[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]
BILLING CODE 4164-01-P