[Federal Register Volume 78, Number 212 (Friday, November 1, 2013)]
[Notices]
[Pages 65667-65670]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2013-25973]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

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


Agency Information Collection Activities; Submission for Office 
of Management and Budget Review; Comment Request; Guidance for Industry 
on Chemistry, Manufacturing, and Controls Postapproval Manufacturing 
Changes To Be Documented in Annual Reports

AGENCY: Food and Drug Administration, HHS.

[[Page 65668]]


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 (the PRA).

DATES: Fax written comments on the collection of information by 
December 2, 2013.

ADDRESSES: 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, OMB, Attn: FDA Desk Officer, 
FAX: 202-395-7285, or emailed to [email protected]. All 
comments should be identified with the title. Also include the FDA 
docket number found in brackets in the heading of this document.

FOR FURTHER INFORMATION CONTACT: FDA PRA Staff, Office of Operations, 
Food and Drug Administration, 1350 Piccard Dr., PI50-400B, Rockville, 
MD 20850, [email protected].

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: ``Guidance for Industry on CMC Postapproval 
Manufacturing Changes To Be Documented in Annual Reports.'' This 
guidance provides recommendations to holders of new drug applications 
(NDAs) and abbreviated new drug applications (ANDAs) regarding the 
types of chemistry, manufacturing, and controls (CMC) postapproval 
manufacturing changes that FDA has determined will likely have a 
minimal potential to have an adverse effect on product quality (i.e., 
drug product identity, strength, quality, purity, or potency), and 
therefore, should be documented by applicants in an annual report under 
21 CFR 314.70(d).
    Description of Respondents: Respondents to this collection of 
information are applicants of approved NDAs and ANDAs for finished drug 
products and active pharmaceutical ingredients (APIs) intended for 
human use.
    Burden Estimate: 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 low risk to the quality of the product and do not need to be 
submitted in supplements. Based on the risk-based evaluation, FDA 
developed a list (attached as Appendix in the ``Guidance for Industry 
on CMC Postapproval Manufacturing Changes To Be Documented in Annual 
Reports'') to provide additional current recommendations to companies 
regarding some postapproval manufacturing changes for NDAs and ANDAs 
that may be considered to have a minimal potential to have an adverse 
effect on product quality, and, therefore, may be classified as a 
change to be documented in the next annual report (i.e., notification 
of a change after implementation) rather than in a supplement.
    FDA is requesting OMB approval for the information collection 
reduction resulting from the annual submissions, as required by 
Sec. Sec.  314.70, 314.71, 314.81(b)(2), and 314.97 (21 CFR 314.70, 
314.71, 314.81(b)(2), and 314.97), described in this document. 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. In addition, Sec.  
314.98(c) requires annual reports and other post-marketing 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 are 
not affected by this notice.
    The guidance describes our current thinking on the interpretation 
of these requirements. Part of the intent for the guidance is to reduce 
the burden of reporting some manufacturing changes. Currently, for 
postapproval changes considered to be major, applicants must submit and 
receive FDA approval of a supplemental application to the NDA or ANDA 
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 the annual report. The 
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 guidance, may now be documented in annual reports. 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 the requirements imposed by the regulations under 
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 
guidance.
    Under the applicable regulations and the guidance, the following 
changes would occur to the current approval by OMB under the PRA for 
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 reduce 
based on the recommendations in the guidance because certain changes 
submitted as supplements would now be documented 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 reduce, the total number of hours 
for preparing supplements would correspondingly reduce. In the Federal 
Register of June 25, 2010 (75 FR 36421), FDA published the notice of 
availability for the draft guidance, including the information 
collection analysis required under the PRA. We received the following 
comments that pertained to the collection of information resulting from 
the guidance.

[[Page 65669]]

