Predictive control of hollow‐fiber bioreactors for the production of monoclonal antibodies

Abstract

The selection of medium feed rates for perfusion bioreactors represents a challenge for process optimization, particularly in bioreactors that are sampled infrequently. When the present and immediate future of a bioprocess can be adequately described, predictive control can minimize deviations from set points in a manner that can maximize process consistency. Predictive control of perfusion hollow-fiber bioreactors was investigated in a series of hybridoma cell cultures that compared operator control to computer estimation of feed rates. Adaptive software routines were developed to estimate the current and predict the future glucose uptake and lactate production of the bioprocess at each sampling interval. The current and future glucose uptake rates were used to select the perfusion feed rate in a designed response to deviations from the set point values. The routines presented a graphical user interface through which the operator was able to view the up-to-date culture performance and assess the model description of the immediate future culture performance. In addition, fewer samples were taken in the computer-estimated cultures, reducing labor and analytical expense. The use of these predictive controller routines and the graphical user interface decreased the glucose and lactate concentration variances up to sevenfold, and antibody yields increased by 10% to 43%.

Simulation of oxygen carrier mediated oxygen transport to C3A hepatoma cells housed within a hollow fiber bioreactor

“…We have shown some success with initial experiments (Gordon and Palmer, 2005), and consequently we are presenting here a model that we have developed describing O 2 transport within a hepatic HF bioreactor that is intended to provide support to our hypothesis. Application of this model will allow a priori optimization of hepatic HF bioreactor operating conditions to improve O 2 delivery to cultured hepatocytes (Dowd et al, 1999), and will be useful in scaling up hepatic HF bioreactors (Gramer and Poeschl, 2000). The O 2 transport model also allows for a priori investigation into the effect of circulating media flow rate, bRBC concentration, and inlet pO 2 on O 2 provision to cells maintained within the device.…”

Glucose‐based optimization of CHO‐cell perfusion cultures

“…Without a dedicated glucose analyzer or a flow-injection-analysis system, a constant glucose environment was mediated using predictive control protocols that depended on daily samples to specify a flowrate profile until the next sampling. Glucose-uptake rates were presented via a graphical user interface to allow the operator to better estimate the current and immediate future of the culture (Dowd et al, 1999). The predictive control protocols were used as a tool to manipulate the reactor glucose concentration, while observing the product concentrations (and their variability) as a function of the extent of glucose usage.…”

Systematic development of predictive mathematical models for animal cell cultures

“…Unstructured models, on the other hand, have been proposed as an appropriate basis for applying control, optimization and process development techniques to the production process of proteins (Dowd et al, 1999;Dhir et al, 2000)). Their main advantages are that they involve extracellular culture variables that are typically monitored during a culture, as well as that their simulation and subsequent in silico applications are computationally tractable.…”