Process-scale bioseparation

All process-scale bioseparations will have implications for project cost and program when developing a new process. 

Where small-scale bioseparations have been developed, particularly in the biopharmaceutical industry, there has been a tendency to retain laboratory type equipment even if this results in more labour and capital intensive processing. The reason for this is often to avoid the need for extended periods of process development work with new equipment designs, which might delay the launch of a product where competitors are not far behind. Manufacturers are also wary of adopting new bioseparation techniques for processes if there is any risk that regulators such as the U.S. Food and Drug Administration (FDA) will require more evidence that the equipment is fit for the purpose. This conservative tendency is understandable and may influence the choice of bioseparation equipment for pharmaceutical manufacturing in particular. 

One of the most difficult and challenging problems facing large-scale biotechnology today is to find and develop appropriate recovery, separation, and purification processes. The area of large-scale bioseparations is one to which biologists, physical biochemists, and particularly biochemical engineers have important contributions to make. Some of the most recent advances and developments that have already started to find practical applications are... 

Although all such chromatographic media may be used for the separation of microsolute species, all three techniques are used extensively for the separation of mixtures of pro-teins/biomacromolecules. On the other hand, when the stationary phase is a liquid coated on solid particles/beads, we have liquid-liquid chromatography (LLC) this technique is used for smaller molecules. We will now provide an extremely brief introduction to each of these elution techniques. A reasonably comprehensive introduction to analytical-scale chromatography using all four techniques is available in Karger etoL (1973). A comprehensive introduction to the first three techniques for bioseparations, including process-scale operations, is available in Ladisch (2001). 

At present, the purification by chromatographic processes is the most powerful high-resolution bioseparation technique for many different products from the laboratory to the industrial scale. In this context, continuous simulated moving bed (SMB) systems are of increasing interest for the purification of pharmaceuticals or specialty chemicals (racemic mixtures, proteins, organic acids, etc.).This is particularly due to the typical advantages of SMB-systems, such as reduction of solvent consumption, increase in productivity and purity obtained as well as in investment costs in comparison to conventional batch elution chromatography [1]. 

M. Zlokarnik. Dimensional Analysis, Scale-Up. In Encyclopedia of Bio process Technology Fermentation, Biocatalysis, Bioseparation. Vol. 2, 840-861. (M.C. Flickinger and S. W. Drew, eds.) Wiley, 1999. 

The diversity of industries that involve bioseparations has led to the development of a wide range of techniques and unit operations for the efficient processing of biological materials. Chapter 16 is planned to aid the scientist or engineer in selecting a method of bioseparation that will be suited to the particular requirements of the process and the product at a commercial scale of operation. 

In moving from laboratory- or pilot-scale processing to full-scale manufacturing, it can be difficult to scale up certain types of bioseparation equipment easily for example, high g centrifuges are available as bench-mounted units (using test tubes), but an equivalent industrial machine with a similar g force is unlikely to be a cost-effective solution, even if it were possible to build a suitable unit. It would not be realistic to consider 10 or 100 identical units as a realistic alternative. Compromises are therefore required as a process is commercialized, to ensure that the process remains technically and economically feasible. 

Allary, M., Saint Blancard, J., Boschetti, E., and Girot, P. (1991). Large scale production of human albumin Three years experience of an affinity chromatography process. Bioseparation 2, 167-175. 

Examples of commonly used bioseparations include sedimentation, coagulation, and filtration. The scale of operation for such bioseparation processes is considerable, because of the volumes of effluent which are processed and the throughputs required. Proprietary aerobic digesters such as the Deep Shaft process may use centrifugation to recover biomass from the treated effluent for recycle as an inoculum for the digester or to reduce the quantity of water before sending the solid material either to incineration or land fill. 

There is an increasing trend toward the production of fine and commodity chemicals on a very large scale using fermentation processes followed by downstream bioseparation and purification. This trend is being driven by the... 

Citric acid and vitamin C are examples of very large scale fermentation processes where the subsequent product isolation involves several bioseparations, including filtration, precipitation, evaporation, crystallization, and drying methods. The scale of operation requires careful choice of equipment which is robust, efficient in separating product from unwanted by-products, and cost effective to be competitive. 

The industries described are diverse but all require bioseparations at various scales. Although not all such manufacturing processes involve fermentation, it is possible to identify common types of bioseparations which are required at particular stages. 

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