Adaptive DO-based control of substrate feeding in high cell density cultures operated under oxygen transfer limitation

The carbon source feeding strategy is crucial for the productivity of many biochemical processes. In high density and shear sensitive cultures the feed of the carbon source is frequently constrained by the bioreactor maximum oxygen transfer capacity. In order to maximise the product formation, these processes should be operated at low dissolved oxygen (DO) concentrations close to the limitation level. This operating strategy may be realised with a closed-loop controller that regulates the DO concentration through the manipulation of the carbon source feed rate. The performance of this controller may have a significant influence on the final product production and should be as accurate as possible. In this work we study the application of adaptive control for solving this problem focusing not only on stability but also on accuracy. Whenever possible the convergence trajectories to the set point are characterised mathematically. Concerning the instrumentation, two situations are covered i) only the DO Tension (DOT) is measured, ii) both DOT and off-gas composition are measured on-line. The controllers are tested in a pilot plant recombinant Pichia pastoris process.