The company works with refiners in virtually every part of the world including the Middle East. The company has been the leading innovator of hydroprocessing catalysts and processes for many years. The SynSat process, which was introduced nearly 10 years ago, was the first process to enable low sulfur, low aromatics diesel production at moderate pressure and remains the one of the choices for making the highest quality diesel.
The company serves its clients in the Middle East through its office in Dubai. It offers catalysts required in the production of a wide range of petrochemical products, including olefins and aromatics such as styrene. In addition, MT-Prop - a highly specific zeolite catalyst- has been developed as the key element of producing propylene from methanol.
For the polymer industry, the company offers custom catalysts for all major polypropylene process technologies used to produce polypropylene. Albemarle Corporation, headquartered in Baton Rouge, Louisiana, is a global developer, manufacturer, and marketer of highly-engineered specialty chemicals and catalysts. The company offers high performing FCC catalysts and additives, HPC catalysts, polyolefin catalysts, chemical catalysts and alternative fuels technologies portfolio of products, and serves its clients in the Middle East from its office located in Dubai.
Albemarle enhances the performance of its catalysts by applying appropriate metal trapping technology and by using unique manufacturing technologies that ensure that a catalyst provides high accessibility for the feed molecules to the zeolite and the matrix. Through its wholly-owned subsidiary Albemarle Netherlands, the company has entered into a joint venture with SABIC to manufacture tonne per year of tri ethyl aluminum, the key co-catalyst used in polyolefin production.
Grace is a global specialty chemicals and materials company operating through two segments, Grace Davison and Grace Construction. Within Grace Davison there are various business groups including refining technologies, which develops and manufactures FCC catalysts and additives. Hydroprocessing catalysts are sold through advanced refining technologies, a joint venture between Grace and Chevron Products. Grace Davison has introduced various new catalyst technologies for the profitable processing of a wide range of feedstocks, from hydrotreated and low-metal feeds through to heavy crudes with high contaminant metal levels.
The company has a strong commitment to the Middle East market. A new refining technologies office has been opened in Dubai where specialists from around the world are located to offer an increasing level of local technical service. The division develops and produces mobile emissions catalysts as well as process catalysts and technologies for a broad range of customers worldwide. BASF scientists with understanding of surface and catalytic chemistry coupled with material science, enables BASF to design and alter the essential physical and chemical properties of catalyst components to develop novel FCC catalysts.
The catalysts products of ExxonMobil Chemical are currently used in more than commercial facilities throughout the world, including the Middle East. A starting material is converted by the biocatalyst in the desired product. Enzymes are differentiated from chemical catalysts particularly with regard to stereoselectivity, regioselectivity, and chemoselectivity. Whereas enzymes were traditionally associated with the metabolic pathway of natural substances, c Immobilized enzymes can be recovered by filtration after completion of the reaction.
Conventional plant equipment can be used without, or only modest, adaptations. The International Union of Biochemistry and Molecular Biology has developed a classification for enzymes. An important application is the synthesis of chiral molecules, especially chiral PFCs about twothirds of chiral products produced on large industrial scale are already made using biocatalysis. Hydrolases, which catalyze the hydrolysis of various bonds. The bestknown subcategory of hydrolases are the lipases, which hydrolyze ester bonds.
In the example of human pancreatic lipase, which is the main enzyme responsible for breaking down fats in the human digestive system, a lipase acts to convert triglyceride substrates found in oils from food to monoglycerides and free fatty acids. Lyases, which cleave various bonds by means other than hydrolysis and oxidation, such as starch to glucose. Isomerases, which catalyze isomerization changes within a single molecule.
Ligases, which join two molecules with covalent bonds.
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Whereas in the past, only about out of known enzymes were used commercially, new developments in technology are increasing this number dramatically. Nonetheless, the commercialization of many enzymatic processes is hampered by the lack of operational stability of many enzymes, coupled with their relatively high price. The highest-volume chemicals made by biocatalysis are bioethanol 70 million MT , high-fructose corn syrup 2 million MT , acrylamide, 6-amino-penicillanic c 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 centers. Although the original synthesis already had been improved by substituting the cumbersome racemate separation see above by a stereo-specific catalytical step, it still presented serious deficiencies due to the physical properties of certain intermediates, such as high boiling points of temperature-sensitive oily substances requiring an ultra-HV distillation, the cost of some raw materials notably 4 equivalents tBu acetate Li salt and boranes , and the overall length of the process.
The enzymatic process for dilthiazem is another landmark. The two main advantages of the process, which was developed by DSM, are an operational simplification much smaller plant, 10 times higher throughput and cost savings on raw materials, mainly 2-amino-thiophenol, which is used on a later stage in the process. Similar rewarding switches from chemical steps to enzymatic ones have also been achieved in steroid synthesis.
