[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]]
_______________________________________________________________________
Part II
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
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
