[Federal Register Volume 61, Number 19 (Monday, January 29, 1996)]
[Proposed Rules]
[Pages 2739-2748]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-1580]



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DEPARTMENT OF HEALTH AND HUMAN SERVICES
21 CFR Parts 314, 600, and 601

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


Changes to an Approved Application

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend 
the biologics regulations for reporting changes to an approved 
application in order to reduce unnecessary reporting burdens on 
applicants holding licenses approved in 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 
proposing to amend the corresponding drug regulations for submitting 
supplements for and reporting changes to an application approved under 
the Federal Food, Drug, and Cosmetic Act (the act) for well-
characterized biotechnology products reviewed in the Center for Drug 
Evaluation and Research (CDER) to harmonize the drug and biologics 
regulations. These actions are part of FDA's continuing effort to 
achieve the objectives of the President's ``Reinventing Government'' 
initiatives.

DATES: Written comments on this proposed rule by April 29, 1996. Submit 
written comments on the information collection requirements by February 
28, 1996, but not later than March 29, 1996. The agency proposes that 
any final rule that may issue based on this proposal become effective 
immediately upon its date of publication in the Federal Register.
ADDRESSES: Submit written comments on this proposed rule to the Dockets 
Management Branch (HFA-305), Food and Drug Administration, 12420 
Parklawn Dr., rm. 1-23, Rockville, MD 20857. Submit written comments on 
the information collection requirements to the Office of Information 
and Regulatory Affairs, OMB, New Executive Office Bldg., 725 17th St. 
NW., rm. 10235, Washington, DC 20503, Attn: Desk Officer for FDA.
FOR FURTHER INFORMATION CONTACT:
    Tracey H. Forfa or Timothy W. Beth, 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-820), 
Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 
301-443-3510.
SUPPLEMENTARY INFORMATION:
I. Introduction
A. Background
    This proposed rule is issued in accordance with the principles set 
forth in the Regulatory Flexibility Act of 1990 (Pub. L. 96-354), 
Executive Order 12866; the President's memorandum of March 4, 1995, 
announcing the ``Regulatory Reinvention Initiative;'' the President's 
memorandum of April 21, 1995, entitled, ``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.'' The Regulatory 
Flexibility Act requires Federal agencies to consider the burden a rule 
may have on small business entities through a regulatory flexibility 
analysis and to periodically review its rules to determine if 
regulatory burdens may be reduced. Executive Order 12866 directs 
Federal agencies and the Office of Information and Regulatory Affairs 
(OIRA) to implement measures that will reform and make the regulatory 
process more efficient. -
    Under Executive Order 12866, FDA published a document in the 
Federal Register on January 20, 1994 (59 FR 3043), that announced FDA's 
plan to review and evaluate all significant regulations for their 
effectiveness in achieving public health goals and in order to avoid 
unnecessary regulatory burden. FDA published two documents in the 
Federal Register of June 3, 1994 (59 FR 28821 and 28822), that 
announced the review of certain general biologics and blood and blood 
product regulations by CBER to identify those regulations that are 
outdated, burdensome, inefficient, duplicative, or otherwise unsuitable 
or unnecessary.
    The President's memorandum of March 4, 1995, entitled ``Regulatory 
Reinvention Initiative'' sets forth four steps toward regulatory 
reform, one of which instructs agencies to revise those regulations 
that are in need of reform. FDA believes that this proposed regulation 
is in keeping with these principles without compromising the agency's 
duty and commitment to protect the public health. The President's 
memorandum of April 21, 1995, directs Federal agencies to reduce the 
frequency of regularly scheduled reports that the public is required, 
by rule or policy, to provide to the Federal government. In addition, 
the November 1995, Presidential National Performance Review report 
entitled ``Reinventing the Regulation of Drugs Made From 
Biotechnology,'' focused on FDA's efforts to reform the regulation of 
biotech drugs used for therapy.

    FDA also held a public meeting on January 26, 1995, to discuss the 
retrospective review effort. The public meeting was a forum for the 
public to voice its comments regarding the retrospective review of 
regulations being undertaken by CBER.

    Many of the comments submitted to the public docket regarding the 
CBER retrospective regulations review were requests to revise 
Sec. 601.12 Changes to be reported (21 CFR 601.12). Most of those 
comments requested revision of the regulation to reduce the burden on 
applicants of reporting changes to an approved application. As part of 
the CBER regulatory review initiative, and in response to the comments 
received, FDA published in the Federal Register of April 6, 1995 (60 FR 
17535), a document entitled, ``Changes to Be Reported for Product and 
Establishment License Applications; Guidance.'' The guidance document 
set forth FDA's current interpretation of Sec. 601.12 and was intended 
to reduce the reporting burden as well as facilitate the timely 
implementation of certain changes by manufacturers. The guidance 
document was the first step in a reinventing Government initiative 
outlined in the April 1995 publication ``Reinventing Drug and Medical 
Device Regulations.''
    Concurrently, CBER's Office of Blood Research and Review (OBRR), in 
letters to applicants and an industry trade organization and in 
presentations at a January 30 and 31, 1995, ``Licensing Blood 
Establishments'' workshop, 

