Thanks for your information, i’ll try to contact the author to correct it
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There are about 15 structures that I am aware fail some of this structural calculators. They have to be program with specific rules beyond the cpca basics. It’s just matter of fine tuning!
Love to see the emerging of all these open-access tools supporting Nitrosamines science!
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@ [Yosukemino] Is the CPCA used to calculate the limit for unknown Nitrosamine which are non NDSRI ???
Thank you for asking me. The definition of nitrosamine drug substance-related impurities (NDSRI) in FDA guidance is a nitrosamine impurity that shares structural similarity to the API (having the API or API fragment in the chemical structure) and is unique to each API. I think the definition does not come from the structure but from the source of nitrosamine like API or API-related-impurity. And one of the most simple NDSRIs is N-nitroso-piperazine in EMA Appendix. It’s not so complex. The border between NDSRI and non-NDSRI looks unclear on a structural basis.
I am unsure what compound you meant, but I think it should be dealt with on a case-by-case basis.
If the non-NDSRI shows a high potency score in CPCA, I expect high AI can be justified because of the steric hindrance or deactivating feature in the compound. The comparison of the results from CPCA, read-across, and 18ng/day(or 26.5ng/day) helps understand the potency of the nitrosamines. Is this an answer to your question?
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Dear Alaaelkazak
Thank you for sharing. Tried this tool for few molecules and working well. Have a question, do we have to set up AI limits for all NDSRIs, irrespective of the pH and nitrites in the drug product.
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@Yosukemino: Thanks for ur prompt reply, I mean in My product N-nitroso cyclic amine is the nitrosamine impunity which in coming from supplier, and it is not NDSRI. Also, AI is not available in any Guideline. Instead, og 18 ng or 26.5 ng can i use CPCA tool ?? Because by CPCA tool impunity AI is 100 ng .
Hi,
Just to give my opinion here, I would consider for non-NDSRI a read across as an option. Normally, non-NSDRI are small molecular weight nitrosamines where surrogates are easier to find and would be scientifically more appropiate.
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It depends on the structure of the nitrosamine but in some cases CPCA is applicable, I think. You can consider it scientifically. And visualization thread may help understand what compounds CPCA is applied to.
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Can you share the these 15 details for understanding?
I’ll be happy to share once I receive authorization to do so. Someone else has done the work and flagged it to me.
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Hello, I am the author of this app. Thanks for your interest in this application. I have checked the issues, it’s because when to comes to scoring procedure, it will first count the alpha hydrogens where [3,3] (3 hydrogens on both carbons) is not included in the list in the guidance. So the app cannot calculate the score due to my pre-defined setting.
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Hi,
I am the author this application, It will be great that you could also share 15 structures with me once you are OK.
Thanks
Jiazhou
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Hi Yosukemino,
Thanks for coming up with beta-methyl issue, In the application, 'there is a requirement for the chain to be branched at the position’ this rule is not counted since it’s not included in the guidance. If this rule is something that should be considered first when to come to count a beta-methyl, I can actually fix it in the application.
Thanks
Jiazhou
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This is the API (Quetipine fumarate) and identified impurities are mentioned below
and i considered these impurities are NDSRIs . Is it correct?>???
Request for ur expert opinion on above question ??
Yes, I’ve also tried it. Looks really promising! Thanks a lot for sharing.
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Yes, all of them could be potential nitrosamines, although the last one looks the least likely
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Previously available as a preprint and not yet subjected to peer review, the work of Jiazhou Zhu, Qu, and Ye (2024) has now been published.
The algorithm quickly and accurately categorized the risks of over 6000 chemicals, with high agreement compared to the dataset labels.
Further analysis revealed a correlation between high pKaH values of the parent amine (the basicity of an amine where the susceptibility to nitrosation is related to the nitrogen basicity of the amine) and low risk of N-nitrosamine.
To ensure the algorithm’s robustness and reliability, testing was conducted on a larger dataset containing NDSRIs. This dataset was obtained from the referenced article:
The Landscape of Potential Small and Drug Substance Related Nitrosamines in Pharmaceuticals
The algorithm accurately calculated the potency category for each chemical within seconds, while also identifying that 16 molecules failed due to an invalid SMILES string.
Since the posting date of the preprint in this community until now, with the article already published, for those who have been using the tool, what new recommendations do you have?
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It is very useful . I have applied in many application and found suitable
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