Highlights of Recent FDA Guidance on Nitrosamine Drug Substance

Current guidance document provides the framework for predicting the mutagenic and carcinogenic potential of nitrosamine drug substance-related impurities (NDSRIs) that could be present in drug products and recommends acceptable intake (AI) limits for NDSRIs.
FDA 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.
Current guidance applies to drugs, including prescription and OTC drug products that are the subject of an approved or pending new drug application (NDA) or abbreviated new drug application (ANDA).
The recommendations provided in the current FDA guidance do not apply to NDSRIs that are detected in products indicated for use in patients with advanced cancers.
Present FDA guidance recommended methodology that uses predicted carcinogenic potency categorization to assign a recommended AI limit to an NDSRI based on the NDSRI’s activating and deactivating structural features.
FDA recommends the AI limits based on the predicted carcinogenic potency categorization approach for NDSRIs. The five predicted Carcinogenic Potency Categories and associated recommended AI Limits for NDSRIs have been proposed.
FDA provides specific recommendations to the Manufacturers and Applicants whose Drug Products contain multiple nitrosamines in this guidance document.
FDA recommends that if NDSRIs were not considered in previous risk assessments, manufacturers and applicants reevaluate the risk within 3 months of publication of this guidance, with a recommended completion date by November 1, 2023, as part of overall risk management.
Confirmatory testing using sensitive and appropriately validated methods should start as soon as the risk of an NDSRI is identified and should begin immediately for drug products considered to be at high risk. Target timelines for the completion of Confirmatory testing and Submission of required changes in drug applications by August 1, 2025.
If any drug product batch found to contain levels of an NDSRI above the FDA recommended AI limit (e.g., associated with its predicted carcinogenic potency category), should not be released by the drug product manufacturer for distribution and may warrant removal from the market. Manufacturers should contact the Agency if a recall is initiated, and FDA may exercise enforcement discretion when warranted to prevent or mitigate a shortage of a drug in the market.

For example,

FDA Recommended AI Limits for Certain Hypothetical NDSRIs