[[Page 2740]]
communicated FDA's interpretation of Sec. 601.12 as it applies to blood 
establishments. OBRR discussed categories of changes that blood 
establishments could implement without supplement submission and FDA 
approval. These categories include noncritical standard operating 
procedures, certain personnel changes, and some facility changes. 
During a 9-month period (October 1994 to June 1995), CBER received over 
850 such submissions that were not required to await FDA approval.
    The agency is proposing to revise Sec. 600.3 (21 CFR 600.3) and 
Sec. 601.12 to permit more substantial report reduction as the second 
step in the President's reinvention initiative. FDA is also proposing 
to add Sec. 314.70(g) (21 CFR 314.70(g)) which would apply to well-
characterized biotechnology products approved under the act to 
harmonize CDER and CBER postapproval reporting requirements. FDA 
published a definition of a well-characterized therapeutic recombinant 
deoxyribonucleic acid (DNA)-derived and monoclonal antibody 
biotechnology product in a document published in the Federal Register 
of December 8, 1995, (60 FR 63048), as follows: -
    A chemical entity(ies) whose identity, purity, impurities, 
potency, and quantity can be determined and controlled.
    Identity:
    a. Recombinant DNA Biotechnology Products -
    The primary structure is known (i.e., amino acid sequence), and
    The secondary structure is known (e.g., disulfide linkage), and
    Post-translational modifications are known (e.g., 
glycosylation), or
    b. Monoclonal Antibodies
    The identity can be determined by rigorous physicochemical and 
immunochemical characterization without fully knowing its chemical 
structure
    Purity and impurities:
    The purity is quantifiable.
    The impurities are quantifiable, and identified if feasible
    Potency and quantity:
    The biological activity is measurable.
    The quantity is measurable.
    Well-characterized therapeutic recombinant DNA-derived or 
monoclonal antibody biotechnology product require proper raw 
materials controls, process validation and controls, and sensitive 
and validated test methods and specifications.
    FDA plans to hold an open public meeting that will be announced in 
a future issue of the Federal Register during the comment period of 
this proposed rule to facilitate public discussion.

B. Summary of the Proposed Rule

1. Summary of Changes to Sec. 600.3--Definitions
    There has been much confusion regarding the use of the words 
``supplement'' and ``amendment'' in relation to license applications 
for biological products approved under section 351 of the PHS Act. In 
order to clarify the use of these terms, and to facilitate a clearer 
understanding of the proposed revision of Sec. 601.12, FDA is proposing 
to amend Sec. 600.3 (21 CFR 600.3) to include definitions of 
``supplement'' and ``amendment.'' Previously, a change submitted to an 
approved biological product license application (PLA) or establishment 
license application (ELA) was termed an ``amendment.'' In order to 
achieve consistency with CDER in implementing the Prescription Drug 
User Fee Act of 1992 (PDUFA)(21 U.S.C. 301, et seq.), CBER began using 
the term ``amendment'' to refer to a change submitted to a pending 
license application or supplement, and the term ``supplement'' to refer 
to a change submitted to an approved license application. A change to 
an unapproved (pending) new drug application (NDA) is also referred to 
as an ``amendment'' and a change submitted to an approved NDA is also 
referred to as a ``supplement.'' Under this proposed rule, Sec.  
600.3(ff) would define the term ``amendment'' as the submission of 
information to an unapproved license application or supplement. Such 
information could include additional information or reanalysis of data 
previously submitted, to revise or modify the application as originally 
submitted. Section Sec. 600.3(gg) would define a ``supplement'' as a 
request to the Director, CBER, to approve a change to an approved 
license application. A supplement would ordinarily contain a 
description of the proposed change and the data and information 
supporting the change.
    FDA believes that defining these terms in the regulations will 
simplify the approval process for applicants, minimize misunderstanding 
between CBER and the biologics industry, and harmonize the use of the 
terms within CBER and CDER.
2. Section 314.70--Changes to an Approved Application
    To ensure consistent treatment of well-characterized biotechnology-
derived products within CBER and CDER, conforming amendments to 
Sec. 314.70 are also being proposed. Specifically, FDA is proposing an 
exception in Sec. 314.70(g) for well-characterized biotechnology 
products that provides that manufacturing changes to these products 
would be handled as described in proposed Sec. 601.12(b), (c), and (d) 
with regard to preapproval, notification, and submission in annual 
reports instead of as described in Sec. 314.70 (a), (b), (c), and (d). 
However, labeling changes would not be affected by the proposed change.
3. Summary of Proposed Sec. 601.12--Changes to an Approved Application
    Section 601.12 currently requires that important proposed changes 
in location, equipment, management and responsible personnel, or in 
manufacturing methods and labeling, be reported to the Director, CBER, 
not less than 30 days in advance of the time such changes are intended 
to be made. Proposed changes in manufacturing methods and labeling may 
not become effective until notification of acceptance is received from 
the Director, CBER.
    In comments made to the public docket and at the January 26, 1995, 
public meeting, representatives from the biologics industry requested 
that FDA modify Sec. 601.12 to be more flexible and less burdensome. 
The representatives also asked that a category system of changes to be 
reported be implemented, which would include changes that could be made 
without prior approval and those that would be required to be described 
in an annual report. Several comments requested that CBER make the 
reporting process comparable to Sec. 314.70 Supplements and other 
changes to an approved application which sets out three categories of 
notification of changes that are reported to FDA. These include: 
Supplements requiring FDA approval before the change is made, 
supplements for changes that may be made before FDA approval (changes 
being effected), and changes described in an annual report. Another 
comment stated that regulations should not stand as a barrier to 
manufacturing process improvement by requiring the filing of a 
supplement and CBER approval for even minor changes and improvements in 
the manufacturing process.
    The regulatory scheme that the agency is now proposing responds to 
these and other requests from the public. In response to the comments, 
FDA undertook an informal review of the types of changes that had 
historically been subject to prior approval and the impact such changes 
had on products and establishments. FDA also examined the existing 
requirements applicable to drugs and devices approved under the act; in 
particular, the regulations found in Secs. 314.70 and 814.39 (21 CFR 

