Document ID: FDA-2020-D-1530-0031
Agency: fda
Document Type: Notice
Title: Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities; Guidance for Industry; Availability
Posted Date: 2023-08-07T04:00Z

[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

[[Page 52184]]

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

[[Page 52185]]

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