[Federal Register Volume 69, Number 68 (Thursday, April 8, 2004)]
[Rules and Regulations]
[Pages 18728-18767]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 04-7532]



[[Page 18727]]

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Part IV





Department of Health and Human Services





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Food and Drug Administration



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



Supplements and Other Changes to an Approved Application; Final Rule



Guidance for Industry on Changes to an Approved NDA or ANDA; 
Availability; Notice

  Federal Register / Vol. 69, No. 68 / Thursday, April 8, 2004 / Rules 
and Regulations  

[[Page 18728]]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

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

[Docket No. 1999N-0193]
RIN 0910-AB61


Supplements and Other 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 its 
regulations on supplements and other changes to an approved application 
to implement the manufacturing changes provision of the Food and Drug 
Administration Modernization Act of 1997 (the Modernization Act). The 
final rule requires manufacturers to assess the effects of 
manufacturing changes on the identity, strength, quality, purity, and 
potency of a drug or biological product as those factors relate to the 
safety or effectiveness of the product. The final rule sets forth 
requirements for changes requiring supplement submission and approval 
before the distribution of the product made using the change, changes 
requiring supplement submission at least 30 days prior to the 
distribution of the product, changes requiring supplement submission at 
the time of distribution, and changes to be described in an annual 
report.

DATES: This rule is effective June 22, 2004.

FOR FURTHER INFORMATION CONTACT: David J. Cummings, Center for Drug 
Evaluation and Research (HFD-357), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-443-5187, or Robert A. Yetter, 
Center for Biologics Evaluation and Research (HFM-10), Food and Drug 
Administration, 1401 Rockville Pike, Rockville, MD 20852, 301-827-0373.

SUPPLEMENTARY INFORMATION:

I. Background

    Section 116 of the Modernization Act (Public Law 105-115) amended 
the Federal Food, Drug, and Cosmetic Act (the act) by adding section 
506A (21 U.S.C. 356a). That section describes requirements and 
procedures for making and reporting manufacturing changes to approved 
new drug and abbreviated new drug applications, to new and abbreviated 
animal drug applications, and to license applications for biological 
products under section 351 of the Public Health Service (PHS) Act (the 
PHS act). Section 506A of the act revises current procedures for 
approving manufacturing changes. Major manufacturing changes, as 
defined in section 506A of the act, are of a type determined by the 
Secretary of Health and Human Services (the Secretary) to have a 
substantial potential to adversely affect the identity, strength, 
quality, purity, and potency as they may relate to the safety and 
effectiveness of a drug. Such changes require prior approval of a 
supplemental application. Section 506A of the act also states that the 
Secretary may require submission of a supplemental application for 
drugs made with manufacturing changes that are not major and may 
establish categories of manufacturing changes for which a supplemental 
application is required. In such a case, the applicant may begin 
distribution of a drug 30 days after FDA has received a supplemental 
application unless the agency notifies the applicant within the 30-day 
period that prior approval of the application is required. Under the 
statute, FDA may also designate a category of manufacturing changes 
that permit the applicant to begin distributing a drug made with such 
changes upon receipt by the agency of a supplemental application for 
the change. Finally, FDA may also authorize applicants to distribute 
drugs manufactured with a change without submitting a supplemental 
application. The law provides that FDA may establish categories of 
manufacturing changes that may be made without submitting a 
supplemental application.

A. Development of the Regulation

    In the Federal Register of June 28, 1999 (64 FR 34608), FDA 
published a proposed rule to implement section 506A of the act for 
human new drug applications (NDAs) and abbreviated new drug 
applications (ANDAs), as well as for licensed biological products (the 
June 1999 proposal). In that same issue of the Federal Register (64 FR 
34660), FDA announced the availability of a draft guidance for industry 
entitled ``Changes to an Approved NDA or ANDA.'' This guidance was 
intended to assist applicants in determining how they should report 
changes to an approved NDA or ANDA under section 506A of the act as 
well as under the proposed revisions to the human drug regulations 
pertaining to supplements and other changes to an approved application. 
In the Federal Register of November 23, 1999 (64 FR 65716), FDA 
announced the availability of a guidance to assist applicants in 
determining how they should report changes to an approved NDA or ANDA 
under section 506A of the act, pending finalization of the June 1999 
proposal. FDA has revised the guidance to conform to this final rule 
and is announcing the availability of the guidance elsewhere in this 
issue of the Federal Register.

B. A Risk-Based Approach

    The publication of this final rule is an important step in the 
process of adopting a risk-based approach to the regulation of 
pharmaceuticals. In the 1990s, FDA sponsored research at the University 
of Maryland and other universities on the types of chemistry and 
manufacturing changes to immediate release solid oral drug products 
that could affect drug performance (i.e., identity, strength, quality, 
purity, and potency) and, therefore, safety and effectiveness. Using 
that research, FDA's Center for Drug Evaluation and Research (CDER) 
began to develop a risk-based approach to the implementation of 
manufacturing changes. The approach provided for a continued high level 
of scrutiny by FDA of changes that were most likely to affect the 
performance of a drug and decreased scrutiny of changes that were not 
likely to affect the performance of a drug.
    The risk-based approach was first explained in a series of guidance 
documents (the Scale-up and Postapproval Changes (SUPAC) guidances) 
that reduced the regulatory burden of obtaining FDA authorization to 
make certain changes. The work continued in regulations issued by the 
Center for Biologics Evaluation and Research (CBER) in 1997 (21 CFR 
601.12). In November 1997, this risk-based approach was codified in 
section 116 of the Modernization Act.
    This final rule implements section 116 of the Modernization Act by 
incorporating the statutory standards for characterizing proposed 
changes as having substantial, moderate, or minimal potential to 
adversely affect the identity, strength, quality, purity, and potency 
of a drug as they may relate to its safety and effectiveness and 
determining submission requirements based on the potential risks 
associated with the changes. For changes with a substantial potential 
to affect the designated characteristics of a drug, FDA must review and 
approve a supplement that contains information showing that the 
proposed change will not adversely affect the drug's characteristics 
(i.e., information developed by the holder of the application to 
validate the effect of the proposed change) before distribution of the 
product made using the change.

[[Page 18729]]

    It was anticipated when section 116 of the Modernization Act was 
written that the science of manufacturing would evolve over time and 
affect whether changes would be considered major or nonmajor. To 
accommodate future technological advancements, section 116 of the 
Modernization Act and this final implementing regulation both provide 
that FDA may, by regulation or guidance, change the designation of a 
particular category of change from major to nonmajor or vice versa. 
This concept of an evolving risk-based approach to manufacturing 
changes also is consistent with the agency's Good Manufacturing 
Practices Initiative (``Pharmaceutical cGMPs for the 21st Century,'' 
www.fda.gov/cder/gmp/index.htm). The goals of that initiative, launched 
in August 2002, include:
     Ensuring that state-of-the-art pharmaceutical 
science is utilized in the regulatory review and inspection policies;
     Encouraging the adoption of new technological 
advances in high quality and efficient manufacturing by the 
pharmaceutical industry;
     Assessing the applicable current good 
manufacturing practice (CGMP) requirements relative to the best quality 
management practices;
     Strengthening public health protection by 
implementing risk-based approaches that focus both industry and FDA 
attention on critical areas for improving product safety and quality; 
and
     Enhancing the consistency and coordination of 
FDA's drug quality oversight activities.
    Specifically, one of the efforts of the CGMP initiative is to 
facilitate continuous improvement and innovation in manufacturing by 
allowing manufacturers to make certain types of changes in their 
processes without prior FDA approval. This rule, in keeping with that 
initiative, provides for a mechanism of continuous improvement through 
the guidance process (21 CFR 10.115) that may provide for less 
burdensome documentation of certain changes as manufacturing processes 
and pharmaceutical science develop.

II. Highlights of Revisions to the Proposed Rule

A. Definitions

    FDA has revised the proposed definition of ``specification'' by 
changing the phrase ``other components including container closure 
systems and in-process materials'' to ``components, in-process 
materials, container closure systems, and other materials used in the 
production of a drug substance or drug product.'' FDA made this change 
for consistency with other regulations. FDA proposed a definition for 
the term ``validate the effects of the change.'' In the final rule, the 
agency has changed the word ``validate'' to ``assess'' and provides a 
definition for the term ``assess the effects of the change.''

B. Changes to an Approved Application

    The proposal required that the holder of an approved application 
validate the effects of manufacturing changes on the identity, 
strength, quality, purity, and potency of the drug as these factors may 
relate to the safety or effectiveness of the drug. FDA has revised this 
provision to require that the holder of an approved application assess 
the effects of manufacturing changes. FDA has deleted the phrase ``on 
the identity, strength, quality, purity, and potency of the drug 
product as these factors may relate to the safety or effectiveness of 
the drug product'' because this information is already included in the 
definition of the term ``assess the effects of the change.''
    Previously, Sec.  314.70(c) (21 CFR 314.70(c)) stated that the 
applicant who submits a changes-being-effected supplement to FDA must 
promptly revise all promotional labeling and advertising to make it 
consistent with any change in the labeling. The proposal retained this 
provision and FDA stated in the preamble that the requirement would 
apply equally to all labeling changes. FDA has revised this provision 
to limit the requirement to those labeling changes submitted in 
supplemental applications and not to those in annual reports.
    The proposal required the applicant to include in a cover letter a 
list of all changes contained in the supplement or annual report. FDA 
has clarified that the requirement to include the list of changes in a 
cover letter applies only to changes contained in a supplement; the 
information is already submitted in an annual report.

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

    FDA has limited the requirement to include only those changes to a 
drug product container closure system that involve changes in the type 
or composition of a packaging component. FDA intends to provide 
additional guidance on container closure systems changes that will be 
considered moderate changes or changes that can be reported in an 
annual report.
    FDA proposed to require that a reference list of relevant standard 
operating procedures (SOPs) be contained in all supplements submitted 
under this section. FDA has revised this provision to specify that a 
reference list of relevant SOPs must be submitted for changes to a 
natural product, a recombinant deoxyribonucleic acid (DNA)-derived 
protein/polypeptide product, or a complex or conjugate of a drug 
substance with a monoclonal antibody, and for changes to the 
sterilization process and test methodologies related to sterilization 
process validation.

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

    FDA has revised the June 1999 proposal to clarify that the 
requirement to submit 12 copies of finished product labeling applies to 
supplements for changes that may be implemented 30 days after FDA 
receives the supplement.
    FDA has clarified that the changes in the container closure system 
submitted in supplements under these moderate changes provisions do not 
include the changes described under the provisions requiring prior 
approval or the changes submitted in an annual report.
    FDA has revised the changes solely affecting a natural protein 
product, a recombinant DNA-derived protein/polypeptide product, or a 
complex or conjugate of a drug with a monoclonal antibody to specify 
the use of ``different equipment'' instead of ``new or different 
equipment'' for changes in production scale, and equipment of ``a 
different design'' instead of ``similar but not identical design and 
operating principle'' for the replacement of equipment.
    FDA is also adding to the moderate changes provisions a change in 
the relaxation of an acceptance criterion or deletion of a test to 
comply with an official compendium that is consistent with FDA 
statutory and regulatory requirements. FDA is not requiring that a 
prior approval supplement be submitted for this type of change because 
the change has been reviewed by the United States Pharmacopeia (USP), 
and FDA and the public have had an opportunity to review, in general, 
the change through the USP process. However, because FDA will not have 
reviewed such a change in the context of each individual application 
affected by the change, a changes-being-effected-in-30-days supplement 
will still be required.
    FDA has revised the proposal to clarify that the applicant may not

[[Page 18730]]

distribute the drug product until the supplement for a change under 
this provision has been amended to provide missing information that has 
been requested by FDA.

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

    FDA has clarified that labeling changes that normally require a 
prior approval supplement may, at the agency's request, be implemented 
when FDA receives a supplement.

F. Changes To Be Described in the Next Annual Report

    FDA has revised the June 1999 proposal to state that any change 
made to comply with an official compendium that is consistent with FDA 
statutory and regulatory requirements may be submitted in the next 
annual report, except a change involving the relaxation of an 
acceptance criterion or deletion of a test to comply with an official 
compendium.
    FDA has revised the June 1999 proposal to clarify that the majority 
of changes concerning replacement of equipment with equipment of the 
same design and operating principles may be submitted in an annual 
report. However, there are certain equipment changes identified in this 
rule that require submission in a changes-being-effected-in-30-days 
supplement or a changes-being-effected supplement.
    FDA has revised the June 1999 proposal to clarify that certain 
changes made to the container closure systems for sterile drug products 
may be submitted in annual reports, as may certain changes for 
nonsterile drug product container closure systems. The changes are 
those based on a showing of equivalency under an approved or official 
compendium protocol.
    FDA has revised the June 1999 proposal to clarify that an extension 
of an expiration dating period that can be reported in an annual report 
can be based on production batches instead of full production batches. 
FDA considers a production batch to be one made at production scale 
using production equipment in a production facility as specified in the 
application. Production scale does not necessarily mean the largest 
batch size produced, but a batch of a size or within a batch size range 
that has been approved in the application.
    FDA has deleted the requirement that an annual report contain a 
list of all products involved in the changes. FDA has also clarified 
that an annual report must include the date each change was implemented 
instead of the date each change was made. FDA considers ``the date each 
change was implemented'' to be the date that the condition established 
in the approved application is changed, not when the product made with 
the change is distributed. FDA has also revised the June 1999 proposal 
to clarify when validation protocols and SOPs must be included in an 
annual report submission.

G. Other Information

    FDA has revised the June 1999 proposal to clarify that a protocol 
must be submitted as a prior approval supplement if the protocol was 
not already included in an approved application or when changing an 
approved protocol. In the June 1999 proposal, FDA used the terms 
``drug,'' ``drug product,'' ``drug substance,'' and ``product.'' The 
agency has standardized the terminology throughout the final rule and 
used the terms ``drug product,'' ``drug substance,'' and/or ``product'' 
as appropriate. In addition, the agency has made minor edits to the 
final rule in response to former President Clinton's June 1, 1998, memo 
on plain language in Government writing.

III. Responses to Comments on the June 1999 Proposal

    FDA received comments on most aspects of the June 1999 proposal 
from more than 30 pharmaceutical companies, pharmaceutical industry 
associations, and other interested persons. The comments and the 
agency's responses follow.

A. General Comments

    (Comment 1) Many comments said the June 1999 proposal does not meet 
the intent of Congress when establishing section 506A of the act. The 
comments said that Congress expected the following: (1) Significant 
changes in FDA's past practices on manufacturing changes; (2) 
substantial improvement in the management of technical supplements for 
manufacturing changes; (3) regulatory relief without compromising 
quality, safety, or efficacy of drugs; (4) appropriate action on the 
marketing of regulated products in a manner that does not unduly impede 
innovation or product availability; (5) reduction in reporting and 
regulatory requirements; and (6) a small number of major manufacturing 
changes that require prior approval, but that most changes would 
require a less burdensome means of reporting than has been required in 
the past. Several comments said the June 1999 proposal generates new 
requirements for making regulatory submissions, adds new categories for 
making those submissions, and increases the documentation burden on 
industry. One comment also noted that the SUPAC guidances\1\ would not 
fulfill the Congressional intent because they were published before the 
Modernization Act.
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    \1\ As explained in the June 1999 proposal, FDA developed the 
SUPAC guidances to ease preapproval requirements by categorizing 
certain manufacturing changes according to whether they had a minor, 
moderate, or major potential to affect product quality and 
performance.
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    FDA believes that these regulations are consistent with the intent 
of Congress and that the regulatory requirements and reporting 
categories are consistent with section 506A of the act. Section 506A of 
the act provides FDA with considerable flexibility to determine the 
information and filing mechanism required for the agency to assess the 
effect of manufacturing changes in the safety and effectiveness of the 
product. There is a corresponding need to retain such flexibility in 
the proposed regulations implementing section 506A of the act to ensure 
that the least burdensome means for reporting changes are available. 
FDA believes that such flexibility will allow it to be responsive to 
increasing knowledge of and experience with certain types of changes 
and help ensure the efficacy and safety of the products involved. For 
example, a change that may currently be considered to have a 
substantial potential to have an adverse effect on the safety or 
effectiveness of the product may, at a later date, based on new 
information or advances in technology, be determined to have a lesser 
potential to have such an adverse effect. Conversely, a change 
originally considered to have a minimal or moderate potential to have 
an adverse effect on the safety or effectiveness of the product may 
later, as a result of new information, be found to have an increased, 
substantial potential to adversely effect the product.
    The agency believes it can more readily respond to knowledge gained 
from manufacturing experience, further research and data collection, 
and advances in technology by issuing regulations that set out broad, 
general categories of manufacturing changes and by using guidance 
documents to provide FDA's current thinking on the specific changes 
that fall into those general categories. The regulations provide for a 
new approach to regulating postapproval manufacturing changes. The 
approach is based on the potential for a change to adversely affect the 
identity, strength, quality, purity, or potency of drug products as 
these factors relate to the safety and effectiveness of the product. 
The

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regulations and companion guidance ``Changes to an Approved NDA or 
ANDA'' will provide significant regulatory relief by allowing 
postapproval manufacturing changes to be implemented more rapidly, 
while still ensuring the identity, strength, quality, purity, and 
potency of drug products.
    The regulation reduces the overall number of supplements requiring 
FDA approval prior to product distribution. In addition, many changes 
that are currently reported in supplements would be reported in annual 
reports. The regulation will not increase the number of annual reports 
but will allow applicants to include in an annual report information 
currently required to be reported to the agency in a supplemental 
application. The number of manufacturing changes currently reported in 
supplements that will be reported in annual reports is approximately 
1,283.
    For example, under the previous regulations, all manufacturing site 
changes for drug products required prior approval. Now only a few types 
of drug product manufacturing site changes must be submitted in a prior 
approval supplement. The majority can be submitted in a changes-being-
effected-in-30-days supplement or in an annual report. Moreover, FDA 
further reduced many reporting requirements from the levels recommended 
in previous FDA guidances. For example, the SUPAC guidances recommended 
notification in an annual report when moving production operations 
between buildings at the same manufacturing site. Now, generally no 
notification is required for such changes affecting drug products that 
were covered under the following SUPAC guidances: (1) ``Immediate-
Release Solid Oral Dosage Forms: Scale-Up and Post-Approval Changes: 
Chemistry, Manufacturing and Controls, In Vitro Dissolution Testing, 
and In Vivo Bioequivalence Documentation'' (SUPAC-IR); (2) ``Modified 
Release Solid Oral Dosage Forms: Scale-Up and Post-Approval Changes: 
Chemistry, Manufacturing and Controls, In Vitro Dissolution Testing, 
and In Vivo Bioequivalence Documentation'' (SUPAC-MR); and (3) 
``Nonsterile Semisolid Dosage Forms: Scale-Up and Post-Approval 
Changes: Chemistry, Manufacturing and Controls, In Vitro Release 
Testing, and In Vivo Bioequivalence'' (SUPAC-SS).
    FDA believes that the approach to postapproval changes embodied in 
the SUPAC guidances is consistent with section 506A of the act. 
However, certain aspects of these documents need to be updated to be 
consistent with specific requirements included in the act. For example, 
the new reporting category for changes-being-effected-in-30-days 
supplements needs to be incorporated. FDA intends to update these 
guidances in the near future.
    (Comment 2) Several comments said that FDA should adopt a 
``decision tree'' or ``key questions'' approach in implementing section 
506A of the act. The comments contend that this approach would allow a 
new approach to manufacturing changes that bases the regulatory 
reporting requirements on the results of scientific comparison of pre- 
and post-change material rather than allowing the reporting category to 
be determined by the potential for a change to have an adverse effect. 
The decision tree would focus on answering the key questions rather 
than exhaustive categorization of potential types of changes. One 
comment provided examples of decision trees for consideration.
    FDA agrees that decision trees are a viable approach to 
postapproval manufacturing changes. However, a decision tree must 
consider the potential for a change to have an adverse effect to be 
consistent with section 506A of the act. The act bases the reporting 
category for a change on the potential for that change to have an 
adverse effect, not on the outcome of assessment studies. In some 
cases, based on the potential for an adverse effect, the act would 
require FDA to review a change prior to distribution of the drug 
product with the change, even if the applicant concludes that its 
studies and data demonstrate that the change has no significant adverse 
effect. FDA must evaluate whether the studies performed by the 
applicant were sufficient to assess the effect of the change and 
whether the data support the applicant's claim that the change has not 
adversely affected the identity, strength, quality, purity, and potency 
of the drug product as they may relate to the safety or effectiveness 
of a drug product. For example, an applicant may decide to develop an 
in vivo/in vitro correlation (IVIVC) for an extended release oral 
dosage form (see CDER's guidance entitled ``Extended Release Oral 
Dosage Forms: Development, Evaluation, and Application of In vitro/In 
vivo Correlations'' (September 1997)). If an IVIVC is established, the 
dissolution test will be used by the applicant as a surrogate for in 
vivo bioequivalence when it is necessary to document bioequivalence for 
postapproval changes. Establishing an IVIVC has a significant potential 
to affect the identity, strength, quality, purity, and potency of the 
drug product as they may relate to safety and effectiveness of the drug 
product, and requires a prior approval supplement. The applicant, based 
on its evaluation of the data, may believe that an IVIVC has been 
established but the agency, after evaluation of the applicant's data, 
may not concur. If the applicant decided that a prior approval 
supplement was not necessary based on its conclusions that an IVIVC has 
been established and implemented the change without waiting for the 
agency's concurrence, a drug product that is not bioequivalent could be 
distributed to the public.
    FDA regulates a wide range of products, and a decision tree should 
address the fact that the potential for adverse effect will vary 
depending on factors such as the dosage form and route of 
administration. For example, in general, packaging changes that involve 
parenteral drug products are viewed by FDA to have a higher potential 
to have an adverse effect on the quality of the drug product as it 
relates to the safety and efficacy of the drug product than a packaging 
change for a solid oral dosage form product. Leachables from the 
packaging into parenteral drug products are more likely to occur than 
for a solid oral dosage form, and if leaching occurs, there is a higher 
potential for adverse reactions because of the route of administration. 
A safety determination by FDA must be made before the change is 
implemented. An applicant wishing to rely on a decision tree can submit 
the decision tree using an appropriate mechanism, such as submission of 
a comparability protocol containing a decision tree, and FDA will 
evaluate the decision tree for consistency with section 506A of the 
act.
    (Comment 3) Another comment said that the proposal consisted of 
heightened reporting requirements for changes in packaging materials 
for sterile liquid dosage forms.
    Previously, under Sec.  314.70(b), changes in packaging for sterile 
liquid dosage forms routinely required prior approval by FDA before 
they could be implemented. The final rule, at Sec.  314.70(b)(2)(iii), 
still emphasizes the importance, from the safety perspective, of 
ensuring the sterility of drug products by requiring that changes that 
may affect drug product sterility assurance be reported in a prior 
approval supplement. However, the guidance ``Changes to an Approved NDA 
or ANDA,'' announced elsewhere in this issue of the Federal Register, 
includes certain changes in the packaging of these products that can be 
implemented by means other than prior approval supplements. This action 
has reduced, rather than heightened, the regulatory

[[Page 18732]]

burden relating to the packaging of sterile liquid dosage forms. FDA 
has included these changes in the guidance because, as stated in the 
proposal, the agency believes it can more readily respond to knowledge 
gained from manufacturing experience, further research and data 
collection, and advances in technology by issuing regulations that set 
out broad, general categories of manufacturing changes and by using 
guidance documents to provide FDA's current thinking on the specific 
changes that fall into those general categories (64 FR 34608 at 34610). 
Section 506A of the act explicitly provides FDA the authority to use 
guidance documents to determine the type of changes that do or do not 
have a substantial potential to adversely affect the safety or 
effectiveness of the drug product. As discussed previously in this 
document, the use of guidance documents will allow FDA to more easily 
and quickly modify and update important information. Guidance documents 
will be developed according to the procedures set out in FDA's good 
guidance practices (see the Federal Register of September 19, 2000 (65 
FR 56468), and 21 CFR 10.115).
    (Comment 4) Another comment requested that FDA specifically address 
in the final rule and/or guidance or in separate guidance how a change 
in the device aspect of a drug-device combination product is to be 
reported in applications. The comment said that when establishing rules 
for reporting changes in packaging and packaging components, FDA should 
not simply apply the rules for changes to drugs and biologics to the 
device-like aspects of combination products. Rather, the comment said, 
FDA should consider how the equivalent change is managed for the 
analogous medical device and apply that approach.
    CDER and CBER work cooperatively with the Center for Devices and 
Radiological Health (CDRH) in the review of drug-device combinations. 
Determinations as to which regulations apply to a given combination 
product are product and application specific. Sponsors of combination 
products should consult with the Center that provided the approval of 
their application and with the Office of Combination Products to 
determine what requirements are applicable to the changes they wish to 
make to their product.
    (Comment 5) Several comments said that the proposal put an 
overwhelming emphasis on postapproval changes for drug products and 
little on drug substances. The comments identified the following 
concerns: (1) The proposal is written entirely from the perspective of 
NDA and ANDA applicants and includes nothing for Drug Master File (DMF) 
holders; (2) a reporting classification system depending on the 
potential of a change to have an impact may usually work in the drug 
product area but is less apt to work for the drug substance, where the 
actual change may only be gauged by the data obtained when the change 
is made; and (3) the processes used in drug product and drug substance 
manufacturing differ greatly, making it difficult to determine how the 
changes outlined for drug products apply to drug substances. Several 
comments said that a separate document addressing changes relating to 
drug substances should be prepared.
    The regulations emphasize changes in drug products and are written 
for NDA and ANDA applicants because the regulations describe the 
procedures for notifying FDA about changes in conditions established in 
an approved drug product application. Changes in a drug substance are 
only one of many types of changes that may occur in a drug product 
application. FDA has provided specific recommendations on drug 
substance changes in the guidance entitled ``Changes to an Approved NDA 
or ANDA.'' In the Federal Register of February 16, 2001 (66 FR 10699), 
the agency announced a guidance that focuses specifically on 
postapproval manufacturing changes for certain drug substances entitled 
``BACPAC I: Intermediates in Drug Substance Synthesis, Bulk Actives 
Postapproval Changes: Chemistry, Manufacturing, and Controls 
Documentation'' (the BACPAC I guidance). FDA believes that the BACPAC I 
guidance addresses the concerns expressed in the comments.
    (Comment 6) Several comments reiterated comments previously 
provided to the agency on the guidances entitled ``BACPAC I'' and 
``Changes to an Approved NDA or ANDA,'' and asked FDA to consider these 
comments in finalizing the proposed regulation.
    FDA has considered and addressed these resubmitted comments in this 
document to the extent that they were applicable to the proposed 
regulation.
    (Comment 7) Another comment said that FDA should provide for 
realistic and workable filing mechanisms and requirements with regard 
to changes in the manufacturing of drug substances where the 
information is included in DMFs.
    The regulations and companion guidance entitled ``Changes to an 
Approved NDA or ANDA'' provide recommendations on reporting changes in 
the conditions established in an approved application, including 
changes in drug substance covered by DMFs. Issues relating to DMFs and 
how these are used in the application review process are outside the 
scope of this rulemaking.
    (Comment 8) One comment stated that the rule should clearly address 
how changes in the manufacture of pharmaceutical packaging and 
pharmaceutical packaging components are to be handled. The comment said 
that the current regulation and the proposal and guidance address this 
issue incompletely, and frequently packaging and packaging component 
manufacturers are left to try to interpret the regulation as it applies 
to packaging.
    FDA has clarified the requirements for packaging components in the 
final regulations as a result of the public comments and has included 
information on this topic in the guidance ``Changes to an Approved NDA 
or ANDA.''
    (Comment 9) Several comments said that the use of broad and vague 
terms (e.g., any change, may impact) should be minimized. The comments 
said that such terms lend themselves to different interpretations, are 
likely to cause confusion and inconsistent application, and are likely 
to result in more burdensome reporting requirements for changes that 
would be more appropriately categorized as moderate and/or minor 
changes. One comment said that FDA should revise these terms, and 
suggested adding the modifier ``significant'' or ``significantly'' in 
several instances to sharpen the intended meaning. The comment said 
that since the term ``significant'' is itself undefined, it suggests 
that, in this context, ``significant'' means ``likely to adversely 
affect the identity, strength, quality, purity or potency of the 
related product.''
    FDA agrees that the use of broad and vague terms should be 
minimized and has clarified the regulation, as appropriate, in response 
to comments received on the use of such terms as ``any change'' and 
``may impact,'' and those comments suggesting adding the term 
``significant.''
    (Comment 10) One comment asked whether the final regulations will 
contain references to appropriate guidance documents.
    The final regulations do not reference specific guidance documents. 
FDA continues to update and develop guidances to address particular 
regulatory and scientific issues, and any references included in a 
regulation may quickly become outdated. Guidances that provide FDA's 
current thinking on specific topics can be located on the Internet at 
http://www.fda.gov/cder/

[[Page 18733]]

guidance/index.htm and http://www.fda.gov/cber/guidelines.htm.
    (Comment 11) One comment said that although the proposal applies 
only to human drugs and biologics, the Center for Veterinary Medicine 
(CVM) may be preparing a similar proposal and may be compelled to apply 
most if not all of the principles described in the proposed rule. The 
comment said that the animal drug industry is very pleased with the 
successful 1996 CVM initiative, ``Alternate Administrative Process for 
the Implementation and Submission of Supplemental Chemistry, 
Manufacturing and Control Changes (AAP).'' The comment said that its 
support of the Modernization Act was given based on the legal 
interpretation that the Modernization Act did not preclude the 
continuation of the AAP program. The comment said that the AAP program 
succinctly provides a process for determining minor supplemental 
chemistry, manufacturing, and control changes that are reported on a 
biennial basis. The comment continues to strongly support the concepts 
embodied in the AAP and is concerned that implementation of the 
proposed rule would be more burdensome, on both FDA and industry, than 
the AAP. The comment said that CVM and Animal Health Institute (AHI) 
member companies have had 3 years of successful implementation of this 
program and believe that the proposed rule, if applied to animal drugs, 
would be a major step backwards.
    Comments relating to the AAP are outside the scope of this 
rulemaking and should be directed to the proposed rule for veterinary 
drug products entitled ``Supplements and Other Changes to Approved New 
Animal Drug Applications'' (published in the Federal Register of 
October 1, 1999 (64 FR 53281)) (the October 1999 proposal).

