Instrumentation and Control of Bioprocesses

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 following steps are used to operate a bioprocess plant. 

1) A control strategy is established, and set-points for control variables are determined (pH, temperature, feed rate, dissolved oxygen (DO), etc.). These are predetermined through laboratory experiments and day-to-day operation. 

2) Process variables are measured via instrumentation and the use of sensors and measuring devices. 

3) Deviation between the set-point and the measured process variable must be strictly monitored. 

---

To overcome this difficulty, many challenges have been met in the fields of bioprocess control. In this chapter, the basic principles of the instrumentation and control of bioprocess are explained. 

D. Dochain and M. Perrier. Advanced Instrumentation, Data Interpretation, and Control of Biotechnological Processes, chapter Monitoring and Adaptive Control of Bioprocesses, pages 347-400. Kluwer Academic Publishers, 1998. 

The BioView sensor (DELTA Light Optics, Denmark) was developed especially for industrial applications. It is capable of completely automatic optical measurement for monitoring and control of different bioprocesses. The instrument is conceived to withstand harsh industrial environments (e.g., high temperature, moisture) and electromagnetic interference. For data transfer a single-fiber asynchronous modem is used, which allows a distance between the computer and spectrometer of up to several hundred meters. 

Temperature Ihe temperature in a bioreactor is an important parameter in any bioprocess, because all microorganisms and enzymes have an optimal temperature at which they function most efficiently. For example, optimal temperature for cell growth is 37 °C for Escherichia coli and 30 °C for Saccharomyces sp, respectively. Although there are many types of devices for temperature measurements, metal-resistance thermometers or thermistor thermometers are used most often for bioprocess instrumentation. The data of temperature is sufficiently reliable and mainly used for the temperature control of bioreactors and for the estimation of the heat generation in a large-scale aerobic fermentor such as in yeast production or in industrial beer fermentation. 

The principles, sampling systems, control of the measuring device and application of MS for bioprocesses have been summarized by Heinzle [157,158] and Heinzle and Reuss [162]. Samples are introduced into a vacuum (< 10 5 bar) via a capillary (heated, stainless steel or fused silica, 0.3 x 1000 mm or longer) or a direct membrane inlet, for example, silicon or Teflon [72,412]. Electron impact ionization with high energy (approx. 70 eV) causes (undesired) extensive fragmentation but is commonly applied. Mass separation can be obtained either by quadrupole or magnetic instruments and the detection should be performed by (fast and sensitive) secondary electron multipliers rather than (slower and less sensitive) Faraday cups (Fig. 21). 

While these examples illustrate the role of flow cytometry in bioprocess monitoring, the analyses have been conducted off-line thus making their use in bioprocess control impractical. Recently, a portable flow cytometer - the Microcyte - [148] has been described, which due to its small size and lower cost (compared to conventional machines) allows flow cytometry to be used as an at-line technique [149]. Ronning showed that this instrument had a role to play in the determination of viability of starter cultures and during fermentation. The physiological status of each individual cell is likely to be an important factor in the overall productivity of the culture and is therefore a key parameter in optimising production conditions. 

Another crucial area in bioprocess plants is the validation of control systems. Instrumentation calibration must be followed by rigorous checking of control system software. Many biotechnology plants are capable of multiproduct operation and it is essential to oisure that there is no possibility for commonality in product-specific software so that the integrity of GMP for one product does not corrupt a system that has already been validated. 

---