[Federal Register Volume 75, Number 122 (Friday, June 25, 2010)]
[Notices]
[Pages 36421-36423]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2010-15415]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2010-D-0283]


Draft Guidance for Industry on Chemistry, Manufacturing, and 
Controls Postapproval Manufacturing Changes Reportable in Annual 
Reports; Availability

AGENCY:  Food and Drug Administration, HHS.

ACTION:  Notice.

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SUMMARY:  The Food and Drug Administration (FDA) is announcing the 
availability of a draft guidance for industry entitled ``CMC 
Postapproval Manufacturing Changes Reportable in Annual Reports.'' This 
draft guidance provides recommendations to holders of new drug 
applications (NDAs) and abbreviated new drug applications (ANDAs) 
regarding the types of changes that may be reported in annual reports. 
Specifically, the draft guidance describes chemistry, manufacturing, 
and controls (CMC) postapproval manufacturing changes that FDA has 
determined will likely present minimal potential to have adverse 
effects on product quality and, therefore, may be reported by 
applicants in an annual report. (The draft guidance excludes positron 
emission tomography (PET) drug products.)

DATES:  Although you can comment on any guidance at any time (see 21 
CFR 10.115(g)(5)), to ensure that the agency considers your comment on 
this draft guidance before it begins work on the final version of the 
guidance, submit either electronic or written comments on the draft 
guidance by September 23, 2010.

ADDRESSES:  Submit written requests for single copies of the draft 
guidance to the Division of Drug Information, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, rm. 2201, Silver Spring, MD 20993-0002. Send 
one self-addressed adhesive label to assist that office in processing 
your requests. See the SUPPLEMENTARY INFORMATION section for electronic 
access to the draft guidance document.
    Submit electronic comments on the draft guidance to http://www.regulations.gov. Submit written comments, including comments 
regarding the proposed collection of information, to the Division of 
Dockets Management (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Jon Clark, Center for Drug Evaluation 
and Research, Food and Drug Administration, Bldg. 51, rm. 4178, 10903 
New Hampshire Ave., Silver Spring, MD 20993-0002, 301-796-2400.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a draft guidance for industry 
entitled ``CMC Postapproval Manufacturing Changes Reportable in Annual 
Reports.'' This draft guidance provides recommendations to holders of 
NDAs and ANDAs regarding the types of CMC postapproval manufacturing 
changes that FDA has determined will likely present minimal potential 
to have adverse effects on product quality, and therefore, may be 
reported by applicants in an annual report under Sec.  314.70 (21 CFR 
314.70).
    In its September 2004 final report, ``Pharmaceutical Current Good 
Manufacturing Practices (CGMPs) for the 21st Century--A Risk-Based 
Approach'' (Pharmaceutical Product Quality Initiative, http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/QuestionsandAnswersonCurrentGoodManufacturingPracticescGMPforDrugs/ucm137175.htm), FDA stated that to keep pace with the many advances in 
quality management practices in manufacturing and to enable the agency 
to more effectively allocate its limited regulatory resources, FDA 
would implement a cooperative, risk-based approach for regulating 
pharmaceutical manufacturing. As part of this approach, FDA determined 
that to provide the most effective public health protection, its CMC 
regulatory review should be based on an understanding of product risk 
and how best to manage this risk.
    The number of CMC manufacturing supplements for NDAs and ANDAs has 
continued to increase over the last several years. In connection with 
FDA's Pharmaceutical Product Quality Initiative and its risk-based 
approach to CMC review, FDA has evaluated the types of changes that 
have been submitted in CMC postapproval manufacturing supplements and 
determined that many of the changes being reported present very low 
risk to the quality of the product and do not need to be submitted in 
supplements.

[[Page 36422]]

    Based on this recent evaluation, FDA developed a list (attached as 
an appendix to the draft guidance) to provide current recommendations 
to companies regarding which postapproval manufacturing changes for 
NDAs and ANDAs may be considered to have a minimal potential for an 
adverse effect on the identity, strength, quality, purity, or potency 
of the drug product and, therefore, may be classified as a change 
reportable in an annual report (e.g., notification of a change after 
implementation) rather than in a supplement.
    This draft guidance is being issued consistent with FDA's good 
guidance practices regulation (21 CFR 10.115). The draft guidance, when 
finalized, will represent the agency's current thinking on CMC 
postapproval manufacturing changes reportable in annual reports for 
NDAs and ANDAs. It does not create or confer any rights for or on any 
person and does not operate to bind FDA or the public. An alternative 
approach may be used if such approach satisfies the requirements of the 
applicable statutes and regulations.

II. Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) either electronic or written comments regarding this 
document. It is only necessary to send one set of comments. It is no 
longer necessary to send two copies of mailed comments. Identify 
comments with the docket number found in brackets in the heading of 
this document. Received comments may be seen in the Division of Dockets 
Management between 9 a.m. and 4 p.m., Monday through Friday.

