Document ID: FDA-2023-N-1585-0001
Agency: fda
Document Type: Notice
Title: Identification, Assessment, and Control of Nitrosamine Drug Substance-Related Impurities in Human Drug Products; Establishment of a Public Docket; Request for Comments
Posted Date: 2023-05-04T04:00Z

[Federal Register Volume 88, Number 86 (Thursday, May 4, 2023)]
[Notices]
[Pages 28557-28562]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2023-09526]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2023-N-1585]

Identification, Assessment, and Control of Nitrosamine Drug 
Substance-Related Impurities in Human Drug Products; Establishment of a 
Public Docket; Request for Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice; establishment of a public docket; request for comments.

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SUMMARY: The Food and Drug Administration (FDA, Agency, or we) is 
announcing the establishment of a docket to solicit public comments on 
the identification, assessment, and control of N-nitrosamine 
(nitrosamine) drug substance-related impurities (NDSRIs) that may be 
considered by the Agency in its regulation of these types of impurities 
in drug products. This notice identifies scientific and regulatory 
considerations regarding the identification, assessment, and control of 
NDSRIs, including areas that may benefit from collaborative efforts, 
and requests comments on these topics. This notice is not intended to 
communicate FDA's regulatory expectations on these issues but is 
instead intended to seek input from the public to inform scientific 
and/or regulatory approaches as appropriate.

DATES: Either electronic or written comments must be submitted by July 
3, 2023.

ADDRESSES: You may submit comments as follows. Please note that late,

[[Page 28558]]

untimely filed comments will not be considered. The https://www.regulations.gov electronic filing system will accept comments until 
11:59 p.m. Eastern Time at the end of July 3, 2023. Comments received 
by mail/hand delivery/courier (for written/paper submissions) will be 
considered timely if they are received on or before that date.

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-FDA-2023-N-1585 for ``Identification, Assessment, and Control of 
Nitrosamine Drug Substance-Related Impurities in Human Drug Products; 
Establishment of a Public Docket; Request for Comments.'' Received 
comments, those filed in a timely manner (see ADDRESSES), 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.

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, [email protected].

SUPPLEMENTARY INFORMATION:

I. Background

A. Nitrosamines, Including NDSRIs, in Human Drug Products

    FDA has been investigating the presence of nitrosamine impurities 
in certain drug products since June 2018. Nitrosamines are common in 
water and foods, including cured and grilled meats, dairy products, and 
vegetables. Nitrosamines may increase the risk of cancer if people are 
exposed to them above acceptable levels. The acceptable intake (AI) 
limit is a level that approximates an increased cancer risk of one 
additional case in 100,000 people based on a conservative assumption of 
daily exposure to the impurity or impurities over a lifetime (70 years) 
(See FDA guidance for industry ``Control of Nitrosamine Impurities in 
Human Drug Drugs'' (Nitrosamine Guidance) at 10, available at https://www.fda.gov/media/141720/download (Ref. 3).
    When FDA was informed of the presence of an impurity identified as 
N-nitrosodimethylamine (NDMA) in valsartan, an angiotensin II receptor 
blocker (ARB), it began an investigation in which it determined that 
numerous lots of valsartan and a few other ARB drug products from 
different manufacturers contained unacceptable levels of nitrosamines. 
The drug product manufacturers voluntarily recalled the affected 
batches of these drug products, which led to a drug shortage in some of 
the affected products. In addition, FDA evaluated processes used in 
synthesis of the active pharmaceutical ingredient (API) and learned 
that common synthetic pathways could also introduce other types of 
nitrosamine impurities besides NDMA. FDA has continued to learn of the 
existence of nitrosamine impurities such as NDMA in drug products in 
several drug classes (see Ref. 3 at 2-3).
    FDA originally published the Nitrosamine Guidance on September 3, 
2020 (85 FR 55017), and updated the guidance on February 24, 2021 (Ref. 
3). The guidance provides recommendations for industry regarding 
nitrosamines, and NDSRIs are a subcategory of these impurities that 
share structural similarity with the active pharmaceutical ingredient 
in drug products. In the Nitrosamine Guidance, FDA recommends 
manufacturers of APIs and drug products should take steps to detect and 
prevent unacceptable levels of nitrosamine impurities in drug products, 
or avoid their presence when feasible.\1\ Specifically, FDA

