Managing Analytical Procedure Lifecycles: Resolving Longstanding Mass Spectrometry Challenges for Emerging Nitrosamine and NDSRI Impurities

The nitrosamine crisis began in July 2018 when N-nitrosodimethylamine (NDMA) was discovered in valsartan products. The potential carcinogenicity of nitrosamines and nitrosamine drug substance-related impurities (NDSRIs) triggered recalls, global regulatory action, and a significant overhaul of drug quality control to prevent future contamination. In response, FDA laboratories rapidly developed and validated analytical methods for NDSRIs and nitrosamines, primarily using liquid chromatography-mass spectrometry (LC-MS/MS) and gas chromatography-mass spectrometry (GC-MS/MS) techniques.        

The pharmaceutical industries are still facing significant analytical challenges in quantifying NDSRIs and nitrosamines due to their trace-level presence, chemical diversity, and matrix complexity. Additionally, mass spectrometry has not been routinely used in QC environment until recently and the ICH Q2(R1) Validation of Analytical Procedure guideline (2005) did not provide detailed recommendations for mass spectrometry methods. The presentation will discuss best practices for mass spectrometry based on analytical procedures for NDSRIs and nitrosamines based on FDA laboratories’ experience. These best practices and case examples of troubleshooting common analytical challenges shared in this presentation might help industries navigate the complex technical requirements while ensuring patient safety and product quality

Presented by Jinhui Zhang, Chemist at FDA/CDER

Dr. Jinhui Zhang is a Senior Pharmaceutical Scientist at the FDA/CDER. His research at FDA focuses on using advanced mass spectrometry for the characterization of biotherapeutics, complex drug products, as well as bioanalysis in support of clinical pharmacology and bioequivalence. He has given over 60 invited podium presentations at international conferences such as, AAPS, AAPS NBC, ACS, IFPAC etc; and published 50 peer reviewed publications on implementing ICH M10, Q14, Q2(R2) and Q12 guidelines, advanced characterization of complex modalities, clinical and preclinical pharmacokinetics. Dr. Zhang is an associate director advisory committee member of CASSS.

Followed by a live question and answer session