Manufacturing-scale production

Once a satisfactory R D laboratory-scale formulation has been developed, the problem of pilot- and manufacturing-scale production must be solved. In this scale-up step, formulators may encounter problems of mixing and dispersion not found in a small-scale production [212, 213]. 

Product innovation absorbs considerable resources in the fine chemicals industry, in part because of the shorter life cycles of fine chemicals as compared to commodities. Consequently, research and development (R D) plays an important role. The main task of R D in fine chemicals is scaling-up lab processes, as described, eg, in the ORAC data bank or as provided by the customers, so that the processes can be transferred to pilot plants (see Pilot PLANTS AND microplants) and subsequently to industrial-scale production. Thus the R D department of a fine chemicals manufacturer typically is divided into a laboratory or process research section and a development section, the latter absorbing the Hon s share of the R D budget, which typically accounts for 5 to 10% of sales. Support functions include the analytical services, engineering, maintenance, and Hbrary. 

Manufacture and Economics. Nitrogen tritiuoride can be formed from a wide variety of chemical reactions. Only two processes have been technically and economically feasible for large-scale production the electrolysis of molten ammonium acid fluoride and the direct fluorination of the ammonia in the presence of molten ammonium fluoride. In the electrolytic process, NF is produced at the anode and H2 is produced at the cathode. In a divided cell of 4 kA having nickel anodes, extensive dilution of the gas streams with N2 was used to prevent explosive reactions between NF and H2 (17). 

Cyanide Wastes. Ozone is employed as a selective oxidant in laboratory-scale synthesis (7) and in commercial-scale production of specialty organic chemicals and intermediates such as fragrances, perfumes (qv), flavors, antibiotics (qv), hormones (qv), and vitamins (qv). In Japan, several metric tons per day (t/d) of piperonal [120-57-0] (3,4-methylenedioxybenzaldehyde) is manufactured in 87% yield via ozonolysis and reduction of isosafrole [93-16-3], Piperonal (or heHotropine [120-57-0]) has a pleasant odor and is used in perfumery. Oleic acid [112-80-1/, CH3(CH2 )7CH—CH(CH2 ). C02H, from tall oil (qv) is ozonated on a t/d scale to produce pelargonic, GgH2yG02H, and azelaic, H02G(GH2)yG02H, acids. Oleic acid also is ozonated in Japan... 

Fermentative Manufacture. Throughout the years, riboflavin yields obtained by fermentation have been improved to the point of commercial feasibiUty. Most of the riboflavin thus produced is consumed in the form of cmde concentrates for the enrichment of animal feeds. Riboflavin was first produced by fermentation in 1940 from the residue of butanol—acetone fermentation. Several methods were developed for large-scale production (41). A suitable carbohydrate-containing mash is prepared and sterilised, and the pH adjusted to 6—7. The mash is buffered with calcium carbonate, inoculated with Clostridium acetohutylicum and incubated at 37—40°C for 2—3 d. The yield is ca 70 mg riboflavin/L (42) (see Fermentation). 

Boron Triiodide. Boron ttiiodide is not manufactured on a large scale. Small-scale production of BI from boron and iodine is possible in the temperature range 700—900°C (70—72). Excess I2 can be removed as Snl by reaction with Sn, followed by distillation (71). The reaction of metal tetrahydroborates and I2 is convenient for laboratory preparation of BI (73,74). BI can also by synthesized from B2H and HI in a furnace at 250°C (75), or by the reaction of B with excess Agl or Cul between 450—700°C, under vacuum (76). High purity BI has been prepared by the reaction of I2 with mixtures of boron carbide and calcium carbide at elevated temperatures. 

Scale-up in fixed-bed reactors is limited by the maximum size of the matrix that can be manufactured as a monolith. Hence, this system is appHcable for small- to medium-scale production of antibodies and other proteins, usually for the diagnostic market. This system has been described in greater detail ia the Hterature (22). 

In 1900, the Pennsylvania Salt Manufacturing Co. initiated large-scale production in the United States. The Midland Chemical Co., a subsidiary of The Dow Chemical Company, began to manufacture chloroform by reducing carbon tetrachloride in 1903. Chloroform was one of the first organic chemicals produced on a large scale in the United States. 

A chemistry based on the conversion of synthesis gas has been developed and appHed extensively in South Africa to the production of Hquid fuels and many other products. A small-scale production is used in the manufacture of photographic film materials from coal-derived synthesis gas in the Eastman Kodak plant in Kingsport, Tennessee. However, the principal production of chemicals from coal involves the by-products of coke manufacturing. 

The guidance document requires calculation of actual yields and percentages of expected yields. The yield should be recorded at the conclusion of each phase of manufacturing of an API. The expected yield and ranges are established during process validation or from a pilot-scale production run [66]. 

Preparative chromatography has been used for chiral separations for years, but examples of multi-kg separations (and hence larger ones) were rare until recently. The development of SMB techniques (both hardware and simulation software) has made major breakthroughs in this field. The ability of SMB as a development tool has allowed the pharmaceutical manufacturer to obtain kilo grams quantities of enantiopure drug substances as well benefit from the economics of large-scale production. 

Relatively few articles have been published on the industrial manufacturing of liposomes (Fildes, 1981 Rao, 1984 Ostro, 1988 Van Hoogevest and Fankhauser, 1989 Martin, 1989). A large number of patents describing procedures for large-scale production of... 

To a first approximation, the cost of a single MPI is assumed to vary with scale (vessel volume or process throughput) on an exponent of 0.7. The value of this exponent does vary from one plant item type to another and while it typically lies in the range 0.5-0.9 [40, 42] for some equipment types (e.g., centrifuges) it may be at or above unity. This indicates that the purchased cost of equipment per unit production rate, say /(tons per year), generally increases as manufacturing scale decreases well known as economies of scale, related to large bulk chemical plants. 

The factors necessary to achieve quality in a product during the developmental stage have been discussed. The formulator of a new product must consider the manufacturing process to be used for full-scale production of the product. Many new product failures or deficiencies occur because of inability to resolve or foresee production-related problems, rather than to poor product development per se. Therefore, the... 

Process validation is intended to show and document that the process described, when operating within the designated parameters, will produce product of the appropriate quality and demonstrate that the manufacturing process is under full control. Process validation should extend from laboratory-scale and preformulation studies (say to of production scale) to formulation to pilot-scale manufacture (say production scale) to full industrial-scale manufacture, with a clear, logical, and continuous path between these stages. The magnitude of scale-up at each stage should not normally exceed a factor of 10. 

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