[Federal Register: December 19, 2003 (Volume 68, Number 244)]
[Notices]
[Page 70813-70815]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr19de03-75]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 2000N-1449]
Agency Information Collection Activities; Comment Request;
Guidance for Industry--Changes to an Approved New Drug Application or
Abbreviated New Drug Application
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is announcing an
opportunity for public comment on the proposed collection of certain
information by the agency. Under the Paperwork Reduction Act of 1995
(the PRA), Federal agencies are required to publish notice in the
Federal Register concerning each proposed collection of information,
including each proposed extension of an existing collection of
information, and to allow 60 days for public comment in response to the
notice. This notice solicits comments on the collection of information
contained in a guidance for industry entitled ``Changes to an Approved
NDA or ANDA.''
DATES: Submit written or electronic comments on the collection of
information by February 17, 2004.
ADDRESSES: Submit electronic comments on the collection of information
to: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.accessdata.fda.gov/scripts/oc/dockets/edockethome.cfm.
Submit written comments on the collection of information to the
Division of Dockets Management, (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All
comments should be identified with the docket number found in brackets
in the heading of this document.
FOR FURTHER INFORMATION CONTACT: Karen Nelson, Office of Management
Programs (HFA-250), Food and Drug Administration, 5600 Fishers Lane,
Rockville, MD 20857, 301-827-1482.
SUPPLEMENTARY INFORMATION: Under the PRA (44 U.S.C. 3501-3520), Federal
agencies must obtain approval from the Office of Management and Budget
(OMB) for each collection of information they conduct or sponsor.
``Collection of information'' is defined in 44 U.S.C. 3502(3) and 5 CFR
1320.3(c) and includes agency requests or requirements that members of
the public submit reports, keep records, or provide information to a
third party. Section 3506(c)(2)(A) of the PRA (44 U.S.C. 3506(c)(2)(A))
requires Federal agencies to provide a 60-day notice in the Federal
Register concerning each proposed collection of information, including
each proposed extension of an existing collection of information,
before submitting the collection to OMB for approval. To comply with
this requirement, FDA is publishing notice of the proposed collection
of information set forth in this document.
With respect to the following collection of information, FDA
invites comments on these topics: (1) Whether the proposed collection
of information is necessary for the proper performance of FDA's
functions, including whether the information will have practical
utility; (2) the accuracy of FDA's estimate of the burden of the
proposed collection of information, including the validity of the
methodology and assumptions used; (3) ways to enhance the quality,
utility, and clarity of the information to be collected; and (4) ways
to minimize the burden of the collection of information on respondents,
including through the use of automated collection techniques, when
appropriate, and other forms of information technology.
Guidance for Industry--Changes to an Approved NDA or ANDA (OMB Control
Number 0910-0431)--Extension
On November 21, 1997, the President signed the Food and Drug
Administration Modernization Act (the Modernization Act) (Pubic Law
105-115) into law. Section 116 of the Modernization Act amended the
Federal Food, Drug, and Cosmetic Act (the act) by adding section 506A
(21 U.S.C. 356a), which describes requirements and procedures for
making and reporting manufacturing changes to approved new drug
applications (NDAs) and abbreviated new drug applications (ANDAs), to
new and abbreviated animal drug applications, and to license
applications for biological products.
The guidance is intended to assist applicants in determining how
they should report changes to an approved NDA or ANDA under section 116
of the Modernization Act, which provides requirements for making and
reporting manufacturing changes to an approved application and for
distributing a drug product made with such changes.
The guidance provides recommendations to holders of approved NDAs
and ANDAs who intend to make postapproval changes in accordance with
section 506A of the act. The guidance covers recommended reporting
categories for postapproval changes for drugs, other than specified
biotechnology and specified synthetic biological products.
Recommendations are provided for postapproval changes in the following
areas: (1) Components and composition, (2) sites, (3) manufacturing
process, (4) specification(s), (5) package, (6) labeling, and (7)
miscellaneous changes.
Some of the basic elements of section 506A of the act are as
follows:
A drug made with a manufacturing change, whether a major
manufacturing change or otherwise, may be distributed only after the
applicant validates the effects of the change on the identity,
strength, quality, purity, and potency of the drug as these factors may
relate to the safety or effectiveness of the drug (sections 506A(a)(1)
and (b) of the act). This section recognizes that additional testing,
beyond testing to ensure that an approved specification is met, is
required to ensure unchanged identity, strength, quality, purity, or
potency as these factors may relate to the safety or effectiveness of
the drug.
A drug made with a major manufacturing change may be distributed
only after the applicant submits a supplemental application to FDA and
the supplemental application is approved by the agency. The application
is required to contain information determined to be appropriate by FDA
and include the information developed by the applicant when
``validating the effects of the change'' (section 506A(c)(1) of the
act).
A major manufacturing change is a manufacturing change determined
by FDA to have substantial potential to adversely affect the identity,
strength, quality, purity, or potency of the drug as these factors may
relate to the safety or effectiveness of the drug. Such changes include
the following possibilities: (1) A change made in the qualitative or
quantitative formulation of the drug involved or in the specifications
in the approved application or license unless exempted by FDA by
regulation or guidance; (2) a change determined by FDA by regulation or
guidance to require completion of an appropriate clinical study
demonstrating equivalence of the drug to the drug manufactured without
the change; and (3) other changes determined by FDA by regulation or
guidance to have a
[[Page 70814]]
substantial potential to adversely affect the safety or effectiveness
of the drug (section 506A(c)(2) of the act).
