EMA - Appendix 1 - Update

Limits of Nitrosamines
64

Dear hwnra,

you said that the two non-feasibility reports have not been accepted by the authority.

Could you please share with us which was the explanation for the rejection of the authorities?

thanks

Christos

65

Hi,

unfortunately the authority did not diclose any other arguments other than that the impurity is allegedly being offered by some standard vendors. One vendor was named specifically and we of course inquired regarding the availablity of this compound and the answer was, that this impurity is not available for purchase. Several other vendors have not attempted the synthesis before. I also find it worrying, that this kind of approach is used for desicion making by assessors.

Now I am also afraid, that because this impurity is listed in Appendix 1, that the authority does not accept any arguments against the formation of N-nitroso-tizanidine. I think this case should be re-evaluated by the expert group or at least a position paper would be necessary to question the defined impurity.

66

Non-synthesability is part of the quality dossier, doesn’t go to NcWP. Only if the Appendix 1 AI is based on EAT or TGR assay, it is a clear indication synthesis is possible. Sometimes companies ask to assess an AI before they start to design their analytical method (or have a standard in hands) in order to be able to calculate the required LOQ, and if such assessment is done it ends up in Appendix 1. I believe the same can happen for other nitrosos as they have the same AI assessment work flow.

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67

thanks for your feedback,

Which are the authorities you are speaking?

I agree with Wybon regarding the clear evidence of the possibility of synthesis of a nitrosamine.

Ticagrelor case is the most profound. We have defend that the corresponding nitrosamine synthesis is not possible through vendors justification reports and it has been accepted even this nitrosamine is (still) in the EMA appendix 1.

Christos

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68

Thank you very much for your input and sharing your experiences!

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69

Hi all :slight_smile:

EMA published the rev Appendix 1 (01/12/2025). New and updated AIs included in the pdf for ready ref. Also note has been included for previous Acceptable intake.

appendix-1-rev-01dec-2025.pdf (141.7 KB)

hope it helps

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70

Thanks Eleni for the useful summary.

As a side note, I found discrepancies in the numbering of the Appendix 1 Rev 11 document by EMA.

In the xlsx file the document number is EMA/42261/2025, the same as the Rev 8, whereas in the EMA web site the number is EMA/245074/2025, the same as Rev 10.

Maybe someone can clarify the issue.

Ambrogio

71

Thank you Eleni, great work

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72

Dear Eleni,

Thanks a lot for the work done. I note that those updates are date July 2023 in the excel file. Is it an error in the source document? Thank you !

regards

Helene

73

oh sorry, I understand now. The 1st publication date remains. “update” stands for the data, not for the date…

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74

Hi Helene

if you are referring to cases as these included below (indicative), then I think that Jul2023 is the date of first publication

image
image1373×193 19.7 KB

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