Fine chemical - Knowledge

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observed . R&D expenditures in the fine chemical industry are higher than in the commodities industry. They represent around 5–10% versus 2–5% of sales. On the business side, product innovation must proceed at a more rapid pace, because life cycles of fine chemicals are shorter than those of commodities. Therefore, there is an ongoing need for substitution of obsolete products. On the technical side, the higher complexity of the products and the more stringent regulatory requirements absorb more resources. Many economic and technical parameters have been proposed to enable a meaningful assessment of single projects and project portfolios. Examples are attractiveness, strategic fit, innovation, gross/net present value, expected profits, R&D expenditures, development stage, probability of success, technology fit, potential conflicts with other activities of the company and realization time. Most of these parameters cannot be determined quantitatively, at least during the early phases of a project. The best way to take advantage of a project portfolio is to develop and use it in an iterative way. By comparing the entries at regular intervals, for instance, every 3 months, the directions that the projects take can be visualized. If a negative trend persists with one particular project, the project should be put on the watch list.

4309:, the main customer base for fine chemicals, the pharmaceutical industry, is faced with slower growth of demand, patent expirations of many lucrative blockbuster drugs and stalling new product launches. In order to restrain these challenges, the leading companies are implementing restructuring programs. They comprise a reduction of in-house chemical manufacturing and plant eliminations. Outsourcing is moving up from a purely opportunistic to a strategic approach. It is difficult to make a judgment, whether the positive or negative effects of these initiatives will prevail. In a worst-case scenario, a condition could develop, whereby even top-tier mid-sized, family-owned fine-chemical companies with state-of-the-art plants and processes could be relegated to producing small quantities of fine chemicals for new life-science products in late stage of development. In agro fine chemicals, the active ingredients become more sophisticated and performing. Therefore, they require multipurpose instead of dedicated plants prevailing in the industry so far. At the same token, outsourcing is gaining ground. 3966:

multipurpose plant built in the US is shown in Table 9. The investment cost of $ 21 million comprises just the equipment and installation. The building, property and external services are excluded. For comparison purposes, the investment cost per m reactor volume is used. In this case, it is $ 0.9 million. The amount includes the cost of the reaction vessel itself plus an equitable part of the ancillary equipment, like feeding tanks, piping, pumps & process control. If larger or smaller reactors were installed, the unit cost per m would decrease or decrease with the exponent 0.5, respectively. Hence, by increasing the equipment size manufacturing costs on a per kilogram (kg) basis typically decrease substantially. Also, costs for a plant that is used for the production of non regulated intermediates only would be substantially lower. Pharma companies tend to spend up to ten times more for a plant with the same capacity. In contrast, investment costs in developing countries, particularly in India or China, are considerably lower.

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advantage of the Asian producers is going to persist. As the pharmemerging countries mainly use generics, their market share continues to grow to the detriment of originator pharmaceuticals and agrochemicals. This is also the case for biosimilars, the generic versions of biopharmaceuticals. As a consequence of the harsh business climate, many Western fine chemical companies or divisions created during the "irrational exuberance" at the end of the 20th century already have exited from the sector. Others will follow suit or will be acquired by private equity firms. Survival strategies include implementation of lean production principles originally developed by the automotive industry and extending the business model to include also contract research at the beginning and active drug formulation towards the end of the added value chain. This latter strategy, however, is not finding unanimous approval by industry experts.

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commercial scale has to be demonstrated. Trial quantities of the new fine chemical have to be manufactured for market development, clinical tests, and other requirements. The necessary data have to be generated to enable the engineering department to plan the modifications of the industrial-scale plant and in order to calculate production costs for the expected large-volume requirements. Both equipment and plant layout of the pilot plant reflect those of an industrial multipurpose plant, except for the size of reaction vessels (bench-scale laboratory ~10–60 liters; pilot plant ~100–2500 liters) and the degree of process automation. Before the process is ready for transfer to the industrial-scale plant, the following activities have to be completed: Adaptation of the laboratory process to the constraints of a pilot plant,

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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. Their annual turnover rate rarely exceeds $ 25 million. 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 3.2.2), the technology toolboxes of all these companies are similar. 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.

1101:), fine chemicals (e.g. 6-aminopenicillanic acid), and specialties (e.g., food and feed additives). As opposed to green and red biotechnology, which relate to agriculture and medicine, respectively, white biotechnology seeks to improve the economic and sustainable production of existing products, and provide access to new products, especially biopharmaceuticals. It is expected that revenues from white biotechnology will account for 10%, or $ 250 billion, of the global chemical market of $ 2,500 billion by 2013. 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. 3936:. In custom manufacturing, a specialty-chemicals company outsources the process development, pilot plant, and, finally, industrial-scale production of an active ingredient, or a predecessor thereof, to one, or a few, fine chemical companies. The intellectual property of the product, and generally also the manufacturing process, stay with the customer. The customer-supplier relationship is governed by an exclusive supply agreement. At the beginning of cooperation, the customer provides a "tech package", which in its simplest version, includes a laboratory synthesis description and SHE recommendations. In this case, the whole scale up, which comprises a factor of about one million (10 gram → 10 ton quantities), is done by the fine chemical company. 2538:.) alone absorb about one third of all CRO spending. 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. Product CROs (chemical CROs) are providing primarily sample preparation, process research and development services. An overlap between the latter and CMOs exists with regard to pilot plants (100 kg quantities), which are part of the arsenal of both types of enterprise. There are more 100 product CROs. Most of them are privately held and have revenues of $ 10–$ 20 million per year or less, adding up to a total business in the range of $ 1.5-$ 2 billion. Their tasks are described in Chapter 5, Examples of are: 1427:). 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. While there are substantial differences between microbial and mammalian technologies (e.g., the volume / value relationships are 10 $ /kg and 100 tons for microbial, 1,000,000 $ /kg and 10 kilograms for mammalian technology; the cycle times are 2–4 and 10–20 days, respectively), they are even more pronounced between mammalian and synthetic chemical technology (see Table 1). 326:

pursue both a "supply push" strategy, whereby standard products are developed in-house and offered ubiquitously, and a "demand pull" strategy, whereby products or services determined by the customer are provided exclusively on a "one customer / one supplier" basis. The products are mainly used as building blocks for proprietary products. The hardware of the top tier fine chemical companies has become almost identical. The design, lay-out and equipment of the plants and laboratories have become practically the same globally. Most chemical reactions performed go back to the days of the dyestuff industry. Numerous regulations determine the way labs and plants must be operated, thereby contributing to the uniformity.

4213:(oseltamivir phosphate) by many countries in order to prepare for a possible avian flu epidemic. Surprisingly, the main cause for the 2009 slump had not been the general recession, but slow-downs of the growth and, even more so, inventory adjustments by the pharma industry. They resulted in postponements or cancellations of orders. The unfavorable development was in sharp contrast to the very optimistic growth forecasts, which many fine chemical companies, had announced. They had been based on equally promising sector reports from investment banks, which in turn had evolved from forward projections of the preceding boom period. In most cases, these projections have been missed by a large margin. 984:

incorporated in a resin that is contained in a reactor or column. The synthesis sequence starts by attaching the first amino acid to the reactive group of the resin and then adding the remaining amino acids one after the other. In order to ascertain a full selectivity, the amino groups have to be protected in advance. Most developmental peptides are synthesized by this method, which lends itself to automation. As the intermediate products resulting from individual synthetic steps cannot be purified, a selectivity of effectively 100% is essential for the synthesis of larger-peptide molecules. Even at a selectivity of 99% per reaction step, the purity will drop to less than 75% for a

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contacts. Particularly in custom manufacturing, "demand pull" prevails industrial reality. The "new product committee" is the body of choice for evaluating new and monitoring ongoing research activities. It has the assignment to evaluate all new product ideas. It decides whether a new product idea should be taken up in research, reassesses a project at regular intervals and, last but not least decides also about the abandonment of a project, once it becomes evident that the objectives cannot be reached. In a typical project the overall responsibility for the economic and technical success lies with the

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production and merchant market. Pharmaceutical fine chemicals (PFCs) account for two-thirds of the total. Out of the PFC value of $ 55 billion, about $ 23 billion (~40%) are traded, and $ 32 billion (~60%) are the production value of the pharma industry's in-house production. Within life science products, fine chemicals for agro, and —at a distance— for veterinary drugs follow in importance. The production value for fine chemicals used for specialty chemicals other than pharmaceuticals and agrochemicals is estimated at $ 15 billion. As the leading specialty chemical companies,

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offering both contract research and manufacturing services (CRAMS) combine the activities of CROs and CMOs. Their history is either a forward integration of a CRO, which adds industrial scale capabilities or backwards integration of a CMO. As there are only limited synergies (e.g. > 90% of the projects end at the sample preparation stage). It is questionable, though, whether one-stop shops really fulfil a need. Actually, the large fine chemical companies consider the preparation of samples more as marketing tool (and expense ...) rather than a profit contributor.

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Generics, and standard products. Characteristics are high asset intensity, batch production in campaigns in multipurpose plants, above-industry-average R&D expenditures and close, multi-level and multi-functional relationships with industrial customers. The industry is very fragmented. 2000 – 3000 fine chemical companies exist globally, extending from small, "garage-type" outfits in China making just one product, all the way to the big, diversified enterprises, resp. units. The main reason for the fragmentation is the lack of economy of scale (see below).

4302:, biotechnology is rapidly gaining importance. In the synthesis of small molecule fine chemicals, the use of biocatalysts and microbial fermentation enable both a more sustainable and economic production than conventional organic chemistry. In the synthesis of big molecules, such as biopharmaceuticals, it is the method of choice. Biopharmaceuticals are expected to grow 15% per year, three times as fast as small molecule drugs. Five of the top ten drugs were biopharmaceuticals in 2010 (see table 6), and this is expected to grow to eight by 2016 (see table 2). 3952:, over 60 of the top 200 drugs alone, representing aggregated sales of over $ 150 billion, have fallen into the public domain within the past decade. This, along with government-backed incentives, are causing global sales of generics to rapidly increase. Asian companies currently dominate the API-for-Generics business. They have multiple advantages of their low cost basis, their large home markets, and significant previous manufacturing experience compared to western manufacturers in producing for their domestic and other non-regulated markets. 2432:. As most fine chemicals are produced in quantities of not more than a few 10 tons per year in multipurpose plants, there is little or no economy of size. The reactor trains of these plants are similar throughout the industry (see production train of a multipurpose plant). Regardless of the size of the companies, their main constituents, the reaction vessels, have a median size of the 4–6 m. Various products are made throughout a year in campaigns. Therefore, the unit cost per m per hour does practically not vary with the size of the company. 2982:(SHE) issues, (7) materials to be supplied by customer and (8) packaging & shipping information The technical part of a project usually determines its duration. Depending on the quality of the information contained in the "technology package" received from the customer and the complexity of the project as such, particularly the number of steps that have to be performed; it can be any time between 12 and 24 months. Depending on the number of researches involved, the total budget easily amounts to several million US dollars. 3003:(~55%). The global production value of fine chemicals is estimated at $ 85 billion, of which about 2/3, or $ 55 billion are produced captively and $ 30 billion represent the global revenues of the fine chemical industry. The corresponding figures for the major user, the pharmaceutical industry, are $ 32 billion and $ 23 billion, respectively. For a number of reasons, such as the lack of statistical data and the somewhat equivocal definition it is not possible to exactly determine the size of the fine chemical market. 3416:. The innovator pharma companies require mainly custom manufacturing services for their proprietary drug substances. The demand is driven primarily by the number of new drug launches, the volume requirements and the industry's "make or buy" strategy. A summary of the pro's and con's for outsourcing from the pharma industry's perspective is given in Table 7. As extended studies at the Stern Business School of the New York City University have shown, financial considerations clearly favor the "buy" option. 1273:

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

3558:, Denmark follow on the ranks 2 and 3. Apart from these multibillion-dollar companies, there are hundreds of smaller firms with sales of less than $ 50 million per year, mainly in India and China. The incidence of the cost of the active ingredient is about 33%; i.e., much higher than in drugs. Depending on the climatic conditions affecting crop yields, consumption and prices of agrochemicals are subject to wide fluctuations from year to year, impacting also the suppliers. 2970:, who is responsible for the technical success. In custom manufacturing, a typical project starts with the acceptance of the product idea, which originates mainly from business development, by the new product committee, followed by the preparation of a laboratory process, and ends with the successful completion of demonstration runs on industrial scale and the signature of a multiyear supply contract, respectively. The input from the customer is contained in the " 4070:

the conversion cost is a demanding task. Different products with widely differing throughputs are produced in campaigns in multipurpose plants, occupying the equipment to different extents. Therefore, both the production capacity and the equipment utilization for a specific fine chemical are difficult to determine. Moreover, cost elements such as labor, capital, utilities, maintenance, waste disposal, and quality control cannot be allocated unambiguously.

139: 2438:. The company's shares are listed on stock exchanges, and their performance is scrutinized by the financial community. Postponement of a single important shipment can affect a quarterly result. In the small and mid-sized companies the owners typically are the major shareholders, often members of the same family. Their shares are not traded publicly and fluctuations in their financial performance are more easily coped with. 77: 36: 4241: 3868:, are listed in Table 8. Overall, the attractiveness for the fine chemical industry is smaller than the life science industry. The total market, expressed in finished product sales, amounts to $ 150–200 billion, or about one fourth of the pharma market. The embedded fine chemicals account for an estimated $ 15 billion (see Table 5). Further disadvantages are the backward integration of the big players, e.g. 745:". Completion of a single synthetic cycle results in the addition of one nucleotide residue to the growing chain. The maximum length of synthetic oligonucleotides hardly exceeds 200 nucleotide components. From its current range of applications in basic research as well as in drug target validation, drug discovery, and therapeutic development, the potential use of oligonucleotides is foreseen in gene therapy ( 4196:

work are more than offset by better fixed cost absorption. As part of the budgeting process, standard costs for a production campaign of a particular fine chemical are determined on the basis of past experience. The actual results of the campaign are then compared with the standard. The capability of a fine chemical company to make dependable manufacturing cost forecasts is a distinct competitive advantage.

