14 new nitrosamines have been added.
What is interesting to note is that both N-nitroso-doravirine dimer & N-nitroso-nirogacestat which are CPCA Potency Category 1 with 18 ng/day have turned out to be negative in Enhanced Ames Test. This is the first instance that I notice that a Catgeory 1 nitrosamine has turned out to be negative in the EAT. Would love to hear if anybody has insights on this.
That is a sort of surprise the inclusion of N-nitroso-methylaminoantipyrine following CPCA, I wonder how MH are controling it on the final product with such restrict limit, considering that methamizole can be admistred up to 4g a day
It is also surprising since several API suppliers hold an approved CEP without this spec⌠and considering the analytical troubles may be faced ⌠oh this become quite interesting!
I want to raise a query for discussion based on recent observations involving two CPCA Potency Category 1 compounds (N-nitroso-doravirine dimer & N-nitroso-nirogacestat), but both turned out to be negative in the Enhanced Ames Test, leading to a revised acceptable intake of 1500 ng/day by EMA.
Upon structural analysis, both compounds contain features such as:
a. Strong electron-withdrawing groups (e.g. CFâ, F, CN)
b. Sterically hindering groups (e.g. trimethyl substitutions)
Do these features likely reduce electrophilicity, hinder metabolic activation, and prevent DNA interaction? which may explain the lack of mutagenicity despite CPCA indicating it to be highly potent?
If that is the case, then is the current CPCA framework missing out on accounting for certain deactivating structural features that mitigate mutagenic risk?
Dear Sushant,
very nice and well targeted questions.
As it is discussed in other topics, the introduction of nitrosamine case in the ICH M& guideline will come with an update to CPCA rules.
Please look at the below topic
This looks to be the case from the Excel spreadsheet - the EMA just published notification of there being updates yesterday on their âNews and Eventsâ website.
This community is ahead of the announcements, with everyone keeping such a close eye on this, so we were aware on 1st Aug.
Sorry for the confusion, everyone. I couldnât find any updates in the list. There may be some minor changes from the previous version, but I donât think theyâre serious.
As per the latest update published on August 2025 in EMA guideline can anyone confirm impurity â3-[(N-ethylanilino) methyl]benzenesulfonateâ listed as CPCA Category 1 for Dextromethorphan is correct.
Chemical synthesis does not show any possibility for formation of this impurity.
Is there any literature reference available for formation of the above impurity.
i can only think the possibility the corresponding amine to participate in the synthesis of this Dextromethorphan. But without the manufacturing process we cannot concluded on this.
I classified the nitrosamines included in Appendix 1, rev.10, according to the structures of the active pharmaceutical ingredients (APIs). Compared with the results from rev.4, the proportion of nitrosamines derived from tertiary amines and impurities appears to have increased. Several tertiary amine APIs contain piperidine or piperazine structures. Notably, more than 70% of the nitrosamines listed under CPCA Category 1 are derived from tertiary amines.
