Nutritional and engineering aspects of microbial process development

Today we use many drugs produced by microorganisms. However, when these drugs were discovered it was found that the yields were low and a substantial effort had to be put in to develop commercially viable processes. A key part of this endeavor was the studies of the nutritional and the engineering parameters. In this chapter, the basic principles of optimizing the nutritional and engineering aspect of the production process are described with appropriate examples. It was found that two critical components of nutritional medium, carbon and nitrogen source regulated the synthesis of the compounds of interest. Rapidly utilizable carbon source such as glucose supported the growth but led to catabolite repression and alternative carbon sources or methods of addition had to be devised. Inorganic nitrogen sources led to undesirable changes in pH of the medium. Organic nitrogen sources could influence the yields positively or negatively and had to be chosen carefully. Essential nutrients like phosphates often inhibited the synthesis and its concentration had to be maintained below the inhibitory levels. On many occasions, trace nutrients like metal ions and vitamins were found to be critical for good production. Temperature and pH were important environmental variables and their optimum values had to be determined. The media were designed and optimized initially with ‘one variable at a time’ approach and later with experimental design based on statistics. The latter approach is preferred because it is economical, considers interactions between medium components and allows rapid optimization of the process. The engineering aspects like aeration, agitation, medium sterilization, heat transfer, process monitoring and control, become critical as the process is scaled-up to the production size. Aeration and agitation are probably the most important variables. In many processes dissolved oxygen concentration had to be maintained above a critical value to obtain the best yields. The rheological properties of fermentation broth significantly affect the aeration and mixing efficiency. The removal of heat from the large fermentors can be difficult under certain conditions. However, new designs of impellers, availability of sensors to monitor important physiological and process variables and advent of computers have facilitated successful scale-up of fermentation processes.