Conceptual Process Design of Integrated Fermentation, Deacylation, and Crystallization in the Production of β-Lactam Antibiotics

Abstract

Integration of fermentation and downstream steps is required to improve the sustainability of industrial biotechnology processes. In this context, a new integrated process for β-lactam nuclei production is proposed, which has been theoretically investigated and conceptually designed. This process is an integration of fermentation and enzymatic deacylation of adipyl-7-aminodeacetoxycephalosporanic acid (adADCA) in one reactor producing 7-aminodeacetoxycephalosporanic acid (ADCA) directly from glucose. Although the deacylation equilibrium is unfavorable at the fermentation pH, it is pulled to completion because ADCA starts to crystallize and the liberated side chain, adipic acid (AA), is consumed by the fermentation. Therefore the integrated process requires much less AA than the nonintegrated process. In addition, the new process will lead to a reduction in number of downstream processing units, should avoid the use of acids and bases for pH shifts, and might lead to a reduction in waste salts production. A conceptual process was designed including an economic and technical analysis. The design goal was to produce 2000 tons/year of ADCA of 99% purity. Rigorous simulations were performed to evaluate different process options. Among the economic advantages of the new integrated process are 13.4% lower capital investments and 7.8% lower manufacturing costs. An analogous process for 6-aminopenicillanic acid (APA) is not feasible due to chemical degradation of this product.

Dynamic gene expression regulation model for growth and penicillin production in Penicillium chrysogenum

“…Several attempts have been undertaken to develop mathematical models to describe the growth and the penicillin production during cultivations of P. chrysogenum (Bajpai and Reuss, 1980;Birol et al, 2002;Heijnen et al, 1979;Menezes et al, 1994;Roa Engel et al, 2009). It has been found from steady state carbon limited chemostat cultivations carried out at different dilution rates that the specific penicillin production rate (q p ) is strongly dependent on the growth rate (m) of the organism (van Gulik et al, 2000).…”

Industrial biotechnology—the future of green chemistry?

“…A detailed economic analysis was compiled, offering significant improvements for the integrated process. 61 A classical story of success for industrial biotechnology is the production of acrylamide by nitrile hydratases, which is produced more than 50 000 t y -1 62 using a biocatalytic route. It is one of the best examples of the advantages biotechnology can provide in waste management.…”

Large‐scale production of diesel‐like biofuels – process design as an inherent part of microorganism development

“…However, most proofs‐of‐concept have been obtained on the basis of “existing” fermentations, that is, microorganism and fermentation development had already taken place. At the same time, systematic evaluations have shown that the more we integrate, the heavier the demands on the microorganism [10, 11]. Clearly, there is a need to consider a more integrated development process: one where overall process design comes before microorganism development.…”