[[Page 2741]]
814.39). FDA used this information to develop categories of reportable 
changes and criteria for assigning a change to the appropriate 
category.
    FDA is now proposing a three-category scheme for changes in the 
product, production process, equipment, facilities, or responsible 
personnel that would eliminate FDA approval of certain reportable 
changes and create a category of changes that would be described in an 
annual report. In addition to these two categories, there is a category 
of changes which would require approval prior to distribution. The 
agency believes that this proposed rule reduces unnecessary reporting 
and approval of changes for biologics licensed under the PHS Act 
consistent with the corresponding regulations applicable to drugs and 
devices approved under the act. These categories would include: (1) 
Supplement submission and approval prior to distribution of a product 
made using a proposed change that has a substantial potential to have 
an adverse effect on a product's safety, purity, potency, or 
effectiveness; (2) notification not less than 30 days prior to 
distributing a product made using a change that has a moderate 
potential to have an adverse effect on a product's safety, purity, 
potency, or effectiveness; and (3) an annual report describing changes 
that have minimal potential to have an adverse effect on a product's 
safety, purity, potency, or effectiveness. The agency does not intend 
that this rule would apply to normal maintenance and repair which would 
continue to be documented as it is now by firms under applicable 
current good manufacturing practice (CGMP) regulations (21 CFR parts 
210, 211, 606, and 820). The proposed revision also includes new 
Sec. 314.70(g) for well-characterized biotechnology products to make 
the requirements for changes made to such products consistent within 
CBER and CDER.
    The proposed revision also sets out a separate, three-category 
reporting system for biological product labeling changes. This scheme 
differs slightly from the scheme for proposed changes in the product, 
production process, equipment, facilities, or responsible personnel, 
and is consistent with requirements for labeling changes applicable to 
drugs approved under the act. A change to a product package label, 
container label, or package insert would require one of the following: 
(1) Submission of a supplement with FDA approval required prior to 
product distribution; (2) submission of a supplement with product 
distribution allowed prior to FDA approval; or (3) submission of the 
final printed label in an annual report. Promotional labeling and 
advertising would be required to be submitted in accordance with the 
requirements of Sec. 314.81(b)(3)(i)(21 CFR 314.81((b)(3)(i)).
    Although the proposed decrease in reporting and approval 
requirements and the corresponding reduction in the agency's role in 
reviewing changes before they are implemented does present some risks 
to product safety, purity, potency, and effectiveness, the agency 
believes that these risks are minimal. Under the proposed rule the 
applicant would be required to document that each change has no adverse 
effect on the safety, purity, potency, or effectiveness of the product. 
Such documentation would include appropriate validation and/or other 
studies. In some cases clinical data would be necessary and in other 
cases it would not. Applicants would be required to maintain records of 
the validation and study data under existing CGMP requirements. For 
those changes no longer requiring supplement approval, FDA review would 
shift to postmarketing review including inspections of manufacturing 
facilities.
    The proposed rule includes some specific examples of changes that 
fall into a particular category, but does not attempt to set out a 
comprehensive list of the changes included in each category. The agency 
recognizes that scientific and technological advances may change the 
need for supplement approval and/or reporting of many types of changes. 
Moreover, the potential for a particular change to adversely affect a 
product's safety, purity, potency, or effectiveness may differ for 
different products. FDA recognizes that a change made to a less well-
characterized product could fall into a different reporting category 
than the same change made to a product that was adequately 
characterized using analytical and functional tests. For example, scale 
up of a purification process may have a greater impact on a live virus 
vaccine than it may on a well-characterized recombinant DNA-derived 
purified protein. The agency believes that it can more readily respond 
to advances in technology, differences among products, and knowledge 
gained from experience by creating a rule that sets out general 
categories of changes. FDA recognizes, however, that applicants need 
clear guidance on how the agency intends to interpret the rule in order 
to efficiently produce products and adhere to regulatory requirements. 
Accordingly, FDA intends to make available guidance documents to 
describe the agency's current interpretation of specific changes 
falling into each category and to modify the documents as needed to 
reflect changes in science and technology. Notices of availability for 
drafts of guidance documents for reporting changes to most biological 
products and to well-characterized recombinant DNA-derived and 
monoclonal antibody biotechnology products are published elsewhere in 
this issue of the Federal Register. FDA is seeking comment on the use 
of guidance documents in conjunction with a final rule that may result 
from this proposal. FDA is also soliciting comment on the appropriate 
categorization of specific changes enumerated in this proposal and the 
guidance documents. In the Federal Register of October 25, 1995, (60 FR 
54695), FDA announced that a workshop would be held on December 11 
through 13, 1995, to discuss the definition of a well-characterized 
biotechnology product. Information from this workshop will help FDA to 
refine its definition of a well-characterized biotechnology product.
    FDA also anticipates that applicants could consult with the office 
which has product or establishment responsibility in CBER, or the 
Office of New Drug Chemistry in CDER, regarding appropriate objectives 
and design of studies to validate and document the potential for 
adverse effect of a proposed change for a particular product prior to 
committing the resources for such studies. Guidance on the appropriate 
reporting mechanism would also be available from these offices.

    The proposed rule would authorize the Directors of CBER and CDER, 
or their designees under 21 CFR part 5, to make decisions under the 
provisions of the rule as they apply to their respective centers.

    The agency expects that applicants would update their marketing 
applications in an annual report to assure that they accurately reflect 
current conditions. FDA is seeking comments on mechanisms that industry 
and the public believe may be appropriate for the periodic update of 
marketing applications. This proposed rule would require that some 
changes in manufacturing be submitted annually. CBER does not currently 
require, nor would this proposed rule require, that the annual report 
include additional information that is submitted for a drug approved 
under the act under Sec. 314.81(b)(2). FDA requests comment on whether 
the annual report for a biological product licensed under the 