B. Definitions

    FDA proposed to amend the definitions sections of the regulations 
on applications for FDA approval to market a new drug (Sec.  314.3 (21 
CFR 314.3)) and a biological product (Sec.  600.3 (21 CFR 600.3)) by 
adding definitions for ``specification'' and ``validate the effects of 
the change.'' Proposed Sec. Sec.  314.3(b) and 600.3(hh) defined 
``specification'' as the quality standard (i.e., tests, analytical 
procedures, and acceptance criteria) provided in an approved 
application to confirm the quality of drug substances, drug products, 
intermediates, raw materials, reagents, and other components including 
container closure systems, and in-process materials. The term 
``acceptance criteria'' refers to numerical limits, ranges, or other 
criteria for the tests described.
    FDA has revised the proposed definition of specification to make 
the use of the term ``component'' consistent with the definition of 
``component'' at Sec.  210.3 (21 CFR 210.3). FDA has revised the 
definition as follows:
    Specification means the quality standard (i.e., tests, 
analytical procedures, and acceptance criteria) provided in an 
approved application to confirm the quality of drug substances, drug 
products, intermediates, raw materials, reagents, components, in-
process materials, container closure systems, and other materials 
used in the production of a drug substance or drug product. For the 
purpose of this definition, acceptance criteria means numerical 
limits, ranges, or other criteria for the tests described.
    FDA has made the same changes to proposed Sec.  600.3(hh) (new 
Sec.  600.3(jj)) and clarified the definition of specification for 
biological products by replacing the phrase ``drug substances, drug 
products'' with ``products.'' The term ``products'' is defined in Sec.  
600.3(g).
    (Comment 12) Several comments stated that ``intermediates, raw 
materials, reagents, and other components including container closure 
systems, and in-process materials'' should be deleted from the 
definition of specification, and changes for these materials should be 
handled separately from the final rule and final guidance. The comments 
said that the definition is not consistent with the International 
Conference on Harmonisation (ICH) guidance on specifications entitled 
``Test Procedures and Acceptance Criteria for New Drug Substances and 
New Drug Products: Chemical Substances'' (ICH Q6A), which includes only 
drug substance and drug product. The comments said that to include 
items beyond the drug substance and drug product represents a level of 
complexity that would be better dealt with in guidances that can 
adequately evaluate the significance of changes to specific items.
    FDA declines to revise the definition as requested. Section 505 of 
the act (21 U.S.C. 355) requires that a full description of the methods 
used in, and the facilities and controls used for, the manufacture, 
processing, and packing of a drug be provided in an application. The 
regulations at Sec.  314.50(d)(1) (21 CFR 314.50(d)(1)) require that an 
application include specifications as are necessary to ensure the 
identity, strength, quality, purity, and potency of the drug substance 
and drug product. Moreover, the regulation at Sec.  314.50(d)(1)(ii)(a) 
specifically requires that specifications be provided for each 
component. It identifies specifications for container closures systems 
as an example of a specification needed to ensure the identity, 
strength, quality, purity, and potency of the drug product. For 
biologics, an applicant must submit a full description of manufacturing 
methods (Sec.  601.2 (21 CFR 601.2)). Intermediates, raw materials, 
reagents, container closure systems, in-process materials and other 
materials that are used in the manufacture of drug substances, drug 
products, and biologics are considered part of the manufacturing method 
and can have a direct effect on the identity, strength, quality, 
purity, and potency of the drug substance, drug product, or biologic. 
While the extent of a specification (e.g., number or type of tests, 
strictness of acceptance criteria) for these materials may vary 
depending on their use in a given manufacturing process, FDA has 
required specifications for these materials to be included in 
applications as part of the description of the manufacturing method and 
will continue to do so.
    The ICH Q6A guidance and the ICH guidance on specifications 
entitled ``Test Procedures and Acceptance Criteria for Biotechnology/
Biological Products'' (ICH Q6B) are limited in scope. For example, ICH 
Q6A specifically excludes fermentation products. Interpreting the 
limitations of the ICH guidances to mean that specifications are not 
required for fermentation products or other materials outside the scope 
of ICH Q6A or ICH Q6B would be incorrect.
    FDA requires specifications for intermediates, raw materials, 
reagents, container closure systems, in-process materials, and other 
materials used in the manufacturing process to be included in the 
application and, therefore, has included these materials in the 
definition of specification. Any changes in a specification, except 
editorial, must be reported to FDA and applicants need guidance on how 
to implement these changes. FDA declines deferring recommendations on 
these changes to a later guidance and has provided guidance on the 
recommended reporting categories for changes in specifications in FDA's 
guidances entitled ``Changes to an Approved NDA or ANDA'' and ``Changes 
to an Approved Application for Specified Biotechnology and Specified 
Synthetic Biological Products'' (July 1997).
    (Comment 13) One comment said that the term ``specifications and 
test procedures'' was used in part 314 (21 CFR part 314) in the past, 
but the proposal replaced this with the term ``specification,'' which 
is intended to mean both tests and specifications. The comment said 
that using one word to represent several things is confusing

[[Page 18734]]

and recommended retaining the previous terminology.
    FDA declines to revise the use of the term ``specification'' as 
requested. In the past, ``specification'' as used in part 314 meant 
numerical limits, ranges, or other criteria for a test. In developing 
the ICH Q6A and ICH Q6B guidances, FDA agreed to define specification 
differently. A specification, as defined in ICH Q6A and ICH Q6B, 
includes tests, analytical procedures, and acceptance criteria. FDA has 
used the ICH Q6A and ICH Q6B terminology in this rule to promote 
consistency with the ICH documents.
    (Comment 14) One comment identified various types of specification 
changes and recommended how these should be categorized and reported.
    FDA declines to expand the discussion of specification changes in 
the regulation. As stated in the June 1999 proposal, the agency 
believes it can more readily respond to knowledge gained from 
manufacturing experience, further research and data collection, and 
advances in technology by issuing regulations that set out broad, 
general categories of manufacturing changes and by using guidance 
documents to provide FDA's current thinking on the specific changes 
that fall into those general categories (64 FR 34608 at 34610). FDA has 
provided recommendations on specific changes in specifications in FDA's 
guidances entitled ``Changes to an Approved NDA or ANDA'' and ``Changes 
to an Approved Application for Specified Biotechnology and Specified 
Synthetic Biological Products.''
    Proposed Sec. Sec.  314.3(b) and 600.3(ii) defined ``validate the 
effects of the change'' as an assessment of the effect of a 
manufacturing change on the identity, strength, quality, purity, or 
potency of a drug as these factors relate to the safety or 
effectiveness of the drug.
    (Comment 15) Many comments recommended that FDA replace the terms 
validate or validation with assess or assessment. Several comments 
stated that although FDA used the terms consistently with Congress's 
use of the terms in section 506A of the act, they believe that the term 
``validate'' is likely to cause confusion because this term has long 
been associated with and has specific meaning under FDA's CGMP 
regulation.
    FDA agrees and has revised the definition as requested by replacing 
``validate'' with ``assess.'' In addition, as a result of comments 
requesting that the use of the terms drug, drug product, drug 
substance, and product be standardized, FDA has clarified the 
definition in Sec.  314.3(b) by replacing the term ``drug'' with ``drug 
product.'' FDA has clarified the definition in proposed Sec.  600.3(ii) 
(new Sec.  600.3(kk)) by replacing the term ``drug'' with ``product.'' 
The terms drug product and products are defined at Sec. Sec.  314.3(b) 
and 600.3(g), respectively. FDA, on its own initiative, has also 
revised the phrase ``purity, or potency'' to ``purity, and potency'' 
and the phrase ``as these factors relate'' to ``as these factors may 
relate'' to be consistent with section 506A(b) of the act, and the 
phrase ``to assess the effect'' to ``to evaluate the effects'' for 
clarity. FDA notes that while the effect of a manufacturing change on 
the identity, strength, quality, purity and potency of a drug or 
biological product is to be assessed, this assessment could involve 
testing of materials directly affected by a change (e.g., drug 
substance) in addition to or instead of drug or biological product 
testing.
    (Comment 16) Several comments recommended that unambiguous 
definitions of substantial, moderate, and minimal potential for adverse 
effects be added to the regulation, and one comment recommended that 
examples be added for clarification. One comment asked that a 
definition of natural product be added.
    FDA declines to revise the regulation as requested. The regulations 
apply to many types of changes for a broad spectrum of products. The 
meaning of substantial, moderate, and minimal potential for adverse 
effects is most easily illustrated through the use of examples. FDA has 
decided to use guidance documents to provide specific examples of 
changes that are considered to have substantial, moderate, and minimal 
potential to have adverse effect rather than enumerate them in the 
regulation. FDA has provided many examples of types of changes in FDA's 
guidances entitled ``Changes to an Approved NDA or ANDA'' and ``Changes 
to an Approved Application for Specified Biotechnology and Specified 
Synthetic Biological Products.'' In addition, FDA has provided an 
explanation of the term ``natural products'' in the guidance on 
``Changes to an Approved NDA or ANDA.''
    (Comment 17) Concerning the regulations on the content and format 
of an application in Sec.  314.50, one comment noted that Sec.  
314.50(d)(1)(i) and (d)(i)(ii) includes the following statement for 
drug substance and drug product: ``Reference to the current edition of 
the USP/NF [National Formulary] may satisfy the relevant requirements 
in the paragraph.'' The comment said it appeared that this statement 
was being deleted and contended that it should be retained in the 
regulations.
    FDA is clarifying that this sentence has not been deleted from 
Sec.  314.50(d)(1)(i) or (d)(1)(ii). As stated in the June 1999 
proposal, FDA is revising the first two sentences of these paragraphs.

C. Changes to an Approved Application

    Proposed Sec.  314.70(a)(1) set forth general requirements under 
which an applicant must notify FDA about each change in each condition 
established in an approved application beyond the variations already 
provided for in the application. The notice is required to describe the 
change fully. Depending on the type of change, the applicant must 
notify FDA about the change in a supplement under Sec.  314.70(b) or 
(c) or by inclusion of the information in an annual report under Sec.  
314.70(d).
    (Comment 18) One comment said that the statements ``an applicant 
must notify FDA about each change in each condition established in an 
approved application beyond the variations already provided for in the 
application'' and that ``the notice is required to describe the change 
fully'' should be clarified because it could be overly burdensome from 
the standpoint that some changes, for example, changes made to batch 
records submitted as part of the application, may not require reporting 
under Sec.  314.70.
    FDA declines to revise the regulation as requested and notes that 
the agency does not expect to be informed about nonsubstantive 
editorial changes in information included in an application. 
Nonsubstantive editorial changes include such changes as corrections of 
spelling or typographical errors or reformatting of documents (e.g., 
batch records, specification sheets).
    Proposed Sec. Sec.  314.70(a)(2) and 601.12(a)(2) (21 CFR 
601.12(a)(2)) required the holder of an approved application to 
validate the effects of manufacturing changes on the identity, 
strength, quality, purity, or potency of a drug as these factors may 
relate to the safety or effectiveness of the drug before distributing a 
drug made with a manufacturing change.
    (Comment 19) A few comments said that the proposal would increase 
the reporting burden despite the specific provision in the 
Modernization Act for having assessment data at the time of submission 
of manufacturing change supplements. The comment said that the 
Modernization Act specifies that a drug made with a manufacturing 
change may be distributed only after completing studies that assess the 
effects of the change. The comment said

[[Page 18735]]

that the legislative intent of the Modernization Act is that if 
appropriate studies comparing pre- and postchange material are 
performed and no evidence of an adverse effect is found, then a reduced 
reporting category for the evaluated changes is appropriate. The 
comment reasoned that a given proposed manufacturing change can indeed 
have substantial potential for adverse effects at its inception because 
little might be known about the impacts of the change. However, by the 
time actual material has been made with the change and assessment 
studies have been successfully completed, most or all of the potential 
impacts of the change have been eliminated. The comment said that the 
assessment information should permit a reduced reporting requirement.
    FDA disagrees with these comments. Section 506A(c)(2) of the act 
states that a major manufacturing change is ``a change that is 
determined by the Secretary to have substantial potential to adversely 
affect the identity, strength, quality, purity, or potency of the drug 
as they may relate to the safety or effectiveness of a drug'' (emphasis 
added). The act bases the reporting category for a change on the 
potential for that change to have an adverse effect, not on the outcome 
of the assessment studies. The comment implies that the only changes 
that would be reported in a prior approval supplement are those where 
the applicant's studies to assess the effects of the change demonstrate 
that there is in fact an adverse effect on the identity, strength, 
quality, purity, or potency of the drug as they may relate to the 
safety or effectiveness of a drug product. FDA does not believe that 
this was the intent of Congress. Some manufacturing changes have an 
adverse effect on the identity, strength, quality, purity, or potency 
of the drug product. In many cases, the applicant chooses not to 
implement these manufacturing changes, but sometimes the applicant 
wishes to do so. If an assessment indicates that a change has adversely 
affected the identity, strength, quality, purity, or potency of the 
drug product, the change must be submitted in a prior approval 
supplement, regardless of the recommended reporting category for the 
change. For example, a process change recommended for a changes-being-
effected-in-30-days supplement could cause the formation of a new 
degradant that requires qualification and/or identification. The 
applicant may believe that there are no safety concerns relating to the 
new degradant. Even so, the applicant must submit this change in a 
prior approval supplement with appropriate information to support the 
continued safety and effectiveness of the product. During the review of 
the prior approval supplement, FDA will assess the impact of any 
adverse effect on the drug product as this change may relate to the 
safety or effectiveness of the drug product.
    FDA also received comments requesting that the term ``assess'' be 
used instead of ``validate.'' FDA has made this change in Sec. Sec.  
314.70(a)(2) and 601.12(a)(2), where appropriate. In Sec.  
314.70(a)(2), FDA, on its own initiative, has deleted the phrase ``on 
the identity, strength, quality, purity, and potency of the drug 
product as these factors may relate to the safety or effectiveness of 
the drug product'' because ``assess the effects of the change,'' as 
defined in Sec.  314.3(b), includes this phrase.
    Proposed Sec. Sec.  314.70(a)(3) and 601.12(a)(3) stated that 
notwithstanding the supplement submission requirements, an applicant 
must make a manufacturing change in accordance with a regulation or 
guidance that provides for a less burdensome notification of the 
change.
    (Comment 20) Several comments noted that they were pleased that the 
provision that a change can be made ``in accordance with a regulation 
or guidance that provides for a less burdensome notification of the 
change'' was proposed because it permits less burdensome reporting 
mechanisms for changes.
    FDA acknowledges these comments and has retained this provision in 
the final rule.
    Proposed Sec. Sec.  314.70(a)(4) and 601.12(a)(4) stated that the 
applicant must promptly revise all promotional labeling and advertising 
to make it consistent with any labeling change implemented in 
accordance with this section.
    (Comment 21) Several comments said that the previous provisions in 
Sec.  314.70 limited the requirement to promptly revise all promotional 
labeling and advertising to those changes that were to be filed in a 
changes-being-effected supplement, and that this requirement is not 
necessary for the type of labeling changes that would be filed in an 
annual report. The comments suggested that this requirement be limited 
to those labeling changes that would be filed in supplemental 
applications.
    The agency agrees with the comments and has revised Sec.  
314.70(a)(4) to require applicants to revise promotional labeling and 
advertising to make it consistent with labeling changes implemented in 
accordance with Sec.  314.70(b) and (c). In addition, Sec.  
601.12(a)(4) requires applicants to revise promotional labeling and 
advertising to make it consistent with labeling changes implemented in 
accordance with Sec.  601.12(f)(1) and (f)(2).
    Proposed Sec.  314.70(a)(5) stated that, except for a supplement 
providing for a change in the labeling, the applicant must include in 
each supplemental application providing for a change under paragraph 
(b) or (c) a statement certifying that a field copy of the supplement 
has been provided to the applicant's home FDA district office.
    (Comment 22) A few comments requested that FDA clarify whether the 
field copy that is to be sent to the applicant's ``home FDA district 
office'' should be the FDA office where the change is being made or the 
FDA office in the district of the company's corporate headquarters from 
where the submission documents are sent. The comments also said that if 
the field copy should be sent to the office where the change is being 
made, FDA should clarify what FDA office(s) serve for changes made 
internationally. The comment said that the clarification will help to 
ensure that the appropriate documents get to the correct FDA district 
office.
    Mailing information for field copies is provided in Sec.  
314.440(a)(4). Currently, FDA recommends that the ``applicant's home 
FDA district office'' referred to in Sec.  314.440(a)(4) be the 
district office where the applicant's headquarters is located. FDA has 
clarified this provision by cross-referencing Sec.  314.440(a)(4). 
Section 314.440(a)(4) also provides mailing information for 
international applicants. FDA, on its own initiative, has also 
clarified the provision by adding ``amendments to supplements.'' A 
field copy of an amendment to a supplement, which is submitted by an 
applicant to incorporate additional or corrected information into their 
original supplement, is currently required under Sec.  314.440(a)(4).
    Proposed Sec. Sec.  314.70(a)(6) and 601.12(a)(5) added a 
requirement that a list of all changes contained in the supplement or 
annual report must be included in the cover letter for the supplement 
or annual report.
    (Comment 23) Many comments agreed that a list of changes should be 
included in the cover letter for a supplement. However, the comments 
disagreed that a list of all changes contained in the annual report 
should be included in a cover letter. The comments said that including 
a list in a cover letter to an annual report is overburdensome because 
cover letters are not required for annual reports, only a Form FDA 
2252, and a list of changes is already provided

[[Page 18736]]

in a section of an annual report. Several comments said that an 
applicant should have the option of providing the list in a location 
other than the cover letter, such as at the beginning of the 
supplement.
    FDA agrees with the requests to permit the list of changes to be 
provided in the summary section of the annual report and has revised 
Sec. Sec.  314.70(a)(6) and 601.12(a)(5) to require changes to be 
listed in the cover letter only for supplemental applications.
    An annual report is required to contain a brief summary of 
significant new information from the previous year that might affect 
the safety, effectiveness, or labeling of the drug product (Sec.  
314.81(b)(2)(i)). FDA's guidance for industry entitled ``Format and 
Content for the CMC Section of an Annual Report'' (September 1994) 
states, regarding the summary of new information, that the firm should 
include in the annual report ``a brief summary of all changes made to 
the application during the reporting period including changes made in 
accordance with approved supplements under 21 CFR 314.70(b) and * * * 
supplements under 21 CFR 314.70(c)* * *.'' Supplements are not required 
to have a summary section (Sec.  314.50(c)).
    FDA is requiring that a list of changes be provided in both 
supplemental applications and annual reports. FDA proposed this 
requirement as a means to more efficiently locate and identify changes 
in what are often documents of substantial length. The list will also 
allow FDA to quickly assess whether the appropriate reporting category 
was used. To achieve these objectives, it is essential that the list be 
in a consistent location for each type of submission.
    (Comment 24) Several comments were concerned that the list of 
changes, if included in a cover letter, would not be considered 
confidential information.
    The standards for disclosing specific information from a cover 
letter or application do not differ depending on where this information 
is provided. Information that is exempted from disclosure (e.g., trade 
secret or confidential commercial information) is not disclosed whether 
it is in a cover letter or an application (see also Sec. Sec.  314.430 
and 601.51 (21 CFR 601.51)).
    (Comment 25) One comment requested that the phrase ``list of all 
changes'' be revised to ``a brief summary of major changes.''
    FDA declines to revise the regulation as suggested. Each change, 
including moderate and minor changes, should be listed. FDA notes that 
the description of the listed change should be in sufficient detail to 
allow the agency to quickly determine whether the appropriate reporting 
category for the change has been used. For example, describing a change 
as ``a change in the drug product specification'' does not provide 
sufficient detail. A description such as ``deletion of the friability 
test and associated acceptance criteria and analytical procedure from 
the drug product specification'' would allow FDA to quickly assess 
whether the appropriate reporting category was used. The detailed 
information about each change and the information developed to assess 
the effects of the change would be provided in the supplement or 
elsewhere in the annual report.
    (Comment 26) Several comments suggested changes in Form FDA 2252 
that accompanies an annual report.
    FDA declines to revise Form FDA 2252 because it is not within the 
scope of this regulation.

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

    Proposed Sec.  314.70(b)(1) required that a supplement requiring 
prior approval must be submitted for any change in the product, 
production process, quality controls, equipment, or facilities that has 
a substantial potential to have an adverse effect on the identity, 
strength, quality, purity, or potency of the product as these factors 
may relate to the safety or effectiveness of the product.
    (Comment 27) Many comments asked whether a prior approval 
supplement would be required even if the applicant has demonstrated 
that the change has no significant adverse affect.
    Section 506A(c)(2) of the act states that a major manufacturing 
change is ``a change that is determined by the Secretary to have 
substantial potential to adversely affect the identity, strength, 
quality, purity, or potency of the drug as they may relate to the 
safety or effectiveness of a drug.'' The act bases the reporting 
category for a change on the potential for that change to have an 
adverse effect, not on the outcome of the assessment studies. FDA would 
expect a prior approval supplement to be submitted for a change that 
has substantial potential to adversely affect the identity, strength, 
quality, purity, or potency of a drug product even if the applicant 
concludes that their studies and data demonstrate that the change has 
no adverse effect. Prior to distribution of the drug product made with 
the change, FDA must evaluate whether the studies performed by the 
applicant were sufficient to assess the effect of the change and that 
the data support the applicant's claim that the change has not 
adversely affected the identity, strength, quality, purity, or potency 
of the drug product as they may relate to the safety or effectiveness 
of a drug product.
    (Comment 28) One comment said that section 506A of the act 
identifies major changes as formulation, specification, or those 
requiring studies in accordance with part 320 (21 CFR part 320) to 
demonstrate the equivalence of the drug product to the drug product as 
manufactured without the change or to the reference listed drug. The 
comment said that FDA has proposed prior approval supplements for 
changes that are clearly outside of these three major change 
categories. Another comment said it appears that FDA has overutilized 
section 506A(c)(2)(C) of the act.
    FDA disagrees that it has overutilized this part of the act. In 
addition to the three major changes identified previously in this 
document, section 506A(c)(2)(C) of the act states that a major change 
``is another type of change determined by the Secretary by regulation 
or guidance to have a substantial potential to adversely affect the 
safety or effectiveness of the drug.'' In previous regulations, many 
manufacturing changes required prior approval supplements. FDA has used 
this provision of the act to identify a limited number of changes that 
it considers to have a substantial potential to adversely affect the 
identity, strength, quality, purity, or potency of the drug as they may 
relate to the safety or effectiveness of a drug. The regulation reduces 
the overall number of supplements requiring FDA approval prior to 
product distribution. In addition, many changes that are currently 
reported in supplements will be able to be reported in annual reports. 
The regulation will not increase the number of annual reports but will 
allow applicants to include in an annual report information currently 
required to be reported to the agency in a supplemental application. 
Moreover, FDA further reduced many reporting requirements from the 
levels recommended in previous FDA guidances.
    Proposed Sec.  314.70(b)(2)(i) provided that, except as provided in 
Sec.  314.70(c) and (d), prior approval is required for changes in the 
qualitative or quantitative formulation of the drug, including inactive 
ingredients, or in the specifications provided in the approved 
application.
    (Comment 29) A few comments recommended that proposed

[[Page 18737]]

Sec.  314.70(b)(2)(i) be revised to better reflect section 
506A(c)(2)(A) of the act which allows exceptions to the requirement to 
obtain prior approval before changing the qualitative or quantitative 
formulation of the drug. One comment recommended the provision be 
revised to state: ``Except as provided in paragraphs (c) and (d) of 
this section or exempted by regulation or guidance * * *.''
    FDA declines to revise the regulation as requested. Section 
506A(c)(2)(A) of the act states that a prior approval supplement is 
required when a change ``is made in the qualitative or quantitative 
formulation of the drug involved or the specifications in the approved 
application or license * * * (unless exempted by the Secretary by 
regulation or guidance * * *).'' Proposed Sec.  314.70 is consistent 
with the provisions of the act. Exemptions by regulation are provided 
in Sec.  314.70(c) or (d). This language is already included in Sec.  
314.70(b)(2)(i). In addition, FDA may use guidance documents to provide 
for a less burdensome notification of a specific change. This exemption 
is included in Sec.  314.70(a)(3) and applies to Sec.  314.70(b)(2)(i) 
as well as the other changes listed in Sec.  314.70.
    (Comment 30) Several comments noted that the SUPAC guidances 
allowed for some changes in qualitative or quantitative formulation of 
the drug product to be filed in changes-being-effected supplements or 
annual reports. One comment said that the regulations should follow the 
standards in the SUPAC guidances.
    FDA has not incorporated the qualitative and quantitative 
formulation change information from the SUPAC guidances in the 
regulation because, as stated in the proposal, the agency's approach is 
to issue regulations that set out broad, general categories of 
manufacturing changes and use guidance documents to provide FDA's 
current thinking on the specific changes included in those categories.
    (Comment 31) Several comments said that changes in specification to 
comply with an official compendium should not require prior approval 
supplements.
    FDA is not requiring prior approval supplements for specification 
changes made to comply with an official compendium. A complete 
discussion of this issue is provided under section III.F of this 
document, ``Changes To Be Described in the Next Annual Report,'' in 
response to comments on Sec.  314.70(d)(2)(i).
    (Comment 32) One comment recommended the proposed language be 
revised to limit specification changes to those for drug substance or 
drug product.
    FDA considers a specification to be a quality standard (i.e., 
tests, analytical procedures, and acceptance criteria) provided in an 
approved application to confirm the quality of drug substances, drug 
products, intermediates, raw materials, reagents, components, in-
process materials, container closure systems, or other materials used 
in the production of a drug substance or drug product. Therefore, FDA 
declines to revise the proposal as suggested.
    Proposed Sec.  314.70(b)(2)(ii) required prior approval for changes 
requiring completion of studies in accordance with part 320 to 
demonstrate the equivalence of the drug to the drug as manufactured 
without the change or to the reference listed drug.
    (Comment 33) One comment said that reference to part 320 suggests 
that bioequivalence must be addressed for ``a change in the 
manufacturing process * * *.'' The comment said that this will lead to 
significant interpretation issues. The comment said that a selective 
subset of major manufacturing changes that truly have ``substantial 
potential'' should be specified here. Another comment said that when 
the product is a true solution, changes to the manufacturing process 
(not formulation) are highly unlikely to change the formulation and 
additional clinical (bioequivalence) studies should not always be 
required.
    FDA declines to revise the proposal based on these comments. The 
requirements for when a study is needed to demonstrate the equivalence 
of a drug product made with the proposed change to a drug product made 
without the change or to the reference listed drug are provided in part 
320. Part 314 is not intended to supplement, supersede, or clarify 
these requirements. Section 314.70(b)(2)(ii) specifies only that if 
such a study is required under part 320 to support a postapproval 
change, the postapproval change must be submitted using a prior 
approval supplement. Changes that require a study under part 320 are 
considered major changes that have a significant potential to affect 
the identity, strength, quality, purity, or potency of the product as 
it relates to the safety or effectiveness of a product, and FDA would 
need to review such studies before a product made with the change is 
placed into distribution.
    Proposed Sec.  314.70(b)(2)(iii) required prior approval for 
changes that may affect product sterility assurance, such as changes in 
product or component sterilization method(s) or an addition, deletion, 
or substitution of steps in an aseptic processing operation.
    (Comment 34) Many comments stated that the proposed language was 
too broad and should be modified to state ``changes that may 
significantly affect product sterility assurance'' or ``changes that 
significantly affect product sterility assurance''. One comment said 
that the term ``may affect'' is not appropriate because any change may 
affect one or more attributes of a sterile drug.
    Sterility of drug products or drug substances is a fundamental and 
essential quality attribute of these drugs and is a critical aspect of 
the safety assessment. The manufacture of a sterile drug is an 
exacting, difficult, and highly controlled series of processes, 
especially in the case of aseptically processed drugs. The concept of 
significance or ``significantly affect'' implies that a measurement of 
an attribute, such as sterility, can be made. However, no test is 
sensitive enough to detect unacceptable sterility assurance levels 
(i.e., the probability of a nonsterile unit). For example, a batch of 
drug product tested using the standard drug product sterility test 
described in the USP/NF will fail the sterility test only when at least 
14 percent of the batch is contaminated (95 percent confidence level). 
This sterility assurance level is unacceptable. The probability of 
nonsterile units for terminally sterilized and aseptically processed 
drugs is normally expected by FDA to be less than 0.0001 percent and 
0.1 percent, respectively. FDA ensures the safety of sterile drugs by 
assessing the efficacy of a given sterilization process for a specific 
drug and by ensuring that the facilities producing sterile drugs comply 
with CGMPs. The assessment of the efficacy of a sterilization process 
includes review of multiple protocols and scientific experiments 
designed to demonstrate that the sterilization process and associated 
control procedures can reproducibly deliver a sterile product. The data 
derived from the experiments and control procedures allow certain 
conclusions to be drawn about the probability of nonsterile units. A 
properly validated sterilization process will provide the sterility 
assurance level required by FDA to ensure the safety of sterile drugs. 
Because of the lack of adequate test procedures for assessing sterility 
and the complexity in evaluating the process validation and controls 
information to determine the level of sterility assurance that a given 
process provides for a specific drug, FDA has used the term ``may 
affect'' and declines to revise the proposal as suggested.

