Standardization of the Reconstitution Procedure of Protein Lyophilizates as a Key Parameter to Control Product Stability.
Lyophilization of protein formulations is an essential tool for stabilization and is becoming increasingly important for pharmaceutical development. Reconstitution of the lyophilized cakes is crucial to obtain an applicable product. Nowadays, manual reconstitution by patients or medical staff is the common method defined in instructions for marketed lyophilized drug products. Even though this step is influencing the quality of the final solution, it can represent a challenge to develop a standardized manual protocol and the performance is highly dependent on human factors. This study summarizes the implementation and performance of controlled reconstitution studies for protein lyophilizates applying a mechanical reconstitution device. Using automated and standardized protocols, reconstitution time of a bispecific antibody lyophilizate could be reduced effectively from 25 to below 5 min compared to the predeveloped manual protocol. It was shown that the reconstitution protocol is influencing the stability of sensitive proteins. Monomer content as well as formation of subvisible particles differed considerably between the tested protocols emphasizing the relevance of standardized procedures.