[Federal Register Volume 64, Number 212 (Wednesday, November 3, 1999)]
[Notices]
[Pages 59776-59779]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-28793]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
[Docket No. 99N-4614]


Agency Emergency Processing Request Under OMB Review; 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 a 
collection of information has been submitted to the Office of 
Management and Budget (OMB) for emergency processing under the 
Paperwork Reduction Act of 1995 (the PRA). The collection of 
information is contained in a guidance for industry entitled ``Changes 
to an Approved NDA or ANDA.'' The guidance is intended to assist 
applicants in determining how they should report changes to an approved 
new drug application (NDA) or abbreviated new drug application (ANDA) 
under section 116 of the Food and Drug Administration Modernization Act 
(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.

DATES: Submit written comments on the collection of information by 
November 10, 1999.

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: 
Desk Officer for FDA. 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: On November 21, 1997, the President signed 
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 NDA's and ANDA's, to new and abbreviated animal 
drug applications, and to license applications for biological products.
    The guidance for industry entitled ``Changes to an Approved NDA or 
ANDA'' provides recommendations to holders of 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.
    With respect to the collection of information described below, FDA 
invites comment 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,

[[Page 59777]]

when appropriate, and other forms of information technology.

Title: Changes to an Approved NDA or ANDA

    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 (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).
    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 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).
    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 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.
    Description of Respondents: Businesses or other for-profit 
organizations.
    As explained below, FDA estimates the burden of this collection of 
information as follows:

                                 Table 1.--Estimated Annual Reporting Burden \1\
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                                                     Number of
Federal Food, Drug, and Cosmetic      No. of       Responses per   Total Annual      Hours per      Total Hours
          Act Sections              Respondents     Respondent       Responses       Response
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506A(c)(1)
506A(c)(2)
Prior approval supplement
 (supp.)
                                      594               3           1,744             120         209,280
506A(d)(1)(B)
506A(d)(1)(C)

[[Page 59778]]

 
506A(d)(3)(B)(i)
Changes being effected (CBE) in
 30-day supp.
                                      594               5           2,754              80         220,320
506A(d)(1)(B)
506A(d)(1)(C)
506A(d)(3)(B)(ii)
CBE supp.
                                      486               1             486              80          38,880
506A(d)(1)(A)
506A(d)(1)(C)
506A(d)(2)(A)
506A(d)(2)(B)
Annual Report                         704              10           6,929              25         173,225
 
Total                                                                                             641,705
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

    Sections 506A(a)(1) and 506A(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), 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 the 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.
    Sections 506A(c)(1) and 506A(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, 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 sections 506A(c)(1) and 506A(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.
    Under section 506A(d)(1)(B), 506A(d)(1)(C), and 506A(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 2,754 supplements will be 
submitted annually under sections 506A(d)(1)(B), 506A(d)(1)(C), and 
506A(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.
    Sections 506A(d)(1)(A), 506A(d)(1)(C), 506A(d)(2)(A), and 
506A(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 6,929 
annual reports will include documentation of certain manufacturing 
changes as required under sections 506A(d)(1)(A), 506A(d)(1)(C), 
506A(d)(2)(A), and 506A(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

[[Page 59779]]

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. 
(On August 5, 1999, a notice of the meeting was published in the 
Federal Register (64 FR 42625).)
    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 for 
emergency processing.
    FDA is requesting emergency processing of this proposed collection 
of information under section 3507(j) of the PRA and 5 CFR 1320.13. The 
information is needed immediately to implement section 506A of the 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 use of normal information clearance 
procedures would likely result in the prevention or disruption of this 
collection of information because section 506A takes effect on November 
21, 1999. After November 20, 1999, and until final regulations are 
issued revising 21 CFR 314.70, section 506A of the act will be the sole 
basis for FDA's regulation of postapproval manufacturing changes for 
products approved under NDA's or ANDA's. 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. 
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.

    Dated: October 29, 1999.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 99-28793 Filed 11-2-99; 8:45 am]
BILLING CODE 4160-01-F