Be Aggressive! Amorphous Excipients Enabling Single-Step Freeze-Drying of Monoclonal Antibody Formulations

Short freeze-drying cycles for biopharmaceuticals are desirable. Formulations containing an amorphous disaccharide, such as sucrose, are prone to collapse upon aggressive primary drying at higher shelf temperature.

We used 2-hydroxypropyl-betacyclodextrin (HPBCD) in combination with sucrose and polyvinylpyrrolidone (PVP) to develop an aggressive lyophilization cycle for low concentration monoclonal antibody (mAb) formulations. Glass transition temperature and collapse temperature of the formulations were determined, and increasingly aggressive cycle parameters were applied. Using a shelf temperature of +30 C during primary drying, the concept of combining sublimation and desorption of water in a single drying step was investigated. Cake appearance was evaluated visually and by micro-computed tomography. Lyophilisates were further analyzed for reconstitution time, specific surface area, residual moisture, and glass transition temperature.

We demonstrated the applicability of single-step freeze-drying, shortening the total cycle time by 50% and providing elegant lyophilisates for pure HPBCD and HPBCD/sucrose formulations. HPBCD/PVP/sucrose showed minor dents, while good mAb stability at 10 mg/mL was obtained for HPBCD/sucrose and HPBCD/PVP/sucrose when stored at 40 C for 3 months. We conclude that HPBCD-based formulations in combination with sucrose are highly attractive, enabling aggressive, single-step freeze-drying of low concentration mAb formulations, while maintaining elegant lyophilisates and ensuring protein stability at the same time. Download the full MDPI publication here: Be Aggressive! Amorphous Excipients Enabling Single-Step Freeze-Drying of Monoclonal Antibody Formulations

Conclusions Within the present study we demonstrated that scientists can be very aggressive during freeze-drying, using HPBCD-based formulations in combination with sucrose or PVP/sucrose. We were able to reduce cycle time by 50%, obtaining pharmaceutical elegant lyophilisates for pure HPBCD and HPBCD/sucrose, while HPBCD/PVP/sucrose showed minor dents. All other product quality attributes were similar, acceptable, and comparable to the conservatively freeze-dried sucrose formulation. Protein stability was ensured for all formulations upon freeze-drying and combinations of HPBCD/sucrose and HPBCD/PVP/sucrose at 10 mg/mL mAb provided good stability during storage at 40 C for 3 months. We believe that the proposed excipient combinations can be applied for higher concentrated protein formulations as well by adjustment of excipient to protein ratio. We conclude that the proposed single-step freeze-drying cycle using a binary mixture of HPBCD/sucrose has the potential to significantly reduce costs of goods due to more