Thus, it has been possible to reduce the number of steps required for the synthesis of dexamethasone from bile from 28 to 15—and further reductions are in the making! Biosynthesis Biosynthesis by microbial fermentation, that is, 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 c 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 high-molecular-weight HMW peptides and proteins, to the accumulation within so-called inclusion bodies in the cells.
The key elements of fermentation development are strain selection and optimization, media, and process development. For the large-scale industrial production of fine chemicals and proteins, dedicated plants are used. As the volume productivity is low, the bioreactors, called fermenters, are large, with volumes that can exceed m3. Product isolation was previously based on large-volume extraction of the medium containing the product.
Modern isolation and membrane technologies, such as reverse osmosis, ultra- and nano-filtration, or affinity chromatographic methods can help to remove salts and by-products and to concentrate the solution efficiently and in an environmentally friendly manner under mild conditions. The final purification is often achieved by conventional chemical crystallization processes. In contrast to the isolation of small molecules, the isolation and purification of microbial proteins is tedious and often involves a number of expensive large-scale chromatographic operations.
Examples of large-volume LMW products made by modern industrial microbial biosynthetic processes are monosodium glutamate MSG , vitamin B2 riboflavin , and vitamin C ascorbic acid. After the discovery of penicillin in by Sir Alexander Fleming from colonies of the bacterium Staphylococcus aureus, it took more than a decade before Howad Florey and Ernst Chain isolated the active ingredient and developed a powdery form of the medicine.
Since then, many more antibiotics and other secondary metabolites have been isolated and manufactured by microbial fermentation on a large scale. Some important antibiotics besides penicillin are cephalosporins, azithromycin, bacitracin, gentamicin, rifamycin, streptomycin, tetracycline, and vancomycin. More recently, GlaxoSmithKline patented an efficient fermentation route for the biosynthetic production of thymidine thyminedesoxyriboside. Key to the invention is a recombinant strain that efficiently produces high titers of thymidine by blocking some enzymes in the thymidine regulating pathway.
The ability of a particular cell or organism to correctly glycosylate a protein can determine its usefulness to make a given protein. Animal or plant cells, removed from tissues, will continue to grow if supplied with and under the appropriate nutrients and conditions. When carried out outside the natural habitat, the process is called cell culture. Mammalian cell culture fermentation is used mainly for the production of complex big molecules with specific glycosylation patterns and tertiary protein structures, such as therapeutic proteins and monoclonal antibodies mAbs.
Typical biotech APIs obtainable through mammalian cell culture are: viral vaccines, hormones, immunobiologicals such as interleukin, lymphokines, mAbs , blood clot dissolvers tPAs: tissue plasminogen activators , and a number of complex glycosylated proteins Related technologies use plant cell cultures, insect cells, or transgenic animals. In contrast to the mammals, bacteria, plants, and fungi are incapable of glycosylation.
Cell culture processes allow single cells to act as independent units, much like a microorganism such as a bacterium or fungus. The cells are capable of dividing; they increase in size and, in a batch culture, can continue to grow until limited by some culture variable such as nutrient depletion. Mammalian cell culture, also known as recombinant DNA technology, has existed for 50 years.
It serves for producing HMW, or simpler, big-molecule fine chemicals, including glycoproteins and mAbs. The first products made were interferon discovered in , insulin, and somatropin see Section 3. For mammalian cell culture, specific cell lines are developed. It is a uniform cell population that can be cultured continuously. Commonly used cell lines are Chinese hamster ovary CHO cells or plant cell cultures see text below.
The production volumes are very small. The need for cell culture technology stems mainly from the fact that bacteria do not have the ability to perform many of the posttranslational modifications that most large proteins require for in vivo biological activity. These modifications include intracellular processing steps such as protein folding, disulfide linkages, glycosylation, and carboxylation.
Mammalian cell culture, however, is a delicate operation, posing more problems than handling with bacteria. The bioreactor batch requires more stringent controls of operating parameters, since mammalian cells are heat and share sensitive; in addition, the growth rate of mammalian cells is very slow, c Thereby, due to the high costs of growing mammalian cells, this technology is used only when strictly indispensable. While there are substantial differences between microbial and mammalian technologies e.
TABLE 4. Source: Reference . The low productivity of the animal culture makes it very vulnerable to contamination, as a small number of bacteria would soon outgrow a larger population of animal cells. Given the fundamental differences between the two process technologies, plants for mammalian cell culture technologies have to be built ex novo. The production of biopharmaceuticals starts by inoculating a nutrient solution with cells from a cell bank. The latter are allowed to reproduce in stages on a scale of up to several thousand liters.