[[Page 28559]]

recommends a three-step process that manufacturers should take to 
mitigate nitrosamine impurities in their products: (1) conduct risk 
assessments for nitrosamines in their products; (2) conduct 
confirmatory testing if risks are identified; and (3) report changes 
implemented to prevent or reduce the presence of nitrosamine impurities 
in drug products in approved and pending new drug applications (NDAs) 
and abbreviated new drug applications (ANDAs). The Nitrosamine Guidance 
describes some conditions that may introduce or create nitrosamine 
impurities (a nitrosating reaction between secondary, tertiary, or 
quaternary amines and nitrous acid (nitrite salts under acidic 
conditions)) and provides FDA-recommended AI limits for six nitrosamine 
impurities that could be present in drug products (see Ref. 3 at 10).
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    \1\ The Nitrosamine Guidance notes that new drug application 
(NDA) and abbreviated new drug application (ANDA) holders or 
applicants, drug master file holders, and owners of marketed 
products that are not the subject of approved NDAs or ANDAs (such as 
compounded products or products marketed under an over-the-counter 
drug monograph) who are not also the manufacturer of the drug 
products and APIs should work with their contract manufacturers to 
take the steps recommended in the Nitrosamine Guidance. This applies 
to drug products currently available on the U.S. market as well as 
those with pending applications. See Ref. 3 at 1, footnote 3. 
Holders of biologics license applications for biological products 
that contain chemically synthesized fragments or biologic-led 
combination products that contain a drug constituent part also may 
be affected.
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    More recently, and often in response to the risk assessment 
recommended in the Nitrosamine Guidance, FDA has received an increasing 
number of reports of certain types of nitrosamine impurities that have 
formed in drug products across multiple drug classes. These NDSRIs are 
a class of nitrosamines sharing structural similarity to the API, and 
thus, differ in certain respects from small molecule nitrosamine 
impurities (i.e., nitrosamine impurities that do not share structural 
similarity to the API, and are therefore, not considered NDSRIs) 
identified in the Nitrosamine Guidance (see Ref. 3 at 10). NDSRIs can 
be generated during manufacturing, or during the shelf-life storage 
period of the drug product. They can also be generated during the 
synthesis of the drug substance. In some cases, the root cause of NDSRI 
formation has been attributed to nitrite impurities present in 
excipients at parts-per-million amounts. Nitrite impurities have been 
observed in a range of commonly used excipients (as well as water) and 
may lead to the formation of NDSRIs in certain drug products. In 
general, there is a risk of generating nitrosamine impurities when 
nitrites are in the presence of secondary, tertiary, or quaternary 
amines. Secondary or tertiary amines are known to be part of the 
chemical structure of several hundred APIs. Accordingly, depending on 
the formulation and manufacturing process for the drug product, as well 
as ongoing oversight of the quality of materials produced by suppliers, 
there may be a risk of nitrosamine formation in a substantial number of 
drug products.
    In November 2021, FDA alerted the public regarding the presence of 
NDSRIs and indicated that manufacturers could ascertain the presence of 
NDSRIs using the same three-step process identified in the Nitrosamine 
Guidance (Ref. 4). As discussed further below, FDA also conveyed 
possible mitigation strategies, and encouraged applicants to develop 
control strategies or design approaches to reduce NDSRIs to acceptable 
levels or eliminate them (where feasible).
    NDSRIs present unique scientific and regulatory challenges for FDA 
because each NDSRI is unique to the API, and there is limited compound-
specific data that is available to inform safety assessments. 
Additionally, design of validated test methods for identification of 
NDSRIs and modification of existing test methods for assessment of 
their mutagenic potential may raise novel scientific considerations.

