Companies to review manufacturing processes to avoid presence of nitrosamine impurities: EMA
Companies that make sartan blood pressure medicines (also known as angiotensin II receptor blockers) are being required to review their manufacturing processes so that they do not produce nitrosamine impurities.
Companies will have a transition period to make any necessary changes, during which 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 EU.
These recommendations follow EMA’s review of N-nitrosodimethylamine (NDMA) and N nitrosodiethylamine (NDEA), which are classified as probable human carcinogens (substances that could cause cancer) and have been detected in some sartan medicines.
For the vast majority of sartan medicines, impurities were either not found or were present at very low levels.
The review estimated the highest possible cancer risk with these impurities. It concluded that if 100,000 patients took valsartan from Zhejiang Huahai (where the highest levels of impurities were found) every day for 6 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 8 extra cases in 100,000 patients taking the medicine at the highest dose every day for 4 years.
Before June 2018, NDMA and NDEA were not among the impurities identified in sartan medicines and were therefore not detected by routine tests.
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.
Companies must now take measures to avoid the presence of these impurities and carry out rigorous testing of their products.
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.