Our very first Nitrosamines Exchange host live event: โNitrosamines Conversationsโ
On July 7th, the entire Nitrosamine community received the most anticipated update on EMAโs ๐๐ฎ๐๐ฌ๐ญ๐ข๐จ๐ง๐ฌ ๐๐ง๐ ๐๐ง๐ฌ๐ฐ๐๐ซ๐ฌ ๐๐จ๐ซ ๐ฆ๐๐ซ๐ค๐๐ญ๐ข๐ง๐ ๐๐ฎ๐ญ๐ก๐จ๐ซ๐ข๐ฌ๐๐ญ๐ข๐จ๐ง ๐ก๐จ๐ฅ๐๐๐ซ๐ฌ/๐๐ฉ๐ฉ๐ฅ๐ข๐๐๐ง๐ญ๐ฌ ๐จ๐ง ๐ญ๐ก๐ ๐๐๐๐ ๐๐ฉ๐ข๐ง๐ข๐จ๐ง ๐๐จ๐ซ ๐ญ๐ก๐ ๐๐ซ๐ญ๐ข๐๐ฅ๐ ๐(๐) ๐จ๐ ๐๐๐ ๐ฎ๐ฅ๐๐ญ๐ข๐จ๐ง (๐๐) ๐๐จ ๐๐๐/๐๐๐๐ ๐ซ๐๐๐๐ซ๐ซ๐๐ฅ ๐จ๐ง ๐ง๐ข๐ญ๐ซ๐จ๐ฌ๐๐ฆ๐ข๐ง๐ ๐ข๐ฆ๐ฉ๐ฎ๐ซ๐ข๐ญ๐ข๐๐ฌ ๐ข๐ง ๐ก๐ฎ๐ฆ๐๐ง ๐ฆ๐๐๐ข๐๐ข๐ง๐๐ฅ ๐ฉ๐ซ๐จ๐๐ฎ๐๐ญ๐ฌ / Question #10 - ๐๐๐๐๐ ๐ก๐๐ข๐๐ฉ๐จ ๐๐ฅ๐ฅ๐ก๐ฎ ๐๐ค๐ง ๐ฃ๐๐ฉ๐ง๐ค๐จ๐๐ข๐๐ฃ๐๐จ ๐๐ฃ ๐ข๐๐๐๐๐๐ฃ๐๐ก ๐ฅ๐ง๐ค๐๐ช๐๐ฉ๐จ?
We have invited our very own Dr. Raphael Nudelman to join the live conversation to discuss the recent updates, follow-up discussions, and perspective on the impact of such updates to the industry.
On July 7th, the entire Nitrosamine community received the most anticipated update on EMAโs ๐๐ฎ๐๐ฌ๐ญ๐ข๐จ๐ง๐ฌ ๐๐ง๐ ๐๐ง๐ฌ๐ฐ๐๐ซ๐ฌ ๐๐จ๐ซ ๐ฆ๐๐ซ๐ค๐๐ญ๐ข๐ง๐ ๐๐ฎ๐ญ๐ก๐จ๐ซ๐ข๐ฌ๐๐ญ๐ข๐จ๐ง ๐ก๐จ๐ฅ๐๐๐ซ๐ฌ/๐๐ฉ๐ฉ๐ฅ๐ข๐๐๐ง๐ญ๐ฌ ๐จ๐ง ๐ญ๐ก๐ ๐๐๐๐ ๐๐ฉ๐ข๐ง๐ข๐จ๐ง ๐๐จ๐ซ ๐ญ๐ก๐ ๐๐ซ๐ญ๐ข๐๐ฅ๐ ๐(๐) ๐จ๐ ๐๐๐ ๐ฎ๐ฅ๐๐ญ๐ข๐จ๐ง (๐๐) ๐๐จ ๐๐๐/๐๐๐๐ ๐ซ๐๐๐๐ซ๐ซ๐๐ฅ ๐จ๐ง ๐ง๐ข๐ญ๐ซ๐จ๐ฌ๐๐ฆ๐ข๐ง๐ ๐ข๐ฆ๐ฉ๐ฎ๐ซ๐ข๐ญ๐ข๐๐ฌ ๐ข๐ง ๐ก๐ฎ๐ฆ๐๐ง ๐ฆ๐๐๐ข๐๐ข๐ง๐๐ฅ ๐ฉ๐ซ๐จ๐๐ฎ๐๐ญ๐ฌ / Question #10 - ๐๐๐๐๐ ๐ก๐๐ข๐๐ฉ๐จ ๐๐ฅ๐ฅ๐ก๐ฎ ๐๐ค๐ง ๐ฃ๐๐ฉ๐ง๐ค๐จ๐๐ข๐๐ฃ๐๐จ ๐๐ฃ ๐ข๐๐๐๐๐๐ฃ๐๐ก ๐ฅ๐ง๐ค๐๐ช๐๐ฉ๐จ?
