BIOTECHNOLOGY FOR INDUSTRIAL PRODUCTION OF FINE CHEMICALS 439 CHIMIA 50 (IYY6) Nr. Y(Scp'clllbcrl product, is manufactured, apparently com- development include the use of solvent- is even more complex. Process develop- petitively, by a chemical route based on tolerant enzymes and innovative biochem- ment will be required to establish the op- dynamic resolution, by a route involving a ical engineering. timum reaction conditions and, at this point, series of whole cell biotransformations What is needed in order to develop economic issues will begin to become and by a process involving supported en- biotechnology processes successfully? The apparent. Separation and purification may zyme systems. Similarly, chemical and broad principles are the same for chemical present unusual challenges. Co-factors biochemical routes compete in the manu- and biochemical syntheses. The differ- may be needed. Is the precursor easy to facture of captopril and diltiazem. ence lies in the biological component. The synthesise? It is generally acknowledged that there search for an organism suitable for carry- Not surprisingly, these issues have is considerable pressure on the fine chem- ing out a biotransformation, or for one that daunted most fine chemical producers. icals industry to use 'environmentally contains an enzyme that will catalyse the Many have not had the resources to ad- friendly' processes and methods and to required reaction, may be long and diffi- dress the area seriously, have not been dispose of its wastes in the same manner. cult. Even when an organism has been interested or even aware that it exists. Chlorinated hydrocarbons are regarded as di scovered and isolated, the optimum con- However, the evolution of the fine chem- generally undesirable and methylene ditions for organism culture and, if appro- icals market, the increasingly discerning dichloride is coming under increasing pres- priate, the biotransformation, have to be attitude of customers, the increasingly sure as a reaction solvent, principally in established. Increasing the 'activity' of stringent regulation of products and pro- relation to emissions and containment. the organism may involve significant strain cess outputs, economic pressures general- While oxygenated solvents may be suita- development, a process which may in- ly and, finally, the number of new prod- ble substitutes in some processes, in oth- volve modification of the natural genetic ucts emerging from discovery laborato- ers there is a need for alternative reaction material in the organism (genetic engi- ries, all suggest that the future for process- schemes. Biotechnology methods can pro- neering). If the organism is to be used as es broadly falling within the definition of vide opportunities for avoiding the use of the source of an enzyme which is to be biotechnology is full of promise. suspect materials. Other areas for future isolated and further modified, the process Chimia 50 (1996) 439-440 nipulation, cell production and product © Neue Schweizerische Chemische Gesellschaft isolation. The concept of biotransforma- ISSN 0009-4293 tion, where cells or their enzyme products are used to catalyse the interconversion of specific chemicals, is not new and has Biotechnology: Responding to the been practised over much of this century as I and other speakers have often remind- Fine Chemical Market Challenge ed audiences! However, the real strategic impact of this technology has only been recently recognised and accepted, thus in Stephen C. Taylor* many respects, biotransformation is achild of the 1980s and 90s. The first two elements underpin all The broad range of definitions and - the rise in biopharmaceuticals, biotechnology products and much of the products which are increasingly encom- - the emergence of gene and DNA distinctiveness of individual fine chemi- passed by the term 'Fine chemicals', is medicines. cal businesses lies in theirtechnology pack- perhaps only matched by the even broader With relatively few exceptions, the ages in these areas. By way of example, use of the term 'Biotechnology'. To avoid focus for biotechnology in the last decade the range of organisms and gene-expres- the inevitable pitfalls for anyone trying to has been firmly on the pharmaceutical sion systems used, each with their own define specific boundaries, this paper will industry, perhaps not surprising bearing in advantages and disadvantages, is consid- simply offer a personal view of the key mind, the recent dynamics and strong fi- erable: Aspergillus (Gist, Genencor), oth- recent and likely future biotechnology de- nancial performance of this industry cou- er fungi, Pseudomonas, E. coli (Zeneca), velopments that relate to chemicals pro- pled with a constant flow of ever more yeast (several), mammalian