B. Safety Assessments of the Potential for Mutagenic and Carcinogenic 
Risk

    In the Nitrosamine Guidance, FDA recognizes that nitrosamine 
compounds are potent genotoxic agents in several animal species, and 
some have been classified as probable or possible human carcinogens by 
the World Health Organization's International Agency for Research on 
Cancer (see Ref. 3 at 5). The framework for identifying, categorizing, 
qualifying and controlling DNA reactive (mutagenic) impurities to limit 
potential carcinogenic risk is provided in FDA and International 
Council for Harmonisation guidance for industry entitled ``M7(R1) 
Assessment and Control of DNA Reactive (Mutagenic) Impurities in 
Pharmaceuticals To Limit Potential Carcinogenic Risk'' (ICH M7(R1) 
Guidance), available at https://www.fda.gov/media/85885/download (Ref. 
5). (The ICH M7(R1) Guidance was prepared under the auspices of the 
ICH). Nitrosamines as a structural group are referred to as ``cohort of 
concern'' compounds in the ICH M7(R1) Guidance because of their 
classification as high-potency mutagenic carcinogens. It is currently 
unknown if all or some NDSRIs are associated with this classification.
    The ICH M7(R1) Guidance provides guidance to derive AI limits for 
some chemicals that are considered 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 otherwise described in the ICH M7(R1) Guidance (see the Federal 
Register notice issued March 14, 2018 (83 FR 11210). Specifically, the 
ICH M7(R1) Guidance recommends applicants use a hazard assessment, 
which involves an initial analysis of actual and potential impurities 
by conducting database and literature searches for carcinogenicity and 
bacterial mutagenicity data, to classify impurities into one of five 
classes and proposes action for control based on the resulting class 
(with Class 1 being known mutagenic carcinogens and Class 5 being 
impurities with no structural alerts,\2\ or alerting structure with 
sufficient data to demonstrate lack of mutagenicity or carcinogenicity) 
(see Ref. 5 at 10). If data are not available for such a 
classification, a computational toxicology assessment should be 
conducted using two (quantitative) structure-activity relationship 
((Q)SAR) methodologies that can predict the outcome of a bacterial 
mutagenicity test (see Ref. 5 at 9-10). In the ICH M7(R1) Guidance, FDA 
recommends that impurities for each class be controlled at specified 
limits; for example, it recommends Class 1 impurities be controlled at 
or below compound-specific acceptable limits, and Class 5 impurities be 
controlled as non-mutagenic impurities (see Ref. 5 at 10).
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    \2\ The ICH M7(R1) Guidance defines a structural alert in the 
context of the guidance as ``a chemical grouping or molecular (sub) 
structure which is associated with mutagenicity'' (Ref. 5 at 129).
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1. Assessment of Potential Mutagenicity and Carcinogenicity
    FDA typically requests that applicants assess the potential for an 
impurity to be mutagenic by conducting a standard in vitro bacterial 
reverse mutation test (Ames test). If this in vitro mutagenicity 
testing is negative for a nitrosamine impurity, FDA has requested 
further testing because standard methods used for the Ames test may not 
be adequate to characterize the mutagenic potential of nitrosamines, in 
some cases producing negative results with known mutagenic 
nitrosamines. Information in published scientific literature suggests 
that some Ames tests (e.g., those conducted with rat S9) may not be 
sensitive enough to assess the mutagenicity of nitrosamine compounds 
because of species-specific differences in metabolic activation of 
potential mutagens. Additionally, there is limited experience on the 
sensitivity of these tests for NDSRIs, which are more complex 
structures than the more commonly identified nitrosamines in the 
Nitrosamine Guidance. Therefore, FDA's National Center for 
Toxicological Research has been testing different conditions to develop 
an enhanced

[[Page 28560]]

