Monitoring of sartan medicines stepped up: traces of a new foreign substance detected

In October 2020, pharmaceutical companies and Swissmedic found traces of azidomethyl-biphenyl-tetrazole (AZBT) in batches of the active substance irbesartan. This impurity is not a nitrosamine. AZBT can occur as a by-product in certain synthesis steps during the production of sartan active substances but must no longer be detectable in the finished medicinal product. As early as November 2020, individual medicinal product batches were withdrawn from the market in Switzerland. Further precautionary batch recalls are not ruled out.

Since nitrosamine contamination was first detected in 2018 in various medicines – including antihypertensive sartan-based products – Swissmedic, in collaboration with international partner authorities, has introduced measures to prevent such impurities. The European Pharmacopoeia has also been revised accordingly.

Companies were required to assess possible risks of nitrosamine formation during manufacture and, if necessary, adapt their production processes in order to minimise the nitrosamine content. They are also expected to implement a control strategy for detecting and controlling nitrosamine impurities. In connection with these measures, in October 2020 a production-related contamination with the substance azidomethyl-biphenyl-tetrazole^[1] (AZBT) was found in individual sartan active substance batches.

AZBT can form as a result of a starting material (azide) that is used to assemble a specific structural element (tetrazole ring) of active substances in the sartan group. Since new findings indicated that AZBT must now be classed as mutagenic, individual irbesartan batches were withdrawn from the Swiss market due to the detected AZBT levels back in November 2020 as a precautionary measure.

The authorisation holders of sartan preparations were required to check their active substance batches specifically for this impurity. In parallel, Swissmedic's Official Medicines Control Laboratory (OMCL) has developed and validated a new analytical test method for AZBT and now conducts its own investigations with active substance and medicinal product samples. The first results are expected in the summer of 2021. Medicinal product batches with unacceptable levels of AZBT will be withdrawn from the market.

This detection of a previously unidentified impurity in well-known active substances is also attributable to the ever growing sensitivity of the analytical methods used in the quality control of medicines. The analytical monitoring of active substances and medicinal products for by-products or degradation products remains an important task of drug manufacturers and authorities and must be continued and further improved. Swissmedic takes all the measures needed to protect patients and guarantee the quality of medicines on the Swiss market. Depending on the result of the ongoing investigations, Swissmedic will institute any necessary measures and, in particular, order the withdrawal of contaminated batches from the market.

^{[1] (5-(4’-(azidomethyl)-[1,1’-biphenyl]-2-yl)-1H-tetrazole)}