Revision 2 of FDA Guidance on Nitrosamines Published

Date

September 13, 2024

Category

US Regulations

Description

In September 2024 the FDA issued revision 2 of their Guidance for Industry on the “Control of Nitrosamine Impurities in Human Drugs”, which updates the version first published in February 2021.

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.

FDA is also providing certain updated information in connection with this guidance on a web page (unfortunately the published link on the FDA announcement page did not work). This web page will provide the following information:

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.

The notice of the revision can be found at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/control-nitrosamine-impurities-human-drugs