An automated high inoculation density fed-batch bioreactor, enabled through N-1 perfusion, accommodates clonal...

Area of Science:

• Biopharmaceutical Manufacturing
• Biotechnology
• Process Intensification

Background:

• High cost of goods (CoGs) in biotherapeutics manufacturing necessitates increased bioreactor productivity.
• Traditional low inoculation density (LID) fed-batch processes limit overall manufacturing efficiency.

Purpose of the Study:

• To demonstrate an intensified bioprocess for enhanced bioreactor productivity.
• To evaluate the generalizability of the intensified process across diverse CHO cell lines and monoclonal antibodies.

Main Methods:

• Coupling a perfused N-1 seed reactor with a high inoculation density (HID) N-stage reactor.
• Utilizing in-line process analytical technologies (PAT) for automated nutrient feeding in both reactor stages.
• Employing in-line capacitance for N-1 stage feeding and Raman spectroscopy for N-stage monitoring of key nutrients.

Main Results:

• Achieved an average 85% titer increase and 132% space-time yield (STY) increase.
• Demonstrated process generalizability across six CHO cell lines with varying feed requirements.
• Successfully accommodated clonal diversity, leading to reproducible titer uplifts.

Conclusions:

• The intensified HID process significantly enhances bioreactor productivity compared to LID control processes.
• Automated feeding strategies using PAT are effective and generalizable for diverse cell lines.
• This technology platform offers a pathway for further increases in bioreactor productivity and CoGs reduction.