We have invited our very own Dr. Raphael Nudelman to join the live conversation to discuss the recent updates, follow-up discussions, and perspective on the impact of such updates to the industry.
REMINDER โฆ I will be hosting this very timely conversation with Dr. Nudelman tomorrow. We will cover the recent EMA updates, and implications on current and future work for the entire Nitrosamine community.
Please feel free to submit your question here to address them at the live session.
Is there any information to indicate that the FDA will align its guidance to Rev.16 update of the EMA guidance?
And my questions are as follows;
Do you consider Category 5 should be clearly separated from Category 4 in CPCA? The LTL approach over 1.5 ยตg/day during CAPA is only applicable to Category 5 compounds in EMA Q&A Q22, despite AIs being both 1.5 ยตg/day.
Do you consider NMI(Not Mutagenic Impurity) should be only assigned to compounds with negative in vivo tests? Though nitroso-quinapril is NMI in Appendix 1, other nitroso-ACE inhibitors are in Category 5.
Can CPCA apply to compounds with two N-nitroso groups such as N,Nโ-dinitrosopiperazine? It is included in HC guidance but the calculation is not clear.
An essential aspect to consider is the potential utilization of molecular weight variations to calibrate weight-based limitations, contingent upon the number of molecules per mole existing in vivo, as a conservative approach due to the mechanistic connection between NA mutagenicity and the molar quantity, rather than the mass. Although scientifically justified, this approach is presently not embraced by regulatory health authorities (The Nitrosamine โSagaโ: Lessons Learned from Five Years of Scrutiny). Can you provide insights into the current status of discussions regarding the acceptance of this approach?
I am wondering what approach should be taken for nitrosamines excluded from the CPCA, such as nitrosoindoles. Can we say that these compounds do not form? Or are they not genotoxic/carcinogenic? Can they be omitted during the risk analysis?
@conudel will probably take this live, but my perspective is that there are at least two categories to consider - as discussed elsewhere (Ponting & Foster), the original CoC was simply NN=O, so that captures lots of compoundsโฆ
to briefly summarise that paper and other work:
N-nitrosoureas/amides/carbamates: Mostly mutagenic and some exemplars are potent carcinogens. However, much less likely to form (Schlingemann et al) and if they do form no metabolic activation required so current Ames test concerns not so significant - but equally metabolism-derived SAR, such as that that underpins the CPCA, is not applicable - so even if these were part of the current regulatory focus, a different CPCA-like approach would be needed
N-nitrosated aromatic systems, such as N-nitrosoindoles: Can be mutagenic via an alternative mechanism, but not CoC-potent - normal M7 control
Nitrosated heterosubstituted amines: Can be mutagenic via an alternative mechanism, but not CoC-potent - normal M7 control
Nitrosated primary amines: probably unstable
For clarity in discussing these, Iโve tended to push the use of nitrosamine specifically to mean nitrosated secondary amines (nitrogen must be singly bonded to exactly two carbon atoms, those carbon atoms may not be formally multiply bonded to a heteroatom (unless that bond is part of an aromatic system, e.g. a 2-pyridyl group), and used the terms listed above for the other N-nitroso compounds.
Here is Alberto Berardi, from DFE Pharma. A pleasure to join this very interesting community. I have already learnt a lot from the links that you share in LinkedIn, but have decided to join the community to learn even more.
I cannot find the link to the record of the Nitrosamines event with Dr Raphael Nudelman. Unfortunately, I was not able to listen to it live, as I am in a different time zone.
Could you plz share the link to the record, if available?
Hello Nitrosamine community members!
For those that participated in our recent โNitrosamine Conversation,โ Thank youโฆ I hope you enjoyed it as much as I did. Raphy @conudel set the bar very high for any upcoming conversation.
On behalf of the entire community, thank you, Raphy, for sharing your time and knowledge with all of us. Special shout out to @David, who answered and addressed comments here in the community as the conversation was happening!
For those that could not make it, I hope you take the time to watch the recording of our conversation. You will not get better reflections about the recent EMA changes and impact on our industry anywhere else!
It was a great discussion. Especially I loved the part where Raphy showed the gaps in the list. People have been coming up with questions. It was good for many to see that they are not too far in their thoughts. The agencies are in a haste and hence these mistakes.
