Model-based design and control of a small-scale integrated continuous end-to-end mAb platform

Area of Science:

• Biopharmaceutical Manufacturing
• Process Engineering
• Biotechnology

Background:

• Traditional bioprocess development can be lengthy and inefficient.
• Small-scale production is crucial for early-stage drug candidate evaluation.
• Integrated continuous manufacturing offers potential advantages in speed and efficiency.

Purpose of the Study:

• To present a proof-of-concept for a continuous, end-to-end monoclonal antibody production platform at a small scale.
• To integrate a perfusion bioreactor with a fully automated downstream purification process.
• To utilize model-based design and control for process optimization and automation.

Main Methods:

• Utilized a 200 mL alternating tangential flow filtration perfusion bioreactor for continuous cell culture.
• Implemented a compact downstream purification train including Protein A capture, virus inactivation, CEX, and AEX chromatography within a single system.
• Developed a digital twin of the downstream process for model-based control and real-time decision-making.

Main Results:

• Achieved monoclonal antibody titers up to 1.0 mg/mL in high cell density perfusion culture over 17 days.
• Completed downstream purification in under 4 hours with a recovery yield up to 60%.
• Demonstrated at least a 4-log reduction in host cell protein (HCP) levels and consistent glycosylation patterns.

Conclusions:

• The developed continuous integrated bioprocess facilitates efficient and rapid development of monoclonal antibody production.
• Model-based control strategies successfully automated and optimized the integrated process.
• The platform provides a robust solution for small-scale production of therapeutic antibodies with high purity and consistent quality.