Non-Regulated LC–MS/MS Bioanalysis in Support of Early Drug Development: A Novartis Perspective

Scientifically qualified LC–MS/MS methods are essential for the determination of small molecule drug candidates and/or their metabolite(s) in support of various non-regulated safety assessment and in vivo absorption, distribution, metabolism and excretion studies in preclinical development. This article outlines an effective method development workflow to fit for this purpose. The workflow features a ‘universal’ protein precipitation solvent for efficient sample extraction, a mobile phase additive for managing chromatographic resolution and addressing carryover and an internal standard cocktail to select the best analogue internal standard to track the analyte of interest in LC–MS/MS. In addition, good practices are recommended to prevent bioanalytical pitfalls due to instability, non-specific binding and dosing vehicle-induced matrix effect. Proper handling of non-liquid matrix is also discussed.