The cells secrete the desired product, which is then isolated from the solution, purified, and transferred to containers. A process flow sheet for protein production from mammalian cells is shown in photo 8 in the insert. The mammalian cell production process is divided into the following four main steps: 1.
The cells are transferred from the cryogenic cell bank to a liquid nutrient medium, where they are allowed to reproduce. Mammalian cells such as CHO divide about once every 24 h bacterial cells, such as Escherichia coli, usually divide once every 20 min, and thus a sufficient number of cells are obtained in a much shorter time than in traditional fermentation processes.
During the growth phase, the cell culture is transferred to progressively larger culture vessels. The actual production of the biopharmaceutical occurs during this phase. The culture medium contains substances needed for synthesis of the desired therapeutic protein.europeschool.com.ua/profiles/hetudin/seret-aprender-ligar-mujeres.php
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In total, the medium contains around 80 different constituents at this stage, although manufacturers never disclose the exact composition. The industrial-scale bioreactors have capacities of 10, L or multiples. There are both technological and biological constraints on the size of the reactor—the bigger a fermenter is, the more difficult it becomes to create uniform conditions around all the cells contained in it. The fermentation reaction is done in a batch, fed-batch, or perfusion mode see, e. The production of biopharmaceuticals in cells is a one-step process, and the product can be purified immediately after fermentation.
In the simplest case, the cultured cells will have secreted the product into the ambient solution. Thus, the cells are separated from the culture medium e. If, on the other hand, the product remains in the cells following biosynthesis, the cells are first isolated and digested i.
As both the reaction times are long and the product concentration is small, the productivity of this technology is low. For example, a 10,L fermenter yields only a few kilograms of a therapeutic antibody, such as rituximab or trastuzumab. The production steps, including purification, take several weeks. Several more weeks are then needed to test the product. Each product batch is tested for purity to avoid quality fluctuations, and a Only then can the finished product be formulated and shipped.
The final steps in the production of biopharmaceuticals are also demanding. The sensitive proteins are converted to a stable pharmaceutical form and must be safely packaged, stored, transported, and finally administered. Throughout all these steps, the structural integrity of the molecule has to be safeguarded to maintain efficacy. At present, this is possible only in special solutions in which the product can be cryogenically frozen and preserved, although the need for low temperatures does not exactly facilitate transport and delivery.
Biopharmaceuticals are therefore strictly made to order. Because of the sensitive nature of most biopharmaceuticals, their dosage forms are limited to injectable solutions. Therapeutic proteins cannot pass the acidic milieu of the stomach undamaged, nor are they absorbed through the intestinal wall. Although work on alternatives such as inhalers is underway the first commercial application is an insulin inhaler , injection remains the predominant option for administering sensible biopharmaceuticals.
Nowadays, all the steps in the production of biopharmaceuticals are fully automated. Production staff steps in only if problems occur. Even a trace amount of impurities can cause considerable economic loss, as the entire production batch then has to be discarded, the equipment dismantled and cleaned, and the production process restarted from scratch with the cultivation of new cells. Plant cell culture is in an early stage of technology development.
Plants produce a wide range of secondary metabolites, some of which have been found to be pharmacologically active. However, these compounds are generally produced in very small amounts over a long period of time, making commercially viable extraction difficult. The technology shows promise for the selective synthesis of chiral compounds with a polycyclic structure, as found in many cytostatics, such as camptothecin, vinblastine, and paclitaxel see Section The concentration of biologically active molecules within the plant is usually very low.
Apart from pure manufacturing and weather-related factors in manufacturing pharmaceutical substances in living plants, the downstream processing, isolation, and purification technologies that need to be developed are key to the overall process costs. The first API which is about to demonstrate the industrial viability and economy of scale is taliglucerase alfa.
It is derived from a proprietary plant cell-based expression platform using genetically engineered carrot cells. The nonprofit organization counts more than 18, microorganisms, plant viruses, human and animal cell lines, plant cell cultures, and more than cultures deposited for the purpose of patenting. A typical stand-alone site comprises one or more production buildings, an administrative building, laboratories, a warehouse with separate sections for raw materials, quarantine products, and finished products , a power station for steam generation, a utilities building for demineralized water, steam, brine, inert gas, etc.
Of these facilities, only the production building is fine chemical specific. The basic type of plant, batch or continuous, is strongly correlated to the production volume of the products made. Continuous plants are used for the production of all top commodities in terms of production volume.
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For fine chemicals, which per definitionem are produced in smaller quantities, however, the picture is entirely different. Moreover, the product portfolio is regenerated at a fast pace, so that a specific product can be obsolete before the investment for a dedicated plant is recovered. This set of circumstances leads to the multipurpose MP plant as the major, basic configuration for fine chemical production. An MP plant has to be capable of handling a series of unit operations and performing many types of chemical reactions.
