FDA: Guidance on Substance-related Nitrosamine Risks
This month the US FDA issued a 28-page new guidance for immediate implementation, Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs). It provides drug manufacturers and applicants with a framework for a risk-based safety assessment of NDSRIs that could be present in approved and marketed drug products, as well as products under review by the FDA. Ways to predict the mutagenic and carcinogenic risk of NDSRIs and acceptable intake (AI) limits are outlined.
Nitrosamine drug substance-related impurities (NDSRIs) have been identified in many drug products and also could be present in active pharmaceutical ingredients (APIs). Since the publication of the guidance for industry Control of Nitrosamine Impurities in Human Drugs, the FDA has received reports of NDSRIs, which share structural similarities to the API and are unique to each API. Based on the chemical structure of the API, there is a risk of NDSRIs forming in a substantial number of drug products. This guidance is being implemented immediately and it remains subject to comment.
NDSRIs often lack carcinogenicity and mutagenicity study data from which an AI limit can be determined. This guidance provides a recommended methodology for AI limit 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 evaluations of approved and marketed drug products as well as products in development or under review by FDA.
The FDA guidance introduces the Carcinogenic Potency Categorization Approach (CPCA) which is based on an assessment of activating or deactivating structural features present in the molecule. Furthermore, enhanced testing conditions for the Ames assay are recommended.
Good to know:
Both approaches were also recommended by the European Medicines Agency (EMA) in the July revision of its Q&A on nitrosamine impurities (we reported). The sections and tables on CPCA in the two documents are almost identical.
Recommended timeline:
- The FDA asks manufacturers to assess the NDSRI risks within the next three months and to complete their assessment by 1 November 2023, as part of overall risk management.
- By 1 August 2025, manufacturers, and applicants should complete the three-step mitigation strategy based on increased awareness of NDSRIs.
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