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Europe, which is recognized as the cradle of the fine chemical industry. This is e.g. the case for the world's #1 company, Lonza, headquartered in Basel. Switzerland. 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 20. With 4 large companies, the US rank last.

2953:(COGS) by 10-20%, every time the yearly production quantity has doubled. The task extends from fine tuning the currently used synthetic method all the way to the search for an entirely different second generation process. Specific provisions are the increase of overall yield, the reduction of the number of steps, raw material cost, solvent, catalyst, enzyme consumption, environmental impact. 2049:

mastered, the fine chemical companies can be broadly divided into three segments, each of them accounting for approximately the same turnover, namely about $ 10 billion. The top tier, about twenty, has sales in excess of $ 250 million per year (see Table 3). Most are not pure players but divisions or b.u.'s of large, multinational companies. Their share varies between one percent or less for

988:(30 steps). Therefore, for industrial quantities of peptides not more than 10–15 amino acid peptides can be made using the solid-phase method. For laboratory quantities, up to 40 are possible. To prepare larger peptides, individual fragments are first produced, purified, and then combined to the final molecule by liquid phase synthesis. Thus, for the production of Roche's anti-AIDS drug 2799:. Depending on the volume requirements, three different types of equipment are used for process research, development and optimization, namely bench-scale laboratories for gram to 100 gram, kilo-labs for kg to 10 kg and pilot plants for 100 kg to ton quantities. Particularities of laboratory processes that have to be eliminated include the use of large numbers of 4227:%, respectively, in the period 2000–2009, the numbers were 20% and 10–13% in the boom, and 10% and 5% in the bust phases. The factor 2 between the high and low numbers reflects the volatility of the industry's profitability. All in all, the average Western fine-chemical firms have been making a return below the cost of capital, i.e. they are not reinvestment grade. 3150:, Switzerland. All are active in R&D, manufacturing and marketing. Pharmaceuticals containing more than 2000 different active ingredients are in commerce today; a sizable number of them are sourced from the fine chemical industry. The industry also has a track record of above-average growth. The fine chemical industry has a keen interest in the top-selling or " 2514:

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. Half a dozen companies (

905:(e.g., conversions with lithium aluminum hydride, boronic acids) may require temperatures as low as -100 °C, which can be achieved only in special cryogenic reaction units, either by using liquefied nitrogen as coolant or by installing a low-temperature unit. Other reaction-specific equipment, such as filters for the separation of catalysts, 1124:

industrial scale are already made using biocatalysis. 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.g.,

354:, Switzerland, which already had supplied an early intermediate, methyl acetoacetate, during drug development, soon became the main supplier of more and more advanced precursors. The signature of a first, simple supply contract is generally acknowledged as the historical document marking the beginning of the fine chemical industry. 346:(ranitidine hydrochloride) created a strong demand for advanced organic chemicals used in their manufacture. As the in-house production capacities of the originators, the pharmaceutical companies Smith, Kline, & French and Glaxo, could not keep pace with the rapidly increasing requirements, both companies (now merged as 615:(=starting materials), protected amino acids, peptide fragments and peptides themselves. Along the way, the molecular weights increase from about 10 up to 10 and the unit prices from about $ 100 up to $ 10 per kilogram. However, only a small part of the total amino acid production is used for peptide synthesis. In fact, 1029:, US. The latter company produces about 50 fine chemicals up to multi-kilogram quantities in microreactors. From a technological point of view, MRT, a.k.a. continuous flow reactors, represents the first breakthrough development in reactor design since the introduction of the stirred-tank reactor, which was used by 4074:

involved for a more in-depth costing.. The problems it has to address are how to fairly allocate costs for production capacity, which is not used. This can be due to the fact that part of a production bay is idle, because of lack of demand or because, e.g., a reactor is not required for a particular process.

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exuberance" in 2000, the industry suffered a first bust in 2003, as a result of capacity expansions, the advent of Asian competitors and a ruinous M&A activity, several billion dollars of shareholder value were destroyed. The most recent –minor- boom is associated with stockpiling of GlaxoSmithKline's

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An indicative cost structure for a fine chemical company is shown in Table 10. Nowadays, a full 7-day/week operation, consisting of four or five shift teams, each working 8h per day, has become the standard. In terms of production costs, this is the most advantageous scheme. Higher salaries for night

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Contract research organizations (CROs) provide services to the life science industries along product development. There are more than 2000 CROs operating worldwide, representing revenues of more than $ 20 billion. One distinguishes between "Product" and "Patient" CROs. Whereas the production sites of

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Whereas the European and U.S. pharma industry constitutes the main customer base for most fine chemical companies, some have a significant share of products and services for the agrochemical industry. Examples are Archimica, CABB, Saltigo (all Germany), DSM (The Netherlands) and Hikal, India. Several

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Since the late 1970s, fine chemicals have become an important part of the chemical industry. Their global total production value of $ 85 billion is split about 60-40 between in-house production in the life-science industry—the products' main consumers—and companies producing them for sale. The latter

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Although the demand for fine chemicals on the merchant market has not grown to the extent originally anticipated, fine chemicals still provide attractive opportunities for well-run companies, which are fostering the critical success factors, namely running fine chemicals as a core business, pursuing

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Fine chemicals account for about 4% of the universe of chemicals. The latter, valued at $ 2,500 billion, is dominated mainly by oil-, gas-, and mineral-derived commodities (~40%) on one hand and a large variety of specialty chemicals at the interface between industry and the public on the other hand

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in the narrower sense are active in process scale up, pilot plant (trial) production, industrial-scale exclusive and non-exclusive manufacture and marketing. Their product portfolios comprise exclusive products, produced by custom manufacturing, as main activity, non-exclusive products, e.g. API-for

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The fine chemical industry has undergone several boom and bust phases during its almost 30 years of existence. The biggest boom took place in the late 1990s, when high-dosage, high volume anti-AIDS drugs and COX-2 inhibitors gave a big boost to custom manufacturing. After the end of the "irrational

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are the two elements that establish the manufacturing cost for a particular fine chemical. The former is determined primarily by the unit consumption and the purchasing cost of the materials used; the latter, by the throughput in kilograms per day in a given production bay. A precise calculation of

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Investment costs for multipurpose plants are high in comparison with product output. However, they vary considerably, depending on the location, size of equipment and degree of sophistication (e.g., automation, containment, quality of equipment, complexity of infrastructure). An example for a cGMP

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Sales of the top 20 blockbuster drugs are reported in Table 6. The APIs of 12 of them are "small" (LMW) molecules. Averaging a MW of 477, they have quite complex structures. They typically show three cyclic moieties. 10 of them exhibit at least one N-heterocyclic moiety. Five of the top 10, up from

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In Table 5, the approximately $ 85 billion fine chemical market is subdivided into major applications according to their relevance, namely, fine chemicals for pharmaceuticals, agrochemicals and specialty chemicals outside life sciences. Furthermore, a distinction is made between captive (in-house)

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has to design new synthetic routes and sequences. Two approaches are feasible. For simple molecules, the "bottom-up" approach is the method of choice. The researcher converts a commercially available starting material and sequentially adds more reagents until the target molecule is synthesized. For

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The mammalian cell production process, as used for most biopharmaceuticals, is divided into the four main steps: (1) Cultivation, i.e. reproduction of the cells; (2) Fermentation, i.e. the actual production of the protein, typically in 10,000 Liter, or multiples, bioreactors; (3) Purification, i.e.

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i.e. the conversion of organic materials into fine chemicals by microorganisms, is used for the production of both small molecules (using enzymes in whole cell systems) and less complex, non-glycosylated big molecules, including peptides and simpler proteins. The technology has been used for 10,000

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Chapter 8), the estimated annual growth rates for the above-mentioned niche technologies are much higher. Microreactors and the SMB separation technology are expected to grow at a rate of even 50–100% per year. The total size of the accessible market typically does not exceed a few hundred tons per

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With the exception of some stereospecific reactions, particularly biotechnology, mastering these technologies does not represent a distinct competitive advantage. Most reactions can be carried out in standard multipurpose plants. Reaction-specific equipment, such as ozone or phosgene generators, is

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are "very high-molecular-weight" (MW > 100,000) organic compounds, consisting of amino acid sequences linked by peptide bonds. They are essential to the structure and function of all living cells and viruses and are among the most actively studied molecules in biochemistry. They can be made only

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The growing complexity and potency of new pharmaceuticals and agrochemicals requiring production in multipurpose, instead of dedicated plants and, more recently, the advent of biopharmaceuticals had a major impact on the demand for fine chemicals and the evolution of the fine chemical industry as a

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Agrochemical companies are the second largest users of fine chemicals. Most products have a "pharmaceutical heritage". As a consequence of an intensive M&A activity (Mergers and Acquisitions) over the past 10–20 years, the industry now is more consolidated than the pharmaceutical industry. The

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consent to foresee the effects of these different conditions to a certain extent, a direct transfer of a process from the laboratory to the industrial scale is not recommended, because of the inherent safety, environmental, and economic risks. In development, the viability of the process on a semi

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to manufacture at industrial scale, and an estimate of the manufacturing costs in an industrial-scale plant. If the base process is provided by the customer as part of the technology transfer, process, research has to optimize it so that it can be transferred to the bench-scale laboratory or pilot

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The business of CROs is usually done through a "pay for service" arrangement. Contrary to manufacturing companies, invoicing of CROs is not based on unit product price, but on full-time equivalents (FTEs), that is, the cost of a scientist working one year on a given customer assignment. Companies

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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. In terms of size, resources, and complexity of the chemical process technologies

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Strong growth of demand: Today, biopharmaceuticals account for about $ 55–$ 80 billion, or 15% of the total pharmaceutical market. They are growing by 15% per year, i.e. three times faster than LMW drugs and are expected to pass the $ 150 billion per year threshold by 2015. Whereas just one out of

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for enhancing the production of small molecules. It has much to offer compared to traditional organic synthesis. The syntheses are shorter, less energy intensive and generate less waste, hence are both environmentally and economically more attractive. About 2/3 of chiral products produced on large

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Apart from pharmaceuticals, peptides are also used for diagnostics and vaccines. The total production volume (excl. Aspartame) of chemically synthesized, pure peptides is about 1500 kilograms and sales approach $ 500 million on the active pharmaceutical (API) level and $ 10 billion on the finished

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At the end of the "irrational exuberance" at the turn of the millennium and again in 2009 almost half of the industry achieved a return on sales (ROS) of more than 10%, and less than 10% an ROS below 5%. In the worst years, 2003 and 2009, almost half of the companies suffered from an ROS of less

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An approximative calculation can be done by an experienced process development or pilot plant chemist on the basis of (1) the laboratory synthesis procedure and (2) by breaking down the process into unit operations, the standard costs of which have been determined previously Controlling has to be

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There are two main sources of new research projects, namely ideas originating from the researchers themselves ("supply push") and those coming from customers ("demand pull"). Ideas for new processes typically originate from researchers, ideas for new products from customers, respectively customer

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to the industrial scale (the scale up factor from a 10g sample to a 1-ton batch is 100,000); and (3) to optimize existing processes. At all times during this course of action it has to be ensured that the four critical constraints, namely, economics, timing, safety, ecology and sustainability are

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The overall emphasis of fine chemical R&D is more on development than on research. The main tasks are (1) designing, respectively duplicating and adapting in case of custom manufacture, and developing laboratory procedures for new products or processes; (2) transferring the processes from the

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companies with sales in the range of $ 100–$ 250 million per year. 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

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three main types of methods are used, namely chemical synthesis, extraction from natural substances, and biosynthesis. Chemical synthesis is used for smaller peptides made of up to 30–40 amino acids. One distinguishes between "liquid phase" and "solid phase" synthesis. In the latter, reagents are

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from plants and animals. In the production of modern life science products, total synthesis from petrochemicals prevails. The HMW products, respectively large molecules, are obtained mainly through biotechnology processes. Within LMWs, the N-heterocyclic compounds are the most important category;

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with sales below $ 100 million per year. 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;

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The combined revenues of the top 20 fine chemical companies amounted to $ 10 billion in 2009, representing about 30% of the figure for the whole industry. The leading companies are typically divisions of large, diversified chemical companies. In terms of geography, 9 of the top 20 are located in

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in China. 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.

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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

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New developments in expression systems for mammalian and plant cell technology could reduce capacity requirements substantially. Actually, the titer in large-scale mammalian production, actually 2–3 grams/liter. is expected to double to 5–7 by 2015 and once more to 10 by 2020. Furthermore, the

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The likelihood of developing a new biopharmaceutical successfully is significantly greater than in traditional drug development. 25% of biopharmaceuticals that enter Phase I of the regulatory process eventually are granted approval. The corresponding figure for conventional drugs is less than

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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

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A large toolbox of chemical reactions is available for each step of the synthesis of a fine chemical. The reactions have been developed on laboratory scale by academia over the last two centuries and subsequently adapted to industrial scale, for instance for the manufacture of dyestuffs &

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results in a shift of fine chemical production from the industrialized to developing countries. The latter benefit not only from a "low cost / high skill" advantage, but also from a rapidly rising domestic demand for Western medicine. Despite the mantras of Western industry leaders, the cost

3917:

Global sales of proprietary drugs are estimated $ 735 billion in 2010, or almost 90% of the total pharma market. Global sales of generics are about $ 100 billion, or just over 10% of the total pharma market. Due to the much lower unit price, their market share will be close to 30% on an API

3561:

The molecular structures of modern agrochemicals are much more complex than in older products, but lower than of their pharma counterparts. The average molecular weight of the top 10 is 330, as compared with 477 for the top 10. In comparison to reagents used in pharmaceutical fine chemical

606:

are oligomers or polycondensates of amino acids linked together by a carboxamide group. The threshold between the two is as at about 50 amino acids. Because of their unique biological functions, a significant and growing part of new drug discovery and development is focused on this class of

321:

industry plays a big role; however, a significant portion of the fine chemicals total production volume is manufactured in-house by large users. The industry is fragmented and extends from small, privately owned companies to divisions of big, diversified chemical enterprises. The term "fine

555:, such as Vitamin B1 (thiamine), the sulfonamide antibiotics, e.g. Madribon (sulfadimethoxime) and –half a century later– the sulfonyl urea herbicides, e.g. Eagle (amidosulfuron) and Londax (bensulfuron-methyl). Benzodiazepine derivatives are the pivotal structural elements of breakthrough 2688:

The offerings of Patient CROs (Clinical CROs) comprise more than 30 tasks addressing the clinical part of pharmaceutical development at the interface between drugs, physicians, hospitals, and patients, such as the clinical development and selection of lead new drug compounds. As

3908:

USA. Last but not least, innovation is rather based on new formulations of existing products, rather than the development of new fine chemicals. It is most likely to happen in application areas unrelated to human health (where NCEs are subject to very extensive testing).