[[Page 18738]]

    (Comment 35) Many comments stated that the proposed language should 
be clarified to state ``changes that may adversely affect product 
sterility assurance * * *'' or ``changes that may reduce (or decrease) 
product sterility assurance * * *''.
    New Sec.  314.70(b)(1) already identifies that the changes that 
should be submitted in prior approval supplements are those that have a 
substantial potential to have an ``adverse effect.'' FDA declines to 
revise proposed Sec.  314.70(b)(2)(iii) as requested because the 
addition of the term ``adversely'' is redundant. FDA emphasizes that 
the assessment of whether a change may adversely affect sterility 
assurance is a complex and multidimensional analysis. For example, a 
change to a more stringent terminal sterilization process, while in 
theory providing a lower probability of nonsterile units, may damage 
the container closure system so that sterility of individual units 
could not be maintained.
    (Comment 36) Several comments said that the proposed language is 
too restrictive because it indicates that all changes to sterile 
products should be submitted in prior approval supplements. The 
comments said that this contradicts what is in the guidance entitled 
``Changes to an Approved NDA or ANDA,'' which identifies some changes 
that do not have to be filed in prior approval supplements. One comment 
identified specific examples of manufacturing changes for sterile 
products and said that these should not be considered major changes.
    FDA considers changes that may affect the sterility assurance level 
of a drug to have significant potential to affect the safety of the 
drug. Therefore, FDA has identified this change as one that requires 
prior approval. As stated in the June 1999 proposal, this rulemaking 
sets out broad, general categories of manufacturing changes, and the 
agency uses guidance documents to provide FDA's current thinking on the 
specific changes included in those categories. Under Sec.  
314.70(a)(3), an applicant must notify FDA of a manufacturing change in 
accordance with either a regulation or a guidance that addresses the 
same issues as the regulation but that provides for a less burdensome 
notification of the change than the regulation (for example, by 
submission of a supplement that does not require approval prior to 
distribution of the product). For example, in the guidance entitled 
``Changes to an Approved NDA or ANDA,'' FDA has identified less 
burdensome reporting categories for certain changes that it believes 
have less potential to affect sterility assurance and consequently the 
safety of the drug.
    (Comment 37) A few comments said that this provision increases the 
regulatory burden with respect to sterile products. The comments said 
that only fundamental changes to sterile processing require prior 
approval.
    FDA disagrees with this comment. Under the previous regulations at 
Sec.  314.70, manufacturing site, processing, and packaging changes for 
sterile drugs almost always required a prior approval supplement 
(previous Sec.  314.70(b)(1)(iv), (b)(1)(v), (b)(2)(iv), (b)(2)(v), and 
(b)(2)(vi)). Under Sec.  314.70(c) and (d), certain changes related to 
sterile drugs may be submitted in changes-being-effected supplements or 
annual reports (for example, Sec.  314.70(d)(2)(i) and (iii)). In the 
guidance entitled ``Changes to an Approved NDA or ANDA,'' FDA has 
identified many changes related to sterile drugs that may now be 
submitted in changes-being-effected supplements or annual reports.
    Proposed Sec.  314.70(b)(2)(iv) required prior approval for changes 
in the synthesis or manufacture of the drug substance that may affect 
the impurity profile and/or the physical, chemical, or biological 
properties of the drug substance.
    (Comment 38) One comment said that the proposal should be revised 
to state ``Changes in the route of synthesis or * * *.'' Changes such 
as an additional recrystallization step (using the same solvents, and 
so forth) should be considered for changes-being-effected status.
    FDA declines to revise the proposal as suggested. Changes in the 
synthesis, including the route of synthesis, may have an effect on the 
impurity profile and/or the physical, chemical, or biological 
properties of the drug substance. For example, a change in a solvent 
used in the crystallization step may affect the impurity profile and 
physical properties of the drug substance even though this change would 
not be considered a change in the ``route of synthesis.''
    (Comment 39) Several comments stated that the proposed language 
should be clarified to state ``changes that may adversely affect the 
impurity profile * * *'' because changes that improve the quality of 
the drug substance should not require a prior approval supplement.
    New Sec.  314.70(b)(1) states that the changes that should be 
submitted in prior approval supplements are those that have a 
substantial potential to have an ``adverse effect.'' FDA declines to 
revise the provision as requested because the addition of the term 
``adversely'' is redundant.
    (Comment 40) One comment suggested that FDA change ``may affect the 
impurity profile of the drug product'' to ``are likely to affect the 
impurity profile of the drug product.'' The comment said that many 
factors could affect the impurity profile, and this stringent reporting 
requirement should be reserved for factors that are likely to produce a 
change.
    FDA believes the phrase ``may affect'' is appropriate because the 
decision on whether a change should be considered a major, moderate, or 
minor change is based on the potential for the change to adversely 
affect the identity, strength, quality, purity, or potency of the drug 
as they may relate to the safety or effectiveness of a drug product. 
FDA considers a change that ``may affect the impurity profile and/or 
the physical, chemical, or biological properties of the drug 
substance'' to be a change that has a substantial potential to result 
in an adverse effect and declines to delete ``may.''
    (Comment 41) One comment said that inserting the clause ``beyond 
those studied in the pre-clinical studies and requiring a change in the 
approved specifications'' after impurity profile would add clarity. The 
comment said that according to the ICH guidance entitled ``Impurities 
in New Drug Substances'' (ICH Q3A), impurities below a certain 
threshold would not necessarily require registration.
    The process of qualifying impurities and determining if a 
postchange impurity profile for a drug substance is equivalent or 
better than the impurity profile of the prechange material is a complex 
issue. FDA does not believe it is possible to clarify the regulations 
to adequately address the many different types of human drugs it 
regulates. For example, not all drug approvals require preclinical 
studies. FDA declines to revise the proposal as suggested. FDA 
published the BACPAC I guidance to provide recommendations on how to 
evaluate changes in impurity profiles.
    (Comment 42) Several comments said that the proposed regulations 
were not consistent with the BACPAC I guidance. Several comments said 
that the proposal was much more restrictive than what was included in 
the BACPAC I guidance. One comment said that changes in drug substance 
synthesis route, which occur prior to the formation of key 
intermediates, should not be regarded as major changes, since the 
potential to impact the quality, strength, identity, and purity of the 
final product is low.

[[Page 18739]]

    FDA declines to revise the regulations as requested. The BACPAC I 
guidance is an example of a guidance that permits certain specific 
changes that fall under the general category of a change that ``may 
affect the impurity profile and/or the physical, chemical, or 
biological properties of the drug substance'' to be reported using a 
less burdensome method of notification. Under Sec.  314.70(a)(3), an 
applicant must notify FDA of a manufacturing change in accordance with 
either a regulation or a guidance that addresses the same issues as the 
regulation but that provides for a less burdensome notification of the 
change than the regulation (for example, by submission of a supplement 
that does not require approval prior to distribution of the product).
    Proposed Sec.  314.70(b)(2)(v) required prior approval for changes 
in labeling, except those described in Sec.  314.70(c)(6)(iii), 
(d)(2)(ix), or (d)(2)(x).
    On its own initiative, FDA has revised Sec.  314.70(b)(2)(v) to 
add: ``If applicable, any change to a Medication Guide required under 
part 208 of this chapter, except for changes in the information 
specified in Sec.  208.20(b)(8)(iii) and (b)(8)(iv) of this chapter.'' 
This provision, which was previously in Sec.  314.70(b)(3)(ii), was 
inadvertently omitted from the proposed rule.
    (Comment 43) Many comments said that FDA should clarify 
``labeling'' to indicate ``drug product labeling'' because drug 
substance labeling changes need not be submitted.
    FDA declines to revise the regulations as requested. The term 
``labeling'' in Sec.  314.70 is consistent with ``labeling'' as used in 
part 201 (21 CFR part 201). Part 201 applies to the labeling of drugs 
and/or drug products.
    Proposed Sec.  314.70(b)(2)(vi) required prior approval for changes 
in a container closure system that controls drug delivery or that may 
affect the impurity profile of the drug product.
    (Comment 44) Several comments requested that the proposed language 
be clarified to state ``changes that may adversely affect the impurity 
profile * * *'' or ``changes that adversely affect the impurity profile 
***.''
    FDA declines to revise the provision because the addition of the 
term ``adversely'' is redundant. New Sec.  314.70(b)(1) already states 
that the changes that should be filed in prior approval supplements are 
those that have a substantial potential to have an ``adverse effect.'' 
FDA believes the phrase ``may affect'' is appropriate because the 
decision on whether a change should be considered a major, moderate, or 
minor change is based on the potential for the change to adversely 
affect the identity, strength, quality, purity, or potency of the drug 
as they may relate to the safety or effectiveness of a drug product. 
FDA considers a change that ``may affect the impurity profile of the 
drug product'' to be a change that has a substantial potential to 
result in an adverse effect and declines to delete ``may.''
    (Comment 45) One comment requested clarification of what is meant 
by ``controls drug delivery,'' such as quantity dispensed, machine 
calibration, and volume of fill.
    For some drug products, the container closure system itself, rather 
than a person, regulates the amount of drug product that is 
administered to a patient. These container closure systems are 
considered to ``control drug delivery.'' For example, a patient that 
uses a metered dose inhalation product as instructed cannot control the 
amount of drug product the container closure system delivers or verify 
that the appropriate amount has been administered. Where a drug product 
container closure system controls drug delivery, FDA requires 
information to be submitted to support that the container closure 
system can accurately and repeatedly deliver the required amount of 
drug product. The design and operation of these container closure 
systems is critical to ensure that the patient receives the correct 
dose. A drug product may not be safe or effective if a patient receives 
too much or too little of the drug product. Changes in these systems 
are considered to have a substantial potential to adversely affect the 
identity, strength, quality, purity, or potency of the drug as they may 
relate to the safety or effectiveness of a drug product. Container 
closure systems for drug products where a person controls the amount of 
drug product administered and/or which allow for verification that the 
appropriate amount has been administered (e.g., number of tablets, 
milliliters of liquid) are not considered container closure systems 
that ``control drug delivery.''
    (Comment 46) Another comment asked whether this section 
specifically refers to the final packaged product only.
    Changes in ``a container closure system that controls drug 
delivery'' applies only to the marketed drug product container closure 
system, and the language has been revised in the final rule to clarify 
this. Changes that ``may affect the impurity profile of the drug 
product'' applies to any type of container closure system.
    (Comment 47) One comment noted an apparent conflict between Sec.  
314.70(b)(2)(vi), which says that a ``change in a container closure 
system that * * * may affect the impurity profile of the drug product'' 
should be submitted in a prior approval supplement and Sec.  
314.70(c)(2)(i), which says that ``a change in the container closure 
system that does not affect the quality of the final drug product'' 
should be submitted in a changes-being-effected-in-30-days supplement. 
The comment said that this would allow for inconsistent and overly 
conservative interpretations of what might fall into this latter 
category.
    FDA agrees that clarification of the wording in these two 
provisions of the regulations is needed. FDA has particular concerns 
about changes in the type (e.g., glass to high density polyethylene 
(HDPE), HDPE to polyvinyl chloride, vial to syringe) or composition 
(e.g., one HDPE resin to another HDPE resin) of packaging components 
because these changes may affect the impurity profile of the drug 
product. These concerns are compounded by the fact that, in most cases, 
the packaging component manufacturer considers the manufacturing 
process confidential information and discloses it only to FDA. 
Therefore, an applicant does not have knowledge of all potential 
impurities that a different type or composition of a packaging 
component may introduce into a product. Depending on the dosage form 
affected and its route of administration, FDA may have to evaluate the 
safety of changes in the type or composition of a packaging component. 
Because of the safety concerns relating to new impurities from a 
packaging component with this type of change, FDA considers such 
changes to have a substantial potential to adversely affect the 
identity, strength, quality, purity, or potency of the drug as they may 
relate to the safety or effectiveness of a drug product. FDA has 
revised Sec.  314.70(b)(2)(vi) to limit the requirement to situations 
involving changes in the type or composition of a packaging component. 
FDA considers a deletion or addition of a packaging component to fall 
within the meaning of a change in the type of packaging component. FDA 
may, through regulations or guidance, identify certain dosage forms 
and/or routes of administration where there is a lower potential for 
adverse effect and allow changes in type or composition of a packaging 
component in these situations to be reported in changes-being-effected 
supplements or annual reports.
    For consistency with the proposal, FDA has revised Sec.  
314.50(d)(1)(ii)(a) to

[[Page 18740]]

change ``containers and closure systems'' to ``container closure 
systems.''
    Proposed Sec.  314.70(b)(2)(vii) required prior approval for 
changes solely affecting a natural product, a recombinant DNA-derived 
protein/polypeptide product, or a complex or conjugate of a drug with a 
monoclonal antibody for the following:
    (1) Changes in the virus or adventitious agent removal or 
inactivation method(s); (2) changes in the source material or cell 
line; and (3) establishment of a new master cell bank or seed.
    (Comment 48) Several comments requested that FDA delete the 
reference to ``natural products,'' while others requested that FDA 
provide a definition for natural products. A few comments asked whether 
fermentation-based products are considered natural products.
    FDA declines to delete natural products from this provision. The 
changes identified in this provision are considered to be major changes 
and apply equally to a natural product, a recombinant DNA-derived 
protein/polypeptide, or a complex or conjugate of a drug substance with 
a monoclonal antibody. FDA has provided a definition of natural product 
in the guidance entitled ``Changes to an Approved NDA or ANDA'' but 
declines to provide the definition in the regulation because 
advancements in technology may require that the definition be revised. 
FDA has defined natural product in the guidance to mean ``materials 
(e.g., drug substance, excipients) that are derived from plants, 
animals, or microorganisms. The specific recommendations for natural 
products are not applicable to inorganic compounds (e.g., salts, 
minerals).'' Fermentation based products are considered natural 
products.
    (Comment 49) A few comments said that this provision increases the 
regulatory burden with respect to natural products. One comment said 
that there was no need to distinguish a natural product, a recombinant 
DNA-derived protein/polypeptide, or a complex or conjugate of a drug 
substance with a monoclonal antibody from other products.
    FDA disagrees with these comments. Under the previous regulations 
at Sec.  314.70, many manufacturing process changes for drug substances 
and drug products, including those for a natural product, a recombinant 
DNA-derived protein/polypeptide, or a complex or conjugate of a drug 
substance with a monoclonal antibody, required a prior approval 
supplement (previous Sec.  314.70(b)(1)(iv) and (b)(2)(v)). FDA has 
reduced the reporting category for many manufacturing process changes 
relating to these products by allowing them to be reported in changes-
being-effected supplements or annual reports. However, the three 
changes specified in this provision, which are unique to these specific 
types of drugs, are considered to have a substantial potential to 
adversely affect the identity, strength, quality, purity, or potency of 
the drug product as they may relate to the safety or effectiveness of a 
drug product. Virus or adventitious agent removal or inactivation 
processes are the means by which FDA ensures that adventitious agents 
such as porcine parovirus, if present, are removed. Failure to remove 
such adventitious agents has a significant potential to adversely 
affect public safety. Changes in source material or cell line and 
establishment of a new master cell bank or seed have a substantial 
potential to affect the quality of a drug substance. For example, a 
change in source material (e.g., species, geographic region of 
harvesting) could result in different impurities or contaminants (e.g., 
pesticides) than were previously seen or a change in potency.
    Proposed Sec.  314.70(b)(3) stated that the applicant must obtain 
approval of a supplement from FDA before distributing a product using a 
change and specified the information to be included in the supplement.
    (Comment 50) A few comments requested adding ``as appropriate'' as 
follows: ``Except for submissions under paragraph (e) of this section, 
the following shall be contained in the supplement, as appropriate.'' 
The comments said that not all listed material is relevant for every 
submission.
    FDA declines to revise the provision as requested. FDA expects that 
the information specified in Sec.  314.70(b)(3)(i) through (b)(3)(v) 
will be needed for almost all supplemental applications. FDA believes 
that the addition of ``as appropriate'' may incorrectly give the 
impression that this information is not routinely needed and would 
result in supplemental applications being submitted with insufficient 
information. FDA may specify in a guidance that information required in 
Sec.  314.70(b)(3)(i) through (b)(3)(v) is not needed for a particular 
change. However, in the absence of such a recommendation, FDA would 
expect Sec.  314.70(b)(3)(i) through (b)(3)(v) to be addressed in each 
supplemental application. The information in Sec.  314.70(b)(3)(vi) and 
(b)(3)(vii) is needed only in certain situations, and this is clearly 
indicated.
    Proposed Sec.  314.70(b)(3)(vi) stated that for a natural product, 
a recombinant DNA-derived protein/polypeptide product, or a complex or 
conjugate of a drug with a monoclonal antibody, relevant validation 
protocols must be provided in addition to the requirements in Sec.  
314.70(b)(3)(iv) and (b)(3)(v).
    (Comment 51) One comment said that the requirement that relevant 
validation protocols be provided is overly restrictive and burdensome. 
The comment suggested that this statement be rephrased to state 
``validation protocols may be requested by the FDA.'' Another comment 
recommended that this section be deleted because there is no need for 
different requirements for these products. The comment said that this 
information (relevant validation protocols) is available for review 
onsite. The comment said that if FDA disagrees and feels that special 
requirements are warranted, the comment recommended these specific 
details be more appropriately captured in the guidance instead.
    Unless otherwise specified by FDA, validation protocols and data 
need not be filed in the application. For most products, FDA does not 
require the submission of validation protocols and data. However, for a 
natural product, a recombinant DNA-derived protein/polypeptide, or a 
complex or conjugate of a drug substance with a monoclonal antibody, 
FDA does require the submission of validation protocols for certain 
critical manufacturing processes unique to these drug substances and 
drug products. For example, FDA would expect the validation protocol 
for the virus or adventitious agent removal or inactivation process to 
be submitted in an application. FDA currently requires this type of 
information to be submitted in an application and believes it is 
necessary; therefore, FDA declines to revise the regulation as 
suggested.
    Proposed Sec.  314.70(b)(3)(vii) stated that for sterilization 
process and test methodologies, relevant validation protocols must be 
provided in addition to the requirements in Sec.  314.70(b)(3)(iv) and 
(b)(3)(v).
    (Comment 52) One comment said that the inclusion of validation 
protocols for sterilization assurance is new. The comment also said 
that submitting all validation data is different from data summaries 
previously requested and provided for microbiological consults.
    FDA disagrees with this comment. The information on sterility 
assurance FDA expects an applicant to provide in an application and the 
format of the data are described in the guidance

[[Page 18741]]

entitled ``Submission of Documentation of Sterilization Process 
Validation in Applications for Human and Veterinary Drug Products.'' 
The provisions of Sec.  314.70(b)(3)(vii) are consistent with current 
FDA policy.
    (Comment 53) One comment said that clarification is needed that the 
test methodologies and validation protocols referred to in this section 
are for the sterilization process only.
    FDA agrees and has replaced ``test methodologies'' with ``test 
methodologies related to sterilization process validation'' in new 
Sec.  314.70(b)(3)(vii).
    Proposed Sec.  314.70(b)(3)(viii) stated that a reference list of 
relevant SOPs, when applicable, must be contained in the supplement.
    (Comment 54) Many comments recommended that reference to SOPs be 
deleted. Several of these comments said that it was unclear what value 
a reference list of SOPs provides in the division review process and 
that SOPs are generally considered a CGMP issue. One comment said that 
reference to appropriate SOPs is currently required only as it pertains 
to sterilization processes and biologic products. The comment also 
contended that inclusion of a reference list of SOPs in the submission 
for any type of change is not necessary. Several comments said that 
``when applicable'' was too vague and one comment recommended that the 
provision be revised to state ``A reference list of relevant standard 
operating procedures (SOPs) for aseptic processing operations.''
    An applicant is required to submit a ``full description of controls 
used for the manufacture, processing, and packing of a drug'' (section 
505 of the act). This information may be submitted in different forms, 
including SOPs. In most cases, SOPs do not include information relevant 
to the NDA or ANDA review, but rather information relevant to 
determining an applicant's compliance with CGMPs. However, in the case 
of a natural product, a recombinant DNA-derived protein/polypeptide, a 
complex or conjugate of a drug substance with a monoclonal antibody, or 
a sterilization process, information contained in SOPs is often 
relevant to the review of certain aspects of an application. FDA has 
deleted proposed Sec.  314.70(b)(3)(viii) and revised Sec.  
314.70(b)(3)(vi) and (b)(3)(vii) to limit the need for information on 
SOPs in these situations. The agency clarifies that information 
regarding SOPs is needed in some cases. FDA wishes to emphasize that 
while the information is needed for the application review, it is not 
always necessary to submit the actual SOP as long as the required 
information is provided in sufficient detail as part of the 
application.
    On its own initiative, FDA has revised Sec.  314.70(b)(3)(iv) by 
replacing the phrase ``evaluate the effect of the change * * * 
(validating the effects of the change)'' with ``assess the effects of 
the change'' because the term is defined at Sec.  314.3(b). In the 
introductory text of Sec.  314.70(b)(3), FDA replaced the phrase ``the 
following shall'' with ``the following information must'' to add 
clarity.
    Proposed Sec. Sec.  314.70(b)(4) and 601.12(b)(4) provided that an 
applicant may request an expedited review of a supplement if a delay in 
making the change would impose an extraordinary hardship or for public 
health reasons.
    (Comment 55) One comment said that a complete definition of 
expedited review from FDA's ``Manual of Policies and Procedures'' 
(MAPPs) should be incorporated in the regulation. One comment said FDA 
should consider adding mandatory vendor-imposed changes (without 
sufficient reaction time) to the list of ``not reasonably foreseen'' 
events.
    FDA has published two MAPPs on expedited review--MAPP 5420.1 
entitled ``Requests for Expedited Review of Supplements to Approved 
ANDAs and AADAs'' and MAPP 5410.3 entitled ``Requests for Expedited 
Review of NDA Chemistry Supplements.'' These MAPPs contain criteria 
that FDA uses in granting expedited review based on public health need, 
extraordinary hardship on the applicant, or agency need. FDA declines 
to add this detailed information on internal FDA procedures to the 
regulation but encourages applicants to review these MAPPs to see how 
FDA would assess a request for an expedited review. The MAPPs already 
include ``abrupt discontinuation of supply of active ingredient, 
packaging material, or container closure'' as an example of an 
extraordinary hardship that was not reasonably foreseen. An applicant 
is required to submit sufficient documentation to support a need for an 
expedited review. In the case of an abrupt discontinuation of supply, 
FDA will require information to support that the discontinuation was 
abrupt such as when the supplier informed the applicant of the 
discontinuation of supply, the amount of supplies available in-house 
and from the supplier, and the date the supplies are expected to run 
out. FDA emphasizes that inadequate planning on the part of an 
applicant is not a reason for FDA to expedite the review of a 
supplement based on extraordinary hardship.
    (Comment 56) A few comments requested that FDA provide feedback to 
the sponsor on acceptance or refusal of an ``expedited review'' request 
within 30 days.
    FDA's MAPPs 5240.1 and 5310.3 describe procedures for processing 
expedited review requests. All requests for expedited review are 
reviewed promptly, usually within 30 days of receipt. If the review 
division denies the request, the applicant will be contacted. FDA 
declines to specify that it will contact applicants to advise them that 
their expedited review request has been granted or that the decision 
will be made within 30 days. However, applicants can contact the review 
division at any time about the status of their request.

