30th January 1944 Callahan Work In Fermention

A research team led by Chaim Weizmann in Great Britain during the First World War (1914-1918) developed a process for the production of acetone by a deep liquid fermentation using Clostridium acetobutylicum which led to the eventual use of the first truly large-scale aseptic fermentation vessels (Hastings, 1978). Contamination, particularly with bacteriophages, was often a serious problem, especially during the early part of a large-scale production stage. Initially, no suitable vessels were available and attempts with alcohol fermenters fitted with lids were not satisfactory as steam sterilization could not be achieved at atmospheric pressure. Large mild-steel cylindrical vessels with hemispherical tops and bottoms were constructed that could be sterilized with steam under pressure. Since the problems of aseptic additions of media or inocula had been recognized, steps were taken to design and construct piping, joints and valves in which sterile conditions could be achieved and maintained when required. Although the smaller seed vessels were stirred mechanically, the large production vessels were not, and the large volumes of gas produced during the fermentation continually agitated the vessel contents. Thus, considerable expertise was built up in the construction and operation of this aseptic anaerobic process for production of acetone butanol.

The first true large-scale aerobic fermenters were used in Central Europe in the 1930s for the production of compressed yeast (de Becze and Liebmann, 1944). The fermenters consisted of large cylindrical tanks with air introduced at the base via networks of perforated pipes. In later modifications, mechanical impellers were used to increase the rate of mixing and to break up and disperse the air bubbles. This procedure led to the compressed-air requirements being reduced by a factor of 5. Baffles on the walls of the vessels prevented a vortex forming in the liquid. Even at this time it was recognized that the cost of energy necessary to compress air could be 10 to 20% of the total production cost. As early as 1932, Strauch and Schmidt patented a system in which the aeration tubes were provided with water and steam for cleaning and sterilizing.

Prior to 1940, the other important fermentation products besides bakers' yeast were ethanol, glycerol, acetic acid, citric acid, other organic acids, enzymes and sorbose (Johnson, 1971). These processes used highly selective environments such as acidic or anaerobic conditions or the use of an unusual substrate, resulting in contamination being a relatively minor problem compared with the acetone fermentation or the subsequent aerobic antibiotic fermentations.

The decision to use submerged culture techniques for penicillin production, where aseptic conditions, good aeration and agitation were essential, was a very important factor in forcing the development of carefully designed and purpose-built fermentation vessels. In 1943, when the British government decided that surface culture production was inadequate, none of the fermentation plants were immediately suitable for deep fermentation, although the Distillers Company solvent plant at Bromborough only needed aeration equipment to make it suitable for penicillin production (Hastings, 1971). Construction work on the first large-scale plant to produce penicillin by deep fermentation was started on 15th September 1943, at Terre Haute in the United States of America, building steel fermenters with working volumes of 54,000 dm3 (Callahan, 1944). The plant was operational on 30th January 1944. Unfortunately, no other construction details were quoted for the fermenters.

Initial agitation studies in baffled stirred tanks to identify variables were also reported at this time by

Cooper et al. (1944), Foust et al. (1944) and Miller and Rushton (1944). Cooper's work had a major influence on the design of later fermenters.

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