the product, would be 
reported in the annual report for each affected product on or about the 
first anniversary date of the approval of the application for the 
product. In Sec. 601.12(d)(1) of the final rule, FDA is adding a 
provision to permit an applicant to request an alternative date for 
submission of an annual report so that multiple reports may be combined 
into a single combined annual report submission.
    14. One comment on proposed Sec. 601.12(d) asked for a 
clarification as to whether the annual report should include facility 
changes of the type previously contained in an establishment license 
application but for which FDA no longer requires submission in an 
application for a specified biotechnology product (see the final rule 
published in the Federal Register of May 14, 1996 (61 FR 24227)).
    If the change relates to a matter which, under current procedures, 
would not be described in an original application and its supplements, 
reporting of the change is not required.
    15. Two comments on proposed Sec. 601.12(e) (Sec. 601.12(f) in the 
final rule) recommended that Sec. 601.12(e)(4) be replaced by a cross-
reference to Sec. 314.70 so that all changes to advertising and 
promotional labeling for drug and biological products would be covered 
by one set of regulations. One additional comment recommended that 
proposed Sec. 601.12(e) cross-reference Sec. 314.70 for labeling 
changes and recommended that proposed Sec. 601.12(e)(4) regarding 
advertisements and promotional

[[Page 39896]]

labeling replace existing Sec. 601.45 (21 CFR 601.45).
    Section 601.45 applies only to promotional materials relating to 
biological products intended for serious or life-threatening illness 
being considered for accelerated approval. FDA believes these 
requirements continue to be necessary for biological products being 
considered for accelerated approval.
    FDA considered consolidating the requirements for advertising and 
labeling for drugs and biologics under one set of regulations but 
decided that the regulations are more useful if all requirements 
applicable to the reporting of changes to a license of a biological 
product are directly or indirectly included in one separate set of 
regulations. Advertisements and promotional labeling for both licensed 
biological products and drug products with approved NDA must be 
reported in accordance with the same requirements of Sec. 314.81(b)(3), 
except that, as discussed previously in this document, different forms 
will be used until the final revised harmonized form is available.
    16. One comment on proposed Sec. 601.12(e)(2)(i)(D) 
(Sec. 601.12(f)(2)(i)(D) in the final rule), noted that to submit a 
labeling change to ``delete false, misleading, or unsupported 
indications for use or claims for effectiveness'' would be equivalent 
to acknowledging that the product has been misbranded. The comment 
asked for examples of when there might be circumstances when FDA would 
have previously approved a label that so misbranded the product.
    Although this type of labeling change is infrequent, it has 
occurred in the past. For example, analyses of the results of 
postapproval studies may show that information included in the approved 
labeling is false or unsupported. Occasionally, an applicant may 
discover after approval of the product that data obtained from the 
clinical or laboratory studies sponsored by the applicant contained 
false information or, upon reevaluation, does not support claims made 
in the labeling. Also, the applicant may determine that persons using 
the product are making incorrect inferences from wording in the 
labeling and wording changes are necessary to ensure that the product 
is not used inappropriately. Changes made in the above instances would 
be reported in accordance with Sec. 601.12(f)(2)(i)(D).
    17. One comment recommended the deletion of Sec. 610.9 because it 
is redundant with provisions in the proposed rule.
    FDA disagrees with the comment but believes that the relationship 
among Sec. 610.9, a similar regulation in Sec. 640.120, and the 
regulations in the final rule should be clarified. Section 610.9 
provides procedures for a manufacturer of a biological product to 
modify a particular test method or manufacturing process, which is 
specified in the biologics regulations upon demonstrating to FDA that 
the modification will provide assurances of the effects on the safety 
and effectiveness of the biological product equal to or greater than 
the test method or process specified in the regulations. Section 
640.120 provides procedures for licensed and unlicensed manufacturers 
of blood, blood components, and blood products to obtain FDA approval 
for an exception or alternative to any requirement in part 640 (21 CFR 
part 640), subchapter F. Sections 610.9 and 640.120 are intended to 
provide flexibility for an applicant to obtain FDA approval of a change 
to a test method, manufacturing process, or other requirement from that 
specified in the regulations.
    Section 601.12 of the final rule provides for the reporting of 
changes, including those for which approval under Secs. 610.9 or 
640.120 is required. In some cases, a change requiring approval under 
Secs. 610.9 or 640.120 may be eligible for distribution 30 days after 
FDA's receipt of the supplement requesting approval of the change. 
Accordingly, FDA is amending Secs. 610.9 and 640.120 in the final rule 
to clarify that FDA may permit changes submitted under Sec. 610.9 or 
changes submitted by licensed establishments under Sec. 640.120 to be 
distributed as provided in Secs. 601.12(b) and (c) of the final rule.
    FDA is also taking this opportunity to amend Sec. 610.9 to clarify 
that a request for approval of an equivalent method or process can be 
submitted either as part of the original application (or as an 
amendment to the original, pending application) or as a supplement to 
the approved application. Section 610.9 previously specified that the 
request should be submitted as a license supplement.
    18. One comment urged that CBER continue to be directly involved in 
inspections of well-characterized biotechnology products so that the 
agency may provide proper scientific review and oversight of those 
changes not reported before product distribution.
    FDA agrees that appropriate scientific oversight should be given to 
help assure the continued safety and effectiveness of the products, 
particularly when there is a significant change in a method of 
manufacture. The agency will consider the comment when reviewing its 
overall inspectional policies.
    19. One comment recommended that the review and regulation of all 
well-characterized biotechnology products be consolidated into one 
office serving both CDER and CBER.
    This comment is outside the scope of this final rule. FDA is not 
considering such a reorganization at this time.
    20. One comment recommended deletion of parts 610 through 680 (21 
CFR parts 610 through 680) because these requirements are more 
appropriately addressed in approved marketing applications, compendia, 
and guidance documents.
    In the Federal Register of August 1, 1996 (61 FR 40153), FDA issued 
a final rule removing the regulations in parts 620, 630, and 650 in 
their entirety and removing sections of parts 610, 640, 660, and 680. 
The remaining regulations continue to be under review within the agency 
and FDA intends to pursue additional rulemaking at a later date 
proposing to retain, revise, or remove many of the remaining 
regulations.
    21. One comment from a licensed blood establishment recommended 
that a product license application supplement not be required for a 
change relating to a device which has received 510(k) clearance from 
FDA. The comment noted that the applicant should be permitted to 
implement the change with concurrent notification.
    FDA disagrees with the comment. On occasion, a licensed blood 
establishment may change the type of equipment used in the collection 
or processing of blood and blood components. For example, a blood 
establishment may decide to change from using manual pheresis equipment 
for the collection of Source Plasma or other blood components to 
automated equipment which has already been cleared for such use as a 
medical device, either with an approved premarket approval application 
or cleared as substantially equivalent under section 510(k) of the act 
(21 U.S.C. 360(k)). The purpose of the supplement to the product 
license application is to assure that the use of the equipment has been 
properly validated at the blood establishment, that the persons using 
the equipment have been properly trained, and that appropriate standard 
operating procedures are in place to assure the safety of the donors 
from whom the blood components will be collected. FDA believes that a 
change from manual to automated pheresis equipment that is not properly 
implemented may have a substantial potential to have an adverse effect 
on the health of the donors as well as on

