The installation generally is not a critical path on the overall project for developing an industrial-scale process of a new molecule. Whereas the overall demand for outsourced pharmaceutical fine chemicals is expected to increase moderately see Chapter 8 , the estimated annual growth rates for the above-mentioned niche technologies are much higher. However, the total size of the accessible market typically does not exceed a few hundred tons per year at best.
In ten to 15 years it is expected that most amino acids and vitamins and many specialty chemicals will be produced by means of biotechnology Three very different process technologies -biocatalysis, biosynthesis microbial fermentation , and cell cultures- are used. Biocatalysis , a. It has much to offer compared to traditional organic synthesis.
The syntheses are shorter, less energy intensive and generate less waste and hence, are both environmentally and economically more attractive. In the manufacture of fine chemicals, enzymes represent the single most important technology for radical cost reductions. This is particularly the case in the synthesis of molecules with chiral centres. Here, it is possible to substitute the formation of a salt with a chiral compound, e.
Similar rewarding switches from chemical steps to enzymatic ones have also been achieved in steroid synthesis. Thus, it has been possible to reduce the number of steps required for the synthesis of Dexamethasone from bile from 28 to Enzymes differ from chemical catalysts particularly with regard to stereoselectivity , regioselectivity , and chemoselectivity. They can be recovered by filtration after completion of the reaction.
get link Conventional plant equipment can be used with no, or only modest, adaptations. Codexis is the leader in modifying enzymes to specific chemical reactions. The highest-volume chemicals made by biocatalysis are bio-ethanol 70 million metric tons , high-fructose corn syrup 2 million metric tons ; acrylamide , 6-aminopenicillanic acid APA , L-lysine and other amino acids, citric acid and niacinamide all more than 10, metric tons. Biosynthesis i. The technology has been used for 10, years to produce food products, like alcoholic beverages, cheese, yogurt, and vinegar.
In contrast to biocatalysis, a biosynthetic process does not depend on chemicals as starting materials, but only on cheap natural feedstock, such as glucose, to serve as nutrient for the cells. The enzyme systems triggered in the particular microorganism strain lead to the excretion of the desired product into the medium, or, in the case of HMW peptides and proteins, to the accumulation within so-called inclusion bodies in the cells. The key elements of fermentation development are strain selection and optimization, as well as media and process development.
Dedicated plants are used for large-scale industrial production. As the volume productivity is low, the bioreactors, called fermenters , are large, with volumes that can exceed m3. Product isolation was previously based on large-volume extraction of the medium containing the product. Modern isolation and membrane technologies, like reverse osmosis , ultra - and nano-filtration , or affinity chromatography can help to remove salts and by-products, and to concentrate the solution efficiently and in an environmentally friendly manner under mild conditions. The final purification is often achieved by conventional chemical crystallization processes.
In contrast to the isolation of small molecules, the isolation and purification of microbial proteins is tedious and often involves a number of expensive large-scale chromatographic operations. Examples of large-volume LMW products made by modern industrial microbial biosynthetic processes are monosodium glutamate MSG , vitamin B2 riboflavin , and vitamin C ascorbic acid.
After the discovery of penicillin in by Sir Alexander Fleming from colonies of the bacterium Staphylococcus aureus , it took more than a decade before a powdery form of the medicine was developed. Since then, many more antibiotics and other secondary metabolites have been isolated and manufactured by microbial fermentation on a large scale. Some important antibiotics besides penicillin are cephalosporins , azythromycin , bacitracin , gentamycin , rifamycin , streptomycin , tetracycline , and vancomycin.
Cell Cultures Animal or plant cells, removed from tissues, will continue to grow if cultivated under the appropriate nutrients and conditions. When carried out outside the natural habitat, the process is called cell culture.
Mammalian cell culture fermentation, also known as recombinant DNA technology , is used mainly for the production of complex big molecule therapeutic proteins, a. Commonly used cell lines are Chinese hamster ovary CHO cells or plant cell cultures. The production volumes are very small. Fine chemical production by mammalian cell culture is a much more demanding operation than conventional biocatalysis and —synthesis.
The bioreactor batch requires more stringent controls of operating parameters, since mammalian cells are heat and shear sensitive; in addition the growth rate of mammalian cells is very slow, lasting from days to several months.