[[Page 2742]]
PHS act should include the information described in Sec. 314.81(b)(2). 
-
    The proposed rule does not address requirements for submitting 
changes to a pending license application or supplement. Applicants 
currently submit amendments to pending applications in order to comply 
with the requirement in the PHS Act that a biologic product distributed 
for sale, barter, or exchange in interstate commerce must be 
manufactured in accordance with its license, and the regulations in 
Sec. 601.2 that set out the information and data that must be submitted 
in such license applications. FDA intends to consider whether specific 
requirements for submitting amendments to pending applications should 
be included when the agency undertakes a review of the licensing 
requirements in part 601 (21 CFR part 601).
4. Analysis of Sec. 601.12--Changes to An Approved Application-
    a. Changes requiring supplement submission and approval prior to 
distribution of product made using the change. Currently, all important 
proposed changes made by applicants must be reported not less than 30 
days in advance of the time such changes are intended to be made. Such 
changes in manufacturing methods and labeling may not become effective 
until notification of acceptance is received from the Director, CBER. 
Accordingly, CBER requires approval of all important changes in 
manufacturing methods and labeling before such changes are implemented. 
FDA continues to believe that it is important that the agency review 
data regarding any change that has a substantial potential to have an 
adverse effect on the safety, purity, potency, or effectiveness of the 
product, prior to distribution of the product made using the change, to 
assess whether the change will have a detrimental impact on the 
licensed product with regard to its safety, purity, potency, 
effectiveness, and consistency in biological and clinical 
characteristics. -
    Proposed Sec. 601.12(b)(1) would require an applicant to submit a 
supplement for approval to the Director, CBER, for any proposed change 
in the product, production process, equipment, or facilities that has a 
substantial potential to have an adverse effect on the product's 
safety, purity, potency, or effectiveness. These changes have the 
highest probability to adversely affect the product's safety, purity, 
potency, or effectiveness, and, in most instances, are integral to the 
manufacturing process or product production equipment. Proposed 
Sec. 601.12(b)(1) would require the applicant to submit a supplement 
containing a detailed description of the proposed change, the products 
involved, the manufacturing sites or areas affected, a description of 
the methods used and studies performed to evaluate the effect of the 
change on the product's safety, purity, potency, and effectiveness, the 
data derived from clinical and/or nonclinical laboratory studies, 
relevant validation protocols and data, and a reference list of the 
relevant standard operating procedures (SOP's). Approval of the 
supplement by the Director, CBER, would be required prior to 
distributing product made using the change.
    FDA proposes to enumerate the following changes that have a 
substantial potential to have an adverse effect on a product's safety, 
purity, potency, or effectiveness: A new indication, route of 
administration, dosing schedule, dosage form, or formulation; the 
addition, removal, or reordering of the step(s) of the licensed 
production process; and the conversion of a single product 
manufacturing area to a multiproduct manufacturing area. The agency 
believes that the need for FDA premarket approval of these significant 
changes is unlikely to vary with technological advances or due to 
differences among products, and that these changes should be enumerated 
in the rule.
    Other examples of changes that have caused detrimental effects on 
the safety, purity, potency, or effectiveness of products, even where 
applicants performed validation or other studies, include process 
changes or changes in analytical methods that result in a change of 
specification limits and addition of a new location for manufacture. 
FDA believes that the agency's continued prior review and approval of 
such changes is currently necessary to protect the public from products 
whose safety, purity, potency, or effectiveness may be compromised. 
However, FDA is proposing to describe these, and additional, specific 
examples of changes that CBER currently believes have substantial 
potential to adversely affect the product, in guidance, rather than 
enumerate them in the rule. FDA anticipates that scientific advances 
and future experience may reduce the need for premarket approval of 
certain changes and believes that the agency will be able to respond 
readily to changed circumstances by revising guidance that interprets 
the rule.
    b. Changes requiring notification not less than 30 days prior to 
distributing product made using the change. FDA believes that the 
public health can be adequately protected by eliminating agency 
approval of changes that have only a moderate potential to have an 
adverse effect on the safety, purity, potency, or effectiveness of a 
product. Changes that have moderate potential to affect a product's 
safety, purity, potency, or effectiveness are changes that do not have 
as high a probability for causing an adverse effect as those for which 
the agency proposes to require supplement approval. Under current 
Sec. 601.12, the agency requires FDA approval of all important proposed 
changes to a product, and requires that all important proposed changes 
in manufacturing methods and labeling await such approval before they 
may be distributed. FDA is now proposing to require that applicants 
notify the agency not less than 30 days prior to distributing a product 
made with a change in the product, production process, equipment, 
facilities, or responsible personnel that has moderate potential to 
have an adverse effect on the product, but to permit a product to be 
distributed after the 30-day period has elapsed without awaiting FDA 
approval. These notifications would not be considered supplements 
requiring approval. Thus, many changes that now require FDA approval as 
supplements could be implemented rapidly through the notification 
process without the prior submission of a supplement. For example, 
based on FDA's experience in reviewing submissions, the agency 
currently believes that minor changes in fermentation batch size using 
the same equipment and resulting in no change in specifications of the 
bulk or final product, and increases or decreases in the purification 
scale, not associated with a process change or different equipment, 
have moderate potential to have an adverse effect on the product. -
    In the notification, an applicant would be required to provide the 
agency with a clear description of the change, the product or products 
involved, the manufacturing sites or areas involved, a brief 
description of the validation and/or other clinical and/or nonclinical 
laboratory studies conducted to analyze the effect of the change on the 
safety, purity, potency, and effectiveness of the product, the dates of 
any such studies, reference to any SOP's used to complete the studies, 
and a summary of the relevant data or information. During the 30-day 
period, FDA would review the notification to determine if it was 
properly submitted as a notification. If FDA agreed that the change 
described was of the type that had moderate potential to adversely 
affect the safety, purity, potency, or effectiveness of the product, 
and the notification included 

