A Comprehensive Review on the Stability and Degradation of Polysorbates in Biopharmaceuticals

Polysorbates (PS), particularly polysorbate 20 (PS20) and polysorbate 80 (PS80), are widely utilized as non-ionic surfactants in biopharmaceutical formulations. Their primary role is to stabilize therapeutic proteins against interfacial stresses encountered during manufacturing, handling, and storage. Despite their widespread use, PS are complex and heterogeneous mixtures prone to degradation. The two primary degradation pathways are hydrolysis and oxidation. Hydrolytic degradation is often enzyme-mediated, commonly by residual host cell proteins such as lipases and phospholipases. Oxidative degradation can be initiated by light, temperature, metal ions, or peroxides present as impurities in raw materials. PS degradation yields various products, including free fatty acids (FFA), short-chain organic acids, aldehydes, ketones, and peroxides. The complexity of PS and their degradation products necessitates the use of sophisticated analytical methods for comprehensive characterization and monitoring. Techniques such as liquid chromatography coupled with mass spectrometry (LC-MS), charged aerosol detection (CAD), or evaporative light scattering detection (ELSD), as well as specific assays for FFA and peroxides, are employed. A significant concern arising from PS degradation is the formation of visible and subvisible particles, often composed of poorly soluble FFAs. While PS degradation and particle formation may not always impact protein quality attributes such as aggregation or biological activity under certain conditions, their potential consequences on product quality, safety, and compliance require careful consideration. Effective mitigation and control strategies involve stringent raw material qualification, optimization of manufacturing processes, robust formulation development, and comprehensive stability testing with appropriate analytical methods.