[[Page 39897]]

the safety and effectiveness of the products being collected. For this 
reason, FDA believes that a supplement submission to convert from 
manual to automated pheresis equipment should be subject to approval by 
FDA before the change is implemented. FDA notes that for certain other 
types of similar changes, such as changing from one type of automated 
equipment to another, there is less potential for an adverse effect and 
the product made using the change may be distributed 30 days after 
receipt by FDA of the supplement reporting the change.
    22. One comment recommended that FDA not set specific requirements 
for submission of changes to a pending application. This flexibility 
could help expedite the approval of life-saving products, such as a new 
treatment for cancer.
    Former Sec. 601.12 applied both to changes to an approved 
application and to changes to a pending application. In the preamble to 
the proposed rule (61 FR 2739 at 2742), FDA announced its intention to 
consider whether it is appropriate to issue specific requirements for 
submitting amendments to pending license applications as part of its 
review of licensing requirements. The review of licensing requirements 
continues; however, FDA recognizes that its regulations and policies 
must provide adequate flexibility to accommodate the wide variety of 
products which are subject to licensure.
    The agency has already taken a number of steps to ensure the 
expeditious review and approval of important new drugs and biologics, 
including a commitment under the Prescription Drug User Fee Act of 1992 
(Pub. L. 102-571) to endeavor to complete the review of applications 
for ``breakthrough'' drugs and biologics within certain specified 
timeframes. Efforts to improve the system for the review and approval 
of important new drugs and biological products are continuing.
    23. One comment requested that FDA discontinue its policy of 
requiring submission of plateletpheresis products for quality control 
testing as a prerequisite for license approval for such products.
    The comment is beyond the scope of this rulemaking, which deals 
with the procedures for the reporting of changes to a license 
application. FDA notes, however, that for the present time, the agency 
plans to continue its practice of performing quality control testing as 
part of its review of a license application relating to a 
plateletpheresis product. Plateletpheresis is a sophisticated process, 
requiring considerable expertise to perform properly. In recent quality 
control testing, performed in 1996, FDA found that 26 of 279 samples 
submitted did not meet appropriate specifications. Results from 
additional samples indicated problems with pheresis procedures. See 
Sec. 640.25(b) for additional standards regarding quality control 
testing. Because of this relatively high rate of failure, FDA believes 
that continued quality control testing by the agency is necessary to 
assure the continued safety and effectiveness of plateletpheresis 
products.
    24. One comment recommended that FDA provide an applicant with a 
specific, detailed, written explanation for finding a license ``not 
approvable'' and that compliance deficiencies unrelated to the change 
specified in the application should not justify a ``not approvable'' 
decision.
    The comment is beyond the scope of this rulemaking, which deals 
with the procedures for the reporting of changes. The entire licensing 
process, including the review and approval of license supplements, 
continues to be under review within FDA. This comment will be 
considered by the agency as part of its review of the licensing 
process.
    25. One comment recommended that the final rule be made effective 
immediately upon its publication to provide immediate relief from 
excess reporting burdens.
    FDA agrees the final rule should be implemented as soon as 
possible. Additional information regarding effective dates and other 
implementation issues is presented at the end of this preamble.
    26. One comment on the ``Analysis of Impacts'' section of the 
preamble of the proposed rule noted that the analysis did not specify 
how many establishments were involved and whether the proposed 
regulations would truly result in a paperwork reduction. The comment 
requested that FDA describe more clearly the expected reduction in 
paperwork burdens.
    The ``Analysis of Impacts'' sections of the proposed and final 
rules are based on an evaluation of those supplements submitted to FDA 
under the previous regulations during a specified time period. All 
applicants holding licenses for biological products or an NDA for those 
biotechnology products affected by Sec. 314.70(g) are potential 
respondents. The analysis is based on the number of supplements 
submitted in the recent past which would, under the final rule, be 
subject to each form of reporting to FDA. From the burden hours 
associated with each of the possible means of reporting to FDA, 
assuming the types of changes occurring under the final rule are 
comparable to those which were evaluated, the estimated change in costs 
to the applicant can be readily calculated.
    FDA notes that the decrease in paperwork is only part of the relief 
from regulatory burdens achieved by the final rule. Under the new 
regulations many changes may be implemented more expeditiously and the 
product marketed more quickly. FDA believes this ability to readily 
market a product made with improved technology or improved labeling 
will be of considerable economic benefit to the applicant and the 
public. Because these benefits are indirect benefits, FDA does not have 
the information necessary to quantify the economic benefits associated 
with such timely marketing of products.

