Continuous Bioprocessing

The alternative to batch mode operation is continuous operation. In the continuous mode there is a continuous flow of medium into the fermentor and of product stream out of the fermentor. Continuous bioprocesses often use homogenously mixed whole cell suspensions. However, immobilised cell or enzyme processes generally operate in continuous plug flow reactors, without mixing (see Figure 2.1, packed-bed reactors). 

Even when a successful process has been established, continuous improvement is required to meet the challenges of competitors. Ongoing commercial success will rely, therefore, on optimisation of the many diverse stages in the bioprocess through research and development. For a typical bioprocess, the stages may indude ... 

Figure 2.5 Possible technological solutions to bioprocess problems a) Fed-batch culture b) Continuous product removal (eg dialysis, vacuum fermentation, solvent extraction, ion exchange etc) c) Two-phase system combined with extractive fermentation (liquid-impelled loop reactor) d) Continuous culture, internal multi-stage reactor e) Continuous culture, dual-stream multi-stage reactor f) Continuous culture with biomass feedback (cell recycling). (See text for further details).

Aim3 aerobic bioprocess was operated in a continuous mode with nitrogen as the growth limiting nutrient. The steady state biomass concentration (x), the biomass yield coefficient (Yx/S) and the product yield coefficient (Yp/t) were determined at a low and at a high dilution rate (D). 

For antibiotic production, the fermentation broth needs a pretreatment tank to produce crude and highly purified antibiotic products. The bioprocesses involved in producing antibiotics are spray or continuously dried crude solids and pure solid in the form of crystalline antibiotic. 

Saccharomyces cerevisiae is anaerobically grown in a continuous culture at 30°C. Glucose is used as substrate and ammonia as nitrogen source. A mixture of glycerol and ethanol is produced. At steady-state condition mass the flow rate is stated. The following reaction is proposed for the related bioprocess 4,6... 

Continuous and detailed knowledge of process conditions is necessary for the control and optimization of bioprocessing operations. Because of containment and contamination problems, this knowledge must often be obtained without sampling the process stream. At present, conditions such as temperatme, pressure, and acidity (pH) can be measured rapidly and accurately. It is more difficult to monitor the concentrations of the chemical species in the reaction medium, to say nothing of monitoring the cell density and intracellular concentrations of hundreds of compounds. 

Downstream Processing Microfiltration plays a significant role in downstream processing of fermentation products in the pharmaceutical and bioprocessing industry. Examples are clarification of fermentation broths, sterile filtration, cell recycle in continuous fermentation, harvesting mammahan cells, cell washing, mycelia recovery, lysate recovery, enzyme purification, vaccines, and so forth. 

Yazdani, S. and Mukherjee, K. (2004) Continuous-culture studies on the stability and expression of recombinant streptokinase in Escherichia coli. Bioprocess and Biosystems Engineering, 24, 341-346. 

Yang F, Yu J (1996) Development of a bioreactor system using an immobilized white rot fungus. Part II. Continuous decolorization tests. Bioprocess Eng 16 9-11... 

Notice that the structure of the model (16) is not restricted to bioprocesses and it can be used to describe a very large number of chemical processes as well. Examples of this class of processes are continuous reactors, recycle reactors and interconnected reactors where the matrix A t) is normally a function of the plant operating conditions (e.g., the dilution rate(s)). Now, the framework of uncertainties and the minimum knowledge on the system that are necessary to design the observers is formally described. For this purpose the following hypothesis is introduced. 

The produchon of oxidase enzymes in native strains is often not constitutive, since these enzymes are only required under specific conditions, such as nutrient stress. This imposes limitations on their application in continuous bioprocesses and one way of dealing with this issue is to develop improved expression systems. Laccase from Trametes sp. C30, which in its native strain is inducible and only weakly expressed, has been cloned and expressed in yeast to provide a functional recombinant enzyme with the same high activity and low redox potential as the native enzyme [68]. 

The dynamic behavior of the cell metabolism initiated by different external effects (addition of substrates or inhibiting reagents) can be followed via this instantaneous method. These effects can be used to control the overall process and optimize the bioprocess. Meyer and Beyeler [50] developed a control system for a continuous yeast cultivation process. Here the increase up to the optimal dilution rate was controlled via fluorescence monitoring. The dilution rate was only increased when no negative effect on the metabolic state of the cells was observed. During the cultivation of Candida utilis the fluorescence signal was used for the addition of substrate ethanol. The addition was started when... 

Most chemical, biochemical, and physical operations in chemical and bioprocess plants can be performed batchwise or continuously. 

Adsorption is a physical phenomenon in which some components adsorbates) in a fluid (liquid or gas) move to, and accumulate on, the surface of an appropriate solid adsorbent) that is in contact with the fluid. With the use of suitable adsorbents, desired components or contaminants in fluids can be separated. In bioprocesses, the adsorption of a component in a liquid is widely performed by using a variety of adsorbents, including porous charcoal, silica, polysaccharides, and synthetic resins. Such adsorbents of high adsorption capacities usually have very large surface areas per unit volume. The adsorbates in the fluids are adsorbed at the adsorbent surfaces due to van der Waals, electrostatic, biospecific, or other interactions, and thus become separated from the bulk of the fluid. In practice, adsorption can be performed either batchwise in mixing tanks, or continuously in fixed-bed or fluidized-bed adsorbers. In adsorption calculations, both equilibrium relationships and adsorption rates must be considered. 

Liquid-Flow Rate Liquid flow rate is measured when a medium is fed into a biore-actor in continuous and fed-batch operation. The flow rate of cooling water is also monitored in industrial bioprocessing plants. 

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