Ames test that is intended to provide a more reliable assessment of 
potential mutagenicity in small molecule nitrosamine impurities and 
NDSRIs.
    In some circumstances in which the results of an enhanced Ames test 
are negative, the mutagenic potential of the impurity was further 
assessed in an in vivo transgenic gene mutation test to confirm the in 
vitro findings. If further in vivo testing is to be conducted, the 
selection of the in vivo mutagenicity tests should be scientifically 
justified based on knowledge of the mechanism of action of the impurity 
and expected target tissue exposure (see Ref. 5 at 11 and at (Note 3) 
21-22). To avoid potentially duplicative nonclinical in vitro or in 
vivo testing of NDSRIs by manufacturers of drug products containing the 
drug substance, FDA is interested in exploring the feasibility of 
collaborative efforts among applicants and manufacturers of affected 
drug products.
2. Computational Toxicology
    In general, (Q)SAR models are accepted as a scientific tool for 
predicting and classifying the biological activities of untested 
chemicals. A computational toxicology assessment using (Q)SAR 
methodologies can predict, with acceptable confidence, the outcome of 
an Ames test by using two complementary, validated modeling 
methodologies (statistical-based and expert rule-based) and can be used 
to classify an impurity as mutagenic or non-mutagenic (see Ref. 5 at 
10). The methodology uses statistical and/or manual approaches to 
correlate and rationalize variations in the biological activity of a 
series of chemicals with variations in their molecular structures, 
which are often represented by a set of quantities commonly known as 
``structural descriptors.'' Because (Q)SAR models can generate a 
prediction of a chemical's biological activity from structural 
descriptors more rapidly than in vitro or in vivo testing can be 
conducted, they provide a means to efficiently assess nitrosamine 
toxicity when experimental data are unavailable. However, the 
predictive performance of (Q)SAR models depends on many factors, 
particularly on the quality of biological training data, descriptor 
selection, and modeling algorithm. Therefore, FDA has been working with 
model developers and stakeholders to advance predictive toxicology, 
with a focus on the use of (Q)SAR methodologies in assessing potential 
mutagenicity and carcinogenicity of NDSRIs.
3. Determining AI Limits for NDSRIs
    A recommended AI limit is based on a safety assessment that 
includes evaluation of the mutagenic and carcinogenic potential of the 
impurity and represents the level at or below which FDA has determined 
that the impurity or impurities would not pose a safety concern for 
patients taking the drug product. The AI limit is a level that 
approximates an increased cancer risk of 1:100,000 based on a 
conservative assumption of daily exposure to the impurity or impurities 
over a lifetime (70 years) (see Ref. 3 at 10 and Appendix B ``FDA 
Determination of Acceptable Intake Limits''). The AI limit is generally 
described in nanograms per day, and each applicant establishes 
specifications to control for the level of impurity or impurities in 
their drug products (in parts per million) based on the maximum daily 
dose of the drug product under the labeled conditions of use. Once a 
recommended AI limit has been established, applicants and manufacturers 
would generally be expected to control impurities within the 
recommended AI limit (see Ref. 3 at 14, 15). Applicants or 
manufacturers should contact FDA regarding drug products with 
unacceptable levels of nitrosamine impurities that are already in 
distribution (see Ref. 3 at 14, 15). Additionally, applicants and 
manufacturers may need to modify the manufacturing processes or 
reformulate their drug products to control impurities within the 
recommended AI limit \3\ or submit additional testing to FDA that would 
demonstrate the applicant's proposed limit is safe.\4\
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    \3\ For recommendations to API manufacturers and drug 
manufacturers see Ref. 3 at 11-15.
    \4\ See, e.g., generally Ref. 5, which provides a framework for 
the identification, categorization, qualification, and control of 
mutagenic impurities to limit potential carcinogenic risk, at 4 and 
``Table 1: Impurities Classification With Respect to Mutagenic and 
Carcinogenic Potential and Resulting Control Actions,'' at 10. The 
guidance further explains that if an impurity has a positive 
bacterial mutagenicity result and cannot be controlled at an 
appropriate acceptable limit, then it may be recommended that the 
impurity be tested in an in vivo gene mutation assay, which may 
support recommending a compound-specific impurity limit (see Ref. 5 
at 11).
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    Calculating a recommended AI limit for NDSRIs is often more 
challenging than calculating recommended AI limits for small molecule 
nitrosamines, primarily because NDSRIs are unique to each API and there 
is usually limited or no existing safety data (e.g., rodent 
carcinogenicity data) on NDSRIs (see also Ref. 5 at 12 and note 4 on 
calculating a compound-specific AI limit). FDA has published 
recommended AI limits for a limited number of NDSRIs, but unlike more 
commonly known nitrosamines (such as those identified in the 
Nitrosamine Guidance), a recommended AI limit has not yet been 
determined for most NDSRIs.
    If mutagenic potential is identified through toxicological testing 
or computational toxicology models, FDA and applicants have used (Q)SAR 
methods to identify and select a data-rich surrogate that is similar in 
structure and reactivity to the data-poor NDSRI to generate an estimate 
of carcinogenic potency from which an AI limit can be determined. In 
this scenario, surrogates are compounds containing an N-nitroso 
structural alert in the same chemical environment as an NDSRI and for 
which robust carcinogenicity data are available (see Ref. 5 at 11-12). 
The rationale for the choice of surrogate (similar in structure and 
reactivity) is significant because test data from the identified 
surrogate is then used to generate an estimate, either quantitatively 
or qualitatively, for the data-poor compound (commonly referred to as a 
``read-across analysis'').
    The nitrosamine structural alert environment is an important factor 
when selecting appropriate reference compounds for a read-across 
analysis and may include consideration of the degree of substitution, 
steric bulk, electronic influences, potential for metabolic activation, 
stability/reactivity of the resulting metabolites, and overall 
molecular weight. Additionally, the quality of carcinogenicity studies 
in the published scientific literature can be quite variable; however, 
use of less robust data can sometimes be considered acceptable when no 
more complete data exist, given the highly conservative nature of the 
risk assessment (see Ref. 5 at 36).