V. Effective Dates and Other Implementation Issues

    The final rule is effective October 7, 1997. On or after that date, 
FDA will accept supplements submitted in accordance with the final 
rule. For supplements which have already been submitted to FDA and 
which are pending approval, the applicant should notify FDA as to 
whether it believes: (1) The supplement continues to be subject to 
approval by FDA before implementation of the change; (2) the change may 
be implemented but is subject to FDA approval as a supplement; or (3) 
the supplement should be withdrawn because review of the change as a 
supplement is no longer necessary and the change may be implemented and 
reported in an annual report. FDA will inform the applicant within 30 
days of its receipt of this notification if it is not in agreement with 
the applicant's assessment.
    FDA is requesting the submission of the initial annual report 
required by Secs. 314.70(g)(3) and 601.12(d) and (f)(3) within 60 days 
of the first anniversary date of the approval of the application of the 
product occurring on or after January 20, 1998. For products with an 
earlier anniversary date, the annual report shall be submitted within 
60 days of the next anniversary date and should report all applicable 
changes occurring since the time of issuance of the final rule.

VI. Analysis of Impacts

A. Review Under Executive Order 12866 and the Regulatory Flexibility 
Act

    FDA has examined the impact of the final rule under Executive Order 
12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612). Executive 
Order 12866

[[Page 39898]]

