[Federal Register Volume 83, Number 50 (Wednesday, March 14, 2018)]
[Notices]
[Pages 11210-11212]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-05118]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2018-D-0740]


M7(R1): Assessment and Control of Deoxyribonucleic Acid Reactive 
(Mutagenic) Impurities in Pharmaceuticals To Limit Potential 
Carcinogenic Risk; Guidance for Industry; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of availability.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing 
the availability of a guidance entitled ``M7(R1): Assessment and 
Control of Deoxyribonucleic Acid (DNA) Reactive (Mutagenic) Impurities 
in Pharmaceuticals to Limit Potential Carcinogenic Risk.'' This 
guidance updates and replaces the May 2015 guidance for industry ``M7 
Assessment and Control of DNA Reactive (Mutagenic) Impurities in 
Pharmaceuticals to Limit Potential Carcinogenic Risk.'' This guidance 
finalizes the draft guidance ``M7(R1) Addendum to ICH M7: Assessment 
and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals 
to Limit Potential Carcinogenic Risk,'' issued September 28, 2015 (80 
FR 58261).
    The guidance was prepared under the auspices of the International 
Council for Harmonisation (ICH), formerly the International Conference 
on Harmonisation. This M7(R1) document provides guidance on acceptable 
intakes (AIs), or permissible daily exposures (PDEs), derived for some 
chemicals that are considered to be mutagens and carcinogens and, are 
also commonly used in the synthesis of pharmaceuticals or are, useful 
examples to illustrate the principles for deriving compound-specific 
intakes described in ICH M7. This document is intended to provide 
guidance for new drug substances and new drug products during their 
clinical development and subsequent applications for marketing.

DATES: The announcement of the guidance is published in the Federal 
Register on March 14, 2018.

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

[[Page 11211]]

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-2018-D-0740 for ``M7(R1) Assessment and Control of DNA Reactive 
(Mutagenic) Impurities in Pharmaceuticals To Limit Potential 
Carcinogenic Risk.'' 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 office between 9 a.m. and 4 p.m., Monday through 
Friday.
     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.gpo.gov/fdsys/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.
    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 
Administration, 10903 New Hampshire Ave., Bldg. 22, Rm. 4118, Silver 
Spring, MD 20993-0002, 301-796-1036; or Anne Pilaro, Center for 
Biologics Evaluation and Research (HFM-17), Food and Drug 
Administration, 10903 New Hampshire Ave., Bldg. 71, Rm. 4025, Silver 
Spring, MD 20993-0002, 240-402-8341.
    Regarding the ICH: Amanda Roache, Center for Drug Evaluation and 
Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 
51, Rm. 1176, Silver Spring, MD 20993-0002, 301-796-4548.

SUPPLEMENTARY INFORMATION:

I. Background

    In recent years, regulatory authorities and industry associations 
from around the world have participated in many important initiatives 
to promote international harmonization of regulatory requirements under 
the ICH. FDA has participated in several ICH meetings designed to 
enhance harmonization and FDA is committed to seeking scientifically 
based harmonized technical procedures for pharmaceutical development. 
One of the goals of harmonization is to identify and then reduce 
differences in technical requirements for drug development among 
regulatory agencies.
    ICH was established to provide an opportunity for harmonization 
initiatives to be developed with input from both regulatory and 
industry representatives. FDA also seeks input from consumer 
representatives and others. ICH is concerned with harmonization of 
technical requirements for the registration of pharmaceutical products 
for human use among regulators around the world. The six founding 
members of the ICH are the European Commission; the European Federation 
of Pharmaceutical Industries Associations; the FDA; the Japanese 
Ministry of Health, Labour, and Welfare; the Japanese Pharmaceutical 
Manufacturers Association; and the Pharmaceutical Research and 
Manufacturers of America. The Standing Members of the ICH Association 
include Health Canada and Swissmedic. Any party eligible as a Member in 
accordance with the ICH Articles of Association can apply for 
membership in writing to the ICH Secretariat. The ICH Secretariat, 
which coordinates the preparation of documentation, operates as an 
international nonprofit organization and is funded by the Members of 
the ICH Association.
    The ICH Assembly is the overarching body of the Association and 
includes representatives from each of the ICH members and observers. 
The Assembly is responsible for the endorsement of draft guidelines and 
adoption of final guidelines. FDA publishes ICH guidelines as FDA 
guidance.
    In the Federal Register of September 28, 2015 (80 FR 58261), FDA 
published a notice announcing the availability of a draft guidance 
entitled ``M7(R1)

[[Page 11212]]

Addendum to ICH M7; Assessment and Control of DNA Reactive (Mutagenic) 
Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk,'' 
available at https://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf. The notice gave interested persons an opportunity to submit 
comments by November 27, 2015.
    After consideration of the comments received and revisions to the 
guideline, a final draft of the guideline was submitted to the ICH 
Assembly and endorsed by the regulatory Agencies in June 2017.
    This final guidance provides guidance on acceptable intake limits 
derived for some chemicals that are considered to be mutagenic 
carcinogens and are also commonly used in the synthesis of 
pharmaceuticals or are useful examples to illustrate the principles for 
deriving compound-specific intakes described in the ICH M7 guidance. 
This guidance is intended to provide guidance for new drug substances 
and new drug products during their clinical development and subsequent 
applications for marketing. The default method from ICH M7 of linear 
extrapolation from the cancer potency estimate, TD50 is used 
as the primary method to derive the acceptable intakes for carcinogens 
with likely mutagenic mode of action. After consideration of the 
comments received, hydroxylamine monograph was deleted from the final 
guidance. Relevant editorial changes were also made to improve clarity 
and to incorporate the ICH M7(R1) Addendum guidance.
    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: 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. This guidance is not subject to Executive Order 12866.

II. Electronic Access

    Persons with access to the internet may obtain the guidance at 
https://www.regulations.gov, https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm, or 
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

    Dated: March 8, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018-05118 Filed 3-13-18; 8:45 am]
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