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Risk of the presence of mutagenic azido impurities in losartan active substance

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Certification of suitability (CEP)
Chemical purity
News
29 September 2021
Strasbourg, France

In April 2021, the European Directorate for the Quality of Medicines & HealthCare (EDQM) reported that it had received information about the possible presence of potentially mutagenic azido impurities in certain sartan active substances. Investigations requested by the EDQM indicated that only a few sources were impacted. A number of measures were taken to ensure that any active substance containing these impurities above the acceptable level would not be released onto the market. In addition, any impacted holders of a Certificate of Suitability (CEP) were requested to take corrective action to ensure that such impurities do not exceed their acceptable limits in the future. The EDQM review of these actions in the impacted sources has been completed for some manufacturers and is well advanced for others.

These recent investigations recently resulted in the identification of another azido impurity that has so far only been detected in losartan potassium: 5-[4'-[(5-(azidomethyl)-2-butyl-4-chloro-1H-imidazol-1-yl)methyl]-[1,1'-biphenyl]2-yl]-1H-tetrazole (CAS 727718-93-6) (“losartan azido impurity”). This impurity has tested positive in a bacterial mutagenicity (Ames) test.

In the absence of additional information from in vivo studies, it is necessary to ensure that this azido impurity is controlled at or below the Threshold of Toxicological Concern (TTC, see ICH M7 for more details). The sources impacted by this azido issue have been identified and the EDQM’s review of any necessary corrective action taken by companies is currently either complete or well advanced.

Addressing the presence of azido impurities in sartan active substances – and ensuring users of such medicines are protected from any potential risk – is of the highest priority to the EDQM. The EDQM will therefore take any necessary action on CEPs (e.g. suspension) when CEP holders are considered not to be fully engaged in meeting these objectives.

The EDQM reminds all CEP holders of their obligation to provide appropriate information relating to azido impurities to marketing authorisation holders, thus enabling them to use this information to fulfil their legal responsibilities.

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