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 impact; and equity). The agency believes that 
this final rule is consistent with the regulatory philosophy and 
principles identified in the Executive Order. In addition, the final 
rule is a significant regulatory action as defined by the Executive 
Order and is subject to review under the Executive Order because it 
deals with a novel policy issue.
    In accordance with the principles of Executive Order 12866, the 
overall result of the final rule will be a substantial reduction in 
burdens on applicants seeking approval of a product subject to this 
rule. FDA anticipates that the final rule will facilitate an 
applicant's ability to market a product improved by a change in 
manufacturing or labeling without unnecessary delays while reducing the 
overall paperwork burden associated with reporting such a change to 
FDA. In addition, FDA anticipates that the final rule may encourage 
applicants to improve their licensed products, product labeling, and 
methods of manufacture.
    Unless the head of the agency certifies that the rule does not 
impose a significant impact on a substantial number of small entities, 
the Regulatory Flexibility Act requires agencies to analyze regulatory 
options that would minimize any significant economic impact of a rule 
on small entities. The final rule will reduce the overall burdens 
associated with reporting changes in manufacturing and labeling of 
licensed biological products. It also provides increased flexibility 
for applicants in selecting the means of reporting manufacturing 
changes by providing for the use of a comparability protocol through 
which the agency may determine that the change has a decreased 
potential for an adverse effect on the safety and effectiveness of the 
product when compared with the potential generally associated with that 
type of change. In many cases under the final rule, an applicant will 
be able to market a product made using a change in manufacturing more 
rapidly than previously permitted under the regulations.
    Because, as stated above, the overall result of the final rule will 
be a substantial reduction in the regulatory and reporting burdens, the 
Commissioner of Food and Drugs certifies that the final rule will not 
have a significant economic impact on a substantial number of small 
entities. Therefore, under the Regulatory Flexibility Act, no further 
analysis is required.
    Although no further analysis is required, in developing this final 
rule, the agency did consider the impact of the rule on small entities. 
The agency also considered various regulatory options to maximize the 
net benefits of the rule to small entities without compromising the 
agency's ability to assure the continued safety and effectiveness of 
the products to which the rule applies. The following analysis briefly 
examines the potential impact of the final rule on small businesses.
1. The Need for the Regulation
    The purpose of the final rule is to amend the regulations for 
reporting to FDA changes to an approved application for a biological 
product in order to reduce unnecessary reporting burdens on applicants 
holding approved licenses to manufacture biological products and on 
applicants with an approved NDA for specified biotechnology products. 
FDA issued the proposed rule as part of its response to several 
mandates to reduce the burdens associated with government regulation, 
while assuring the continued safety and effectiveness of regulated 
products.
    The final rule takes into account comments submitted to the Dockets 
Management Branch, and discussions and information obtained through 
public participation in the public meeting held on April 19, 1996, to 
discuss and gather information and views on the proposed rule and two 
draft guidance documents. The objective of the final rule is to 
harmonize regulations administered by CDER and CBER in FDA, to reduce 
unnecessary burdens, and improve the consistency in the processes for 
complying with FDA's regulations without diminishing public health 
protection.
    As stated previously, FDA held an open public meeting during the 
comment period to facilitate public comment on this rule. FDA is 
announcing the availability of final guidance documents, revised from 
those proposed as a result of public comment, which are intended to aid 
applicants in complying with the requirements of this final rule.
2. Description of Requirements
    Any applicant holding an approved marketing application for a 
licensed biological product or specified biotechnology product will be 
required to report a change in the approved manufacturing process or in 
labeling by the appropriate procedure described in this final rule. The 
rule applies both to small and large for-profit business entities, and 
to small and large nonprofit organizations.
    The agency believes the regulation is flexible and is consistent 
with contemporary standards. Because this final rule represents a 
decrease in reporting burdens and other economic burdens previously 
applicable to the same products, FDA believes that firms should have no 
problem with complying with these regulations. No particular 
professional skills are needed to assemble the information to be 
reported to FDA.
3. Types and Number of Firms Affected
    Approximately 400 firms are affected by this final rule. 
Approximately half, primarily establishments with licenses for blood 
and blood component products, are nonprofit institutions. The remainder 
are large for-profit businesses.
4. Alternatives
    A number of alternatives were considered in preparing this final 
rule. Each alternative was evaluated as to its adequacy in providing in 
a timely way the information needed for FDA to assure the continued 
safety and effectiveness of the affected products, and evaluated with 
regard to burdens related to paperwork and the applicant's ability to 
market a product made with a changed manufacturing process or 
distributed with revised labeling. The agency decided not to provide 
different reporting requirements for small businesses because such an 
alternative would threaten the continued safety and effectiveness of 
products marketed by small businesses. For all applicants, regardless 
of size, the agency believes it has selected the reporting alternatives 
which impose the minimum burdens upon the applicants while assuring the 
continued safety and effectiveness of the affected products.
5. Response to Comments
    Only one comment was received concerning the Regulatory Flexibility 
Analysis provided in the proposed rule. The comment asked for further 
clarification regarding the projected reduction in burdens associated 
with the revised regulations. Most of the reduction in paperwork 
burdens, now projected as a 10 percent reduction, is associated with 
the fact that some changes which previously were subject to submission 
of a supplement and approval by FDA prior to distribution of the 
product made using the change may now be reported in an annual report

[[Page 39899]]

with a significant reduction in the information that is to be 
submitted. Considerable reduction in economic burdens is expected to 
result from the flexibility included in the final rule to permit the 
distribution of a product made using a change by the most timely means 
possible while assuring the continued safety and effectiveness of the 
product. Because FDA has no data to relate time saved in marketing a 
product with the resulting economic benefit, FDA cannot offer a 
monetary estimate of the savings at this time.

B. Review Under the Paperwork Reduction Act of 1995

    This final rule contains information collection provisions that are 
subject to review by the Office of Management and Budget (OMB) under 
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The title, 
description, and respondent description of the information collection 
provisions are shown below with an estimate of the annual reporting 
burden. Included in the estimate is the time for reviewing 
instructions, gathering and maintaining the data needed, and completing 
and reviewing the collection of information.
    Title: 21 CFR 601.12--Changes to an Approved Application and 21 CFR 
314.70(g)--Exception.
    Description: This final rule revises the requirements for 
respondents to report to FDA changes in the product, labeling, 
production process, equipment, quality controls facilities, or 
responsible personnel established in an approved application for a 
biological product or for a specified biotechnology product. The 
respondent will report a change to FDA in one of the three following 
ways depending on the potential for the change to have an adverse 
effect on the identity, strength, quality, purity, or potency of the 
product as they may relate to the safety or effectiveness of the 
product: (1) Changes that have a significant potential to have an 
adverse effect on the product will 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 the product will be submitted to FDA in a supplement 
not less than 30 days prior to distribution of the product made using 
the change unless FDA permits distribution upon its receipt of the 
supplement; and (3) changes that have a minimal potential to have an 
adverse effect on the product will be submitted by the respondent in an 
annual report.
    Labeling changes for a biological product will also be submitted in 
one of the following ways: (1) A supplement requiring FDA approval 
prior to distribution of product with the revised labeling; (2) a 
supplement requiring FDA approval but permitting the distribution of 
the product with the accompanying revised labeling at the time the 
supplement is submitted; or (3) submission of final printed labeling in 
an annual report. Promotional labeling and advertising will be 
submitted in accordance with Sec. 314.81(b)(3)(i). Labeling changes for 
biotechnology products regulated under the act but not under the PHS 
Act are not addressed in Sec. 314.70(g) and will not be affected by 
this final rule. The agency is developing technology to permit the 
submission of the information required by this rule electronically. The 
agency anticipates that the use of electronic media will substantially 
further reduce the paperwork burden associated with these reporting 
requirements.
    Description of Respondents: All manufacturers and applicants 
holding a biological license approved under section 351 of the PHS Act, 
and all manufacturers and applicants of specified biotechnology 
products holding an approved NDA.
    Burden estimate: As mentioned in the proposed rule, FDA estimates 
that 20 percent of all reports required under these final regulations 
will be prepared by contractors. The burden hours for affected industry 
in the chart below therefore reflect a 20 percent reduction. It is 
estimated that a contractor will charge $40 per hour for the service of 
preparing these reports. The 20 percent burden hours multiplied by $40 
per hour are reflected in the table, under the column labeled 
``Operating and Maintenance Costs.''
    The burden estimate for this final rule differs from the estimate 
given for the proposed rule (see 61 FR 2739 at 2745) in two important 
respects. First, FDA has revised Secs. 314.70(g)(2) and 601.12(c) in 
the final rule to require submission of a supplement rather than a 
notification for changes that have a moderate potential to have an 
adverse effect on the safety or effectiveness of the product. This 
revision will result in an estimated 10 additional burden hours per 
submission (50 for a supplement versus 40 for a notification). Second, 
substantially more supplements concerning changes in manufacturing and 
labeling for biological products are being submitted than during the 
time period used to prepare the estimate in the proposed rule (an 
estimated 2,300 submissions in 1996 versus 1,550 submissions in 1994). 
Although this increase results from increased industry activity, not 
from any modification to the proposed rule, the burden estimate has 
been adjusted to reflect the increase.