Fine Chemicals Manufacture - 1st Edition - ISBN: , . Fine Chemicals Manufacture, Technology and Engineering is intended to show what is. Fine Chemicals Manufacture, Technology and Engineering is intended to show what is needed to make the recipe more useful for process development.
While there are substantial differences between microbial and mammalian technologies e. The mammalian cell production process, as used for most biopharmaceuticals, is divided into the four main steps: 1 Cultivation, i. All steps are fully automated. The low productivity of the animal culture makes the technology expensive and vulnerable to contamination. Actually, as a small number of bacteria would soon outgrow a larger population of animal cells.
Its main disadvantages are low volume productivity and the animal provenance. It is conceivable that other technologies, particularly plant cell production , will gain importance in future.
Given the fundamental differences between the two process technologies, plants for mammalian cell culture technologies have to be built ex novo. The inherent risks of the mammalian cell technology led several companies to opt out of mammalian cell technology or to substantially reduce their stake.
In conclusion, biocatalysis should be, or become, part of the technology toolbox of any fine chemical company. Mammalian 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.
Within the chemical universe, the fine chemical industry is positioned between the commodity, their suppliers, and specialty chemical industries, their customers. Depending on the services offered, there are two types of fine chemical companies. The Fine Chemical Companies are active in industrial scale production, both of standard and exclusive products.
Their product portfolios comprise exclusive products, produced by custom manufacturing, as main activity, non-exclusive products, e. API-for Generics, and standard products. The industry is very fragmented.
The main reason for the fragmentation is the lack of economy of scale see below. The industry is subject to a high degree of regulation  even more so than the chemical industry as a whole, particularly if pharmaceutical fine chemical production is involved. The European correspondent is the European Medicines Agency EMEA , which is manly responsible for the scientific evaluation of medicines developed by pharmaceutical companies for use in the European Union.
The U. Pharmacopeia  codifies quality standards for Active Pharmaceutical Ingredients. As these standards are observed worldwide, they contribute also to the emergence of a uniform worldwide set-up of the top tier fine chemical companies. Most are not pure players but divisions or b. All have extensive resources in terms of chemists and other specialists, plants, process knowledge, backwards integration, international presence, etc.
The leading companies are typically divisions of large, diversified chemical companies. In terms of geography, 9 of the top 20 are located in Europe, which is recognized as the cradle of the fine chemical industry.
This is e. Custom manufacturing prevails in northern Europe; the manufacture of active substances for generics, in southern Europe. The second largest geographic area is Asia, housing 7 of the top With 4 large companies, the US rank last. Whereas the European and U. Several large pharmaceutical companies market fine chemicals as subsidiary activity to their production for captive use, e.
Large fine chemical companies, in contrast to mid-sized and small ones, are characterized by. Their portfolios comprise both custom manufacturing and API-for-generics. They include both independents and subsidiaries of major companies. A number of these companies are privately owned and have grown mainly by reinvesting the profits. Customers prefer to do business with mid-sized companies, because communications are easier —they typically deal directly with the decision maker— and they can better leverage their purchasing power.
Most of them are located in Asia. They often specialize in niche technologies. The minimum economical size of a fine chemical company depends on the availability of infrastructure. If a company is located in an industrial park, where analytical services; utilities, safety, health, and environmental SHE services, and warehousing are readily available, there is practically no lower limit. New fine chemical plants have come on-stream mostly in Far East countries over the past few years. All big and medium-size fine chemical companies have cGMP-compliant plants that are suitable for the production of pharmaceutical fine chemicals.
With the exception of biopharmaceuticals, which are manufactured by only a few selected fine chemical companies, see section 3. This means that they can carry out practically all types of chemical reactions. They differentiate on the basis of the breadth and quality of the service offering. Contract research organizations CROs provide services to the life science industries along product development. Whereas the production sites of CMOs are multipurpose plants, allowing for the production of tens to hundreds of tons of fine chemicals, the work places of patient CROs are the test persons volunteers for the clinical trials and those of the product CROs are the laboratory benches.
Major customers for CRO services are the large global pharmaceutical companies.
As for CMOs also for CROs, biotech start-up companies with their dichotomy between ambitious drug development programs and limited resources are the second most promising prospects. There are more product CROs. Their tasks are described in Chapter 5, Examples of are:.