Process bioseparation industry

This section describes some general processes used for protein purification, including methods and tools currently employed by the bioseparation industry to achieve clarification, capture, and removal of impurities. 

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]. 

Bioseparation processes make use of many separation techniques commonly used in the chemical process industries. However, bioseparations have distinct characteristics that are not common in the traditional separations of chemical processes. Some of the unique characteristics of bioseparation products can be listed as follows ... 

The economic feasibility of a bioreaction process clearly depends on the characteristics of the associated bioseparation process, especially in the usual case when the product is present at low concentration in a complex mixture. For example, the existence of an extremely efficient and low-cost separation process for a particular compound could significantly lower the final concentration of that compound required in the bioreactor to achieve a satisfactory overall process. After noting that special approaches and processes are needed for efficient recovery of small molecules (ethanol, amino acids, antibiotics, etc.) from the dilute aqueous product streams of current bioreactors, I shall discuss further only separations of proteins. These are the primary products of the new biotechnology industry, and their purification hinges on the special properties of these biological macromolecules. 

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. 

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. 

In the industries using bioseparations described above, there is a great variation in terms of production scale and product quality between waste water treatment and pharmaceutical production. This will obviously affect the choice of equipment for the process, although in many cases the principle on which bioseparation is based will be common. For example, centrifuga-... 

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. 

The complexity of many industrial bioseparation equipment items means that the design and construction can be time consuming, particularly if process development is required to test the equipment on a typical product to see if it will work at the larger scale. It is not unusual to have 6 to 9 month delivery periods for this type of equipment, and even when delivered, it will be necessary to install, commission, and validate it. Therefore, the project program must recognize the long duration for introducing commercial bioseparation equipment. 

Cross-flow filtration is also referred to as tangential flow filtration or microfiltration, but all three terms refer to a process by which membranes are used to separate components in a liquid solution (or suspension) on the basis of their size. The development of robust membranes in polymeric and ceramic materials has provided a powerful new technology for bioseparations, which is already widespread in the process industries as well as for water treatment processes. 

Cell disruption techniques are used to recover materials produced within the cell, for example, industrial enzymes and some pharmaceutical proteins. Generally this stage of bioseparation will follow cell recovery, for example, by centrifugation, and precede the isolation of the desired product from the cell debris which is also produced during the disruption process. 

Following the initial stages of product recovery from a fermentation broth, a number of purification stages will be required in all but the simplest industrial processes. In the case of high-purity pharmaceutical products, a large number of separation stages are usually required to remove all impurities from the desired final product. By identifying some difference between the product and its impurities, either physical or chemical, the desired bioseparation can be achieved. 

At industrial scale, careful consideration of the materials of construction for the bioseparation equipment is vital to ensure that the product does not become contaminated, by rust, for example, and also to assure long plant life with good reliability to maximize throughput. Materials that were suitable on a laboratory or pilot scale may no longer be appropriate, where the process and mechanical demands on the equipment may be greater. For example, the plant could be located outside where there are greater extremes of temperature in summer and winter, or equipment may need to be steam sterilized in situ rather than being autoclaved. 

In all industrial processes, the safety of operators and staff, as well as the general public in surrounding areas, is of paramount importance. Every effort should be made during design and construction to ensure that the bioseparation plant is safe to operate with all risks identified and minimized through appropriate precautions. 

The bioseparation technique which is probably the most readily adapted to modern process control techniques is extraction. Liquid-liquid extraction is a mature unit process with application in industrial-scale protein separation.30 Control techniques used on similar systems in other industrial applications should be readily adaptable to bioprocessing, the primary difficulty being the lack of data on the partitioning and related behavior of the product. 

Finally, more such studies must be carried out on real-life examples and made available in the literature. No doubt such studies are available in the different pharmaceutical industries, but due to economic and obvious reasons, they are restricted to only in-house circulation. This is an unfortunate aspect of the economics of bioseparation of different processes. Hopefully, people in the universities, at least, will pay more attention to this aspect, and fill this critical gap in the complete analysis of bioseparation processes. 

Sirkar KK, Membrane separations Newer concepts and applications for the food industry, In Singh RK, and Rizvi SSH, eds. Bioseparation Processes in Foods, Marcel Dekker, New York, 1995 pp. 351—374. 

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