Europe – Sartans Article 31 referral – CHMP assessment report

1. Information on the procedure

The EU authorities were notified on June 2018 that an Active Pharmaceutical Ingredient (API) manufacturer (Zhejiang Huahai Pharmaceutical, China) has detected the presence of a previously undetected process impurity, N-nitrosodimethylamine (NDMA, also known as dimethylnitrosamine) in the valsartan API manufactured at its site in Chuannan. Zhejiang Huahai (ZH) is one of the API manufacturers that are supplying valsartan for medicinal products authorised in the EU.
NDMA is a genotoxic and carcinogenic agent in animals and it is classified as probably carcinogenic to humans (Class 2A carcinogen) by the International Agency for Research on Cancer (IARC, WHO). ZH provided an initial investigation report on the root cause of the presence of NDMA upon request from the supervisory authority in Italy (AIFA). This initial investigation report by the manufacturer indicated that NDMA is formed at the tetrazole ring-forming step in ZH’s valsartan API manufacturing process, (which includes quenching of remaining azide with nitrous acid) and the level of NDMA present may depend on the reaction conditions used.
On 5 July 2018 the EC triggered a referral under Article 31 of Directive 2001/83/EC and requested the CHMP to assess the impact of the above concerns on the benefit-risk balance of valsartan-containing medicinal products and to issue a recommendation on whether the relevant marketing authorisations should be maintained, varied, suspended or revoked.
After the referral procedure started, NDMA was also identified in valsartan from some other API manufacturers, including Zhejiang Tianyu. In addition, further N-nitroso impurities were identified in some valsartan batches and in batches of other sartans.
During the CHMP plenary meeting in September 2018, the scope of the referral was widened to include all sartans with a tetrazole moiety in their molecular structure…