Analytical lifecycle management for comprehensive and universal nitrosamine analysis in various pharmaceutical...

Since the detection of nitrosamines (NA) in valsartan pharmaceuticals, over two years have passed. At present, the occurrence of NAs can be limited to a few drug substances and drug products, but it is already becoming apparent that the issue appears to be much bigger than initially thought. The impact on the global pharmaceutical market has been tremendous and the problem can be attributed mainly to uncritically adopted approval changes and the lack of suitable, modern analytical methods to detect those impurities in time. We hereby demonstrate how lifecycle management (LCM) can be used to develop and improve suitable and universal analytical methods within short time. The resulting SFC-MS/MS method is intended for a universal nitrosamine investigation in drug substances and drug products. Successful NA analysis was demonstrated for seven sartans, metformin, pioglitazone and ranitidine. Additionally, combination drug products, containing also amlodipine, hydrochlorothiazide, vildagliptin and sitagliptin, were analyzed successfully. The method achieved separation of 16 NAs in 4 min with a total run time of 11.5 min, utilizing a Supel Carbon porous graphitic carbon (PGC) column. Carbon dioxide together with 0.1% TFA in methanol as modifier were used as eluents and 0.35% formic acid in methanol as make-up solvent for mass spectrometric NA detection. By implementing LCM in this case study, development time was reduced and knowledge was implemented fast. At the same time, a high adaptability of this "vital" method was achieved, which makes it possible to implement the constantly changing regulatory requirements within the shortest possible time. Supplemental development data, according to the ICH guidelines Q8, Q12 and the proposed Q14 are disclosed, demonstrating the scientific Quality-by-Design (QbD) development approach, the "fitness for use" and the robustness of the analytical procedure. This method contributes to the still ongoing risk assessment process of the pharmaceutical industry and the regulatory agencies, in order to understand root causes of NA formation, maintain the drug supply and prevent drug shortage.