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

    Proposed Sec.  314.70(c)(1) required that a supplement be submitted 
for any change in the product, production process, quality controls, 
equipment, or facilities that has a moderate potential to have an 
adverse effect on the identity, strength, quality, purity, or potency 
of the product as these factors may relate to the safety or 
effectiveness of the product. If the change concerns labeling, 12 
copies of the final printed labeling must be included.
    (Comment 57) One comment said that in the preamble to the final 
rule, FDA should further clarify the criteria to be used to distinguish 
between changes-being-effected supplements that can be implemented 
immediately and those where distribution cannot occur until 30 days 
after FDA receives the supplement.
    The decision by FDA as to whether a moderate change should be 
classified as one that can be implemented by an applicant when FDA 
receives a supplement or one requiring supplement submission at least 
30 days prior to distribution of the drug product made using the change 
depends on many factors. Some of these factors include the need for FDA 
to verify compliance status, dosage form, route of administration, or 
whether, based on FDA's experience, a particular type of change is 
usually complete and provides the proper information. It is not 
possible to provide a general list of factors considered because 
different factors are considered by FDA for each type of change.
    (Comment 58) A few comments requested changes in the format of this 
section. One comment said that supplements for changes being effected 
in 30 days as well as changes being

[[Page 18742]]

effected immediately are defined as ``moderate changes.'' The comment 
asked whether there can be different verbiage for these two categories 
to allow differentiation. Another comment suggested that the two types 
of changes-being-effected supplements should be separated into 
different paragraphs under this section.
    FDA declines to revise the regulations as requested. FDA believes 
that the format and terms are adequate and will not be unclear when 
individuals become more familiar with the regulations and the guidance.
    (Comment 59) One comment said it recognizes that the supplements 
for changes being effected in 30 days is a statutory classification. 
The comment said that, unfortunately, the provision does not provide 
material advantage over a changes-being-effected supplement for either 
the agency or the industry, especially for new chemical entities 
(NCEs). The comment said that, instead, the provision adds a 30-day 
wait period that does not currently exist for NCEs. The comment said 
that, from FDA's point of view, the reviewer will be spending twice the 
amount of time on the same application, first for an administrative 
review for the completeness of the information and later to actually 
review the application. The comment said that from industry's point of 
view, the 30-day wait period does not necessarily provide increased 
assurance of an approval action. The comment suggested that any change 
that can be the subject of a changes-being-effected-in-30-days 
supplement could just as easily be reclassified as a changes-being-
effected supplement. The comment said that this would save time for 
both FDA and industry.
    FDA declines to revise the regulation as requested. The changes-
being-effected-in-30-days provision allows certain changes previously 
requiring prior approval to be implemented rapidly, thus reducing the 
percentage of supplements requiring prior approval. FDA recognizes that 
the public health can be adequately protected without requiring 
approval of certain manufacturing changes prior to distribution of the 
product made with the change. FDA continues to believe that it is 
important that such changes be documented and validated so there is a 
mechanism for assessing the consequences of the changes and that the 
agency approve such changes. Ready access to information regarding such 
changes through submission of a supplement 30 days before distribution 
of the product would protect against the distribution of unsafe or 
ineffective products while speeding the availability of improved 
products. The provision is intended to benefit the public health 
because it permits FDA to stop or delay a product from being 
distributed to the public when the product is made with a major change 
(i.e., one with a substantial potential to have an adverse effect on 
the identity, strength, quality, purity, or potency of the product as 
these factors may relate to the safety or effectiveness of the product) 
that is improperly categorized as a moderate change. The provision also 
permits the agency to act when information necessary to demonstrate 
that the change has not adversely affected product quality is not 
provided.
    (Comment 60) Several comments recommended inserting ``only'' in the 
last sentence to read: ``If the change concerns only labeling, include 
12 copies of final printed label.'' One comment said that there are 
changes that have minor impacts on labeling (for example, signature 
changes) that, if implemented as stated, would result in an increased 
regulatory burden to provide finished product labeling prior to change 
implementation.
    FDA declines to revise the regulation as requested because changes-
being-effected supplements (within 30 days and immediately) that 
include both manufacturing changes and labeling changes must also 
include 12 copies of the final printed labeling, if appropriate. 
However, FDA has clarified that the only labeling changes that require 
submission of 12 copies of finished product labeling at the time of 
supplement submission are those classified as a moderate change. 
Changes-being-effected manufacturing supplements that result in 
labeling changes that are classified as minor under Sec.  314.70(d) do 
not have to include copies of final printed labeling. The final printed 
labeling for these minor labeling changes can be submitted in the next 
annual report in accordance with Sec.  314.81(b)(2)(iii).
    FDA has clarified Sec.  314.70(c)(1) to explain when final printed 
labeling must be submitted by revising the last sentence to read ``If 
the supplement provides for a labeling change under paragraph 
(c)(6)(iii) of this section, 12 copies of the final printed labeling 
must be included.''
    (Comment 61) One comment said that FDA should delete the 
requirement to provide 12 copies of the final printed labeling with a 
changes-being-effected labeling supplement. The comment said that 
although the specified changes may be submitted in a changes-being-
effected supplement, at times they may not be implemented until after 
the submission. The comment said that to print final labeling 
specifically for the changes-being-effected supplement is unnecessarily 
expensive and complicates the normal labeling printing process. The 
comment said that an alternative would be to submit a typed copy of the 
labeling and submit the final printed labeling in the annual report.
    FDA declines to revise the regulation as requested. Moderate 
labeling changes, which are those that have a moderate potential to 
have an adverse effect on the identity, strength, quality, purity, or 
potency of the product as these factors may relate to the safety or 
effectiveness of the product, can be implemented immediately without 
FDA's prior approval. In FDA's experience, errors that occurred when 
draft labeling was converted to final printed labeling have made the 
final printed labeling unacceptable. Also, FDA reviews not only the 
content of labeling for accuracy but also the format (e.g., layout, 
size of print) for clarity. A typed copy of the labeling does not 
always accurately reflect the format of the final printed labeling. The 
labeling should be available for review at the time of submission 
whether or not the applicant intends to implement the change 
immediately upon FDA receipt of the supplement.
    (Comment 62) One comment stated that current Sec.  314.70(c)(3) 
permits a different facility to be used for the production of the drug 
substance under certain conditions. The comment said that the proposal 
does not include this provision, and that FDA intends to provide 
recommendations concerning this in certain guidance documents. The 
comment said that this provision of current Sec.  314.70 should be 
retained in the revised regulation because the industry is familiar 
with the provision and has used it for years.
    FDA declines to revise the proposal as requested. As stated in the 
proposal, the agency's approach is to issue regulations that set out 
broad, general categories of manufacturing changes and use guidance 
documents to provide FDA's current thinking on the specific changes 
included in those categories. FDA has provided recommendations on 
changes in manufacturing sites in FDA's guidance entitled ``Changes to 
an Approved NDA or ANDA.''
    Proposed Sec.  314.70(c)(2)(i) stated that changes requiring 
supplement submission at least 30 days prior to distribution of the 
drug product made using the change (moderate changes) includes the 
following change: A change in the container closure system that does 
not affect the quality of the final drug product.

[[Page 18743]]

    (Comment 63) Many comments recommended that the requirement should 
be changed to include ``significant change'' and/or ``adversely 
affect,'' so that the regulation would read: ``A significant change in 
the container closure system that does not adversely affect the quality 
of the final drug product.''
    FDA declines to revise the provision as requested. New Sec.  
314.70(c)(1) already states that the changes that should be filed in 
changes-being-effected supplements are those that have a moderate 
potential to have an ``adverse effect.'' Adding the word ``adversely'' 
to this provision is redundant. Adding the term ``significant'' is also 
inappropriate because any change, whether big or small, should not 
adversely affect the quality of the final drug product. Some 
manufacturing changes have an adverse effect on the identity, strength, 
quality, purity, or potency of the drug product. In many cases, the 
applicant chooses not to implement these manufacturing changes, but 
sometimes the applicant wishes to do so. If an assessment indicates 
that a change has adversely affected the identity, strength, quality, 
purity, or potency of the drug product, the change should be submitted 
in a prior approval supplement, regardless of the recommended reporting 
category for the change. For example, a process change recommended for 
a changes-being-effected-in-30-days supplement could cause the 
formation of a new degradant that requires qualification and/or 
identification. The applicant may believe that there are no safety 
concerns relating to the new degradant. Even so, the applicant should 
submit this change in a prior approval supplement with appropriate 
information to support the continued safety and effectiveness of the 
product. During the review of the prior approval supplement, FDA will 
assess the impact of any adverse effect on the drug product as this 
change may relate to the safety or effectiveness of the drug product.
    (Comment 64) One comment noted an apparent conflict between 
proposed Sec.  314.70(b)(2)(vi), which stated that a ``change in a 
container closure system that * * * may affect the impurity profile of 
the drug product'' should be filed in a prior approval supplement, and 
proposed Sec.  314.70(c)(2)(i), which stated that ``a change in the 
container closure system that does not affect the quality of the final 
drug product'' should be filed in a changes-being-effected-in-30-days 
supplement. The comment said that this would allow for inconsistent and 
overly conservative interpretations of what might fall under Sec.  
314.70(b)(2)(vi).
    FDA agrees and has clarified the wording in these two provisions. 
Changes to proposed Sec.  314.70(b)(2)(vi) were discussed previously 
under section III.C of this document. For consistency, Sec.  
314.70(c)(2)(i) was revised to exclude changes that would be included 
under Sec.  314.70(b) and (d).
    FDA emphasizes that the container closure system and packaging 
component changes identified in Sec.  314.70(b) must be filed in a 
prior approval supplement even if an applicant concludes that the 
quality of the drug product has not been adversely affected. The 
provision has also been revised to standardize terminology, as 
requested, by changing ``final drug product'' to ``drug product.''
    Proposed Sec.  314.70(c)(2)(ii) stated that changes requiring 
supplement submission at least 30 days prior to distribution of the 
drug product made using the change (moderate changes) included the 
following change: Changes solely affecting a natural protein product, a 
recombinant DNA-derived protein/polypeptide product or a complex or 
conjugate of a drug with a monoclonal antibody, including the 
following: (1) An increase or decrease in production scale during 
finishing steps that involves new or different equipment; and (2) 
replacement of equipment with that of similar, but not identical, 
design and operating principle that does not affect the process 
methodology or process operating parameters.
    (Comment 65) Several comments said that having special requirements 
for this category of products represents additional regulatory 
reporting requirements beyond current practice. A few comments 
recommended that this section be deleted. One comment said that these 
products should not be regulated differently than the traditional 
products. The comment said that if FDA disagrees and feels that this 
requirement is warranted, the specific details be captured in the 
guidance instead.
    FDA declines to revise the regulation as requested. There are 
specific issues and concerns relating to the production of proteins 
that are not routinely associated with other classes of drugs; 
therefore, FDA has specified certain requirements for proteins. 
Proteins are susceptible to denaturation. Denaturation can be caused by 
changes in sheer force as a result of scale and/or equipment changes. 
Also, proteins differentially adsorb to surfaces. The identity, 
strength, quality, purity, or potency of the product could be affected 
by changes in scale or equipment because of these characteristics.
    (Comment 66) A few comments requested that FDA clarify whether this 
section applies to drug products or drug substance.
    FDA agrees and has clarified the proposed language, which is 
intended to apply to both drug substance and drug product.
    (Comment 67) A few comments recommended that FDA delete reference 
to ``natural protein products.'' The comments also requested 
clarification as to whether the definition natural products includes 
fermentation products.
    FDA declines to revise the regulation as requested. Issues about 
scale and equipment and concerns associated with proteins are the same 
whether the protein is derived from a natural source or by other means, 
such as DNA technology. The definition of natural products was 
discussed in comment number 48 of this document. Natural proteins are a 
subset of natural products.
    (Comment 68) One comment said that this section applies to both an 
increase and decrease in batch size involving new equipment. The 
comment asked whether new equipment includes replacement equipment.
    FDA agrees and has clarified the proposed language. The phrase 
``new or different equipment'' has been replaced by the phrase 
``different equipment.'' Different equipment can include new models, 
changes in capacity, construction materials (e.g., glass-lined tanks to 
stainless steel), equipment design, and/or equipment operating 
principles. If a scale change involves replacing equipment with 
equipment that is identical in all critical aspects (e.g., same model 
and capacity, same construction materials), this is a type of change 
that could be reported in an annual report. For the same reasons, FDA 
is revising Sec.  601.12(c)(2)(ii) to delete the word ``new.''
    (Comment 69) A few comments requested clarification of ``finishing 
steps.''
    FDA declines to revise the regulations to provide clarification of 
the term ``finishing steps.'' In general, finishing steps are 
considered those steps in the manufacturing process where the 
stability, or the property and performance, of a protein product is 
less likely to be affected by changes in scale or equipment. The steps 
in a manufacturing process that would be considered finishing steps 
depend on the manufacturing process and the specific protein being 
manufactured. A particular manufacturing step may be

[[Page 18744]]

considered a finishing step for one product but not for another. An 
applicant is encouraged to discuss with FDA which steps would be 
considered finishing steps for a particular product and process. This 
discussion should occur as early in the process as possible, including 
during investigational new drug (IND) meetings.
    (Comment 70) A few comments requested clarification of the 
difference between equipment that is ``similar but not identical,'' 
proposed as a changes-being-effected-in-30-days supplement, and the 
SUPAC terminology of equipment of the ``same design and operating 
principle,'' which is already defined in the SUPAC guidances and the 
June 1999 proposal as an annual report change. The comment said that 
the difference is not readily apparent and may lead to varying 
interpretations of regulatory submission requirements. The comments 
said that for equipment changes that are of different operating 
principle and design, FDA should consider the major change category, 
and for equipment changes that are of the same operating principle but 
different design, FDA should consider the moderate change category.
    FDA agrees and has clarified the requirement by replacing the 
phrase ``of similar, but not identical, design and operating principle 
that'' with the phrase ``that of a different design that.'' Equipment 
of a different design may or may not have a different operating 
principle.
    (Comment 71) One comment suggested inserting the word ``adversely'' 
before ``affect'' to read: ``Replacement of equipment with that of 
similar, but not identical, design and operating principle that does 
not adversely affect the process methodology or process operating 
parameters.'' The comment said that replacement of equipment that does 
not adversely affect the process methodology or operating parameters 
and/or positively affects process methodology or operating parameters 
should be reported as a minor change.
    FDA declines to revise the provision as requested. New Sec.  
314.70(c)(1) already states that the changes that should be filed in 
changes-being-effected supplements are those that have a moderate 
potential to have an ``adverse effect.'' Adding the word ``adversely'' 
to this provision is redundant.
    Proposed Sec.  314.70(c)(4) stated that pending approval of the 
supplement by FDA, except as provided in paragraph (c)(6), 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 Sec.  
314.70(b)(3)(i) through (b)(3)(viii) must be contained in the 
supplement.
    (Comment 72) One comment said that the last sentence in Sec.  
314.70(c)(4) should be revised to read: ``The information listed in 
paragraphs (b)(3)(i) through (b)(3)(vii) * * *'' because currently CGMP 
validation information, including a reference to appropriate SOPs, is 
required to be submitted in applications only as it pertains to 
sterilization processes.
    FDA has revised Sec.  314.70(c)(4) to make it consistent with the 
changes made in Sec.  314.70(b)(3) to address the concerns raised by 
the comment (see discussion in comment numbers 50 through 54 in section 
III.C of this document) and also to clarify the term ``product.''
    (Comment 73) One comment said that a time line and dispute 
resolution process needs to be defined by regulation or guidance in 
case of disputes regarding the type of information needed to support a 
change.
    FDA does not believe it is necessary to revise proposed Sec.  
314.70 to address this issue. Actions by reviewers or other Center 
officials may be appealed through the appeals mechanism already in 
place in each Center to the Center Director and, ultimately, to the 
Commissioner of Food and Drugs. Dispute resolution procedures are 
detailed in 21 CFR 10.75 and 21 CFR 312.48, and Sec. Sec.  314.103 and 
601.12(h). FDA has also provided additional information in guidance 
documents. In the Federal Register of March 7, 2000 (65 FR 12019), FDA 
issued a guidance entitled ``Formal Dispute Resolution; Appeals Above 
the Division Level.'' The guidance describes the mechanism for 
resolution of procedural (including administrative) and scientific 
disputes in CDER and CBER.
    Proposed Sec.  314.70(c)(5) stated that the applicant must not 
distribute the product made using the change if, within 30 days 
following FDA's receipt of the supplement, FDA informs the applicant 
that either: (1) The change requires approval prior to distribution of 
the product in accordance with paragraph (b); or (2) any of the 
information required under Sec.  314.70(c)(4) is missing. The applicant 
must not distribute the product made using the change until FDA 
determines that compliance is achieved.
    (Comment 74) One comment said that if FDA determines within 30 days 
of receipt of the supplement that the change is properly submitted but 
the required information is incomplete, the applicant would be required 
to supply the missing information and wait until FDA determines that 
the supplement is in compliance before distributing the product. The 
comment contended that as long as the firm submits the data requested 
by FDA, it should be able to go to market and not wait until FDA 
determines that the supplement is ``in compliance,'' which could take 
months since FDA is not now bound by the 30-day requirement.
    FDA agrees and has clarified the requirement based on this comment. 
FDA has revised Sec.  314.70(c)(5) to provide that, in the case of 
missing information, the applicant must not distribute the drug product 
until the supplement has been amended to provide the missing 
information.
    (Comment 75) One comment asked, when additional information is 
provided, whether FDA's determination of compliance with the 
requirements of this section is equivalent to an approval of the 
supplement.
    FDA has revised this section, and this comment is no longer 
applicable. However, FDA clarifies that it sends a formal letter to an 
applicant stating that a particular supplement is approved and that no 
other communication from FDA should be construed as an approval.
    Proposed Sec.  314.70(c)(7) stated that if the agency disapproves 
the supplemental application, it may order the manufacturer to cease 
distribution of the drug products made with the manufacturing change.
    (Comment 76) A few comments recommended that FDA replace this 
requirement with the following: ``If FDA later determines that the 
supplemental application is not immediately approvable, the agency will 
work with the applicant to resolve all issues and to assure the 
continued availability of the drug.'' Another comment recommended that 
this requirement be limited to only those cases where an adverse effect 
on safety or efficacy can be demonstrated. One comment said that 
although this is the language contained in section 506A(d)(3)(B)(iii) 
of the act, it is a reversal of long-time FDA policy of allowing firms 
to respond to deficiencies and get the supplement approved without 
interfering with distribution. The comment said that FDA should 
continue its long-standing policy.
    FDA declines to revise the provision as requested. The regulation 
is consistent with section 506A(d)(3)(B)(iii) of the act. There may be 
some instances where FDA determines, after the drug product made using 
the change has been distributed, that the information submitted in the 
supplement fails to adequately demonstrate the continued safety and

[[Page 18745]]

effectiveness of the drug product. In such cases, FDA will make all 
possible efforts to resolve problems with the applicant concerning the 
supplement submission without requiring the removal of the drug product 
from the marketplace. In cases where FDA determines that there may be a 
danger to public health due to continued marketing of the drug product 
or when FDA determines that the issues may not otherwise be resolved, 
the agency may require that the applicant cease distribution of the 
drug product made using the change or that the product be removed from 
distribution pending resolution of the issues related to the change.
    (Comment 77) One comment said that if FDA disapproves a changes-
being-effected-in-30-days supplement, the sponsor should be notified 
within 30 days of this submission as stated in Sec.  314.70(c)(5)(ii).
    FDA declines to revise the regulation based on this comment. FDA 
intends during the 30-day period to focus its review on determining 
whether the applicant reported the change using the appropriate 
mechanism and, if so, whether any of the required information is 
missing. FDA intends to perform the substantive review of the 
submission as expeditiously as possible, but this is unlikely to occur 
within 30 days of receipt of the supplement.

F. Changes For Which Distribution of the Drug Product Involved May 
Commence When FDA Receives a Supplement (Moderate Changes)

    Proposed Sec.  314.70(c)(6) stated that FDA may designate a 
category of changes for which the holder of an approved application 
making such a change may begin distribution of the drug upon receipt by 
FDA of a supplemental application for the change. These changes 
include, under Sec.  314.70(c)(6)(i), an addition to a specification or 
changes in the methods or controls to provide increased assurance that 
the drug will have the characteristics of identity, strength, quality, 
purity, or potency that it purports or is represented to possess.
    (Comment 78) Several comments recommended that an addition to a 
specification or change in the methods or controls to provide increased 
assurance that the drug will have the characteristics of identity, 
strength, quality, purity, or potency that it purports or is 
represented to possess should be considered to have a minimal potential 
to have an adverse effect and should be allowed to be filed in the 
annual report.
    FDA declines to revise the regulation as requested. FDA has 
identified certain specific changes that provide increased assurance 
that may be submitted in an annual report, such as the tightening of an 
acceptance criterion. However, this is a general provision and the 
assessment of whether or not a change provides ``increased assurance'' 
is subjective and must be supported by studies and data, as 
appropriate. FDA must have the opportunity to concur with an 
applicant's assessment that a change provides ``increased assurance'' 
in a timely manner. Reporting of such changes in an annual report would 
not afford FDA this opportunity because a change may be in effect for 
up to a year before FDA would have the opportunity to review the 
change. Changes that do not necessarily provide increased assurance may 
be a type of change that must be submitted in a changes-being-effected-
in-30-days supplement or a supplement that requires approval prior to 
distribution of the product made using the change.
    (Comment 79) One comment recommended that FDA change ``addition to 
a specification or changes in the methods or controls'' to ``addition 
to a specification or changes in the tests, analytical procedures, or 
acceptance criteria.''
    FDA declines to revise the regulation as requested. The phrase 
``methods or controls'' is not used by FDA to mean tests, analytical 
procedures, or acceptance criteria. Methods and controls relate to the 
manufacturing process.
    Proposed Sec.  314.70(c)(6)(ii) included the following category: A 
change in the size and/or shape of a container for a nonsterile drug 
product, except for solid dosage forms, without a change in the labeled 
amount of product or from one container closure system to another.
    (Comment 80) A few comments recommended adding ``a sterile drug 
product, or a sterile drug substance'' to read ``* * * container for a 
nonsterile drug product, except for solid dosage forms, a sterile drug 
product, or a sterile drug substance without a change.'' The comments 
said that changes in the size and shape of containers for sterile drug 
substances or sterile drug products have only moderate potential 
impact. The comments said that this is especially true when the nature 
of the size/shape changes are very minor, as is often the case when 
suppliers make minute adjustments in their packaging components.
    FDA declines to revise the regulation as requested. As discussed in 
the comments for Sec.  314.70(b)(2)(iii) in section III.C of this 
document, sterility of drug products or drug substances is a 
fundamental and essential quality attribute of these drugs and is a 
critical aspect of the safety assessment. Changes in the container 
closure system, even if minimal, may affect the sterility assurance of 
the drug product and are a major change. For sterile drug substances, 
the effect of changes in the size and/or shape of the container closure 
system is considered by FDA to be of lower risk because of the 
differences in procedures for sterilizing drug substances and drug 
products, but the risk is still higher than for nonsterile products. 
Therefore, FDA declines to specify in the regulations that these 
changes can be submitted in a changes-being-effected supplement. 
Additional information on changing container closure systems for 
sterile drug substances or drug products is included in the guidance 
``Changes to an Approved NDA or ANDA.''
    (Comment 81) Several comments pertained to the phrase ``without a 
change in the labeled amount of product.'' The comments said that 
proportional changes (i.e., ratio of the amount of drug product to size 
of container) are not expected to adversely affect the drug product, 
and one of these comments recommended that FDA should add ``and a 
change in the labeled amount of product as long as the size of the 
container/closure system is changed proportionally.'' Other comments 
said that a corresponding change in fill quantity, along with a change 
in container size, is expected and readily acceptable and that it is 
illogical to assume that a change in the amount of product would 
present any greater risk than a change in container size.
    FDA declines to revise the regulation as requested or with similar 
language included in Sec.  314.70(d)(2)(iv). The phrase ``labeled 
amount of product'' refers to the total quantity of drug product (e.g., 
milliliters, grams). FDA has included the phrase ``without a change in 
the labeled amount of product'' because of the agency's concern about 
the proliferation of unit-of-use containers that may invite the misuse 
of drug products. A unit-of-use container is one that contains a 
specific quantity of a drug product and that is intended to be 
dispensed to the patient without further modification except for the 
addition of appropriate labeling. Although few in number, some drug 
products may cause life-threatening side effects, such as permanent 
liver damage, if used for longer periods of time than recommended in 
the labeling. Similarly, certain drugs must be used for a specific 
length of time (e.g., antibiotics) or the treatment may be ineffective. 
Unit-of-

[[Page 18746]]

use containers that contain a quantity of drug product that invite 
underuse or overuse of the product as recommended in the labeling may 
be a public health risk. FDA considers changes in the labeled amount of 
a nonsterile drug product in a unit-of-use container to have a moderate 
potential to adversely affect the safety and efficacy of the drug 
product and expects that these changes would normally be submitted in a 
changes-being-effected-in-30-days supplement under Sec.  
314.70(c)(2)(i). This would give FDA an opportunity to raise a concern 
about a package presentation prior to distribution of the product.
    FDA's concern is less when the ``labeled amount of product'' is 
changed in multiple-unit containers for nonsterile drug products. FDA 
considers this change to have the same level of risk as a change in the 
size and/or shape of the container. A multiple-unit container is a 
container that permits withdrawal of successive portions of the 
contents without changing the strength, quality, or purity of the 
remaining portion. This type of container is not for direct 
distribution to patients, but is used by health care practitioners who 
dispense the drug in smaller amounts in accordance with a physician's 
instructions. While FDA declines to revise the regulations to specify 
the distinction between unit-of-use and multiple-use containers because 
of the complexity of the issue, FDA will address this issue when 
revising the guidances ``Changes to an Approved NDA or ANDA'' and 
``Changes to an Approved Application for Specified Biotechnology and 
Specified Synthetic Biological Products.''
    Proposed Sec.  314.70(c)(6)(iii)(C) included as a moderate change a 
change in the labeling to add or strengthen an instruction about dosage 
and administration that is intended to increase the safe use of the 
product.
    (Comment 82) One comment said that FDA should replace the words 
``and administration'' in Sec.  314.70(c)(6)(iii)(C) with the words 
``administration and storage.''
    FDA declines to revise the regulation as requested. The addition or 
strengthening of a storage statement could reflect a change in the 
expected characteristics or quality of a drug product and would be a 
major change. Also, one of FDA's objectives is to have the same drug 
products stored similarly to avoid confusion in the marketplace. FDA 
would need to review the proposed change prior to implementation to 
determine if: (1) The change is appropriate, (2) any changes in product 
quality causing the labeling change significantly impact the safety or 
effectiveness of the drug, and (3) there are other issues that need to 
be addressed either on an individual company basis or globally.
    Proposed Sec.  314.70(c)(6)(iii)(E) included as a moderate change 
any other change specifically requested by FDA.
    (Comment 83) One comment said that any changes made to the labeling 
that are specifically required by the FDA should be reportable in the 
annual report.
    FDA declines to revise the June 1999 proposal as requested but has 
revised Sec.  314.70(c)(6)(iii)(E) to provide clarification. As stated 
in the June 1999 proposal, FDA proposed adding this section to allow 
labeling changes that normally require prior approval to be submitted 
in a changes-being-effected supplement when FDA specifically requests 
the change. FDA has clarified Sec.  314.70(c)(6)(iii)(E) as follows: 
``Any labeling change normally requiring a supplement submission and 
approval prior to distribution of the drug product that FDA 
specifically requests be submitted under this provision.'' FDA has also 
clarified Sec.  601.12(f)(2)(i)(E) as follows: ``Any labeling change 
normally requiring a supplement submission and approval prior to 
distribution of the product that FDA specifically requests be submitted 
under this provision.''

