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, 65667-65670 [2013-25973]
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65667
Federal Register / Vol. 78, No. 212 / Friday, November 1, 2013 / Notices
TABLE 2—ESTIMATED ANNUAL RECORDKEEPING BURDEN 1—Continued
Number of
records per
recordkeeper
Number of
recordkeepers
21 CFR section
101.105(t); recordkeeping pertaining to disclosure requirements for food not accurately labeled for quantity
of contents ....................................................................
100
Total ..........................................................................
........................
1 There
Total
annual
records
1
Average
burden per
recordkeeping
100
..........................
Total hours
1
........................
100
..........................
676,150
are no capital costs or operating and maintenance costs associated with this collection of information.
TABLE 3—ESTIMATED ANNUAL REPORTING BURDEN 1
Number of
responses per
respondent
Number of
respondents
21 CFR section/form No.
Total
annual
responses
Average
burden per
response
Total hours
101.9(j)(18) and 101.36(h)(2); procedure for small business nutrition labeling exemption notice using Form
FDA 3570 .........................................................................
101.12(h); petitions to establish or amend a RACC ...........
101.69; petitions for nutrient content claims ........................
101.70; petitions for health claims .......................................
101.108; written proposal for requesting temporary exemptions from certain regulations for the purpose of conducting food labeling experiments ...................................
10,000
5
3
5
1
1
1
1
10,000
5
3
5
8
80
25
80
80,000
400
75
400
1
1
1
40
40
Total ..............................................................................
........................
........................
........................
........................
80,915
emcdonald on DSK67QTVN1PROD with NOTICES
1 There
are no capital costs or operating and maintenance costs associated with this collection of information.
The estimated annual third party
disclosure, recordkeeping, and reporting
burdens are based on our
communications with industry and our
knowledge of and experience with food
labeling and the submission of petitions
and requests to us.
As noted, we are revising this
collection to include previously
approved third party disclosure burdens
associated with the requirement to
declare the amount of trans fatty acids
present in a food, including dietary
supplements. The third party disclosure
burden hours formerly associated with
OMB control number 0910–0515
(collection titled, ‘‘Food Labeling: Trans
Fatty Acids in Nutrition Labeling’’) are
represented by the citation to § 101.9 on
line 4 of table 1 and the citation to
§ 101.36 on line 17 of table 1. For this
revision, we have not added burden
hours to line 4 or line 17 of table 1
because, based on our experience with
food labeling, the 4 hours estimated for
meeting the labeling requirements of
§ 101.9 and the 4 hours estimated for
meeting the labeling requirements of
§ 101.36 are appropriate estimates of the
total time it takes a respondent to meet
our requirements for nutrition labeling
in §§ 101.9 and 101.36.
We are also revising this collection to
include previously approved third party
disclosure burdens associated with the
voluntary declaration of the quantitative
amount and the percent of Daily Value
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of a dietary ingredient on a ‘‘per day’’
basis in addition to the required ‘‘per
serving’’ basis. The third party
disclosure burden hours formerly
associated with OMB control number
0910–0395 (collection titled, ‘‘Food
Labeling: Nutrition Labeling of Dietary
Supplements on a ‘Per Day’ Basis’’) are
represented by the citation to § 101.36
on line 17 of table 1 and the addition
of 300 hours to our previous estimate of
48,000 hours. For this revision, we
added 300 burden hours to line 17 of
table 1 because voluntary labeling on a
‘‘per day’’ basis is in addition to the
required ‘‘per serving’’ basis. We
estimate that ‘‘per day’’ information
would generally be placed on at most 10
percent of the estimated 12,000
disclosures, for a total of 1,200 annual
disclosures, and that a respondent will
spend 15 minutes (0.25 hours) per
disclosure, for a total of 300 hours.
Thus, the total estimated burden on line
17 of table 1 is 48,300 hours and average
burden per disclosure on line 17 of table
1 has been increased from 4.0 to 4.025
hours, to represent an averaging of the
burden hours across all of the estimated
12,000 disclosures.
We expect that the burden hours for
submissions under § 101.108 will be
insignificant. Section 101.108 was
originally issued to provide a procedure
whereby we could grant exemptions
from certain food labeling requirements.
Exemption petitions have infrequently
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been submitted in the recent past; none
have been submitted since publication
on January 6, 1993, of the final
regulations implementing section 403(q)
and (r) of the FD&C Act. Thus, in order
to maintain OMB approval of § 101.108
to accommodate the possibility that a
food producer may propose to conduct
a labeling experiment on its own
initiative, we estimate that we will
receive one or fewer submissions under
§ 101.108 in the next 3 years.
Dated: October 28, 2013.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2013–25975 Filed 10–31–13; 8:45 am]
BILLING CODE 4160–01–P
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.