706:

is a big step forward regarding administration of peptide and protein drugs. The method offers the two-fold advantage of substituting injection by oral administration and reducing the dosage, and therefore the cost of the treatment. The pioneer company in this field is

373:

of ranitidine, the second H2 receptor antagonist, marketed as Zantac by Glaxo. Other pharmaceutical and agrochemical companies gradually followed suit and started outsourcing the procurement of fine chemicals. An example in case is F.I.S., Italy, which partnered with

2994:. The latter are obtained either by direct formulation or after chemical/biochemical transformation of intermediates to active substances. Life sciences, primarily pharmaceutical, agrochemical and food and feed industries are the main consumers of fine chemicals. 1277:

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

4559:

Examples: Swiss Federal Institute of Technology (ETHZ), Switzerland; Massachusetts Institute of Technology (MIT), USA; Institut für Mikrotechnik (IMM), Germany; University of Washington (WU), USA; Micro-Chemical ProcessTechnology Research Association (MCPT),

3505:

companies focus on R&D. albeit on just a few lead compounds. They typically originate mostly from academia. Therefore, their R&D strategy is more focused on the elucidation of the biological roots of diseases rather than developing synthesis methods.

1976:

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

1942:

Legislation and regulation of biotechnology is not well defined yet and leads to differences in interpretation and other uncertainties. In the US, legislation is not yet in place for biosimilars, the generic counterpart of generics in small molecule

3926:

The products and services offered by the fine chemical industry fall into two broad categories: (1) "Exclusives", a.k.a. custom manufacturing (CM) and (2) "standard" or "catalogue" products. "Exclusives", provided mostly under contract research or

3494:(see also chapter 6.3.2). They differ from their competitors not only in sales revenues but also because they are strongly backwards integrated and have proprietary drugs in their portfolios. They also vie for the promising biosimilars market. 3931:

arrangements, prevail in business with life science companies; "standards" prevail in other target markets. Service-intense custom manufacturing (CM) constitutes the most prominent activity of the fine chemical industry. CM is the antonym of

1295:

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

431:

As aromatic compounds have been exhausted to a large extent as building blocks for life science products, N-heterocyclic structures prevail nowadays. They are found in many natural products, such as chlorophyll, hemoglobin, and the vitamins

992:(enfuvirtide), three fragments of 10–12 amino acids are first made by solid-phase synthesis and then linked together by liquid-phase synthesis. The preparation of the whole 35 amino acid peptide requires more than 130 individual steps. 1128:, crystallization, salt breaking and recycling of the chiral auxiliary, resulting in a theoretical yield of not more than 50%, with a one step, high yield reaction under mild conditions and resulting in a product with a very high 1608:

separation of the cells from the culture medium and purification, mostly by chromatography, (4) Formulation, i.e. conversion of the sensitive proteins to a stable form. All steps are fully automated. The low productivity of the

2012:

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 most important regulatory authorities are the

927:

molecules has become an important competency. Two types of processes are used, namely the physical separation of the enantiomers and the stereo specific synthesis, using chiral catalysts. Among the latter, enzymes and synthetic

607:

biomolecules. Their biological functions are determined by the exact arrangement or sequence of different amino acids in their makeup. For the synthesis of peptides, four categories of fine chemicals, commonly referred to as

281:

and sold for more than $ 10/kg (see the comparison of fine chemicals, commodities and specialties). The class of fine chemicals is subdivided either on the basis of the added value (building blocks, advanced intermediates or

1175:

enzyme catalyst step. 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

1311:

has been substituted completely by a microbial one-step process, allowing a 95% waste reduction and an approximately 50% manufacturing cost reduction. In ascorbic acid, the five-step process (yield ≈ 85%) starting from

762:

drugs. They are linked with a monoclonal antibody, a big molecule which is of little or no therapeutic value in itself, but extremely discriminating for its targets, the cancer cells. The first commercialized ADCs were

3543:, GM seed businesses already account for more than 50% of total sales. 100 new LMW agrochemicals have been launched in the period 2000–2009. However, only 8 products achieved sales in excess of $ 100 million per year. 2496:, Portugal. 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. The 1994: 1033:, when they established a factory on the banks of what was then the Grand Junction Canal in London in 1857 to produce mauveïne, the first-ever synthetic purple dye. For a comprehensive coverage of the subject see 667:

drug level, respectively. The bulk of the production of peptide drugs, which comprise also the first generation anti-AIDS drugs, the "...navirs", is outsourced to a few specialized contract manufacturers, such as

1862:

High entry barriers because of demanding technology. The construction of a large-scale plant for the production of biopharmaceuticals by cell culture fermentation costs around $ 500 million and takes four to six

1372:

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.

1917: 2770:

focuses on the design of new, efficient, stable, safe, and scalable synthetic routes to a target fine chemical. It represents an essential link between process research and commercial production. The resulting

913:

generators, can be purchased in many different sizes. The installation of special equipment generally is not a critical path on the overall project for developing an industrial-scale process of a new molecule.

2022: 1866:

As the specifications of the plant and process types for biopharmaceuticals differ substantially from traditional chemical synthesis, they cannot be produced in conventional multipurpose fine chemical plants.

4077:

Manufacturing costs usually are reported on a per kilogram product basis. For the purpose of benchmarking (both internal and external), the volume x time / output (VTO), as mentioned above, is a useful aid.

3684:

Apart from life sciences, specialty chemicals -and therefore also their active ingredients, commodities or fine chemicals, as the case may be- are used ubiquitously, in both industrial applications, such as

900:

reactions, particularly biotechnology, mastering these technologies does not represent a distinct competitive advantage. Most reactions can be carried out in standard multipurpose plants. The very versatile

2949:. Once a new chemical process has been introduced successfully on an industrial scale, process optimization is called upon to improve the economics. As a rule of thumb it should be attempted to reduce the 2764:, or de-construction, is chosen. Key fragments of the target molecule are first identified, then synthesized individually, and finally combined to form the desired molecule through convergent synthesis. 1282:, are large, with volumes that can exceed 250 m3. Product isolation was previously based on large-volume extraction of the medium containing the product. Modern isolation and membrane technologies, like 2031:") and control the implementation, to be in charge of drug registration, draw up criteria for marketing authorization and formulate national essential medicines lists. The European correspondent is the 631:

are used in large quantities as food and feed additives. About 50 peptide drugs are commercialized. The number of amino acids that make up a specific peptide varies widely. At the low end are the

334:

The term "fine chemicals" was in use as early as 1908. The emergence of the fine chemical industry as a distinct entity dates to the late 1970s, when the overwhelming success of the histamine H

406:

In terms of molecular structure, one distinguishes first between low-molecular-weight (LMW) and high-molecular-weight (HMW) products. The generally accepted threshold between LMW and HMW is a

1827: 398:

was used only in exceptional cases, such as capacity shortfalls, processes requiring hazardous chemistry or new products, where uncertainties existed about the chance of a successful launch.

2753:(IPR) and to determine whether patent applications are indicated. Patent research is particularly important for evaluation of the feasibility of taking up R&D for new APIs-for-generics. 1196:" are those fixed on solid supports. They can be recovered by filtration after completion of the reaction. Conventional plant equipment can be used with no, or only modest, adaptations. The 932:(2,2'–Bis(diphenylphosphino)–1,1'–binaphthyl) types are used most frequently. Large volume (> 103 mtpa) processes using chiral catalysts include the manufacture of the perfume ingredient 3881: 2039: 2015: 289:

Fine chemicals are produced in limited volumes (< 1000 tons/year) and at relatively high prices (> $ 10/kg) according to exacting specifications, mainly by traditional

1912:

are investing heavily in in-house manufacturing capacity. With three plants in the US, two in Japan and one each in Germany and Switzerland, Roche has the largest production capacity.

1876:

Unlike the biopharmaceutical start-ups, the emerging big biopharmaceutical companies are adopting the same opportunistic outsourcing policy as larger pharmaceutical companies. Thus,

394:

distinct entity. For many years, the life science industry continued considering captive production of the active ingredients of their drugs and agrochemicals as a core competency.

1617:, 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. 3739:

Typical a.h. products derive from human medicines, e.g. Reconzile, dubbed "puppy Prozac". Paraciticides are the largest product category. Good growth prospects in fish farming.

1628:

the world's top ten drugs was a biopharmaceutical in 2001, the number went up to five in 2010 (see table 6) and is expected to increase further to eight by 2016 (see Table 2).

1001:(MRT), making part of "process intensification", is a relatively new tool that is being developed at several universities, as well as leading fine chemical companies, such as 575:, such as diphenylpyrazolopyrazoles, quinacridones, and engineering plastics, such as polybenzimidazoles, polyimides, and triazine resins, exhibit an N-heterocyclic structure. 3547: 965: 741:

of natural or chemically modified nucleosides. The oligonucleotide chain assembly proceeds in the direction from 3'- to 5'-terminus by following a procedure referred to as a "

3582:, are more frequently used. Agrochemical companies sometimes outsource just these steps, which require specialized equipment, on toll conversion deals. With exception of the 2481: 2066: 2693:

represent the largest expense in pharmaceutical research, the market for patient CROs is larger than for their product counterparts. Thus, the sales of the top tier firms,

3154:", i.e. those with worldwide annual sales in excess of $ 1 billion. Their number has increased steadily, from 27 in 1999 to 51 in 2001, 76 in 2003, and then levelled off. 1869:

High financial exposure: (1) high capital intensity ('massive investments are needed at a time when chances of success are still very low' and (2) risk of batch failures (

4217:

than 5%. Whereas during the period under review, 2000–2009. the average EBITDA / sales and EBIT / sales ratios of representative companies, resp. divisions were 15% and 7

1125: 2610: 2551: 2372:

11.-20.: Jubilant Organosys. India,800/470; Dr. Reddy's, India, 1370/370; Evonik-Degussa, Germany, 18,900/350; Johnson Matthey, UK 12,500/350; Aurobinda, India 665/340;

1947:

The inherent risks of the mammalian cell technology led several companies to opt out of mammalian cell technology or to substantially reduce their stake. Examples are

1920:', considered by experts as 'the hottest buzz in town'. It advantageously substitutes for stainless steel production trains, at least for short production campaigns. 708: 683: 608: 2809: 2790: 2780: 2776: 2485: 1375: 2813: 1924: 1614: 3535:, USA have a share of almost 95% of the total 2,000,000 tons / $ 48.5 billion pesticide output in 2010. Since the 1990s the R&D effort is focused mainly on 4997: 3928: 3528: 2571: 2069:

Italy. All have extensive resources in terms of chemists and other specialists, plants, process knowledge, backwards integration, international presence, etc.

969: 636: 3639: 2974:". Its main constituents are (1) reaction scheme, (2) target of project & deliverables (product, quantity, required dates, specifications), (3) list of 2950: 2766: 1321: 877: 2803:, dilute reaction mixtures, vast quantities of solvents for extraction, evaporation to dryness, drying of solutions with hygroscopic salts. Although modern 3865: 3795:

Mostly based on large volume aromatic compounds, e.g., letter acids .Asian dyestuff prod, > 10 mtpa. Some niche products, e.g. colour shifting pigments

3520: 2971: 1120: 1065:

readily available. The installation generally is not a critical path on the overall project for developing an industrial-scale process of a new molecule.

923:

fine chemicals has increased steadily. They constitute about half of both existing and developmental drug APIs. In this context, the ability to synthesize

3151: 2376:, North China Pharmaceutical, China, 718/300; Divi's Laboratories, India, 250/250; Pfizer, US, 50,000/250; Cambrex, US, 235/235; F.I.S., Italy, 230/230 2038:, which is manly responsible for the scientific evaluation of medicines developed by pharmaceutical companies for use in the European Union. The role of 1810:

Small number of custom manufacturers with industrial-scale manufacturing capabilities in this demanding technology. In the Western hemisphere, primarily

3945: 2755: 2657: 2649: 1168: 1030: 738: 699: 3837:

Mainly amino acids (L-lysine , L-methionine, ...), vitamins (C , niacin, riboflavin, ...), artificial sweeteners (aspartame, splenda) and carotenoids

3809:

Sizeable and growing demand for fine chemicals, e.g. octafluorocyclobutane for etching. for liquid crystals and organic light emitting diodes (OLED).

3753:

Uses extend from household, e.g. paper gluing, to high-tech specialty products for assembling electronic parts, automotive and aircraft construction.

4066: 3949: 3665: 3551: 2761: 2745: 2714: 2559: 1928: 1287: 742: 620: 616: 1981:

are active in industrial scale production, both of standard and exclusive products. If the latter prevails, they are referred to as Fine Chemical /

4738: 4546: 3885: 2673: 2586: 1061:. According to experts in the field, 70% of all chemical reactions could be done in microreactors, however only 10-15% are economically justified. 1022: 1010: 513: 3130:

The pharmaceutical industry constitutes the most important customer base for the fine chemical industry (see Table 4). The largest companies are

2653: 1964: 1368: 1172: 521: 3586:, which are photostable modifications of naturally occurring pyrethrums, active ingredients of agrochemicals rarely are chiral. Examples within 2772: 2598: 1089:, such as sugar or vegetable oils, and the more efficient transformation of conventional raw materials into a wide range of commodities (e.g., 872:, respectively reduction (both catalytic and chemical) are most frequently mentioned on the websites of individual companies. Optically active 788: 730: 3944:

Non-exclusives, "standard" or "catalogue products" constitute the second most important outlet for fine chemicals after custom manufacturing.