FDA may require submission of a supplemental application for drugs
made with manufacturing changes that are not major (section
506A(d)(1)(B) of the act) and establish categories of manufacturing
changes for which a supplemental application is required (section
506A(d)(1)(C) of the act). In such a case the applicant may begin
distribution of the drug 30 days after FDA receives a supplemental
application unless the agency notifies the applicant within the 30 day
period that prior approval of the application is required (section
506A(d)(3)(B)(i) of the act). 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 (section 506A(d)(3)(B)(ii) of
the act). If FDA disapproves a supplemental application, the agency may
order the manufacturer to cease the distribution of drugs that have
been made with the disapproved change (section 506A(d)(3)(B)(iii) of
the act).
FDA may authorize applicants to distribute drugs without submitting
a supplemental application (section 506A(d)(1)(A) of the act) and may
establish categories of manufacturing changes that may be made without
submitting a supplemental application (section 506A(d)(1)(C) of the
act). The applicant is required to submit a report to FDA on such a
change and the report is required to contain information the agency
deems to be appropriate and information developed by the applicant when
validating the effects of the change. FDA may also specify the date on
which the report is to be submitted (section 506A(d)(2)(A) of the act).
If during a single year an applicant makes more than one manufacturing
change subject to an annual reporting requirement, FDA may authorize
the applicant to submit a single report containing the required
information for all the changes made during the year (annual report)
(section 506A(d)(2)(B) 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 guidance on 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 affect the product. The guidance
enables the agency to respond more readily to knowledge gained from
manufacturing experience, further research and data collection, and
advances in technology. The guidance describes the agency's current
interpretation of specific changes falling into the four filing
categories. 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. The use of guidance
documents allows FDA to more easily and quickly modify and update
important information.
As explained in the next paragraph, FDA estimates the burden of
this collection of information as follows:
Table 1.--Estimated Annual Reporting Burden
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Number of Total
Federal Food, Drug, and Cosmetic Number of Responses Per Annual Hours Per Total Hours
Act Section Respondents Respondent Responses Response
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506A(c)(1) and (c)(2) Prior 263 5.8 1,517 150 227,550
Approval Supplement
506A(d)(1)(B), (d)(1)(C), and 274 8.5 2,322 95 220,590
(d)(3)(B)(i) Changes being
effected (CBE) in 30-days
Supplement
506A(d)(1)(B), (d)(1)(C), and 202 9.7 1,959 95 186,105
(d)(3)(B)(ii) CBE Supplement
506A(d)(1)(A), (d)(1)(C), 580 13.2 7,639 35 267,365
(d)(2)(A), and (d)(2)(B) Annual
Report
Total .................. .................. ........... ........... 901,610
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There are no capital costs or operating and maintenance costs associated with this collection of information.
Section 506A(a)(1) and (b) of the act requires 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, no separate estimates are
provided for these sections in table 1 of this document; estimates for
validation requirements are included in the estimates for supplements
and annual reports. The guidance 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, and
bioequivalence) of a product as they may relate to the safety or
effectiveness of the product.
Section 506A(c)(1) and (c)(2) of the act sets forth requirements
for changes requiring supplement submission and approval prior to
distribution of the product made using the change (major changes).
Under these sections of the act, a supplement 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
[[Page 70815]]
the product as these factors may relate to the safety or effectiveness
of the product. The applicant must obtain approval of a supplement from
FDA prior to distribution of a product made using the change.
Based on data concerning the number of supplements received by the
agency, FDA estimates that approximately 1,517 supplements will be
submitted annually under section 506A(c)(1) and (c)(2) of the act. FDA
estimates that approximately 263 applicants will submit such
supplements, and that it will take approximately 150 hours to prepare
and submit to FDA each supplement.
Section 506A(d)(1)(B), (d)(1)(C), and (d)(3)(B)(i) sets forth
requirements for changes requiring supplement submission at least 30
days prior to distribution of the product made using the change
(moderate changes). Under these sections, a supplement must 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. Distribution of the product made using
the change may begin not less than 30 days after receipt of the
supplement by FDA.
Based on data concerning the number of supplements received by the
agency, FDA estimates that approximately 2,322 supplements will be
submitted annually under section 506A(d)(1)(B), (d)(1)(C), and
(d)(3)(B)(i) of the act. FDA estimates that approximately 274
applicants will submit such supplements, and that it will take
approximately 95 hours to prepare and submit to FDA each supplement.
Under section 506A(d)(3)(B)(ii) of the act, 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 upon receipt by the agency of a
supplement for the change. Based on data concerning the number of
supplements received by the agency, FDA estimates that approximately
1959 supplements will be submitted annually under section
506A(d)(3)(B)(ii) of the act. FDA estimates that approximately 202
applicants will submit such supplements, and that it will take
approximately 95 hours to prepare and submit to FDA each supplement.
Section 506A(d)(1)(A), (d)(1)(C), (d)(2)(A), and (d)(2)(B) of the
act sets forth requirements for changes to be described in an annual
report (minor changes). Under these sections, 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.
Based on data concerning the number of supplements and annual
reports received by the agency, FDA estimates that approximately 7,639
annual reports will include documentation of certain manufacturing
changes as required under section 506A(d)(1)(A), (d)(1)(C), (d)(2)(A),
and (d)(2)(B). FDA estimates that approximately 580 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.
Dated: December 16, 2003.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 03-31412 Filed 12-17-03; 1:28 pm]
BILLING CODE 4160-01-S