                                                            Estimated Annual Reporting Burden                                                           
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                      Number of                                         
                  21 CFR Section                      Number of       Hours Per       Number of     Responses Per  Total Operating and   Total Hours Per
                                                     Respondents      Response        Responses      Respondent     Maintenance Costs      Regulation   
--------------------------------------------------------------------------------------------------------------------------------------------------------
601.12(b)                                                391              80             900               2.3           $576,000            57,600     
601.12(c)                                                391              50             720               1.8           $288,000            28,800     
601.12(d)                                                391              10             120               0.3             $9,600               960     
601.12(f)(1)                                             391              40             200               0.51           $64,000             6,400     
601.12(f)(2)                                             391              20              20               0.05            $3,200               320     
601.12(f)(3)                                             391              10             220               0.56           $17,600             1,760     
601.12(f)(4)                                             391              10             110               0.28            $8,800               880     
314.70(g)(1)                                               4              80              50              12.5            $32,000             3,200     
314.70(g)(2)                                               2              50               3               1.5             $1,200               120     
314.70(g)(3)                                               6              10              20               3.33            $1,600               160     
TOTALS                                                                                                                 $1,002,000          $100,200     
--------------------------------------------------------------------------------------------------------------------------------------------------------
There are no capital costs associated with this collection of information.                                                                              

    As required by section 3506(c)(2)(B) of the Paperwork Reduction Act 
of 1995 (the PRA), FDA provided an opportunity for public comment on 
the information collection provisions of the proposed rule. All 
comments received

[[Page 39900]]

agreed that FDA's proposal to modify the requirements for reporting 
changes to approved applications would reduce the burden to industry 
without diminishing public health protection. Even with the increase in 
burden in the final rule as compared with the proposed rule, FDA 
estimates that the modified reporting requirements will achieve a net 
burden reduction of approximately 10,000 hours per year.
    As required by section 3507(d)(1)(A) of the PRA, FDA submitted the 
information collection provisions of the proposed rule to OMB. Although 
these provisions were approved, FDA has submitted the information 
collection provisions of the final rule to OMB for review because of 
the revised requirement to submit a supplement rather than a 
notification for changes that have a moderate potential to have an 
adverse effect on the safety or effectiveness of the product. Prior to 
the effective date of this final rule, FDA will publish a notice in the 
Federal Register of OMB's decision to approve, modify, or disapprove 
the information collection provisions in the final rule. An agency may 
not conduct or sponsor, and a person is not required to respond to, a 
collection of information unless it displays a currently valid OMB 
control number.

C. Environmental Impact

    The agency has determined under 21 CFR 25.24(a)(8) 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.

List of Subjects

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.

21 CFR Part 610

    Biologics, Labeling, Reporting and recordkeeping requirements.

21 CFR Part 640

    Blood, Labeling, Reporting and recordkeeping requirements.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and the 
Public Health Service Act, and under the authority delegated to the 
Commissioner of Food and Drugs, 21 CFR parts 314, 600, 601, 610 and 640 
are amended as follows:

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

    1. The authority citation for 21 CFR part 314 continues to read as 
follows:

    Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701, 
704, 721 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 
331, 351, 352, 353, 355, 356, 357, 371, 374, 379e).

