[Federal Register: March 16, 2004 (Volume 69, Number 51)]
[Notices]               
[Page 12331-12334]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr16mr04-73]                         

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 2000N-1449]

 
Agency Information Collection Activities; Submission for Office 
of Management and Budget Review; Comment Request; Changes to an 
Approved New Drug Application or Abbreviated New Drug Application

AGENCY:  Food and Drug Administration, HHS.

ACTION:  Notice.

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SUMMARY:  The Food and Drug Administration (FDA) is announcing that a 
proposed collection of information has been submitted to the Office of 
Management and Budget (OMB) for review and clearance under the 
Paperwork Reduction Act of 1995.

DATES: Fax written comments on the collection of information by April 
15, 2004.

ADDRESSES:  OMB is still experiencing significant delays in the regular 
mail, including first class and express mail, and messenger deliveries 
are not being accepted. To ensure that comments on the information 
collection are received, OMB recommends that written comments be faxed 
to the Office of Information and Regulatory Affairs,

[[Page 12332]]

OMB, Attn: Fumie Yokota, Desk Officer for FDA, FAX: 202-395-6974.

FOR FURTHER INFORMATION CONTACT:  Karen L. Nelson, Office of Management 
Programs (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.

Changes to an Approved New Drug Application or Abbreviated New Drug 
Application--(OMB Control Number 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 (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 these 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 (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 
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 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

[[Page 12333]]

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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                                                                                No. of Responses Per     Total Annual      Hours Per
     Federal Food, Drug, and Cosmetic Act Section         No. of Respondents         Respondent           Responses         Response       Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
506A(c)(1) and (c)(2)--Prior Approval Supplement                         263             5.8                    1,517              150          227,550
506A(d)(1)(B),(d)(1)(C), and (d)(3)(B)(i)--Changes                       274             8.5                    2,322               95          220,590
 being effected (CBE) in 30-days Supplement
506A(d)(1)(B), (d)(1)(C), and (d)(3)(B)(ii)--CBE                         202             9.7                    1,959               95          186,105
 Supplement
506A(d)(1)(A), (d)(1)(C), (d)(2)(A), and (d)(2)(B)--                     580            13.2                    7,639               35          267,365
 Annual Report
Total                                                   .....................  ......................  ...............  ...............        901,610
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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 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 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 
1,959 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.
    In the Federal Register of December 19, 2003 (68 FR 70813), FDA 
published a 60-day notice requesting public comment on the information 
collection

[[Page 12334]]

provisions. One comment was received. The comment did not specifically 
address the information collection burden estimates. The comment stated 
that parenteral drug products do not have postapproval change guidance 
documents, and that this has caused the company to evaluate changes 
from a very conservative viewpoint, resulting in a high number of man-
hours involved in the assembly and submission of postapproval changes. 
The comment recommended the incorporation of risk-based analysis.
     FDA response: The recommendations provided in the guidance have 
significantly lowered the filing requirements for postapproval changes 
to parenteral drug products. For example, under 21 CFR 314.70(b)(2)(v), 
a change to the method of manufacture of a drug product required a 
prior approval supplement. Under the guidance, elimination of in-
process filtration performed as part of the manufacture of a terminally 
sterilized product (section VII.C.2.a of the guidance at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/guidance/2766fnl.htm#1
) would be submitted as a 

changes-being-effected supplement. The agency is continuing to work to 
further address filing requirements for postapproval changes of 
parenteral drug products.

    Dated: March 9, 2004.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 04-5832 Filed 3-15-04; 8:45 am]

BILLING CODE 4160-01-S