Updated EMA-Acceptable intakes (AIs) established for N-nitrosamines

Updated EMA-Acceptable intakes (AIs) established for N-nitrosamines.pdf (1.2 MB)

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Thank you for sharing the updated AI list, @ranjithrnd. The link to the original Appendix 1 is here. The URL means “pdf”, but the file is made in Excel.

New or updated compounds/ Category or Study/ AI(ng/day)
5-chloro-4-methyl-2-[(2S)-2-methyl-1-nitrosopyrrolidin-2-yl]-1H-benzimidazole/ Cat.5/ 1500
N-nitroso-ambroxol/ EAT? Nega/ 1500
N-nitroso-calcium folinate/ in vivo Nega/ NMI
N-nitroso-celiprolol/ Cat.5/ 1500
N-nitroso-desethyllidocaine/ Cat.2/ 100
N-nitroso-desmethyl-azelastine/ Cat.2/ 100
N-nitroso-desvenlafaxine/ Cat.1/ 18
N-nitroso-dorzolamide/ Cat.2/ 100
N-nitroso-esmolol/ Cat.4/ 1500
N-nitroso-ethylenediamine-triacetic acid/ Cat.4/ 1500
N-nitroso-iminodiacetic acid/ Cat.4/ 1500
N-nitroso-indapamide/ Cat.5/ 1500
N-nitroso-leniolisib/ Cat.5/ 1500
N-nitroso-N-methylaniline(NMPA)/ Cat.2/ 100
N-nitroso-tetracaine/ Cat.3/ 400
N-Nitroso-ticagrelor/ Cat.5/ 1500

NMPA is updated from 34.3ng/day to Cat.2(100ng/day).

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Interestingly, Nitroso-Indapamide = Indapamide Impurity A is included in the Ph. Eur. Indapamide monograph with a limit of 5 ppm. It appears as a contradiction to deal with.
There was a previous discussion on the topic on the site

N-Nitrosoiminodiacetic acid and N-nitroso-ethylenediamine-triacetic acid are included with an AI of 1.5µg/day, originating from Isosorbide mononitrate. N-Nitrosoiminodiacetic acid has negative data in LCDB, however they are not considered reliable.

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My answer for the indapamide case would be the same as in that thread - the monograph limits appear to be limits based on achievable quality standards and the existing batches on the market (independent of the toxicity of the impurities, there is real value in having drug substances as pure and well-characterised as possible) rather than the safety-threshold-determined limit that would be permissible under the CPCA or any other guidance.

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So NMPA has moved from a limit of 34.3 ng/day to 100 ng/day based upon it falling into Category 2 if you put it through the CPCA calculation.

Does this mean that we could see the limit changing for NMPA from the FDA as well, where it is still currently 26.5 ng/day?

I hadn’t considered putting the original small molecules back through the calculation.

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Hi everyone :slight_smile:
(and thanks to all that have contribute until now, particularly Yosukemino ¡! )

Apart of the format change (PDF to Excel Table)…some new columns added or am I driving crazy? e.g. I do not remember seeing “Structures” in previous list in PDF

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Indeed, now structures, that is more visually appealing :slight_smile:

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Smiles are very useful for searching nitrosamines in QSAR and DB. Similarity search is also available for read-across. That’s great progress!!

As far as I know, the FDA never changed the AI from the original except for the interim limit. The AI of varenicline is still different between FDA and EMA(37 vs 400). And NMPA is separated from NDSRIs.

As @conudel explained in the webinar today, there are lots of gaps in policy between the FDA and the EMA. We should pay attention to the FDA’s next approach.

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It was fantastic presentation by @conudel today. I hope Lhasa made available the recording soon, the cases and the regulatory gaps was very insightful.

Eye opening to me: “Aproximately 25% of NDSRIs are positive in vitro mutagens and have a good chance of being positive in vivo. Currently, no method is available to use positive in vivo mutagenicity data to rank the potency of NDSRIs”

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One of the reasons, something not as harsh to perfom as a carcinogenic study is needed. The nitrosamine topic is still long to be solved.

The CPCA even with its limitations helped quite a bit. But this is one of the reasons the joint cooperation between industry and regulators is needed. To focus a bit more on positive Ames compounds rather than putting efforts on compounds that are out of the CoC. Where nonetheless, more evidence is coming of certain drug classes for example.

