[Federal Register Volume 65, Number 174 (Thursday, September 7, 2000)]
[Notices]
[Pages 54279-54282]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-22948]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 00N-1449]


Agency Information Collection Activities; Proposed Collection; 
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 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 November 6, 2000.

ADDRESSES: Submit written comments on the collection of information to 
the Dockets Management Branch (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Submit electronic 
comments on the collection of information on the Internet at: http://www.accessdata.fda.gov/scripts/oc/dockets/comments/commentdocket.cfm. 
All comments should be identified with the docket number found in 
brackets in the heading of this document.

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: 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, 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: (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 No. 0910-0431)--Extension

    On November 21, 1997, the President signed the Food and Drug 
Administration Modernization Act (the Modernization Act) (Public 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

[[Page 54280]]

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. 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 (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.
     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 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 below, FDA estimates the burden of this collection of 
information as follows:

[[Page 54281]]



                                 Table 1.--Estimated Annual Reporting Burden \1\
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                                                     Number of
Federal Food, Drug, and Cosmetic     Number of     responses per   Total annual      Hours per      Total hours
          Act Sections              respondents     respondent       responses       response
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506A(c)(1)                            594               3           1,744             120          209,280
 506A(c)(2)
 Prior approval supplement
 (supp.)
506A(d)(1)(B)                         594               5           2,754              80         220,320
 506A(d)(1)(C)
 506A(d)(3)(B)(i)
 Changes being effected (CBE) in
 30-days supp.
506A(d)(1)(B)                         486               1             486              80          38,880
 506A(d)(1)(C)
 506A(d)(3)(B)(ii)
 CBE supp.
506A(d)(1)(A)                         704              10           6,929              25         173,225
 506A(d)(1)(C)
 506A(d)(2)(A)
 506A(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.

    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 section 506A in table 1; 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 set forth requirements 
for changes requiring supplement submission and 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 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 1,744 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 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 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 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 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), (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 this section of the act, 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 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.


[[Page 54282]]


    Dated: August 30, 2000.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 00-22948 Filed 9-6-00; 8:45 am]
BILLING CODE 4160-01-F