(697e) Oxygen Transfer in Bioreactors with High Cell Densities

There is an urgent need to increase the production of antibody drug products manufactured from mammalian cells. This need has motivated a more rigorous analysis of existing bioreactor systems, and whether they can be extended to support order-of-magnitude step-increases in cell density and process yield. Systems with high cell densities present a unique challenge to process design and operation. Unlike traditional cell growth processes, which have modest gassing and oxygen transfer requirements, systems with high cell densities require oxygen transfer rates that can exceed 30 1/hr and gas flow rates in excess of 0.1 VVM. These high flow rates make a priori design and scale-up of such systems difficult, since most bioreactor design correlations are tailored for systems with more modest gassing rates.

In this work, we use lattice-Boltzmann simulation with Lagrangian bubble tracking to develop a mechanistic model for predicting the behavior of these high cell density bioreactors. All physics are coupled in space and time and mechanistically motivated by first principles. The bubbles evolve according to Newtons’ second law using the local and instantaneous fluid velocity to compute a drag force. The fluid evolves according to the transient Navier-Stokes equations. The instantaneous fluid force from the bubbles on the fluid are incorporated as a body force. The species field is solved according to the advection-diffusion equation using the instantaneous fluid velocities. The bubbles act as species sources and sinks. In parallel with validation against experimental data, we use this model to examine the physics driving oxygen transfer within such high cell count systems. We then use the model to show how the operating conditions of the reactor can be tuned to achieve ideal oxygen transfer rates across the vessel.