[Federal Register Volume 68, Number 244 (Friday, December 19, 2003)]
[Notices]
[Pages 70813-70815]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-31412]


-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 2000N-1449]


Agency Information Collection Activities; Comment Request; 
Guidance for Industry--Changes to an Approved New Drug Application or 
Abbreviated New Drug Application

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

-----------------------------------------------------------------------

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 February 17, 2004.

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

FOR FURTHER INFORMATION CONTACT: Karen Nelson, Office of Management 
Programs (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, including 
each proposed extension of an existing 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 these topics: (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 
Number 0910-0431)--Extension

    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 (NDAs) and abbreviated new drug applications (ANDAs), 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 NDAs 
and ANDAs 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 the following 
areas: (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 
the following possibilities: (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

[[Page 70814]]

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 in the next paragraph, FDA estimates the burden of 
this collection of information as follows:

                                   Table 1.--Estimated Annual Reporting Burden
----------------------------------------------------------------------------------------------------------------
                                                            Number of         Total
 Federal Food, Drug, and Cosmetic       Number of         Responses Per       Annual     Hours Per   Total Hours
           Act Section                 Respondents         Respondent       Responses     Response
----------------------------------------------------------------------------------------------------------------
506A(c)(1) and (c)(2) Prior              263                   5.8               1,517          150      227,550
 Approval Supplement
506A(d)(1)(B), (d)(1)(C), and            274                   8.5               2,322           95      220,590
 (d)(3)(B)(i) Changes being
 effected (CBE) in 30-days
 Supplement
506A(d)(1)(B), (d)(1)(C), and            202                   9.7               1,959           95      186,105
 (d)(3)(B)(ii) CBE Supplement
506A(d)(1)(A), (d)(1)(C),                580                  13.2               7,639           35      267,365
 (d)(2)(A), and (d)(2)(B) Annual
 Report
Total                              ..................  ..................  ...........  ...........      901,610
----------------------------------------------------------------------------------------------------------------
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 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, 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 sets 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

[[Page 70815]]

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 1,517 supplements will be 
submitted annually under section 506A(c)(1) and (c)(2) of the act. FDA 
estimates that approximately 263 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) 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 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 2,322 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 274 
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 
supplements received by the agency, FDA estimates that approximately 
1959 supplements will be submitted annually under section 
506A(d)(3)(B)(ii) of the act. FDA estimates that approximately 202 
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 sets 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 7,639 
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). FDA estimates that approximately 580 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.

    Dated: December 16, 2003.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 03-31412 Filed 12-17-03; 1:28 pm]
BILLING CODE 4160-01-S