    Comments on Issue One: Several comments noted that, in addition to 
FDA regulations on postapproval changes at Sec. Sec.  314.70 and 
314.71, FDA has issued multiple guidances that provide recommendations 
on how the Agency wishes to be notified of postapproval changes. These 
guidances include the ``Guidance for Industry on Changes to an Approved 
NDA or ANDA,'' the ``Guidance for Industry on Changes to an Approved 
NDA or ANDA--Questions and Answers,'' the ``Guidance for Industry on 
Scale-Up and PostApproval Changes (SUPAC),'' the ``Guidance for 
Industry on Bulk Active Chemicals--Postapproval Changes II (BACPAC),'' 
the ``Draft Guidance for Industry on CMC Postapproval Manufacturing 
Changes Reportable in Annual Reports'' (the guidance that is the 
subject of this Federal Register notice), and others.
    The comments said that this adds duplication, complexity, 
redundancy, and the potential for confusion to the postapproval CMC 
regulatory environment. For example, the comments noted that while some 
of the changes described in the ``Draft Guidance for Industry on CMC 
Postapproval Manufacturing Changes Reportable in Annual Reports'' are 
already included in the existing ``Guidance for Industry on Changes to 
an Approved NDA or ANDA,'' other changes to be documented in annual 
reports such as a move to a different manufacturing site for secondary 
packaging and labeling described in the ``Guidance for Industry on 
Changes to an Approved NDA or ANDA'' are not contained in the ``Draft 
Guidance for Industry on CMC Postapproval Manufacturing Changes 
Reportable in Annual Reports.''
    The comments recommended that all CMC changes to be documented in 
annual reports be consolidated into a single, updated guidance document 
to help ensure consistency, avoid confusion, and simplify the process 
for assessing change. The comments also recommended that the ``Draft 
Guidance for Industry on CMC Postapproval Manufacturing Changes 
Reportable in Annual Reports'' be withdrawn and that its 
recommendations be incorporated into an updated version of the 
``Guidance for Industry on Changes to an Approved NDA or ANDA.''
    FDA Response on Issue One: The ``Final Guidance for Industry on CMC 
Postapproval Manufacturing Changes To Be Documented in Annual Reports'' 
now includes Appendices A and B, which provides examples of chemistry, 
manufacturing, and control-related postapproval changes to be 
documented in annual reports. Section V. ``Resources'' of the guidance 
lists other previously published CMC guidances in which CMC changes to 
be documented in annual reports also are mentioned, along with changes 
that are required to be documented according to Sec.  314.70(b) and 
(c).
    Comments on Issue Two: Several comments said that some of the 
examples given in the draft guidance for changes previously submitted 
under manufacturing supplements that should now be documented in an 
annual report (because the Agency has determined those change to be of 
generally low risk to product quality) are problematic because some of 
these changes are current good manufacturing practice changes (CGMPs) 
and would not have previously been reported at all but kept on file for 
FDA inspection. The comments said that changes that do not have an 
adverse effect on product quality data can be made available to FDA on 
request or during an inspection and do not need to be documented in the 
annual report. The comment said that the recommendations of the draft 
guidance to document these changes in the annual report will increase, 
not reduce, industry's regulatory reporting burden.
    In addition, the comments noted that the draft guidance's 
recommendation that CMC changes to be documented in annual reports be 
supported by, among other things, a reference to affected validation 
protocols, standard operating procedures, and policies also would 
increase industry's regulatory reporting burden because these documents 
are frequently updated and revised, and FDA's CGMP regulations require 
this information to be kept on file and presented to FDA on request or 
during an inspection.
    FDA Response on Issue Two: The guidance clarifies that executed 
batch records, standard operating procedures (SOPs), and data from 
studies and tests performed to assess the effects of each change listed 
in Appendix A should be kept on file and made available to the Agency 
on request (e.g., during an inspection). Section IV. ``Contents of 
Annual Report Notification'' of the guidance has been revised from the 
draft guidance to address many of industry's comments stated in the 
previous paragraph. Summary of data, cross references to change control 
and change validation protocols, and SOPs that were used to assess or 
demonstrate the effect of the change are recommended for inclusion in 
the annual report. These are expected to allow the Agency to 
efficiently determine whether the appropriate reporting category has 
been used.
    Comments on Issue Three: One comment said that many of the 
recommendations found in Appendix A, Sections 1-3 of the draft guidance 
(Components and Composition, Manufacturing Sites, and Manufacturing 
Process) reference information that FDA regulations do not require. The 
comment said that this may result in an overly conservative approach to 
annual reports and the submission of a large amount of unnecessary 
information. As an example, the comment said that Appendix A, Section 
1.2 (lines 147-149) of the draft guidance states that the following can 
be documented in an annual report: ``New supplier of inactive 
ingredients that have a minimal effect on product performance in the 
drug product, providing that acceptance criteria remain unchanged.'' 
The comment noted that if the inactive ingredient meets compendial 
standards, the supplier need not be specified in the original 
application, and if the supplier of that inactive ingredient is later 
changed, that information does not need to be submitted to FDA if the 
inactive ingredient also is a compendial standard. As another example, 
the comment said that Appendix A, Section 2.2 (lines 161-162) of the 
draft guidance states that: ``Addition of barriers to prevent routine 
in-process human intervention in a filling or compounding area that is 
qualified and validated by established procedures.'' The comment said 
that this is not routinely required to be documented in an annual 
report.
    FDA Response on Issue Three: In response to the comments received 
on the draft guidance, the Agency has clarified the applicable 
circumstance when information on the new supplier(s) of inactive 
ingredient should be documented in the annual report. It is clarified 
that documenting the ``addition of barriers within a conventional fill 
area'' in an annual report would apply to the manufacturing of sterile 
products.
    The estimates described in this document are based on FDA's data of 
the number of supplements and annual reports submitted annually to NDAs 
and ANDAs, as well as the Agency's familiarity with the time needed to 
prepare supplements and annual reports. The total number of supplements 
submitted per year is estimated to reduce based on the recommendations 
in the guidance. Based on the number of CMC manufacturing supplements 
received for NDAs and ANDAs, FDA estimates that it will receive 
annually approximately 800 responses under Sec. Sec.  314.70 and

[[Page 65670]]

314.71 for NDAs and approximately 2,075 responses under Sec.  314.97 
for ANDAs. The number of annual frequencies per response is estimated 
to decrease. 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.
    As set forth in the following table, the estimated annual reporting 
burden for this information collection is 286,000 hours. In the future, 
it is estimated that the Agency would reduce the currently approved 
burden (OMB Control Number 0910-0001) for Sec. Sec.  314.70 and 314.71 
for NDAs and Sec.  314.97 for ANDAs by reducing the number of 
supplements for those postapproval CMC changes that can be documented 
in annual reports as recommended in the ``Guidance for Industry on CMC 
Postapproval Manufacturing Changes To Be Documented in Annual 
Reports.''
    FDA estimates the burden on this collection of information as 
follows:

                                                       Table 1--Estimated Annual Reporting Burden
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                                                                              Annual
                Activity                      Number of respondents        frequency per   Total annual         Hours per response          Total hours
                                                                             response        responses
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Supplements and Annual Reports for NDAs  281 (same as currently                     2.85             800  150 (same as currently                 120,000
                                          approved).                                                       approved).
Supplements and Annual Reports for       215 (same as currently                     9.65           2,075  80 (same as currently                  166,000
 ANDAs.                                   approved).                                                       approved).
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    Total Hours........................                                                                                                          286,000
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    Dated: October 25, 2013.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2013-25973 Filed 10-31-13; 8:45 am]
BILLING CODE 4160-01-P