Limit for Nitroso Ciprofloxacin

It seems that regulatory bodies are inquiring manufacturers to demonstrate the absence of Nitroso-Ciprofloxacin.

SMILES: O=NN1CCN(C2=C(F)C=C(C(C(C(O)=O)=CN3C4CC4)=O)C3=C2)CC1

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Just for context, I found an article from water research that study the reactivity of Ciprofloxacin under nitrosating conditions and demonstrated the formation of the Nitroso-compound.
https://www.sciencedirect.com/science/article/abs/pii/S0043135420308290

Perhaps the recent post on the FDA structural similarity poster can provide guidance. The authors also refer to the Dobo et al. publication

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1-Nitrosopiperazine can be a surrogate.
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1-methyl-4-nitrosopiperazine can also be consider. Moreover EMA and Health Canada has published limit for 1-methyl-4-nitrosopiperazine.
Health Canada limit: 96.0 ng/day while EMA limit: 26.5 ng/day
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@MichaelBurns @David

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I would like report a new article on this topic:
Setting limits for N-nitrosamines in drugs: A defined approach based on read-across and structure-activity relationship for N-nitrosopiperazine impurities

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Thanks you a lot! It´s a tricky questions…

We may not use AI 1300 ng/day, because N-nitroso ciprfloxacin has pipeazine ring not piperidine ring

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AI- in still evaluation

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May i ask the source of AI 140ng/day? read-across from which?

Please note that is based on my subjective opinion (It can be subjected to correction)- Not published value. Still in the process of evaluation. Conservatively that is the least value that can be defended considering all piperazine based nitrosamines.

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Read across from TriMNP will give an AI of 153 ng/day. TriMNP is the most potent nitroso-piperazine in the LCDB and it has robust carcinogenicity data, so it should be accepted as a valid surrogate for other nitroso-piperazines such as nitroso-ciprofloxacin.

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Thanks @conudel. Agree to some extent. It looks like the most potent among all N-nitroso piperazines is 1-methyl-4-nitrosopiperazine. There is difference between 1,2,6-trimethyl-4-nitrosopiperazine and 1-methyl-4-nitrosopiperazine in terms of carcinogenicity.
Structurally 1-methyl-4-nitrosopiperazine looks more closer to N-nitroso Ciprofloxacin.
with absence of beta methyl substituents.

The MW difference should also be accounted for when doing a read across. You’re expecting the functional groups to contribute to the toxicity, not the MW generically.

Agree. Molecular weight has role.

Summary

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Agree MW also important. The problem with NDSRIs are it is tough to get both MW wise and structural wise the closer analogues.

Let me explain better. Don’t worry about the MW when identifying the closest surrogate. Sure, steric hinderances, etc. should be accounted for, but the last step in the process is:

AI (surrogate) * MW (molecule of interest) / MW (surrogate)

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Dear @jason.brown. I Understand what you are referring to. Definitely one should not worry about MW for finding analogue because for NDSRI it is tough.
In regard to Molecular weight correction with respect to AI- could you please let me know does agency accepting such approaches.

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We actually have a good thread here: Calculating Nitrosamine Limits (MasterClass) - Limits of Nitrosamines - Nitrosamines Exchange (usp.org)

This topic is covered at about 29 min. in the video

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Hi!
It is rumored that we will soon see a pronouncement on limits (ciprofloxacin) in Europe . Does anyone know anything about this topic?

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Really ? that’s very good ! looking forward to the news.

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Has just recently been included in the updated Appendix 1 (EMA/517258/2023, 20 Nov 2023):
https://www.ema.europa.eu/en/documents/other/appendix-1-acceptable-intakes-established-n-nitrosamines_.pdf

Most likely ofloxacin (belonging to same group of fluorchinolones) and other group compounds will follow soon.

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