AI for en Indole struktur (N-Nitroso melatonin)

Limits of Nitrosamines
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Hej,

Jeg har en udfordring med at sætte korrekt limit for en indole, da EMA Q&A rev.17 angiver at fremgangsmåden ikke kan bruges for nitroserede indole.

Er der nogen, der har haft samme problem?

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Apologies for replying in English, but there have been several discussions about nitrosated indoles recently!

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 another thread: 🗓 Nitrosamines Conversation Event w/ Dr. Raphael Nudelman - #13 by David

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One of the beauties of the language platform, Amanda can read in her local language through the automatic translation!

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Thanks for your reply, very helpful.

We have been told by the authorities to test our product for N-nitrosomelatonin, but during development we see that the standard impurity, N-nitroso melatonin, is very unstable as we assumed based on literature. But we have tried with literature to argue that this N-nitrosomelatonin is not a regular nitrosamine and therefore should not be considered as one. This has not been accepted and therefore we are trying to develop a method.

In order to further support our findings, does anyone know whether it could work to perform an AMES test in an aprotic suspension if we see that the nitrosamine impurity is unstable in an aqueous solution?

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Hi, Amanda.

To the best of my knowledge, the solvent mixture used in the Ames test should always contain water (I don’t know how much is the minimum quantity) in order to keep alive the Salmonella strains. However, the potential mutagenicity of nitrosomelatonin is discussed in the following (free) article:

-Nitrosomelatonin; synthesis, chemical properties, potential prodrug

I hope that it may be useful for you.

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Dear @Amanda
greetings and a happy new year :slight_smile:

since we are also coping now with N-Nitrosomelatonin, could you please let me know whether EU or US Authorities asked for an Ames test?

Thank you in advance

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It looks from @paliog article that you could do Ames assay with this but you need modified conditions.

My suggestion is rather focusing on aprotic solvents, you can modify the assay with few conditions and check. However, it looks N-nitroso melatonin was well discussed and it could not be cohort of concern and very unstable.

So you have good chance to prove its safety.

All the best!

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Dear @elenipoliti,

Sorry for my late reply on your question. We had just got questions from the EU authorities, but we managed to use articles in our response and therefore Ames test was not necessary.

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Hi @Amanda

Thank you for your response.

So I assume that you concluded that N-nitrosomelatonin is not a CoC impurity and there is no need to control it as nitrosamine. Do you control is under ICH M7 principles (TTC 1.5ug/d) ?

Have a nice day ahead :slight_smile:

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hi @Amandaribeiro
I am coming back to this thread since now EMA has updated Appendix 1 including AI for NoMel.
I am also of the opinion that there is adequate literature data supporting that NoMel is of minimal risk. are there any updates from your end?

thank you