The situation is different for active pharmaceutical ingredients APIs -for-generics. Source: IMS Health. As the markets are more predictable and stable, and production volumes are higher, dedicated plants are used often. In the same plant, up to 20 or more different process steps can be executed per year. Separate regulations apply for food and feed additives, personal care products, and flavors and their advanced intermediates. Drug Enforcement Agency to stop illicit manufacture of narcotics, anabolic steroids, and similar compounds.
A helpful overview of different MP plant concepts can be found in Rauch . This is a. Continuous plants are used for large volume fine chemicals made from gaseous or liquid raw materials. Microreactors are more and more used if one or more of the following conditions apply: strongly exothermic, endothermic, or otherwise hazardous reaction conditions, low volume requirements, gaseous or liquid reagents see Section 4.
Before embarking on a project for a new plant, the following options for creating additional production capacity within existing plants should be considered. Creation of additional capacity by process intensification, that is, increasing the efficiency of processes for existing products. Obviously, a combination of two or more of these measures is particularly effective.
Expansion of an existing plant by adding production bays, preferably in spare space in existing buildings. Thus, one takes advantage of existing infrastructure. A third possibility, which cannot be ranked in terms of financial attractiveness, is the purchase of an existing fine chemical plant. Depending on the prevailing market conditions, the purchase price can be anywhere between a nominal fee and a large EBITDA multiple.
Apart from the status of the fixed assets, a decisive element in the valuation of candidates is the goodwill, particularly the existing manufacturing agreements and the solidness of the business plan. The lack of multipurpose capabilities is often an issue. The feasibility study represents the first step in a design phase. Typically, the project champion will be responsible for implementing the project. Already in this very first design phase appropriate measures have to be taken, if the plant needs to operate according to cGMP rules. Already the design itself has to undergo a qualification process, namely, the design qualification DQ.
The qualification process is a procedure proving and documenting that equipment and ancillary systems are properly installed, works in accordance to the design definition, and actually lead to the c DQ—documented verification that the proposed design of the system is suitable for the intended purpose. Installation qualification IQ —documented verification that the system, as installed or modified, complies with the approved design.
Operational qualification OQ —documented verification that the system performs as intended throughout the anticipated operating ranges. Performance qualification PQ —documented verification that the system, as connected together, can perform effectively and reproducibly according to the approved process method and specifications.
After alternatives have been checked and the definition of the project is found to be acceptable, the next design phase, the basic design, is initiated. At this point of time, it is appropriate to involve an external contractor. Engineering companies that are experienced in designing and building fine chemical plants are, a. The environmental impact of the project and all relevant permitting issues need also to be resolved during this phase.
The detail engineering finally will provide the necessary information needed to execute the project. In the design of a fine chemical plant, the number of components and size of the equipment, especially the volume of the reaction vessels, are critical. Depending primarily on the differing quantities of the fine chemicals to be produced in the same multipurpose unit, the concentration of substances in the reaction mixture, and the reaction time, there is, however, an upper limit for the size of the reaction vessel and the ancillary equipment.
Working capital—if the equipment is oversized with regard to the requirement for any particular fine chemical, the interval between two production campaigns becomes too long, and excessive inventory is built up. The dimensions of existing buildings, tank farms, and the capacity of utilities often determine an upper limit of the equipment size.
In commercial plants, the volume of the reactors ranges typically between 4 and 6 m3 sometimes between 1 m3 and 10 m3, or in rare cases, even larger. As a rule of thumb, the annual capacity for a one-step synthesis process averages approximately 15—30 MT of product per 1 m3 reactor volume. Therefore, a production bay, which is equipped with 4 and 6 m3 reaction vessels, is suitable for the production of around MT of a step per year. As illustrated in Figure 5. Flexibility, however, always has its price. Exotic or highly specialized equipment should to be installed only in an MP plant, if there is a specific need.
Excessive flexibility is counterproductive. In the industrial practice, it has proved to be a good solution to provide space for special equipment in the basic design, and to order and install it only in case of a real demand. Beside traditional stainless steel and glass lining as materials of construction, more exotic materials such as hastelloy, tantalum, zirconium, and inconel alloys are increasingly used.
Instead of adding special equipment to individual production bays, it is also possible to place them centrally in the dry or wet section of the plant, respectively. In this way, they can be connected as needed to different production bays. Another option is to create semi-specific production bays, For example, for hydrogenations, phosgenizations, Friedel—Crafts alkylations, and Grignard reactions.
The choice of the proper piping concept is essential for a valid MP plant design. The basic requirements for a piping system are, beside corrosion resistance for a wide array of substances, ease of cleanability due to quality and costs and, of course, a high degree of flexibility in order to ensure the needed multipurpose character of the plant.
