On Friday 4th August 2023, the United States Food and Drug Administration (FDA) provided some important updates on N-nitrosamine impurities in human medicinal products – “Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs) – Guidance for Industry.”1 The release also includes updated information on “Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs).”2

These documents are aligned with the recent releases from the European Medicines Agency3,4 and Health Canada5 which outline different approaches for deriving Acceptable Intake (AI) limits for substances without carcinogenicity data, including a carcinogenic potency categorization approach (CPCA). The CPCA is a decision tree in which the N-nitrosamine impurity may be assigned to one of five potency categories based on its chemical environment. The CPCA is based on structure-activity relationship (SAR) concepts, as it identifies structural features that directly increase or decrease the favorability of metabolic activation of nitrosamines (or that increase the clearance of the nitrosamine by other biological pathways). This information is used to assign an AI based on the potency category resulting from the nitrosamine structure.

Instem is currently engaged in providing functionality within the Leadscope Model Applier™ to support potency category calculations, providing an easy-to-use solution for rapidly generating the CPCA potency categories and their associated AI limits based on the latest guidance from authorities. The validated tool will automatically and consistently calculate the potency category and associated AI limits in seconds avoiding the need to manually process the detailed and complex chemistry rules.

If you would like to discuss these updates and solutions to consistently apply this updated information to N-nitrosamine impurities, please contact us (Kevin Cross, kevin.cross@instem.com).


  1. Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs) (fda.gov)
  2. Updated Information | Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs) | FDA
  3. https://www.ema.europa.eu/documents/referral/nitrosamines-emea-h-a53-1490-questions-answers-marketing-authorisation-holders/applicants-chmp-opinion-article-53-regulation-ec-no-726/2004-referral-nitrosamine-impurities-human-medicinal-products_en.pdf
  4. https://www.ema.europa.eu/documents/other/appendix-1-acceptable-intakes-established-n-nitrosamines_en.pdf
  5. Nitrosamine impurities in medications: Guidance – Canada.ca

Published by Glenn Myatt

Glenn J. Myatt is the co-founder of Leadscope and currently Senior Vice President, In Silico & Translational Science Solutions at Instem with over 30 years’ experience in computational chemistry/toxicology. He holds a Bachelor of Science degree in Computing, a Master of Science degree in Artificial Intelligence and a Ph.D. in Chemoinformatics. He has published 37 papers, 11 book chapters and three books.