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

    Proposed Sec.  314.70(d)(1) required that changes in the product, 
production process, quality controls, equipment, or facilities that 
have a minimal potential to have an adverse effect on the identity, 
strength, quality, purity, or potency of the product as these factors 
may relate to the safety or effectiveness of the product must be 
documented by the applicant in the next annual report in accordance 
with Sec.  314.81(b)(2).
    Proposed Sec.  314.70(d)(2)(i) required the following change to be 
documented in the next annual report: Any change made to comply with an 
official compendium that is consistent with FDA requirements and 
provides increased assurance that the drug will have the 
characteristics of identity, strength, quality, purity, or potency that 
it purports or is represented to possess.
    FDA received 18 comments on this provision. Fifteen comments 
requested that FDA change this requirement to read ``Any change to 
comply with an official compendium;'' two comments requested that FDA 
change this requirement to read ``Any change made to comply with an 
official compendium that is consistent with FDA requirements;'' and one 
comment did not provide a suggested revision.
    FDA declines to revise the provision as requested in the comments 
but has revised the provision to provide further clarification. The 
basis for this decision is discussed below. The majority of the 
comments pertained to drugs regulated under, and the statutory 
requirements regarding official compendia included in, the act. 
Therefore, FDA has responded to the comments from this perspective. FDA 
has made corresponding changes to Sec.  601.12(c) and (d) for biologics 
regulated under section 351 of the PHS Act.
    (Comment 84) Many comments said that the proposal to require 
supplemental applications for some changes that are made to comply with 
an official compendium fails to recognize the legal status of the USP/
NF under the act and undermines the authority of the USP/NF as official 
compendia and sources of standards. One comment stated that if a drug 
product meets compendial requirements, it is considered unadulterated 
under the act. Another comment stated that the USP is the responsible 
compendial body for regulatory specifications.
    Under section 501(b) of the act (21 U.S.C. 351(b)), a drug that is 
recognized in an official compendium may be considered adulterated if 
its strength differs from, or its quality or purity fall below, the 
standards set in the compendium. Determinations of adulteration under 
this provision of the act must be made in accordance with the 
analytical procedures set in the compendium. When there is no 
analytical procedure prescribed in the compendium or the tests 
prescribed in the compendium are insufficient, the agency can follow 
the process outlined in the statute and issue a regulation to provide 
an appropriate analytical procedure. As stated in the act, no drug 
defined in an official compendium will be considered adulterated under 
section 501(b) of the act because its strength differs from, or its 
quality or purity fall below, the standards set in the compendium if 
the differences from the standard are stated in its label. Under 
section 502(g) of the act (21 U.S.C. 352), a drug that is recognized in 
an official compendium may be considered misbranded if the drug is not 
packaged and labeled as prescribed in the compendium.
    The agency is aware of the legal status of the USP/NF under the act 
as a standard for determining whether a drug may be considered 
adulterated or misbranded. A compendial product that fails to comply 
with USP/NF standards

[[Page 18747]]

may be considered to be adulterated or misbranded under the act. 
However, a compendial product can still be considered adulterated or 
misbranded under other provisions of sections 501 or 502 of the act, 
even if it complies with USP/NF standards.
    While the standards in the USP/NF are legally enforceable standards 
for determining whether a product is considered adulterated under 
section 501 of the act, these standards are not considered the complete 
regulatory specification. The agency is responsible for establishing 
regulatory specifications as part of the approval of an application. 
Under sections 505(b) and 505(j) of the act (21 U.S.C. 355(b) and 
355(j)) , an application must include a full description of the methods 
used in and the facilities and controls used for, the manufacture, 
processing, and packing of the drug. If the specifications included in 
the description are considered inadequate to ensure and preserve the 
identity, strength, quality, purity, or potency of the drug, the agency 
will refuse to approve the application. Standards established by an 
official compendium may be inadequate for the purposes of approving an 
application under section 505 of the act. The USP acknowledges that:
    While one of the primary objectives of the Pharmacopeia is to 
assure the user of official articles of their identity, strength, 
quality, and purity, it is manifestly impossible to include in each 
monograph a test for every impurity, contaminant, or adulterant that 
might be present, including microbial contamination. These may arise 
from a change in the sources of the material or from a change in the 
processing, or may be introduced from extraneous sources. Tests 
suitable for detecting such occurrences, their presence of which is 
inconsistent with applicable good manufacturing practice or good 
pharmaceutical practice, should be employed in addition to the tests 
provided in the individual monograph. (USP 25, General Notices, page 
7).
    Similarly, while the labeling requirements in the USP/NF are 
legally enforceable standards for determining whether a product is 
misbranded under section 502 of the act, use of these standards alone 
does not ensure compliance with the act. The USP states ``articles in 
this Pharmacopeia are subject to compliance with such labeling 
requirements as may be promulgated by governmental bodies in addition 
to the Pharmacopeial requirements set forth for the articles.'' (USP 
25, General Notices, page 12).
    Not all compendial standards or changes in existing compendial 
standards are: (1) Adequate to ensure and preserve the identity, 
strength, quality, purity, or potency of the drug or (2) consistent 
with other requirements of the act. For example, a deletion of an 
impurity test may result in an inadequate standard for ensuring the 
purity of the drug. Therefore, the agency does not believe that all 
changes made to comply with an official compendium are of a type that 
should be reported in an annual report.
    (Comment 85) Many comments stated that the phrases ``which are 
consistent with FDA requirements'' and ``provides increased assurance 
that the drug will have the characteristics of identity, strength, 
quality, purity, or potency that it purports or is represented to 
possess'' are unclear. Several comments stated that ``consistent with 
FDA requirements'' allows for individual review interpretations. 
Several comments said that deleting or widening a specification due to 
a change in the USP should be allowed in an annual report.
    FDA concurs that the provisions regarding changes to comply with an 
official compendium should be clarified. Separate discussions of 
labeling, analytical procedures, and acceptance criteria and test 
changes follow, along with a discussion of the phrase ``consistent with 
FDA requirements.''
    Labeling: Under section 502(g) of the act, a drug recognized in an 
official compendium may be considered misbranded if the drug is not 
packaged and labeled as prescribed in the compendium. The method of 
packing may be modified with the consent of the agency. One comment 
stated that there would be confusion in the marketplace if compendial 
labeling changes were not instituted uniformly. The agency concurs that 
all labeling changes made to comply with an official compendium that 
are consistent with FDA requirements should be reported in an annual 
report. These changes have minimal potential to have an adverse effect 
on the identity, strength, quality, purity, or potency of the product 
as these factors may relate to the safety and effectiveness of the 
product. Consistent labeling promotes the safe use of products and 
reduces confusion in the marketplace.
    Analytical procedures: For compendial drugs, the determination of 
whether the drug is adulterated under section 501(b) of the act must be 
made in accordance with the analytical procedures set in the compendium 
except when no analytical procedure is prescribed in the compendium or 
the tests prescribed in the official compendium are insufficient. In 
these situations, the agency can follow the process outlined in the 
statute and issue a regulation to provide an appropriate analytical 
procedure. Because of the legal status of compendial analytical 
procedures in the act and other requirements relating to analytical 
procedures in the statute, the agency concurs that changes in 
analytical procedures to comply with an official compendium may be 
filed in an annual report, except for changes to comply with an 
official compendium that result in the deletion of a test or the 
relaxation of an acceptance criterion. The agency wishes to emphasize 
that under FDA's CGMPs, the suitability of all analytical procedures, 
including compendial procedures, must be verified under actual 
conditions of use. For example, an assay analytical procedure where 
degradation products, impurities, or excipients interfere with the 
analysis is not considered an acceptable analytical procedure. The use 
of unacceptable analytical procedures, even if specified in an official 
compendium, can be considered a violation of the act. The agency also 
wishes to emphasize that a change from an approved analytical procedure 
that is capable of quantifying impurities to a compendial analytical 
procedure that cannot quantify impurities is in essence a deletion of 
an impurities test. This change of procedure should not be reported in 
an annual report, but should be reported as any other request for 
deletion of an approved test.
    Tests and acceptance criteria: Under sections 505(b) and 505(j) of 
the act, an application must include a full description of the methods 
used in and the facilities and controls used for, the manufacture, 
processing, and packing of the drug. If the specifications included in 
the description are considered inadequate to ensure and preserve the 
identity, strength, quality, purity, or potency of the drug, the agency 
will refuse to approve the application. As previously discussed in this 
document, the standards established by an official compendium may be 
inadequate for approving an application under section 505 of the act.
    As part of the detailed application review process and in 
accordance with section 505 of the act, FDA requires that the 
application include tests and acceptance criteria that the agency 
believes are necessary to ensure and preserve the identity, strength, 
quality, purity, and potency of the product. The specifications 
included in the application are legally binding upon the applicant, and 
a product that fails to comply with the specifications included in the 
application can be considered an unapproved drug under section 505 of 
the act. Compendial standards are often

[[Page 18748]]

used in evaluating the specifications proposed in the application. 
However, compendial standards must often be supplemented with 
additional tests, such as a specific test for impurities, to ensure the 
identity, strength, quality, purity, and potency of the drug. Also, the 
tests and acceptance criteria in an application are often approved 
without benefit of a compendial standard for a drug because no 
compendial standard has been established. Situations could arise where, 
for example, FDA requires tests and acceptance criteria for specific 
impurities as part of approval of an application. These impurities are 
not specified in an existing monograph or are not included in a 
monograph published subsequent to the approval of the drug. If FDA 
allowed all changes to comply with an official compendium to be 
included in an annual report, the applicant could interpret this 
provision as allowing them to delete the tests which were required as a 
condition of approving the application.
    A change to relax an acceptance criterion or delete a test is 
considered a major change. The agency needs to review a request for 
this type of change in the context of a particular NDA or ANDA to 
determine if the change will adversely affect the identity, strength, 
quality, purity, or potency of the product. Changes such as these, when 
requested solely at the initiative of the applicant, must be filed in a 
prior approval supplement. Reporting these changes in an annual report 
is not appropriate. However, when a change to relax an acceptance 
criterion or delete a test is made to comply with a change to an 
official compendium, the change is considered to have a moderate 
potential to have an adverse effect on the identity, strength, quality, 
purity, or potency of the product as these factors may relate to the 
safety and effectiveness of the product. The change is considered 
moderate because: (1) The change has been reviewed by an independent 
group that has the goal of promoting public health and (2) the agency 
has had the opportunity through the USP process of reviewing the 
proposed change in general, but not necessarily in the context of each 
individual application affected by the change. Based on these factors, 
the agency will require a changes-being-effected-in-30-days supplement 
for a change to relax an acceptance criterion or delete a test to 
comply with a change to an official compendium. A change made to comply 
with an official compendium that results in a tightening of an approved 
acceptance criterion or an addition of a test is considered a minor 
change and may be filed in an annual report.
    (Comment 86) FDA proposed that changes to comply with an official 
compendium could be reported in an annual report only if they were 
consistent with FDA requirements. Several comments stated that 
``consistent with FDA requirements'' allows for individual review 
interpretations.
    FDA declines to delete this phrasing but wishes to clarify that the 
term requirements means the requirements of the act or the applicable 
provisions in the Code of Federal Regulations (CFR). An annual report 
or changes-being-effected-in-30-days supplement should not be used to 
implement a change to comply with an official compendium when that 
change is not consistent with other FDA statutory or regulatory 
requirements. An example of this is a change to a compendial analytical 
procedure, when a different analytical procedure is specified in the 
regulations (e.g., 21 CFR part 610) because the use of the compendial 
analytical procedure is not consistent with FDA regulations. Another 
example of this is a change to a compendial analytical procedure that 
is proven not to be suitable under actual conditions of use because the 
use of such an analytical procedure, even if specified in an official 
compendium, is not consistent with CGMPs (21 CFR 211.194). If 
situations like this occur, applicants should contact the agency, 
inform them of the situation, and request advice.
    For the reason discussed previously in this document, the agency is 
adding Sec. Sec.  314.70(c)(2)(iii) and 601.12(c)(2)(iv) to require a 
changes-being-effected-in-30-days supplement for a relaxation of an 
acceptance criterion or deletion of a test to comply with an official 
compendium that is consistent with FDA statutory and regulatory 
requirements. The agency is revising Sec.  314.70(d)(2)(i) as follows: 
``Any change made to comply with an official compendium, except a 
change described in paragraph (c)(2)(iii) of this section, that is 
consistent with FDA statutory and regulatory requirements.'' The agency 
is also revising Sec.  601.12(d)(2)(i) as follows: ``Any change made to 
comply with an official compendium, except a change described in 
paragraph (c)(2)(iv) of this section, that is consistent with FDA 
statutory and regulatory requirements.''
    (Comment 87) Several comments stated that a drug must comply with 
the compendial quality standards or it may be considered adulterated or 
misbranded. The comments went on to say that when the USP makes a 
change and a company cannot comply until FDA approves the change, the 
marketed drug in the intervening period technically may be misbranded 
or adulterated if it fails to meet the changed compendial requirements.
    The agency wishes to clarify as part of this final rule the 
circumstances under which a supplemental application must be submitted 
for changes to comply with an official compendium. A supplemental 
application must be submitted only when the change involves a 
relaxation of an acceptance criterion or deletion of a test. The 
standards for the drug will differ from the standards prescribed in the 
official compendium until the agency approves the change. However, 
under these circumstances, the drug as marketed will have tighter 
specifications or more testing will be performed than has been 
specified in the official compendium. Therefore, the drug will not fall 
below the standards set in the official compendium and would not be 
considered adulterated under section 501(b) of the act.
    (Comment 88) One comment said that the proposed language implies 
that there may be separate and/or different requirements to fulfill USP 
and FDA criteria. Other comments said that the same product, from 
different applicants, should be held to the same standards.
    As discussed previously in this document, while the specifications 
in an official compendium are legally enforceable standards under 
section 502(b) of the act for determining whether a product is 
considered adulterated, these standards may not be sufficient to ensure 
and preserve the identity, strength, quality, purity, and potency of 
the drug as required under section 505 of the act for approval to 
market a drug. Generally, FDA uses compendial standards in evaluating 
the specifications proposed in an application. However, compendial 
standards must often be supplemented with additional tests to ensure 
the identity, strength, quality, purity, or potency of the drug. 
Similarly, while the labeling requirements in USP/NF are legally 
enforceable standards for determining whether a product is misbranded 
under section 502(g) of the act, use of these standards alone does not 
ensure compliance with the act. The statutory requirements regarding 
compendial standards as well as other statutory requirements must be 
considered to ensure compliance with the act.
    The requirements under sections 501(b) and 502(g) of the act for 
determining whether a product is adulterated or misbranded and of

[[Page 18749]]

section 505 of the act for approving an application are applied 
consistently to all products. Under sections 505(b) and 505(j) of the 
act, the specifications included in the application must be considered 
adequate to ensure and preserve the identity, strength, quality, 
purity, and potency of the drug or else the agency must refuse to 
approve the application. However, this does not mean that the 
specifications approved in different applications for the same drug are 
identical. For example, different analytical procedures may be approved 
as long as the analytical procedures are appropriate and valid. Another 
example is that where solvents are used, the agency routinely and 
consistently requests tests and acceptance criteria for residual 
solvents. However, because different manufacturers use different 
solvents, the tests and acceptance criteria will vary depending on the 
solvents used. In all cases, the approved specifications will have been 
determined by the agency to be adequate to ensure and preserve the 
identity, strength, quality, purity, and potency of the drug.
    (Comment 89) Many comments stated that FDA is involved in the USP 
revision process and should use this process to resolve any differences 
between compendial requirements and FDA requirements and ensure that 
compendial changes do not compromise safety and efficacy. Once this is 
accomplished, all changes to comply with a compendial change should be 
submitted in an annual report.
    The USP process for developing or changing a monograph, general 
notice, or general chapter is an open process. Anyone who is interested 
in a particular issue has the opportunity to comment. FDA participates 
in many USP activities, including joint committees and public forums, 
and has designated persons throughout the agency to act as liaisons to 
the USP.
    FDA recognizes that public standards such as those instituted by 
the USP are beneficial. However, the USP is a nongovernmental 
organization that works independently from FDA, and FDA has no 
authority to stop USP from implementing a new or revised standard. FDA 
must ensure the identity, strength, quality, purity, and potency of 
drugs by requiring appropriate specifications. Compendial standards are 
not always sufficient to provide this assurance. Moreover, certain 
changes in a public standard, such as deletion of a test or relaxation 
of an acceptance criterion, cannot always be considered an improvement 
in the standard, nor is it always clear that the change will not lessen 
the assurance of the identity, strength, quality, purity, or potency of 
the products affected by the change. After review of a change such as 
these in the context of a specific NDA or ANDA, FDA may confirm that 
the change does not adversely affect the drug. However, allowing such a 
change to be documented in an annual report would not provide the 
opportunity for the agency to assess the effect of the change in a 
timely manner. FDA considers the provisions in the final rule necessary 
to ensure the safety and effectiveness of drugs.
    (Comment 90) Several comments said that the proposed provision 
regarding changes to comply with an official compendium was 
inconsistent with the intent of the Modernization Act.
    FDA disagrees with these comments. Section 506A of the act requires 
a change in the specifications in the approved application to be 
submitted in a supplemental application and approved by the agency 
prior to the applicant distributing the product affected by the change 
(section 506A(c)(2)(A) of the act). The act does not distinguish 
between changes in compendial and noncompendial specifications. The act 
allows the Secretary to exempt by regulation or guidance the 
requirement that changes in specifications may be submitted in prior 
approval supplements. However, the act also requires the agency to 
establish the reporting category for a change based on the potential 
for the change to adversely affect the identity, strength, quality, 
purity, and potency of the drug as they may relate to the safety and 
effectiveness of the drug. The agency believes the provisions in the 
final rule regarding changes to comply with changes in an official 
compendium are consistent with the intent of the Modernization Act.
    (Comment 91) One comment also said that the proposal was not 
consistent with the initiatives under the National Partnership for 
Reinventing Government (REGO), the National Technology Transfer and 
Advancement Act (the NTTAA) of 1995 and the Paperwork Reduction Act of 
1995 (the PRA).
    FDA disagrees with this comment. The comment states that one of 
FDA's goals under REGO is a more efficient drug development process and 
review process that will lower the development costs and reduce by an 
average of 1 year the time required to bring important new drugs to the 
American people. This REGO goal relates to initiatives for drugs prior 
to approval by FDA and is not pertinent to this rule. However, one REGO 
initiative was to reduce the number of manufacturing changes that 
require agency preapproval for biological products and FDA revised its 
regulations to achieve this goal (see the Federal Register of January 
29, 1996 (61 FR 2739), and July 24, 1997 (62 FR 39890)). FDA supports 
the REGO objective to transform FDA into a customer-oriented, results-
driven organization and believes that the final rule, which reduces 
regulatory burden with respect to postapproval changes for both 
biological products and human drugs, achieves this objective.
    The National Technology Transfer Act of 1995 (NTTAA) (Public Law 
104-113, 15 U.S.C. 3701 (1996)) encourages the use of voluntary 
consensus standards by Federal agencies as a means to carry out policy 
objectives and puts into law the policies of OMB Circular A-119 (see 
the Federal Register of February 19, 1998 (63 FR 8546)). The standards 
set by USP/NF are not voluntary standards because the standards are 
recognized in sections 501 and 502 of the act for the purposes of 
determining if a compendial drug is adulterated or misbranded. 
Therefore, the NTTAA is not pertinent. FDA is authorized to cooperate 
with associations and scientific societies in the revision of the USP 
(21 U.S.C. 377). FDA is a committed participant in this endeavor and in 
developing other voluntary and nonvoluntary consensus standards.
    The purposes of the PRA (44 U.S.C. 3501-3520) include minimizing 
paperwork for business resulting in collection of information for the 
government, ensuring the greatest public benefit from the information 
collected, and minimizing the cost to the government of the collection 
of information. Section 506A(b) of the act states that a drug made with 
a manufacturing change (whether a major manufacturing change or 
otherwise) may be distributed only if, before distribution of the drug 
as so made, the holder involved validates the effect of the change on 
the identity, strength, quality, purity, and potency of the drug as 
these factors may relate to the safety and effectiveness of the drug. 
Moreover, each supplemental application or annual report must contain 
such information as the Secretary determines to be appropriate and 
include the information developed by the applicant to validate the 
effects of the change (sections 506A(c)(1), (d)(2)(A), and (d)(3)(A) of 
the act). The information that will be submitted to support a change is 
independent of the reporting category for the change. FDA will require 
the same type of information to be submitted to support a change in a 
compendial specification regardless of whether the change is reported 
in a supplemental application or annual

[[Page 18750]]

report. There is no additional paperwork burden based solely on the 
designation of a reporting category for a particular change.
    (Comment 92) Many comments said that requiring compendial changes 
to be reported in anything other than an annual report was an increase 
in regulatory burden over what has been done in the past. Several 
comments said that there has been no public discussion about any 
concerns with the previous policy to allow changes to comply with 
compendial changes to be filed in an annual report.
    FDA recognizes that there has been confusion about the provision in 
previous Sec.  314.70(d)(1) that allowed any change made to comply with 
an official compendium to be reported in an annual report. In the 
Federal Register of June 4, 1986 (51 FR 20310), FDA published a 
proposed rule to clarify and limit the types of compendial changes that 
could be made in an annual report. FDA was preparing to issue a final 
rule regarding this proposal when Congress initiated discussions about 
postapproval manufacturing changes. FDA delayed publishing the final 
rule and incorporated revisions regarding reporting of changes to 
comply with an official compendium into its proposed rule implementing 
section 506A of the act. The provisions in the final rule for changes 
made to comply with an official compendium might be viewed by some as 
an increase in burden over how FDA has been interpreting this 
regulation in the past. However, FDA believes that the provisions are 
necessary and consistent with the requirements of section 506A of the 
act to establish a reporting category for a change based on the 
potential for the change to adversely affect the identity, strength, 
quality, purity, or potency of the drug product as they may relate to 
the safety and effectiveness of the drug product. As explained 
previously, the information that will be submitted to support a change 
is independent of the reporting category for the change. FDA will 
require the same type of information to be submitted to support a 
change in a compendial specification regardless of whether the change 
is reported in a supplemental application or annual report. There is no 
additional paperwork burden based solely on the designation of a 
reporting category for a particular change.
    (Comment 93) One comment stated that changes made to comply with 
changes in an official compendium should not have to include all the 
information needed for noncompendial products. The comment went on to 
say that a full description of the test methods and limits should not 
be necessary and that the company should not have to submit data 
demonstrating the suitability of a compendial change for the drug 
product if the compendial change is for a test method change or other 
change not specifically affecting the quality or the morphology of the 
material in question.
    As previously discussed in this document, under section 506A of the 
act, each supplemental application or annual report must contain the 
information that the agency has determined to be appropriate and must 
include the information developed by the applicant to validate the 
effects of the change. Guidance on the information that should be 
submitted to support compendial and noncompendial analytical procedures 
is available from FDA.
    Under proposed Sec.  314.70(d)(2)(ii), the following change was to 
be documented in the next annual report: The deletion or reduction of 
an ingredient intended to affect only the color of the product.
    (Comment 94) One comment recommended changing the requirement to 
read ``the deletion, reduction or replacement with a color previously 
used in other CDER/CBER approved products.''
    FDA declines to revise the regulation as requested. FDA believes 
that any recommendations it may make concerning notification in an 
annual report of changes involving replacement of colors are best 
handled in guidance documents so that the issues and conditions 
associated with such changes can be fully explained.
    (Comment 95) One comment said that changes in formulation, 
regardless of the intended purpose of the ingredient, are more 
appropriately addressed in terms of percent change allowed at each 
level as delineated in the SUPAC guidances.
    FDA agrees that the issues relating to changes in components and 
composition for specific dosage form drug products are better handled 
in guidance documents, where they can be discussed in detail, rather 
than in the regulations. FDA included this specific provision in the 
proposed regulations because this annual report change, with minor 
editing changes, has been in the regulation since 1985.
    Under proposed Sec.  314.70(d)(2)(iii), the following change was to 
be documented in the next annual report: Replacement of equipment with 
that of the same design and operating principles except for equipment 
used with a natural protein product, a recombinant DNA-derived protein/
polypeptide product, or a complex or conjugate of a drug with a 
monoclonal antibody.
    (Comment 96) Several comments suggested that FDA delete all words 
after ``principles'' to read: ``Replacement of equipment with that of 
the same design and operating principles.'' One comment said that it is 
reasonable to report in an annual report replacement with equipment of 
the same design and operating principles for these (i.e., protein) 
products.
    FDA declines to revise the regulation as requested but has revised 
it to provide clarity. As discussed in section III.D of this document 
in response to comments on ``Changes Requiring Supplement Submission at 
Least 30 Days Prior to Distribution of the Drug Product Made Using the 
Change (Moderate Change),'' changes to identical equipment used in the 
production of proteins could be reported in an annual report. However, 
a change to equipment of the same design and operating principle, but 
not identical equipment (e.g., capacity), is not considered a minor 
change for protein products.
    FDA has revised Sec.  314.70(d)(2)(iii) as follows: ``Replacement 
of equipment with that of the same design and operating principles 
except those equipment changes described in paragraph (c) of this 
section.''
    (Comment 97) One comment said the replacement of equipment of the 
same design and operating principles should not have to be reported. 
The comment said that for consistency with the existing SUPAC 
guidances, only a SUPAC subclass (i.e., design) change should be 
reported.
    FDA declines to revise the regulation as requested. FDA's 
requirement to report changes in equipment of the same design and 
operating principle in an annual report is consistent with the existing 
SUPAC guidances. In the future, FDA may issue guidance lessening the 
reporting requirements in this area for specific cases. However, 
because of the diversity of drug products and manufacturing processes 
regulated, FDA is unable at this time to lower the requirements as 
suggested in the comments.
    Under proposed Sec. Sec.  314.70(d)(2)(iv) and 601.12(d)(2)(v), the 
following change was to be documented in the next annual report: A 
change in the size and/or shape of a container containing the same 
number of dosage units for a nonsterile solid dosage form, without a 
change from one container closure system to another.
    (Comment 98) Several comments said that FDA should delete 
``containing the same number of dosage units.'' The comments said that 
proportional changes (i.e., ratio of the amount of drug

[[Page 18751]]

product to size of container) are not expected to adversely affect the 
drug product, that a corresponding change in fill quantity, along with 
a change in container size, is expected and readily acceptable, and 
that it is illogical to assume that a change in the amount of product 
would present any greater risk than a change in container size.
    FDA declines to revise the regulation as requested. As discussed in 
the response to comment 81 of this document, FDA is concerned about the 
proliferation of unit-of-use containers that may invite the misuse of 
drug products.
    Under proposed Sec. Sec.  314.70(d)(2)(v) and 601.12(d)(2)(iv), the 
following change was to be documented in the next annual report: A 
change within the container closure system for a nonsterile drug 
product, based upon a showing of equivalency to the approved system 
under a protocol approved in the application or published in an 
official compendium.
    (Comment 99) One comment said that the proposal, without further 
explanation, alters the reporting category applicable to changes within 
the container/closure system for sterile liquid drugs that are made 
based on a showing of equivalency to the approved system under a 
protocol approved in the application or published in an official 
compendium (for example, the USP). The comment said that under current 
Sec.  314.70(d)(6), these changes are described in the annual report 
and do not require FDA prior approval. The comment said that FDA has 
not provided any rationale for its proposal to require a supplement to 
be filed in connection with any change within a packaging material for 
a sterile liquid drug, even in situations in which the change is based 
on a showing of equivalency to the approved system under a protocol 
approved in the application or published in an official compendium, and 
recommended that ``nonsterile'' be deleted. The comment said that in 
the same way, it would be unduly burdensome to require FDA prior 
approval for a change within a container/closure system for a material 
based on a determination of equivalency made in accordance with a USP 
monograph that is specifically designed for that purpose. The comment 
said, for example, the USP chapter for ``Polyethylene Terephthalate 
(PET) Bottles and Polyethylene Terephthalate G (PETG) Bottles'' 
provides standards and tests to characterize PET and PETG bottles 
``that are interchangeably suitable for packaging liquid oral dosage 
forms'' (USP 25, General Chapter <661 (2002 ed.)). The 
comment said that FDA is provided with the opportunity to review and 
comment on USP monographs before they are published in final form; 
thus, the requirement for an additional FDA prior review of a change 
made in accordance with USP monograph is unnecessary.
    FDA declines to revise the regulation as requested. All container 
closure systems changes must be supported with data to demonstrate that 
various characteristics of the drug product and/or container closure 
system are unchanged or equivalent (e.g., physical, chemical). For a 
sterile drug product, however, data must also be provided to support 
that the sterility assurance level and the maintenance of sterility for 
the product has not been affected. Sterility of drug products is a 
fundamental and essential quality attribute of these drugs and is a 
critical aspect of the safety assessment. FDA would consider an 
assessment of the effects of a change in a container closure system for 
a sterile product to be inadequate if it did not include tests and data 
relating to sterility assurance and maintenance of sterility. FDA 
considers changes in the container closure system for sterile drug 
products to be changes that may affect the sterility assurance and/or 
maintenance of sterility of a drug and, therefore, may have significant 
potential to affect the safety of the drug. Therefore, FDA has 
identified this change as one that requires prior approval (see comment 
34 of this document).
    As stated in the June 1999 proposal, this rulemaking sets out 
broad, general categories of manufacturing changes, and the agency uses 
guidance documents to provide FDA's current thinking on the specific 
changes included in those categories. Through guidance, FDA may 
identify certain container closure system changes for sterile drug 
products that can be reported other than by submission of a prior 
approval supplement. Furthermore, an applicant could submit a 
comparability protocol that would allow it to implement postapproval 
changes in sterile container closure systems without a prior approval 
supplement. FDA notes that, as of 2002, no official compendia has 
finalized an equivalency protocol for container closure systems for 
sterile drug products. If such a protocol is published in the future, 
FDA will consider identifying in a guidance a reporting category other 
than a prior approval supplement for the compendial protocol if the 
protocol adequately addresses the appropriate scientific issues.
    FDA specifically wishes to address the comment's implication that 
changes made under the USP monograph for ``Polyethylene Terephthalate 
Bottles and Polyethylene Terephthalate G Bottles'' could be submitted 
in an annual report under this provision. As with any change and as 
required by the act, the applicant must assess the effects of the 
change on the identity, strength, quality, purity, and potency of the 
drug product as these factors may relate to the safety and 
effectiveness of the product. Moreover, USP <661 states that 
``the suitability of a specific PET or PETG bottle for use in the 
dispensing of a particular pharmaceutical liquid oral dosage form must 
be established by appropriate testing.'' Testing solely by the 
standards set in this general chapter would not usually be considered 
by FDA to be sufficient to assess the effects of the change because the 
interaction between a specific drug product and specific container and 
closure system should be assessed.
    Under proposed Sec. Sec.  314.70(d)(2)(vi) and 601.12(d)(2)(iii), 
the following change was to be documented in the next annual report: An 
extension of an expiration dating period based upon full shelf life 
data on full production batches obtained from a protocol approved in 
the application.
    (Comment 100) Many comments recommended changes relating to the 
phrase ``full production batches.'' A few comments recommended deleting 
the phrase because this requirement would unnecessarily increase 
regulatory burden, is unnecessarily restrictive, and/or because 
applicants should be allowed to use either pilot or production batches 
to extend an expiration date. One comment further said that pilot 
batches can be used to support the safety and efficacy of the product 
and for approval of an NDA expiration date; therefore, pilot batches 
should be allowed to support an extension of an expiration dating 
period. Another comment recommended that ``full'' be replaced by 
``production-scale.'' The comment said that the word ``full'' may cause 
confusion, where batch scale for a product may be varied. The comment 
said that ``full'' could be interpreted as that only the largest size 
batch of an approved batch size range could be used to support an 
extension of an expiration dating period. One comment said that it 
should be clarified that the batch need not have been sold. One comment 
said that production lots should be defined in the ``definitions'' 
section to include validation/scale-up batches manufactured by the 
representative production process within a ten-fold batch size for 
consistency with SUPAC/BACPAC.