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65668
ACTION:
Federal Register / Vol. 78, No. 212 / Friday, November 1, 2013 / Notices
Notice.
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 oira_
submission@omb.eop.gov. 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,
PRAStaff@fda.hhs.gov.
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
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SUMMARY:
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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 §§ 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,
§ 314.98(c) requires annual reports and
other post-marketing reports for ANDAs.
The estimate for annual reports for
ANDAs is included under
§ 314.81(b)(2). Other postmarketing
reports under § 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
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Sfmt 4703
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 §§ 314.70 and 314.71;
(2) the submission of annual reports to
FDA (Form FDA 2252) in accordance
with § 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 § 314.98(c),
of which the estimate for annual reports
is included under § 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 §§ 314.70 and 314.71 and
supplements to ANDAs under § 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.
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Federal Register / Vol. 78, No. 212 / Friday, November 1, 2013 / Notices
Comments on Issue One: Several
comments noted that, in addition to
FDA regulations on postapproval
changes at §§ 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
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17:40 Oct 31, 2013
Jkt 232001
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 § 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
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65669
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 §§ 314.70 and
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Federal Register / Vol. 78, No. 212 / Friday, November 1, 2013 / Notices
314.71 for NDAs and approximately
2,075 responses under § 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 §§ 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 §§ 314.70 and 314.71 for
NDAs and § 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
Number of
respondents
Activity
Supplements and Annual Reports for NDAs.
Supplements and Annual Reports for ANDAs.
Annual
frequency
per response
281 (same as currently approved).
215 (same as currently approved).
Total annual
responses
2.85
800
9.65
2,075
Hours per response
150 (same as currently approved).
80 (same as currently approved).
Total Hours ......................
BILLING CODE 4160–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA–2011–N–0179]
Agency Information Collection
Activities; Proposed Collection;
Comment Request; Prior Notice of
Imported Food Under the Public Health
Security and Bioterrorism
Preparedness and Response Act of
2002
Food and Drug Administration,
HHS.
Notice.
The Food and Drug
Administration (FDA or we) 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 information
collection provisions of our regulations
requiring that the Agency receive prior
notice before food is imported or offered
for import into the United States.
emcdonald on DSK67QTVN1PROD with NOTICES
SUMMARY:
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Jkt 232001
Submit either electronic or
written comments on the collection of
information by December 31, 2013.
ADDRESSES: Submit electronic
comments on the collection of
information to https://
www.regulations.gov. 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: FDA
PRA Staff, Office of Operations, Food
and Drug Administration, 1350 Piccard
Dr., PI50–400B, Rockville, MD 20850,
301–796–3793, PRAStaff@fda.hhs.gov.
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, we are publishing this
notice of the proposed collection of
information set forth in this document.
DATES:
[FR Doc. 2013–25973 Filed 10–31–13; 8:45 am]
ACTION:
120,000
166,000
286,000
Dated: October 25, 2013.
Leslie Kux,
Assistant Commissioner for Policy.
AGENCY:
Total hours
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Fmt 4703
Sfmt 4703
With respect to the following
collection of information, we invite
comments on these topics: (1) Whether
the proposed collection of information
is necessary for the proper performance
of our functions, including whether the
information will have practical utility;
(2) the accuracy of our 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.
Prior Notice of Imported Food Under
the Public Health Security and
Bioterrorism Preparedness and
Response Act of 2002—21 CFR 1.278 to
1.285 (OMB Control Number 0910–
0520)—Revision
The Public Health Security and
Bioterrorism Preparedness and
Response Act of 2002 (the Bioterrorism
Act) added section 801(m) of the
Federal Food, Drug, and Cosmetic Act
(FD&C Act) (21 U.S.C. 381(m)), which
requires that we receive prior notice for
food, including food for animals, that is
imported or offered for import into the
United States. Sections 1.278 to 1.282 of
our regulations (21 CFR 1.278 to 1.282)
set forth the requirements for submitting
prior notice; §§ 1.283(d) and 1.285(j) (21
CFR 1.283(d) and 1.285(j)) set forth the
procedure for requesting our review
after we have refused admission of an
article of food under section 801(m)(1)
of the FD&C Act or placed an article of
food under hold under section 801(l) of
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]]>Agencies
[Federal Register Volume 78, Number 212 (Friday, November 1, 2013)]
[Notices]
[Pages 65667-65670]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2013-25973]
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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 oira_submission@omb.eop.gov. 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, PRAStaff@fda.hhs.gov.
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
--------------------------------------------------------------------------------------------------------------------------------------------------------
Annual
Activity Number of respondents frequency per Total annual Hours per response Total hours
response responses
--------------------------------------------------------------------------------------------------------------------------------------------------------
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).
----------------------------------------------------------------------------------------------------------------
Total Hours........................ 286,000
--------------------------------------------------------------------------------------------------------------------------------------------------------
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
