[Federal Register: December 21, 2000 (Volume 65, Number 246)]
[Notices]
[Page 80440-80442]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr21de00-82]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 00N-1449]
Agency Information Collection Activities; Submission for OMB
Review; Comment Request; Guidance for Industry: Changes to an Approved
NDA or ANDA
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is announcing that the
proposed collection of information listed below has been submitted to
the Office of Management and Budget (OMB) for review and clearance
under the Paperwork Reduction Act of 1995.
DATES: Submit written comments on the collection of information by
January 22, 2001.
ADDRESSES: Submit written comments on the collection of information to
the Office of Information and Regulatory Affairs, OMB, New Executive
Office Bldg., 725 17th St. NW., rm. 10235, Washington, DC 20503, Attn:
Wendy Taylor, Desk Officer for FDA.
FOR FURTHER INFORMATION CONTACT: Karen L. Nelson, Office of Information
Resources Management (HFA-250), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-827-1482.
SUPPLEMENTARY INFORMATION: In compliance with 44 U.S.C. 3507, FDA has
submitted the following proposed collection of information to OMB for
review and clearance.
Guidance for Industry: Changes to an Approved NDA or ANDA
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 (NDA's) and abbreviated new drug applications (ANDA's), 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 NDA's
and ANDA's 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: (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: (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 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
[[Page 80441]]
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.
FDA estimates the burden of this collection of information as
follows:
Table 1.--Estimated Annual Reporting Burden \1\
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Annual
Federal Food, Drug, and Cosmetic No. of Frequency per Total Annual Hours per Total Hours
Act Section Respondents Response Responses Response
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506A(c)(1) and (c)(2) 594 3 1,782 150 267,300
Prior approval supplement
506A(d)(1)(B), (d)(1)(C), and 594 5 2,970 95 282,150
(d)(3)(B)(i)
Changes being made (CBE) in 30-
day supplement
506A(d)(1)(B), (d)(1)(C), and 486 1 486 95 46,170
(d)(3)(B)(ii)
CBE supplement
506A(d)(1)(A), (d)(1)(C), 704 10 7,040 35 246,400
(d)(2)(A), and (d)(2)(B)
Annual report
Total 842,020
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\1\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 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, 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 set 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 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 1,782 supplements will be
submitted annually under section 506A(c)(1) and (c)(2) of the act. 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.
Section 506A(d)(1)(B), (d)(1)(C), and (d)(3)(B)(i) of the act set
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 2,970 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 594
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
[[Page 80442]]
supplements received by the agency, FDA estimates that approximately
486 supplements will be submitted annually under section
506A(d)(3)(B)(ii) of the act. 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.
Section 506A(d)(1)(A), (d)(1)(C), (d)(2)(A), and (d)(2)(B) of the
act set 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 7,040
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) of the act. 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.
In the Federal Register of September 7, 2000 (65 FR 54279), the
agency requested comments on the proposed collections of information.
FDA received one comment which, disagreed with the ``hours per
response'' burden. The comment estimated that it would take
approximately 182 hours to prepare and submit prior approval
supplements; 130 hours for changes-being effected supplements; and 50
hours for changes to be described in an annual report.
FDA has considered the comment as well as other information it has
received, and it has revised the burden estimates. The estimate for
preparing and submitting prior approval supplements has been increased
to 150 hours, from the previous estimate of 120 hours; the estimate for
changes-being-effected supplements has been increased to 95 hours, from
previous estimate of 80 hours; and the estimate for changes to be
described in an annual report has been increased to 35 hours, from the
previous estimate of 25 hours.
The comment also recommended that FDA summarize reporting
requirements in a tabular format in addition to the discussion provided
in the guidance, and that flow charts should be developed to aid
sponsors through the process of determining the proper reporting
mechanism. The comment also stated that it would be helpful to have
easy access to ``such things as inks used in CDER-approved products and
GMP status.''
FDA declines to discuss these suggestions in this notice. The
purpose of this notice and the September 7, 2000, notice is to obtain
comments on the agency's estimates of the information collection burden
that would result from the Guidance ``Changes to an Approved NDA or
ANDA.'' The above comments pertain to the guidance document itself and
should be directed to Docket Number 99D-0529 (see the notice announcing
the availability of the guidance document that published in the Federal
Register of November 23, 1999 (64 FR 65716).
Dated: December 14, 2000.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 00-32614 Filed 12-20-00; 8:45 am]
BILLING CODE 4160-01-F