[Federal Register Volume 65, Number 246 (Thursday, December 21, 2000)]
[Notices]
[Pages 80440-80442]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-32614]


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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