[[Page 18752]]

    FDA has revised Sec. Sec.  314.70(d)(2)(vi) and 601.12(d)(2)(iii) 
by replacing the term ``full production batch'' with ``production 
batch.'' FDA declines to include a definition of production batch in 
the regulations. A definition is included in the ICH guidance entitled 
``Stability Testing of New Drug Substances and Drug Products.'' FDA 
considers a production batch to be one made at production scale using 
production equipment in a production facility as specified in the 
application. Production scale does not necessarily mean the largest 
batch size produced, but a batch of a size or within a batch size range 
that has been approved in the application. The batch need not have been 
sold, but should be one that is eligible to be sold (e.g., must pass 
its specification). In certain cases, FDA allows data from pilot 
batches to be used to support approval of an application. This is 
consistent with FDA's efforts to reduce the time it takes to bring new 
drugs to market. Often there are changes when moving from a pilot 
manufacturing process to a production process. Although these are 
usually minor in nature and not expected to affect the stability of the 
product, the definitive data to support an expiration date should be 
based on production batches; therefore, FDA declines to revise the 
regulation to include pilot batches. FDA would expect requests for an 
extension of an expiration dating period based on data from pilot 
batches to be submitted in a prior approval supplement.
    Under proposed Sec. Sec.  314.70(d)(2)(vii) and 601.12(d)(2)(vii), 
the following change is documented in the next annual report: ``The 
addition, deletion, or revision of an alternate analytical procedure 
that provides the same or increased assurance of the identity, 
strength, quality, purity, or potency of the material being tested as 
the analytical procedure described in the approved application.'' FDA, 
on its own initiative, is clarifying these sections as follows: ``The 
addition or revision of an alternative analytical procedure that 
provides the same or increased assurance of the identity, strength, 
quality, purity, or potency of the material being tested as the 
analytical procedure described in the approved application, or deletion 
of an alternative analytical procedure.''
    Under proposed Sec.  314.70(d)(2)(viii), the following change is to 
be documented in the next annual report: The addition by embossing, 
debossing, or engraving of a code imprint to a solid oral dosage form 
drug product other than a modified release dosage form, or a minor 
change in an existing code imprint.
    (Comment 101) A few comments requested that FDA revise this 
provision to allow the addition of an ink imprint. One comment further 
said that under part 206 (21 CFR part 206) (Imprinting of Solid Oral 
Dosage Form Drug Products For Human Use), which has been in effect for 
over 5 years, all solid dosage forms are required to have imprints and 
that the requirement to imprint includes an ink code imprint. Another 
comment said it is not clear whether the provision includes ink 
printing, and a cross-reference to part 206 may also be helpful. One 
comment requested that wording should be added to allow for ink 
printing on modified dosage forms, as this should not impact drug 
release.
    FDA declines to revise the regulation as requested and is 
clarifying that inks are not included in this provision. FDA believes 
that any recommendations on how to report the addition of inks is best 
handled in guidance documents so that the issues and conditions 
associated with such changes can be fully explained. For example, FDA 
would expect that any colors used in an ink imprint would have an 
acceptable status under FDA regulation (e.g., 21 CFR parts 73 and 74).
    (Comment 102) One comment said that FDA should delete the word 
``minor'' from the phrase ``minor change'' in the code imprint 
provision (proposed Sec.  314.70(d)(2)(viii)).
    FDA declines to revise the provision as requested. The term 
``minor'' has been included in this part of the regulation since 1985. 
Based on FDA's experience, this wording has not been found to be 
unclear, nor has it resulted in inconsistent implementation of such 
changes.
    Under proposed Sec.  314.70(d)(2)(x), the following change was to 
be documented in the next annual report: An editorial or similar minor 
change in labeling.
    (Comment 103) A few comments requested that FDA provide in the 
regulations specific examples of editorial or similar minor changes in 
labeling.
    FDA declines to provide specific examples in the regulations. As 
stated in the June 1999 proposal, the agency's approach is to issue 
regulations that set out broad, general categories of manufacturing 
changes and use guidance documents to provide FDA's current thinking on 
the specific changes included in those categories. FDA has provided 
recommendations on and examples of specific changes in specifications 
in FDA's guidances entitled ``Changes to an Approved NDA or ANDA'' and 
``Changes to an Approved Application for Specified Biotechnology and 
Specified Synthetic Biological Products.''
    Proposed Sec.  314.70(d)(3)(i) and (d)(3)(ii) required that, for 
changes described in the annual report, the applicant must submit a 
list of all products involved, a statement by the holder of the 
approved application that the effects of the change have been 
validated, and a full description of the manufacturing and controls 
changes, including the manufacturing site(s) or area(s) involved.
    (Comment 104) Many comments recommended that the term ``validated'' 
be replaced with ``assessed'' or ``assessed, as appropriate''. The 
comments' reasoning was similar to that discussed previously in similar 
comments for Sec.  314.3(b) under section III.A of this document 
entitled ``Definitions.''
    FDA has replaced the term ``validated'' with ``assessed.'' However, 
FDA declines to add the term ``as appropriate.'' Section 506A of the 
act requires an applicant to assess the effects of each change. FDA 
believes that the addition of ``as appropriate'' may incorrectly give 
the impression that this information is not routinely needed and would 
result in changes being submitted with insufficient information.
    (Comment 105) Concerning the phrase ``a list of all products 
involved,'' one comment asked whether the same changes, proposed for 
multiple products, have to be included in this list, and whether FDA 
wants to be notified as to all of the products that are affected in all 
annual reports. The comment asked for clarification.
    FDA has deleted the phrase ``a list of all products involved.'' FDA 
does not expect the listing of cross references to drug products 
approved in other applications. FDA does expect the changes to be 
described fully (Sec.  314.70(d)(3)(ii)). If there are multiple 
products in an application (e.g., strengths), FDA would expect the 
description to identify which products in the application are affected 
by the change.
    (Comment 106) One comment said including a statement that a change 
has been validated or assessed presents undue additional burden to the 
applicant. The comment said that assessment is guaranteed in the filing 
via provision of relevant supportive data and that restating this fact 
of compliance with regulatory requirements is redundant.
    FDA disagrees that the requirement to include this statement is an 
undue

[[Page 18753]]

additional burden and declines to revise the regulation as requested.
    (Comment 107) A few comments said that specifying details of exact 
``areas involved'' is inappropriate, since this information is not 
typically part of the NDA filing, but is subject to field inspection. 
The comment said it should not be provided in the annual report.
    FDA disagrees that this information is only necessary for field 
inspections and declines to make the revision. This information may not 
be essential in all cases. However, it is necessary for many 
manufacturing site changes. For example, FDA requires the specific 
filling line/room for sterile products to be identified in the 
application.
    Proposed Sec.  314.70(d)(3)(iii) required that, for changes 
described in the annual report, the applicant must submit the date each 
change was made, a cross-reference to relevant validation protocols 
and/or SOPs, and relevant data from studies and tests performed to 
evaluate the effect of the change on the identity, strength, quality, 
purity, or potency of the product as these factors may relate to the 
safety or effectiveness of the product (validation).
    (Comment 108) One comment recommended that Sec.  314.70(d)(3)(iii) 
be deleted entirely because it represents additional reporting 
requirements that are not consistent with the act.
    FDA declines to delete Sec.  314.70(d)(3)(iii). Section 
506A(d)(2)(A) of the act requires that an annual report contain such 
information as FDA determines to be appropriate and the information 
developed to assess the effects of the change. FDA is specifying the 
type of information it expects to be included in an annual report, and 
this action is consistent with the act.
    (Comment 109) A few comments recommended that FDA should delete the 
phrase ``the date each change was made.'' The comments included the 
following reasons for this recommendation: (1) Specifying an exact 
implementation date would present an undue burden on both manufacturing 
and regulatory affairs personnel, (2) the addition of this information 
to existing practice would result in increased regulatory burden, (3) 
the requirement is ambiguous as to whether the date is to be the date 
the product was made with the change or some other date such as the 
date the product made with the change was put into market distribution, 
and (4) the data represent information best suited for a field 
inspection. Some comments stated that the fact that an applicant has 
reported a change in an annual report covering a specified time period 
should be sufficient for agency review.
    FDA declines to revise the regulation as requested. The date when a 
change is implemented is important to identify the production batches 
that may be affected by the change. This is important for various 
reasons, including allowing reviewers to compare data from different 
batches prepared at different times to determine if a change has 
affected product quality. FDA has required the date of implementation 
for changes reported in annual reports since 1985 under Sec.  
314.81(b)(2)(iv)(b) and does not believe that this provision can be 
construed as an undue or additional burden or the sole purview of a 
field inspection.
    To maintain consistency with Sec.  314.81(b)(2)(iv)(b), FDA has 
revised the phrase to read: ``The date each change was implemented.'' 
FDA considers ``the date each change was implemented'' to be the date 
that the condition established in the approved application is changed, 
not when the product made with the change is distributed.
    (Comment 110) Many comments said that the phrase ``a cross-
reference to relevant validation protocols and/or SOP's'' should be 
deleted. The comments included the following reasons for this 
recommendation: (1) The addition of this information to existing 
practice would result in increased regulatory burden, (2) the 
requirement is ambiguous as validation protocols and/or SOPs are needed 
only in certain situations, and (3) the data represent information best 
suited for a field inspection.
    FDA has revised this provision to clarify when a cross-reference to 
validation protocols and SOP's are needed. As discussed earlier in this 
document in response to similar comments on Sec.  314.70(b)(3), 
validation protocols and data need not be submitted in the application, 
unless otherwise specified by FDA, but should be retained at the 
facility and be available for review by FDA at the agency's discretion. 
For most products, FDA does not require the submission of validation 
protocols and data. However, for a natural product, a recombinant DNA-
derived protein/polypeptide, a complex or conjugate of a drug substance 
with a monoclonal antibody, or sterilization process, FDA does require 
the submission of validation protocols for certain critical 
manufacturing processes unique to these drug substances and drug 
products. In addition, an applicant is required to submit a ``full 
description of controls used for, the manufacture, processing, and 
packing of a drug'' (section 505 of the act). This information may be 
submitted in different forms, including SOPs. In most cases, SOPs do 
not include information relevant to the NDA or ANDA review, but rather 
information relevant to determining an applicant's compliance with 
CGMPs. However, in the case of a natural product, a recombinant DNA-
derived protein/polypeptide, a complex or conjugate of a drug substance 
with a monoclonal antibody, or a sterilization process, information 
contained in SOPs is often relevant to the review of certain aspects of 
an application.
    (Comment 111) A few comments recommended that the term 
``validation'' be deleted. FDA also received comments requesting that 
the use of the terms drug, drug product, drug substance, and product be 
standardized.
    FDA, on its own initiative, has divided proposed Sec.  
314.70(d)(3)(iii) into three paragraphs to provide clarity. FDA has 
clarified the information originally proposed in Sec.  
314.70(d)(3)(iii) by making changes consistent with Sec.  
314.70(b)(3)(vi) and (b)(3)(vii) and deleting the term ``validation.'' 
On its own initiative, FDA is replacing the statement ``evaluate the 
effect of the change on the identity, strength, quality, purity, or 
potency of the product as these factors may relate to the safety or 
effectiveness of the product (validation)'' with ``assess the effects 
of the change'' because this phrase is defined in Sec.  314.3(b).

H. Protocols

    Proposed Sec.  314.70(e) stated that an applicant may submit one or 
more protocols describing the specific tests and validation studies and 
acceptable limits to be achieved to demonstrate the lack of adverse 
effect for specified types of manufacturing changes on the identity, 
strength, quality, purity, or potency of the drug as these factors may 
relate to the safety or effectiveness of the drug. Such protocols, or 
changes to a protocol, would be submitted as a supplement requiring 
approval from FDA prior to distribution of a drug produced with the 
manufacturing change. The supplement, if approved, may subsequently 
justify a reduced reporting category because of the reduced risk of an 
adverse effect.
    (Comment 112) Many comments recommended that protocols be submitted 
in changes-being-effected supplements. The reasons for this 
recommendation included: (1) The expected brevity of the review of the 
protocol, (2) the proposed change could be implemented and approved in 
the time it takes for approval and execution of the protocol, and (3) 
the ability to implement a protocol faster would bring

[[Page 18754]]

much needed regulatory relief. One comment said that mandatory limits 
on protocol review times should be established, otherwise there may be 
less of an incentive for applicants to adopt this procedure. Another 
comment said that requiring prior approval for these protocols may be 
construed as an increase in regulatory burden.
    FDA declines to revise the regulation as requested. The time it 
takes FDA to review information is not a factor in determining how the 
change should be submitted. However, FDA does expect that it will take 
a substantial amount of time to review such a protocol. It is expected 
that applicants will use protocols to justify a reduced reporting 
category for a particular change. For example, applicants may request 
that they be allowed to implement a major change without prior approval 
by FDA. These protocols will in effect reduce regulatory oversight of 
the specified changes, and FDA considers this reduced oversight to have 
a substantial potential to have an adverse effect on the identity, 
strength, quality, purity, or potency of the drug product as these 
factors may relate to the safety or effectiveness of the drug product. 
Therefore, these protocol submissions are classified as major changes.
    Whether or not a proposed change could be implemented and approved 
in the time it takes for approval and execution of the protocol would 
be a factor in an applicant's decision to submit a protocol. However, 
increased efficiency could be achieved overall because a protocol can 
be used repeatedly for changes within the scope of the protocol. Also, 
fewer or no deficiencies are expected with a change implemented using a 
protocol, if properly executed, than with a change for which the 
specific tests, studies, and acceptance criterion were not discussed 
with the agency prior to the submission of the information.
    FDA continually strives to reduce review times, including the time 
it takes to approve manufacturing changes. In addition, this rule 
reduces the overall regulatory burden by allowing many changes to be 
implemented without prior approval by FDA. As previously discussed in 
this document, FDA considers a protocol submission to be a major 
change. Therefore, FDA declines to allow these changes to be submitted 
in a changes-being-effected supplement to effect faster implementation. 
FDA also declines to establish mandatory limits on protocol review 
times. The timing of a review of a supplement for a protocol will be in 
accordance with current practice for reviewing supplements requiring 
FDA approval prior to implementation.
    FDA does not agree that requiring prior approval for these 
protocols is an increase in regulatory burden. Where previously allowed 
by regulations, these changes were specified as requiring prior 
approval, and this rule just extends that option of submitting 
protocols for all human drugs. FDA emphasizes that the submission of a 
protocol is voluntary, and if an applicant decides that submission of a 
protocol is not beneficial, the applicant can make changes to an 
approved application by other means specified in the regulations.
    (Comment 113) One comment said it would like to operate with the 
understanding that if a relevant protocol is subsequently published in 
an official compendium or FDA document, the less burdensome protocol 
may be applied.
    FDA is unable to address this question in a general manner because 
of the complexity of the issues and the newness of comparability 
protocols for human drugs. A comparability protocol is an applicant and 
drug product specific document. Whether a comparability protocol could 
be superseded would depend on the product and changes covered by a 
comparability protocol.
    (Comment 114) FDA received many comments requesting specific 
guidance on developing protocols. A few comments recommended that FDA 
issue a guidance document that includes specific examples of 
comparability protocols that are approvable. Another comment said that 
the comparability protocol guidance should contain a sufficient level 
of detail on testing requirements. One comment said it would welcome 
FDA's involvement in drafting ``common'' comparability protocols, so 
that consistent requirements are imposed on all sponsors. The comment 
said that, alternatively, FDA guidance on comparability protocol format 
and content would be helpful.
    In the Federal Register of February 25, 2003 (68 FR 8772), FDA 
published a draft guidance on comparability protocols. FDA wishes to 
advise applicants that while in certain cases FDA may be able to 
provide specific examples of acceptable protocols or ``common'' 
comparability protocols, it is likely that these will be limited 
because a comparability protocol is an applicant- and drug product-
specific document. Applicants will, in most cases, be responsible for 
developing their own protocols.
    (Comment 115) One comment said that, in a manner similar to the 
procedure developed for disseminating bioequivalence guidance 
information, comparability protocols that have been reviewed and 
approved by the agency should be made available under the Freedom of 
Information Act. The comment said that this practice will help promote 
harmonization within the agency with respect to postapproval change and 
may provide interested parties with guidance on the agency's general 
submission requirements.
    After FDA issues an approval letter, data and information in an 
application will be eligible for public disclosure to the extent 
permitted by the applicable statutes and agency regulations (see, for 
example, the Freedom of Information Act (5 U.S.C. 552), the Trade 
Secrets Act (18 U.S.C. 1905), 21 CFR part 20, and Sec. Sec.  314.430 
and 601.51).
    (Comment 116) One comment recommended that FDA encourage the use of 
packaging equivalency protocols to reduce regulatory reporting burdens, 
expedite approval of manufacturing changes, and simplify reporting 
coordination for packaging manufacturers. The comment noted that 
submission of these protocols was sometimes discouraged by FDA in the 
past. The comment also suggested that such protocols may be submitted 
within Type III drug master files (DMFs) to expedite the implementation 
of manufacturing changes at the packaging and packaging component 
manufacturer level.
    Protocols, including packaging equivalency protocols, may be 
submitted for FDA consideration. Under certain circumstances, such as 
changes affecting a large number of applications, FDA may review a 
protocol submitted to a Type III DMF that will be used to support 
changes affecting drug product applications. Information in a DMF is 
not approved or disapproved; therefore, any protocol submitted to a DMF 
cannot be approved (Sec.  314.420). Administrative issues relating to 
review of protocols in a DMF present some unique challenges, and a DMF 
holder should coordinate with the agency prior to submitting such a 
protocol.
    (Comment 117) One comment requested that the words ``validation 
studies'' be clarified. The comment asked whether this means 
``assessment studies'' to assess the impact of the change, or does it 
refer to CGMP validation studies. The comment said that if it refers to 
CGMP validation studies, it should only be applicable for sterility 
validation. A few comments requested that the provision be clarified to 
state that a protocol can be submitted in an original application.

[[Page 18755]]

    FDA has clarified the provision by deleting the word ``validation'' 
and indicating that a protocol may be submitted in an original 
application. Various types of studies, including validation studies, 
may be needed in a protocol. A comparability protocol can be submitted 
in an original application or after approval of the application in a 
supplement requiring approval from FDA prior to distribution of a drug 
product produced with the manufacturing change.
    On its own initiative FDA has revised Sec.  314.70(e) by replacing 
the phrase ``acceptance limits'' with ``acceptance criteria'' to 
promote consistency in the terminology used in the definition of 
specification and the phrase ``purity, or potency'' with ``purity, and 
potency'' for consistency with section 506A of the act.

I. Implementation of the Final Rule and Guidance

    (Comment 118) Several comments urged FDA to withdraw the June 1999 
proposal and guidance and develop new documents and permit an 
opportunity for comment. The comments encouraged FDA to work in 
collaboration with the industry and the public in crafting improved 
versions of these documents. The comments contended that the June 1999 
proposal and guidance fail to realize the intent of Congress to relieve 
regulatory burden; that a substantial number of individual issues in 
the June 1999 proposed rule and guidance require revision; that there 
was a lack of industry and public involvement in drafting the 
documents; and, too short a time period was given for comments and 
subsequent revisions.
    FDA declines to withdraw the June 1999 proposal and guidance. FDA's 
procedures for rulemaking are governed by the Administrative Procedure 
Act (5 U.S.C. 553) and set forth in FDA regulations at 21 CFR 10.40 and 
10.80. Guidances are developed in accordance with the procedures set 
out in FDA's good guidance practices regulation (see the Federal 
Register of September 19, 2000 (65 FR 56468), and 21 CFR 10.115). As 
discussed previously in this document, the use of guidance documents 
will allow FDA to more easily and quickly modify and update important 
information. Moreover, section 506A of the act explicitly provides FDA 
the authority to use guidance documents to determine the type of 
changes that do or do not have a substantial potential to adversely 
affect the safety or effectiveness of the drug product. In the June 
1999 proposal, FDA proposed to implement section 506A of the act for 
human NDAs and ANDAs and for licensed biological products. In that same 
issue of the Federal Register, FDA announced the availability of a 
draft guidance for industry entitled ``Changes to an Approved NDA or 
ANDA'' to assist applicants in determining how they should report 
changes to an approved NDA or ANDA under section 506A of the act and 
under the proposed revisions to the human drug regulations pertaining 
to supplements and other changes to an approved application. FDA 
allowed for public participation in the development of the regulation 
and guidance consistent with FDA regulations and policy and to the 
extent practicable. The time period to provide public comment was 
consistent with FDA's regulations and statutory requirements. FDA also 
held a public meeting on August 19, 1999, to hear comments on the 
guidance and the proposed rule. In the Federal Register of November 23, 
1999 (64 FR 65716), FDA announced the availability of a final guidance 
to assist applicants in determining how they should report changes to 
an approved NDA or ANDA under section 506A of the act (the November 
1999 guidance). FDA has carefully considered the public comments and 
has revised the regulation and the guidance as appropriate. FDA 
believes that the final regulation and guidance provide for significant 
reduction in regulatory burden and therefore fulfill the intent of 
Congress.
    (Comment 119) One comment recommended that FDA publish the final 
rule as soon as possible to minimize confusion during the transition 
period when section 506A of the act will govern changes.
    FDA has carefully considered the public comments submitted on the 
June 1999 proposal and has issued a final rule as expeditiously as 
possible.
    (Comment 120) One comment stated that the final rule should be 
implemented through a ``phasing in'' of the regulation in order to 
educate industry and agency reviewers. The comment stated that the 
final promulgation and implementation of the proposed rule should be 
undertaken in conjunction with an industry-wide educational effort. The 
comment said that due to the cost and broad scope of the proposal, 
seminars or public workshops on the final rule would be of value and 
would allow for additional input from all affected parties. The comment 
stated that the impact of the proposed rule will affect regulatory 
practices and expectations of manufacturers, and by carrying out 
seminars, FDA could publicize and prepare all concerned for the new 
requirements. The comment also stated that the public seminars would 
serve to clarify regulatory expectations and interpretations.
    FDA does not believe that phasing-in the regulation is necessary 
because section 506A has been in effect since November 20, 1999, but 
does intend to discuss the revised regulation and final guidance in 
public forums. FDA has already held public forums, such as the American 
Association of Pharmaceutical Scientists (AAPS)/FDA Workshop on 
Streamlining the CMC Regulatory Process for NDAs and ANDAs (June 11-13, 
2002) to obtain feedback on postapproval changes. FDA will consider the 
information obtained from this workshop in any future updates of the 
guidance. FDA does not expect its reviewers to encounter many 
difficulties in the implementation of this regulation as FDA reviewers 
have been working with section 506A of the act since it became 
effective.
    (Comment 121) Another comment said that FDA should issue a written 
explanation or hold a public meeting to discuss the impact of allowing 
the current statute to expire without a new rule being formally 
approved. The comment said that FDA should not allow the proposal to be 
implemented without adequate public comment and review simply because 
the statute may expire.
    The statute has not expired, and FDA assumes that the comment 
refers to the expiration of Sec.  314.70. Congress mandated that 
section 506A of the act ``takes effect upon the effective date of 
regulations promulgated by the Secretary of Health and Human Services 
to implement such amendment, or upon the expiration of the 24-month 
period beginning on the date of the enactment of this Act, whichever 
occurs first'' (section 116(b) of the Modernization Act). Since 
November 20, 1999, FDA's regulation of NDA and ANDA postapproval 
changes has been based on section 506A of the act. The guidance 
entitled ``Changes to an Approved NDA or ANDA'' has represented FDA's 
current thinking on how to apply the requirements of section 506A of 
the act. FDA has allowed for public participation consistent with 
applicable regulations and statutes.
    (Comment 122) One comment requested that FDA consider 
``grandfathering'' changes already in progress by industry based upon 
already approved SUPAC guidances. The comment said that its ability to 
continue to supply product to the marketplace can be adversely affected 
by now having

[[Page 18756]]

to redefine the reporting requirements and extend the time to 
implementation.
    FDA declines to provide for grandfathering of changes already in 
progress. FDA does not believe that this is necessary. FDA carefully 
considered the existing SUPAC guidances when developing the regulations 
and the guidance ``Changes to an Approved NDA or ANDA'' and does not 
believe that there will be situations where implementation time will be 
significantly extended. There may be a limited number of cases where 
implementation may be delayed for 30 days because of the new reporting 
category specified in section 506A of the act ``Supplement--changes 
being effected in 30 days,'' but FDA does not believe this is an undue 
hardship.
    (Comment 123) A comment noted that a number of relevant guidance 
documents required to support the proposed regulations are not yet 
implemented (e.g., stability), nor is the guidance ``Changes to an 
Approved NDA or ANDA.'' The comment recommended that a finite period be 
established in which these guidance documents be completed and issued. 
A few comments recommended that all affected guidance documents, such 
as the SUPAC guidances, be revised expeditiously to minimize confusion 
regarding conflicting information. One comment recommended related 
guidances be reviewed within 60 days after issuance of the final rule.
    In the Federal Register of November 23, 1999, FDA announced the 
availability of a final version of the guidance for industry entitled 
``Changes to an Approved NDA or ANDA.'' This guidance has been revised 
to conform to this final rule revising Sec.  314.70. FDA continues to 
update and develop guidances to address particular regulatory and 
scientific issues. FDA publishes these guidances as expeditiously as 
possible given its resources and priorities. If guidance for either 
recommended filing categories and/or information that should be 
submitted to support a particular postapproval manufacturing change is 
not available, the appropriate FDA staff can be consulted for advice.
    (Comment 124) One comment requested that during the transition 
period, FDA permit industry to use the guidance document that provides 
the least burdensome regulatory requirement and the lowest reporting 
category.
    Section 506A of the act and the final regulations provide for a new 
approach to establishing the reporting category for postapproval 
changes and for an additional reporting category. To accommodate these 
changes, FDA has stated that to the extent the recommendations on 
reporting categories in the guidance ``Changes to an Approved NDA or 
ANDA'' are found to be inconsistent with guidance published before the 
``Changes to an Approved NDA or ANDA'' guidance was finalized, the 
recommended reporting categories in the previously published guidances 
are superseded.
    (Comment 125) One comment noted that the preamble to the June 1999 
proposal stated that to the extent that the recommendations on 
reporting categories in the draft guidance, when finalized, are 
inconsistent with previously published guidance, such as the SUPAC 
guidances, the recommended reporting categories in such prior guidance 
will be superseded by this new guidance upon its publication in final 
form. The comment said that CDER intends to update the previously 
published guidances such as SUPAC, to make them consistent with this 
new guidance. The comment said it wholly supports the creation and use 
of guidance documents and, in this particular instance, recommends that 
the SUPAC provisions relating to changes in the qualitative or 
quantitative formulation of the drug be retained. The comment said that 
any revisions to current guidance documents should not result in more 
burdensome requirements.
    The recommendations in the SUPAC guidances regarding qualitative 
and quantitative formulation changes can still be used. FDA intends to 
revise current documents as appropriate.