    2. Section 314.70 is amended by adding a new paragraph (g) to read 
as follows:

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

* * * * *
    (g) Exception. An applicant proposing to make a change of a type 
described in paragraphs (a), (b)(1), (b)(2), (c)(1), (c)(3), (d)(1), 
and (d)(4) through (d)(9) of this section affecting a recombinant DNA-
derived protein/polypeptide product or a complex or conjugate of a drug 
with a monoclonal antibody regulated under the Federal Food, Drug, and 
Cosmetic Act shall comply with the following:
    (1) Changes requiring supplement submission and approval prior to 
distribution of the product made using the change (major changes). (i) 
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 they may relate 
to the safety or effectiveness of the product.
    (ii) These changes include, but are not limited to:
    (A) Changes in the qualitative or quantitative formulation or other 
specifications as provided in the approved application or in the 
regulations;
    (B) Changes requiring completion of an appropriate human study to 
demonstrate the equivalence of the identity, strength, quality, purity, 
or potency of the product as they may relate to the safety or 
effectiveness of the product;
    (C) Changes in the virus or adventitious agent removal or 
inactivation method(s);
    (D) Changes in the source material or cell line;
    (E) Establishment of a new master cell bank or seed; and
    (F) Changes which 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.
    (iii) The applicant must obtain approval of the supplement from FDA 
prior to distribution of the product made using the change. Except for 
submissions under paragraph (g)(4) of this section, the following shall 
be contained in the supplement:
    (A) A detailed description of the proposed change;
    (B) The product(s) involved;
    (C) The manufacturing site(s) or area(s) affected;
    (D) 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 they may relate to the safety or 
effectiveness of the product;
    (E) The data derived from such studies;
    (F) Relevant validation protocols and data; and
    (G) A reference list of relevant standard operating procedures 
(SOP's).
    (2) Changes requiring supplement submission at least 30 days prior 
to distribution of the product made using the change. (i) 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 they may relate to the safety or 
effectiveness of the product. The supplement shall be labeled 
``Supplement--Changes Being Effected in 30 Days'' or, if applicable 
under paragraph (g)(2)(v) of this section, ``Supplement--Changes Being 
Effected.''
    (ii) These changes include, but are not limited to:
    (A) Change in the site of testing from one facility to another;
    (B) An increase or decrease in production scale during finishing 
steps that involves new or different equipment; and
    (C) Replacement of equipment with that of similar, but not 
identical, design and operating principle that does not affect the 
process methodology or process operating parameters.
    (iii) Pending approval of the supplement by FDA, and except as 
provided in paragraph (g)(2)(v) 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 paragraph 
(g)(1)(iii)(A) through

[[Page 39901]]

(g)(1)(iii)(G) of this section shall be contained in the supplement.
    (iv) If within 30 days following FDA's receipt of the supplement, 
FDA informs the applicant that either:
    (A) The change requires approval prior to distribution of the 
product in accordance with paragraph (g)(1) of this section; or
    (B) Any of the information required under paragraph (g)(2)(iii) 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.
    (v) In certain circumstances, FDA may determine that, based on 
experience with a particular type of change, the supplement for such 
change is usually complete and provides the proper information, and on 
particular assurances that the proposed change has been appropriately 
submitted, the product made using the change may be distributed 
immediately upon receipt of the supplement by FDA. These circumstances 
may include substantial similarity with a type of change regularly 
involving a ``Supplement--Changes Being Effected'' supplement, or a 
situation in which the applicant presents evidence that the proposed 
change has been validated in accordance with an approved protocol for 
such change under paragraph (g)(4) of this section.
    (3) Changes to be described in an annual report (minor changes). 
(i) Changes in the product, production process, quality controls, 
equipment, or facilities that have a minimal potential to have an 
adverse effect on the identity, strength, quality, purity, or potency 
of the product as they 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)(iv).
    (ii) These changes include, but are not limited to:
    (A) Any change made to comply with an official compendium that is 
consistent with FDA requirements;
    (B) The deletion of an ingredient intended only to affect the color 
of the product;
    (C) An extension of an expiration date based upon full shelf life 
data obtained from a protocol approved in the application;
    (D) A change within the container and closure system for solid 
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;
    (E) A change in the size of a container for a solid dosage form, 
without a change from one container and closure system to another;
    (F) The addition by embossing, debossing, or engraving of a code 
imprint to a solid dosage form drug product other than a modified 
release dosage form, or a minor change in an existing code imprint; and
    (G) The addition or deletion of an alternate analytical method.
    (4) An applicant may submit one or more protocols describing the 
specific tests and validation studies and acceptable limits to be 
achieved to demonstrate the lack of adverse effect for specified types 
of manufacturing changes on the identity, strength, quality, purity, or 
potency of the product as they may relate to the safety or 
effectiveness of the product. Any such protocols, or change to a 
protocol, shall be submitted as a supplement requiring approval from 
FDA prior to distribution of the product which, if approved, may 
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.
* * * * *

PART 600--BIOLOGICAL PRODUCTS: GENERAL

    3. The authority citation for 21 CFR part 600 continues to read as 
follows:

    Authority: Secs. 201, 501, 502, 503, 505, 510, 519, 701, 704, of 
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 
353, 355, 360, 360i, 371, 374); secs. 215, 351, 352, 353, 361, 2125 
of the Public Health Service Act (42 U.S.C. 216, 262, 263, 263a, 
264, 300aa-25).

    4. Section 600.3 is amended by adding new paragraphs (ff) and (gg) 
to read as follows:

Sec. 600.3  Definitions.

* * * * *
    (ff) Amendment is the submission of information to a pending 
license application or supplement, to revise or modify the application 
as originally submitted.
    (gg) Supplement is a request to the Director, Center for Biologics 
Evaluation and Research, to approve a change in an approved license 
application.

