Co-Ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) has written to a marketing authorisation for a sartan-containing medicinal product informing that the impurity 5-(4’-(azidomethyl)-[1,1’-biphenyl]-2yl)-1H-tetrazole (CAS number 152708-24-2) has tested positive in two independent bacterial mutagenicity (Ames) tests.
Further informed that in the absence of additional information from in vivo studies it is necessary to ensure that 5-(4’- (azidomethyl)-[1,1’-biphenyl]-2yl)-1H-tetrazole and related azido compounds are 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.
Agency asked MA holder to review if there is a risk of contamination of your sartan-containing medicinal product with the before mentioned or related azido-compounds above the TTC.
EDQM is also contacting holders of CEPs for relevant sartans. If at any stage of the process an azide is used as a reagent, this should be seen as a risk.
In line with the considerations for marketed products outlined in ICH M7, if MA holder identify a risk of contamination that has so far not been considered or is so far not appropriately controlled, MA holder are required to take action to ensure that the level of these impurities is below the TTC and to put in place an appropriate control strategy. This may require a variation to the marketing authorisation.
If confirmatory testing reveals that batches of medicinal product currently on the market in the EEA exceed the applicable TTC limit, regulatory action may be needed, and the Quality Defect should be reported to the relevant competent authority as soon as possible as set out in Article 13 of Directive 2003/94/EC.