Nitrosamine impurities currently belong to a “cohort of concern” because of their potential to be potent mutagenic carcinogens, as described in the ICH M7 guideline1.
They are also coming under increasing regulatory scrutiny with the US Food and Drug Administration and European Medicines Agency recently issuing new guidelines2,3 for examination of this class. These guidelines include computational approaches to establish limits for N-Nitrosamine impurities.
In supporting these important guidelines, Kevin Cross from Leadscope (an Instem company) in combination with others has established a Nitrosamine SAR working group comprising over 46 members and 20 companies. One important activity is the development of predictive strategies for N-Nitrosamine carcinogenicity potency, including documenting a comprehensive understanding of the structure-activity relationships (SAR) for N-Nitrosamines. This assessment is based upon analysis of carcinogenicity and genotoxicity data, reaction mechanisms and structural similarity. It is leading to the definition of categorical alerts to predict several carcinogenic potency categories.
SAR analysis is focused on understanding the impact of several reactivity sites near the N-Nitrosamine functional group that involve different reaction mechanisms leading to differences in potency severity. These reactivity sites include the nitrogen-nitrogen bond, the α-carbon and the β-carbon. Access to these sites (e.g. steric hinderance), along with electronic effects impacts reactivity and consequently, potency. By considering both reaction mechanism and specific substituents at these positions, N-Nitrosamines may be assigned to very-high, high, medium, or low potency categories4.
Through examination of both structural similarity and an examination of the dominant mechanism, categorical alerts can be established to predict N-Nitrosamine potency. This approach will provide a scientifically defendable methodology for establishing potency categories and corresponding exposure limits and will also avoid “activity cliffs” where the structural similarity concept breaks down.
If you would like to learn more, or collaborate on this important project, please reach out to me at email@example.com or Kevin at firstname.lastname@example.org.
1. Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk M7(R1)
2. US Food and Drug Administration’s Guidance for Industry: US FDA Control of Nitrosamine Impurities in Human Drugs, September 2020
3. European’s Medicines Agency, Nitrosamine impurities in human medicinal products, EMA/369136/2020, 25th June 2020
4. K.P. Cross “Predicting Nitrosamine Activity from Structure-Activity Relationships”, Informa Nitrosamines Impurities Forum. 26th August 2020. Slides with audio presentation available email@example.com.