PART 601--LICENSING

    5. The authority citation for 21 CFR part 601 continues to read as 
follows:

    Authority: Secs. 201, 501, 502, 503, 505, 510, 513-516, 518-520, 
701, 704, 721, 801, of the Federal Food, Drug, and Cosmetic Act (21 
U.S.C. 321, 351, 352, 353, 355, 360, 360c-360f, 360h-360j, 371, 374, 
379e, 381); secs. 215, 301, 351, 352, of the Public Health Service 
Act (42 U.S.C. 216, 241, 262, 263); secs. 2-12 of the Fair Packaging 
and Labeling Act (15 U.S.C. 1451-1461).

    6. Section 601.12 is revised to read as follows:

Sec. 601.12  Changes to an approved application.

    (a) General. As provided by this section, an applicant shall inform 
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). Before distributing a product made using a change, an 
applicant shall demonstrate through appropriate validation and/or other 
clinical and/or non-clinical 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.
    (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, facilities, or 
responsible personnel that has a substantial potential to have an 
adverse effect on the identity, strength, quality, purity, or potency 
of the product as they may relate to the safety or effectiveness of the 
product.
    (2) These changes include, but are not limited to:
    (i) Changes in the qualitative or quantitative formulation or other 
specifications as provided in the approved application or in the 
regulations;
    (ii) Changes requiring completion of an appropriate human study to 
demonstrate the equivalence of the identity, strength, quality, purity, 
or potency of the product as they may relate to the safety or 
effectiveness of the product;
    (iii) Changes in the virus or adventitious agent removal or 
inactivation method(s);
    (iv) Changes in the source material or cell line;
    (v) Establishment of a new master cell bank or seed; and
    (vi) Changes which 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.
    (3) The applicant must obtain approval of the supplement from FDA 
prior to distribution of the product made using the change. Except for

[[Page 39902]]

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 they may relate to the safety or 
effectiveness of the product;
    (v) The data derived from such studies;
    (vi) Relevant validation protocols and data; and
    (vii) A reference list of relevant standard operating procedures 
(SOP's).
    (c) Changes requiring supplement submission at least 30 days prior 
to distribution of the product made using the change. (1) A supplement 
shall be submitted for any change in the product, production process, 
quality controls, equipment, facilities, or responsible personnel that 
has a moderate potential to have an adverse effect on the identity, 
strength, quality, purity, or potency of the product as they may relate 
to the safety or effectiveness of the product. The supplement shall be 
labeled ``Supplement--Changes Being Effected in 30 Days'' or, if 
applicable under paragraph (c)(5) of this section, ``Supplement--
Changes Being Effected.''
    (2) These changes include, but are not limited to:
    (i) Change in the site of testing from one facility to another;
    (ii) An increase or decrease in production scale during finishing 
steps that involves new or different equipment; and
    (iii) 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) Pending approval of the supplement by FDA, and except as 
provided in paragraph (c)(5) 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 paragraph 
(b)(3)(i) through (b)(3)(vii) of this section shall be contained in the 
supplement.
    (4) 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)(3) 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.
    (5) In certain circumstances, FDA may determine that, based on 
experience with a particular type of change, the supplement for such 
change is usually complete and provides the proper information, and on 
particular assurances that the proposed change has been appropriately 
submitted, the product made using the change may be distributed 
immediately upon receipt of the supplement by FDA. These circumstances 
may include substantial similarity with a type of change regularly 
involving a ``Supplement--Changes Being Effected'' supplement or a 
situation in which the applicant presents evidence that the proposed 
change has been validated in accordance with an approved protocol for 
such change under paragraph (e) of this section.
    (d) Changes to be described in an annual report (minor changes). 
(1) Changes in the product, production process, quality controls, 
equipment, facilities, or responsible personnel that have a minimal 
potential to have an adverse effect on the identity, strength, quality, 
purity, or potency of the product as they may relate to the safety or 
effectiveness of the product shall be documented by the applicant in an 
annual report submitted each year within 60 days of the anniversary 
date of approval of the application. The Director, Center for Biologics 
Evaluation and Research, may approve a written request for an 
alternative date to combine annual reports for multiple approved 
applications into a single annual report submission.
    (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;
    (ii) The deletion 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 date based upon full shelf-life 
data obtained from a protocol approved in the application;
    (iv) A change within the container and closure system for solid 
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;
    (v) A change in the size of a container for a solid dosage form, 
without a change from one container and closure system to another;
    (vi) The addition by embossing, debossing, or engraving of a code 
imprint to a solid dosage form biological product other than a modified 
release dosage form, or a minor change in an existing code imprint; and
    (vii) The addition or deletion of an alternate analytical method.
    (3) The following information for each change shall be contained in 
the annual report:
    (i) A list of all products involved; and
    (ii) A full description of the manufacturing and controls changes 
including: the manufacturing site(s) or area(s) involved; the date the 
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 they may relate to the safety or 
effectiveness of the product.
    (4) The applicant shall submit the report to the FDA office 
responsible for reviewing the application. The report shall include all 
the information required under this paragraph for each change made 
during the annual reporting interval which ends on the anniversary date 
in the order in which they were implemented.
    (e) An applicant may submit one or more protocols describing the 
specific tests and validation studies and acceptable limits to be 
achieved to demonstrate the lack of adverse effect for specified types 
of manufacturing changes on the identity, strength, quality, purity, or 
potency of the product as they may relate to the safety or 
effectiveness of the product. Any such protocols, or change to a 
protocol, shall be submitted as a supplement requiring approval from 
FDA prior to distribution of the product which, if approved, may 
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) Labeling changes. (1) Labeling changes requiring supplement 
submission--FDA approval must be obtained before distribution of the 
product with the labeling change. Except as described in paragraphs 
(f)(2) and (f)(3) of this section, an applicant shall submit a 
supplement describing a proposed change in the package insert, package 
label, or container label, and include the information necessary to

