Process Integration in Biochemical Engineering

Rational and efficient process development in chemical technology always makes heavy use of process analysis in terms of balances, kinetics, and thermodynamics. While the first two of these concepts have been extensively used in biotechnology, it appears that thermodynamics has received relatively little attention from biotechnologists. This state of affairs is one among several reasons why development and design of biotechnological processes is today mostly carried out in an essentially empirical fashion and why bioprocesses are often not as thoroughly optimized as many chemical processes. Since quite a large body of knowledge in the area of bio thermodynamics already existed in the early nineties, the Steering Committee of a European Science Foundation program on Process Integration in Biochemical Engineering identified a need to stimulate a more systematic use of thermodynamics in the area. To this effect, a bianual course for advanced graduate students and researchers was developed. The present contribution uses the course structure to provide an outline of the area and to characterize very briefly the achievements, the challenges, and the research needs in the various sub-topics.

The purpose of strategies for the integration of fluid dynamics and physiology is the development of more reliable simulation tools to accelerate the process of scale-up. The rigorous mathematical modeling of the richly interactive relationship between the dynamic response of biosystems and the physical environment changing in time and space must rest on the link between coupled momentum, energy and mass balances and structured modeling of the biophase. With the exponential increase in massive computer capabilities hard- and software tools became available for simulation strategies based on such holistic integration approaches. The review discusses fundamental aspects of application of computational fluid dynamics (CFD) to three-dimensional, two-phase turbulence flow in stirred tank bioreactors. Examples of coupling momentum and material balance equations with simple unstructured kinetic models for the behavior of the biophase are used to illustrate the application of these strategies to the selection of suitable impeller configurations. The examples reviewed in this paper include distribution of carbon and energy source in fed batch cultures as well as dissolved oxygen fields during aerobic fermentations.

A more precise forecasting of the impact of the multitude of interactions must, however, rest upon a rigorous understanding of the response of the cell factory to the complex dynamic stimulation due to space- and time-dependent concentration fields.The paper also introduces some ideas for fast and very fast experimental observations of intracellular pool concentrations based on stimulus response methods. These observations finally lead to a more complex integration approach based on the coupling of CFD and structured metabolic models.

Modern biotechnology, in combination with chemistry and process technology, is crucial for the development of new clean and cost effective manufacturing concepts for fine-chemical, food specialty and pharmaceutical products. The impact of biocatalysis on the fine-chemicals industry is presented, where reduction of process development time, the number of reaction steps and the amount of waste generated per kg of end product are the main targets. Integration of biosynthesis and organic chemistry is seen as a key development.

The advances in bioseparation technology need to keep pace with the rate of development of novel bio-or chemocatalytic process routes with revised demands on process technology. The need for novel integrated reactors is also presented. The necessary acceleration of process development and reduction of the time-to-market seem well possible, particularly by integrating high-speed experimental techniques and predictive modelling tools. This is crucial for the development of a more sustainable fine-chemicals industry.

The evolution of novel ‘green’ production routes for semi-synthetic antibiotics (SSAs) that are replacing existing chemical processes serves as a recent and relevant case study of this ongoing integration of disciplines.We will also show some challenges in this specific field.

This chapter summarizes the use of membrane reactors in extractive bioconversions as process integration systems leading to in situ product recovery. Several membrane reactor configurations are analyzed, taking into account the type of bioconversion, biocatalyst type and location (either in the aqueous phase or in the membrane), membrane chemistry and morphology, solvent (extractant) type and its biocompatibility. Modeling of liquid-liquid extractive membrane bioreactors operation is also analyzed considering kinetics and mass-transfer aspects. The chapter includes examples from the authors’ laboratory as well as other published in the field. Both enzyme and whole cell-based bioconversions are considered. Relevant aspects related to the solvent (extractant) toxicity and how the membrane could protect the biocatalytic activity are analyzed. Trends in this field are also given.

This review sums up the activity in the field of in situ product removal in whole cell bioprocesses over the last 20 years. It gives a complete summary of ISPR operations with microbial cells and cites a series of interesting ISPR applications in plant and animal cell technology. All the ISPR projects with microbial cells are categorized according to their products, their ISPR techniques, and their applied configurations of the ISPR set-up. Research on ISPR application has primarily increased in the field of microbial production of aromas and organic acids such lactic acid over the last ten years. Apart from the field of de novo formation of bioproducts, ISPR is increasingly applied to microbial bioconversion processes. However, despite of the large number of microbial whole cell ISPR projects (approximately 250), very few processes have been transferred to an industrial scale. The proposed processes have mostly been too complex and consequently not cost effective. Therefore, this review emphasizes that the planning of a successful whole cell ISPR process should not only consider the choice of ISPR technique according to the physicochemical properties of the product, but also the potential configuration of the whole process set-up. Furthermore, additional process aspects, biological and legal constraint need to be considered from the very beginning for the design of an ISPR project. Finally, future trends of new, modified or improved ISPR techniques are given.