2665: 2602: 985: 1167:(montelukast), where the reduction of a ketone to S-alcohol, which had required stoichiometric amounts of expensive and moisture sensitive " 2661: 2563: 1279: 2444:. Flexibility and Responsiveness are in jeopardy. Customer complaints, for instance, are difficult to resolve in a straightforward manner. 1383:, is used mainly for the production of complex big molecule therapeutic proteins, a.k.a. biopharmaceuticals. The first products made were 2669: 2641: 2637: 1952: 960:(sitagliptin). The physical separation of chiral mixtures and purification of the desired enantiomer can be achieved either by classical 933: 410:

of about 700. LMW fine chemicals, also designated as small molecules, are produced by traditional chemical synthesis, by microorganisms (

3781:

Catalysts (automotive, polymers, petroleum processing, chemicals) / enzymes (detergents / technical enzymes, food & feed) = 80 / 20

3117:

are backward-integrated, the share of in-house production is estimated at 75%, leaving a merchant market of approximately $ 5 billion.

2618: 2606: 2590: 2575: 1823: 844:. About 10% of the 26,000 synthetic methods described therein are currently used on an industrial scale for fine chemicals production. 729:), a nitrogenous base (either a pyrimidine or a purine) and 1–3 phosphate groups. The best known representative of a nucleotide is the 501: 2633: 2622: 2547: 2058: 1948: 1399:(CHO) cells or plant cell cultures. The production volumes are very small. They exceed 100 kg per year for only three products: 640: 590:(HMW) molecules, are mostly oligomers or polymers of small molecules or chains of amino acids. Thus, within pharmaceutical sciences, 322:

chemicals" is used in distinction to "heavy chemicals", which are produced and handled in large lots and are often in a crude state.

3652:, a new class, are growing rapidly and already have captured more than 30% of the $ 10 billion global fungicide market. Syngenta's 2794: 2555: 3851:

Aerospace: Fluorinated poly ethylene/propylene,, Polyether ether ketones , Polyimides, Precision parts: Aramides , polybenzazoles

3642:

is the most important representative of Du Pont's award-winning anthranilic diamide family of broad spectrum insecticides. Within

1332:

have been isolated and manufactured by microbial fermentation on a large scale. Some important antibiotics besides penicillin are

350:) outsourced part of the manufacturing to chemical companies experienced in producing relatively sophisticated organic molecules. 3657: 2489: 1990: 758:

constitute a combination between small and big molecules. The small molecule parts, up to four different APIs, are highly potent

468:). In synthetic life science products, N-heterocyclic moieties are widely used in both pharmaceuticals and agrochemicals. Thus, 5143: 4334: 3823:~3000 molecules are used, e.g. (-) menthol ,polycyclic musks , vanilline, linalool, geraniol, heterocyclics, 2-phenylethanol) 2461: 2278: 961: 2369:

Author's estimate (non figures published by the company) HMW, high molecular weight, LMW, low molecular weight fine chemicals

1328:, it took more than a decade before a powdery form of the medicine was developed. Since then, many more antibiotics and other 690:(mAb) prevail among human-made proteins. About a dozen of them are approved as pharmaceuticals. Important modern products are 5073: 5026: 4953: 4859: 4783: 4620: 4365: 2373: 2460:

A comprehensive list of about 1400 fine chemical companies (including traders) can be found in the "event catalogue" of the

2450:. The key functions, such as production, R&D, and M&S, are located on different sites, often in different countries. 203: 1324:

as pivotal intermediate. After the discovery of penicillin in 1928 by Sir Alexander Fleming from colonies of the bacterium

1236:

is the leader in modifying enzymes to specific chemical reactions. The highest-volume chemicals made by biocatalysis are

175: 3668:, Bayer CropScience, and Monsanto are developing new compounds in this class. Combination pesticides, such as Monsanto's 964:(having a "low-tech" image but still widely used), carried-out in standard multipurpose equipment or by various types of 314: 2717:, India; are in the $ 1–$ 2 billion range, whereas the largest product CROs have revenues of a few 100 million dollars. 2706: 517: 369:

with SKF. In a similar way, Fine Organics, UK became the supplier of the thioethyl-N'-methyl-2-nitro-1,1-ethenediamine

2397:

large pharmaceutical companies market fine chemicals as subsidiary activity to their production for captive use, e.g.

4458: 4425: 4285: 240: 222: 182: 120: 63: 2425:(formerly Upjohn), US. Large fine chemical companies, in contrast to mid-sized and small ones, are characterized by 102: 3546:

Generics play a bigger role in the agro than in the pharma industry. They represent some 70% of the global market.

4320:

niche technologies—primarily biotechnology—and taking advantage of the opportunities offered by the Asian market.

817:

Extraction from animals, microorganisms, or plants; isolation and purification, used, for example, for alkaloids,

5153: 4651:

C. Chassin; P. Pollak (January–February 2004). "Outlook for chemical and biochemical manufacturing, PharmaChem".

2779:, the manufacture of semi commercial quantities in the pilot plant, the assessment of the ecological impact, the 3483: 2979: 2940: 1986: 189: 160: 156: 87: 49: 17: 2385:

The first number refers to the total sales, the second one to the fine chemical sales. Both are in $ million

1844:

Similar business types: custom manufacturing of proprietary drugs; opportunities for generic versions, called

559:, such as Librium (chlordiazepoxide) and Valium (diazepam). Pyridine derivatives are found in both well-known 3697:

and household products. The active ingredients extend from high-price / low-volume fine chemicals, used for

1939:

and plants, such as tobacco plants possess the potential to become economically and industrially successful.

1620:

The pros and cons of an involvement of a fine chemical company in cell culture technology are listed below:

1307:(ascorbic acid). In vitamin B2, riboflavin, the original six- to eight-step synthetic process starting from 1068:

Whereas the overall demand for outsourced pharmaceutical fine chemicals is expected to increase moderately (

5089: 5042: 4969: 4875: 4799: 4504: 4360:

Pollak, Peter (2011). Fine Chemicals – The Industry and the Business (2nd. rev. ed.). J. Wiley & Sons.

2750: 827:

of proteins, especially when combined with ion exchange chromatography, used, for instance, for amino acids

659:(N-L-α-Aspartyl-L-phenylalanine 1-methyl ester) is a dipeptide. At the high end there is the anticoagulant 2816:. The main differences between laboratory synthesis and industrial scale production are shown in Table 4. 2788:

plant. Furthermore, it has to be adapted to the specific characteristics of available production trains.

171: 2028: 411: 365:

In subsequent years, the business developed and Lonza was the first fine chemical company entering in a

5148: 3536: 2694: 1380: 2749:. Provisions have to be made for a periodic examination of all acquired research results to safeguard 2027:, respectively. Their main responsibilities comprise formulating comprehensive supervision policies (" 2033: 1002: 889: 4922: 4673: 4450: 5065: 4945: 4417: 3669: 1249: 1241: 1192:. They can also be modified ("reshuffled") for specific reactions, for use in chemical synthesis. " 902: 753: 5018: 4851: 4775: 944:(dimethenamid-P) herbicides. Examples of originator drugs, which apply asymmetric technology, are 803:

Chemical synthesis, either from petrochemical starting materials or from natural products extracts

357: 3698: 2978:, (4) process development opportunities (stepwise assessment), (5) list of required reports, (6) 2710: 1291: 671:, Switzerland; Chengu GT Biochem, China; Chinese Peptide Company, China; Lonza, Switzerland, and 277:

processes. They are described by exacting specifications, used for further processing within the

149: 98: 2775:" description provides the necessary data for the determination of preliminary raw material and 2042:(Registration, Evaluation, Authorization and Restriction of Chemicals) is self-explanatory. The 2062: 1822:

of India (through the acquisition of a former Avecia operation) and the joint ventures between

734: 419: 297:. Biotechnical processes are gaining ground. Fine chemicals are used as starting materials for 4539: 4386: 2448:

A Heterogeneous portfolio of small companies, accumulated over time through M&A activities

1159:(atorvastatin), where the pivotal intermediate R-3-Hydroxy-4-cyanobutyrate is now made with a 831:

Chemical synthesis and biotechnology are most frequently used; sometimes also in combination.

253: 4909: 4660: 4610: 3135: 2936: 2804: 2402: 2328: 1396: 1329: 1325: 1180:

from bile from 28 to 15. Enzymes differ from chemical catalysts particularly with regard to

764: 687: 375: 366: 361:

The beginning: supply contract between Smith Kline French and Lonza for cimetidine precursors

5057: 5010: 4937: 4843: 4767: 4442: 4409: 1320:

in 1933, is being gradually substituted by a more straightforward fermentative process with

4349: 3690: 3579: 3098: 2945: 2531: 2406: 2366:

part of the sales do not derive from fine chemicals, e.g., generics, catalysts, excipients

2130: 1889: 1811: 1424: 1296: 488:(imazapyr) and pharmaceuticals, e.g. the antiulcerants Tagamet (cimetidine. see above) and 196: 3767:

Largest applications are wood conversation and water treatment. A.I.'s mainly commodities

2739:

R&D has to manage the following functions in order to deliver the requested services:

8: 5058: 5011: 4938: 4844: 4768: 4443: 4410: 4339: 3901: 3601: 3593: 2991: 2784: 2398: 1193: 1129: 1086: 1082: 1037:. Examples for reactions that have worked in microreactors include aromatics oxidations, 973: 776: 298: 635:. The most important drugs with a dipeptide (L-alanyl-L-proline) moiety are the "-pril" 5083: 5036: 4963: 4869: 4793: 4732: 4527: 4517: 4498: 4267: 2975: 2928: 1936: 857: 441: 370: 306: 283: 273:, produced in limited quantities in multipurpose plants by multistep batch chemical or 270: 94: 55: 5124:

Costs of Asian Fine Chemical Producers close-up to European Levels – Facts or Fiction?

1143: 5069: 5022: 4949: 4855: 4779: 4616: 4454: 4421: 4361: 4329: 4251: 3550:, a.k.a. ChemChina Group, is the world's largest supplier of generic farm chemicals. 2179: 2044: 1901: 1317: 1181: 1108: 1042: 919: 893: 861: 415: 290: 278: 3392:

none in 2005, are biopharmaceuticals. The largest-selling non-proprietary drugs are

1085:", is increasingly impacting the chemical industry, enabling both the conversion of 3611: 3571: 3532: 3401: 2963: 1819: 1274: 1189: 1185: 840:

pigments. The most comprehensive handbooks describing organic synthetic methods is

599: 407: 274: 4722: 799:

Several key technologies are used for the production of fine chemicals, including

3540: 3139: 2967: 2800: 2690: 2519: 1404: 1308: 1283: 1201: 1058: 628: 624: 347: 302: 1432:

Table 1: Key Characteristics of Biotechnological and Chemical API Manufacturing

3702: 3661: 3623: 3143: 2932: 2523: 2477: 2410: 1609: 1333: 1151:

Further examples of modern drugs, where enzymes are used in the synthesis, are

897: 896:

are promoted by only a limited number of companies. With the exception of some

853: 818: 691: 668: 379: 294: 286:), or the type of business transaction, namely standard or exclusive products. 5137: 4829:

Active Pharmaceutical Ingredients: Development, Manufacturing, and Regulation

4687: 4344: 3694: 3413: 2535: 2229: 2155: 1960: 1870: 1841:

Same customer category: life science, especially the pharmaceutical industry.

1416: 1200:(IUBMB) has developed a classification for enzymes. The main categories are 1177: 1112: 1098: 1050: 1026: 1014: 953: 881: 869: 477: 310: 4599:

Secretary: Prof. M.P. Walsh. University of Calgary, Calgary, Canada T2N 4N1

4261: 3653: 3649: 3631: 3627: 3606: 3563: 1357: 1353: 1337: 1268: 1205: 1104: 1046: 1038: 995: 873: 865: 849: 811: 807: 726: 568: 564: 318: 4638:

Handbook of Industrial Cell Culture: Mammalian, Microbial, and Plant Cells

4080: 3968: 3418: 3156: 3005: 2818: 2071: 1631: 1429: 775:(gemtuzumab ozogamicin). Examples of ADCs in phase III of development are 469: 4440: 4407: 4257: 3933: 3619: 3583: 3405: 3393: 2727: 2645: 2567: 2527: 2105: 1881: 1845: 1815: 1261: 1257: 1237: 1133: 1018: 945: 937: 780: 718: 672: 612: 552: 525: 505: 395: 351: 4569: 3450:

eliminate long lead times to build and validate a manufacturing facility

737:), MW 507.2. Oligonucleotides are chemically synthesized from protected 257:

Definition of Fine Chemicals (as opposed to Commodities and Specialties)

4831:(2nd ed.). Taylor&Francis Group, Boca Raton FL. pp. 9–91. 3869: 3644: 3597: 3588: 3409: 3397: 3114: 3094: 2741: 2418: 2204: 1392: 1384: 1361: 1345: 1341: 1300: 1245: 1209: 941: 824: 768: 703: 632: 509: 481: 473: 453: 445: 437: 343: 4520:

Science of Synthesis: Houben-Weyl Methods of Molecular Transformations

3897: 3873: 3861: 3673: 3615: 3555: 2614: 1905: 1893: 1885: 1835: 1349: 1313: 1304: 1225: 1164: 1160: 1090: 1054: 845: 784: 759: 746: 656: 648: 556: 497: 262: 4904:

B. Lev (Winter 1999). "Journal of Applied Corporate Finance". 21–35.

4587:), Industrial Biotechnology: Sustainable Growth and Economic Success 3893: 3463:

loss of tax benefits resulting from production of APIs in tax havens

138: 105:. Statements consisting only of original research should be removed. 3905: 3889: 3686: 3635: 3575: 3567: 3524: 3516: 3147: 3110: 1897: 1420: 1253: 1006: 910: 772: 695: 644: 595: 591: 572: 493: 485: 461: 4254:, speculative material, or accounts of events that might not occur 3008:

Table 5: Breakdown of Fine Chemicals Market by Major Applications

27:

Pure chemical substances produced by and for the chemical industry

5121: 4210: 4206: 2702: 2698: 2594: 2493: 2414: 2303: 2000: 1400: 1388: 1233: 1229: 1221: 1213: 1156: 1137: 1116: 1094: 957: 885: 660: 652: 383: 339: 4944:(2nd. rev. ed.). Table 10.2: J. Wiley & Sons. pp. 4518:

D. Bellus, S. V. Ley, R. Noyori et al. (Series editors) (2010).

4387:"XX.- Fine Chemicals, Alkaloids, Essential Oils, & Extracts" 1851:

Similar regulatory environment: FDA regulations, especially GMP.

