Multiple approaches to reduce reconstitution time of lyophilized drug products with high protein concentration

Abstract

Lyophilized drug products with high protein concentration often perform long reconstitution time, which is inconvenient for clinical use. The objective of this work is to achieve short reconstitution time with multiple and combined strategies. In this paper, we describe the following approaches that lead to reduction of reconstitution time. In terms of lyophilization process, using annealing step during freezing can increase the pore size of lyophilized cake, and decreasing headspace pressure in vial before stoppering can also help solvent penetrate through lyophilized cake. Regarding to formulations, it is an effective strategy of decreasing protein concentration or reducing diluent volume to achieve high protein concentration after reconstitution. Considering container size, high surface-area-to-height ratio of the cakes is also beneficial for reduction of reconstitution time. In addition, reconstitution methods, for example, increasing frequency of swirling and diluent temperature are also helpful to reduce reconstitution time. Among these strategies, reducing diluent volume to achieve high protein concentration and reducing headspace pressure show markedly reduction of reconstitution time. Moreover, we propose combined strategies to mitigate the reconstitution time, at the same time, to achieve same target dose in clinics. The combination of all factors can achieve the overall reduction ratio of 98%, and will not influence the product quality. Therefore, this paper provides insights on the application of multiple strategies to accelerate the reconstitution of lyophilized drug products with high concentration, and facilitates their widespread clinical application.