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Here is the link to Lhasa webinar “How to establish acceptable intake limits for NDSRIs” 22nd Nov 2023
How to establish acceptable intake limits for NDSRIs (vimeo.com)

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The updated AI list by EMA is now available. (15/12/2023)
https://www.ema.europa.eu/system/files/documents/other/appendix-1-nitrosamines-ai-rev1_en.xlsx

Five new nitrosamines are included.

N-nitroso-cinacalcet: 400ng/day
N-nitroso-desmethyl-citalopram: 18ng/day
N-nitroso desmethyl nintedanib: 400ng/day
N-nitroso imatinib: 1500ng/day
N-Nitroso Quetiapine HEEP Impurity: 1500ng/day(Limit based on negative bacterial reverse mutation test)

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The latest version of Appendix 1 (https://www.ema.europa.eu/system/files/documents/other/nitrosamines-qa_appendix1_excel-ema-rev-2_en.xlsx) includes new or updated 16 compounds.

1-(2,3-dichlorophenyl)-4-nitrosopiperazine: 400ng/day
N-nitroso-azacyclonol: 400ng/day
N-nitroso-betaxolol: 1500ng/day
N-nitroso-dabigatran etexilate: 1500ng/day (negative bacterial reverse mutation test)
N-nitroso-desmethyl-sildenafil: 400ng/day
N-nitroso-desmethyl-sumatriptan: 18ng/day
N-nitroso-desmethyl-terbinafine: 18ng/day
N-nitroso-dorzolamide: 1500ng/day (negative bacterial reverse mutation test)
N-nitroso-mirtazapine: 400ng/day
N-nitroso-ranolazine impurity 1: 400ng/day
N-nitroso-ribociclib impurity 1: 400ng/day
N-nitroso-rivaroxaban amide: 1500ng/day
N-nitroso-rivaroxaban open-ring acid: 1500ng/day
N-nitroso-terbinafine degradant: 18ng/day
N-nitroso-terbinafine impurity A: 18ng/day
N-nitroso-urapidil: 1500ng/day

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The precursor secondary amine is a metabolite of the API and the probability for the formation of corresponding Nitrosamine (the one listed in the update) endogenously is evident. How should we proceed with amine precursors that are found to be metabolites?

Thank you for asking. As far as I know, nitrosamine guidance does not include such metabolic considerations that are included in ICH M7. Many NDSRIs may be generated as metabolites in our bodies after taking medicines. In reality, those NDSRIs are required to be controlled under acceptable intake.

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Hi to everyone…Yosuke thanx (once again) for the updating.
I would like to highlight the appearance of N-nitroso-ranolazine impurity 1.
Given the fact that for Ranolazine another NDSRI is also included in this list (nitroso impurity C’’ [N-(2,6-dimethylphenyl)-2-(4-nitrosopiperazin-1-yl)acetamide]) make the situation complicated for final products of Ranolazine in cases that both of those nitrosamined appeared in the final prodcut.
But, if for the nitroso impurity C, its formation was anticipated, for this one its formation seems to me more difficult to be explained.
According to my knowledge in organic chemistry it seems to me very difficult its formation due to the degradation of Ranolazine. So, most probably it comes from the synthesis of API and this needs more thoroughly investigation.
To be honest i am wondering if this is again a ‘‘false alarm’’ similar to N-nitrosoticagrelor. If someone receive a wrong standard and release the ‘‘kraken’’ one more time.
best regards

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Thank you for asking, @chrischar. As explained in the following @ccdw 's post, the AIs of nitrosamines in Appendix 1 are submitted to NS OEG for checking before publishment. The selection of the compounds is MAH’s responsibility and nitrosamines in Appendix 1 are not necessarily contaminated in the products.

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Dear Yosuke,
i am asking because for example, N-nitrosoticagrelor is presented in this list, which means that the check from NS OEG is not deep as it should be. Furthermore, our experience has shown that when a compound is presented in this EMA appendix 1, the European authorities directly ask for confirmatory test independently of the power of the risk assessment.
My question was also for anyone inside the forum who has work with this N-nitrosoranolazine impurity 1 and has a feedback on the commercial standard (possitive or negative).
thanks for answering

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I think NS OEG confirms only the justification of AIs. Your concerns look different from NS OEG’s work. MAHs should explain the reason why the NAs are out of scope if required.

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