Two scale-down tools for the optimization of perfusion bioreactors for the manufacture of biopharmaceuticals

As the occurrences of cancer rise and the requirement for biotherapeutics increases, there is a growing demand for cost-efficient methods to manufacture mammalian cell-based biopharmaceuticals. Currently, the most cost-efficient manufacturing solution is the cultivation of cells in perfusion mode. Perfusion allows for high cell densities of up to 200 million viable cells per mL (MVC mL⁻¹) to be achieved, resulting in an increase in yield and volumetric productivity, which is the production of product per unit volume and time. However, culturing in perfusion mode requires large volumes of media, which is a significant expense in process development. Therefore, methods that allow rapid optimization of perfusion media are desirable to decrease operating costs and increase productivity. In this work, a quasi-perfusion methodology using microwell plates (MWP) is used for media optimization to culture CHO-S cells producing IgG1 monoclonal antibodies (mAb) known as trastuzumab, which have clinical applications treating HER2+ breast cancer. Results show blending glucose-rich supplements and sodium butyrate with perfusion-specific base media can lead to an 8-fold increase in monoclonal antibody titre compared with traditional fed-batch media. The original and optimized media were then scaled-up to a custom made, mini bioreactor (MBR) running in perfusion mode. Two-fold higher cell density is achieved in the MBR compared with the MWP, however, when normalizing for cell density, mAb productivity is comparable between the two methodologies. The combined MWP and 250 mL MBR methodology is an optimization tool that enables process development cost savings due to reduced volume of media utilization.