FDA Releases Guidance on Intake Limits for Nitrosamine Drug Substance-Related Impurities

On Aug. 4, 2023, FDA released a guidance document, Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs). The guidance gives both applicants and manufacturers of drugs recommendations for estimating the mutagenic and carcinogenic potential of NDSRIs that could be in drug products and gives acceptable intake (AI) limits for NDSRIs.

NDSRIs are a subcategory of nitrosamine impurities that share structural similarity to the API in drug products; NDSRIs often lack the compound-specific mutagenicity and carcinogenicity data necessary for informed safety assessments. FDA wrote in the guidance document that 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.”

FDA wrote that it will provide updated NDSRI-specific information on its website to be viewed in tandem with the guidance. The updated information will include suggested AI limits for specific NDSRIs based on “compound-data or read-across analysis from a surrogate”, suggested interim AI limits for NDSRIs, suggested testing methods for corroborative testing of specific NDSRIs, and suggested safety testing methods for NDSRIs. It will also include suggested AI limits for specific NDSRIs based on “predicted carcinogenicity potency categorization listed by APIs that hypothetically could be at risk of forming such NDSRIs.”

Source: FDA