Typically, the following approaches are available: A preinstalled piping system with an adequate number of manifolds and coupling stations, according to the required flexibility see Fig. This system is also ideal in cases when the campaign lengths are expected to be short, that is, when frequent product changes are likely.
The process-specific piping concept generally minimizes the needed amount of fixed-installation pipes. Connections between reactors, head tanks, receivers, pumps, filtration units, and other components are installed only as needed, on a strictly campaign-to-campaign basis. In addition, suitable hoses are installed instead of solid piping whenever possible.
Full process control computerization for an MP plant is much more complex than for a dedicated single-product plant and therefore will be also much more expensive. Whenever possible, all efforts have to be made to choose standard process control systems and to apply standard control software; this is a proven measure to control the investment costs in this segment and will also minimize the risk of having excessive investment and start-up costs due to initiating problems with the computer control system.
The fact that automation systems need to be validated has become a critical aspect of all automation systems that are being applied for cGMP productions. Some guidelines on this topic can be found in the U. Code of Federal Regulations [7a]. Good manufacturing guidelines apply also to heating, ventilation, and air-conditioning HVAC systems. They have to be designed to exclude contamination. To comply with all pertinent quality requirements regarding safety, hygiene, and cGMP, if applicable. According to the nature of the substances involved, specific segregation within the production area might be necessary.
Depending on the nature of the products, the unloading of dryers might have to take place in a segregated area e. In case of cGMP productions, both the people and material flow have to follow strict rules. Three examples of state-of-the-art MP plants are described in Figures 5. Operating principles of MP plant example 1 Fig. A typical bay consists of two to three multipurpose reactors up to a maximum volume of 10 m3 each , one filtration unit nutsche or centrifuge , and one dryer.
Production flow of the plant—charging of starting materials level 4 , reaction level 3 , crystallization level 2 , filtration level 1 , and drying and blending level 0. Material flow area—reserved zone for material flow. Open structure—manufacturing in a maximum flexibility and minimal segregation environment, six bays in the same area. Source: Lonza, Switzerland. This approach also allows for a maximum capacity utilization. Containment area—manufacturing combined with maximum segregation; six compartments, each housing one bay.
Infrastructure—chiller, off-gas treatment, air-conditioning systems, process water, spares, and other facilities, located in the basement or as open-air installations on the roof of the plant. Operating principles of MP plant example 2 Fig. The building complex, which tops 42 m in height, has a diameter of 88 m, and a working area of over 28, m2, is operated by over well-bayed chemical operators, engineers, and chemists. The satellite buildings contain service areas, laboratories, storage areas, offices, and various utilities ventilation, electricity, brine, steam, inert gas, and water for fire protection.
For the processing flow, a top-down approach was chosen, utilizing gravitational force whenever possible. The plant houses six segregated and independent manufacturing areas, in order to separate, for example, corrosive chemistry from final purification steps of APIs. Production takes place in strictly closed equipment and is controlled by a state-of-the-art process control system.
The core of the hexagon-shaped building is used for the central services, and supply of liquid and gaseous media via a ring pipe. Operating principles of MP plant example 3 Fig.
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Floor 4 houses a contained cabin for charging solid raw materials and intermediates and an agitated 1. The latter is connected to a plate filter for catalyst and charcoal recovery, a filling station for big bags, and an overhead condenser. The jacketed 6. The mother liquor is discharged to a holding tank. The filter cake is discharged to a silo and then filled in big bags or drums. It is further processed in a separate drying—sieving—filling station.
The building will also contain absorption columns for the pretreatment of waste gases as well as distillation columns for solvent recovery. A generous infrastructure is available on site. Next to the building, a tank farm for solvents with and m3 tanks will be built. Storage of intermediates and finished products takes place in a state-of-the-art warehouse. For fire protection, the air in the warehouse is diluted with nitrogen, thus reducing the oxygen concentration to Utilities comprise electric power from a nearby hydroelectric power station, steam generated in the waste incinerator, and nitrogen from an onsite air separation plant.
The production of fine chemicals using biotechnological processes fundamentally follows the same pattern as the one for synthetic fine chemicals: preparation and charging of the raw material, reaction, liquid—solid crude product separation, product purification, and packaging. Depending on the specific bioprocess used, there are, however, generally substantial differences in the design and operation of the plant. Simple fermentations used for specific steps in low-molecular-weight fine chemicals e. This is particularly the case if enzymes fixed on a solid support are used as catalysts.
The production of modern highmolecular-weight biopharmaceuticals by the use of recombinant processes requires specifically designed plants, where utmost attention is paid to the safeguard of sterility see Section 4. Fine chemical plants have only evolved in few aspects and discrete steps such as containment and automatic process control over the past 25 years. Different initiatives for radical improvements are underway.
