LAUSR

ABSTRACT The study explores new benefits of controlled ice nucleation during lyophilization. A highly concentrated monoclonal antibody product was lyophilized using conventional (uncontrolled) and controlled ice nucleation freezing and the processes were compared for their impact on process performance, reconstitution time, and product quality attributes. Glass fogging was observed during the conventional ice nucleation freezing step and is investigated. A mechanical stress study was also conducted on the lyophilized product manufactured using uncontrolled and controlled ice nucleation to measure and compare propensity toward aggregation upon physical stresses associated with shipping and handling. Reduction in primary drying time and reconstitution time was achieved with controlled ice nucleation. In contrast to significant fogging observed for uncontrolled nucleation, glass fogging was absent in vials subjected to controlled ice nucleation. Uncontrolled nucleation freezing produced higher number of particles when subjected to mechanical stress prior to reconstitution compared to controlled nucleation lyophilized samples. The study confirms published benefits of controlled ice nucleation (e.g. reduction in primary drying time). The manuscript reports for the first time the advantage that controlled ice nucleation may offer in regards to glass fogging during lyophilization. The reduced number of particles in the controlled nucleated samples exposed to mechanical stress suggest that frictional forces play an important role in governing the stability of protein in the lyophilized state.