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, doesnā€™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!

1 Like
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

13 Likes
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. ā€œupdateā€ stands for the data, not for the dateā€¦

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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
image1373Ɨ193 19.7 KB

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75

Dear all,
new update of Appendix 1 (01/03/2026 - rev12).

New and updated AIs included in the pdf for ready ref. Also note has been included for previous Acceptable intake.

new-and-update-251201-260301.pdf (400.7 KB)

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EMA Q&A Appendix 1 update posted on 13 March 2026
76

This one is a very interesting one.

image
image2432Ɨ142 19.7 KB

Iā€™ve been trying to work out what the change to this is, as I didnā€™t remember seeing it before in relation to the Brilliant Blue.

Looking at the current TGA website (which is normally a few days behind the EMA) then it is currently listed as the source being Dextromethorphan.

Is the correction this time around the actual source of the nitrosamine??? :open_mouth:

77

i can find some discussion here: EMA has updated its AI limits on 01 Aug 2025 - #15 by chrischar
and * N-Nitroso Brilliant Blue Impurity-1: Synthesis Attempts and Failure Report which, however, refers to another Brilliant blue impurity.
i know not much helpā€¦

1 Like
78

Thanks @elenipoliti

The same supplier does offer the impurity in the EMA list, though they donā€™t say how it has been formed, so whether it is possible to form from the dye, or of they have achieved the formation via another route.

3-((Ethyl(nitroso)amino)methyl)benzenesulfonic acid - Veeprho

1 Like
79

Dear MarkS,

In revision 5, the source of Nā€‘M8 was not described. But the Rev. 11 included the source as Dextromethorphan. Since the ā€œcorrectionā€ appears to be indicated in bold, it seems that the invalid source was the portion being corrected.