Analysis of Nitrosamines in APIs

In the summer of 2018, the pharmaceutical landscape for the manufacture of small molecules changed forever with the discovery of a small genotoxic compound in a batch of pharmaceuticals manufactured in China. Zhejiang Huahai pharmaceuticals produce valsartan, which is a prescription-only drug to treat high blood pressure and heart failure. It is a selective angiotensin II receptor blocker (ARB) which dilates blood vessels and so consequently reduces blood pressure. It is often given to patients directly after a heart attack. In performing the routine analysis, the quality control (QC) chemists found that there were approaching 60 ppm of N-nitrosodimethylamine (NDMA), which is high enough to cause one extra case of cancer in 500 patients. On the 5th July 2018, the European Medical Agency gave notice on their website that selected batches of valsartan were to be recalled with immediate effect. Since 2018, NDMA and other nitrosamines have been observed in a range of different pharmaceuticals.

This webinar will begin with a brief overview of nitrosamine formation, the chronological developments since 2018 and impacts on the regulatory landscape. We will then focus on the development of a LC-MS/MS method for the analysis of eight targeted nitrosamines. The method development will investigate how careful analysis of the physiochemical data can allow a better separation to be developed, in particular how the pH can affect both peak shape and retention time of individual nitrosamines. A The impact that the use of the mass spectrometer as a detector can have on the integrity of the analytical data will be thoroughly investigated. This will include an insight into the impact that ion suppression can have when analyzing real samples and also the impact that different calibration models have on the determination of a working LOD. The presentation will be summarized with a review of the data produced from a validatable method that can be applied to the analysis of nitrosamines in an active API. Potential issues arising from coelution of NMDA with DMF will be discussed, along with potential solutions, including an assessment of alternative column selectivity.