Metal-Catalyzed Degradation of Polysorbates in Biopharmaceutical Formulations: Mechanisms, Analytical Approaches, and Mitigation Strategies

Polysorbate 20 and polysorbate 80 are the most widely used nonionic surfactants in biopharmaceutical formulations, and they serve as critical excipients protecting therapeutic proteins from interfacial damage and aggregation. Traditionally considered chemically inert, polysorbates are now known to undergo substantial degradation, compromising formulation stability. Polysorbate degradation proceeds via chemical hydrolysis, enzymatic hydrolysis, and oxidative pathways. In particular, trace transition metal ions initiate catalytic oxidation through Fenton and Haber–Weiss reactions to generate reactive oxygen species, triggering a self-amplifying cascade of polysorbate autoxidation and subsequent protein oxidative damage. Metal contaminants originate from raw materials, manufacturing equipment, and primary packaging, and degradation can be induced at trace concentrations, posing considerable challenges for contamination tracing and risk control. Despite the ubiquity of metal contaminants, the current literature lacks systematic and integrated mechanistic analyses of metal-catalyzed polysorbate degradation. This review comprehensively describes the structural characteristics, differential degradation profiles, metal-mediated oxidation mechanisms, and contamination sources of polysorbates before discussing the analytical methodologies and multi-barrier mitigation strategies used to address polysorbate use. The knowledge gaps identified and future research recommendations provided in this review offer mechanistic insights into quality optimization, risk management, and long-term stability control of biotherapeutic formulations.