Introduction to Downstream Processing

The production of high-value biological products has intensified many times over in the last few decades. Since the original sourcing of natural products from the likes of plants, animals and microbes, the advent of recombinant DNA technology has allowed researchers and industrialists alike the ability to produce almost any biological product that one might desire to a relatively large scale and with consistent reproducibility.
Whether using ‘natural’ sources of biological products (e.g. blood, plants, microorganisms) or recombinant material expressed intracellularly or secreted into culture medium and feedstocks, in almost all cases it is necessary to purify (at least partially) the product of interest from other biological contaminants. This process is termed downstream processing and refers to the recovery of target biological products such as proteins, peptides, DNA and virus particles from other contaminants.
With the growing demand for biological products and increased protein yields from fermentation processes, particularly from mammalian expression systems, downstream bioprocessing has become both a major expense and a bottleneck in the production of biological products at large scale. Indeed, since the 1980s, developments in the use of mammalian cell culture for the expression of high-value therapeutic proteins have seen productivities and yields increase by over 100-fold,1 and this has resulted in pressure on the ability to deliver efficient and cost-efficient downstream processing of these molecules. Although improvements in product yields per unit volume are economically beneficial, unfortunately this does not directly correlate with downstream processing. In most cases, where chromatography is central to downstream processing, it is the total mass of the product that determines the amount of chromatography resin required and therefore cost.Currently it is estimated that industrial downstream bioprocessing of biopharmaceuticals constitutes over 40%of the manufacturing cost, and this is sure to rise as yields are further increased. The design of downstream processing systems on an industrial scale must therefore be carefully undertaken and optimised, although this is not necessarily as crucial for academic or small-scale industrial laboratory-based processes.
Traditionally, downstream processing has been, and continues to be, heavily reliant upon adsorptive chromatographic procedures, although high-performance liquid chromatography (HPLC) and size-exclusion chromatography (SEC) also play key roles. The actual approach andseries of st eps undertaken during the downstream processing for any given biomolecule are determined by a number of factors, including the nature of the molecule, the source and how the material is presented for processing. Further, on an industrial scale, the number of steps involved, recoveries, requirements and cost of the process as a whole must be carefully considered before designing the approach to be taken. Hence the selection of all unit operations to be utilised throughout a processing workflow must be assessed before designing and undertaking any system.
The variables involved in such systems and the interactions between these have recently been investigated using two case studies. We note that throughout the work process it is necessary to monitor continually the integrity and authenticity of the molecule of interest using an array of analytical technologies, and this must be integrated into the workflow.
Here we restrict ourselves to the purification of proteins from in vitro cultured expression systems (e.g. E. coli, mammalian cells) to illustrate the typical workflow and processes involved in downstream bioprocessing.

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