5064:(2nd. rev. ed.). Table 7.3: J. Wiley & Sons. pp. 5017:(2nd. rev. ed.). Table 7.1: J. Wiley & Sons. pp. 4850:(2nd. rev. ed.). Table 6.1: J. Wiley & Sons. pp. 4774:(2nd. rev. ed.). Table 2.2: J. Wiley & Sons. pp. 4727:(4th ed.). John Wiley & Sons, Hoboken NJ. p. 857. 3877: 3487: 3443:

deploy your financial resources for more profitable investments

3131: 3106: 3102: 2515: 2422: 2054: 1956: 1909: 1831: 1408: 1217: 1152: 1140:(rosuvastatin), see Chemical / Enzymatic Synthesis of Crestor. 989: 949: 924: 814:(fermentation), and, for big molecules, cell culture technology 722: 694:(Binocrit, NeoRecormon, erythropoietin), Enbrel (etanercerpt), 560: 551:

A vast array of pharmaceuticals and agrochemicals are based on

537: 533: 529: 489: 433: 387: 4755:. The U.S Pharmacopeial Convention, Inc., Rockville, MD. 2011. 4635: 4083:

Table 10: Indicative Cost Structure of a Fine Chemical Company

4584: 3592:

are the world's longstanding top-selling product, Monsanto's

2760:

more complex molecules, a "top-down" approach, also known as

2677: 1932: 1877: 1412: 929: 906: 717:

are a third category of big molecules. They are oligomers of

4707: 3693:

in cooling water towers, and consumer applications, such as

3438:

concentrate on core activities (innovation & marketing)

721:, which in turn are composed of a five-carbon sugar (either 543: 4723:

Samuel L. Tuthill, Norman C. Jamieson, Kirk-Othmer (2000).

2821:

Table 4: Laboratory Synthesis vs. Industrial Scale Process

2253: 2050: 888:, oligonucletides, peptide (both liquid- and solid-phase), 567:

herbicides, and in modern nicotinoid insecticides, such as

711:

which has developed a PEGylated erythropoietin (PEG-EPO).

4987:(15th ed.). BCPC Publications, Alton, Hampshire, UK. 1198:

International Union of Biochemistry and Molecular Biology

378:, Switzerland for custom manufacturing precursors of the 5122:

P. Pollak; A. Badrot; R. Dach; A. Swadi (Nov–Dec 2011).

4473: 4441:

A. Kleemann; J. Engel; B. Kutscher; D. Reichert (2009).

4408:

A. Kleemann; J. Engel; B. Kutscher; D. Reichert (2009).

3421:

Table 7: Pro's and Con's for Outsourcing API Manufacture

1147:

Chemical / Enzymatic Synthesis of Crestor (rosuvastatin)

4570:

V. Hessel; A. Renken; J.C. Shouten; J. Yoshida (2009).

4491:

Amino Acids, Peptides and Proteins in Organic Chemistry

3857:*fine chemicals merchant market size, growth potential 2074:

Table 3: Leading Fine Chemical Companies (resp. Units)

5103:

Guy Villax (Nov–Dec 2008). "Family owned businesses".

3971:

Table 9: Investment Cost for a cGMP Multipurpose Plant

3860:

Examples of applications in eight areas, ranging from

3679: 1854:

Existing infrastructure (utilities, etc.) can be used.

1559:

Scale-up factor (1st lab process to industrial scale)

4765: 4650: 3447:

benefit from F.C. industry's know how and expertise

163:. Unsourced material may be challenged and removed. 2990:Fine chemicals are used as starting materials for 2508: 2379:Σ11-20 ~ 2,900 million; ΣΣ1-20 ~ $ 10,000 million 682:by advanced biotechnological processes; primarily 663:, MW ≈ 7000, which is composed of 65 amino acids. 3539:. At both Monsanto and DuPont's seed subsidiary, 3475:under-utilization of in-house production capacity 1995:Contract Research and Manufacturing Organizations 917:Since the mid-1990s the commercial importance of 834: 5135: 4893:. New York University, Stern School of Business. 4826: 4298:Two main trends impinge on the industry. On the 3948:are the most important sub-category. Because of 3701:to large-volume / low-price amino acids used as 1224:, Companies specializing in making enzymes are 423:within HMWs they are the peptides and proteins. 4888: 4391:The Journal of the Society of Chemical Industry 3912: 3710:Table: 8: Other Specialty Chemicals Industries 2931:is required. It consists of the three elements 1651:Small Molecular Weight (conventional chemical) 5060:Fine Chemicals – The Industry and the Business 5013:Fine Chemicals – The Industry and the Business 4940:Fine Chemicals – The Industry and the Business 4846:Fine Chemicals – The Industry and the Business 4770:Fine Chemicals – The Industry and the Business 4493:. Volumes 1-5: John Wiley & Sons, Hoboken. 2023:(Chinese) State Food & Drug Administration 2006:Fine chemical / Custom Manufacturing companies 2001:Fine Chemical / Custom Manufacturing Companies 1918:single-use disposable bioprocessing technology 771:and, more recently, Pfizer's (formerly Wyeth) 4982: 4891:R&D Productivity in the Chemical Industry 4612:Fine Chemicals: The Industry and the Business 3596:(glyphosate). Syngenta's cyclohexadione-type 1807:The traditionally large share of outsourcing. 4737:: CS1 maint: multiple names: authors list ( 3656:was the first product launched. Also BASF's 2436:A Dichotomy between Ownership and Management 1115:, makes use of natural or modified isolated 749:drugs), disease prevention and agriculture. 4708:A. Gosh; S. Ray; G. Jain; A. Arora (2011). 3453:free capacity for new product introductions 3159:Table: 6 Top 10 (20) Proprietary Drugs 2010 2720: 2295:API-for-Generics, e.g. HIV / AIDS, sartans 1684:High Molecular Weight (biopharmaceuticals) 655:(enalapril). Also the artificial sweetener 64:Learn how and when to remove these messages 5102: 4270:by removing unsourced speculative content. 1818:of Switzerland; in the Eastern hemisphere 702:(rituximab), and Herceptin (trastuzumab). 484:are found both in modern herbicides, e.g. 4636:Victor A. Vinci; Sarad R. Parekh (2010). 4545:CS1 maint: multiple names: authors list ( 4286:Learn how and when to remove this message 1983:Custom Manufacturing Organizations (CMOs) 1504:Product concentration in reaction mixture 241:Learn how and when to remove this message 223:Learn how and when to remove this message 121:Learn how and when to remove this message 4985:The Pesticide Manual: A World Compendium 4585:Wim Soetaert; Erick J. Vandamme (2010). 3456:avoid risks of using hazardous chemistry 1989:(CROs) are their research laboratories. 1471:Production per m reactor volume and year 1142: 547:Chemical Structure of Diovan (valsartan) 542: 356: 252: 4753:The U.S. Pharmacopeia 34 (USP 34 –NF29) 3921: 1081:Industrial biotechnology, also called " 14: 5136: 5055: 5008: 4935: 4903: 4841: 4608: 4488: 4335:Commercial classification of chemicals 4060: 4033:Investment per piece of main equipment 3466:dissemination of Intellectual Property 2927:In case of cGMP fine chemicals also a 2417:), Japan; Johnson & Johnson, USA; 2279:CSPC Shijiazhuang Pharmaceutical Group 1935:, fungal or yeast expression systems, 1496:≈ $ 5 million (20,000 liter fermenter) 821:(especially penicillins), and steroids 4384: 4153:QC, maintenance, waste disposal, etc. 4065:The raw material consumption and the 3562:syntheses, hazardous chemicals, e.g. 3013: 2956: 4816:. Messe Frankfurt, UBM plc., London. 4766:Adapted from: Pollak, Peter (2011). 4234: 4142:depreciation and interest on capital 3939: 1828:Beijing E-Town Harvest International 1264:(all more than 10,000 metric tons). 842:Methods of Molecular Transformations 161:adding citations to reliable sources 132: 70: 29: 4725:Encyclopedia of Chemical Technology 4710:CRAMS India: Overview & Outlook 4474:E. Reeder; L. H. Sternbach (1968). 3960: 3882:Everlight Chemical Industrial Corp. 3680:Other specialty chemical industries 3676:are more and more frequently used. 3207:Bristol-Myers Squibb Sanofi-Aventis 1482:Sales per m reactor volume and year 806:Biotechnology, for small molecules 24: 4814:CPhI Worldwide, 25-27 October 2011 4589:. J. Wiley & Sons, Hoboken NJ. 3229:J&J, Merck, Mitsubishi, Tanabe 3125: 1434:(all figures are indicative only) 426: 25: 5165: 3120: 2016:(US) Food and Drug Administration 1927:systems are emerging. They (e.g. 1540:many, doubling of actual capacity 602:constitute the major categories. 45:This article has multiple issues. 4688:"Expected Top Ten Drugs by 2016" 4239: 4199: 4036:Investment per m3 reactor volume 3509: 1076: 940:(metolachlor) as well as BASF's 578: 382:class of tranquilizers, such as 137: 75: 34: 5115: 5096: 5049: 5002: 4991: 4976: 4929: 4897: 4882: 4835: 4820: 4806: 4759: 4745: 4716: 4701: 4680: 4644: 4629: 4609:Pollak, Peter (29 March 2011). 4602: 4593: 4355: 4030:Investment per production train 3994:Reactor vessels (volume = 4 m) 2812:(HAZOP) analysis, execution of 2509:Contract research organizations 2480:, Switzerland; Dishman, India; 2454:A Cohabitation with Other Units 1997:are hybrids (see section 4.2). 1987:Contract Research Organizations 1971: 1634:Table 2: Top Ten Drugs by 2016 1460:Investment per m reactor volume 1395:. Commonly used cell lines are 794: 492:(omeprazole), the antimycotics 148:needs additional citations for 53:or discuss these issues on the 5105:Chimica Oggi / Chemistry Today 4578: 4563: 4553: 4511: 4482: 4467: 4434: 4401: 4378: 3634:and pyrazoles, such as BASF's 2997: 2980:Safety, Health and Environment 2941:continued process verification 2471:consists of several dozens of 2442:Complicated Business Processes 835:Traditional chemical synthesis 13: 1: 5144:Products of chemical industry 4371: 3986:Description of main equipment 3955: 3622:are being substituted for by 2877:Stainless steel, glass lined 2734: 2550:; Delmar; NAEJA, all Canada. 2196:incl. some polymer additives 4574:. Wiley-VCH Verlag, Weiheim. 4250:possibly contains unsourced 4120:electric power, steam, brine 3913:Target products and services 3548:China National Chemical Corp 3077:Total fine-chemical industry 2751:Intellectual Property Rights 1963:and Siegfried in Europe and 1379:fermentation, also known as 966:chromatographical separation 892:(e.g., perfluorination) and 7: 4522:. Thieme Verlag, Stuttgart. 4323: 3309:Bristol-Myers Squibb Otsuka 3063:Various specialty chemicals 2797:and Pilot Plant Development 2625:, Switzerland, Netherlands. 2364:as per author's definition 2029:Good Manufacturing Practice 1916:widespread application of ' 1601:45% of chemical production 1590:25% of chemical production 1537:Capacity expansion projects 968:, such as standard column, 472:are structural elements of 401: 386:(chlordiazepoxide HCl) and 101:the claims made and adding 10: 5170: 4889:D. Aboody; B. Lev (2001). 4489:Hughes, Andrew B. (2011). 4262:reliable published sources 4230: 4161:research & development 3996:.... Total reactor volume 3618:, and pyrethroids such as 2985: 2695:Charles River Laboratories 2057:, all the way to 100% for 1441:Mammalian cell technology 1381:recombinant DNA technology 1240:(70 million metric tons), 962:fractional crystallization 516:are pivotal parts of the " 329: 269:are complex, single, pure 4827:Stanley H. Nusim (2009). 4640:. Humana Press, New York. 4615:. John Wiley & Sons. 4572:Micro Process Engineering 4449:(5th ed.). pp. 4445:Pharmaceutical Substances 4416:(5th ed.). pp. 4412:Pharmaceutical Substances 4182: 4171: 4113: 4110: 4099: 4088: 4017: 3984: 3828:Food & Feed Additives 3814:Flavours & Fragrances 3515:top 10 companies, led by 3377: 3076: 3062: 3031: 3015: 2833:Industrial scale process 2611:Nerviano Medical Sciences 2430:A Lack of Economy in Size 2363: 2349: 2034:European Medicines Agency 1985:. The main assets of the 1683: 1650: 1639: 1580: 1569: 1558: 1547: 1536: 1525: 1514: 1503: 1492: 1481: 1470: 1459: 1448: 1438: 1316:, originally invented by 1244:(2 million metric tons); 1035:Micro Process Engineering 1003:Bayer Technology Services 890:electrochemical reactions 868:(esp. chlorination), and 528:cilexetil (candesartan), 5088:: CS1 maint: location ( 5041:: CS1 maint: location ( 4968:: CS1 maint: location ( 4874:: CS1 maint: location ( 4798:: CS1 maint: location ( 4503:: CS1 maint: location ( 4209:(zanamivir) and Roche's 4026:Total capital investment 3786:Dyestuffs & Pigments 3744:Adhesives & Sealants 3537:gene modified (GM) seeds 3243:salmeterol + fluticasone 2966:. He is assisted by the 2721:Research and development 2094:Sales 2009 ($ million) 2088:Sales 2009 ($ million) 1782:J&J/Merck & Co. 1698:AbbVie (Before: Abbott) 1543:few, mainly in Far East 1526:Process development time 1449:Worldwide reactor volume 1250:6-aminopenicillanic acid 1242:high-fructose corn syrup 1163:, and Merck & Co.'s 903:organometallic reactions 754:Antibody-drug conjugates 611:(PBBs), are key, namely 4186:administrative services 3977:Equipment / Investment 3772:Catalysts & Enzymes 3699:liquid crystal displays 3490:are by far the largest 3353:AbbVie (Before: Abbott) 2855:Throughput (kg/m/hour) 2711:Quintiles Transnational 2413:(after the takeover of 1979:Fine Chemical Companies 1676:Salmeterol /fluticasone 1570:Plant construction time 1565:≈ 10 (10 g → 10 tons) 1507:≈ 2 - 6 (-10) g / Liter 1292:affinity chromatography 1256:and other amino acids, 1171:" is now replaced by a 709:Prolong Pharmaceuticals 684:mammalian cell cultures 609:peptide building blocks 5154:Life sciences industry 5056:Pollak, Peter (2011). 5009:Pollak, Peter (2011). 4983:C.D.S. Tomlin (2011). 4936:Pollak, Peter (2011). 4917:Cite journal requires 4842:Pollak, Peter (2011). 4668:Cite journal requires 4256:. Information must be 4131:shift and daytime work 3364:Diovan & Co-Diovan 2866:Kg, ton, hours, shift 2863:G, mL, mol; min. hours 2810:hazard and operability 2791:Bench-scale Laboratory 2781:regulatory submissions 2777:product specifications 2500:includes thousands of 2486:Poli Industria Chimica 2476:profits. Examples are 2270:incl. some excipients 2221:#1 in liquid crystals 2215:Life Science Solutions 1532:2 – 3 months per step 1510:≈ 100 g / Liter (10%) 1488:≈ $ 250,000 - 500,000 1387:(discovered in 1957), 1376:Mammalian cell culture 1148: 1126:(+)-α-phenylethylamine 1119:, enzyme extracts, or 735:Adenosine triphosphate 548: 362: 258: 4385:Stahl, A. F. (1908). 4172:marketing & sales 4164:inclusive pilot plant 3918:volume/volume basis. 3268:Amgen, Pfizer, Takeda 2937:process qualification 2830:Laboratory synthesis 2814:demonstration batches 2805:reaction calorimeters 2532:Johnson & Johnson 2403:Bayer Schering Pharma 1925:transgenic production 1890:Johnson & Johnson 1830:in China and between 1615:plant cell production 1515:Typical reaction time 1477:several 1000 kg 1452:≈ 3000 m (fermenters) 1425:Johnson & Johnson 1397:Chinese hamster ovary 1330:secondary metabolites 1326:Staphylococcus aureus 1146: 810:(enzymatic methods), 688:Monoclonal antibodies 604:Peptides and proteins 588:high molecular weight 546: 367:strategic partnership 360: 338:receptor antagonists 256: 4350:Speciality chemicals 4117:utilities and energy 3929:custom manufacturing 3922:Custom manufacturing 3902:Procter & Gamble 3800:Electronic Chemicals 3691:corrosion inhibitors 3580:phosphorus chlorides 3529:BASF Crop Protection 2946:Process Optimization 2572:Irix Pharmaceuticals 2407:Boehringer-Ingelheim 2131:Boehringer-Ingelheim 1812:Boehringer-Ingelheim 1581:share of outsourcing 1529:≈ 3 years (one step) 1444:Chemical technology 1297:monosodium glutamate 1136:'s blockbuster drug 1132:(ee). An example is 970:simulated moving-bed 637:cardiovascular drugs 315:Custom manufacturing 157:improve this article 4712:. ICRA Ltd. Mumbai. 4340:Commodity chemicals 4175:inclusive promotion 4085: 4061:Manufacturing costs 3973: 3712: 3640:Chloranthaniliprole 3602:paraquat dichloride 3423: 3176:sales 2010 ($ bn) 3161: 3010: 2992:specialty chemicals 2951:costs of goods sold 2915:Liquid / solid sep. 2823: 2785:technology transfer 2767:Process Development 2320:a.o. agrochemicals 2076: 2063:Divi's Laboratories 1636: 1435: 1322:2-ketogluconic acid 1194:Immobilized enzymes 1130:enantiomeric excess 1087:renewable resources 1083:white biotechnology 1017:, The Netherlands; 974:supercritical fluid 952:(esomeprazole) and 878:cyclopolymerization 500:(ketoconazole) and 299:specialty chemicals 271:chemical substances 5126:. Contract Pharma. 