Do we worry too much about polysorbate degradation? An industry-wide perspective with real-life case studies

Polysorbates are commonly used in biotherapeutic drug formulations, but their stability over the course of the product's shelf life is a matter of concern. An industry-wide survey involving 15 biopharmaceutical companies found that 23 biotherapeutic drug products (DPs) in clinical development exhibited significant reductions in polysorbate (PS) content during long-term storage at 2-8 °C. In all cases, this decline did not impact critical quality attributes (CQAs), except for the formation of fatty acid (FA)-related sub-visible particles (SVP) in 7 DPs and FA-visible particles (VP) in 1 DP. Particle formation predominantly resulted from enzymatic or uncharacterized degradation mechanisms, not oxidative pathways. Corrective measures, such as optimization of downstream purification or reformulation, were undertaken only when SVP levels exceeded acceptable thresholds. For PS20 and PS80, the levels of FAs generated were estimated and translated into predicted SVP levels based on theoretical assumptions. Additionally, the current understanding of PS degradation in biopharmaceuticals, based on the latest literature, is summarized, with consideration of safety and immunogenicity aspects related to the primary PS degradation products. Overall, PS degradation is considered manageable and not problematic under practical conditions. Enzymatic hydrolysis of PS is generally deemed acceptable, provided that all CQAs are maintained within specified limits. If FA-related particles are formed it is recommended that the PS degradation pathway is well characterized, and an appropriate control strategy be implemented.