(692c) Foam Control in the Mammalian Cell Culture Process through Extrinsic and Intrinsic Methods

Authors: 
Chang, K., Biogen
Osborne, D., Biogen
Ferguson, R., Biogen
Gilmore, R. III, Biogen
Grismer, D. A., North Carolina State University
Velev, O. D., North Carolina State University
During biopharmaceutical manufacturing, the formation of foam within bioreactors has been an industry-wide issue for decades. As the product throughput has increased over the years, higher viable cell densities have increased oxygen demand. To support this higher uptake, agitation and aeration rates have also increased, leading to more foam generation. This results in a myriad of problems, including cell entrapment within foam, cell damage caused by bubbles bursting at the surface, interruption of gas transfer across the air/liquid interface, and equipment failure due to clogged vent filters. To optimize bioreactor conditions, Biogen has been working on different methods of monitoring, removing, and controlling foam in bioreactors to dramatically reduce antifoam addition and prevent the regeneration of foam. While focusing on extrinsic methods of monitoring and removing foam through automation, the intrinsic characteristics of foam generation and stability are also being studied to find alternative methods of eliminating the foam in the cell culture process. New methods for monitoring and controlling the foam in bioreactors include using a digital camera to image the culture surface within the vessel. Antifoam is then programmed to be fed automatically based on the percentage of foam coverage. Studies of the delivery of antifoam have also shown that spraying antifoam as a mist reduces the required dose to remove the foam layer, while not significantly interrupting the mass transfer. It not only reduces the foam regeneration rate, but also protects cells from shear damage by allowing for a lower gas entrance velocity from the sparger. The foam generated during cell culture manufacturing processes has been characterized as stable Pickering foam, with slower foam decay. The foam stability was correlated to the accumulation of biomass within the culture. This stability reduces the efficacy of the traditional antifoam remediation strategy over time. Therefore, alternative methods of foam removal are now being investigated to improve the cell culture processes. Overall, the systematic ways of controlling foam have notably reduced the likelihood of equipment failure and improved bioreactor success rates.