C. FDA's Ongoing Work on Nitrosamine Risk Assessment and Mitigation

    Since the issuance of the Nitrosamine Guidance, FDA has continued 
to work to better understand the root causes of nitrosamines, develop 
mitigation strategies that can eliminate or minimize the presence of 
nitrosamines in drug products, and improve approaches to risk 
assessment (mutagenicity and carcinogenicity) of NDSRIs in drug 
substances and drug products that can inform recommended AI limits.
    As FDA learned more about NDSRI formation and received increasing 
numbers of reports from industry on the presence of NDSRIs, the Agency 
identified on its web page two examples of mitigation strategies 
related to formulation design to assist

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manufacturers in reducing the levels of NDSRIs in drug products. One 
mitigation strategy was derived from published literature reports that 
demonstrated that commonly used antioxidants, such as ascorbic acid 
(vitamin C) or alpha-tocopherol (vitamin E), inhibit the formation of 
nitrosamines in vivo, based on data from human gastric fluid in vitro 
studies (see Ref. 4). FDA advised that recent work preliminarily 
demonstrated that the addition of these antioxidants to formulations 
may significantly inhibit the formation of NDSRIs in drug products. FDA 
also presented a second possible mitigation strategy related to 
formulation design based on the fact that the formation of nitrosamines 
typically occurs under acidic conditions, whereas, in a neutral or 
basic environment, the kinetics of these reactions are significantly 
reduced (Ref. 4). FDA has encouraged manufacturers to consider these as 
well as other innovative strategies to reduce the formation of NDSRIs 
to acceptable levels in drug products.

D. Regulatory Challenges

    The identification of a new impurity, such as an NDSRI, may have 
implications for a cohort of pending or approved NDAs (including 
applications submitted pursuant to section 505(b)(2) of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 355(b)(2))) and ANDAs and also 
creates unique challenges from a regulatory perspective. For example, a 
generic drug applicant typically may qualify the level of an impurity 
that does not have a limit in an applicable U.S. Pharmacopeia monograph 
or that does not otherwise have a recommended AI limit (e.g., as 
described in applicable guidance) by comparing its proposed product to 
the observed amounts of the impurity in the previously approved drug 
product (the reference listed drug) on which it relies for approval 
(see Refs. 1 and 2). This approach reflects that identification and 
evaluation of certain impurities to establish the biological safety of 
the impurity at the level(s) present in the API or drug product 
typically occurs before approval of the NDA for the reference listed 
drug, and subsequently, ANDA applicants can conduct comparative testing 
of their products and the reference listed drug to qualify impurities. 
However, challenges arise when each applicant in a cohort of pending or 
approved NDAs (including section 505(b)(2) applications) and ANDAs 
concurrently conducts risk assessments for the presence of an NDSRI in 
their drug products and, if present, develops data to support an AI 
limit and specifications for controlling the impurity in their drug 
products.
    Moreover, information on impurities in drug products that may 
reveal an aspect of an applicant's manufacturing method or process 
generally has been protected from public disclosure, unless such 
information has been previously disclosed by the applicant or is 
otherwise publicly available. Thus, FDA may be limited in the impurity 
information that it can disclose to facilitate efficient evaluation of 
other products and to inform applicants of actions they can take to 
mitigate nitrosamine risk. In addition, there are considerations that 
may constrain FDA's ability to disclose certain information provided by 
an applicant in FDA's evaluation of other applicants' submissions to 
FDA, which can lead to potentially duplicative nonclinical tests (which 
may include animal testing) to characterize the risk and inform a 
recommended AI limit. This can be a significant concern when a newly 
identified NDSRI may have implications for a cohort of pending or 
approved marketing applications. For example, there are circumstances 
in which potential constraints regarding disclosure could hamper FDA's 
ability to quickly and publicly identify a compound-specific 
recommended AI limit for an NDSRI that may be applicable to all drug 
products that contain the API. Potential constraints related to 
disclosure of certain information regarding impurities could also lead 
to delays in providing applicants, including follow-on and generic drug 
products, with information to develop drug products with acceptable 
impurity profiles. Additionally, uncertainty about the presence and/or 
acceptability of the level of an impurity raises additional regulatory 
challenges and could lead to some applicants conducting unnecessary 
studies or even discontinuing drug products from the market, 
potentially resulting in drug shortages. These difficulties can impact 
patient access to medications, including drugs that are considered 
medically necessary.
    To avoid these potential issues, at times, FDA generates and makes 
publicly available information or research to support the development 
of recommended AI limits by conducting additional studies, developing 
enhanced Ames testing, or using (Q)SAR methodology to identify 
appropriate surrogates from which read-across can be used to estimate 
carcinogenic potency. Applicants can use this FDA-generated information 
to set individual drug product specifications. The absence of publicly 
available data to support a recommended AI limit for an NDSRI can 
result in potentially duplicative studies to support a recommended AI 
limit. Moreover, if in vivo animal studies are necessary to assess the 
risk of a particular NDSRI, such potentially duplicative testing may 
not align with FDA's policy to replace, reduce, and refine the use of 
animals for safety testing (the 3R principles), where possible (see, 
e.g., Ref. 6 at 1).

