Potential risk factors of protein aggregation in syringe handling during antibody drug dilution for intravenous administration

Abstract

Protein aggregation, a major concern in biopharmaceutical quality control, can be accelerated by various stresses during clinical handling. This study investigated potential aggregation risk factors during dilution process with syringe handling for intravenous administration. Using γ-globulin and IgG solutions as surrogate models of antibody therapeutics, we examined the effects of high sliding speeds and piston operations of the syringe on protein aggregation during saline dilution. Our results revealed that elevated sliding speeds promoted proteinaceous subvisible and/or visible particle formation, which was further enhanced by piston operations. The proteinaceous particle formation was presumed to be caused by fine air bubbles generated due to rapid pressure changes arising from shear stress during needle passage. While polysorbate 20 effectively suppressed the particle formation induced by the syringe handling at sufficient concentrations, its protective effect became inadequate under high dilution conditions, as exemplified by those encountered in low-body-weight patient protocols. Different proteins exhibited varying susceptibility to the syringe-induced aggregation. These findings demonstrate that the combination of syringe handling and dilution conditions could significantly impact protein stability during clinical handling, particularly for less stable biopharmaceuticals. A deeper understanding of these factors is crucial for developing more robust formulations and establishing safer handling practices for biopharmaceuticals.