Biocatalysis companies

What will matter is the extent to which a biocatalysis company manages to focus on the market, on the development of biocatalysts to address market needs, and on the ability to compare the potential of biocatalysts and chemical alternatives. Finally, it is possible to list some of the properties of that company that is likely to emerge as the premier biocatalysis company in the next decade ... 

Another advantage of biocatalysis is that chemo-, regio-, and stereoselectivities are attainable that are difficult or impossible to achieve by chemical means. A pertinent example is the production of the artificial sweetener, aspartame, which has become somewhat of an industrial commodity. The enzymatic process (Fig. 2.31), operated by the Holland Sweetener Company (a joint venture of DSM and Tosoh), is completely regio- and enantiospecific (Oyama, 1992). 

It is interesting to speculate on the development of such a focused biocatalysis-based chemical industry. It is Ukely that at least one more decade will pass before a significant biocatalysis-driven company emerges. A very important attribute of such a company will be the ability of management not to be side-tracked by nonissues, examples of which are ... 

In conclusion, biocatalysis should be, or become, part of the technology toolbox of any fine-chemical company. Cell culture fermentation, on the other hand, should be considered only by large fine-chemical companies with a full war chest and a long-term strategic orientation. 

The first company based upon applied biocatalysis also dates back to the 19 century. In 1874 Christian Hansen started a company in Copenhagen, Denmark. His company— named Christian Hansen s Laboratory to this day—was the first in the industrial market with a standardized enzyme preparation, rennet, for cheese making. Rennet, a mixture of chymosin (also called rennin) and pepsin, was and still is obtained by salt extraction of the fonrth stomach of suckling calves. 

Enzymes that are suited for application in biocatalysis are mostly hydrolases, bnt also oxidorednctases, lyases and, to a lesser extent, transferases are useful. Obviously, the focus of bulk enzyme producers is different from the main interests of those who want to apply enzymes in biocatalytic applications. Fortunately, a growing number of companies has become active in the field of enzyme prodnction for biotransformations and by now a large nnmber of enzymes suited for biotransformations has become commercially available (Table 5.1). 

For the successful coinmerciahsation of almost all biocatalysis products, patent protection is essential since without patent protection, and the prospect of a period of enforceable monopoly in which to recoup investment and make a profit, it is unlikely that the substantial investment required for bringing a product process to the market will occur. Frequently, the compare making the invention does not wish to, or is not able to, bring the invention to the market itself. Instead, it enters into an alhance with a partner which is better able to do this. In this case, and especially in the period where it is still uncertain that the product will be useful or commercially successful, patents and patent applications, and the know-how associated with the product or processes, may be the most valuable asset of the company. 

It is clear that if these aspirational E factor targets are to be met, then improvements are desirable in many areas of chemistry, including waste minimization in medicinal chemistry, greener synthetic methods in primary manufacture, increased use of chemo and biocatalysis, and more collaborative efforts between pharmaceutical companies. These areas are aU discussed in the remainder of this chapter. Although Sheldon focused on primary manufacture, it is also important to think about secondary manufacture (formulating tablets, capsules, or other dosage forms), which is also covered in this chapter. 

Applications of biocatalysis in large-scale processes in industry advance only slowly against established chemical processes, even with stoichiometry-based chemistry. Introduction of biocatalysis into existing processes often requires process modifications that are not economical in view of the short life span of the product and/or the low fixed costs of the existing process owing to written-off plant. It should be emphasized that the desire to reduce chemical wastes, imposed by either company policy or governmental measures, needs to be matched by favorable process economics. Therefore, the introduction of biocatalytic options at the very beginning of product and process development is of the utmost importance. 

Although biocatalysis is the new kid on the block, more and more companies are using enzymes for chemical manufacture. One reason for this is that biocatalysts give sustainable alternatives to chemical manufacture, and not just for making chiral products. The synthesis of acrylamide via an enzyme-catalyzed water addition to acrylonitrile (2-propenenitrile) is a classic example (Figure 1.15). It uses the Rhodo-coccus enzyme nitrile hydratase. Commercialized in 1985 by Nitto Chemicals in... 

