Improving cultivation processes for recombinant protein production

Abstract

An new cascade control system is presented that reproducibly keeps the cultivation part of recombinant protein production processes on its predetermined track. While the system directly controls carbon dioxide production mass and carbon dioxide production rates along their setpoint profiles in fed-batch cultivation, it simultaneously keeps the specific biomass growth rates and the biomass profiles on their desired paths. The control scheme was designed and tuned using a virtual plant environment based on the industrial process control system SIMATIC PCS 7 (Siemens AG). It is shown by means of validation experiments that the simulations in this straightforward approach directly reflect the experimentally observed controller behaviour. Within the virtual plant environment, it was shown that the cascade control is considerably better than previously used control approaches. The controller significantly improved the batch-to-batch reproducibility of the fermentations. Experimental tests confirmed that it is particularly suited for cultivation processes suffering from long response times and delays. The performance of the new controller is demonstrated during its application in Escherichia coli fed-batch cultivations as well as in animal cell cultures with CHO cells. The technique is a simple and reliable alternative to more sophisticate model-supported controllers.

Virtual bioreactor cultivation for operator training and simulation: application to ethanol and protein production

“…An OTS combines dynamic process models and computer graphics . The computer graphics emulate a laboratory, plant or machine that allows the user to operate and control the process by using virtual actuators and controllers and other automation equipment …”

“…6,7 An OTS combines dynamic process models and computer graphics. 8,9 The computer graphics emulate a laboratory, plant or machine that allows the user to operate and control the process by using virtual actuators and controllers and other automation equipment. 5,7,10 -13 A valuable application of process simulators is to support process development by reducing the number of laboratory and plant experiments.…”

Practical Solutions for Specific Growth Rate Control Systems in Industrial Bioreactors

“…Therefore, the X(t) online estimation problem complicates the practical realization of this control approach. To eliminate this shortcoming, simplified SGR control systems were developed and experimentally tested in bacterial and mammalian cell cultivation processes [41][42][43]. The main idea behind these control systems is to use the predetermined time profiles of CPR set (t) as the system's time-varying set-point, and the mass of CO 2 (t) produced during the process (mCO 2set ) as an indirect metric for SGR control purposes.…”

Bioreactor control improves bioprocess performance

“…This can be done by a sequence of two PID controllers where the first takes the mass pattern, here m O 2 , and the second its derivative, the total oxygen uptake rate tOUR as the controlled variable. Such a construction was successfully applied to a CHOcell culture producing EPO [47].…”