Losartan azide impurity confirmed as not an in vivo mutagen compound

[thiago.borges]

As published by EMA/CMDh/587072/2022

Report from the CMDh meeting held on 21-22 June 2022

In September 2021 the CMDh has published a letter addressed to MAHs of losartan-containing medicinal products to ask them to review if there is a risk of contamination of their product with an azido impurity (5-[4’ -[(5-(Azidomethyl)-2-butyl-4-chloro-1 H-imidazol-1-yl)methyl]-[1,1’-biphenyl]2-yl]-1H-tetrazole (CAS 727718-93-6) (‘losartan azide impurity’)).

This request was issued after it was confirmed that this impurity has tested positive in a bacterial mutagenicity (Ames) test and that therefore it should be ensured that the impurity is controlled at or below the Threshold of Toxicological Concern (TTC) as outlined in ICH M7 for known mutagens with unknown carcinogenic potential (class 2) via a suitable control strategy.

In November 2021 the CMDh communicated that uncertainties regarding the validity of the Ames test have been raised. It has now been confirmed by this new information that the losartan azide impurity is not an in vivo mutagen.

This means that losartan azide is classified as a class 5 impurity in accordance with ICH M7(R1) and can be controlled as a nonmutagenic impurity in accordance with ICH Q3A/B.

Actual publication:
CMDH PRESS RELEASES

Previous publication:
Azido impurity in losartan confirmed positive in bacterial mutagenicity test - action needed (informa.com)

[Naiffer_Host]

Fantastic development, thanks for sharing @thiago.borges
It will be quite insightful if we understand the investigation details…

[MonazBmysorewala]

Thank you Thiago for sharing information.
May we get hold on information that which type of in vivo assay was conducted and justification for selection of species?
Thanking you in advance.
Regards.

[Yosukemino]

Hi, @MonazBmysorewala.

@conudel explained details on it in another topic. I think it is helpful to you.

Sufficient AMES test, parameters

Indeed Losartan Azide has been determined to be nonmutagenic in the in vivo comet assay after it was positive in the Ames test. This has now been confirmed also by CMDh and it is now accepted as a Class 5 impurity that can be controlled in accordance with ICH Q3A/B. However, this is true for the azido impurity and currently this method is not accepted for nitrosamines by the health authorities. Namely, the comet assay is not considered by the HAs as a valid test for nitrosamines, and currently …

[minhluan]

CMDh_press_release_-_June_2022_01.pdf (215.8 KB)
Updated July 18, 2022. Sincerely,

[IreneNS]

Hello:
I write to inform and ask for help if someone in the forum knows the subject. Could you point us to the comet assay study?
For Japan this note is not allowed.

According to Japan, since the source is not clear and PDMA does not have any current reference to losartan azide, they do not consider the criteria of the press release valid.
Thank you very much for your help
Irene