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Working together to address the potential presence of nitrosamine impurities in medications

Lhasa Limited, in collaboration with Leadscope, Inc., are leading a working group of pharmaceutical toxicologists and consultants investigating the carcinogenic potency and structure-activity relationships of N-nitrosamines. This is in response to the recent discovery of N-nitrosamines in marketed pharmaceuticals and the regulatory changes that have resulted. The working group is coordinated on an informal basis (i.e. members contribute by sharing their expertise rather than financially) by Lhasa Limited Senior Scientist Dr. David Ponting and Leadscope Vice President of Product Engineering Dr. Kevin Cross.

Key points in the current regulatory environment, from the point of view of Lhasa Limited members and Leadscope customers, have been driven by the European Medicines Agency (EMA)1 and United States Food and Drug Administration (U.S. FDA)2. They are: N-nitrosamine compounds, being typically potent mutagens and carcinogens, must be controlled to an exposure limit of 18 ng/day, unless they have reliable carcinogenicity data or there is a close analogue with reliable carcinogenicity data. The working group has several topics under consideration as a result:

– What mechanism(s), in addition to the main alpha-carbon hydroxylation mechanism that leads to potent carcinogenic response, may occur?

– Which compounds have reliable carcinogenicity data that can be read-across to, and what is the best potency estimate we can derive for those compounds by meta-analysis of all available data?

– How should the best read-across analogue for a novel N-nitrosamine be selected?

– If there is no single read-across analogue with sufficient data, can a combination of analogues give sufficient information?

– Are there any compounds or substructures where clear toxicity and mechanistic information indicates that the cohort of concern limits may not be applicable?

– What improvements can we make to the structure-activity relationships for N-nitrosamines?

The working group has also received donations of data, using Lhasa Limited’s trusted data donation process, in order that group members’ chemical space can be considered alongside public data curated by Lhasa Limited and Leadscope in the analysis of structure-activity relationships. Ultimately, the working group is writing a series of papers on these topics, so that the expertise developed and shared within the group becomes the foundation for consistent analysis of N-nitrosamines both within the workgroup membership and more broadly. If you have any unpublished carcinogenicity or mutagenicity data for N-nitrosamines that could be useful for the working group, please get in touch!



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