Bioreactor process control

Bioprocess Control An industrial fermenter is a fairly sophisticated device with control of temperature, aeration rate, and perhaps pH, concentration of dissolved oxygen, or some nutrient concentration. There has been a strong trend to automated data collection and analysis. Analog control is stiU very common, but when a computer is available for on-line data collec tion, it makes sense to use it for control as well. More elaborate measurements are performed with research bioreactors, but each new electrode or assay adds more work, additional costs, and potential headaches. Most of the functional relationships in biotechnology are nonlinear, but this may not hinder control when bioprocess operate over a narrow range of conditions. Furthermore, process control is far advanced beyond the days when the main tools for designing control systems were intended for linear systems. 

Now, from its essential notion, we have the feedback interconnection implies that a portion of the information from a given system returns back into the system. In this chapter, two processes are discussed in context of the feedback interconnection. The former is a typical feedback control systems, and consists in a bioreactor for waste water treatment. The bioreactor is controlled by robust asymptotic approach [33], [34]. The first study case in this chapter is focused in the bioreactor temperature. A heat exchanger is interconnected with the bioreactor in order to lead temperature into the digester around a constant value for avoiding stress in bacteria. The latter process is a fluid mechanics one, and has feedforward control structure. The process was constructed to study kinetics and dynamics of the gas-liquid flow in vertical column. In this second system, the interconnection is related to recycling liquid flow. The experiment comprises several superficial gas velocity. Thus, the control acting on the gas-liquid column can be seen as an open-loop system where the control variable is the velocity of the gas entering into the column. There is no measurements of the gas velocity to compute a fluid dynamics... 

Stirred bioreactors are common in animal cell culture, as they offer a homogenous enviroiunent, representative sampling, better access to process control and an increased oxygen transfer. Several of these techniques (spinner flasks and stirred vessel bioreactors) have been tested successfully for the cultivation of hematopoietic cells [58,64-67]. 

As with refining and petrochemical processes, bioprocesses must be operated automatically so as to achieve a consistent production of various bioproducts in a cost-effective way. In particular, there is a strong demand to optimize bioprocesses by controlling them automatically to promote labor-saving operations. To achieve this, it is necessary to understand what is happening in a bioreactor (instrumentation) and to properly manipulate the control variables that affect the performance of a bioreactor operation (control). 

The goal of bioprocess control is to maintain important process variables in a bioreactor at a desired level regardless of time-dependent environmental changes. Process control will be performed by the following two steps based on the information obtained through the instrumentation. 

A closed-loop system with feedback, which is illustrated in Figure 13.2, is the central feature of a control system in bioprocess control, as well as in other processing industries. First, a set-point is established for a process variable. Then, the process variable measured in a bioreactor is compared with the set-point value to determine a deviation e. Based on the deviation, a controller uses an algorithm to calculate an output signal O that determines a control action to manipulate a control variable. By repeating this cycle during operation, successful process control is performed. The controller can be the operator when manual control is being employed. 

Flow chart of a typical control loop showing temperature control elements a desired temperature value (set-point) is compared to the measured value by the thermometer (sensor) and, based on the error measurement, a signal to the electric resistance (actuator) is generated by the controller, that will heat up the bioreactor (process). 

Due to the inherent variability of animal cell-based systems, in-process control and strict adherence to GMP are of critical importance for obtaining quality products. Carefully planned facilities, together with bioreactor design and in-process control systems, determine product quality at feasible manufacturing costs. The regulatory agencies (EC, 1998a CFR, 2003) clearly state that the premises and equipment must follow GMP standards. 

The process-control scheme contains loops for maintaining concentration of the absorbent (by manipulating the fresh FeEDTA2- feed), the pH and the Redox potential in the bioreactor (by addition of acid/base and ethanol, respectively). Other control loops maintain the liquid level in the sump of the absorber, and the level in the bioreactor. 

The pilot plant is equipped with two gauges one at the membrane entrance and the other at the exit. The plant is also equipped with two flowmeters one located at the entrance to the membranes to record the pumped flow and the other in the permeate stream to measure the discharge flow. The plant has a control panel, for starting and stopping the process and for controlling the blower and pump that feeds the bioreactor. The control panel can be set to automatic and the level inside the reactor is kept constant by means of the differential control. 

On the basis of the kinetics of the biocatalysts and the foregoing decisions, the reactor configuration must then be chosen standard or novel Here, availability, experience, desired mixing, and mass-transfer properties play a dominant role. The mode of operation of the bioreactor can be (fed-)batch or continuous. In making this decision, the kinetics, stability and form of the biocatalyst, desired substrate conversion and product concentration, and need for process control all play a role. 

Many factors play a role at this decision level. Type of kinetics, operational stability of the biocatalyst, form of biocatalyst, type of bioreactor, bioreactor operating costs, necessity of process control, compatibility with down-stream processing, tonnage or scale of operation, existing facilities and experience, feedstock, type of product, GMP, and others, are all involved in an intricate... 

In spite of these hurdles, the last two decades have seen an immense leap in animal cell culture technology both at the laboratory scale as well as the industrial scale. A variety of bioreactors and instrumentation have been ingeniously been devised for the scale up and process control of animal cell cultures. Serum-free media development has considerably reduced the downstream processing costs in the recombinant protein production and purification process. The capability to induce some cell lines to lose anchorage dependence has also been an important breakthrough. 

Ramkrishna, D. On modeling of bioreactors for control. J. Process Control 2003, 13 (7), 581-589. Shuler, M.L. Kargi, F. Bioprocess Engineering, Basic Concepts Prentice Hall Englewood Cliffs, NJ, 2002. 

Aqueous-phase bioreactors provide good process control, can be configured in several treatment trains to treat a variety of wastes, and potentially can achieve very low contaminant concentrations. A drawback of bioreactor treatment is that, unlike composting systems which bind contaminants to humic material, bioreactors accumulate the products of biotransformation. In addition, bioreactors have been shown to remediate explosives only at laboratory scale, so the cost of full-scale bioreactor treatment is unknown. Full-scale bioreactors will have to incorporate a variety of safety features that will add to their total cost. 

Critical care as well as process control and food industry require enzyme electrodes for invasive and in situ analysis. However, direct application in bioreactors is associated with significant difficulties ... 

Despite our very hmited ability to influence these processes in the way we operate the bioreactor, it is still essential to understand their influence on the system. Understanding how and when microscale processes control process performance can prevent unfruitful attempts to improve performance by manipulating the operational variables of the bioreactor. Such understanding might point to more useful strategies. For example, for a process controlled by intraparticle mass transfer, it might be possible to disrupt barriers to diffusion within the substrate particle, such as plant cell walls. Independently of these reasons, characterization of at least some of the microscale phenomena is necessary for the construction of appropriate expressions to include in macroscale material and energy balances. 

Readers should note that for purposes of process control the flow rate of the feed stream can be determined at any time using equation (M) and the value of the total weight of biomass in the bioreactor at that time. When the fed batch phase of operation is initiated, the requisite feed rate is 14.4 mL/h, and at the end of this phase the necessary feed rate is 35.5 mL/h. 

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