🤷‍♂️ FAQ: How do I calculate the CPCA of my Nitrosamine Impurity?

[Yosukemino]

About the exception of CPCA (Nitrosamines where the N-nitroso group is within an aromatic ring (e.g., nitrosated indole))

EMA Q&A Rev. 16 EMA/409815/2020 - MAJOR UPDATE

For the nitrosated indoles, they aren’t nitrosamines per se; the indole nitrogen is not a secondary amine. Definitely still worth mentioning in the assessment if you consider there is risk of formation or have evidence thereof (don’t conceal anything is normally good advice!), but the implausibility of diazonium formation means that I would argue very strongly for treating these as conventional impurities under ICH M7 rather than as part of the cohort of concern. I recently summarised this on a…

EMA Q&A Rev. 16 EMA/409815/2020 - MAJOR UPDATE

As I see, David has provided a response to your questions. There have been a lot of studies on nitroso indoles which are well known. Many of them are mutagenic. My recommendation will be to look for surrgates with do have nitroso indole group and again, they are not “nitrosamines”. So, dont mix them up and provide separate analysis. Like the nitroso carbamates and nitroso guanidines, they do not need metabolic activation to show their mutagenicity in Ames. Look at this paper, which may give you …

An example of deactivating feature (a 6-membered ring fused with another ring)

EMA Q&A Rev. 16 EMA/409815/2020 - MAJOR UPDATE

For this structure, I would say: The hydrogen count is indeed (2,2) for one point The six-membered ring is not strictly a piperidine, because of the aromatic thiazole fused to it (and the six-membered ring is definitely not aromatic itself, fails Huckel’s rule) - piperidine implies all ring bonds are single. However, the CPCA rule gives two points both to piperidines and to all 6-membered rings other than sulphur-containing and morpolines, so still two points That fused thiazole, though, mean…