4538:has generic name ( 4103:inclusive solvents 4081: 4019:Capital investment 3992:Production trains 3969: 3866:specialty polymers 3842:Specialty Polymers 3719:Sales ($ billion) 3708: 3610:, the traditional 3521:Bayer Cropsciences 3492:generics companies 3419: 3157: 3016:Size ($ billion) 3006: 2976:analytical methods 2972:technology package 2957:Project management 2929:process validation 2899:Heating / cooling 2844:Chemical engineer 2841:Laboratory chemist 2819: 2502:small independents 2072: 1937:transgenic animals 1740:Roche/Biogen Idec 1632: 1485:≈ $ 5 – 10 million 1474:several 10 kg 1430: 1303:(riboflavin), and 1149: 1121:whole-cell systems 976:(SCF) techniques. 549: 363: 307:biopharmaceuticals 284:active ingredients 259: 86:possibly contains 5149:Organic chemistry 5075:978-0-470-62767-9 5028:978-0-470-62767-9 4955:978-0-470-62767-9 4861:978-0-470-62767-9 4785:978-0-470-62767-9 4622:978-1-118-00222-3 4366:978-0-470-62767-9 4330:Chemical industry 4296: 4295: 4288: 4193: 4192: 4058: 4057: 3998:Filtration units 3940:Standard products 3855: 3854: 3497:Several thousand 3481: 3480: 3389: 3388: 3321:Mabthera/ Rituxan 3152:blockbuster drugs 3090: 3089: 2925: 2924: 2390: 2389: 2180:Sumitomo Chemical 2045:U.S. Pharmacopeia 1800: 1799: 1640:Proprietary name 1605: 1604: 1562:≈ 10 (μg → 1 ton) 1318:Tadeus Reichstein 1220:, Isomerases and 1182:stereoselectivity 1109:biotransformation 1031:Perkin & Sons 920:single-enantiomer 894:steroid synthesis 416:biotransformation 342:(cimetidine) and 291:organic synthesis 279:chemical industry 251: 250: 243: 233: 232: 225: 207: 131: 130: 123: 88:original research 68: 16:(Redirected from 5161: 5128: 5127: 5119: 5113: 5112: 5100: 5094: 5093: 5087: 5079: 5063: 5053: 5047: 5046: 5040: 5032: 5016: 5006: 5000: 4995: 4989: 4988: 4980: 4974: 4973: 4967: 4959: 4943: 4933: 4927: 4926: 4920: 4915: 4913: 4905: 4901: 4895: 4894: 4886: 4880: 4879: 4873: 4865: 4849: 4839: 4833: 4832: 4824: 4818: 4817: 4810: 4804: 4803: 4797: 4789: 4773: 4763: 4757: 4756: 4749: 4743: 4742: 4736: 4728: 4720: 4714: 4713: 4705: 4699: 4698: 4696: 4694: 4684: 4678: 4677: 4671: 4666: 4664: 4656: 4648: 4642: 4641: 4633: 4627: 4626: 4606: 4600: 4597: 4591: 4590: 4582: 4576: 4575: 4567: 4561: 4557: 4551: 4550: 4543: 4537: 4533: 4531: 4523: 4515: 4509: 4508: 4502: 4494: 4486: 4480: 4479: 4471: 4465: 4464: 4448: 4438: 4432: 4431: 4415: 4405: 4399: 4398: 4382: 4291: 4284: 4280: 4277: 4271: 4243: 4242: 4235: 4226: 4225: 4221: 4183:general overhead 4086: 3974: 3961:Investment costs 3946:API-for-Generics 3713: 3707: 3612:organophosphates 3533:Dow Agrosciences 3469:loss of know how 3424: 3402:ethinylestradiol 3246:Glaxo SmithKline 3240:Advair/ Seretide 3162: 3011: 2964:project champion 2824: 2756:Process Research 2658:Biocon / Syngene 2077: 1943:pharmaceuticals. 1820:Nicholas Piramal 1793:insulin glargine 1679:GlaxoSmithKline 1637: 1554:cGMP, ISO 14000 1493:Value of 1 batch 1436: 1275:inclusion bodies 1190:chemoselectivity 1186:regioselectivity 1169:(-)-DIP chloride 1059:Suzuki couplings 739:phosphoramidites 715:Oligonucleotides 700:MabThera/Rituxin 651:(imidapril) and 600:oligonucleotides 408:molecular weight 293:in multipurpose 275:biotechnological 246: 239: 228: 221: 217: 214: 208: 206: 165: 141: 133: 126: 119: 115: 112: 106: 103:inline citations 79: 78: 71: 60: 38: 37: 30: 21: 5169: 5168: 5164: 5163: 5162: 5160: 5159: 5158: 5134: 5133: 5132: 5131: 5120: 5116: 5101: 5097: 5081: 5080: 5076: 5054: 5050: 5034: 5033: 5029: 5007: 5003: 4996: 4992: 4981: 4977: 4961: 4960: 4956: 4934: 4930: 4918: 4916: 4907: 4906: 4902: 4898: 4887: 4883: 4867: 4866: 4862: 4840: 4836: 4825: 4821: 4812: 4811: 4807: 4791: 4790: 4786: 4764: 4760: 4751: 4750: 4746: 4730: 4729: 4721: 4717: 4706: 4702: 4692: 4690: 4686: 4685: 4681: 4669: 4667: 4658: 4657: 4649: 4645: 4634: 4630: 4623: 4607: 4603: 4598: 4594: 4583: 4579: 4568: 4564: 4558: 4554: 4544: 4535: 4534: 4525: 4524: 4516: 4512: 4496: 4495: 4487: 4483: 4472: 4468: 4461: 4439: 4435: 4428: 4406: 4402: 4383: 4379: 4374: 4358: 4326: 4292: 4281: 4275: 4272: 4265: 4244: 4240: 4233: 4223: 4219: 4218: 4202: 4111:conversion cost 4067:conversion cost 4063: 4052:$ 0.9 million 4049:$ 2.1 million 4046:$ 11.5 million 4011: 4009: 4007: 3999: 3997: 3995: 3963: 3958: 3950:patent expiries 3942: 3924: 3915: 3896:, Switzerland, 3872:, Netherlands; 3722:Attrac-tiveness 3682: 3666:kresoxim-methyl 3630:and Syngenta's 3626:, like Bayer's 3552:Mahkteshim Agan 3541:Pioneer Hi-Bred 3531:, Germany, and 3519:, Switzerland; 3512: 3140:GlaxoSmithKline 3138:, Switzerland, 3128: 3126:Pharmaceuticals 3123: 3035:Pharmaceuticals 3000: 2988: 2968:project manager 2959: 2921:Centrifugation 2904:Liquid handling 2882:Process control 2801:unit operations 2762:retro synthesis 2746:Patent Research 2737: 2726:laboratory via 2723: 2715:TCG Lifescience 2713:, all USA, and 2691:clinical trials 2589:, Switzerland; 2560:Cambridge Major 2520:GlaxoSmithKline 2511: 2345:a.o. ibuprofen 2160:The Netherlands 2003: 1974: 1929:transgenic moss 1838:in South Korea. 1814:of Germany and 1796:Sanofi-Aventis 1673:Advair/Seretide 1548:Governing rules 1405:Roche-Genentech 1309:barbituric acid 1288:nano-filtration 1284:reverse osmosis 1216:(subcategory), 1202:Oxidoreductases 1079: 1025:, France, and 1021:, Switzerland; 1009:, Switzerland; 936:and Syngenta's 837: 797: 743:synthetic cycle 629:L-phenylalanine 625:L-aspartic acid 621:D, L-methionine 617:L-glutamic acid 581: 536:(losartan) and 467: 459: 451: 429: 427:Small molecules 404: 348:GlaxoSmithKline 337: 332: 303:pharmaceuticals 301:, particularly 295:chemical plants 247: 236: 235: 234: 229: 218: 212: 209: 172:"Fine chemical" 166: 164: 154: 142: 127: 116: 110: 107: 92: 80: 76: 39: 35: 28: 23: 22: 15: 12: 11: 5: 5167: 5157: 5156: 5151: 5146: 5130: 5129: 5114: 5095: 5074: 5048: 5027: 5001: 4999:29 August 2017 4990: 4975: 4954: 4928: 4919:|journal= 4896: 4881: 4860: 4834: 4819: 4805: 4784: 4758: 4744: 4715: 4700: 4679: 4670:|journal= 4643: 4628: 4621: 4601: 4592: 4577: 4562: 4552: 4510: 4481: 4466: 4459: 4433: 4426: 4400: 4376: 4375: 4373: 4370: 4357: 4354: 4353: 4352: 4347: 4342: 4337: 4332: 4325: 4322: 4294: 4293: 4247: 4245: 4238: 4232: 4229: 4201: 4198: 4191: 4190: 4187: 4184: 4180: 4179: 4176: 4173: 4169: 4168: 4165: 4162: 4158: 4157: 4154: 4151: 4150:plant overhead 4147: 4146: 4143: 4140: 4136: 4135: 4132: 4129: 4125: 4124: 4121: 4118: 4115: 4114:plant specific 4112: 4108: 4107: 4104: 4101: 4097: 4096: 4093: 4090: 4089:Cost elements 4062: 4059: 4056: 4055: 4054: 4053: 4050: 4047: 4039: 4038: 4037: 4034: 4031: 4022: 4021: 4015: 4014: 4002: 3989: 3988: 3982: 3981: 3978: 3962: 3959: 3957: 3954: 3941: 3938: 3923: 3920: 3914: 3911: 3886:Evonik-Degussa 3853: 3852: 3849: 3846: 3843: 3839: 3838: 3835: 3832: 3829: 3825: 3824: 3821: 3818: 3815: 3811: 3810: 3807: 3804: 3801: 3797: 3796: 3793: 3790: 3787: 3783: 3782: 3779: 3776: 3773: 3769: 3768: 3765: 3762: 3759: 3755: 3754: 3751: 3748: 3745: 3741: 3740: 3737: 3734: 3731: 3727: 3726: 3723: 3720: 3717: 3703:feed additives 3681: 3678: 3662:pyraclostrobin 3624:neonicotinoids 3572:methyl sulfide 3554:, Israel, and 3511: 3508: 3503:virtual pharma 3479: 3478: 3477: 3476: 3473: 3470: 3467: 3464: 3459: 3458: 3457: 3454: 3451: 3448: 3445: 3440: 3432: 3431: 3428: 3387: 3386: 3381: 3375: 3374: 3371: 3368: 3365: 3362: 3358: 3357: 3354: 3351: 3346: 3340: 3336: 3335: 3332: 3329: 3324: 3318: 3314: 3313: 3310: 3307: 3302: 3299: 3295: 3294: 3291: 3288: 3283: 3277: 3273: 3272: 3269: 3266: 3261: 3255: 3251: 3250: 3247: 3244: 3241: 3238: 3234: 3233: 3230: 3227: 3222: 3216: 3212: 3211: 3208: 3205: 3202: 3199: 3195: 3194: 3191: 3188: 3185: 3182: 3178: 3177: 3174: 3171: 3168: 3165: 3146:, France, and 3144:Sanofi Aventis 3127: 3124: 3122: 3121:Target markets 3119: 3088: 3087: 3084: 3081: 3078: 3074: 3073: 3070: 3067: 3064: 3060: 3059: 3056: 3053: 3050: 3046: 3045: 3042: 3039: 3036: 3033: 3029: 3028: 3025: 3022: 3018: 3017: 3014: 2999: 2996: 2987: 2984: 2958: 2955: 2933:process design 2923: 2922: 2919: 2916: 2912: 2911: 2908: 2905: 2901: 2900: 2897: 2894: 2890: 2889: 2886: 2883: 2879: 2878: 2875: 2872: 2868: 2867: 2864: 2861: 2857: 2856: 2853: 2850: 2846: 2845: 2842: 2839: 2835: 2834: 2831: 2828: 2736: 2733: 2722: 2719: 2682: 2681: 2674:NARD Institute 2672:, all India; 2626: 2587:Carbogen-Amcis 2579: 2536:Merck & Co 2524:Sanofi-Aventis 2510: 2507: 2458: 2457: 2451: 2445: 2439: 2433: 2411:Daiichi-Sankyo 2388: 2387: 2361: 2360: 2358: 2353: 2347: 2346: 2343: 2340: 2337: 2334: 2331: 2326: 2322: 2321: 2318: 2315: 2312: 2309: 2306: 2301: 2297: 2296: 2293: 2290: 2287: 2284: 2281: 2276: 2272: 2271: 2268: 2265: 2262: 2259: 2256: 2251: 2247: 2246: 2244: 2241: 2238: 2235: 2232: 2227: 2223: 2222: 2219: 2216: 2213: 2210: 2207: 2202: 2198: 2197: 2194: 2191: 2188: 2185: 2182: 2177: 2173: 2172: 2170: 2167: 2164: 2161: 2158: 2153: 2149: 2148: 2147:HMW/LMW=84/16 2145: 2142: 2139: 2136: 2133: 2128: 2124: 2123: 2122:HMW/LMW~55/45 2120: 2117: 2116:Custom. Manuf. 2114: 2111: 2108: 2103: 2099: 2098: 2095: 2092: 2089: 2086: 2083: 2080: 2002: 1999: 1973: 1970: 1945: 1944: 1940: 1921: 1913: 1874: 1867: 1864: 1856: 1855: 1852: 1849: 1842: 1839: 1808: 1805: 1798: 1797: 1794: 1791: 1788: 1784: 1783: 1780: 1777: 1774: 1770: 1769: 1766: 1763: 1760: 1756: 1755: 1752: 1749: 1746: 1742: 1741: 1738: 1735: 1732: 1728: 1727: 1724: 1721: 1718: 1714: 1713: 1710: 1707: 1704: 1700: 1699: 1696: 1693: 1690: 1686: 1685: 1681: 1680: 1677: 1674: 1671: 1667: 1666: 1663: 1660: 1657: 1653: 1652: 1648: 1647: 1644: 1641: 1630: 1629: 1610:animal culture 1603: 1602: 1599: 1596: 1592: 1591: 1588: 1585: 1582: 1578: 1577: 1574: 1571: 1567: 1566: 1563: 1560: 1556: 1555: 1552: 1549: 1545: 1544: 1541: 1538: 1534: 1533: 1530: 1527: 1523: 1522: 1519: 1516: 1512: 1511: 1508: 1505: 1501: 1500: 1497: 1494: 1490: 1489: 1486: 1483: 1479: 1478: 1475: 1472: 1468: 1467: 1464: 1461: 1457: 1456: 1453: 1450: 1446: 1445: 1442: 1439: 1417:Merck & Co 1334:cephalosporins 1078: 1075: 1073:year at best. 1051:hydrogenations 1011:Evonik-Degussa 954:Merck & Co 898:stereospecific 858:Friedel–Crafts 854:esterification 836: 833: 829: 828: 822: 819:antibacterials 815: 804: 796: 793: 698:(infliximab); 643:(lisinopril), 586:, also called 580: 577: 571:. Even modern 532:(irbesartan), 514:tetrazolidines 496:(miconazole), 465: 457: 449: 428: 425: 403: 400: 380:benzodiazepine 335: 331: 328: 267:fine chemicals 249: 248: 231: 230: 145: 143: 136: 129: 128: 83: 81: 74: 69: 43: 42: 40: 33: 26: 18:Fine chemicals 9: 6: 4: 3: 2: 5166: 5155: 5152: 5150: 5147: 5145: 5142: 5141: 5139: 5125: 5118: 5110: 5106: 5099: 5091: 5085: 5077: 5071: 5067: 5062: 5061: 5052: 5044: 5038: 5030: 5024: 5020: 5015: 5014: 5005: 4998: 4994: 4986: 4979: 4971: 4965: 4957: 4951: 4947: 4942: 4941: 4932: 4924: 4911: 4900: 4892: 4885: 4877: 4871: 4863: 4857: 4853: 4848: 4847: 4838: 4830: 4823: 4815: 4809: 4801: 4795: 4787: 4781: 4777: 4772: 4771: 4762: 4754: 4748: 4740: 4734: 4726: 4719: 4711: 4704: 4689: 4683: 4675: 4662: 4654: 4647: 4639: 4632: 4624: 4618: 4614: 4613: 4605: 4596: 4588: 4581: 4573: 4566: 4556: 4548: 4541: 4529: 4521: 4514: 4506: 4500: 4492: 4485: 4477: 4470: 4462: 4460:9781621983774 4456: 4452: 4447: 4446: 4437: 4429: 4427:9781621983774 4423: 4419: 4414: 4413: 4404: 4396: 4392: 4388: 4381: 4377: 4369: 4367: 4363: 4351: 4348: 4346: 4345:Petrochemical 4343: 4341: 4338: 4336: 4333: 4331: 4328: 4327: 4321: 4317: 4314: 4313:Globalization 4310: 4308: 4303: 4301: 4290: 4287: 4279: 4269: 4263: 4260:and based on 4259: 4255: 4253: 4248:This section 4246: 4237: 4236: 4228: 4214: 4212: 4208: 4200:Profitability 4197: 4188: 4185: 4181: 4177: 4174: 4170: 4166: 4163: 4160: 4159: 4155: 4152: 4149: 4148: 4144: 4141: 4138: 4137: 4134:10–15 % 4133: 4130: 4127: 4126: 4122: 4119: 4116: 4109: 4105: 4102: 4100:raw materials 4098: 4094: 4091: 4087: 4084: 4079: 4075: 4071: 4068: 4051: 4048: 4045: 4044: 4043: 4040: 4035: 4032: 4029: 4028: 4027: 4024: 4023: 4020: 4016: 4013: 4003: 4001: 3991: 3990: 3987: 3983: 3979: 3976: 3975: 3972: 3967: 3953: 3951: 3947: 3937: 3935: 3930: 3919: 3910: 3907: 3903: 3899: 3895: 3891: 3887: 3883: 3879: 3875: 3871: 3867: 3863: 3858: 3850: 3847: 3844: 3841: 3840: 3836: 3833: 3830: 3827: 3826: 3822: 3819: 3816: 3813: 3812: 3808: 3805: 3802: 3799: 3798: 3794: 3791: 3788: 3785: 3784: 3780: 3777: 3774: 3771: 3770: 3766: 3763: 3760: 3757: 3756: 3752: 3749: 3746: 3743: 3742: 3738: 3735: 3732: 3730:Animal Health 3729: 3728: 3724: 3721: 3718: 3715: 3714: 3711: 3706: 3704: 3700: 3696: 3695:personal care 3692: 3688: 3677: 3675: 3671: 3667: 3663: 3660:Series, a.o. 3659: 3655: 3651: 3647: 3646: 3641: 3637: 3633: 3629: 3625: 3621: 3617: 3613: 3609: 3608: 3603: 3599: 3595: 3591: 3590: 3585: 3581: 3577: 3573: 3569: 3565: 3559: 3557: 3553: 3549: 3544: 3542: 3538: 3534: 3530: 3526: 3522: 3518: 3510:Agrochemicals 3507: 3504: 3500: 3495: 3493: 3489: 3485: 3474: 3471: 3468: 3465: 3462: 3461: 3460: 3455: 3452: 3449: 3446: 3444: 3441: 3439: 3436: 3435: 3434: 3433: 3429: 3426: 3425: 3422: 3417: 3415: 3414:ascorbic acid 3411: 3407: 3403: 3399: 3395: 3385: 3382: 3380: 3376: 3372: 3369: 3366: 3363: 3360: 3359: 3355: 3352: 3350: 3347: 3344: 3341: 3338: 3337: 3333: 3330: 3328: 3325: 3322: 3319: 3316: 3315: 3311: 3308: 3306: 3303: 3300: 3297: 3296: 3292: 3289: 3287: 3284: 3281: 3278: 3275: 3274: 3270: 3267: 3265: 3262: 3259: 3256: 3253: 3252: 3248: 3245: 3242: 3239: 3236: 3235: 3231: 3228: 3226: 3223: 3220: 3217: 3214: 3213: 3209: 3206: 3203: 3200: 3197: 3196: 3192: 3189: 3186: 3183: 3180: 3179: 3175: 3172: 3169: 3166: 3164: 3163: 3160: 3155: 3153: 3149: 3145: 3141: 3137: 3133: 3118: 3116: 3112: 3108: 3104: 3100: 3096: 3085: 3082: 3079: 3075: 3071: 3068: 3065: 3061: 3057: 3054: 3051: 3049:Agrochemicals 3048: 3047: 3043: 3040: 3037: 3034: 3032:Life sciences 3030: 3026: 3023: 3020: 3019: 3012: 3009: 3004: 2995: 2993: 2983: 2981: 2977: 2973: 2969: 2965: 2954: 2952: 2948: 2947: 2942: 2938: 2934: 2930: 2920: 2917: 2914: 2913: 2909: 2906: 2903: 2902: 2898: 2896:Reaction time 2895: 2893:Critical path 2892: 2891: 2887: 2884: 2881: 2880: 2876: 2873: 2870: 2869: 2865: 2862: 2859: 2858: 2854: 2851: 2848: 2847: 2843: 2840: 2837: 2836: 2832: 2829: 2826: 2825: 2822: 2817: 2815: 2811: 2806: 2802: 2798: 2796: 2792: 2786: 2782: 2778: 2774: 2769: 2768: 2763: 2758: 2757: 2752: 2748: 2747: 2743: 2732: 2729: 2718: 2716: 2712: 2708: 2704: 2700: 2696: 2692: 2686: 2680:, both Japan. 