Fed-batch mode of operation

In many cases, problems cannot be overcome by biological means. This is especially true for those related to inhibition by substrate or product. There may, however, be technical solutions to these problems. Nowadays, complicated feed strategies with different substrates can be achieved through the use of flow injection analysis, on-line sensors, mass flow meters and sophisticated computer control. Such control coupled to a fed-batch mode of operation (Figure 2.5) can often eleviate problems caused by substrate inhibition. For some processes, continuous product removal can avoid the problems associated with product inhibition the various options include ... 

In fed-batch mode residual substrate concentration may be maintained at very low levels. Ibis would reduce substrate costs, may remove catabolic repressive effects and may avoid possible toxic effects of the substrate. The fed-batch mode of operation may also avoid oxygen depletion of the culture during rapid growth. 

The associated disadvantages include (1) requirements for large quantities of nutrients (growth medium) relative to batch and fed batch modes of operation (2) high material costs associated with purchase and preparation/sterilization of the growth medium (3) elevated waste treatment costs and (4) fouling of the surfaces of permselective membranes or conventional or membrane microfiltration devices, which can lead to marked decreases in the flux of... 

One way of expressing the material balance on the total mass of snbsirate present in the reactor during the fed batch mode of operation is... 

It often becomes necessary in biochemical reactions to continuously add one (or more) substrate(s), a nutrient, or any regulating compound to a batch reactor, from which there is no continuous removal of product. A reactor in which this is accomplished is conventionally termed the semibatch reactor (Chapter 4) but is referred to as a fed-batch reactor in biochemical language. The fed-batch mode of operation is very useful when an optimum concentration of the substrate (or one of the substrates in a multisubstrate system) or of a particular nutrient is desirable. This can be achieved by imposing an optimal feed policy. 

Continuous operation is the preferred mode of operation for many processes. For fermentation reactors, however, often a batch or fed-batch mode of operation is preferred to be able to exhaust the feed sufficiently. If continuous operation is used, feed rates that can be realized are rather low, to achieve a large residence time. This means that the typical residence times of seconds to minutes for chemical reactors cannot be reahzed for continuous fermentation reactors. 

Fed-batch bioreactors—This method begins as a batch mode of operation as cells undergo their initial growth phase. However, run time, cell mass, and product titer are increased with the addition of supplemental nutrients, or feeds, to the bioreactor. These reactors are cost effective to run because higher product titers can be achieved from a single extended reactor run, increasing volumetric productivity. However, volumetric output is fundamentally restricted by the size of the vessel, and formation of toxic cellular metabolites can limit the duration of each reactor run. 

Process A Genetic instability Substrate repression Multi-step synthesis Product (volatile) inhibition Mode of operation Batch Fed-batch Continuous... 

Many industrial reactors operate in the fed-batch mode. It is also called the semibatch mode. In this mode of operation, reactants are charged to the system at various times, and products are removed at various times. Occasionally, a heel of material from a previous batch is retained to start the new batch. 

Yet, in spite of these benefits linked to PI, there are still significant barriers [7] that hinder changes in chemical industry. One of these, it is now well admitted, is the transposition from batch to continuous operation, which has to be carefully addressed since this generally allows operating under radically different operating conditions in comparison with the those for batch operations, and sometimes under conditions even nonreachable with a fed-batch mode. 

Retentate product recovery employs the batch, fed-batch, or continuous processing systems, and concentration or diafiltration modes of operation (see general membrane section). Beer and wine dealcoholization uses batch diafiltration. 

Batch or Fed-Batch Operation This mode of operation is typical of biologicals and juice processing where high solicfs and low fluxes require multiple passes, and batch operation is characteristic of the manufacturing process. Formulas in Table 20-19 can be used to calculate the required volume reduction factor X, diafiltration volumes... 

A new alternative approach for Stage I screening in liquid phase is the use of bubble column-type reactors. These parallel bubble columns can operate in batch and fed-batch mode regarding the reaction mixture, while a continuous stream of gas is used as reactant (H2, 02, or others) as well as for the intense agitation of the reaction mixture (Figure 11.39). 

The basic system was operated as a fed-batch reactor and as a continuous reactor. The fed batch was used as a first implementation due to its simplicity of operation. However, in such a reactor dilution takes place during operation and therefore the operation conditions should involve a low flow rate and high volume of reaction mixture. Also, this mode of operation requires sizable amounts of the soluble enzymes, and the total operation time is limited. 

The bioreactor operation mode is normally defined at the outset of process configuration. Insect cells have been cultured in almost all known cultivation modes batch [10], repeated-batch [70], perfusion [71-74], fed-batch [75, 76], semi-continuous [77,78] and continuous [79]. In spite of this multitude of different strategies, the batch or, eventually, fed-batch mode is normally preferred due to the lytic infection cycle of the baculovirus. 

Bioreactors that use enzymes but not microbial cells could be regarded as fermentors in the broadest sense. Although their modes of operation are similar to those of microbial fermentors, fed-batch operation is seldom practiced for enzyme reactors. The basic equations for batch and continuous reactors for... 

A semi batch reactor comes in two flavors. The first is when some material is fed to the reactor during the batch cycle. There is an initial charge of some of the reactants, but the rest of the reactants or catalysts are continuously fed into the reactor during the cycle. This is called a fed-batch reactor. Many batch polymerization reactors operate in the fed-batch mode, with monomer fed into the reactor during the batch cycle. The fed-batch reactor has the inherent advantage that the concentration of the limiting reactant (or catalyst) can be kept low enough to prevent runaway reactions. 

For batch reactors in which two reactants are involved, the problems encountered with a pure batch reactor can sometimes be reduced if only one of the reactants is initially charged to the vessel and the other reactant is fed gradually at a rate such that the heat removal capacity is not exceeded. We will study this mode of operation in the next section. 

Reactors can operate at low temperature (e.g., C4 sulfuric acid alkylation reactors run at 10°C) and at high temperatures (hydrodealkylation of toluene reactors run at 600°C). Some reactors operate in a batch or fed-batch mode, others in a continuous mode, and still others in a periodic mode. Beer fermentation is conducted in batch reactors. Ammonia is produced in a continuous vapor-phase reactor with a solid promoted iron catalyst. 

The most important characteristic of the fed-batch mode is the fact that, in spite of its more complex operation compared with batch cultures, the productivity is increased significantly. Furthermore, when compared with perfusion operation, the runs are considerably shorter, making process validation easier. For this reason, a relatively large number of biotechnological companies have developed their production processes based on this technology (Chu and Robinson, 2001). 

The design of bioreactors for perfusion operation is more sophisticated, which makes the equipment more expensive. However, the productivity increases obtained by perfusion operation allow the use of much more compact systems than those operated under batch or fed-batch mode. In this way, perfusion bioreactors can be up to 10-fold smaller for a given production scale (Bibila and Robinson, 1995), decreasing the costs not only of the bioreactors themselves, but also of storage tanks and downstream processing equipment. 

When the cell culture is operated in batch or fed-batch mode, the cell separation is conducted after the end of the cultivation period (Figure... 

The mode of operation, which can be batch, fed-batch, or continuous, should be considered during the preliminary stages of large-scale design. Batch operation often involves simplicity in maintenance of aseptic conditions and minimizes operating losses due to contamination or equipment failure. 

Industrial mammalian cell culture can be divided into three primary modes of operation batch, fed-batch, and perfusion. Each mode of operation has its attributes and drawbacks, which are described in detail below. 

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