With modular MP plants, an efficient combination of the flexibility of batch plants with the high performance and easier scale-up of continuous flow chemistry is sought. The study has evaluated 72 process intensification technologies; 46 of them have been retained for a detailed evaluation and description in technology reports. Hessel et al. It means Flexible, Fast, and Future Factory and is an ambitious private—public project aimed at developing the chemical plant of the future, which is capable of widespread implementation throughout the chemical industry. It is targeted to be more economic, eco-efficient, and c In order to demonstrate the technical feasibility, a modular continuous plant is being built at Chempark Leverkusen, Germany.
It consists of a dozen major chemical and pharmaceutical companies a. The actual capacity utilization in a given time period is determined both by business and technical factors. There are both short- and long-term aspects to production planning. A useful tool for shortterm planning is a rolling month sales forecast, with binding commitments for the first 2—6 months and more flexibility for the rest of the periods. Taking advantage of the experience of the automotive industry, which is the forerunner in lean production, a much more sophisticated methodology, called Overall Equipment Effectiveness OEE , is gaining ground also in the fine chemical industry.
OEE considers the expenditure of resources for any goal other than the creation of value for the customer to be wasteful, and thus a target for elimination. As different products with widely varying throughputs in terms of kilograms per annum are produced during the course of a year, production planning is a very demanding task. It is, however, a rather imprecise measure c With regard to the former, already the type of equipment, which determines the reactor volume, is not well defined: Does one consider only the reaction vessels as such or also crystallization vessels and buffer tanks?
Furthermore, in MP plants, some pieces of equipment may not be used at all for the production of a specific fine chemical. This is for instance the case, when a liquid product is produced in a bay that is equipped with an expensive filternutsche. OEE allows determining how a production bay actually performs in comparison to an ideal one, which runs at maximum throughput, without production interruptions, and without reworks of out-of-spec product.
As shown in Figure 5. In practice, OEE values are much lower than expected. The arduous task of improvement of OEE begins with a meticulous search, and documentation of commercially available software is becoming increasingly accessible, which efficiently supports the complex task of production planning in MP plants. Plant operators play an important role in reducing lost time, which can be caused for instance by late arrival of starting material, instable processes, long changeover times, delays in in-process testing, mechanical deficiencies of equipment e. Identify deviations from specifications Figure 5.
Responsible Care is a voluntary program, initiated be the U. Responsible Care continues to strengthen its commitments and enhances the public credibility of the industry. About 30, substances existing prior to and new substances produced or traded in Europe in quantities of more than 1 ton per year will be affected. PFCs produced and processed under strictly controlled conditions are exempt. In order to reduce animal testing, manufacturers of the same chemicals must pool their animal tests. Quality and documentation aspects in general have become an increasingly important success factor in the fine chemical business.
This is even truer for cGMP production. Because fine chemicals are sold according to stringent specifications, adherence to constant and strict specifications, at risk because of the batchwise production and the use of the same equipment for different products in MP plants, is a necessity for fine chemical companies. The ISO management system standards, which are implemented and recognized worldwide, play an important role.
These guidelines were developed within the Expert Working Group of the International Conference on Harmonization ICH of the technical requirements for registration of pharmaceuticals for human use. Since , the document has been applied by the regulatory bodies of the European Union, Japan, and the United States. A firm producing pharmaceuticals has to be approved by national authorities. If the products are intended for the U.
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The inspectors use three classifications for their observations, namely NAI no action indicated , if the firm is compliant, VAI voluntary action indicated , if a firm has several violations that have to be corrected as soon as possible, and OAI official action indicated , if the findings are significant.
General standards for drugs are typically published in the so-called national pharmacopoeia. The names of the different national pharmacopoeia are formed by pharmacop o eia combined with the name of the country, for example, the United States Pharmacopeia and National Formulary USP—NF.
Attempts to generalize and unify the different national pharmacopoeia have continued for over a century. The European Community signed a convention that resulted in issuance of the European Pharmacopoeia . The latter two product categories, with the exception of reagent chemicals used as diagnostics, are not subject to cGMP regulations.
A comprehensive training program for all employees is another essential element to secure adequate quality and safety standards. The program has to incorporate the entire workforce involved into any aspect of the manufacturing process and needs to be documented. All quality aspects within a company are to be controlled by an independent organizational unit. Beside the quality control unit, of course, the quality assurance activities are also part of this operation.
Reviewing and approving qualification reports. Reviewing and approving validation reports. Approving all specifications and master production instructions. Making sure that critical deviations are investigated and resolved. Establishing a system to release or reject raw materials and labeling materials. Approving changes that potentially affect intermediate or API quality.