[[Page 2743]]
all of the required information, the applicant could begin distribution 
of a product made using the change 30 days after FDA's receipt of the 
notification.
    Under the proposed rule, FDA would ordinarily contact the applicant 
before the expiration of the 30-day period if the agency determined 
that the change was improperly submitted as a notification. If FDA 
informed the applicant within the 30-day period that the submission did 
not meet the requirements for a notification, the applicant would be 
required to correct the deficiencies in the information submitted 
before distributing the product. Depending on the problem, FDA would 
respond in one of two ways: (1) If the change was of the type that 
presented a substantial potential to adversely affect the safety, 
purity, potency, or effectiveness of the product, the agency would 
inform the applicant that the change should be submitted as a 
supplement and the applicant would be required to await FDA approval 
before product produced with the change could be distributed; or (2) if 
the change was of the type that could properly be submitted as a 
notification, but the required information was incomplete, the 
applicant would be required to supply the missing information and wait 
until FDA determined compliance with this section before distributing 
the product.
    FDA intends, during the 30 days, to focus its review on determining 
whether the applicant reported the change under the appropriate 
mechanism, and, if so, whether any of the required information was 
missing. Under the proposed rule, FDA would not ordinarily contact the 
applicant if the notification was properly submitted in accordance with 
Secs. 601.12(c) or 314.70(g)(2). FDA anticipates that applicants would 
use a method of delivery for notifications that would allow 
confirmation of the submission having been received by FDA.
    FDA would also ordinarily review the substantive information 
contained in a notification and request the applicant to clarify the 
submission if necessary. If the agency's review determined that 
additional studies or information were necessary to document the lack 
of an adverse effect on the safety, purity, potency, or effectiveness 
of the product, the agency could request that additional data be 
collected. Failure to comply with the proposed requirements and 
existing CGMP requirements to properly validate the change could result 
in enforcement action. Following the agency's review, FDA would send to 
the applicant a stamped copy of the cover letter for the notification 
indicating that FDA had placed the submission in the applicant's 
license application file. FDA anticipates that the agency could conduct 
a more extensive review of data supporting the notification during 
inspections if necessary.
    FDA believes that a notification process, as described above, for 
changes that have a moderate potential to affect the safety, purity, 
potency, or effectiveness of the product would protect against the 
distribution of unsafe or ineffective products while speeding the 
availability of improved products. Under the proposed rule, applicants 
would be required to demonstrate, through appropriate validation or 
other studies, that a change has no adverse effect on the safety, 
purity, potency, and effectiveness of the product. Applicants would be 
required to briefly describe the studies and data in the notification. 
While a full description of the studies would not be required to be 
submitted in a notification, as it generally would be in a supplement, 
applicants would be required to maintain the data in records that are 
available for FDA inspection under existing CGMP's. The 30-day period 
that would be required to elapse before products made using the change 
could be distributed would permit the agency to redirect submissions 
for changes that could substantially affect product safety, purity, 
potency, or effectiveness to the supplement approval process before the 
product entered the market. In addition, the agency could identify 
applicants that, through an incomplete submission, failed to establish 
that they had followed the necessary steps to validate and implement a 
change. Applicants would be required to submit the missing information 
before they could distribute the product.
    c. Changes to be described in an annual report. FDA recognizes that 
there are changes in the product, production processes, equipment, 
facilities, and responsible personnel that have minimal potential to 
have an adverse effect on the product's safety, purity, potency, or 
effectiveness. Under the current Sec. 601.12, the agency has required 
many of these changes to await supplement approval before they could be 
implemented. FDA believes that prior agency approval of these changes 
is unnecessary, and is proposing in Sec. 601.12(d) that such changes 
would not be required to be approved by the agency. FDA continues to 
believe that it is important that such changes be documented and 
validated so that there is a mechanism for assessing the consequences 
of the change. FDA is therefore proposing that changes that have 
minimal potential to have an adverse effect on the product's safety, 
purity, potency, or effectiveness be required to be described by the 
applicant in an annual report. The annual report would be required to 
be submitted each year within 60 days of the anniversary date of 
approval of the application. FDA believes that the agency can 
effectively assess compliance with this section and CGMP requirements 
for changes that have minimal potential to adversely affect the 
product's safety, purity, potency, or effectiveness by having ready 
access to information regarding such changes through the submission of 
an annual report and by inspection. Applicants would be required to 
include in the annual report a listing of all products involved, a 
brief description of and reason(s) for the change, the manufacturing 
sites or areas involved, the date each change was made, and a cross-
reference to any validation protocols and/or SOP's. Both the applicant 
and FDA could use this information to assess whether problems which may 
arise with products are related to such changes. Under proposed 
Sec. 601.12(a), the applicant would be required to perform appropriate 
validation or other studies to demonstrate the lack of adverse effect 
on the safety, purity, potency, and effectiveness of the product. 
Applicants would maintain records of such studies under existing CGMP 
requirements.
    As a result of FDA's experience in reviewing changes, the agency 
believes that changes that have a minimal potential to have an adverse 
effect on the product would include such changes as a change in storage 
conditions of in-process intermediates based on data derived from 
studies following a protocol in the approved license application; 
modifications in analytical procedures with no change in the basic test 
methodology or existing release specifications; relocation of 
analytical testing laboratories within a licensed facility; and area 
upgrades such as the installation of improved finishes on floors or 
walls.
    d. Labeling. Under the current Sec. 601.12, all important proposed 
labeling changes are required to be submitted for FDA approval before 
they may be implemented. The agency recognizes, however, that some 
labeling changes may not have a substantial impact on the safe and 
effective use of the product. For other changes, such as updates of 
important safety information, it is important that prescribers and 
patients have access to current information as soon as it becomes 
available. Therefore, the agency is proposing to revise the biological 
products reporting requirements for 