J. Comments Specific to Biological Products

    (Comment 126) A few comments discussed the need for FDA to issue 
guidance for the blood banking industry for changes to an approved 
application. The comments specifically requested clarification on the 
submission of information pertaining to annual reports, comparability 
protocols, changes in the site of testing from one facility to another, 
and equipment upgrades even when a change is due to equipment upgrades 
that have already received 501(k) clearance. In addition, the comments 
said that FDA needed to consider the least burdensome mechanism for 
submitting the various changes.
    FDA agrees that guidance for the blood banking industry is needed 
in this area, and in the Federal Register of August 7, 2001 (66 FR 
41247), FDA issued the guidance ``Guidance for Industry: Changes to an 
Approved Application: Biological Products: Human Blood and Blood 
Components Intended for Transfusion or for Further Manufacture.''
    The guidance is intended to assist manufacturers of Whole Blood, 
Blood Components, Source Plasma, and Source Leukocytes in determining 
which reporting mechanism is appropriate for a change to an approved 
license application. Under each section of the guidance, FDA provides 
categories of changes to be reported under Sec.  601.12. A list of 
various changes that falls under each category is also provided. The 
lists are not intended to be all-inclusive. The guidance describes the 
format for the annual report and further explains the comparability 
protocol. The guidance also addresses facility and equipment changes.
    The 510(k) clearance of a device to be used in a blood bank setting 
provides assurance that the device is substantially equivalent to a 
legally marketed device for which premarket approval was not required. 
For equipment upgrades related to a 510(k) device, the clearance of the 
device does not address implementation of the device in a specific 
blood bank setting nor does it address the procedures used by the 
establishment, the qualification and training of staff operating the 
equipment, onsite validation of processes, and ongoing process control 
and quality control. The category for which a change is to be reported 
depends on the impact of the change upon the specific biological 
product.
    (Comment 127) One comment asked what analysis FDA has performed to 
determine what types of changes should be reviewed by the agency. For 
example, in the Federal Register of August 3, 1993 (58 FR 41348), FDA, 
in adding requirements to the labeling CGMP regulations, provided an 
analysis that labeling errors accounted for an inordinate number of 
recalls. FDA then issued regulations to address this problem. The 
comment said, however, that labeling changes are not addressed in 
CBER's guidance on change control and historically have not been 
emphasized during review of supplements and other changes to an 
approved application. The comment asked if CBER has done any 
systematic, methodical, written review of warning letters, revocations, 
suspensions, recalls, injunctions, 483-items, and so forth, so that 
review of supplements is focused on problems that FDA knows are likely 
to result in public health concerns, regulatory, or legal action.
    Prior to the January 29, 1996 (61 FR 2739), proposed revision of 
Sec.  601.12, FDA performed an informal retrospective review of 
supplements. It

[[Page 18757]]

was the intent of that review to focus the review of manufacturing 
changes on those with the greatest potential for adverse effect on the 
products. Labeling changes, although not generally tracked as 
supplements at that time, were also considered in the review. FDA does 
not agree with the comment that labeling changes have not been 
emphasized during review of supplements. Until the publication of the 
July 24, 1997 final rule (62 FR 39890) (the July 1997 final rule) that 
revised Sec.  601.12, all labeling changes required approval prior to 
implementation. The July 1997 final rule allowed certain minor 
editorial changes to be part of an annual report. Other changes 
intended to enhance the safety of use of the product could be reported 
as a changes-being-effected supplement. Substantive changes to labeling 
still require approval prior to implementation.
    (Comment 128) One comment said that in the July 1997 final rule, 
FDA has asserted that revision of the change-reporting regulations will 
reduce the burden of reporting changes to the agency. The comment asked 
whether this is synonymous with reducing the number of reports of 
changes to the agency. If not, the comment asked what is meant by 
``reducing the burden:'' for example, reduction of the amount of time 
between submission and approval, or reduction of the amount of data 
submitted. The comment asked whether FDA has actually analyzed the 
number of supplements submitted since the original changes to the 
reporting requirements, and whether the number of supplements has been 
reduced. The comment asked whether the analysis includes supplements 
due to labeling changes. The comment noted that FDA allowed for the 
submission of ``comparability protocols.'' The comment said that once a 
comparability protocol is reviewed and approved, the change still must 
be reported, albeit a preapproval supplement may be reduced to a 
changes-being-effected supplement, and so forth, for each category of 
change. The comment asked whether FDA has considered these types of 
submissions in determining if the number of submissions has been 
reduced and if the total review time for a change has been reduced.
    Fewer reports was only part of the reduction of reporting burden 
mentioned in the July 1997 final rule. The revision of Sec.  601.12 was 
also intended to allow for more rapid implementation of certain 
manufacturing changes and to decrease the amount of information 
required for those changes contained in an annual report. While the 
comparability protocol was included in the assessment, without 
experience it was difficult to determine whether it would actually 
result in decreased reporting or increased efficiency. There is still 
insufficient experience with these supplements to make a clear 
determination on that point.
    No formal comparison has been made of numbers of supplements 
received in CBER before and after the revision of Sec.  601.12. 
Multiple changes to regulatory approaches make a direct comparison very 
difficult. Labeling changes, while requiring approval, were not tracked 
as supplements prior to the revision. Consequently, numbers of labeling 
changes are not readily available through an automated data system. The 
change to the Biologics License Application from the Product License 
Application/Establishment License Application approach also has had an 
effect on the number of submissions to CBER. Further, as the comment 
points out, there are now more applicants submitting supplements on 
more products. Even if a comparison of supplement submission numbers 
were done, the results would be difficult to evaluate.
    (Comment 129) One comment said that the June 1999 proposal may 
perpetuate some existing confusion about the applicability of the 
regulations set forth in part 600 (21 CFR part 600). Current part 600 
does not include the term drug; however, in the definitions section of 
proposed Sec.  600.3(hh) and (ii), as well as in several other places 
in the June 1999 proposal, the term ``drug'' is used rather than 
biological product. The comment requested that FDA revise the June 1999 
proposal to clarify those sections that apply exclusively to biological 
products, and those that apply to both drugs and biological products.
    FDA agrees with the comment. FDA is clarifying the definitions in 
proposed Sec.  600.3(hh) and (ii) (new Sec.  600.3(jj) and (kk)) by 
replacing the terms ``drug substance(s)'' and ``drug product(s)'' with 
``product(s).'' The term ``products'' is defined in Sec.  600.3(g). For 
new drugs, the terms ``drug substance(s)'' or ``drug product(s)'' are 
now used consistently throughout part 314 in this rule.
    (Comment 130) One comment said that Sec.  601.12(d)(3)(iii) would 
require blood establishments to submit a statement that the effects of 
the change have been validated. The comment said that this is an 
additional, although minor, increase in the documentation and reporting 
burden for the blood industry. Because blood establishments are already 
required to keep validation documentation on file, and blood 
establishments are inspected on a regular basis, the comment requested 
that the requirement to submit such a statement be deleted for blood 
establishments.
    FDA disagrees with the comment that blood establishments should be 
exempt from the requirements of Sec.  601.12(d)(3)(iii). These 
establishments are already required to report the items listed in Sec.  
601.12(d)(3)(i) and (d)(3)(ii). Adding a statement that the effects of 
the change have been assessed does not add burden beyond the existing 
requirement and provides valuable information to the agency concerning 
the establishment's change controls.
    (Comment 131) One comment said that the June 1999 proposal would 
require that a supplement or annual report include in the cover letter 
a list of all changes contained in the supplement or annual report. The 
comment said that this new requirement will increase the reporting 
burden for blood establishments. The comment said that CBER has stated 
that Form FDA 356h is a cover letter. The comment asked why then must 
blood establishments fill out this additional new ``cover letter.'' The 
comment also said that to require blood establishments to reiterate all 
of the changes that they have compiled and reported in their annual 
reports in a cover letter accompanying that annual report is 
duplication of effort. The comment said that the annual report itself 
is an increase in the reporting burden of blood establishments and was 
not required before the implementation of the form with its intended 
paperwork reduction and regulatory efficiency goals. The comment 
requested that multiple cover letters and the requirement to reiterate 
all of the changes contained in the report be deleted.
    FDA agrees in part with the comment. Proposed Sec.  601.12(a)(5) 
has been revised to remove the reference to a cover letter for annual 
reports. The need for a list of the changes contained in the supplement 
results from the practice of including more than a single change in a 
supplement. This list is necessary to ensure that all changes are 
properly identified and addressed in a timely manner. The comment 
misinterprets statements by CBER on the nature and use of Form FDA 
356h. FDA has explained that Form FDA 356h is essentially a cover sheet 
that provides FDA with information necessary for the identification and 
administrative processing of a submission. It does not provide detailed 
information on the content of a submission, such as the number of 
changes that might be

[[Page 18758]]

covered. This necessary information may be conveyed most easily in a 
simple cover letter that is provided with the supplemental application. 
It is not FDA's intent that information in the completed Form FDA 356h 
be duplicated in a cover letter.
    (Comment 132) One comment said FDA requires that a field copy of a 
supplement (except for labeling) be provided to an applicant's local 
FDA office. As the field inspection force is now routinely involved in 
the inspection of biologics, the comment asked whether FDA has 
considered making this a requirement with regard to CBER supplements.
    FDA disagrees with the comment. FDA has considered extending the 
field copy requirement to CBER supplements. The field inspection force 
is involved in the inspection of biological products through the Team 
Biologics Initiative. Under this program, a cadre of inspectors has 
been drawn from field offices throughout FDA. Consequently, it is 
unlikely that the personnel participating in a given inspection would 
be assigned to that applicant's home FDA office. FDA does not believe 
that extending the field copy requirement to CBER supplements has 
sufficient benefit to the agency to justify the additional paperwork 
requirements.
    (Comment 133) One comment said that the proposal to allow an 
applicant to request an expedited review of a supplement if a delay in 
making the change would impose an extraordinary hardship or for public 
health reasons should be reserved for manufacturing changes made 
necessary by catastrophic events (for example, fire). These requests 
should be limited to events that could not be reasonably foreseen and 
for which the applicant could not plan.
    The policy of CBER and CDER has been that applicants requesting 
expedited review because of catastrophic events should do so only when 
the event could not be reasonably foreseen. Requests for expedited 
review will be evaluated on a case-by-case basis and it should be 
understood that not all requests will be granted.
    (Comment 134) One comment noted that the proposal states that if 
FDA disapproves a supplemental application, FDA may order the 
manufacturer to cease distribution of the drug products made using the 
manufacturing change. The comment said that many blood establishments 
will not even attempt to use this provision because of the possibility 
of a recall being required by FDA if the manufacturer has misjudged the 
categorization of the supplement. The comment said that this 
uncertainty has already resulted in blood establishments pursuing an 
unnecessarily conservative approach to reporting certain types of 
changes and, consequently, implementing new technologies slower than 
necessary. The comment said that to help blood establishments implement 
process improvements more efficiently, the proposal should be revised 
to include examples of circumstances under which a cease distribution 
and subsequent recall would likely be ordered and those under which it 
would not.
    FDA disagrees with the comment about the blood industry's failure 
to use the provision. The reason for the 30-day delay associated with 
the changes-being-effected-in-30-days supplement is to allow the agency 
to notify the applicant before the product is distributed that they 
have selected the wrong category for the supplement. In the case where 
the category is correctly chosen but the supplement cannot be approved, 
the agency will work with the applicant to minimize the impact of that 
decision. As discussed previously in this document, CBER has published 
a guidance for the Blood Industry that clarifies what categories 
changes should fall into and what information should be submitted to 
decrease the possibility of an error that might result in a recall. As 
previously mentioned in this document, the availability of the guidance 
was announced in the Federal Register of August 7, 2001 (66 FR 41247).
    (Comment 135) One comment noted that the June 1999 proposal states 
that additions, deletions, or revisions to alternative analytical 
procedures (that provide the same or increased assurance of the 
identical strength, quality, purity, or potency of the material being 
tested as the analytical procedure described in the approved 
application) be included in the annual report. The comment said that 
blood establishments currently are permitted to use Sec.  640.120 to 
obtain approval for alternate procedures. The comment said that since 
FDA will already be aware of this change on the date they have granted 
the approval, such change should not need to be included in blood 
industry annual reports. The comment said that in keeping with the 
paperwork reduction principles of the Modernization Act, this section 
should be revised so reporting of changes already approved under Sec.  
640.120 requests is not required in an annual report.
    The comment has misinterpreted the concept of an ``alternative'' 
analytical procedure (one procedure that can be substituted for 
another) with the concept of an alternative or an exception to a 
requirement in the regulations that the applicant views as providing 
equivalent safety or efficacy. In the case of the latter, the applicant 
must request approval under Sec.  640.120 before implementing otherwise 
they will be in violation of the regulatory requirement. An alternative 
or exception approved under Sec.  640.120 does not have to be included 
in an annual report.
    (Comment 136) One comment concerned proposed Sec.  
601.12(f)(2)(i)(E) which provides that labeling changes that normally 
require a prior approval supplement be submitted in a changes being 
effected supplement when FDA specifically requests the change. The 
comment said that industry-wide labeling changes should be categorized 
as an annual report for blood establishments since uniform labeling 
requirements already exist, and the blood establishment would simply be 
reporting that they have adopted the change. In addition, FDA already 
permits reporting of changes to procedures initiated at the request of 
FDA to be reported in an annual report. The comment requested that for 
blood establishments, FDA require that industry-wide labeling changes 
be reported to FDA in an annual report.
    FDA agrees in part with the comment. Many industry-wide labeling 
changes are initiated by the agency through guidance. If labeling 
changes include specific language consistent with FDA recommendations, 
changes to that specific labeling may be reported in the annual report. 
For example, a majority of the blood industry uses the American 
Association of Blood Banks circular of information that FDA reviews and 
recognizes as acceptable before it is printed for use by the blood 
industry. In this case, FDA does not need to review individual 
submissions. However, if an establishment uses an individually prepared 
circular, FDA would want any change to be submitted to FDA, at a 
minimum, at the time the change is effected because of the impact the 
change may have on the safe and effective use of a product. Generally, 
guidance on recommended changes to labeling will include information on 
how to report the change.

IV. Conforming Amendments

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

[[Page 18759]]

V. Analysis of Impacts

    FDA has examined the impacts of the final rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and 
the Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory alternatives and, when regulation is necessary, to 
select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). Executive Order 12866 
classifies a rule as significant if it meets any one of a number of 
specified conditions, including having an annual effect on the economy 
of $100 million or adversely affecting in a material way a sector of 
the economy, competition, or jobs. Under the Regulatory Flexibility 
Act, if a rule has a significant economic impact on a substantial 
number of small entities, an agency must analyze regulatory options 
that would minimize any significant impact of the rule on small 
entities. Section 202 of the Unfunded Mandates Reform Act requires that 
agencies prepare a written assessment of anticipated costs and benefits 
before proposing any rule that may result in an expenditure by State, 
local, and tribal governments, in the aggregate, or by the private 
sector of $100 million in any one year (adjusted annually for 
inflation).
    The agency believes that this rule is consistent with the 
regulatory philosophy and principles identified in Executive Order 
12866 and in these two statutes. As shown in the following paragraphs, 
the rule will not be significant as defined by the Executive order and 
the Unfunded Mandates Reform Act, and the agency certifies that the 
rule will not have a significant economic impact on a substantial 
number of small entities.
    The purpose of the rule is to implement section 506A of the act and 
to reduce the number of manufacturing changes subject to supplements 
requiring FDA approval prior to product distribution. The rule affects 
all drug manufacturers that submit manufacturing supplements and will 
result in a substantial reduction in burdens to applicants making 
manufacturing changes subject to the regulation. The rule permits 
earlier implementation of the changes and quicker marketing of products 
improved by manufacturing or labeling modifications. Faster 
implementation can result in marked gains in production efficiency. For 
example, a report by the Eastern Research Group, Inc. (ERG), an FDA 
contractor, on the effects of the SUPAC-IR found that reducing the 
number of changes that require preapproval gives companies greater 
control over their production resources, which could lead to 
significant net savings to industry (ERG, Pharmaceutical Industry Cost 
Savings Through Use of the Scale-Up and Post-Approval Guidance for 
Immediate Release Solid Oral Dosage Forms (SUPAC-IR), January 7, 1998, 
Contract No. 223-94-8301). ERG estimated that companies may already 
have saved $71 million in 1997 due to the agency's implementation of 
more flexible reporting procedures for chemistry, manufacturing, and 
control changes. This rule would lead to additional savings because it 
expands these changes to other drug products to improve product 
labeling and manufacturing methods.
    Because the rule will benefit manufacturers regardless of size and 
impose no additional costs, the agency certifies that this rule will 
not have a significant adverse economic impact on a substantial number 
of small entities.

VI. Paperwork Reduction Act of 1995

    This final rule contains collections of information that are 
subject to review by OMB under the PRA (44 U.S.C. 3501-3520). 
``Collection of information'' includes any request or requirement that 
persons obtain, maintain, retain, or report information to the agency, 
or disclose information to a third party or to the public (44 U.S.C. 
3502(3) and 5 CFR 1320.3(c)). The title, description, and respondent 
description of the information collection are shown under this section 
of the document 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: Supplements and Other Changes to an Approved Application.
    Description: The final rule sets forth requirements for 
manufacturing changes requiring supplement submission and FDA approval 
prior to the distribution of the product made using the change, changes 
requiring supplement submission at least 30 days prior to the 
distribution of the product, changes requiring supplement submission at 
the time of distribution, and changes to be described in an annual 
report. The regulation reduces the rate of increase in the number of 
manufacturing changes subject to supplements and the overall number of 
supplements requiring FDA approval prior to product distribution. Many 
changes that are currently reported in supplements will be able to be 
reported in annual reports. Supplement submissions contain more 
burdensome reporting requirements than a submission through an annual 
report. The regulation will not increase the number of annual reports 
but will allow applicants to include in an annual report information 
currently required to be reported to the agency in a supplemental 
application. The number of manufacturing changes currently reported in 
supplements that will be reported in annual reports is approximately 
1,283.
    Sections 314.70(a)(2) and 601.12(a)(2) require, generally, that the 
holder of an approved application must assess the effects of a 
manufacturing change before distributing a drug product made with the 
change. This section implements section 506A(a)(1) and 506A(b) of the 
act, which require the holder of an approved application to validate 
the effects of a manufacturing change on the identity, strength, 
quality, purity, or potency of the drug as these factors may relate to 
the safety or effectiveness of the drug before distributing a drug made 
with the change. Under section 506A(d)(3)(A) of the act, information 
developed by the applicant to validate the effects of the change 
regarding identity, strength, quality, purity, and potency is required 
to be submitted to FDA as part of the supplement or annual report. 
Thus, estimates for validation requirements are included in the 
estimates for supplements and annual reports; no separate estimates are 
provided for Sec. Sec.  314.70(a)(2) and 601.12(a)(2) in table 1 of 
this document. Furthermore, no estimates are required for the guidance 
entitled ``Changes to an Approved NDA or ANDA,'' because it does not 
provide recommendations on the specific information that should be 
developed by the applicant to validate the effect of the change on the 
identity, strength (e.g., assay, content uniformity), quality (e.g., 
physical, chemical, and biological properties), purity (e.g., 
impurities and degradation products), or potency (e.g., biological 
activity, bioavailability, bioequivalence) of a product as they may 
relate to the safety or effectiveness of the product.
    Sections 314.70(a)(4) and 601.12(a)(4) require, generally, that the 
applicant must promptly revise all promotional labeling and advertising 
to make it consistent with any labeling changes implemented. The 
transmittal to FDA of advertisements and promotional labeling for drugs 
and biologics is accompanied by Form FDA 2253 and regulated by 
Sec. Sec.  314.81(b)(3)(i) and 601.12(f)(4). This information 
collection

[[Page 18760]]

is approved by OMB until October 31, 2004, under OMB control number 
0910-0376. Therefore, the burden for this requirement is not estimated 
in table 1 of this document.
    Section 314.70(a)(5) requires the applicant to include in each 
supplement (except for a supplement providing for a change in the 
labeling) and amendment to each supplement a statement certifying that 
a field copy has been provided in accordance with Sec.  314.440(a)(4). 
The information collection for submitting a field copy under Sec.  
314.440(a)(4) is approved by OMB until March 31, 2005, under OMB 
control number 0910-0001. Based on data concerning the number of 
supplements and amendments to supplements currently received by the 
agency, FDA estimates that approximately 8,556 certifications will be 
submitted annually as required by Sec.  314.70(a)(5). FDA estimates 
that approximately 594 applicants will submit these certifications. FDA 
estimates that preparation of a statement certifying the field copy 
will take applicants an average of 5 minutes.
    Sections 314.70(a)(6) and 601.12(a)(5) require the applicant to 
include a list of all changes contained in the supplement or annual 
report; for supplements, this list must be provided in the cover 
letter. The information collection for submitting an annual report 
under Sec.  314.81(b)(2) is approved by OMB until March 31, 2005, under 
OMB control number 0910-0001. Based on data concerning the number of 
supplements currently received by the agency, FDA estimates that 
approximately 4,984 lists of all changes in the supplement will be 
submitted annually as required by Sec.  314.70(a)(6). FDA estimates 
that approximately 594 applicants will submit these lists. Because the 
information required would be generated in preparing the supplement, 
the agency estimates that, under Sec.  314.70(a)(6), it will take 
approximately 1 hour to include a list of changes in a cover letter for 
a supplement. FDA estimates that approximately 2,983 lists of all 
changes in the supplement or annual report will be submitted annually 
as required by Sec.  601.12(a)(5). FDA estimates that approximately 190 
applicants will submit these lists. Because the information required 
would be generated in preparing the supplement or annual report, the 
agency estimates that, under Sec.  601.12(a)(5), it will take 
approximately 1 hour to include a list of changes for a supplement or 
an annual report.
    Section 314.70(b) and current Sec.  601.12(b) set forth 
requirements for changes requiring supplement submission and approval 
prior to distribution of the product made using the change (major 
changes). Section 314.70(b)(1) and current Sec.  601.12(b)(1) provide, 
generally, that a supplement must be submitted for any change in the 
drug substance, drug 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 drug product as these factors may relate to the safety or 
effectiveness of the drug product. Section 314.70(b)(3) and current 
Sec.  601.12(b)(3) specify the information that must be contained in 
the supplement.
    Based on data concerning the number of supplements currently 
received by the agency, FDA estimates that approximately 1,744 
supplements will be submitted annually under Sec.  314.70(b)(1) and 
(b)(3). FDA estimates that approximately 594 applicants will submit 
such supplements, and that it will take approximately 150 hours to 
prepare and submit to FDA each supplement. FDA estimates that 
approximately 903 supplements will be submitted annually under Sec.  
601.12(b)(1) and (b)(3). FDA estimates that approximately 190 
applicants will submit such supplements, and that it will take 
approximately 150 hours to prepare and submit to FDA each supplement.
    Under Sec. Sec.  314.70(b)(4) and 601.12(b)(4), an applicant may 
ask FDA to expedite its review of a supplement for public health 
reasons or if a delay in making the change described in it would impose 
an extraordinary hardship on the applicant. Such a supplement and its 
mailing cover should be marked: ``Prior Approval Supplement-Expedited 
Review Requested.'' The burden for an applicant's request for an 
expedited review of a supplement by marking the mailing cover is 
minimal and is included in the burden hour estimates for submitting a 
supplement under Sec.  314.70(b)(1) and (b)(3) and Sec.  601.12(b)(1) 
and (b)(3).
    Section 314.70(c) and current Sec.  601.12(c) set forth 
requirements for changes requiring supplement submission at least 30 
days prior to distribution of the product made using the change 
(moderate changes). Section 314.70(c)(1) and current Sec.  601.12(c)(1) 
require, generally, that a supplement must be submitted for any change 
in the drug substance, drug 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 drug product as these factors may relate to the safety 
or effectiveness of the drug product. Under Sec.  314.70(c)(3) and 
current Sec.  601.12(c)(1), the supplement must give a full explanation 
of the basis for the change and identify the date on which the change 
is to be made. The supplement must be labeled ``Supplement--Changes 
Being Effected in 30 Days.'' Under Sec.  314.70(c)(4) and current Sec.  
601.12(c)(3), the information listed previously for Sec.  314.70(b)(3) 
and current Sec.  601.12(b)(3) must be contained in the supplement.
    Based on data concerning the number of supplements currently 
received by the agency, FDA estimates that approximately 2,754 
supplements will be submitted annually under Sec.  314.70(c)(1), 
(c)(3), and (c)(4). FDA estimates that approximately 594 applicants 
will submit such supplements, and that it will take approximately 95 
hours to prepare and submit to FDA each supplement. FDA estimates that 
approximately 255 supplements will be submitted annually under Sec.  
601.12(c)(1) and (c)(3). FDA estimates that approximately 98 applicants 
will submit such supplements, and that it will take approximately 95 
hours to prepare and submit to FDA each supplement.
    Under Sec.  314.70(c)(6) and current Sec.  601.12(c)(5), FDA may 
designate a category of changes for the purpose of providing that, in 
the case of a change in such category, the holder of an approved 
application may commence distribution of the drug product upon receipt 
by the agency of a supplement for the change. The supplement must be 
labeled ``Supplement--Changes Being Effected.'' If the supplement 
provides for a labeling change, 12 copies of the final printed labeling 
must be included.
    Based on data concerning the number of supplements currently 
received by the agency, FDA estimates that approximately 486 
supplements will be submitted annually under Sec.  314.70(c)(6). FDA 
estimates that approximately 486 applicants will submit such 
supplements, and that it will take approximately 95 hours to prepare 
and submit to FDA each supplement. FDA estimates that approximately 47 
supplements will be submitted annually under Sec.  601.12(c)(5). FDA 
estimates that approximately 34 applicants will submit such 
supplements, and that it will take approximately 95 hours to prepare 
and submit to FDA each supplement.
    Section 314.70(d) and current Sec.  601.12(d) set forth 
requirements for changes to be described in an annual report (minor 
changes). Section 314.70(d)(1) and current Sec.  601.12(d)(1)

[[Page 18761]]

provide, generally, that changes in the drug substance, drug 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 drug product as these 
factors may relate to the safety or effectiveness of the drug product 
must be documented in the next annual report. Section 314.70(d)(3) and 
current Sec.  601.12(d)(3) (including proposed Sec.  601.12(d)(3)(iii)) 
list the information that must be included in the annual report for 
describing changes under this section.
    Based on data concerning the number of supplements and annual 
reports currently received by the agency, FDA estimates that 
approximately 6,929 annual reports will include documentation of 
certain manufacturing changes as required under Sec.  314.70(d)(1) and 
(d)(3). FDA estimates that approximately 704 applicants will submit 
such information, and that it will take approximately 35 hours to 
prepare and submit to FDA the information for each annual report. FDA 
estimates that approximately 227 annual reports will include 
documentation of certain manufacturing changes as required under 
current Sec.  601.12(d)(1) and (d)(3). FDA estimates that approximately 
166 applicants will submit such information, and that it takes 
approximately 35 hours to prepare and submit to FDA the information for 
each annual report.
    Section 314.70(e) and current Sec.  601.12(e) state, generally, 
that an applicant may submit one or more protocols describing the 
specific tests and studies and acceptance criteria to be achieved to 
demonstrate the lack of adverse effect for specified types of 
manufacturing changes on the identity, strength, quality, purity, and 
potency of the drug product as these factors may relate to the safety 
or effectiveness of the drug product. Any such protocols, if not 
included in the approved application, or changes to an approved 
protocol, must be submitted as a supplement requiring approval from FDA 
prior to distribution of a drug product produced with the manufacturing 
change. The supplement, if approved, may subsequently justify a reduced 
reporting category for the particular change because the use of the 
protocol for that type of change reduces the potential risk of an 
adverse effect.
    Based on data concerning the number of supplements currently 
received by the agency, FDA estimates that approximately 50 protocols 
will be submitted annually under Sec.  314.70(e). FDA estimates that 
approximately 50 applicants will submit such protocols, and that it 
will take approximately 200 hours to prepare and submit to FDA each 
protocol. FDA estimates that approximately 20 protocols will be 
submitted annually under Sec.  601.12(e). FDA estimates that 
approximately 14 applicants will submit such protocols, and that it 
will take approximately 200 hours to prepare and submit to FDA each 
protocol.
    Current Sec.  601.12(f) sets forth the requirements for supplement 
submission for labeling changes for biological products. Current Sec.  
601.12(f)(2)(i)(A) through (f)(2)(i)(D) specify those labeling changes 
for which an applicant must submit a supplement to FDA at the time the 
change is made. Section 601.12(f)(2)(i)(E) adds to these types of 
changes ``any labeling change normally requiring a supplement 
submission and approval prior to distribution of the product that FDA 
specifically requests be submitted under this provision.'' Based on 
data concerning the number of supplements currently received by the 
agency, FDA estimates that approximately 12 labeling supplements will 
be submitted annually under current Sec.  601.12(f)(1). FDA estimates 
that approximately 12 applicants will submit these supplements, and 
that it will take approximately 40 hours to prepare and submit to FDA 
each supplement. FDA estimates that approximately 10 labeling 
supplements will be submitted annually under current Sec.  
601.12(f)(2), including those that will be submitted under new Sec.  
601.12(f)(2)(i)(E). FDA estimates that approximately 10 applicants will 
submit these supplements, and that it will take approximately 20 hours 
to prepare and submit to FDA each supplement. FDA estimates that 
approximately 100 annual reports for labeling changes will be submitted 
under current Sec.  601.12(f)(3). FDA estimates that approximately 70 
applicants will submit these reports, and that it will take 
approximately 10 hours to prepare and submit to FDA each report. FDA 
estimates that approximately 1,495 labeling supplements will be 
submitted annually under current Sec.  601.12(f)(4). FDA estimates that 
approximately 61 applicants will submit these supplements, and that it 
will take approximately 10 hours to prepare and submit to FDA each 
supplement.
    Section 314.70(f) states that an applicant must comply with the 
patent information requirements under section 505(c)(2) of the act. 
Section 314.70(g) states that an applicant must include any applicable 
exclusivity information with a supplement as required under Sec.  
314.50(j). Patent and exclusivity information collection requirements 
are approved by OMB until March 31, 2005, under OMB control number 
0910-0001. Therefore, this requirement is not estimated in table 1 of 
this document.
    Comments Received on FDA's Proposed Information Collection Burden 
Estimates:
    Concerning the accuracy of FDA's estimate of the burden of the 
proposed collection of information, including the validity of the 
methodology and assumptions used, one comment said that FDA has 
underestimated the information collection burden. The comment suggested 
the following revised estimates: For Sec.  314.70(b)(1) and (b)(3), the 
comment estimated 160 hours per response; for Sec.  314.70(c)(1), 
(c)(3), and (c)(4), 80 hours per response; for Sec.  314.70(c)(6), 80 
hours per response; for Sec.  314.70(d)(1) and (d)(3), 25 hours per 
response; for Sec.  314.70(e), 240 hours per response. The comment 
assumed that the number of hours estimated refers to the number of 
hours required by regulatory affairs personnel to collect, assemble, 
and prepare data required for a submission. Other related activities, 
such as manufacturing validation lots and conducting stability studies, 
are not part of the estimates, since they are manufacturing activities 
that would be conducted, as appropriate, regardless of the reporting 
requirements. The comment said its estimates are based on an average 
time required for submissions, and the actual time required for a 
particular submission can vary, based on the complexity of the 
submitted change. The comment said that although the proposal would 
change the reporting level of changes, the associated ``paperwork'' for 
these changes is not significantly reduced and in some cases is 
increased.
    Concerning the proposed requirement in Sec.  314.70(e) that an 
applicant may submit one or more protocols, the comment noted that 
these protocols must be submitted as a supplement requiring approval 
from FDA prior to distribution of a drug produced with the 
manufacturing change. The comment said that, based on its experience, 
the estimate of 20 hours for these protocol submissions is 
significantly underestimated and that 240 hours is a more reasonable 
estimate. The comment said that these protocols are, in effect, 
supplements requiring prior approval and, therefore, would require the 
same number of hours to prepare as a prior approval supplement under 
Sec.  314.70(b)(1) and (b)(3). Additionally, once the data for the 
change has been generated, the change requires an additional submission 
in order to implement the change. Assuming the data generated could be 
submitted

[[Page 18762]]

under Sec.  314.70(c), the number of hours to submit changes under 
proposed Sec.  314.70(e) would be a combination of the number of hours 
required to submit a change under Sec.  314.70(b) and (c).
    Another comment said that the estimated time in the proposal to 
collect the requested information for each type of supplement is low. 
The comment said that FDA underestimated the time to prepare the 
documents addressed in the proposal and that FDA should take greater 
care in evaluating the necessary steps required in preparing a 
supplement or report, not just the document preparation. For prior 
approved supplements under Sec.  314.70(b), the comment said that the 
estimate of 80 hours is low and should be increased by at least 10 
hours. The only time saving that can be gained under this requirement 
is when a firm can submit multiple supplements for the same change 
(site change), which is an uncommon occurrence; smaller firms submit 
one supplement at a time. For changes-being-effected supplements under 
Sec.  314.70(c), the comment said that 50 hours for these types of 
supplements is low. The comment asked what is the difference between 
this type of supplement and prior approval supplements other than the 
filing mechanism. For annual reports under Sec.  314.70(d), the comment 
said that 10 hours is low and that the data that go into such a report 
is collected over the entire year before the report may be put 
together. The comment said that an average of 20 hours is more 
reasonable. Concerning protocols under Sec.  314.70(e), the comment 
said that 20 hours to prepare a suitability protocol is a large 
underestimate, and that firms will spend a large amount of time to 
determine just which tests and specifications to include in the 
protocol, in addition to preparing the protocol itself. The comment 
also said that the analysis and reporting of the results of the 
completed protocols was not included in the estimate.
    FDA has considered the above comments as well as other information 
it has received and has revised the proposed information collection 
burden estimates. The estimate for ``hours per response'' for 
Sec. Sec.  314.70(b)(1) and (b)(3) and 601.12(b)(1) and (b)(3) has been 
increased from 80 hours to 150 hours; the estimate for Sec. Sec.  
314.70(c)(1), (c)(3), and (c)(4) and 601.12(c)(1) and (c)(3) has been 
increased from 50 hours to 95 hours; the estimate for Sec. Sec.  
314.70(c)(6) and 601.12(c)(5) has been increased from 50 hours to 95 
hours; the estimate for Sec. Sec.  314.70(d)(1) and (d)(3) and 
601.12(d)(1) and (d)(3) has been increased from 10 hours to 35 hours; 
and the estimate for Sec. Sec.  314.70(e) and 601.12(e) has been 
increased from 20 hours to 200 hours.
    Description of Respondents: Business or other for-profit 
organizations.

