[Federal Register Volume 88, Number 141 (Tuesday, July 25, 2023)]
[Notices]
[Pages 47886-47888]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2023-15645]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket Nos. FDA-2022-D-0055 and FDA-2020-N-1790]


M7(R2) Assessment and Control of Deoxyribonucleic Acid Reactive 
(Mutagenic) Impurities in Pharmaceuticals To Limit Potential 
Carcinogenic Risk, M7(R2) Addendum, and M7(R2) Questions and Answers; 
International Council for Harmonisation; Guidances for Industry; 
Availability

AGENCY: Food and Drug Administration, HHS.

[[Page 47887]]


ACTION: Notice of availability.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing 
the availability of a final guidance for industry entitled ``M7(R2) 
Assessment and Control of DNA Reactive (Mutagenic) Impurities in 
Pharmaceuticals to Limit Potential Carcinogenic Risk'' (M7(R2) 
Guidance) and two supplemental documents entitled ``M7(R2) Addendum: 
Application of the Principles of the ICH M7 Guidance to Calculation of 
Compound-Specific Acceptable Intakes'' (M7(R2) Addendum) and ``M7(R2) 
Assessment and Control of DNA Reactive (Mutagenic) Impurities in 
Pharmaceuticals to Limit Potential Carcinogenic Risk Questions and 
Answers'' (M7(R2) Questions and Answers). The M7(R2) Guidance, M7(R2) 
Addendum, and M7(R2) Questions and Answers were prepared under the 
auspices of the International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH). The guidance and 
supplemental documents are intended to harmonize the considerations for 
assessment and control of DNA reactive (mutagenic) impurities. The 
M7(R2) Guidance and M7(R2) Addendum replace the guidance for industry 
entitled ``M7(R1) Assessment and Control of DNA Reactive (Mutagenic) 
Impurities in Pharmaceuticals To Limit Potential Carcinogenic Risk,'' 
issued on March 14, 2018. The M7(R2) Guidance, M7(R2) Addendum, and 
M7(R2) Questions and Answers, also finalize the draft guidances for 
industry entitled ``M7(R2) Addendum: Application of the Principles of 
the ICH M7 Guideline to Calculation of Compound-Specific Acceptable 
Intakes'' and ``M7 Assessment and Control of DNA Reactive (Mutagenic) 
Impurities in Pharmaceuticals To Limit Potential Carcinogenic Risk--
Questions and Answers'' issued on April 7, 2022, and September 29, 
2020, respectively.

DATES: The announcement of the guidance is published in the Federal 
Register on July 25, 2023.

ADDRESSES: You may submit either electronic or written comments on 
Agency guidances at any time as follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2022-D-0055 for ``M7(R2) Assessment and Control of DNA Reactive 
(Mutagenic) Impurities in Pharmaceuticals to Limit Potential 
Carcinogenic Risk,'' and ``M7(R2) Addendum: Application of the 
Principles of the ICH M7 Guidance to Calculation of Compound-Specific 
Acceptable Intakes,'' or Docket No. FDA-2020-N-1790 for ``M7(R2) 
Assessment and Control of DNA Reactive (Mutagenic) Impurities in 
Pharmaceuticals to Limit Potential Carcinogenic Risk Questions and 
Answers.'' Received comments will be placed in the docket and, except 
for those submitted as ``Confidential Submissions,'' publicly viewable 
at https://www.regulations.gov or at the Dockets Management Staff 
between 9 a.m. and 4 p.m., Monday through Friday, 240-402-7500.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, 240-402-7500.
    You may submit comments on any guidance at any time (see 21 CFR 
10.115(g)(5)).
    Submit written requests for single copies of this guidance to the 
Division of Drug Information, Center for Drug Evaluation and Research, 
Food and Drug Administration, 10001 New Hampshire Ave., Hillandale 
Building, 4th Floor, Silver Spring, MD 20993-0002, or the Office of 
Communication, Outreach and Development, Center for Biologics 
Evaluation and Research (CBER), Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 71, Rm. 3128, Silver Spring, MD 20993-0002. Send 
one self-addressed adhesive label to assist that office in processing 
your requests. The guidance may also be obtained by mail by calling 
CBER at 1-800-835-4709 or 240-402-8010. See the SUPPLEMENTARY 
INFORMATION section for electronic access to the guidance document.

