FDA Releases New Acceptable Intake Levels for Nitrosamine Drug Substance-Related Impurities

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August 15, 2023

2023 guidance establishes a Predicted Carcinogenic Potency Categorization Approach for deriving AIs  

On Aug. 4, the Food and Drug Administration finalized and released a guidance document titled Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities for immediate implementation. This guidance provides a recommended framework for predicting the mutagenic and carcinogenic potential of nitrosamine drug substance-related impurities (NDSRIs) — including deriving acceptable intake (AI) limits — as well providing guidance on the implementation of the framework. 

The 2023 guidance document provides further clarification and updates to the nitrosamine guidance document that FDA released in 2021, including the following:

  • Establishes a Predicted Carcinogenic Potency Categorization Approach:A standardized rule-based approach for deriving AIs for NDSRIs with limited to no mutagenic or carcinogenic data. The approach relies on structural-activity relationships common across the nitrosamine chemical class that are predictive of mutagenic and carcinogenic potential. Based on these key structural features, an NDSRI is assigned to a potency category and each category is associated with a specific AI (i.e., 26.5, 100, 400, or 1,500 ng/day). 
    • This potency categorization approach has been endorsed by Health Canada and the European Medicines Agency for nitrosamine assessments. 
    • FDA has also provided a list of recommended AIs for 247 NDSRIs that can hypothetically form from amine-containing active pharmaceutical ingredients based on the Predicted Carcinogenic Potency Categorization Approach. This is a significant update, as AIs for only six nitrosamines had previously been recommended in FDA's 2021 guidance. 
    • Note that FDA still recommends, when possible, the use of compound-specific data or test data from an identified surrogate that are then used to generate an estimate, either quantitatively or qualitatively, for the data-poor compound (commonly referred to as a read-across analysis). 
  • Provides specific recommended timelines for implementing risk assessments, confirmatory testing, and submission of required changes for NDSRIs: 
    • For NDSRIs that were not considered in previous risk assessments, manufacturers and applicants should reevaluate the risk within three months of publication of the new guidance, with a recommended completion date of Nov. 1, 2023. 
    • Manufacturers and applicants should ensure that any NDSRIs in their drug products meet FDA-recommended AI limits by Aug. 1, 2025. 

FDA notes that if a batch of drug product in distribution has NDSRI above the recommended limit, and manufacturing changes are likely to lead to a disruption in the drug supply, then the agency would evaluate the circumstance on case-by-case basis, including consideration of an interim AI.

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Exponent's multidisciplinary teams provide unparalleled expertise for navigating nitrosamine FDA regulatory compliance matters, including analytical, toxicological, manufacturing, and risk assessment support. We have specific experience justifying read-across analyses for nitrosamines, implementing the potency categorization approach, identifying key risk areas for nitrosamine formation throughout the supply chain, and performing root-cause analysis.