BIOTECHNOLOGY FOR INDUSTRIAL PRODUCTION OF FINE CHEMICALS 438

CHI MIA 50(1996) Nr. 9 (Sep•• mh

Chimia 50 (1996) 438-439 These examples are representative of © Neue Schweizerische Chemische Gesellschaft biotechnology methods in fine chemical ISSN 0009-4293 manufacture, and cover chemicals made on scales many thousands oftonnes (lysine, viLamin C, penicillin) down to a few thou- Fine Chemicals and sand kilograms (prednisolone). \yhile there is no obvious connection Biotechnology: The Business between most of the products listed in the table, closer examination reveals many of and the Markets the products could also be obtained by purely chemical methods, that the target molecule itself is labile and may be sensi- Michael S. Barber* tive to chemical attack from conventional reagents, or that several of the products listed are required in homochiral form. Defining 'fine chemicals' is like de- bring about the improvements required. While a discussion of chirality would not scribing an elephant! It is not easy to do, Thus, the application of biotechnology be appropriate to this paper, it is worth but you know one when you see one! It is to the fine chemicals business can be con- noting that the increasing use of compu- difficu It to val ue the market for fi ne chem- sidered to embrace the whole range of ter-assisted molecular design techniques icals but a broad assessment ofthe value of bioprocesses and biochemical methodol- in discovery processes is generating an the market for the various segments of the ogies. These may be superior to conven- increasing requirement for stereospecific- business is shown in Table 1. These fig- tional chemical processes (most antibiot- synthesis capability. Indeed, if a molecule ures are indicative only and are not intend- ics), competitive with them (L-lysine and is required in homochiral form, a bio- ed to be an accurate representation of (-)-D-(P-hydroxyphenyl)glycine) or un- chemical (or biotechnology) route should market sizes. competitive. Whatever the competitive be considered from the beginning. [f it is difficult to define fine chemi- status in economic terms of any particular Whether or not a biochemical method cals, it is even more difficult to define process is, 'biotechnology' methods now is finally chosen often depends upon com- biotechnology! If the narrow definition of have to be considered as legitimate means parative economics and there may be no a biotechnology as the manipulation of the for making many types offine chemicals. priori reason why one method should be genetic material of living cells in order to Examples of typical biotechnology-based more efficient than any other. (-)-D-(p- produce in quantity a natural substance fine chemicals are shown in Table 2. Hydroxyphenyl)glycine, a homochiral that cannot be obtained by other means, the direct impact of biotechnology on fine Table 1. Indicative Value of Fine Chemical Market Segments - ]996 chemicals is minimal and will remain so. Biotechnology is an enabling technol- ogy and has evolved to become the appli- cation of molecular biology to chemical Phanna.:cullcal ,ICli\ l.: ingredlcnt. and .tll\iliancs processes. The old name for this, bio- Crop prol 'eLlOn and pc. licidc~ chemistry, has been regarded by chemists as something that took place in living FooU anll feed chemlcah. \llamins. na\'our :lnd frdgmn c organisms, with minimal relevance to in- DycslulT • pigment, col uranl. P Iymer 'hcmicah and aUullI\C dustrial processes. Fermentation process- Iher ,pecial crfell chcn1Jcals es were used to produce useful substances TOlal appro imaldy but this was not, of course, biotechnology! L' ••hich·\' lumc bulk produ IS - ,a) A greater understanding of the role of enzymes in fermentation and biochemical TO\a1- line chernl 'ah reactions, and the use of isolated enzymes as chemical catalysts, led to the view that the demarcations were no longer appro- Table 2. Examples of Biotechnology Processes and Products for Fine Chemicals priate. Fermentations gave rise to biotrans- formations, to processes involving simple cchnology Produ Is reactions with cell-free enzyme extracts and to processes utilising enzymes immo- -cmlentallon nublollcs-p'niclllln.cl)lhromycil1.('{ : \mlllo:lcit!. -Iym', bilised on solid supports. The need to I' . Vilamin BI': cid' - ciln', ghICl)llU,; la \I a 'it! improve the yields of the end products from these various processes led to inten- Biolran,fomlalion 11a 1111n sive research on the genetics of the micro- organisms used and to the discovery of ways of manipulating genetic material to ell- ree en/} mallnn (-HH.I'-hydro. yphcny\)glycmc; \'pOUlaIllC *Correspondence: Dr. M.S. Barber nplopnl iniennedillll' Michael Barber and Associates

18 Croydon Road upponcd en] me ,y,h:ms 6-AP. 7- DC .7- ; (-)-I -(p-h}Jrllxyph 11 Ilgl}cinc: Caterham \1all acid: Dillhvem inlcrm 'dial' Surry CR9 6QB, UK 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