Adaptive set-point control system for microbial cultivation processes

A control system for set-point control of microbial cultivation process parameters is developed, in which a tendency model is applied for controller adaptation to process nonlinearity and time-varying operating conditions. The tendency model is updated on-line and introduced into control algorithm for prediction of steady-state control action and returning of feedback controller. The control system was tested for controlling dissolved oxygen concentration in batch operating mode bioreactor under extreme operating conditions. In simulation experiments, the control system demonstrates fast adaptation, robust behaviour and significant improvement in control performance compared to that of fixed gain controller

Application of In-Situ and Soft-Sensors for Estimation of Recombinant P. pastoris GS115 Biomass Concentration: A Case Analysis of HBcAg (Mut+) and HBsAg (MutS) Production Processes under Varying Conditions

Microbial biomass concentration is a key bioprocess parameter, estimated using various labor, operator and process cross-sensitive techniques, analyzed in a broad context and therefore the subject of correct interpretation. In this paper, the authors present the results of P. pastoris cell density estimation based on off-line (optical density, wet/dry cell weight concentration), in-situ (turbidity, permittivity), and soft-sensor (off-gas O2/CO2, alkali consumption) techniques. Cultivations were performed in a 5 L oxygen-enriched stirred tank bioreactor. The experimental plan determined varying aeration rates/levels, glycerol or methanol substrates, residual methanol levels, and temperature. In total, results from 13 up to 150 g (dry cell weight)/L cultivation runs were analyzed. Linear and exponential correlation models were identified for the turbidity sensor signal and dry cell weight concentration (DCW). Evaluated linear correlation between permittivity and DCW in the glycerol consumption phase (<60 g/L) and medium (for Mut+ strain) to significant (for MutS strain) linearity decline for methanol consumption phase. DCW and permittivity-based biomass estimates used for soft-sensor parameters identification. Dataset consisting from 4 Mut+ strain cultivation experiments used for estimation quality (expressed in NRMSE) comparison for turbidity-based (8%), permittivity-based (11%), O2 uptake-based (10%), CO2 production-based (13%), and alkali consumption-based (8%) biomass estimates. Additionally, the authors present a novel solution (algorithm) for uncommon in-situ turbidity and permittivity sensor signal shift (caused by the intensive stirrer rate change and antifoam agent addition) on-line identification and minimization. The sensor signal filtering method leads to about 5-fold and 2-fold minimized biomass estimate drifts for turbidity- and permittivity-based biomass estimates, respectively

Simple Gain-Scheduled Control System for Dissolved Oxygen Control in Bioreactors

An adaptive control system for the set-point control and disturbance rejection of biotechnological-process parameters is presented. The gain scheduling of PID (PI) controller parameters is based on only controller input/output signals and does not require additional measurement of process variables for controller-parameter adaptation. Realization of the proposed system does not depend on the instrumentation-level of the bioreactor and is, therefore, attractive for practical application. A simple gain-scheduling algorithm is developed, using tendency models of the controlled process. Dissolved oxygen concentration was controlled using the developed control system. The biotechnological process was simulated in fed-batch operating mode, under extreme operating conditions (the oxygen uptake-rate’s rapidly and widely varying, feeding and aeration rate disturbances). In the simulation experiments, the gain-scheduled controller demonstrated robust behavior and outperformed the compared conventional PI controller with fixed parameters

Adaptive Control of Biomass Specific Growth Rate in Fed-Batch Biotechnological Processes. A Comparative Study

This article presents a comparative study on the development and application of two distinct adaptive control algorithms for biomass specific growth rate control in fed-batch biotechnological processes. A typical fed-batch process using Escherichia coli for recombinant protein production was selected for this research. Numerical simulation results show that both developed controllers, an adaptive PI controller based on the gain scheduling technique and a model-free adaptive controller based on the artificial neural network, delivered a comparable control performance and are suitable for application when using the substrate limitation approach and substrate feeding rate manipulation. The controller performance was tested within the realistic ranges of the feedback signal sampling intervals and measurement noise intensities. Considering the efforts for controller design and tuning, including development of the adaptation/learning algorithms, the model-free adaptive control algorithm proves to be more attractive for industrial applications, especially when only limited knowledge of the process and its mathematical model is available. The investigated model-free adaptive controller also tended to deliver better control quality under low specific growth rate conditions that prevail during the recombinant protein production phase. In the investigated simulation runs, the average tracking error did not exceed 0.01 (1/h). The temporary overshoots caused by the maximal disturbances stayed within the range of 0.025–0.11 (1/h). Application of the algorithm can be further extended to specific growth rate control in other bacterial and mammalian cell cultivations that run under substrate limitation conditions

Model Based Escherichia Coli Bacteria Fermentation

Model-based fed-batch cultivation approach of non-recombinant Escherichia coli bacteria are presented. Aim of current research was to utilize mathematical modeling of fermentation process to precisely calculate exponential feeding rates for succesive biomass growth processes. In this case were used models which state mass balance for biomass (X), substrate (S), acetate (A), vessel volume (V) and additional model for bioreactor mass flows (F). In such a way we achieved controlled and predefined biomass growth according to the process model. Using well defined fed-batch media which consisted from salts and glucose, in most successive runs were achieved E. coli cultures with biomass concentrations up to 60 g/l

From Physics to Bioengineering: Microbial Cultivation Process Design and Feeding Rate Control Based on Relative Entropy Using Nuisance Time

For historic reasons, industrial knowledge of reproducibility and restrictions imposed by regulations, open-loop feeding control approaches dominate in industrial fed-batch cultivation processes. In this study, a generic gray box biomass modeling procedure uses relative entropy as a key to approach the posterior similarly to how prior distribution approaches the posterior distribution by the multivariate path of Lagrange multipliers, for which a description of a nuisance time is introduced. The ultimate purpose of this study was to develop a numerical semi-global convex optimization procedure that is dedicated to the calculation of feeding rate time profiles during the fed-batch cultivation processes. The proposed numerical semi-global convex optimization of relative entropy is neither restricted to the gray box model nor to the bioengineering application. From the bioengineering application perspective, the proposed bioprocess design technique has benefits for both the regular feed-forward control and the advanced adaptive control systems, in which the model for biomass growth prediction is compulsory. After identification of the gray box model parameters, the options and alternatives in controllable industrial biotechnological processes are described. The main aim of this work is to achieve high reproducibility, controllability, and desired process performance. Glucose concentration measurements, which were used for the development of the model, become unnecessary for the development of the desired microbial cultivation process