[Federal Register Volume 88, Number 150 (Monday, August 7, 2023)]
[Notices]
[Pages 52183-52185]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2023-16814]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2020-D-1530]
Recommended Acceptable Intake Limits for Nitrosamine Drug
Substance-Related Impurities; 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, Agency, or we) is
announcing the availability of a final guidance for industry entitled
``Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-
Related Impurities (NDSRIs).'' This guidance provides applicants and
manufacturers of drugs, including prescription and over-the-counter
(OTC) drug products, with a recommended framework for predicting the
mutagenic and carcinogenic potential of NDSRIs that could be present in
drug products and recommends acceptable intake (AI) limits for NDSRIs.
NDSRIs, which are a subcategory of nitrosamine impurities that share
structural similarity to the active pharmaceutical ingredient (API) in
drug products, typically lack compound-specific mutagenicity and
carcinogenicity data to inform safety assessments. This guidance
provides a recommended methodology for AI determination that uses
structural features of NDSRIs to generate a predicted carcinogenic
potency categorization and corresponding recommended AI limit that
manufacturers and applicants can apply, in the absence of other FDA-
recommended AI limits, in their evaluation of potential impurities in
their drug products.
DATES: The announcement of the guidance is published in the Federal
Register on August 7, 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-2020-D-1530 for ``Recommended Acceptable Intake Limits for
Nitrosamine Drug Substance-Related Impurities (NDSRIs).'' 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
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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 the guidance to the
Division of Drug Information, Center for Drug Evaluation and Research,
Food and Drug Administration, 10001 New Hampshire Ave., Hillandale
Bldg., 4th Floor, 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
guidance document.
FOR FURTHER INFORMATION CONTACT: Jason Bunting, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 6366, Silver Spring, MD 20993-0002, 301-
796-1292.
SUPPLEMENTARY INFORMATION:
I. Background
FDA is announcing the availability of a guidance for industry
entitled ``Recommended Acceptable Intake Limits for Nitrosamine Drug
Substance-Related Impurities (NDSRIs).'' FDA is implementing this
guidance without prior public comment because we have determined that
prior public participation is not feasible or appropriate (Sec.
10.115(g)(2)). FDA made this determination because of the importance of
providing additional timely information to manufacturers and applicants
regarding recommended AI limits of NDSRIs, a class of nitrosamine
impurities that has been identified in many drug products and also
could be present in APIs. This guidance applies to drugs, including
prescription and OTC drug products that are the subject of an approved
or pending new drug application (NDA) or abbreviated new drug
application (ANDA), as well as products \1\ not marketed under a drug
application, including nonprescription drugs subject to section 505G
(21 U.S.C. 355h) of the Federal Food, Drug, and Cosmetic Act (FD&C Act)
(i.e., OTC monograph drugs) or are otherwise subject to current good
manufacturing practice. This guidance also applies to prescription and
OTC drug products in clinical development. In addition, this guidance
applies to certain biological products that contain chemically
synthesized fragments or biologic-led combination products that contain
a drug constituent part whether such products are in development or the
subject of an approved or pending biologics license application (BLA).
The recommendations in this guidance apply to both drug product and
drug substance manufacturers.
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\1\ For the purposes of this guidance, we use the term ``drug''
or ``drug product'' to refer to human drug and biological products,
including drug-led and biologic-led combination products, regulated
by the Center for Drug Evaluation and Research, unless otherwise
specified.
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This guidance provides manufacturers and applicants of drugs with a
recommended framework for predicting the mutagenic and carcinogenic
potential of NDSRIs that could be present in drug products and
recommends AI limits for NDSRIs. This approach will assist
manufacturers and applicants in taking steps to detect and prevent
unacceptable levels of nitrosamine impurities in drug products.
Although this guidance document is immediately in effect, it remains
subject to comment in accordance with FDA's good guidance practices
regulation (Sec. 10.115(g)(3)(D)).
