Managing Nitrite Impurities: A Supplier Manufacturer Approach to Mitigating Nitrosamine Risk

Nitrosamines first emerged as a public health concern in 2018 when N-nitrosodimethylamine (NDMA) was discovered in products containing valsartan, an angiotensin II receptor blocker. Subsequently, other pharmaceuticals with unacceptable levels of nitrosamine impurities were identified, including ranitidine, nizatidine, and metformin HCl. NDMA is a genotoxic and carcinogenic agent in animals and is classified as probably carcinogenic to humans by the International Agency for Research of Cancer. A comprehensive assessment of active pharmaceutical ingredients (APIs), formulated drug products, and packaging revealed the presence of nitrosamine drug-substance-related impurities (NDSRIs). The formation of NDSRIs may result from the presence of potentially nitrosatable secondary or tertiary amine moieties in APIs or API impurities and nitrosating agents formed from low levels of nitrite present as impurities. In response to these concerning findings, regulatory authorities published guidance requiring pharmaceutical companies to assess both chemical and biological products for the possible presence of nitrosamines and define appropriate mitigation actions. Our white paper provides a detailed overview of the formation of NDSRIs and the regulatory guidance that requires pharmaceutical companies to assess both chemical and biological products for the possible presence of nitrosamines and define appropriate mitigation actions. It also includes a case study highlighting strategies to avoid NDMA formation in metformin drug products, making it an essential read for those aiming to enhance their approach to pharmaceutical safety and risk management.