E. Collaborative Efforts To Develop NDSRI Data

    FDA has encouraged collaborative efforts by applicants and other 
stakeholders, together with the Agency as appropriate, to help address 
the challenges presented by NDSRIs. FDA also has collaborated with 
international regulatory agencies through the Nitrosamines 
International Strategic Group and the Nitrosamines International 
Technical Working Group, which were formed to share scientific 
knowledge and current thinking on technical safety and quality topics 
related to nitrosamines and to promote technical convergence among 
member jurisdictions, where possible. In other areas, FDA is 
collaborating on multi-laboratory projects being organized by the 
Health and Environmental Sciences Institute's Genetic Toxicology 
Technical Committee that include industry stakeholders and regulatory 
agencies such as Health Canada and European Medicines Agency. 
Additionally, FDA has been actively engaged with model developers and 
stakeholders to advance predictive toxicology with a focus on the use 
of (Q)SAR methodologies in assessing potential mutagenicity and 
carcinogenicity of NDSRIs.
    Development of laboratory test methods to identify NDSRIs is an 
area that could benefit from collaborative efforts. In the Nitrosamine 
Guidance, FDA encourages manufacturers or laboratories to make 
validated test methods publicly available (e.g., by posting on the 
method developer's website) to facilitate faster testing of other 
similar drug products. FDA also accepts requests to post privately 
developed methods on FDA's website if FDA's review of the method 
protocol finds it scientifically sound and if the method owner provides 
written authorization for posting by FDA (see Ref. 3 at 11, footnote 
37). As another example, a positive bacterial mutagenicity result may 
warrant an additional in vivo gene mutation assay, typically a 
transgenic mutation assay, to understand the relevance of the bacterial 
mutagenicity test under in vivo conditions (see Ref. 5 at 11 and (Note 
3)

[[Page 28562]]

(identifying the transgenic mutation assay as appropriate for followup 
for any positive bacterial mutagenicity test as opposed to other tests, 
which are recommended under more limited circumstances). When such in 
vivo testing is warranted, industry collaboration on the testing to 
develop robust data and share results among themselves could enhance 
scientific analyses and could facilitate regulatory decision-making. 
Similarly, we have encouraged applicants to publish scientific research 
and test results to further scientific knowledge on NDSRIs and 
facilitate regulatory decision-making, as appropriate.

II. Issues for Consideration and Request for Comments

    FDA is requesting comments from the public regarding the 
identification, assessment, and control of NDSRIs in drug product 
development and regulatory review to provide interested parties an 
opportunity to comment on scientific and regulatory considerations, 
including areas that may benefit from collaborative efforts. FDA is 
also interested in any challenges preventing industry from identifying, 
assessing, and controlling NDSRIs that may assist FDA in its analysis.
    The questions posed below are not meant to be exhaustive. FDA is 
interested in other pertinent information that stakeholders would like 
to provide on issues and challenges related to addressing NDSRIs. FDA 
is particularly interested in comments on the following topics:

A. General Questions

    1. What additional topics related to the evaluation of nitrosamines 
should be a priority for the Agency to address through guidance 
documents?
    2. What factors should FDA consider in prioritizing its evaluation 
of NDSRIs on a compound-specific basis?
    3. What additional mitigation strategies should be considered for 
reducing NDSRI formation or eliminating these impurities (where 
feasible)?

