Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities; Guidance for Industry; Availability, 52183-52185 [2023-16814]

Download as PDF ddrumheller on DSK120RN23PROD with NOTICES1 Federal Register / Vol. 88, No. 150 / Monday, August 7, 2023 / Notices strengths, these strengths have also been discontinued. On our own initiative, we have also determined whether these strengths were withdrawn for safety or effectiveness reasons. After considering the citizen petition and reviewing Agency records and based on the information we have at this time, FDA has determined under § 314.161 that CUBICIN (daptomycin) Powder for Injection, 250 mg/vial and 500 mg/vial, and CUBICIN RF (daptomycin) Powder for Injection, 500 mg/vial, were not withdrawn from sale for reasons of safety or effectiveness. The petitioner has identified no data or other information suggesting that these drug products were withdrawn for reasons of safety or effectiveness. We have carefully reviewed our files for records concerning the withdrawal of CUBICIN (daptomycin) Powder for Injection, 250 mg/vial and 500 mg/vial, and CUBICIN RF (daptomycin) Powder for Injection, 500 mg/vial, from sale. We have also independently evaluated relevant literature and data for possible postmarketing adverse events. We have found no information that would indicate that these drug products were withdrawn from sale for reasons of safety or effectiveness. Accordingly, the Agency will continue to list CUBICIN (daptomycin) Powder for Injection, 250 mg/vial and 500 mg/vial, and CUBICIN RF (daptomycin) Powder for Injection, 500 mg/vial, in the ‘‘Discontinued Drug Product List’’ section of the Orange Book. The ‘‘Discontinued Drug Product List’’ delineates, among other items, drug products that have been discontinued from marketing for reasons other than safety or effectiveness. ANDAs that refer to these drug products may be approved by the Agency as long as they meet all other legal and regulatory requirements for the approval of ANDAs. If FDA determines that labeling for these drug products should be revised to meet current standards, the Agency will advise ANDA applicants to submit such labeling. DEPARTMENT OF HEALTH AND HUMAN SERVICES Dated: August 2, 2023. Lauren K. Roth, Associate Commissioner for Policy. 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 [FR Doc. 2023–16775 Filed 8–4–23; 8:45 am] BILLING CODE 4164–01–P VerDate Sep<11>2014 18:58 Aug 04, 2023 Jkt 259001 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. 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 SubstanceRelated 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 FDArecommended 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: SUMMARY: PO 00000 Frm 00076 Fmt 4703 Sfmt 4703 52183 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 E:\FR\FM\07AUN1.SGM 07AUN1 52184 Federal Register / Vol. 88, No. 150 / Monday, August 7, 2023 / Notices 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-201509-18/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: ddrumheller on DSK120RN23PROD with NOTICES1 I. Background FDA is announcing the availability of a guidance for industry entitled ‘‘Recommended Acceptable Intake Limits for Nitrosamine Drug SubstanceRelated Impurities (NDSRIs).’’ FDA is implementing this guidance without prior public comment because we have determined that prior public participation is not feasible or appropriate (§ 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 VerDate Sep<11>2014 18:58 Aug 04, 2023 Jkt 259001 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. 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 (§ 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 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. PO 00000 Frm 00077 Fmt 4703 Sfmt 4703 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 FDArecommended AI limit for a specific NDSRI, manufacturers and applicants should apply that recommended AI E:\FR\FM\07AUN1.SGM 07AUN1 Federal Register / Vol. 88, No. 150 / Monday, August 7, 2023 / Notices 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. ddrumheller on DSK120RN23PROD with NOTICES1 III. Electronic Access Persons with access to the internet may obtain the document at https:// www.fda.gov/drugs/guidancecompliance-regulatory-information/ guidances-drugs, https://www.fda.gov/ regulatory-information/search-fdaguidance-documents, or https:// www.regulations.gov. VerDate Sep<11>2014 18:58 Aug 04, 2023 Jkt 259001 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 DEPARTMENT OF HEALTH AND HUMAN SERVICES Indian Health Service Notice of Purchased/Referred Care Delivery Area Redesignation for the Confederated Tribes of Grand Ronde