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

Area of Science:

• Pharmaceutical Sciences
• Biotechnology
• Materials Science

Background:

• Freeze-drying (lyophilization) is crucial for biopharmaceutical stability.
• Amorphous disaccharide formulations, like sucrose, risk collapse during aggressive drying.
• Optimizing lyophilization cycles is key for efficient biomanufacturing.

Purpose of the Study:

• To develop an aggressive, single-step lyophilization cycle for low concentration monoclonal antibody (mAb) formulations.
• To evaluate the use of 2-hydroxypropyl-betacyclodextrin (HPBCD) in combination with sucrose and polyvinylpyrrolidone (PVP).
• To assess the impact of aggressive freeze-drying on cake appearance, reconstitution, and protein stability.

Main Methods:

• Formulation development using HPBCD, sucrose, and PVP.
• Determination of glass transition and collapse temperatures.
• Application of aggressive primary drying at +30 °C shelf temperature.
• Evaluation of lyophilisate quality (visual, micro-CT, residual moisture, SSA, reconstitution time).
• Assessment of mAb stability under accelerated storage conditions.

Main Results:

• Single-step freeze-drying successfully reduced total cycle time by 50%.
• HPBCD and HPBCD/sucrose formulations yielded elegant lyophilisates.
• HPBCD/PVP/sucrose formulations showed minor surface defects but maintained good mAb stability.
• Monoclonal antibody stability was confirmed for HPBCD/sucrose and HPBCD/PVP/sucrose formulations after 3 months at 40 °C.

Conclusions:

• HPBCD-based formulations, particularly with sucrose, enable aggressive, single-step freeze-drying for low concentration mAb formulations.
• This optimized approach maintains elegant cake structures and ensures long-term protein stability.
• HPBCD offers a promising strategy for efficient and stable lyophilization of biopharmaceuticals.