Downstream processing product isolation

It was not until the twentieth century that furfural became important commercially. The Quaker Oats Company, in the process of looking for new and better uses for oat hulls found that acid hydrolysis resulted in the formation of furfural, and was able to develop an economical process for isolation and purification. In 1922 Quaker announced the availability of several tons per month. The first large-scale appHcation was as a solvent for the purification of wood rosin. Since then, a number of furfural plants have been built world-wide for the production of furfural and downstream products. Some plants produce as Httie as a few metric tons per year, the larger ones manufacture in excess of 20,000 metric tons. 

When ionic liquids are used as replacements for organic solvents in processes with nonvolatile products, downstream processing may become complicated. This may apply to many biotransformations in which the better selectivity of the biocatalyst is used to transform more complex molecules. In such cases, product isolation can be achieved by, for example, extraction with supercritical CO2 [50]. Recently, membrane processes such as pervaporation and nanofiltration have been used. The use of pervaporation for less volatile compounds such as phenylethanol has been reported by Crespo and co-workers [51]. We have developed a separation process based on nanofiltration [52, 53] which is especially well suited for isolation of nonvolatile compounds such as carbohydrates or charged compounds. It may also be used for easy recovery and/or purification of ionic liquids. 

Downstream purification and isolation of proteins and biomolecules is often the most expensive and challenging aspect of their production [91]. Many of the downstream separation processes used by industry today, e.g., ultraliltration, chromatography, and centrifugation, are slow, inherently batch, nonspecific, expensive, overconsume energy, and generate wastes, particularly for downstream product purification, an important cate-... 

Whole-cell biotransformations frequently showed insufficient stereoselectivities and/or undesired side reactions because of competing enzymatic activities present in the cells. These side reactions can modify the substrates and/or products. Furthermore, whole-cell biotransformations are limited due to the intrinsic need to grow biomass, which generates its own metabolites that are not related to the biotransformation reactions and, therefore, which need to be removed during the downstream process. Both the cells themselves and the unrelated metabolites produced are impurities that need to be removed after the biotransformation reaction. With isolated enzymes, there are no organism and unrelated metabolites to remove after the biotransformation processes. 

Organic synthesis, the powerful chemistry developed by humankind, still often uses a simple step-by-step approach to convert a starting material A into a final product D, in which intermediate products B and C are isolated and purified for each next conversion step (Fig. 13.1). Catalytic steps are mostly combined with stoichiometric steps in the preparation of precursors or in the further downstream processing. Obvious disadvantages are low space-time yields (kg L-1 h-1), laborious recycle loops and large amounts of waste. 

The application of the SMB-technique to the downstream processing of biotechnological products requires some specific changes to meet the special demands of bioproduct isolation. Some exemplary applications are given including separations of sugars, proteins, monoclonal antibodies, ionic molecules and optical isomers and for desalting. 

Product isolation and purification capabilities (downstream processing) are usually ineffective and/or expensive so that the yield, quality and cost of product is poor. 

Because of the high potential of alkaloid-based alkylations for synthesis of amino acids, several groups focused on the further enantiomeric enrichment of the products [20]. In addition to product isolation issues, a specific goal of those contributions was improvement of enantioselectivity to ee values of at least 99% ee during downstream-processing (e.g. by crystallization). For pharmaceutical applications high enantioselectivity of >99% ee is required for optically active a-amino acid products. 

Downstream processing involves employment of a purifying system that can isolate the product in as few steps as possible using the simplest purification technology that will achieve the required purity. While purity is a critical consideration for both small-molecule pharmaceuticals and biopharmaceuticals, the nature of biopharmaceutical administration (typically via injection) and the nature of biotechnology processes require that additional considerations be paid to the purity of biopharmaceuticals. The final product must meet regulatory purity and sterility standards and must be below the maximally acceptable cellular or microbial contamination (Ho and Gibaldi, 2003). 

The isolation and purification of fermentation products is often collectively referred to as downstream processing. The early part of the separation of a bioproduct is the primary recovery process, whereas the elements further downstream may include purification, concentration, and formulation. The overall goal of downstream processing and formulation is to recover the product of interest cost effectively at high yield, purity, and concentration, and in a form that is stable, safe, and easy to use in a target application. 

The last step in downstream processing is the final purification and conditioning of the product. Chemicals and proteins are often recrystallized and heat or freeze dried. They are stored and sold in hags or drums. Very sensitive products are not fully isolated hut sold as concentrates. Liquid products like ethanol or acetic acid are distilled and sold in tanks, drums, or bottles. 

Besides that, fermentation can only be industrially attractive if the process provides highest yields and exhibits an efficient isolation and purification process (downstream processing) with only minimal product losses. Additionally, suitable substrates must be commercially available at low cost. Finally, the generation of flavours by fermentation in bioreactors will only be profitable if the desired product, be it a pure substance or a complex flavour extract, is not obtainable with comparable quality by inexpensive classical techniques. 

The production of flavour substances by cell or tissue cultures is still a dream for the future in most cases. Today the extraction of product from intact living plants is still less expensive than the production by isolated cells and tissues. On the other hand, it is very attractive to make use of the secondary metabolism of plant cells for the synthesis of natural flavours in a controlled way to avoid contaminating by-products and thus considerably simplify downstream processing. Further advantages of such cell culture systems would be the independence from agriculture combined with the risk for possible shortage and variances in product quality, the ability to scale-up the process to create an inexhaustible source of well-defined product. 

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