CCCs may obtain chiral compounds by classical resolution, kinetic resolution using chemical or enzymatic metlrods, biocatalysis (enzyme systems, whole cells, or cell isolates), fermentation (from growing whole microorganisms), and stereoselective chemistry (e.g., asymmetric reduction, low-temperature reactions, use of chiral auxiliaries). CCCs may also be CCEs by capitalizing on a key raw material position and going downstream. Along with companies manufacturing chiral molecules primarily for other purposes, such as amino acid producers, these will be the key sources for the asymmetric center. 

The problem of chiral synthesis is critical in making pharmaceuticals. Researchers at GlaxoSmithKline, AstraZeneca and Pfizer have examined 128 syntheses from their own companies and found that as many as half of the drug compounds made by their process R D groups are not only chiral but also each contains an average of two chiral centers [ 15 2]. To meet regulatory requirements, enantiomeric purities of 99.5% were found to be necessary. Biocatalysis is thus an essential tool for pharmaceutical research, and contributes to the development of more sustainable processes. 

If you have reached this point in the chapter with the feeling that enzymes are all very well for the experts but that you are unlikely ever to use one, then this section is for you. Immobilized enzymes are now freely available from several companies and pharmaceutical companies use them on a large scale almost as a matter of routine. There are still problems of course and most asymmetric synthesis is not done with enzymes. In this section we set out to convince you that enzymes are practical reagents in organic solvents as well as in water and that practical minded chemists use them. An excellent review may convince you more.49 Recently a whole issue of the journal Organic Process Research and Development (2002, 6, issue 4, 420 ff.) was devoted to biocatalysis and the introductory article50 makes the point too. 

A number of smaller enzyme-producing companies focus on thermophilic micro-organisms (and other extremophiles) to identify and produce new types of thermostable enzymes Unitika, Pacific Enzymes, Genis, Diversa (formerly Recombinant BioCatalysis), and others. One extremozyme that has already found commercial application is the heat-stable DNA polymerase from Thermus aquaticus (Taq-polymerase) that gave rise to the polymerase chain reaction (PCR). Using PCR, nucleic acids or segments of DNA can by amplified in vitro without having to replace the enzyme after each amplification cycle when the DNA template is denatured by heat. A number of new hyperthermophilic enzymes with temperature optima between 75 and 118°C have been described in the past few years [81], such as... 

NSF I/UCRC for Biocatalysis and Bioprocessing of Macromolecules, Polytechnic University, Six Metrotech Center, Brooklyn, NY 11201 Rohm and Haas Company, P.O. Box 904, Spring House, PA 19477 National Synchrotron Light Source, Brookhaven National Laboratory,... 

The production of 3-lactam nuclei triggered the development of processes for SSpLA, mostly based on chemical synthesis. However, the situation began to change as a consequence of the advances in biocatalysis and the increasing environmental regulations imposed to the production companies (Bruggink 2001). 

There has been much recent corporate investment in the field of biocatalysis with leading fine chemical companies now beginning to supplement traditional chemical and metal catalysis with biocatalysis. This will lead to more and more practical industrial uses... 

Ionic liquids are still in the research phase. Therefore, there are only a few industrial applications known (Fig. 20.3). However, there is a large field of potentially interesting applications (Table 20.3). Several pilots or industrial processes using ILs were publicly announced. There are few reviews which describe those applications in detail [1]. Most of the potential applications are as solvents or catalysts in many chemical reactions such as Diels-Alder, Friedel-Crafts reactions, and biocatalysis. Applications in other fields such as in separations, fluid applications, and analytical applications, are lower in numbers. There are now many companies who supply ionic liquids in gram scale to multi-ton scale. Some of the key suppliers are listed in Table 20.4. In this chapter, maiifly the applications in the pilot-plant and industrial phase will be discussed. Aspects of ionic liquid stability, cost, recycling, and waste disposal will be also discussed at the end of this chapter. 

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