Polysorbate degradation and particle formation in a high concentration mAb: formulation strategies to minimize effect of enzymatic polysorbate degradation.

Abstract Polysorbate (PS) 20 and 80 are the most common surfactants in monoclonal antibody (mAb) drug product (DP) formulations. Residual host cell proteins (HCP) present at extremely low concentrations in DP formulations can maintain enough enzymatic activity to degrade PS surfactants. Over time, the hydrolysis of surfactant causes the accumulation of minimally soluble free fatty acids resulting in precipitation and formation of subvisible and visible particulates. This manuscript summarizes the investigation of a batch of high concentration (>100 mg/mL) mAb DP where subvisible particles formed abruptly after prolonged storage at 5C°. The work also summarizes the effectiveness of different strategies for managing host cell proteins and fatty acid particles. The concentration and fatty acid composition of polysorbates were found to be significant factors in particle development. Solubilizers and alternative surfactants were all shown to be effective means of preventing particle formation. Lipase inhibitors proved to be a simple means to identify the problem but are more difficult to utilize as a solution.