Summary of Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs) Guidance for Industry

In August of 2023, the FDA Center for Drug Evaluation and Research (CDER) published a guidance document for evaluating the acceptable intake limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs). This guidance provides manufacturers and applicants of drugs with a tool to calculate a recommended acceptable intake (AI) limit for NDSRIs.  Prior guidance by the FDA set the AI limit for nitrosamine compounds at 26.5 ng/day, which was the known toxicological threshold for the most potent, robustly tested nitrosamine, N-nitrosodiethylamine (NDEA).  Most NDSRIs have not been robustly tested or toxicologically evaluated, although many are considered to have mutagenic and carcinogenic risks that are lower than that of NDEA. The FDA has outlined predictive methodologies that include the use of structure-activity relationship (SAR) concepts to assess and classify the mutagenic and carcinogenic risk for the purpose of assigning a more appropriate AI limit. The guidance includes flow charts and calculation tools to calculate the “predicted carcinogenic potency categorization” for NDSRIs. There are 5 Potency Categories that have corresponding recommended AI limits:

  • Category 1: AI limit of 26.5 ng/day
  • Category 2: AI limit of 100 ng/day
  • Category 3: AI limit of 400 ng/day
  • Category 4: AI limit of 1500 ng/day
  • Category 5: AI limit of 1500 ng/day

Categorizing a particular NDSRI is done through the calculation of a “Potency Score”, which is equal to the sum of the α-Hydrogen Score + Deactivating Score + Activating Score. The calculated Potency Score is taken through a flow chart that determines which Potency Category and corresponding AI limit are appropriate for the evaluated NDSRI. The guidance allows for assigning AI limits for NDSRIs based on sound toxicological risk concepts. This removes uncertainty about the appropriate limits for the presence of NDSRIs in drug products and hopefully will reduce or eliminate drug manufacturers from conducting unnecessary studies or discontinuing drug products that are on the market. BA Sciences is able to aid drug manufacturers and developers in the testing and monitoring of nitrosamines, including NDSRIs. We can also assist in the proper application of this new FDA guidance.

Click here to read in full detail the update on these guidelines.