in the State of Oregon Indian Health Service, HHS. Notice. AGENCY: ACTION: This Notice advises the public that the Indian Health Service (IHS) proposes to expand the geographic boundaries of the Purchased/Referred Care Delivery Area (PRCDA) for the Confederated Tribes of Grand Ronde (CTGR) in the State of Oregon to include the county of Clackamas in the State of Oregon. The current PRCDA for the CTGR includes the Oregon counties of Washington, Polk, Yamhill, Marion, Multnomah, and Tillamook. The CTGR members residing outside of the PRCDA are eligible for direct care services, however, they are not eligible for Purchased/Referred Care (PRC) services. The sole purpose of this expansion would be to authorize additional CTGR members and beneficiaries to receive PRC services. DATES: Comments must be submitted September 6, 2023. ADDRESSES: Because of staff and resource limitations, we cannot accept comments by facsimile (FAX) transmission. You may submit comments in one of four ways (please choose only one of the ways listed): 1. Electronically. You may submit electronic comments on this regulation to https://www.regulations.gov. Follow the ‘‘Submit a Comment’’ instructions. 2. By regular mail. You may mail written comments to the following address ONLY: Carl Mitchell, Director, Division of Regulatory and Policy Coordination, Indian Health Service, 5600 Fishers Lane, Mail Stop: 09E70, Rockville, Maryland 20857. Please allow sufficient time for mailed comments to be received before the close of the comment period. 3. By express or overnight mail. You may send written comments to the above address. 4. By hand or courier. If you prefer, you may deliver (by hand or courier) your written comments before the close SUMMARY: PO 00000 Frm 00078 Fmt 4703 Sfmt 4703 52185 of the comment period to the address above. If you intend to deliver your comments to the Rockville address, please call telephone number (301) 443– 1116 in advance to schedule your arrival with a staff member. FOR FURTHER INFORMATION CONTACT: CAPT John Rael, Director, Office of Resource Access and Partnerships, Indian Health Service, 5600 Fishers Lane, Mail Stop: 10E85C, Rockville, Maryland 20857. Telephone (301) 443– 0969 (This is not a toll-free number). SUPPLEMENTARY INFORMATION: Inspection of Public Comments: All comments received before the close of the comment period are available for viewing by the public, including any personally identifiable or confidential business information that is included in a comment. Background: The IHS provides services under regulations in effect as of September 15, 1987, and republished at 42 CFR part 136, subparts A–C. Subpart C defines a Contract Health Service Delivery Area (CHSDA), now referred to as a PRCDA, as the geographic area within which PRC will be made available by the IHS to members of an identified Indian community who reside in the PRCDA. Residence within a PRCDA by a person who is within the scope of the Indian health program, as set forth in 42 CFR 136.12, creates no legal entitlement to PRC, but only potential eligibility for services. Services needed, but not available at an IHS/Tribal facility, are provided under the PRC program depending on the availability of funds, the person’s relative medical priority, and the actual availability and accessibility of alternate resources in accordance with the regulations. The regulations at 42 CFR part 136, subpart C provide that, unless otherwise designated, a PRCDA shall consist of a county which includes all or part of a reservation and any county or counties which have a common boundary with the reservation, 42 CFR 136.22(a)(6). The regulations also provide that after consultation with the Tribal governing body or bodies on those reservations included within the PRCDA, the Secretary may from time to time, redesignate areas within the United States for inclusion in or exclusion from a PRCDA, 42 CFR 136.22(b). The regulations require that certain criteria must be considered before any redesignation is made. The criteria are as follows: (1) The number of Indians residing in the area proposed to be so included or excluded; E:\FR\FM\07AUN1.SGM 07AUN1

Agencies

[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.

-----------------------------------------------------------------------

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.
---------------------------------------------------------------------------

    \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.
---------------------------------------------------------------------------

    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
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