Fermentation process industrial-scale

Figure 30.12 represents a cell factory model to produce several categories of products via fermentation and biocatalysis processes. Industrial-scale manufacturing aspects such as uses, synthesis methods, and costs of some of these products are reviewed below as well as in Chapter 32. 

Fuchs, R., Ryu, D.D.Y., and Humphrey, A.E. (1971), Effect of surface aeration on scale-up proceedures for fermentation process, Industrial <6 Engineering Chemistry Process Design and Development, 10(2) 190-196. 

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. 

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). 

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...

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. 

Improvement of microbial strains for the overproduction of natural metabolites has been the hallmark of all commercial fermentation processes. Therefore, the aim of this chapter is to highlight several aspects of process improvement to yield natural products for industry at the laboratory, pilot plant and factory scales. 

A brilliant example for the industrial-scale application of plant cell fermentation is the new process for the production of the anticancer drug paclitaxel developed by Bristol-Myers Squibb (see Figure 15.1). It starts with clusters of paclitaxel producing cells from the needles of the Chinese yew, T. chinensis, and was introduced in 2002. The API is isolated from the fermentation broth and is purified by chromatography and crystallization. The new process substitutes the previously used semisynthetic route. It started with lO-deacetylbaccatin(III), a compound that contains most of the structural complexity of paclitaxel and can be extracted from leaves and twigs of the European yew, T. baccata. The chemical process to convert 10-deacetylbaccatin(III) to paclitaxel is complex. It includes 11 synthetic steps and has a modest yield. 

A new method for the preparation of soy sauce has been developed. The new scaled-up method divides the moromi process into two processes autolysis and fermentation. Because of the utilization of high temperatures, the new process permits the production of a NaCl free autolyzate from koji. Division of the fermentation process into two separated processes permit better control of lactic acid fermentation and alcohol fermentation processed which used to require great skill. The new scale-up procedure for soy sauce production yields a product in half the time required by the traditional (conventional) method and still produces a soy sauce with high levels of the desirable Bavor component, glutamic acid. Utilization of this protocol by the soy sauce producing industry should have significant economic impact to bo producers and consumers. 

Weizmann discovered a process to produce butyl alcohol and acetone from the bacterium Clostridium acetobutylicum in 1914. With England s urgent demand for acetone, Winston Churchill (1874-1965) enlisted Weizmann to develop the Weizmann process for acetone production on an industrial scale. Large industrial plants were established in Canada, India, and the United States to provide the allies with acetone for munitions. Weizmann, who is considered the father of industrial fermentation, obtained significant status from his war contributions and used this to further his political mission of establishing a Jewish homeland. Weizmann was a leader of the Zionist movement and campaigned aggressively until the nation of Israel was established in 1948. He was the first president of Israel. 

A good example of a white biotech process in the pharmaceutical area is our route to the antibiotic cephalexin, practiced on a large industrial scale for several years now. By advanced enzyme and metabolic engineering we were able to replace the traditional 10-step, mainly chemical synthesis (Fig. 29.3A) by a fermentative route followed by two mild enzymatic steps (Fig. 29.3 B). The white biotech process has been shown recently to use far less energy (-65%), less input of (harsh) chemicals (-65%), is water-based, generates less waste, and is very cost-effective (-50%) (Bruggink, A.). Again, this is a bio-based process where environmental and economic benefits go hand in hand and for which there is no competitive chemical alternative (EuropaBio and McKinsey Company, 2003 DSM position document, 2004). 

The use of recombinant microorganisms for cofermentation is one of the most promising approaches in the field of bioethanol production, though their use for large-scale industrial processes still requires fine-tuning of the reliability of the entire process (2). The technical hurdles of cofermentation increase when real biomass hydrolysates have to be fermented. In fact, whatever the biomass pretreatment, the formation of degradation byproducts that could inhibit the fermentation usually requires the addition of a further detoxification step. Therefore, the production of ethanol from hydrolysates should be considered in its entirety, from the optimal pretreatment to the choice of the proper fermentation process. 

Adding up the times of all steps, an industrial scale production takes roughly 3 weeks, of which 2 weeks are devoted to the fermentation and about 1 week is required for the downstream processing. Derivatization at positions 3 and 7 to yield an API is not included. Starting from 7-ACA, these processes may take 1 day each for the derivatization plus the time for purification, crystallization, and drying. The resulting bulk active cephalosporin can then be sterilized and formulated for marketing. 

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