[Federal Register Volume 65, Number 68 (Friday, April 7, 2000)]
[Notices]
[Pages 18338-18340]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-8599]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 99D-0529]


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 (PRA).

DATES: Submit written comments on the collection of information by May 
8, 2000.

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 into law the FDA 
Modernization Act (the Modernization Act) (Public Law 105-115). 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 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.
    Section 116 of the Modernization Act amended the act by adding 
section 506A, which includes the following provisions:
    1. 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 (section 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.
    2. A drug made with a major manufacturing change may be distributed 
only after the applicant submits a supplement 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).
    3. 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

[[Page 18339]]

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(2) of the act).
    4. 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).
    5. 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 also may 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 filling 
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 Burden1
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                                                    Number of
    Federal Food, Drug, and         Number of     Responses per   Total Annual      Hours per      Total Hours
      Cosmetic Act Section         Respondents     Respondent       Responses       Response
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506A(c)(1) and (c)(2) Prior          594               3           1,744             120                209,280
 approval supplement
506A(d)(1)(C), and (d)(3)(B)(i)      594               5           2,754              80                220,320
 CBE\2\ in 30-day supplement
506A(d)(1)(B), (d)(1)(C), and        486               1             486              80                 38,880
 (d)(3)(B)(ii) CBE\2\
 supplement
506A(d)(1)(A), (d)(1)(C),            704              10           6,929              25                173,225
 (d)(2)(A), and (d)(2)(B)
 Annual report
Total                                                                                                  641,705
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.
\2\ CBE means changes being effected.

    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, 
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

[[Page 18340]]

approval prior to distribution of the product made using the change 
(major changes). Under this section, a supplement must be submitted for 
any change in the product, production process, quality controls, 
equipment, or facilities that have a substantial potential to have an 
adverse effect on the identity, strength, quality, purity, or potency 
of the product as the 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 1,744 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 120 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 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 this section, 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 the data concerning the number of supplements received by 
the agency, FDA estimates that approximately 2,754 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 80 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 the data concerning the number of 
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 80 hours to prepare and submit to FDA each supplement.
    Section 506A(d)(1)(A), (d)(1)(C), and (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 this section, 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 the data concerning the number of supplements and annual 
reports received by the agency, FDA estimates that approximately 6,929 
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 25 hours to prepare and submit to FDA the information for 
each annual report.
    In the Federal Register of June 28, 1999 (64 FR 34608), FDA 
published a proposed rule to implement section 116 of the Modernization 
Act by revising current regulations at 21 CFR 314.70 on supplements and 
other changes to an approved application. In that same issue of the 
Federal Register (64 FR 34660), FDA published a notice of availability 
of a draft guidance for industry entitled ``Changes to an Approved NDA 
or ANDA.'' On August 19, 1999, FDA held a public meeting to discuss and 
receive comments on the proposed regulations and the draft guidance (64 
FR 42625, August 5, 1999).
    The period for public comment on the proposed regulations closed on 
September 13, 1999 and FDA is currently reviewing the comments and 
preparing a final rule. The comment period for the draft guidance 
closed on August 27, 1999, and FDA has considered these comments when 
preparing the guidance that is the subject of this request.
    FDA published in the Federal Register of January 6, 2000 (65 FR 
779), a 60-day notice requesting comments on the extension of the 
proposed collection of information in this guidance. In response to 
this notice, no comments were received by the agency.
    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.

    Dated: March 30, 2000.
William K. Hubbard,
Senior Associate Commissioner for Policy, Planning, and Legislation.
[FR Doc. 00-8599 Filed 4-6-00; 8:45 am]
BILLING CODE 4160-01-F