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GUIDANCE DOCUMENT

Control of Nitrosamine Impurities in Human Drugs Guidance for Industry September 2024

Download the Final Guidance Document
Final Level 1 Revised Guidance
Docket Number:
FDA-2020-D-1530
Issued by:
Guidance Issuing Office
Center for Drug Evaluation and Research

The Food and Drug Administration (FDA, Agency, or we) is announcing the availability of a final guidance for industry entitled “Control of Nitrosamine Impurities in Human Drugs.” This guidance recommends steps manufacturers of active pharmaceutical ingredients (APIs) and drug products should take to detect and prevent unacceptable levels of nitrosamine impurities in pharmaceutical products. The guidance describes two general structural classes of nitrosamine impurities: small-molecule nitrosamine impurities (i.e., nitrosamine impurities that do not share structural similarity to the API), and nitrosamine drug substance-related impurities (NDSRIs), which share structural similarity to the API and are generally unique to each API. The guidance discusses the potential root causes of the presence of nitrosamine impurities, detection of nitrosamine impurities, and recommendations for risk assessments, testing, and implementation of controls and other appropriate strategies to prevent or reduce the presence of nitrosamine impurities in APIs and drug products. Recommendations for an alternative bioequivalence approach if manufacturers and applicants decide to reformulate their products to mitigate nitrosamine impurities are also provided in the guidance. This guidance revises the final guidance of the same name issued on February 24, 2021.

To reflect the evolving and highly technical nature of the relevant information, FDA is providing certain updated information in connection with this guidance, at this web page: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cder-nitrosamine-impurity-acceptable-intake-limits. Specifically, FDA intends to include on this web page updated information on: (1) recommended AI limits for certain nitrosamine impurities, based on their  predicted carcinogenic potency categorization (CPCA), including certain recommended AI limits for drug products with a hypothetical risk of forming NDSRIs; (2) recommended AI limits for certain nitrosamine impurities based on compound-specific data from carcinogenicity and mutagenicity data or read-across analysis from a surrogate; (3) recommended interim AI limits for certain nitrosamine impurities; (4) recommended implementation timelines; (5) other emerging scientific and technical issues; (6) recommended analytical methods for confirmatory testing of certain nitrosamines impurities; and (7) recommended safety testing methods for nitrosamine impurities.

 

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