In 2018, regulatory authorities were alerted that several products containing valsartan, a blood pressure medication, also had a nitrosamine impurity. Over long periods of exposure, nitrosamine impurities may increase the risk of cancer if people are exposed above acceptable levels. Medicines containing valsartan were immediately recalled and a review was triggered to better understand how this happened. The review determined that the use of a solvent known as dimethylformamide combined with sodium nitrite in the presence of an acid led to the formation of the nitrosamine impurity during the manufacture of sartan active pharmaceutical ingredients (APIs). The subsequent review made recommendations covering prevention, incident management, market surveillance, communication and international cooperation. The recent Committee for Medicinal Products for Human Use (CHMP) report and FDA guidance advocate companies to take measures to limit the presence of nitrosamines in human medicines as far as possible and to ensure levels of these impurities do not exceed set limits.
This case demonstrated the need for revisions to the regulatory framework to improve transparency throughout the pharmaceutical industry. Better communication between marketing authorization holders, API manufacturers and others over patient safety could have prevented this impurity from appearing in products containing valsartan. The study also showed the importance of improving risk management tools, particularly for post-approval activities. Many of the potential revisions to the key post approval guidelines focus on thorough process understanding and risk evaluations, even in the case of traditionally considered ‘minor changes.’