Nitrosamine compounds have the potential to be potent genotoxic
agents in several animal species, and some are classified as probable
or possible human carcinogens. Nitrosamines are included in a group of
high potency mutagenic carcinogens referred to as ``cohort of concern''
compounds in the International Council for Harmonisation (ICH) guidance
for industry entitled ``M7(R1) Assessment and Control of DNA Reactive
(Mutagenic) Impurities in Pharmaceuticals To Limit Potential
Carcinogenic Risk'' (March 2018). In 2020, FDA published a guidance for
industry, ``Control of Nitrosamine Impurities in Human Drugs,'' (85 FR
55017, September 3, 2020) (Nitrosamine Guidance), recommending that
manufacturers of APIs and drug products take steps to detect and
prevent unacceptable levels of nitrosamine impurities in drug products,
or avoid their presence when feasible, and updated the guidance on
February 24, 2021.
NDSRIs are a class of nitrosamines sharing structural similarity to
the API, and thus, differ in certain respects from small molecule
nitrosamine impurities specified in the Nitrosamine Guidance. NDSRIs
are unique to each API and are generally formed in a drug product
through nitrosation of APIs (or API fragments) that have secondary or
tertiary amines when exposed to nitrosating agents such as residual
nitrites in excipients used to formulate the drug product. NDSRIs that
have been recently identified in a number of drug products generally
lack carcinogenicity and mutagenicity data (typically from animal
studies) from which an AI can be determined. Based on the chemical
structure of certain drugs, there is a risk of NDSRIs forming in a
substantial number of drug products; however, it is currently unknown
if all or some NDSRIs are in fact high-potency mutagenic carcinogens.
It is challenging to establish an AI limit for NDSRIs because of the
lack of available mutagenicity data and robust carcinogenicity data
from which applicants would otherwise determine AI limits. These
challenges have led to some applicants and manufacturers conducting
unnecessary studies or, in some cases, discontinuing drug products from
the market.
FDA is recommending a predicted carcinogenic potency categorization
method that assigns a recommended AI limit to an NDSRI based on the
NDSRI's activating and deactivating structural features. Predicted
carcinogenic potency categories enable manufacturers to determine
recommended AI limits for NDSRIs in APIs and drug products and to
facilitate development of methods for confirmatory testing. Potency
categorization offers a scientifically based predictive solution to
recommending AI limits for data-poor NDSRIs, for which suitable
surrogates with robust carcinogenicity data are not available.
The recommendations in this guidance provide a risk-based safety
assessment of NDSRIs and can be used by applicants and manufacturers to
identify AI limits for NDSRIs in their drug products and APIs in
conjunction with the recommendations in the Nitrosamine Guidance. If
FDA communicates another FDA-recommended AI limit for a specific NDSRI,
manufacturers and applicants should apply that recommended AI
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limit rather than the AI limit recommended in this guidance based on
predicted carcinogenic potency. In general, FDA would expect
manufacturers and applicants to control impurities within the
recommended AI limit. Additionally, manufacturers and applicants should
continue to pursue mitigation efforts to reduce or remove NDSRIs in
their drug products.
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 ``Recommended Acceptable Intake Limits for
Nitrosamine Drug Substance-Related Impurities (NDSRIs).'' 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 this guidance contains no collection of information, it does
refer to previously approved FDA collections of information. The
previously approved collections of information are subject to review by
Office of Management and Budget (OMB) under the Paperwork Reduction Act
of 1995 (44 U.S.C. 3501-3521). The collections of information in 21 CFR
parts 210 and 211 pertaining to current good manufacturing practice
have been approved under OMB control number 0910-0139. The collections
of information in 21 CFR part 312 pertaining to investigational new
drug applications have been approved under OMB control number 0910-
0014. The collections of information in 21 CFR part 314 pertaining to
NDAs and ANDAs have been approved under OMB control number 0910-0001.
The collections of information in 21 CFR part 601 pertaining to BLAs
have been approved under OMB control number 0910-0338. The collections
of information in 21 CFR part 201 pertaining to OTC monograph drug
products have been approved under OMB control number 0910-0340.
III. Electronic Access
Persons with access to the internet may obtain the document at
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs, https://www.fda.gov/regulatory-information/search-fda-guidance-documents, or https://www.regulations.gov.
Dated: August 2, 2023.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2023-16814 Filed 8-4-23; 8:45 am]
BILLING CODE 4164-01-P