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FDA announces final guidance recommending Acceptable Intake (AI) Limits for NDSRI

FDA has recently published final Guidance for Industry, entitled “Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs). This guidance document provides recommendations for manufacturers and applicants of drugs on how to determine the acceptable intake (AI) limits for nitrosamine drug substance-related impurities (NDSRIs).

NDSRIs are a class of nitrosamine impurities that are unique to each active pharmaceutical ingredient (API) with a potential for mutagenicity and carcinogenicity. They are formed in drug products through nitrosation of APIs (or API fragments) that have secondary or tertiary amines when exposed to nitrosating agents such as residual nitrites in excipients used to formulate the drug product.

NDSRIs often lack carcinogenicity and mutagenicity study data (typically from animal studies) from which an AI limit can be determined. This guidance document 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.

The recommended AI limits for NDSRIs are based on the predicted carcinogenic potency of the impurity. The predicted carcinogenic potency score, which is calculated based on selected structural features present in NDSRIs. Based on these scores, NDSRIs are categorized into 5 levels with corresponding limits recommended by FDA.

Table 1. The Five Predicted Carcinogenic Potency Categories and Associated Recommended AI Limits for NDSRIs

The guidance document also provides recommendations on how to implement the recommended AI limits for NDSRIs, including timelines for conducting risk assessments, confirmatory testing, and submitting required changes to the FDA.

The guidance document is intended to help manufacturers and applicants of drugs to assess the risks of NDSRIs and to ensure that the levels of these impurities in drug products are safe.

Here are some key points from the guidance document:

  • The FDA recommends using a predicted carcinogenic potency categorization approach to determine AI limits for NDSRIs.

  • The predicted carcinogenic potency categorization is based on the structural features of NDSRIs.

  • The recommended AI limits for NDSRIs based on carcinogenic potency scores.

  • The FDA recommends that manufacturers and applicants of drugs implement the recommended AI limits for NDSRIs as soon as possible.

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