| Autor: Wiebke Ganter, Dr. Benjamin Lehmann

Nitrosamines: From valsartan to metformin – notorious impurities in drug products

Since June 2018, various N-nitrosamines have been detected worldwide in active pharmaceutical ingredients (APIs) of multiple manufacturers. Two referral procedures were started in the EU, referring to sartans (July 2018) and to ranitidine (September 2019).

N-nitrosamines are classified as probably carcinogenic to humans. Strict interim limits up to less than 1 ppm in the APIs have been established. This will be lowered to 30 ppb after a transitional period of 2 years. These limits represent a major challenge for the current technical state of ultra-trace analytics. Analytical methods must be a) highly sensitive to achieve reliable and reproducible detection of the analyte in the lower to middle ppb range and b) highly selective to enable precise determination in the presence of high amounts of matrix. Eligible methods include either liquid or gas chromatography coupled with a mass spectrometer. Due to the multitude and diversity of nitrosamines, it is impossible to develop one screening method that covers all of them, especially in the ultra-trace range. Therefore, each method must not only be specifically tailored to the API and its "own" set of N-nitrosamines, but also validated for each testing laboratory, the API and the change in composition.

By 26 March 2020, the manufacture of all medicinal products containing chemically synthesized APIs must be reviewed in detail to identify any risk of potential nitrosamines formation. All products at risk must be tested in order of priority. To ensure nitrosamine-free medicinal products, the MAH must implement appropriate control strategies and changes of the manufacturing process until September 2022.

Learn more: Article pharmind | 03/2020


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