[Federal Register Volume 89, Number 172 (Thursday, September 5, 2024)]
[Notices]
[Pages 72408-72410]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2024-19883]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2020-D-1530]
Control of Nitrosamine Impurities in Human Drugs; 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 final guidance for industry entitled ``Control of
Nitrosamine Impurities in Human Drugs.'' This guidance recommends steps
manufacturers of active pharmaceutical ingredients (APIs) and drug
products should take to detect and prevent unacceptable levels of
nitrosamine impurities in pharmaceutical products. The guidance
describes two general structural classes of nitrosamine impurities:
small-molecule nitrosamine impurities (i.e., nitrosamine impurities
that do not share structural similarity to the API), and nitrosamine
drug substance-related impurities (NDSRIs), which share structural
similarity to the API and are generally unique to each API. The
potential root causes of small-molecule nitrosamine impurities and
NDSRI formation, detection of nitrosamine impurities, and
recommendations for risk assessments, testing, and implementation of
controls and other appropriate strategies to prevent or reduce the
presence of small-molecule nitrosamine impurities and NDSRIs are
provided. This guidance revises the final guidance of the same name
issued on February 24, 2021.
DATES: The announcement of the guidance is published in the Federal
Register on September 5, 2024.
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.''
[[Page 72409]]
Instructions: All submissions received must include the Docket No.
FDA-2020-D-1530 for ``Control of Nitrosamine Impurities in Human Drugs;
Guidance for Industry; Availability.'' 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. 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: Susan Zuk, Center for Drug Evaluation
and Research, Food and Drug Administration, 10903 New Hampshire Ave.,
Bldg. 75, Rm. 6684, Silver Spring, MD 20993-0002, 240-402-9133,
[email protected].
SUPPLEMENTARY INFORMATION:
I. Background
FDA is announcing the availability of a guidance for industry
entitled ``Control of Nitrosamine Impurities in Human Drugs.'' FDA is
issuing this guidance consistent with its good guidance practices (GGP)
regulation (Sec. 10.115 (21 CFR 10.115)). FDA is implementing this
guidance without prior public comment because it has determined that
prior public participation is not feasible or appropriate (see section
701(h)(1)(C)(i) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C.
371(h)(1)(C)(i)) and Sec. 10.115(g)(2)). FDA made this determination
because of the importance of providing timely information to
manufacturers and applicants regarding nitrosamine impurities, and the
resulting recommendations to conduct risk assessments, testing, and
other appropriate actions to prevent or reduce the presence of
nitrosamine impurities, including NDSRIs, in APIs and drug products.
Although this guidance document is immediately in effect, it remains
subject to comment in accordance with FDA's GGP regulation. This
guidance recommends steps manufacturers of APIs and drug products
should take to detect and prevent unacceptable levels of nitrosamine
impurities in pharmaceutical products. The guidance also describes
conditions that may introduce nitrosamine impurities. The unexpected
finding of nitrosamine impurities, which are possible and probable
human carcinogens, in certain drug products has made clear the need for
a risk assessment strategy for potential nitrosamines in any
pharmaceutical product at risk for their presence.
This guidance revises the final guidance of the same title issued
on February 24, 2021. The following changes were made to the guidance:
The guidance describes two general structural classes of
nitrosamine impurities: small-molecule nitrosamine impurities (i.e.,
nitrosamine impurities that do not share structural similarity to the
API), and NDSRIs, which share structural similarity to the API and are
generally unique to each API. NDSRIs are also addressed in the guidance
for industry entitled ``Recommended Acceptable Intake Limits for
Nitrosamine Drug Substance-Related Impurities (NDSRIs),'' available at
https://www.fda.gov/media/170794/download. This revision provides
additional information on potential root causes of NDSRI formation,
controls, and mitigation strategies to prevent or reduce the presence
of NDSRIs. This guidance recommends mitigation strategies to reduce or
eliminate nitrosamine impurities, and includes new recommendations for
stability data and bioequivalence studies to support approval of drug
products reformulated using such strategies.
The guidance provides new recommendations for
implementation of nitrosamine impurity control strategies. The guidance
clarifies how manufacturers should assess test results to determine
whether specifications for nitrosamine impurities are warranted, and
provides recommendations for how to report revised specifications, when
and how to contact the Agency, and recommended alternative approaches
to establishing total nitrosamine impurity limits.
This guidance provides a recommended timeline for
implementation of the recommendations described within. FDA notes that
manufacturers and applicants should have completed the 3-step process
for evaluating small molecule nitrosamines in their drug products by
October 1, 2023. In addition, due to the more recent discovery of NDSRI
impurities, FDA recommends conclusion of confirmatory testing of drug
products and submission of changes for approved applications that may
have NDSRIs by August 1, 2025.
To reflect the evolving and highly technical nature of the
relevant information, FDA intends to provide certain information in an
incorporated web page that will be updated, as appropriate, to provide
current information in connection with this guidance, including
recommended acceptable intake limits, emerging scientific and technical
issues, recommended analytical methods for confirmatory testing of
certain nitrosamine impurities, recommended safety testing methods for
nitrosamine impurities, and recommended timelines for implementing the
mitigation recommendations.
[[Page 72410]]
This guidance represents FDA's current thinking on ``Control of
Nitrosamine Impurities in Human Drugs.'' 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
the Office of Management and Budget (OMB) under the Paperwork Reduction
Act of 1995 (PRA) (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, including meetings at the ``pre-
NDA'' stage, have been approved under OMB control number 0910-0014. The
collections of information in 21 CFR part 314 pertaining to new drug
applications, abbreviated new drug applications, amendments and
supplemental applications, and formal meetings with FDA about drug
development programs have been approved under OMB control number 0910-
0001. The collections of information in 21 CFR part 601 pertaining to
biologics license applications have been approved under OMB control
number 0910-0338. The collections of information pertaining to over-
the-counter monograph drug products have been approved under OMB
control number 0910-0340. The collections of information pertaining to
meetings related to generic drug development, including controlled
correspondences, have been approved under OMB control number 0910-0727.
III. Electronic Access
Persons with access to the internet may obtain the guidance 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 29, 2024.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2024-19883 Filed 9-4-24; 8:45 am]
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