Making sure that internal quality audits are performed. Making sure that effective systems are used for maintaining and calibrating critical equipment. These criteria are mandatory for cGMP products; however, it is recommended practice to utilize, whenever possible, the same criteria for non-cGMP products as well. A new program at FDA called process analytical technology PAT allows the use of continuous process control systems that measure and assess quality during the manufacturing process rather than between batches .
The framework specifies the development of manufacturing processes that can consistently ensure a predefined quality at the end of the manufacturing run. The main tasks are 1 designing, respectively duplicating and adapting in case of contract manufacture, and developing laboratory procedures for new products or processes; 2 transferring the processes from the laboratory via pilot plant to the industrial scale the scaleup factor from a g sample to a 1-ton batch is , ; 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 observed. 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. The growth of the business as such can kick off only once this backlog is filled. On the technical side, the higher complexity of the products and the more stringent regulatory requirements absorb more resources.
The project portfolio enables an overview on the ongoing research activities. Numerous economic and technical parameters have been proposed to provide a meaningful picture. Most of these parameters cannot be determined quantitatively, at least during the early phases of a project. The probability of success, for instance, depends on a number of factors. On the technical side, it is the likeliness that the laboratory results in terms of yield, throughput, and quality can be matched on the industrial scale within the planned timeframe.
On the business side, it is the likeliness of realizing the forecasted sales and profit figures. In custom manufacturing, a twofold risk is incurred. 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. Literature and Patent Research An efficient literature and patent search capacity has to be made available. Provisions have to be made for a periodic examination of all acquired research results to safeguard Intellectual Property Rights IPR and to determine whether patent applications are indicated.
Aside from its organization linear in fashion, building from one topic section to the next so as to create an ordered course of study , the value of this manuscript is in its greater social importance: When researchers come to understand the exact way each different drug class acts on human cell structure, they will then be able to design better medicines with fewer side effects and a more complete ability to counter-act disease.
This will result in better medicines at more cost-effective pricing, in turn boosting the world-wide economy. Recommended as a teaching text in any Pharmacy or Medicinal Chemistry course which concentrates on teaching students how to dissect the mechanics of drug action on human cell structure. Further recommended to all Health Science libraries as a general reference text.
This is a hugely important volume relevant to a multiplicity of disciplines, offering practical analysis of myriad compounds as it sets out to identify and then unlock the secrets of biochemical reaction. The authors whose work has been stitched together serve as the veritable experts in their field, and this work proves representative of the vastness of science itself — dissecting the way that compounds function and move and react while simultaneously evincing the intricacies of the universe.
In addition, recommended to all practicing chemists and laboratory researchers working in various chemical industries such as the world of pharmaceuticals. Topics of coverage here include the selective reactions of alkenes; discussion of the Overman Route to Gelsemine; and exploration of both the Stork Synthesis of - - Reserpine and synthesis of - - Littoralisone to name random highpoints.
Although Taber is a scientist, he is nonetheless able to order his presentation with the deft hand of a journalist — building one subject analysis onto the next as a means to bring continuity to topics that often suffer from fragmentation when locked in book form. Additionally, the creative impulse of this series is noteworthy, since it seeks to offer chemists a way to keep pace with vital new information without having to invest hours of library time. This series is recommended to all practicing chemists, researchers and instructors as a way to stay current with developments in the field of Organic Synthesis.
In this volume, readers will gain a fundamental understanding of physical chemistry though the concurrent study of biological and biochemical topics. Here, Allen uses a unique approach that does not presume a supreme knowledge of mathematical theory. Instead, instructors are allowed to tailor lesson plans and lectures to the level of the classroom so that students are able to gain an understanding of fundamental scientific concepts a tact which should naturally result in better problem-solving skills and deeper competence in terms of scientific study.
Topics of discussion include analysis of the theoretical basis of hydrogen-transfer, in addition to exploration of the most up-to-date techniques used to monitor and measure typical transfer reactions with expert review of hydrogen-transfer in both natural and artificial systems.
Noted for its superior organization which allows readers to navigate chapters quite easily. Augmented by various graphics and illustrations which serve to clarify complicated points of study. Relevant to students in any chemistry, physics and pharmaceutical-research course that explores hydrogen-transfer reactions. In addition, this book provides an indispensable reference for all university-level libraries — a book that is likely never to be surpassed in tone or breadth. In this era, flavor is everything — from beverages to food stuffs, manufactures are constantly looking for more piercing flavors with which to tantalize consumers.
Here, 40 contributors come together in a one-of-a-kind tome that examines how flavorings are produced, applied, regulated and created. Chapter topics include complete exploration of the manufacturing process including physical and biotechnological aspects ; the raw materials and ingredients used in flavorings; how different ingredients are blended in order to build different taste sensations; how flavorings are used in products like beverages, candies, baked goods, ice cream and myriad dairy products; quality control and quality analysis; microbiological testing; toxicological considerations; and religious considerations regarding the use of flavorings in different parts of the world.