[[Page 2744]]
labeling changes. The regulations in Sec. 314.70(b), (c), and (d), 
governing how labeling changes are reported for products regulated by 
CDER, are not affected by the proposal. In fact, the proposed revision 
of Sec. 601.12(e) is consistent with requirements for labeling changes 
applicable to drugs approved under the act.
    Changes to labeling would be submitted to CBER 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 product with 
the accompanying revised labeling prior to such approval, or (3) 
submission of final printed labeling in an annual report. It is 
expected that proposed Sec. 601.12(e) would significantly decrease the 
number of labeling submissions that currently require approval prior to 
use of the labeling.
    Under proposed Sec. 601.12(e)(2), an applicant would be required to 
submit a supplement, but could disseminate the revised labeling with 
the product, at the time the supplement was submitted. Such revisions 
to the labeling would include any information that adds or strengthens 
a contraindication, warning, precaution, or adverse reaction; adds or 
strengthens a statement about abuse, dependence, psychological effect, 
or overdosage; adds or strengthens an instruction about dosage and 
administration that is intended to increase the safe use of the 
product; or deletes false, misleading, or unsupported indications for 
use or claims for effectiveness.
    FDA believes that permitting these labeling changes to be effected 
and product distributed prior to FDA approval would facilitate labeling 
changes intended to adequately inform prescribers and patients of the 
risks and benefits of a biological product and thereby allow 
prescribers and patients earlier access to important new information on 
the safe use of the product. Proposed Sec. 601.12(e)(2) would require 
that the supplement clearly identify any changes being made and include 
necessary supporting data. Under the proposed rule, the changes 
identified in Sec. 601.12(e)(2) could be implemented prior to agency 
approval. FDA could, however, deny approval of a supplement for a 
labeling change that has already been disseminated with the product. In 
assessing an applicant's plans to correct a problem, FDA would consider 
the applicant's reasons for making the change and the alternatives 
available to the applicant. If the circumstances warranted, FDA could 
require the labeling change to be immediately discontinued. However, 
when circumstances permit, the agency would allow the applicant to 
correct a problem with minimal expense and without unnecessary waste. -
    Under proposed Sec. 601.12(e)(3), an applicant making editorial or 
other minor changes, or a change in the information on how the biologic 
is supplied that does not involve a change in the dosage strength or 
dosage form, would be required to submit a description of the changes 
and all final printed labeling incorporating the changes in an annual 
report to be submitted to the Director, CBER. For all changes in the 
package insert, package label, and container label that would not fall 
under Sec. 601.12(e)(2) or (e)(3), an applicant would be required to 
submit a supplement supporting the proposed change and await FDA 
approval prior to distribution.
    Under proposed Sec. 601.12(e)(4), promotional labeling and 
advertising would be submitted in accordance with 21 CFR 
314.81(b)(3)(i), which requires that an applicant submit specimens of 
mailing pieces and any other labeling or advertising devised for 
promotion of the product at the time of initial dissemination of the 
labeling and at the time of initial publication of the advertisement 
for a prescription product.
    e. Failure to comply. FDA is proposing in Sec. 601.12(f) that in 
the event of repeated failure of the applicant to comply with 
Sec. 601.12, the Director, CBER, may require that the applicant submit 
a supplement for any proposed change and obtain CBER approval prior to 
distributing the product made using the change. This measure would be 
in addition to other remedies available in applicable laws and 
regulations, including suspension or revocation of licenses, seizure of 
products, and injunction, among others. With this proposed rule, FDA is 
undertaking to significantly reduce the number of changes that are 
reported, reviewed, and approved by the agency. Continued protection of 
the public from products with compromised safety, purity, potency, or 
effectiveness will depend on applicants' adherence to the proposed 
requirements to conduct validation and/or other studies to document the 
lack of adverse effect on the product and utilization of the 
appropriate mechanism to inform the agency of such changes. In 
determining repeated failure to comply with the Sec. 601.12 and whether 
an applicant would be required to file future submissions as 
supplements, the agency would consider, among other things, the 
applicant's compliance history and the significance of the 
deficiencies.
    f. Administrative review. Proposed Sec. 601.12(g) provides that an 
applicant may request a review of FDA employee decisions made pursuant 
to section Sec. 601.12 in accordance with Sec. 10.75 (21 CFR 10.75). 
Section 10.75 provides a mechanism for internal agency review of 
decisions. FDA proposes to include the reference to Sec. 10.75 in 
Sec. 601.12(g) so that applicants who wish agency review of a decision 
made under the provisions of the rule are made aware of the mechanism 
for such review. The internal agency review of a decision would be 
based on the information in the administrative file. FDA believes that 
it is important for the agency to apply regulations affecting regulated 
products consistently and fairly, and believes that agency review 
should be available to resolve a disputed issue.

II. Analysis of Impacts

A. Method of Analysis

    To determine the impact of the proposed rule, CBER undertook an 
analysis of changes approved as supplements during the 9-month period 
between October 1, 1994, and June 1, 1995. CBER has determined that the 
proposed rule as currently written would result in an overall 32 
percent reduction in submissions requiring prior agency approval before 
an applicant could commence distributing product made using the change. 
The extent of the reduction would be greater for certain products. 
Under the proposed regulation, 88 of 175 submissions reviewed as 
supplements under the current regulation (for changes to biological 
products other than blood products and blood component products) would 
be supplements requiring prior approval, 62 would be notifications to 
CBER not requiring FDA approval, and 25 would be described in an annual 
report. For blood and blood components, of 177 supplements approved in 
a 2-month portion of the 9-month period, 128 would be supplements 
requiring prior approval under the proposed rule, 36 would be 
notifications, and 13 would be described in an annual report.

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

    FDA has examined the impact of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354). 
Executive Order 12866 directs agencies to assess all costs and benefits 
of available regulatory alternatives and, when regulation is necessary, 
to select the regulatory 

[[Page 2745]]
approaches that maximize net benefits (including potential economic, 
environmental, public health and safety, and other advantages; 
distributive impacts; and equity). The agency believes that this 
proposed rule is consistent with the regulatory philosophy and 
principles identified in the Executive Order. The proposed 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 proposed rule would be a substantial reduction in 
reporting burden for applicants and in review burden for the agency. In 
addition, FDA anticipates that the proposed rule would encourage 
applicants to improve their licensed products and methods of 
manufacture.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because, as stated above, the overall result of the 
proposed rule would be a substantial reduction of the regulatory and 
reporting burden, the agency certifies that the proposed 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.

