Scaling Up Controlled Nucleation in Freeze Drying: Translating Vacuum-Induced Surface Freezing from Laboratory to GMP.

The freezing step often causes batch inhomogeneity and issues during freeze drying process transfer. The nucleation temperature at which the first ice is formed during freezing differs from vial to vial, and significantly between scales. To solve this issue, Controlled Ice Nucleation techniques can be applied to induce ice nucleation at a defined product temperature across the whole batch. This study describes the application of vacuum-induced surface freezing (VISF) for a therapeutic antibody formulation, including the process transfer from laboratory scale through pilot scale to a GMP line. The VISF method could be successfully implemented on all scales of freeze dryers without equipment adaptation. Some scale-dependent changes in pressure control and degassing were necessary to achieve nucleation in all vials and avoid defects. The resulting lyophilized products were characterized and further analyzed in a stability study. While most critical quality attributes were comparable for product manufactured with and without Controlled Nucleation, the appearance of cakes processed using VISF was much better, which could be linked to different product morphology due to freeze-concentration. The results of this study allow direct comparison of the application of controlled nucleation for an antibody formulation at different scales and confirm the applicability of the technology.