[[Page 39903]]

support the proposed change. The supplement shall clearly highlight the 
proposed change in the labeling. The applicant shall obtain approval 
from FDA prior to distribution of the product with the labeling change.
    (2) Labeling changes requiring supplement submission--product with 
a labeling change that may be distributed before FDA approval. (i) An 
applicant shall submit, at the time such change is made, a supplement 
for any change in the package insert, package label, or container label 
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 abuse, dependence, 
psychological effect, or overdosage;
    (C) To add or strengthen an instruction about dosage and 
administration that is intended to increase the safety of the use of 
the product; and
    (D) To delete false, misleading, or unsupported indications for use 
or claims for effectiveness.
    (ii) Pending approval of the supplement by FDA, the applicant may 
distribute a product with a package insert, package label, or container 
label bearing such change at the time the supplement is submitted. The 
supplement shall clearly identify the change being made and include 
necessary supporting data. The supplement and its mailing cover shall 
be plainly marked: ``Special Labeling Supplement--Changes Being 
Effected.''
    (3) Labeling changes requiring submission in an annual report. (i) 
An applicant shall submit any final printed package insert, package 
label, or container label incorporating the following changes in an 
annual report submitted to FDA each year as provided in paragraph 
(d)(1) of this section:
    (A) Editorial or similar minor changes; and
    (B) A change in the information on how the product is supplied that 
does not involve a change in the dosage strength or dosage form.
    (ii) The applicant may distribute a product with a package insert, 
package label, or container label bearing such change at the time the 
change is made.
    (4) Advertisements and promotional labeling. Advertisements and 
promotional labeling shall be submitted to the Center for Biologics 
Evaluation and Research in accordance with the requirements set forth 
in Sec. 314.81(b)(3)(i) of this chapter, except that Form FDA-2567 
(Transmittal of Labels and Circulars) or an equivalent form shall be 
used.
    (g) Failure to comply. In addition to other remedies available in 
law and regulations, in the event of repeated failure of the applicant 
to comply with this section, FDA may require that the applicant submit 
a supplement for any proposed change and obtain approval of the 
supplement by FDA prior to distribution of the product made using the 
change.
    (h) Administrative review. Under Sec. 10.75 of this chapter, an 
applicant may request internal FDA review of FDA employee decisions 
under this section.

PART 610--GENERAL BIOLOGICAL PRODUCTS STANDARDS

    7. The authority citation for 21 CFR part 610 continues to read as 
follows:

    Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the 
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 
355, 360, 371); secs. 215, 351, 352, 353, 361 of the Public Health 
Service Act (42 U.S.C. 216, 262, 263, 263a, 264).

    8. Section 610.9 is revised to read as follows:


Sec. 610.9  Equivalent methods and processes.

    Modification of any particular test method or manufacturing process 
or the conditions under which it is conducted as required in this part 
or in the additional standards for specific biological products in 
parts 620 through 680 of this chapter shall be permitted only under the 
following conditions:
    (a) The applicant presents evidence, in the form of a license 
application, or a supplement to the application submitted in accordance 
with Sec. 601.12(b) or (c), demonstrating that the modification will 
provide assurances of the safety, purity, potency, and effectiveness of 
the biological product equal to or greater than the assurances provided 
by the method or process specified in the general standards or 
additional standards for the biological product; and
    (b) Approval of the modification is received in writing from the 
Director, Center for Biologics Evaluation and Research, Food and Drug 
Administration, 1401 Rockville Pike, Rockville, MD 20852-1448.

PART 640--ADDITIONAL STANDARDS FOR HUMAN BLOOD AND BLOOD PRODUCTS

    9. The authority citation for 21 CFR part 640 continues to read as 
follows:

    Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the 
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 
355, 360, 371); secs. 215, 351, 352, 353, 361 of the Public Health 
Service Act (42 U.S.C. 216, 262, 263, 263a, 264).

    10. Section 640.120 is amended by revising paragraph (a) to read as 
follows:

Sec. 640.120  Alternative procedures.

    (a) The Director, Center for Biologics Evaluation and Research, may 
approve an exception or alternative to any requirement in subchapter F 
of chapter I of title 21 of the Code of Federal Regulations regarding 
blood, blood components, or blood products. Requests for such 
exceptions or alternatives shall ordinarily be in writing. Licensed 
establishments shall submit such requests in accordance with 
Sec. 601.12 of this chapter. However, in limited circumstances, such 
requests may be made orally and permission may be given orally by the 
Director. Oral requests and approvals must be promptly followed by 
written requests and written approvals.
* * * * *

    Dated: May 27, 1997.
William B.Schultz,
Deputy Commissioner for Policy.
[FR Doc. 97-19427 Filed 7-23-97; 8:45 am]
BILLING CODE 4160-01-F