Fermentation processes scale

In spite of its wide application, the mechanisms of this reaction remain obscure. Many diverse arguments have been published since the reaction was first investigated in 1897 (Bl, C5, C9, F7, J6, M5, P9, R2, S5, W2, W4, Yl, Y4). Cooper et al. (C9) introduced this method as a yardstick for the measurement of volumetric mass-transfer coefficients in gas-liquid contacting. Karow et al. (Kl) later concluded that the sulfite oxidation is suitable for fermentation process scale-up studies. Cooper et al. established that the reaction proceeds at a rate independent of sulfite ion concentration over wide concentration ranges. In their work they considered the sulfite oxidation to be of zero order with respect to both sulfite and sulfate concentration. 

Production through fermentation process scaled up to make enough penicillin to treat 100.000 patients per year. 

Even for the simple stirred, aerated fermenter, there is no one single solution for the scale-up of aeration-agitation which can be applied with high probability of success for all fermentation processes. Scale-up methods based on aeration efficiency (kio) or power consumption/unit volume have become the standard practice in the fermentation field. 

The final fermentation process scaled up to 6,600 gallon fermentations averaged yields of about 6 DU/ml. in four to five days. 

Some of the economic hurdles and process cost centers of this conventional carbohydrate fermentation process, schematically shown in Eigure 1, are in the complex separation steps which are needed to recover and purify the product from the cmde fermentation broths. Eurthermore, approximately a ton of gypsum, CaSO, by-product is produced and needs to be disposed of for every ton of lactic acid produced by the conventional fermentation and recovery process (30). These factors have made large-scale production by this conventional route economically and ecologically unattractive. 

Fermentation. Much time and effort has been spent in undertaking to find fermentation processes for vitamin C (47). One such approach is now practiced on an industrial scale, primarily in China. It is not certain, however, whether these processes will ultimately supplant the optimized Reichstein synthesis. One important problem is the instabiUty of ascorbic acid in water in the presence of oxygen it is thus highly unlikely that direct fermentation to ascorbic acid will be economically viable. The successful approaches to date involve fermentative preparation of an intermediate, which is then converted chemically to ascorbic acid. 

Brassylic Acid. This acid is commercially available from Nippon Mining Company (Tokyo, Japan). It is made by a fermentation process (76). Several years ago, Emery Group, Henkel Corp. (Cincinnati, Ohio) produced brassyUc acid via ozonization of emcic acid primarily for captive use in making dimethyl brassylate and ethylene brassylate. A pilot-scale preparation based on ozonization of emcic acid has been described in which brassyUc acid yields of 72—82% were obtained in purities of 92—95%. Recrystallization from toluene gave purities of 99% (77). 

Based on the practical history of scale-up, most fermentation processes for alcohol and organic acid production have followed the concepts of geometric similarity and constant power per unit volume. From the above concept, and as a strong basis for translation of process criteria, only physical properties of the process were considered in the scale-up calculation. For power consumption in an agitated vessel, there is a fixed relation between impeller speed, N, and impeller diameter, l)t. The constant power per unit volume, for a mechanical agitated vessel is given by ... 

The power per unit volume is constant. From power consumptions in a bench-scale bioreactor, the necessary agitation rate is calculated for the scale up ratio, using Equation (13.2.1). The choice of criterion is dependent on what type of fermentation process has been studied. The following equation expresses relations for the impeller size and agitation rate in small and large bioreactors. 

The constant shear concept has been applied for bioreactor scale-up that utilises mycelia, where the fermentation process is shear sensitive and the broth is affected by shear rate of impeller tip velocity. For instance, in the production of novobicin, the yield of antibiotic production is dependent on impeller size and impeller tip velocity. 

Polysaccharides. Many strains of bacteria produce succinoglycan (1). The Rhizobia, particularly, grow very slowly, and the rate of polymer production is low. Much effort was spent obtaining a strain which produced succinoglycan at a high rate and of good quality (2.3). An organism was selected and a fermentation process developed at laboratory scale. The process has been scaled up successfully and operated at 220 cubic metre scale. 

The most widespread biological application of three-phase fluidization at a commercial scale is in wastewater treatment. Several large scale applications exist for fermentation processes, as well, and, recently, applications in cell culture have been developed. Each of these areas have particular features that make three-phase fluidization particularly well-suited for them Wastewater Treatment. As can be seen in Tables 14a to 14d, numerous examples of the application of three-phase fluidization to waste-water treatment exist. Laboratory studies in the 1970 s were followed by large scale commercial units in the early 1980 s, with aerobic applications preceding anaerobic systems (Heijnen et al., 1989). The technique is well accepted as a viable tool for wastewater treatment for municipal sewage, food process waste streams, and other industrial effluents. Though pure cultures known to degrade a particular waste component are occasionally used (Sreekrishnan et al., 1991 Austermann-Haun et al., 1994 Lazarova et al., 1994), most applications use a mixed culture enriched from a similar waste stream or treatment facility or no inoculation at all (Sanz and Fdez-Polanco, 1990). 

Table 21. Examples of Pilot and Large Scale Applications of Three-Phase Biofluidization to Fermentation Processes...

Figure 5.8 Typical industrial-scale fermentation equipment as employed in the biopharmaceutical sector (a). Control of the fermentation process is highly automated, with all fermentation parameters being adjusted by computer (b). Photographs (a) and (b) courtesy of SmithKline Beecham Biological Services, s.a., Belgium. Photograph (c) illustrates the inoculation of a laboratory-scale fermenter with recombinant microorganisms used in the production of a commercial interferon preparation. Photograph (c) courtesy of Pall Life Sciences, Dublin, Ireland...

In addition to the above extracellular parameters, cell concentration and cell activity are two important cell-associated parameters that determine how well a fermentation process is performing. The manufacturing of biological products (antibiotics, amino acids, monoclonal antibodies, and other protein products) at large scales requires that cells be cultured at high cell densities and stay metabolically active. Consequently, much effort has been expended to develop techniques that can allow the estimation of cell concentration and cell activity in real time during a fermentation. 

Because of the speed and high resolution of CZE separations as well as the small sample volumes required to yield information about complex protein samples, CE is increasingly being used to assess protein purity in multistep purification protocols in laboratory, pilot plant, and process scales. Similarly, it is being considered as a candidate for monitoring fermentation. 

As a matter of fact, most of the processes currently developed to generate biochemicals out of biomass involve fermentation of starch originating from corn, wheat, or rice, for example. The various chemicals obtainable from theses processes and their end applications are listed in Table 10.3. A lot of these fermented biochemicals, however, are not yet economically competitive compared with their petrochemical equivalent, essentially due to the large capital investment in equipment and land needed to implement the fermentation process on an industrial scale. An additional disadvantage of this route is that it competes with feedstock needed by the food industry. More research to reduce the costs of fermentation technology is needed. 

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