EMA To Require Companies To Review Mfg Process for Nitrosamine Impurities in Sartan Products

By Patricia Van Arnum - DCAT Editorial Director

February 8, 2019

The European Medicines Agency (EMA) has announced that companies that make “sartan” blood-pressure medicines (also known as angiotensin II receptor blockers) are now required to review their manufacturing processes so that they do not produce nitrosamine impurities. The requirement follows a review and investigation by the EMA dating back to 2018 of “sartan” products containing N-nitrosodimethylamine (NDMA) and N‑nitrosodiethylamine (NDEA), which are classified as probable human carcinogens and that were detected in some sartan medicines.

The review involved the “sartans” of candesartan, irbesartan, losartan, olmesartan and valsartan. These sartan medicines have a specific ring structure (tetrazole) whose synthesis could potentially lead to the formation of nitrosamine impurities. Other medicines of the class that do not have this ring, such as azilsartan, eprosartan, and telmisartan, were not included in the review. These medicines are used to treat patients with hypertension (high blood pressure) and those with certain heart or kidney diseases. They work by blocking the action of angiotensin II, a hormone that constricts blood vessels and causes blood pressure to rise.

The review of valsartan medicines was triggered by the European Commission in July 2018 and was extended in September 2018 to include medicines containing candesartan, irbesartan, losartan, and olmesartan. The review was carried out by EMA’s Committee for Medicinal Products for Human Use (CHMP), responsible for questions concerning medicines for human use, which adopted the EMA’s opinion. The CHMP opinion will now be forwarded to the European Commission, which will issue a final legally binding decision applicable in all European Union member states.

Companies will have a transition period to make any necessary changes during which the EMA said that “strict temporary limits on levels of these impurities will apply.” After this period, companies will have to demonstrate that their sartan products have no quantifiable levels of these impurities before they can be used in the European Union (EU).

These recommendations follow the EMA’s review of NDMA and NDEA that were detected in some sartan medicines. The EMA said that for the vast majority of sartan medicines, impurities were either not found or were present at very low levels. The EMA said that its review estimated the highest possible cancer risk with these impurities. It concluded that if 100,000 patients took valsartan from Zhejiang Huahai, a Linhai, China-based pharmaceutical company, for which the highest levels of impurities were found, every day for six years at the highest dose, there could be 22 extra cases of cancer due to NDMA over the lifetimes of those 100,000 patients. NDEA in these medicines could lead to eight extra cases in 100,000 patients taking the medicine at the highest dose every day for four years.

Before June 2018, NDMA and NDEA were not among the impurities identified in sartan medicines and were therefore not detected by routine tests, said the EMA. The agency said it is now known that these impurities can form during the production of sartans that contain a specific ring structure known as a tetrazole ring under certain conditions and when certain solvents, reagents, and other raw materials are used. In addition, it is possible that impurities were present in some sartans because manufacturers had inadvertently used contaminated equipment or reagents in the manufacturing process.

The EMA said that while the goal is to have no quantifiable nitrosamine impurities in sartans, interim limits have been set for NDMA and NDEA in line with current international guidelines. Products containing either impurity above these limits or products containing both nitrosamines at whatever level will not be allowed in the EU. 

The limits are based on the maximum daily intake for each impurity derived from animal studies: 96.0 nanograms for NDMA and 26.5 nanograms for NDEA. Dividing these by the maximum daily dose for each active substance gives the limit in parts per million.

The transition period, which will last for two years, will allow companies to make the necessary changes to their manufacturing processes and to put in place testing regimes able to detect the smallest amounts of these impurities. After the transition period, companies must exclude the presence of even lower levels of NDEA or NDMA in their products (< 0.03 parts per million).

The EMA said it and national authorities will continue investigating the presence of nitrosamine impurities in medicines, including other impurities such as N-nitrosoethylisopropylamine (EIPNA), N-nitrosodiisopropylamine (DIPNA) and N-nitroso-N-methylamino butyric acid (NMBA).

EMA’s recommendations for NDMA and NDEA will now be sent to the European Commission for a legally binding decision. An assessment report with further details about the review will be published on the EMA’s website.

In a related development, the US Food and Drug Administration provided an update of its investigation into sartan products and possible shortages related to subsequent product recalls. 

Source: European Medicines Agency