C. Review under the Paperwork Reduction Act of 1995

    This proposed rule contains information collections which are 
subject to review by the Office of Management and Budget (OMB) under 
the Paperwork Reduction Act of 1995. The title, description, and 
respondent description of the information collection 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.
    With respect to the following collection of information, FDA 
invites comments on: (1) Whether the proposed collection of information 
is necessary to for proper performance of FDA's functions, including 
whether the information will have practical utility; (2) the accuracy 
of FDA's estimate of the burden of the proposed collection of 
information, including the validity of the methodology and assumptions 
used; (3) ways to enhance the quality, utility, and clarity of the 
information to be collected; and (4) ways to minimize the burden of the 
collection of information on respondents, including through the use of 
automated collection techniques, when appropriate, and other forms of 
information technology.
Title: 21 CFR 601.12--Changes to an Approved Application and 21 CFR 
314.70(g) Exception.
Description: This proposed rule would change the requirements for 
respondents to report to FDA changes in the product, labeling, 
production process, equipment, facilities, or responsible personnel 
established in an approved application for a biological product or for 
a well-characterized biotechnology product. The respondent would report 
the change to FDA in one of the three following ways depending on the 
potential for the change to have an adverse effect on the safety, 
purity, potency or effectiveness of the product: (1) Changes that have 
a significant potential to have an adverse effect on the product would 
be submitted in a supplement requiring prior approval by FDA before 
distribution of a product made using the change; (2) changes that have 
a moderate potential to have an adverse effect on the product would be 
submitted to FDA in a notification not less than thirty days prior to 
distribution of the product made using the change; and (3) Changes that 
have a minimal potential to have an adverse effect on the product would 
be submitted by the respondent in an annual report.
    Labeling changes for a biological product would 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 
product with the accompanying revised labeling prior to such approval; 
or (3) submission of final printed labeling in an annual report. 
Promotional labeling and advertising would be submitted in accordance 
with 314.81(b)(3)(i). Labeling changes for well-characterized 
biotechnology products would not be affected by this proposed rule.
Description of Respondents: All manufacturers and applicants holding a 
biological license approved under section 351 of the Public Health 
Services Act and all manufacturers and applicants of well-characterized 
biotechnology products holding an approved NDA would report (Business 
or other for-profit). -
    These estimates are an approximation of the average time expected 
to be necessary for a collection of information. They are based on such 
information as is available to FDA. There are no capital costs 
associated with this information collection. It is estimated that 20 
percent of all reports required under these proposed regulations are 
being prepared by contractors. The burden hours in the chart below 
therefore reflect a 20 percent reduction per regulation because these 
burden hours will not be expended by the affected industry rather they 
will be expended by the contractors. 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 column labeled ``Operating and Maintenance Costs.''
    The agency seeks comments on these estimates, particularly the 
industry's view of the number of firms and products affected by the 
collections of information contained in this proposed rule.

                                                                                                                                                                                                
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                     Estimated Annual Burden                                                                                    
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
                                 Number of                               Number of          Number of Responses Per                                                                             
    Regulation (21 CFR)         Respondents     Hours Per Response       Responses                 Respondent             Total Operating and Maintenance Costs     Total Hours Per Regulation  
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
601.12(b)                   391                 80                  610                 1.56                             $390,400                                39,040                         
601.12(c)                   391                 40                  280                 0.72                             $89,600                                 8,960                          
601.12(d)                   391                 10                  110                 0.28                             $8,800                                  880                            
601.12(e)(1)                391                 40                  200                 0.51                             $64,000                                 6,400                          
601.12(e)(2)                391                 20                  20                  0.05                             $3,200                                  320                            
601.12(e)(3)                391                 10                  220                 0.56                             $17,600                                 1,760                          
601.12(e)(4)                391                 10                  110                 0.28                             $8,000                                  800                            

[[Page 2746]]
                                                                                                                                                                                                
314.70(g)(1)                4                   80                  50                  12.5                             $32,000                                 3,200                          
314.70(g)(2)                2                   40                  3                   1.5                              $960                                    96                             
314.70(g)(3)                6                   10                  20                  3.33                             $1,600                                  160                            
                                                                                                                                                                                                
Totals                                                                                                                   Total O&M Costs = $616,160              Total Hours = 61,616           
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------


    The agency has submitted a copy of this proposed rule to OMB for 
its review and approval of these information collections. Interested 
persons are requested to send comments regarding this information 
collection, including suggestions for reducing this burden to the 
Office of Information and Regulatory Affairs, OMB, New Executive Office 
Bldg., 725 17th St. NW., rm. 10235, Washington, DC 20503, Attn: Desk 
Officer for FDA. Submit written comments on the information collection 
by February 28, 1996, but not later than March 29, 1996.

D. Review Under the National Environmental Policy Act

    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.
    Interested persons may, on or before April 29, 1996, submit to the 
Dockets Management Branch (address above) written comments regarding 
the proposal. Two copies of any comments are to be submitted, except 
that individuals may submit one copy. Comments are to be identified 
with the docket number found in brackets in the heading of this 
document. Received comments may be seen in the office above between 9 
a.m. and 4 p.m., Monday through Friday. Submit comments on the 
information collection requirements to the Office of Information and 
Regulatory Affairs, OMB, (address above).
    As stated previously, FDA plans to hold an open public meeting 
during the comment period to facilitate public comment on this proposed 
rule. The time and location of this meeting will be announced in a 
future issue of the Federal Register.

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.
    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, it is proposed that 21 CFR parts 314, 
600, and 601 be 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 new paragraph (g) as 
follows:
Sec. 314.70   Supplements and other changes to an approved application.

* * * * *
     (g) Exception. An applicant proposing to make a change in a well-
characterized biotechnology product of the type described in 
Sec. 314.70(a), (b)(1), (b)(2), (c)(1), (c)(3), (d)(1), and (d)(4) 
through (d)(9) shall comply with the following:
    (1) Changes requiring supplement submission and approval prior to 
distribution of product made using the change. (i) A supplement shall 
be submitted for any proposed change in the product, production 
process, equipment, or facilities that has substantial potential to 
have an adverse effect on the safety, purity, potency, or effectiveness 
of the product. These changes include but are not limited to:
    (A) A new indication, route of administration, dosage form, dosing 
schedule or formulation;
    (B) Addition, removal, or reordering of the step(s) of the 
production process; and
    (C) Change from production of a single product to production of 
multiple products at a facility.
    (ii) The applicant shall obtain FDA approval of the supplement 
prior to distribution of the product made using the change. The 
following information 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 product's safety, purity, 
potency, and effectiveness;
    (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 notification not less than 30 days prior to 
distributing product made using the change. (i) An applicant shall 
inform FDA, in a written notification labeled ``Notification--Changes 
being effected in 30 days,'' of any change in the product, production 
process, equipment, facilities, or responsible personnel that has 
moderate potential to have an adverse effect on the safety, purity, 
potency, or effectiveness of the product. Distribution of the product 
manufactured after the change was instituted may not begin until 30 
days after FDA notification. The following information shall be 
contained in the notification:
    (A) A clear, brief description of the change;
    (B) The products(s) involved;
    (C) The manufacturing site(s) or area(s) involved;
    (D) A brief description of the validation and/or other studies 

