Substantial gradient mitigation in simulated large‐scale bioreactors by optimally placed multiple feed points

The performance of large‐scale stirred tank and bubble column bioreactors is often hindered by insufficient macromixing of feeds, leading to heterogeneities in pH, substrate, and oxygen, which complicates process scale‐up. Appropriate feed placement or the use of multiple feed points could improve mixing. Here, theoretically optimal placement of feed points was derived using one‐dimensional diffusion equations. The utility of optimal multipoint feeds was evaluated with mixing, pH control, and bioreaction simulations using three‐dimensional compartment models of four industrially relevant bioreactors with working volumes ranging from 8 to 237 m(3). Dividing the vessel axially in equal‐sized compartments and locating a feed point or multiple feed points symmetrically in each compartment reduced the mixing time substantially by more than a minute and mitigated gradients of pH, substrate, and oxygen. Performance of the large‐scale bioreactors was consequently restored to ideal, homogeneous reactor performance: oxygen consumption and biomass yield were recovered and the phenotypical heterogeneity of the biomass population was diminished.