FOR FURTHER INFORMATION CONTACT: 
    Regarding the guidance: Aisar Atrakchi, Center for Drug Evaluation 
and Research, Food and Drug

[[Page 47888]]

Administration, 10904 New Hampshire Ave., Bldg. 22, Rm. 4118, Silver 
Spring, MD 20993-0003, 301-769-1036.
    Regarding the ICH: Jill Adleberg, Center for Drug Evaluation and 
Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 
51, Rm. 6364, Silver Spring, MD 20993-0002, 301-796-5259, 
[email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a guidance for industry 
entitled ``M7(R2) Assessment and Control of DNA Reactive (Mutagenic) 
Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk.'' 
The guidance was prepared under the auspices of ICH. ICH seeks to 
achieve greater regulatory harmonization worldwide to ensure that safe, 
effective, high-quality medicines are developed, registered, and 
maintained in the most resource-efficient manner.
    By harmonizing the regulatory requirements in regions around the 
world, ICH guidelines enhance global drug development, improve 
manufacturing standards, and increase the availability of medications. 
For example, ICH guidelines have substantially reduced duplicative 
clinical studies, prevented unnecessary animal studies, standardized 
the reporting of important safety information, and standardized 
marketing application submissions.
    The six Founding Members of the ICH are FDA; the Pharmaceutical 
Research and Manufacturers of America; the European Commission; the 
European Federation of Pharmaceutical Industries Associations; the 
Japanese Ministry of Health, Labour, and Welfare; and the Japanese 
Pharmaceutical Manufacturers Association. The Standing Members of the 
ICH Association include Health Canada and Swissmedic. ICH membership 
continues to expand to include other regulatory authorities and 
industry associations from around the world (refer to https://www.ich.org/).
    ICH works by engaging global regulatory and industry experts in a 
detailed, science-based, and consensus-driven process that results in 
the development of ICH guidelines. The regulators around the world are 
committed to consistently adopting these consensus-based guidelines, 
realizing the benefits for patients and for industry.
    As a Founding Regulatory Member of ICH, FDA plays a major role in 
the development of each of the ICH guidelines, which FDA then adopts 
and issues as guidance for industry. FDA's guidance documents do not 
establish legally enforceable responsibilities. Instead, they describe 
the Agency's current thinking on a topic and should be viewed only as 
recommendations, unless specific regulatory or statutory requirements 
are cited.
    In the Federal Register of April 7, 2022 (87 FR 20435), FDA 
published a notice announcing the availability of a draft guidance for 
industry entitled ``M7(R2) Addendum: Application of the Principles of 
the ICH M7 Guideline to Calculation of Compound-Specific Acceptable 
Intakes,'' which included ICH assembly approved changes, including the 
separation of the main guidance and addendum into two separate 
documents. In the Federal Register of September 29, 2020 (85 FR 61009), 
FDA published a notice announcing the availability of a draft guidance 
for industry entitled ``M7 Assessment and Control of DNA reactive 
(Mutagenic) Impurities in Pharmaceuticals To Limit Potential 
Carcinogenic Risk--Questions and Answers.'' The notices gave interested 
persons an opportunity to submit comments by May 9, 2022, and December 
28, 2020, respectively.
    After consideration of the comments received and revisions to the 
guidances, final drafts of the guidance and supplemental documents were 
submitted to the ICH Assembly and endorsed by the regulatory Agencies 
on May 24, 2022, and April 3, 2023.
    These guidances finalize the above draft guidances issued on April 
7, 2022, and September 29, 2020, with no significant changes. The 
M7(R2) Guidance is intended to be read in conjunction with two 
accompaniment documents, the M7(R2) Addendum and the M7(R2) Questions 
and Answers. The core M7(R2) Guidance includes information on mutagenic 
impurities and changes to HIV treatment duration. The M7(R2) Addendum 
contains monographs for mutagenic chemicals that are common in 
pharmaceutical manufacturing or are useful to illustrate the principles 
for deriving compound-specific intakes described in the core guidance. 
The M7(R2) Questions and Answers facilitate consistent implementation 
by clarifying issues and concerns identified since the first version of 
the final guidance for industry, ``M7 Assessment and Control of DNA 
Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential 
Carcinogenic Risk,'' published in 2014.
    This guidance is being issued consistent with FDA's good guidance 
practices regulation (21 CFR 10.115). The guidance represents the 
current thinking of FDA on ``M7(R2) Assessment and Control of DNA 
Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential 
Carcinogenic Risk.'' It does not establish any rights for any person 
and is not binding on FDA or the public. You can use an alternative 
approach if it satisfies the requirements of the applicable statutes 
and regulations.

II. Paperwork Reduction Act of 1995

    While these guidances contains no collection of information, they 
do refer to previously approved FDA collections of information. 
Therefore, clearance by the Office of Management and Budget (OMB) under 
the Paperwork Reduction Act of 1995 (PRA) (44 U.S.C. 3501-3521) is not 
required for these guidances. The previously approved collections of 
information are subject to review by OMB under the PRA. The collections 
of information in 21 CFR part 601 have been approved under OMB control 
number 0910-0338. The collections of information pertaining to 21 CFR 
parts 312 and 314 have been approved under OMB control numbers 0910-
0014 and 0910-0001, respectively. The collections of information in 21 
CFR parts 210 and 211 pertaining to current good manufacturing practice 
requirements have been approved under OMB control number 0910-0139.

III. Electronic Access

    Persons with access to the internet may obtain the guidance at 
https://www.regulations.gov, https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs, https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances, or https://www.fda.gov/regulatory-information/search-fda-guidance-documents.

    Dated: July 19, 2023.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2023-15645 Filed 7-24-23; 8:45 am]
BILLING CODE 4164-01-P