From Harmonisation to Practice: A Critical Appraisal of the Global Implementation of ICH M10 for Bioanalytical Method Validation and Study Sample Analysis

Abstract

Concentration measurements of drugs and their metabolites in biological matrices underpin regulatory decisions on safety, efficacy and labelling, and the technical requirements governing those measurements were, for three decades, set regionally. Guideline M10 of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, adopted at Step 4 in May 2022, replaced the principal regional texts with a single harmonised standard covering chromatographic and ligand binding assays for chemical and biological drugs. Four years of implementation experience now exist, yet the literature describing that experience has not been critically synthesised. This review appraises what harmonisation of the written standard has and has not achieved in practice. Adoption across regulatory authorities was staggered rather than simultaneous, and a substantial regulatory population remains outside the harmonised text. Convergence is asserted mainly through workshop reports, closed industry forums and annual white papers, with almost no primary quantitative evidence comparing regulatory outcomes before and after adoption. Four fault lines recur: cross-validation is mandated without an acceptance criterion; incurred sample reanalysis retains a fixed sampling burden whose diagnostic yield appears low; provisions for endogenous analytes and surrogate matrices have required substantial post hoc elaboration by professional bodies; and partial validation and method transfer remain under-specified for multi-site programmes. The exclusion of biomarkers and immunogenicity assays has produced a harmonisation paradox in which a guideline that disclaims these applications is nonetheless directed as their validation template in at least one region. The uniform criterion architecture, largely inherited rather than re-derived, is increasingly challenged by proposals for context-of-use-driven validation. The evidence base is concentrated in a small number of overlapping author networks and geographical regions, is predominantly consensus-based, and provides weak support for strong claims in either direction. Priorities for research include regulator-side outcome data, statistically justified acceptance criteria, and prospective evaluation of context-of-use frameworks.