[[Page 2747]]
    conducted to analyze the effect of the change on the safety, purity, 
potency, and effectiveness of the product;
    (E) The dates of the studies;
    (F) Reference to relevant SOP's used to complete the studies; and
    (G) A summary of the relevant data or information.
    (ii) If within 30 days following FDA's receipt of the notification 
FDA informs the applicant that either:
    (A) The change requires supplement submission in accordance with 
paragraph (g)(1) of this section; or
    (B) Any of the information required under paragraph (g)(2)(i) of 
this section is missing, the applicant shall not distribute the product 
made with the change until FDA determines that compliance with this 
section is achieved.
    (3) Changes to be described in an annual report. Changes in the 
product, production process, equipment, facilities, or responsible 
personnel that have minimal potential to have an adverse effect on the 
product's safety, purity, potency, or effectiveness, 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 annual report shall contain the following information for each 
change:
    (i) A list of all products involved;
    (ii) A brief description of and reason(s) for the change; -
    (iii) The manufacturing sites or areas involved;
    (iv) The date each change was made; and
    (v) A cross-reference to relevant validation protocol(s) and/or 
SOP's.
* * * * *

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 in this section, an applicant shall inform 
the Director, Center for Biologics Evaluation and Research (CBER), 
about each change in the product, labeling, production process, 
equipment, facilities, or responsible personnel 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 nonclinical laboratory studies 
the lack of adverse effect of the change on the safety, purity, 
potency, and effectiveness of the product. Single copies of Food and 
Drug Administration (FDA) guidance describing FDA's current 
interpretation of this regulation may be obtained from the 
Congressional and Consumer Affairs Branch (HFM-12), Center for 
Biologics Evaluation and Research, Food and Drug Administration, 1401 
Rockville Pike, Rockville, MD 20852-1448.
    (b) Changes requiring supplement submission and approval prior to 
distribution of product made using the change.
    (1) A supplement shall be submitted to the Director, CBER, for any 
proposed change in the product, production process, equipment, or 
facilities that has substantial potential to have an adverse effect on 
the safety, purity, potency, or effectiveness of the product. These 
changes include but are not limited to the following:
    (i) A new indication, route of administration, dosage form, dosing 
schedule or formulation;
    (ii) Addition, removal, or reordering of the step(s) of the 
licensed production process; and
    (iii) Change from production of a single product to production of 
multiple products at a licensed facility;
    (2) The applicant shall obtain approval of the supplement from the 
Director, CBER, prior to distribution of the product made using the 
change. The following information 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 product's safety, purity, 
potency, and effectiveness;
    (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 notification not less than 30 days prior to 
distributing product made using the change. (1) An applicant shall 
inform the Director, CBER, in a written notification labeled ``Changes 
being effected in 30 days,'' of any change in the product, production 
process, equipment, facilities, or responsible personnel that has 
moderate potential to have an adverse effect on the safety, purity, 
potency, or effectiveness of the product. Distribution of the product 
manufactured after the change was instituted may not begin until 30 
days after receipt of the notification by CBER. The following 
information shall be contained in the notification:
    (i) A clear, brief description of the change;
    (ii) The product(s) involved;
    (iii) The manufacturing site(s) or area(s) involved;
    (iv) A brief description of the validation and/or other studies 
conducted to analyze the effect of the change on the safety, purity, 
potency, or effectiveness of the product;
    (v) The dates of the studies;
    (vi) Reference to relevant SOP's used to complete the studies; and
    (vii) A summary of the relevant data or information.
    (2) If within 30 days following FDA receipt of the notification, 
the Director, CBER informs the applicant that either:
    (i) The change requires supplement submission in accordance with 
paragraph (b) of this section; or
    (ii) Any of the information required under paragraph (c)(1) of this 
section is missing, the applicant shall not distribute the product made 
with the change until compliance with this section is achieved.
    (d) Changes to be described in an annual report. (1) Changes in the 
product, production process, equipment, facilities, or responsible 
personnel that have minimal potential

[[Page 2748]]

to have an adverse effect on the product's safety, purity, potency, or 
effectiveness, 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 annual report shall contain the following 
information for each change: -
    (i) A list of all products involved;
    (ii) A brief description of and reason(s) for the change; -
    (iii) The manufacturing sites or areas involved;
    (iv) The date each change was made; and
    (v) A cross-reference to relevant validation protocol(s) and/or 
SOP's.
    (2) 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 section obtained for each change 
made during the annual reporting interval which ends on the anniversary 
date.
    (e) Labeling changes--(1) Label changes requiring supplement 
submission--distribution of a product with a label change must await 
FDA approval. An applicant shall submit to CBER a supplement describing 
a proposed change in the package insert, package label, or container 
label, except those described in paragraphs (e)(2) and (e)(3) of this 
section, and include the information necessary to support the proposed 
change. The supplement shall clearly highlight the proposed change in 
the label. The applicant shall obtain approval from the Director, CBER, 
prior to distributing a product with the label change. -
    (2) Label changes requiring supplement submission; product with a 
label change may be distributed before FDA approval. (i) An applicant 
shall submit to CBER, 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, overdosage;
    (C) To add or strengthen an instruction about dosage and 
administration that is intended to increase the safe use of the 
product; or
    (D) To delete false, misleading, or unsupported indications for use 
or claims for effectiveness.
    (ii) 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 should be plainly marked: ``Special Labeling 
Supplement--Changes Being Effected.''
    (3) Label 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 to CBER in an 
annual report submitted each year within 60 days of the anniversary 
date of approval of the application:
    (A) Editorial or similar minor changes; or
    (B) A change in the information on how the drug 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 in 
accordance with the requirements set forth in Sec. 314.81(b)(3)(i) of 
this chapter, except that Form FDA-2567 shall be used in lieu of Form 
FDA-2253.
    (f) 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, the Director, CBER, may require that the 
applicant submit a supplement for any proposed change to, and obtain 
approval of the supplement from, the Director, CBER, prior to 
distributing a product made using the change. -
    (g) Administrative review. Under Sec. 10.75 of this chapter, an 
applicant may request internal FDA review of CBER employee decisions 
under this section.

    Dated: January 16, 1996.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 96-1580 Filed 1-25-96; 10:41 am]
BILLING CODE 4160-01-F