[Federal Register: April 8, 2004 (Volume 69, Number 68)]
[Rules and Regulations]
[Page 18727-18767]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr08ap04-14]
[[Page 18727]]
-----------------------------------------------------------------------
Part IV
Department of Health and Human Services
-----------------------------------------------------------------------
Food and Drug Administration
-----------------------------------------------------------------------
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
[[Page 18728]]
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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,''
http://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.
---------------------------------------------------------------------------
\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.
---------------------------------------------------------------------------
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
[[Page 18731]]
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