                                 Table 1.--Estimated Annual Reporting Burden\1\
----------------------------------------------------------------------------------------------------------------
                                                                         No. of
                                                             No. of     Responses    Total      Hours     Total
                     21 CFR Section                       Respondents      per       Annual      per      Hours
                                                                       Respondent  Responses  Response
----------------------------------------------------------------------------------------------------------------
314.70(a)(5)                                                    594          14       8,556         5       713
                                                                                              minutes
----------------------------------------------------------------------------------------------------------------
314.70(a)(6)                                                    594           8       4,984         1     4,984
----------------------------------------------------------------------------------------------------------------
314.70(b)(1), (b)(3)                                            594           3       1,744       150   261,600
----------------------------------------------------------------------------------------------------------------
314.70(c)(1), (c)(3), (c)(4)                                    594           5       2,754        95   261,630
----------------------------------------------------------------------------------------------------------------
314.70(c)(6)                                                    486           1         486        95    46,170
----------------------------------------------------------------------------------------------------------------
314.70(d)(1), (d)(3)                                            704          10       6,929        35   242,515
----------------------------------------------------------------------------------------------------------------
314.70(e)                                                        50           1          50       200    10,000
----------------------------------------------------------------------------------------------------------------
601.12(a)(5)                                                    190          16       2,983         1     2,983
----------------------------------------------------------------------------------------------------------------
601.12(b)(1), (b)(3)                                            190           5         903       150   135,450
----------------------------------------------------------------------------------------------------------------
601.12(c)(1), (c)(3)                                             98           3         255        95    24,225
----------------------------------------------------------------------------------------------------------------
601.12(c)(5)                                                     34           1          47        95     4,465
----------------------------------------------------------------------------------------------------------------
601.12(d)(1), (d)(3)                                            166           1         227        35     7,945
----------------------------------------------------------------------------------------------------------------
601.12(e)                                                        14           1          20       200     4,000
----------------------------------------------------------------------------------------------------------------
601.12(f)(1)                                                     12           1          12        40       480
----------------------------------------------------------------------------------------------------------------
601.12(f)(2)                                                     10           1          10        20       200
----------------------------------------------------------------------------------------------------------------
601.12(f)(3)                                                     70           1         100        10     1,000
----------------------------------------------------------------------------------------------------------------
601.12(f)(4)                                                     61          25       1,495        10    14,950
----------------------------------------------------------------------------------------------------------------
Total                                                                                                   1,023,31
                                                                                                              0
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

    The information collection provisions in this final rule have been 
approved under OMB control number 0910-0538. This approval expires 
August 31, 2005. 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.

[[Page 18763]]

VII. Environmental Impact

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

VIII. Federalism

    FDA has analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has determined that the rule 
does not contain policies that have substantial direct effects on the 
States, on the relationship between the National Government and the 
States, or on the distribution of power and responsibilities among the 
various levels of government. Accordingly, the agency has concluded 
that the rule does not contain policies that have federalism 
implications as defined in the order, and, consequently, a federalism 
summary impact statement is not required.

List of Subjects

21 CFR Parts 206 and 250

    Drugs.

21 CFR Part 314

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

21 CFR Part 600

    Biologics, Reporting and recordkeeping requirements.

21 CFR Part 601

    Administrative practice and procedure, Biologics, Confidential 
business information.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR parts 
206, 250, 314, 600, and 601 are amended as follows:

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

0
1-3. The authority citation for 21 CFR part 206 continues to read as 
follows:

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


Sec.  206.10  [Amended]

0
4. Section 206.10 Code imprint required is amended in the first 
sentence of paragraph (b) by removing the phrase ``Sec.  
314.70(b)(2)(xi) or (b)(2)(xii)'' and by adding in its place the phrase 
``Sec.  314.70(b)''.

PART 250--SPECIAL REQUIREMENTS FOR SPECIFIC HUMAN DRUGS

0
5. The authority citation for 21 CFR part 250 continues to read as 
follows:

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


Sec.  250.250  [Amended]

0
6. Section 250.250 Hexachlorophene, as a component of drug and cosmetic 
products is amended in the last sentence of paragraph (c)(4)(ii) by 
removing the phrase ``Sec.  314.70(c)(2)'' and by adding in its place 
the phrase ``Sec.  314.70(c)(6)(iii)''.

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

0
7. The authority citation for 21 CFR part 314 continues to read as 
follows:

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

0
8. Section 314.3 is amended in paragraph (b) by alphabetically adding 
the definitions for ``Assess the effects of the change'' and 
``Specification'' to read as follows:


Sec.  314.3  Definitions.

* * * * *
    (b) * * *
    Assess the effects of the change means to evaluate the effects of a 
manufacturing change on the identity, strength, quality, purity, and 
potency of a drug product as these factors may relate to the safety or 
effectiveness of the drug product.
* * * * *
    Specification means the quality standard (i.e., tests, analytical 
procedures, and acceptance criteria) provided in an approved 
application to confirm the quality of drug substances, drug products, 
intermediates, raw materials, reagents, components, in-process 
materials, container closure systems, and other materials used in the 
production of a drug substance or drug product. For the purpose of this 
definition, acceptance criteriameans numerical limits, ranges, or other 
criteria for the tests described.
* * * * *

0
9. Section 314.50 is amended:
0
a. In paragraph (d)(1)(ii)(b) by removing the phrase ``specifications 
and test procedures'' and by adding in its place the word 
``specification'';
0
b. In paragraph (d)(1)(v) by removing the phrase ``Except for a foreign 
applicant, the'' and by adding in its place the word ``The'';
0
c. In paragraph (d)(3)(i) by adding the word ``procedures'' after the 
word ``analytical'';
0
d. In paragraph (d)(3)(ii) by removing the phrases ``specifications or 
analytical methods'' and ``specification or analytical methods'' each 
time they appear and by adding in their places the phrase ``tests, 
analytical procedures, and acceptance criteria'';
0
e. In paragraph (d)(4)(iv) by removing the word ``methods'' and by 
adding in its place the word ``procedures'';
0
f. In the last sentence of paragraph (e)(1) introductory text and in 
the first sentence of paragraph (e)(2)(i) by removing the word 
``methods'' each time it appears and by adding in its place the word 
``procedures''; and
0
g. By revising the first two sentences of paragraphs (d)(1)(i) and 
(d)(1)(ii)(a) to read as follows:


Sec.  314.50  Content and format of an application.

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

[[Page 18764]]

dating. The application may provide additionally for the use of 
alternatives to meet any of these requirements, including alternative 
components, manufacturing and packaging procedures, in-process 
controls, and analytical procedures. * * *
* * * * *


Sec.  314.60  [Amended]

0
10. Section 314.60 Amendments to an unapproved application is amended 
in paragraph (c) by removing the phrase ``, other than a foreign 
applicant,''.

0
11. Section 314.70 is revised to read as follows:


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

    (a) Changes to an approved application. (1) The applicant notify 
FDA about each change in each condition established in an approved 
application beyond the variations already provided for in the 
application. The notice is required to describe the change fully. 
Depending on the type of change, the applicant must notify FDA about it 
in a supplement under paragraph (b) or (c) of this section or by 
inclusion of the information in the annual report to the application 
under paragraph (d) of this section.
    (2) The holder of an approved application under section 505 of the 
act must assess the effects of the change before distributing a drug 
product made with a manufacturing change.
    (3) Notwithstanding the requirements of paragraphs (b) and (c) of 
this section, an applicant must make a change provided for in those 
paragraphs in accordance with a regulation or guidance that provides 
for a less burdensome notification of the change (for example, by 
submission of a supplement that does not require approval prior to 
distribution of the product or in an annual report).
    (4) The applicant must promptly revise all promotional labeling and 
advertising to make it consistent with any labeling change implemented 
in accordance with paragraphs (b) and (c) of this section.
    (5) Except for a supplement providing for a change in the labeling, 
the applicant must include in each supplement and amendment to a 
supplement providing for a change under paragraph (b) or (c) of this 
section a statement certifying that a field copy has been provided in 
accordance with Sec.  314.440(a)(4).
    (6) A supplement or annual report must include a list of all 
changes contained in the supplement or annual report. For supplements, 
this list must be provided in the cover letter.
    (b) Changes requiring supplement submission and approval prior to 
distribution of the product made using the change (major changes). (1) 
A supplement must be submitted for any change in the drug substance, 
drug 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 drug 
product as these factors may relate to the safety or effectiveness of 
the drug product.
    (2) These changes include, but are not limited to:
    (i) Except those described in paragraphs (c) and (d) of this 
section, changes in the qualitative or quantitative formulation of the 
drug product, including inactive ingredients, or in the specifications 
provided in the approved application;
    (ii) Changes requiring completion of studies in accordance with 
part 320 of this chapter to demonstrate the equivalence of the drug 
product to the drug product as manufactured without the change or to 
the reference listed drug;
    (iii) Changes that may affect drug substance or drug product 
sterility assurance, such as changes in drug substance, drug product, 
or component sterilization method(s) or an addition, deletion, or 
substitution of steps in an aseptic processing operation;
    (iv) Changes in the synthesis or manufacture of the drug substance 
that may affect the impurity profile and/or the physical, chemical, or 
biological properties of the drug substance;
    (v) The following labeling changes:
    (A) Changes in labeling, except those described in paragraphs 
(c)(6)(iii), (d)(2)(ix), or (d)(2)(x) of this section;
    (B) If applicable, any change to a Medication Guide required under 
part 208 of this chapter, except for changes in the information 
specified in Sec.  208.20(b)(8)(iii) and (b)(8)(iv) of this chapter.
    (vi) Changes in a drug product container closure system that 
controls the drug product delivered to a patient or changes in the type 
(e.g., glass to high density polyethylene (HDPE), HDPE to polyvinyl 
chloride, vial to syringe) or composition (e.g., one HDPE resin to 
another HDPE resin) of a packaging component that may affect the 
impurity profile of the drug product.
    (vii) Changes solely affecting a natural product, a recombinant 
DNA-derived protein/polypeptide, or a complex or conjugate of a drug 
substance with a monoclonal antibody for the following:
    (A) Changes in the virus or adventitious agent removal or 
inactivation method(s);
    (B) Changes in the source material or cell line; and
    (C) Establishment of a new master cell bank or seed.
    (viii) Changes to a drug product under an application that is 
subject to a validity assessment because of significant questions 
regarding the integrity of the data supporting that application.
    (3) The applicant must obtain approval of a supplement from FDA 
prior to distribution of a drug product made using a change under 
paragraph (b) of this section. Except for submissions under paragraph 
(e) of this section, the following information must be contained in the 
supplement:
    (i) A detailed description of the proposed change;
    (ii) The drug product(s) involved;
    (iii) The manufacturing site(s) or area(s) affected;
    (iv) A description of the methods used and studies performed to 
assess the effects of the change;
    (v) The data derived from such studies;
    (vi) For a natural product, a recombinant DNA-derived protein/
polypeptide, or a complex or conjugate of a drug substance with a 
monoclonal antibody, relevant validation protocols and a list of 
relevant standard operating procedures must be provided in addition to 
the requirements in paragraphs (b)(3)(iv) and (b)(3)(v) of this 
section; and
    (vii) For sterilization process and test methodologies related to 
sterilization process validation, relevant validation protocols and a 
list of relevant standard operating procedures must be provided in 
addition to the requirements in paragraphs (b)(3)(iv) and (b)(3)(v) of 
this section.
    (4) An applicant may ask FDA to expedite its review of a supplement 
for public health reasons or if a delay in making the change described 
in it would impose an extraordinary hardship on the applicant. Such a 
supplement and its mailing cover should be plainly marked: ``Prior 
Approval Supplement-Expedited Review Requested.''
    (c) Changes requiring supplement submission at least 30 days prior 
to distribution of the drug product made using the change (moderate 
changes). (1) A supplement must be submitted for any change in the drug 
substance, drug product, production process, quality controls, 
equipment, or facilities that has a moderate potential to have an 
adverse effect on the identity, strength,

[[Page 18765]]

quality, purity, or potency of the drug product as these factors may 
relate to the safety or effectiveness of the drug product. If the 
supplement provides for a labeling change under paragraph (c)(6)(iii) 
of this section, 12 copies of the final printed labeling must be 
included.
    (2) These changes include, but are not limited to:
    (i) A change in the container closure system that does not affect 
the quality of the drug product, except those described in paragraphs 
(b) and (d) of this section; and
    (ii) Changes solely affecting a natural protein, a recombinant DNA-
derived protein/polypeptide or a complex or conjugate of a drug 
substance with a monoclonal antibody, including:
    (A) An increase or decrease in production scale during finishing 
steps that involves different equipment; and
    (B) Replacement of equipment with that of a different design that 
does not affect the process methodology or process operating 
parameters.
    (iii) Relaxation of an acceptance criterion or deletion of a test 
to comply with an official compendium that is consistent with FDA 
statutory and regulatory requirements.
    (3) A supplement submitted under paragraph (c)(1) of this section 
is required to give a full explanation of the basis for the change and 
identify the date on which the change is to be made. The supplement 
must be labeled ``Supplement--Changes Being Effected in 30 Days'' or, 
if applicable under paragraph (c)(6) of this section, ``Supplement--
Changes Being Effected.''
    (4) Pending approval of the supplement by FDA, except as provided 
in paragraph (c)(6) of this section, distribution of the drug product 
made using the change may begin not less than 30 days after receipt of 
the supplement by FDA. The information listed in paragraphs (b)(3)(i) 
through (b)(3)(vii) of this section must be contained in the 
supplement.
    (5) The applicant must not distribute the drug product made using 
the change if within 30 days following FDA's receipt of the supplement, 
FDA informs the applicant that either:
    (i) The change requires approval prior to distribution of the drug 
product in accordance with paragraph (b) of this section; or
    (ii) Any of the information required under paragraph (c)(4) of this 
section is missing; the applicant must not distribute the drug product 
made using the change until the supplement has been amended to provide 
the missing information.
    (6) The agency may designate a category of changes for the purpose 
of providing that, in the case of a change in such category, the holder 
of an approved application may commence distribution of the drug 
product involved upon receipt by the agency of a supplement for the 
change. These changes include, but are not limited to:
    (i) Addition to a specification or changes in the methods or 
controls to provide increased assurance that the drug substance or drug 
product will have the characteristics of identity, strength, quality, 
purity, or potency that it purports or is represented to possess;
    (ii) A change in the size and/or shape of a container for a 
nonsterile drug product, except for solid dosage forms, without a 
change in the labeled amount of drug product or from one container 
closure system to another;
    (iii) Changes in the labeling to accomplish any of the following:
    (A) To add or strengthen a contraindication, warning, precaution, 
or adverse reaction;
    (B) To add or strengthen a statement about drug abuse, dependence, 
psychological effect, or overdosage;
    (C) To add or strengthen an instruction about dosage and 
administration that is intended to increase the safe use of the drug 
product;
    (D) To delete false, misleading, or unsupported indications for use 
or claims for effectiveness; or
    (E) Any labeling change normally requiring a supplement submission 
and approval prior to distribution of the drug product that FDA 
specifically requests be submitted under this provision.
    (7) If the agency disapproves the supplemental application, it may 
order the manufacturer to cease distribution of the drug product(s) 
made with the manufacturing change.
    (d) Changes to be described in an annual report (minor changes). 
(1) Changes in the drug substance, drug 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 drug product as these factors may relate to 
the safety or effectiveness of the drug product must be documented by 
the applicant in the next annual report in accordance with Sec.  
314.81(b)(2).
    (2) These changes include, but are not limited to:
    (i) Any change made to comply with a change to an official 
compendium, except a change described in paragraph (c)(2)(iii) of this 
section, that is consistent with FDA statutory and regulatory 
requirements.
    (ii) The deletion or reduction of an ingredient intended to affect 
only the color of the drug product;
    (iii) Replacement of equipment with that of the same design and 
operating principles except those equipment changes described in 
paragraph (c) of this section;
    (iv) A change in the size and/or shape of a container containing 
the same number of dosage units for a nonsterile solid dosage form drug 
product, without a change from one container closure system to another;
    (v) A change within the container closure system for a nonsterile 
drug product, based upon a showing of equivalency to the approved 
system under a protocol approved in the application or published in an 
official compendium;
    (vi) An extension of an expiration dating period based upon full 
shelf life data on production batches obtained from a protocol approved 
in the application;
    (vii) The addition or revision of an alternative analytical 
procedure that provides the same or increased assurance of the 
identity, strength, quality, purity, or potency of the material being 
tested as the analytical procedure described in the approved 
application, or deletion of an alternative analytical procedure;
    (viii) The addition by embossing, debossing, or engraving of a code 
imprint to a solid oral dosage form drug product other than a modified 
release dosage form, or a minor change in an existing code imprint;
    (ix) A change in the labeling concerning the description of the 
drug product or in the information about how the drug product is 
supplied, that does not involve a change in the dosage strength or 
dosage form; and
    (x) An editorial or similar minor change in labeling.
    (3) For changes under this category, the applicant is required to 
submit in the annual report:
    (i) A statement by the holder of the approved application that the 
effects of the change have been assessed;
    (ii) A full description of the manufacturing and controls changes, 
including the manufacturing site(s) or area(s) involved;
    (iii) The date each change was implemented;
    (iv) Data from studies and tests performed to assess the effects of 
the change; and,
    (v) For a natural product, recombinant DNA-derived protein/
polypeptide, complex or conjugate of a drug substance with a monoclonal 
antibody, sterilization process or test methodology

[[Page 18766]]

related to sterilization process validation, a cross-reference to 
relevant validation protocols and/or standard operating procedures.
    (e) Protocols. An applicant may submit one or more protocols 
describing the specific tests and studies and acceptance criteria to be 
achieved to demonstrate the lack of adverse effect for specified types 
of manufacturing changes on the identity, strength, quality, purity, 
and potency of the drug product as these factors may relate to the 
safety or effectiveness of the drug product. Any such protocols, if not 
included in the approved application, or changes to an approved 
protocol, must be submitted as a supplement requiring approval from FDA 
prior to distribution of a drug product produced with the manufacturing 
change. The supplement, if approved, may subsequently justify a reduced 
reporting category for the particular change because the use of the 
protocol for that type of change reduces the potential risk of an 
adverse effect.
    (f) Patent information. The applicant must comply with the patent 
information requirements under section 505(c)(2) of the act.
    (g) Claimed exclusivity. If an applicant claims exclusivity under 
Sec.  314.108 upon approval of a supplement for change to its 
previously approved drug product, the applicant must include with its 
supplement the information required under Sec.  314.50(j).


Sec.  314.81  [Amended]

0
12. Section 314.81 Other postmarketing reports is amended in paragraph 
(b)(1)(ii) by removing the word ``specifications'' and by adding in its 
place the word ``specification''.


Sec.  314.94  [Amended]

0
13. Section 314.94 Content and format of an abbreviated application is 
amended in the second sentence of paragraph (d)(2) by removing the word 
``methods'' each time it appears and by adding in its place the word 
``procedures''.


Sec.  314.410  [Amended]

0
14. Section 314.410 Imports and exports of new drugs is amended in 
paragraph (b)(2) by removing the word ``specifications'' and by adding 
in its place the word ``specification''.


Sec.  314.430  [Amended]

0
15. Section 314.430 Availability for public disclosure of data and 
information in an application or abbreviated application is amended in 
paragraph (e)(6) by removing the word ``method'' both times it appears 
and by adding in its place the word ``procedure''.

PART 600--BIOLOGICAL PRODUCTS: GENERAL

0
16. The authority citation for 21 CFR part 600 continues to read as 
follows:

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

0
17. Section 600.3 is amended by adding paragraphs (jj) and (kk) to read 
as follows:


Sec.  600.3  Definitions.

* * * * *
    (jj) Assess the effects of the change, as used in Sec.  601.12 of 
this chapter, means to evaluate the effects of a manufacturing change 
on the identity, strength, quality, purity, and potency of a product as 
these factors may relate to the safety or effectiveness of the product.
    (kk) Specification, as used in Sec.  601.12 of this chapter, means 
the quality standard (i.e., tests, analytical procedures, and 
acceptance criteria) provided in an approved application to confirm the 
quality of products, intermediates, raw materials, reagents, 
components, in-process materials, container closure systems, and other 
materials used in the production of a product. For the purpose of this 
definition, acceptance criteria means numerical limits, ranges, or 
other criteria for the tests described.

PART 601--LICENSING

0
18. The authority citation for 21 CFR part 601 continues to read as 
follows:

    Authority: 15 U.S.C. 1451-1561; 21 U.S.C. 321, 351, 352, 353, 
355, 356b, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C. 
216, 241, 262, 263, 264; sec 122. Pub. L. 105-115, 111 Stat. 2322 
(21 U.S.C. 355 note).

0
19. Section 601.12 is amended by revising paragraphs (a), (b)(2)(i), 
(c)(2)(ii), (d)(2)(i) through (d)(2)(v), and (d)(2)(vii); by adding 
paragraphs (b)(4), (c)(2)(iv), (c)(6), (d)(3)(iii), and (f)(2)(i)(E); 
and by removing and reserving paragraph (c)(2)(i) to read as follows:


Sec.  601.12  Changes to an approved application.

    (a) General. (1) As provided by this section, an applicant must 
inform the Food and Drug Administration (FDA) about each change in the 
product, production process, quality controls, equipment, facilities, 
responsible personnel, or labeling established in the approved license 
application(s).
    (2) Before distributing a product made using a change, an applicant 
must assess the effects of the change and demonstrate through 
appropriate validation and/or other clinical and/or nonclinical 
laboratory studies the lack of adverse effect of the change on the 
identity, strength, quality, purity, or potency of the product as they 
may relate to the safety or effectiveness of the product.
    (3) Notwithstanding the requirements of paragraphs (b), (c), and 
(f) of this section, an applicant must make a change provided for in 
those paragraphs in accordance with a regulation or guidance that 
provides for a less burdensome notification of the change (for example, 
by submission of a supplement that does not require approval prior to 
distribution of the product or in an annual report).
    (4) The applicant must promptly revise all promotional labeling and 
advertising to make it consistent with any labeling change implemented 
in accordance with paragraphs (f)(1) and (f)(2) of this section.
    (5) A supplement or annual report must include a list of all 
changes contained in the supplement or annual report. For supplements, 
this list must be provided in the cover letter.
    (b) * * *
    (2) * * *
    (i) Except as provided in paragraphs (c) and (d) of this section, 
changes in the qualitative or quantitative formulation, including 
inactive ingredients, or in the specifications provided in the approved 
application;
* * * * *
    (4) An applicant may ask FDA to expedite its review of a supplement 
for public health reasons or if a delay in making the change described 
in it would impose an extraordinary hardship on the applicant. Such a 
supplement and its mailing cover should be plainly marked: ``Prior 
Approval Supplement-Expedited Review Requested.
    (c) * * *
    (2) * * *
    (i) [Reserved]
    (ii) An increase or decrease in production scale during finishing 
steps that involves different equipment; and
* * * * *
    (iv) Relaxation of an acceptance criterion or deletion of a test to 
comply with an official compendium that is consistent with FDA 
statutory and regulatory requirements.
* * * * *
    (6) If the agency disapproves the supplemental application, it may 
order the manufacturer to cease distribution of

[[Page 18767]]

the products made with the manufacturing change.
    (d) * * *
    (2) * * *
    (i) Any change made to comply with a change to an official 
compendium, except a change described in paragraph (c)(2)(iv) of this 
section, that is consistent with FDA statutory and regulatory 
requirements.
    (ii) The deletion or reduction of an ingredient intended only to 
affect the color of the product, except that a change intended only to 
affect Blood Grouping Reagents requires supplement submission and 
approval prior to distribution of the product made using the change in 
accordance with the requirements set forth in paragraph (b) of this 
section;
    (iii) An extension of an expiration dating period based upon full 
shelf life data on production batches obtained from a protocol approved 
in the application;
    (iv) A change within the container closure system for a nonsterile 
product, based upon a showing of equivalency to the approved system 
under a protocol approved in the application or published in an 
official compendium;
    (v) A change in the size and/or shape of a container containing the 
same number of dosage units for a nonsterile solid dosage form product, 
without a change from one container closure system to another;
* * * * *
    (vii) The addition or revision of an alternative analytical 
procedure that provides the same or increased assurance of the 
identity, strength, quality, purity, or potency of the material being 
tested as the analytical procedure described in the approved 
application, or deletion of an alternative analytical procedure.
    (3) * * *
    (iii) A statement by the holder of the approved application or 
license that the effects of the change have been assessed.
* * * * *
    (f) * * *
    (2) * * *
    (i) * * *
    (E) Any labeling change normally requiring a supplement submission 
and approval prior to distribution of the product that FDA specifically 
requests be submitted under this provision.

    Dated: March 24, 2004.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 04-7532 Filed 4-7-04; 8:45 am]
BILLING CODE 4160-01-S