Recommended Acceptable Intake Limits for Nitrosamine Drug Substance

GUIDANCE DOCUMENT

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.

To reflect the evolving and highly technical nature of the relevant information, FDA is providing certain updated NDSRI-specific information, in connection with this guidance, at Updated Information - Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs). Specifically, FDA intends to include updated information on: (1) recommended AI limits for certain NDSRIs based on predicted carcinogenicity potency categorization listed by APIs that hypothetically could be at risk of forming such NDSRIs; (2) recommended AI limits for certain NDSRIs based on compound-specific data or read-across analysis from a surrogate; (3) recommended interim AI limits for certain NDSRIs; (4) recommended testing methods for confirmatory testing of certain NDSRIs; and (5) recommended safety testing methods for NDSRIs.

You can submit online or written comments on any guidance at any time (see 21 CFR 10.115(g)(5))

If unable to submit comments online, please mail written comments to:

Dockets Management Food and Drug Administration 5630 Fishers Lane, Rm 1061 Rockville, MD 20852

All written comments should be identified with this document's docket number: FDA-2020-D-1530.

08/04/2023

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