Feasibility of culture process development using high throughput low volume microbioreactors

Mammalian cell culture is a complex production system and is sensitive to different bioprocessing conditions. Over the years, the industry has moved toward automated, high-throughput platforms to improve both process consistency and to accelerate the process development timeline and thus reducing the time required for molecules to reach the clinic. Here we compare the cell culture performance in 15 mL working volume microbioreactors (TAP Biosystems ambr^TM) to those in the traditional lab scale 2 L vessels and then to the 12,000 L manufacturing scale to demonstrate the predictability and suitability of using these high throughput, automated microbioreactors. Fed-batch experiments were performed using a highly productive Chinese ovary hamster cell line and commercially available production media. Different seeding densities, pH and DO setpoints, and feed rates were examined to determine whether similar trends can be reproduced at this micro scale. Online signal trends demonstrate a good separation between different pH control ranges and the ability to control dissolved oxygen at low concentrations with minimal fluctuation. Cell growth profiles and product titers were shown to be comparable across the three different scales although some slight differences in key metabolites were observed. Interestingly, the 15 mL microbioreactor was able to mimic the dissolved carbon dioxide profile more closely to the 12,000 L vessel than the conventional 2 L bench top glass bioreactor, which remains to be an inherent scale-up challenge. Overall the results demonstrate the usefulness of the microbioreactor system as a complementary platform for mammalian process development.