LAUSR

Aggregates and particles may be generated by positive displacement piston pumps during fill-finishing operations for protein formulations. We investigated potential factors that might contribute to aggregation in intravenous IgG (IVIG) formulations during pumping, including electrostatic interactions between protein molecules and pump surfaces, cavitation, and aggregate nucleation from particles shed from pumps. Electrostatic interactions were investigated by modifying pump surface chemistry. Cavitation as a potential cause of particle formation was investigated by changing pumping speeds, and the possibility that particles shed from pump surfaces act to nucleate protein aggregation was explored by spiking pre-pumped buffer solutions into IVIG formulations. Neither cavitation nor particles shed from pump surfaces played dominant roles in generating particles. Per pump cycle, production of particles and protein aggregates was constant, and corresponded with the amount of protein expected to adsorb on pump surfaces at monolayer coverage. More sub-visible particles and protein aggregates were generated in formulations containing higher concentrations of IVIG, but they reached a plateau at protein concentrations above 2 mg/mL, where adsorption isotherms saturated. Negatively charged pump surfaces interacted with the positively-charged IVIG to produce more particles and aggregates than positively charged surfaces, an effect ascribed to electrostatic interactions that moderated rates of protein adsorption.