III. Paperwork Reduction Act of 1995

    Under the Paperwork Reduction Act (44 U.S.C. 3501-3520) (the PRA), 
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 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.
    Title: CMC Postapproval Manufacturing Changes Reportable in Annual 
Reports.
    Description of Respondents: Respondents to this collection of 
information are applicants of approved NDAs and ANDAs.
    Burden Estimate: FDA is requesting public comment on estimates of 
annual submissions from these respondents, as required by Sec.  314.70 
and Sec. Sec.  314.71, 314.81(b)(2), and 314.97 (21 CFR 314.71, 
314.81(b)(2), and 314.97) and described in this draft guidance. 
Sections 314.70 and 314.71 require that supplements be submitted to FDA 
for certain changes to an approved application. Section 314.81(b)(2) 
requires that annual reports be submitted to FDA (Form FDA 2252). 
Section 314.97 sets forth requirements for submitting supplements to an 
approved ANDA for changes that require FDA approval. Section 314.98(c) 
requires annual reports and other postmarketing reports for ANDAs. The 
estimate for annual reports for ANDAs is included under Sec.  
314.81(b)(2). Other postmarketing reports under Sec.  314.98(c) are not 
implicated by this notice.
    The draft guidance describes our current thinking on the 
interpretation of these requirements. Part of the intent for this draft 
guidance is to reduce the burden of reporting some manufacturing 
changes. Currently, for postapproval changes considered to be major, 
applicants of NDAs and ANDAs must submit and receive FDA approval of a 
supplement before the product made with the manufacturing change is 
distributed. If a change is considered to be moderate, an applicant 
must submit a supplement at least 30 days before the product is 
distributed or, in some cases, submit a supplement at the time of 
distribution. If a change is considered to be minor, an applicant may 
proceed with the change, but must notify FDA of the change in an annual 
report. When a change is approved via a supplemental application, these 
changes currently also must be reported in the annual report. The draft 
guidance describes the types of postapproval changes that applicants of 
NDAs and ANDAs currently submit in supplements to NDAs or ANDAs but 
that, under the draft guidance, may now be reported only in annual 
reports and do not need prior FDA approval. As a result, applicants 
would no longer need to submit supplements for such changes.
    FDA currently has OMB approval for the collection of information 
entitled, ``Application for Food and Drug Administration Approval to 
Market a New Drug'' (OMB Control Number 0910-0001). This collection of 
information includes all information requirements imposed by the 
regulations under part 314 (21 CFR part 314) on applicants who apply 
for approval of an NDA or ANDA to market or change an approved 
application. In particular, among other things, this collection of 
information includes: (1) The submission of supplements to FDA for 
certain changes to an approved application in accordance with 
Sec. Sec.  314.70 and 314.71; (2) the submission of annual reports to 
FDA (Form FDA 2252) in accordance with Sec.  314.81(b)(2); (3) the 
submission of supplements to an approved ANDA for changes that require 
FDA approval; and (4) other postmarketing reports for ANDAs in 
accordance with Sec.  314.98(c), of which the estimate for annual 
reports is included under Sec.  314.81(b)(2). Therefore, this 
information collection includes the supplements to NDAs and ANDAs and 
the annual reports for NDAs and ANDAs that are described in the draft 
guidance.
    Under the applicable regulations and the draft guidance, the 
following change to the current approval by OMB under the PRA is 
estimated: Supplements to NDAs under Sec. Sec.  314.70 and 314.71 and 
supplements to ANDAs under Sec.  314.97. Although the submission of 
supplements to NDAs and ANDAs is approved under OMB Control Number 
0910-0001, the total number of supplements submitted per year is 
estimated to be reduced based on the recommendations in the draft 
guidance because certain changes submitted as supplements would now be 
submitted in annual reports. Therefore, for such changes, the 
information collection with respect to the submission of supplements 
will be reduced. Because the number of supplements per year is 
estimated to be reduced, the total number of hours for preparing 
supplements is also estimated to be reduced.

[[Page 36423]]

    Based on FDA's knowledge of supplements and annual reports to NDAs 
and ANDAs, as well as the agency's familiarity with the time needed to 
prepare supplements and annual reports, our estimates for this 
information collection are as follows: The total number of supplements 
submitted per year is estimated to be reduced based on the 
recommendations in the draft guidance. Based on the number of CMC 
manufacturing supplements received for NDAs and ANDAs during 2008, FDA 
estimates that it will receive annually approximately 800 responses 
under Sec. Sec.  314.70 and 314.71 for NDAs and approximately 2,075 
responses under Sec.  314.97 for ANDAs. The number of annual 
frequencies per response will decrease accordingly. FDA estimates that 
approximately the same number of respondents will submit responses 
under Sec. Sec.  314.70, 314.71, and 314.97 and each response will take 
approximately the same amount of time to prepare as in the information 
collection currently approved under OMB Control Number 0910-0001.

                                                     Table 1.--Estimated Annual Reporting Burden\1\
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                                                                          Annual Frequency       Total Annual          Hours Per
                  21 CFR Section                    No. of Respondents      per Response           Responses           Response           Total Hours
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314.70 and 314.71                                         281 (same as                  2.85                 800        150 (same as             120,000
                                                             currently                                                     currently
                                                             approved)                                                     approved)
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314.97                                                    215 (same as                  9.65               2,075         80 (same as             166,000
                                                             currently                                                     currently
                                                             approved)                                                     approved)
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Total Hours                                                                                                                                      286,000
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.

    Therefore, the estimated annual reporting burden for this 
information collection is 286,000 hours.

IV. Electronic Access

    Persons with access to the Internet may obtain the document at 
either http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm or http://www.regulations.gov.

    Dated: June 21, 2010.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2010-15415 Filed 6-24-10; 8:45 am]
BILLING CODE 4160-01-S