In addition, the secondary lesson here is to remind readers and students that science has far-reaching tentacles that extend into the markets where our food is kept. Noted for its original tone and stance and for the way it brings this somewhat secret area of science to immediate life. The Morley Medal is awarded annually to a chemist located in the Cleveland, Ohio area for major contributions to the sciences. Darla Henderson, Senior Editor at Wiley. In addition to his full-length book manuscripts, Prasad has published more than scientific papers, while holding positions in the departments of chemistry, physics, medicine, and electrical engineering at the State University of New York at Buffalo UB.
John Wiley and Sons was founded in , and it continues to provide scientific, technical, and medical journals, encyclopedias, books, and on-line products to the academic and scientific communities. This volume, edited by Rice, collects a broad assortment of the latest advancements in the ever-evolving field of Chemical Physics — effectively summarizing the most-recent data in one place while allowing for stimulating give-and-take analysis among the pre-eminent experts in the field.
The practice of alchemy has captivated people for centuries, its mystic roots driving seekers in myriad realms — including literature, philosophy and science.
In this recent treatise from P. Maxwell-Stuart University of St. Andrews , the history of alchemy and its practitioners is examined in detail. Here, Maxwell-Stuart strives to build a timeline and then place alchemy in a definite historical context documenting its role in the grand evolution of modern science. Topics of coverage are vast and build into well-detailed chapters of amazing depth. Highlights from this edition include discussion of Amino Acids and Metabolism; Lipid Metabolism; DNA Replication; digestion and absorption; and the principles of nutrition.
Simply, the intent here is to allow the student to test himself as he works through the next concept, a style that promotes thorough and precise understanding of the subject as whole. In this era when the world lives under the threat of several different biohazards, the importance of this material cannot be over-emphasized.
In addition to lingering threats of bioterrorism and nuclear war, the discovery of the Avian Flu has made renewed study into the correlation between cell structure, antigen and disease imperative. And by doing this, the author has artfully drawn a link between mechanical classroom concepts of Science and the practical walls that house the Clinician. In the end, this text will be as useful to the student as it is to the laboratory researcher who might require a refresher course on the interplay between the biochemical process and human disease. Recommended as a primary teaching text in Biochemistry courses: noted for its depth and organization, well-written and grand in scope, the chapters moving at a perfect pace to give the student a lasting lesson in the biochemical process.
Further recommended to Health Science libraries as a general reference text. Finally, would be useful to infectious disease researchers for its ability to link flaws in the biochemical process together with the onset of human disease. The destruction from flooding during Hurricane Katrina last August proved how susceptible this country is to natural disaster.
In addition, debate is on-going as to whether steps could -or should- have been taken place to mitigate the damage from these storms. For starters, I think that city planners and engineers could have better designed the New Orleans drainage system so that water run-off would have been more efficient. What all this proves to me is that everyone needs to go back to the starting point and re-evaluate myriad systems from ground-zero.
Here, Conklin engages us in a thorough discussion of soil analysis, beginning with the basics and moving at a steady pace through more advanced concepts. As Conklin notes, the key for any scientist studying soil is to be able to understand exactly what characteristics influence its analytical exploration. Readers must remember, however, that soil is not a one-dimensional entity; instead, it is a complex mix of both inorganic and organic solids, liquids and gases that flow together to create one of the building blocks of life itself. Consequently, because of its complexity, science must approach its investigation carefully and systematically, attentive to every nuance of detail.
To this end, Conklin has drafted a dependable guide that covers the central points of soil study, including data on horizonation, peds, color, naming, landscape, bonding, the components of soil in combination, the biological and organic components of soil, soil air, and titration among many other topics. Recommended as a teaching text in all Chemistry courses that cover soil analysis. Would also prove useful to city planners and environmental scientists focused on analyzing soil for construction purposes. Recommended to all college-level libraries as a general reference with long-term value.
Volume Edited by Hugo Kubinyi and Gerhard Muller. This hallmark text marks a breakthrough in the field in that it aligns the primary concepts of chemistry and biology, then takes the process one step further, applying chemistry to genomics and proteomics. Here, Muller a scientific researcher from Munich and Kubinyi a medicinal chemist from the University of Heidelberg have drafted a study that allows these fundamental platforms of scientific study to be applied to medicinal chemistry: the goal is for the health researcher to be able to understand exactly how drugs impact the body and why these reactions are occurring.
Once this is done, the possibility for the development of more efficient drugs with less troublesome side effects is possible. Edited by Matthias Beller and Carsten Bolm.
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