B. NDSRI Risk Assessment

    1. What scientific and technical factors should FDA consider in 
developing best practices for conducting testing for NDSRIs (e.g., Ames 
test, enhanced Ames test, followup in vitro mutagenicity, in vivo 
transgenic gene mutation test) in support of establishing AI limits?
    a. Are there other tests recommended for assessing mutagenic 
potential of NDSRIs, and how supportable are these methods?
    b. Would ``short-term'' carcinogenicity testing (e.g., 6-month 
transgenic mouse model) be informative to evaluate the risk associated 
with NDSRIs?
    c. If so, what are the advantages and disadvantages to such 
testing?
    d. Are there other types of studies that may further inform FDA 
about the risk associated with NDSRI (e.g., in vitro/in vivo 
metabolism, DNA biomarkers, identification of reactive intermediates)?
    2. FDA recommended in the Nitrosamine Guidance that confirmatory 
testing of drug products and submission of required changes in drug 
applications be concluded on or before October 1, 2023 (see Ref. 3 at 
17). Would an extension of the recommended timeline for submission of 
changes in drug applications as described in the guidance to June 1, 
2024, allow for additional assessment of NDSRIs and enable 
collaborative efforts among affected applicants? How can FDA further 
support manufacturers' efforts toward completion of confirmatory 
testing?

C. Collaborative Efforts To Develop NDSRI Data and Establish and 
Implement Recommended AI Limits

    1. How can FDA facilitate collaborative efforts to generate 
reliable compound-specific data on NDSRIs and reduce the need for 
additional and potentially duplicative testing?
    2. Are there obstacles that industry has encountered when engaging 
in collaborative efforts that could allow companies to share data to 
assess the safety of NDSRIs, particularly with the intent of reducing 
redundant testing and integrating the 3R principles? Such examples of 
collaboration may include enhancing (Q)SAR methods and models, 
conducting in vitro mutagenicity testing and/or in vivo transgenic gene 
mutation tests. If there are such obstacles, are there ways that FDA 
could facilitate collaboration?

D. Establishing and Implementing Recommended AI Limits and Access to 
Medications

    1. In implementing recommendations for controlling nitrosamines, 
including NDSRIs, have manufacturers or suppliers experienced 
difficulties with meeting recommended AI limits that has led to 
discontinuation of manufacturing or distribution?

III. References

    The following references are on display at the Dockets Management 
Staff (see ADDRESSES) and are available for viewing by interested 
persons between 9 a.m. and 4 p.m., Monday through Friday; they are also 
available electronically at https://www.regulations.gov. FDA has 
verified the website addresses, as of the date this document publishes 
in the Federal Register, but websites are subject to change over time.

    1. Food and Drug Administration (FDA) guidance for industry 
``ANDAs: Impurities in Drug Substances,'' June 2009, available at 
https://www.regulations.gov/document/FDA-1998-D-0021-0008.
    2. FDA guidance for industry ``ANDAs: Impurities in Drug 
Products,'' November 2010, available at https://www.fda.gov/media/71351/download.
    3. FDA guidance for industry ``Control of Nitrosamine Impurities 
in Human Drugs,'' February 2021, available at https://www.fda.gov/media/141720/download.
    4. FDA, ``Updates on Possible Mitigation Strategies To Reduce 
the Risk of Nitrosamine Drug Substance-Related Impurities in Drug 
Products,'' available at https://www.fda.gov/drugs/drug-safety-and-availability/updates-possible-mitigation-strategies-reduce-risk-nitrosamine-drug-substance-related-impurities. Last accessed April 
14, 2023.
    5. FDA and International Council for Harmonisation guidance for 
industry ``M7(R1) Assessment and Control of DNA Reactive (Mutagenic) 
Impurities in Pharmaceuticals To Limit Potential Carcinogenic 
Risk,'' March 2018, available at https://www.fda.gov/media/85885/download.
    6. FDA and International Council for Harmonisation guidance for 
industry, ``M3(R2) Nonclinical Safety Studies for the Conduct of 
Human Clinical Trials and Marketing Authorization for 
Pharmaceuticals'' January 2010, available at https://www.fda.gov/media/71542/download.

    Dated: May 1, 2023.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2023-09526 Filed 5-3-23; 8:45 am]
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