UK Regulators Recall Batches of “Sartan” Drug for Azido Impurities

The UK Medicines and Healthcare products Agency (MHRA) is recalling 25 batches of irbesartan-containing products as a precautionary measure due to contamination with an azido impurity, which the agency says has mutagenic potential. The batches are being recalled for the level of contamination being above the acceptable limit for the impurity, 5-(4’-(azidomethyl)-[1,1’-biphenyl]-2yl)-1H-tetrazole.

The azido impurity is a new impurity cited by regulators in “sartan” products, in this case for irbesartan, an anti-hypertensive and cardiovascular drug. In 2018, the FDA and the European Medicines Agency initiated investigations of nitrosamine impurities in certain “sartan”-containing APIs, such as valsartan, candesartan, irbesartan, losartan, and olmesartan. They later broadened those investigations into prescription and over-the-counter forms of ranitidine, a H2 (histamine-2) blocker used to decrease the amount of acid created by the stomach, and later metformin extended-release products, drugs to treat Type II diabetes. The agencies subsequently issued recommendations on the steps manufacturers of active pharmaceutical ingredients (APIs) and drug products should take to detect and prevent unacceptable levels of nitrosamine impurities in pharmaceutical products.

The current recall for the azido impurity applies to certain batches of Sanofi’s Aprovel and CoAprovel and film-coated irbesartan tablets made by Zentiva, a Prague, Czech Republic-based generics company. The recall also extends to parallel distributors of the select batches: Doncaster Pharmaceuticals, MPT Pharma, PCO Manufacturing, and Gowrie Laxmico. The recall is for pharmacies and wholesalers and is not a patient-level recall.

The current recall is a second recent recall by the MHRA for azido impurities in sartan-containing products. In June (June 2021), the MHRA recalled select batches of irbesartan-containing products by Bristol Laboratories, a Berkhamsted Hertfordshire, UK-based generic-drug company, and Brown & Burk, a generic-drug company in Kent, UK, as well as a recall of select lots of losartan-containing products by Teva.

In April (April 2021), the European Directorate for the Quality of Medicines & HealthCare (EDQM), a quality and standards-setting organization for the European Union, first identified azido impurities in sartan APIs with a tetrazole ring. At that time, the EDQM said that its review of data received, performed according to the requirements of a guideline by the International Conference on Harmonization (ICH) on the safety and quality risk management in establishing levels of mutagenic impurities, showed that only a few sources were related to the azido impurity and that appropriate actions were being taken to ensure that the level of azido impurities was below the threshold of toxicological concern in these sources.