2679: 2675: 2671: 2667: 2663: 2659: 2655: 2654:Aptuit Laurus 2651: 2648:, all China; 2647: 2643: 2639: 2635: 2631: 2627: 2624: 2620: 2616: 2612: 2608: 2604: 2600: 2596: 2592: 2588: 2584: 2580: 2577: 2573: 2569: 2565: 2561: 2557: 2553: 2549: 2545: 2544:North America 2541: 2540: 2539: 2537: 2533: 2529: 2525: 2521: 2517: 2506: 2503: 2499: 2495: 2492:, India, and 2491: 2487: 2483: 2479: 2474: 2470: 2465: 2463: 2455: 2452: 2449: 2446: 2443: 2440: 2437: 2434: 2431: 2428: 2427: 2426: 2424: 2420: 2416: 2412: 2408: 2404: 2400: 2394: 2386: 2384: 2380: 2377: 2375: 2370: 2367: 2362: 2359: 2357: 2354: 2352: 2351:Total Top Ten 2348: 2344: 2341: 2338: 2335: 2332: 2330: 2327: 2324: 2323: 2319: 2316: 2313: 2310: 2307: 2305: 2302: 2299: 2298: 2294: 2291: 2288: 2285: 2282: 2280: 2277: 2274: 2273: 2269: 2266: 2263: 2260: 2257: 2255: 2252: 2249: 2248: 2245: 2242: 2239: 2236: 2233: 2231: 2230:Sigma-Aldrich 2228: 2225: 2224: 2220: 2217: 2214: 2211: 2208: 2206: 2203: 2200: 2199: 2195: 2192: 2189: 2186: 2183: 2181: 2178: 2175: 2174: 2171: 2168: 2165: 2162: 2159: 2157: 2154: 2151: 2150: 2146: 2143: 2140: 2137: 2134: 2132: 2129: 2126: 2125: 2121: 2118: 2115: 2112: 2109: 2107: 2104: 2101: 2100: 2096: 2093: 2090: 2087: 2084: 2081: 2079: 2078: 2075: 2070: 2068: 2065:, India, and 2064: 2060: 2056: 2052: 2047: 2046: 2041: 2037: 2035: 2030: 2026: 2024: 2019: 2017: 2010: 2007: 1998: 1996: 1992: 1988: 1984: 1980: 1969: 1966: 1965:WuXi App Tech 1962: 1958: 1954: 1950: 1941: 1938: 1934: 1930: 1926: 1922: 1919: 1914: 1911: 1907: 1903: 1899: 1895: 1891: 1887: 1883: 1879: 1875: 1872: 1871:contamination 1868: 1865: 1861: 1860: 1859: 1853: 1850: 1847: 1843: 1840: 1837: 1834:in India and 1833: 1829: 1825: 1821: 1817: 1813: 1809: 1806: 1802: 1801: 1795: 1792: 1789: 1786: 1785: 1781: 1778: 1775: 1772: 1771: 1767: 1764: 1761: 1758: 1757: 1753: 1750: 1747: 1744: 1743: 1739: 1736: 1733: 1730: 1729: 1725: 1722: 1719: 1716: 1715: 1711: 1708: 1705: 1702: 1701: 1697: 1694: 1691: 1688: 1687: 1682: 1678: 1675: 1672: 1669: 1668: 1664: 1661: 1658: 1655: 1654: 1649: 1645: 1643:Generic Name 1642: 1638: 1635: 1626: 1625: 1624: 1621: 1618: 1616: 1611: 1600: 1597: 1594: 1593: 1589: 1586: 1583: 1579: 1575: 1572: 1568: 1564: 1561: 1557: 1553: 1550: 1546: 1542: 1539: 1535: 1531: 1528: 1524: 1520: 1517: 1513: 1509: 1506: 1502: 1498: 1495: 1491: 1487: 1484: 1480: 1476: 1473: 1469: 1465: 1463:≈ $ 5 million 1462: 1458: 1454: 1451: 1447: 1443: 1440: 1437: 1433: 1428: 1426: 1422: 1418: 1414: 1410: 1406: 1402: 1398: 1394: 1390: 1386: 1382: 1378: 1377: 1371: 1370: 1369:Cell Cultures 1365: 1363: 1359: 1355: 1351: 1347: 1343: 1339: 1335: 1331: 1327: 1323: 1319: 1315: 1310: 1306: 1302: 1298: 1293: 1289: 1286:, ultra- and 1285: 1281: 1276: 1271: 1270: 1265: 1263: 1259: 1255: 1251: 1247: 1243: 1239: 1235: 1231: 1227: 1223: 1219: 1215: 1211: 1207: 1203: 1199: 1195: 1191: 1187: 1183: 1179: 1178:Dexamethasone 1174: 1173:ketoreductase 1170: 1166: 1162: 1158: 1154: 1145: 1141: 1139: 1135: 1131: 1127: 1122: 1118: 1114: 1113:bioconversion 1110: 1106: 1102: 1100: 1099:succinic acid 1096: 1092: 1088: 1084: 1077:Biotechnology 1074: 1071: 1066: 1062: 1060: 1056: 1052: 1048: 1047:halogenations 1044: 1041:conversions, 1040: 1036: 1032: 1028: 1027:Sigma-Aldrich 1024: 1020: 1016: 1012: 1008: 1004: 1000: 997: 993: 991: 987: 982: 977: 975: 971: 967: 963: 959: 955: 951: 947: 943: 939: 935: 931: 926: 922: 921: 915: 912: 908: 904: 899: 895: 891: 887: 883: 882:ionic liquids 879: 875: 871: 870:hydrogenation 867: 863: 859: 855: 851: 847: 843: 832: 826: 823: 820: 816: 813: 809: 805: 802: 801: 800: 792: 790: 786: 782: 778: 774: 770: 766: 761: 757: 755: 750: 748: 744: 740: 736: 732: 728: 724: 720: 716: 712: 710: 705: 701: 697: 693: 689: 685: 680: 676: 674: 670: 664: 662: 658: 654: 650: 647:(captopril), 646: 642: 638: 634: 630: 626: 622: 618: 614: 610: 605: 601: 597: 593: 589: 585: 584:Big molecules 579:Big molecules 576: 574: 570: 566: 562: 558: 554: 545: 541: 540:(valsartan). 539: 535: 531: 527: 523: 522:hypertensives 519: 515: 511: 507: 503: 499: 495: 491: 487: 483: 480:antibiotics, 479: 478:cephalosporin 475: 471: 463: 455: 447: 443: 439: 435: 424: 421: 417: 413: 409: 399: 397: 391: 389: 385: 381: 377: 372: 368: 359: 355: 353: 349: 345: 341: 327: 323: 320: 316: 312: 311:agrochemicals 308: 304: 300: 296: 292: 287: 285: 280: 276: 272: 268: 264: 255: 245: 242: 227: 224: 216: 205: 202: 198: 195: 191: 188: 184: 181: 177: 174: – 173: 169: 168:Find sources: 162: 158: 152: 151: 146:This article 144: 140: 135: 134: 125: 122: 114: 104: 100: 96: 90: 89: 84:This article 82: 73: 72: 67: 65: 58: 57: 52: 51: 46: 41: 32: 31: 19: 5123: 5117: 5108: 5104: 5098: 5059: 5051: 5012: 5004: 4993: 4984: 4978: 4939: 4931: 4910:cite journal 4899: 4890: 4884: 4845: 4837: 4828: 4822: 4813: 4808: 4769: 4761: 4752: 4747: 4724: 4718: 4709: 4703: 4691:. Retrieved 4682: 4661:cite journal 4652: 4646: 4637: 4631: 4611: 4604: 4595: 4586: 4580: 4571: 4565: 4555: 4519: 4513: 4490: 4484: 4475: 4469: 4444: 4436: 4411: 4403: 4394: 4390: 4380: 4359: 4356:Bibliography 4318: 4312: 4311: 4306: 4304: 4299: 4297: 4282: 4273: 4266:Please help 4249: 4215: 4203: 4194: 4139:capital cost 4082: 4076: 4072: 4064: 4042:$ 21 million 4041: 4025: 4018: 4005: 3993: 3985: 3970: 3964: 3943: 3925: 3916: 3859: 3856: 3709: 3683: 3654:azoxystrobin 3650:strobilurins 3643: 3632:thiamethoxam 3628:imidacloprid 3620:γ-cyhalotrin 3607:insecticides 3605: 3587: 3564:sodium azide 3560: 3545: 3513: 3502: 3498: 3496: 3491: 3482: 3442: 3437: 3420: 3390: 3383: 3379:Total Top 10 3378: 3348: 3342: 3326: 3320: 3305:aripiprazole 3304: 3285: 3279: 3263: 3257: 3224: 3218: 3187:atorvastatin 3158: 3129: 3091: 3007: 3001: 2989: 2960: 2944: 2926: 2820: 2789: 2773:base process 2765: 2754: 2740: 2738: 2724: 2687: 2683: 2629: 2599:Clauson-Kaas 2582: 2543: 2512: 2501: 2497: 2472: 2468: 2466: 2464:exhibition. 2459: 2453: 2447: 2441: 2435: 2429: 2395: 2391: 2382: 2381: 2378: 2371: 2368: 2365: 2355: 2350: 2073: 2043: 2032: 2021: 2014: 2011: 2005: 2004: 1982: 1978: 1975: 1972:The industry 1946: 1857: 1665:AstraZeneca 1662:rosuvastatin 1633: 1622: 1619: 1606: 1576:2 – 3 years 1499:≈ $ 500,000 1466:≈ $ 500,000 1431: 1374: 1367: 1366: 1358:tetracycline 1354:streptomycin 1338:azithromycin 1269:Biosynthesis 1267: 1266: 1232:(Genencor). 1206:Transferases 1197: 1150: 1105:Biocatalysis 1103: 1080: 1069: 1067: 1063: 1039:diazomethane 1034: 998: 996:Microreactor 994: 980: 978: 918: 916: 874:cyanohydrins 866:halogenation 850:condensation 841: 838: 830: 812:biosynthesis 808:biocatalysis 798: 795:Technologies 789:Aprinocarsen 779:'s / Isis's 752: 751: 731:coenzyme ATP 727:desoxyribose 714: 713: 678: 677: 665: 603: 587: 583: 582: 569:Imidacloprid 565:Chlorpyrifos 550: 430: 412:fermentation 405: 392: 390:(diazepam). 364: 333: 324: 319:life science 288: 266: 260: 237: 219: 213:October 2021 210: 200: 193: 186: 179: 167: 155:Please help 150:verification 147: 117: 111:January 2021 108: 85: 61: 54: 48: 47:Please help 44: 4693:11 December 4536:|last= 4307:demand side 4300:supply side 4252:predictions 4128:plant labor 4123:4–5 % 3934:outsourcing 3900:, Denmark, 3888:, Germany; 3584:pyrethroids 3523:, Germany: 3406:amoxicillin 3394:paracetamol 3286:bevacizumab 3204:clopidogrel 2998:Market size 2888:Automatic 2874:Glass flask 2728:pilot plant 2666:Chempartner 2646:WuXi AppTec 2609:, Germany; 2605:, Ukraine; 2603:Enamine Ltd 2601:, Denmark; 2593:, Germany; 2568:Innocentive 2528:AstraZeneca 2469:second tier 2421:, Germany; 2409:, Germany; 1955:in the US, 1892:(J&J), 1882:Biogen Idec 1846:biosimilars 1765:trastuzumab 1751:bevacizumab 1584:early stage 1573:4 – 6 years 1455:≈ 80,000 m 1262:niacinamide 1258:citric acid 1238:bio-ethanol 1134:AstraZeneca 1013:, Germany; 1005:, Germany; 986:dekapeptide 946:AstraZeneca 781:Alicaforsen 719:nucleotides 675:, Denmark. 673:Polypeptide 613:amino acids 553:pyrimidines 526:Candesartan 520:" class of 506:isoconazole 396:Outsourcing 5138:Categories 4476:US 3371085 4372:References 4276:March 2022 4268:improve it 4258:verifiable 4189:15 % 4156:10 % 4145:15 % 4106:30 % 4008:.... 24 m 3956:Financials 3884:, Taiwan; 3880:, France; 3870:Akzo-Nobel 3645:fungicides 3604:. Within 3598:mesotrione 3589:herbicides 3472:job losses 3410:pyridoxine 3398:omeprazole 3349:adalimumab 3264:etanecerpt 3225:infliximab 3115:Mitsubishi 3095:Akzo Nobel 3021:total A.I. 2918:Filtration 2742:Literature 2735:Objectives 2662:Chembiotek 2617:, Sweden; 2597:, Russia; 2578:, all USA. 2564:ChemBridge 2498:third tier 2419:Merck KGaA 2339:Fine Chem. 2289:Fine Chem. 2264:Fine Chem. 2205:Merck KGaA 2190:Fine Chem. 2166:Fine Chem. 2141:Fine Chem. 2091:F.C. unit 1779:infliximab 1695:adalimumab 1595:commercial 1551:cGMP, BLA 1521:≈ 6 hours 1393:somatropin 1385:interferon 1362:vancomycin 1346:gentamicin 1342:bacitracin 1301:vitamin B2 1280:fermenters 1246:acrylamide 1210:Hydrolases 1055:nitrations 999:Technology 825:Hydrolysis 769:Fomivirsen 704:PEGylation 639:, such as 633:dipeptides 510:Tetrazoles 482:imidazoles 474:penicillin 464:(vitamin B 456:(vitamin B 454:riboflavin 448:(vitamin B 446:pyridoxine 438:folic acid 420:extraction 183:newspapers 95:improve it 50:improve it 5084:cite book 5037:cite book 4964:cite book 4870:cite book 4794:cite book 4733:cite book 4528:cite book 4499:cite book 4178:5 % 4167:8 % 3898:Novozymes 3876:, Japan; 3874:Ajinomoto 3862:adhesives 3725:Products 3674:SmartStax 3616:malathion 3556:Cheminova 3367:valsartan 3327:rituximab 3027:merchant 2871:Equipment 2670:ProCitius 2642:Pharmaron 2638:Medicilon 2621:, Italy; 2615:Recipharm 2613:, Italy; 2488:, Italy; 2329:Albemarle 2085:Location 1953:Dowpharma 1906:Genentech 1894:Medimmune 1886:Eli Lilly 1836:Celltrion 1762:Herceptin 1748:Avastatin 1737:rituximab 1723:denosumab 1709:etanecept 1518:≈ 20 days 1419:. ), and 1350:rifamycin 1314:D-glucose 1305:vitamin C 1226:Novozymes 1165:Singulair 1161:nitrilase 1107:, a.k.a. 1091:cellulose 1043:Grignards 972:(SMB) or 934:l-Menthol 846:Amination 785:Eli Lilly 760:cytotoxic 747:antisense 657:Aspartame 557:CNS Drugs 498:Fungarest 470:β-lactams 418:), or by 263:chemistry 99:verifying 56:talk page 4655:: 23–26. 4324:See also 4092:Details 3980:Numbers 3906:Unilever 3890:Givaudan 3758:Biocides 3716:Industry 3687:biocides 3636:fipronil 3594:round-up 3576:phosgene 3568:halogens 3525:Monsanto 3517:Syngenta 3370:Novartis 3219:Remicade 3173:Company 3148:Novartis 3111:Chemtura 2910:Pumping 2838:Operator 2619:Serichim 2607:Girindus 2591:Chemcomm 2576:PharmEco 2473:midsized 2097:Remarks 2082:Company 1898:Novartis 1824:AutekBio 1776:Remicade 1646:Company 1421:Remicade 1254:L-lysine 1007:Clariant 981:peptides 911:phosgene 886:nitrones 862:Grignard 773:Mylotarg 696:Remicade 679:Proteins 645:Captoril 596:proteins 592:peptides 573:pigments 502:Travogen 494:Daktarin 462:thiamine 402:Products 317:for the 5111:(6): 8. 4453:–1191. 4305:On the 4231:Outlook 4222:⁄ 4211:Tamiflu 4207:Relenza 4000:Dryers 3670:Genuity 3614:, like 3527:, USA; 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