cells (Cel/- duction. It will thus: complex new product introductions. Al- tech), animals (Genzyme), plants (Mon- i) map out and illustrate the range of though there are notable examples of bio- santo). Similarly, there is variance and applications of biological methods to technologically derived products to be differentiation in cell production meth- the manufacture of chemicals, found in the sphere of agrochemicals and ods, e.g., my own business's expertise in ii) seek to identify the key strenghts and flavours and fragrances, the pharmaceuti- large scale continuous fermentation or weaknesses of biotechnology in this cal sector will be the main theme taken in Kelco/NSC Technology expertise in vis- type of use and this paper and should serve to illustrate the cous fermentations. Developments in these iii) consider how the technology might major technology issues and development evolve further to meet the future mar- needs. ket challenges in particular: All biotechnology processes can be *Correspondellce: Dr. S.C. Taylor Zelleca LifeScience Molecules - the need for faster process develop- broken down into four generic activity BioMolecules ment and scale-up, boxes (Fig.). Anti-infectives derived by P.O. Box 2 - the continued drive for more cost- microbial fermentation and the newer pro- Belasis Avenue effective production methods, tein biopharmaceutics draw upon cell ma- Billingham, Cleveland, UK BIOTECHNOLOGY FOR INDUSTRIAL PRODUCTION OF FINE CHEMICALS 440 CHIMIA 50 (1996) Nr. 9 (September) biocatalysts that can be even more amena- ble to routine use and, secondly, es"tablish- Cell isolation. identification and gene manipulation ing cost-effective and robust methods for using reduction and oxidation enzymes in biotransformations. Some recent develop- ments point the way forward such as Zene- ca's work on biocatalyst-drying technolo- gy [1] and the innovative enzyme-crystal Cell Production Biotransformation crosslinking techniques of Altus Biologics - microbial - enzymes [2]. There are now a few good examples of - animal - cells - plant the use of redox enzymes, largely based on the application of intact, viable microbial ce1ls rather than isolated enzymes [3]. Al- though effective, this does take it out of the hands of the traditional organic chemist, and history would suggest that without Product Isolation easy application by this dominant commu- Figure. Generic nity in the industry, the technology may process flows never realise its ful1 potential. However, confidence in biotechnology meeting this cha1lenge remains high in the biotransfor- areas are ongoing and perhaps the most fully its potential for fine chmicals pro- mation science base. important aspect will be in facilitating duction. The recent exciting development of faster construction and growth of new The growth in biotransformation has pharmaceuticals based on ON A structures strains expressing specific new products probably been the major recent biotechno- and analogues by biotechnology compa- through the use of 'generic' organisms logical development in a fine chemicals nies such as Isis, offers a new area for and molecular biology cassettes. This wi1l context. This development has essentially applying biotechnology. Whetherthe pro- be an essential pre-requisite to meeting the paralleled the recognition of the impor- duction of specific sequences of ON A for challenging time scales for even faster tance of chirality to drug development cou- gene-therapy treatments comes within the development being required by the phar- pled with the lack of good scalable conven- banner of' Fine Chemicals' may be a poi nt maceutical industry. tional chemical catalytic methods for these for debate. It is clear however, that if such Methodologies for the isolation ofbio- compounds. The use of enzymes to resol ve products arecommercia1\y successful, bio- technological products are many and range racemic mixtures is now we1l-established technology wil1 play an important role in from we1l-proven solvent and chromato- at a1l scales from its application in labora- the production systems used. graphic methods to the newer supercriti- tory screening to over 1000 tpa fu1l scale cal fluid extraction systems. Recognising plant operation with highly competitive [I] Eur. Pat. 366303, Zeneca; 13/12/95. the trend towards lower quantities of more economics. Numerous chal1enges need to [2] 1.1. Lalonde, C. Govardhan, N. Khalef, specific, more active and often biological be met in order to widen the base of product A.G. Martinez, K. Visuri, A.L. Margolin, molecules, the point may be near when applications of biotransformation. Perhaps J. Am. Chern. Soc. 1995, / /7,6845. affinity chromatography starts to realise the two major ones are establishing stable [3] Pat. WO 93GB 1776, Zeneca.