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It was Howard Florey, Ernst Chain and their colleagues at the Sir William Dunn School of Pathology at Oxford University who turned penicillin from a laboratory curiosity into a life-saving drug.

Their work on the purification and chemistry of penicillin began in earnest in 1939, just when wartime conditions were beginning to make research especially difficult.

To carry out a program of animal experiments and clinical trials the team needed to process up to 500 liters a week of mold filtrate.

They began growing it in a strange array of culture vessels such as baths, bedpans, milk churns and food tins. Later, a customized fermentation vessel was designed for ease of removing and, to save space, renewing the broth beneath the surface of the mold.

A team of "penicillin girls" was employed, at ?2 a week, to inoculate and generally look after the fermentation.

In effect, the Oxford laboratory was being turned into a penicillin factory.

Meanwhile, biochemist Norman Heatley extracted penicillin from huge volumes of filtrate coming off the production line by extracting it into amyl acetate and then back into water, using a countercurrent system. Edward Abraham, another biochemist who was employed to help step up production, then used the newly discovered technique of alumina column chromatography to remove impurities from the penicillin prior to clinical trials. In 1940, Florey carried out vital experiments, showing that penicillin could protect mice against infection from deadly Streptococci.

Then, on February 12, 1941, a 43-year old policeman, Albert Alexander, became the first recipient of the Oxford penicillin. He had scratched the side of his mouth while pruning roses, and had developed a life-threatening infection with huge abscesses affecting his eyes, face, and lungs. Penicillin was injected and within days he made a remarkable recovery. But supplies of the drug ran out and he died a few days later. Better results followed with other patients though and soon there were plans to make penicillin available for British troops on the battlefield.

War-time conditions made industrial production of penicillin difficult.

A number of British companies, including Glaxo (now GlaxoSmithKline) and Kemball Bishop, a London firm later bought by Pfizer, took up the challenge. Penicillin Production in the United States during WWII. Substantial amounts of penicillin would be needed for the extensive clinical trials required to confirm the promise of the early results and to provide adequate supplies of the drug for therapeutic use if it did live up to its potential.

Florey recognized that large-scale production of penicillin was probably out of the question in Britain, where the chemical industry was fully absorbed in the war effort. With the support of the Rockefeller Foundation, Florey and his colleague Norman Heatley traveled to the United States in the summer of 1941 to see if they could interest the American pharmaceutical industry in the effort to produce penicillin on a large scale.

Yale physiologist John Fulton helped to put his British colleagues in touch with individuals who might be able to assist them in their goal.

They were referred to Robert Thom of the Department of Agriculture, a foremost mycologist and authority on the Penicillium mold, and eventually to the Department's Northern Regional Research Laboratory (NRRL) in Peoria, Illinois, because of the expertise of its Fermentation Division. This contact proved to be crucial to the success of the project, as the NRRL was a key contributor of innovations that made large-scale production of penicillin possible.

Orville May, Director of the NRRL, agreed to have the Laboratory undertake a vigorous program to increase penicillin yields under the direction of Robert Coghill, Chief of the Fermentation Division. It was agreed that Heatley would remain in Peoria to share his expertise with his American colleagues. Within a few weeks, Andrew Moyer found that he could significantly increase the yield of penicillin by substituting lactose for the sucrose used by the Oxford team in their culture medium. Shortly thereafter, Moyer made the even more important discovery that the addition of corn-steep liquor to the fermentation medium produced a ten-fold increase in yield.

Corn-steep liquor was a by-product of the corn wetmilling process, and the NRRL, in an attempt to find a use for it, tried it in essentially all of its fermentation work. Later, the Peoria laboratory increased the yield of penicillin still further by the addition of penicillin precursors, such as phenylacetic acid, to the fermentation medium. It was recognized that the Oxford group's method of growing the mold on the surface of a nutrient medium was inefficient, and that growth in submerged culture would be a superior process. In submerged culture fermentation, the mold is grown in large tanks in a constantly agitated and aerated mixture, rather than just on the surface of the medium.

Florey's Penicillium culture, however, produced only traces of penicillin when grown in submerged culture. Under the direction of Kenneth Raper, staff at the NRRL screened various Penicillium strains and found one that produced acceptable yields of penicillin in submerged culture.

Soon a global search was underway for better penicillin producing strains, with soil samples being sent to the NRRL from around the

world

Although Florey was disappointed in the immediate results of his trip, three of the companies (Merck, Squibb and Lilly) had actually conducted some penicillin research before Florey's arrival and Pfizer seemed on the verge of investigating the drug as well.

At this time, however, the promise of penicillin was still based on only limited clinical trials. Florey next visited his old friend Alfred Newton Richards, then vice president for medical affairs at the University of Pennsylvania.

More importantly, Richards was chair of the Committee on Medical Research (CMR) of the Office of Scientific Research and Development (OSRD). The OSRD had been created in June, 1941, to assure that adequate attention was given to research on scientific and medical problems relating to national defense.

Richards had great respect for Florey and trusted his judgment about the potential value of penicillin. He approached the four drug firms that Florey indicated had shown some interest in the drug (Merck, Squibb, Lilly and Pfizer) and informed them that they would be serving the national interest if they undertook penicillin production and that there might be support from the federal government. Richards convened a meeting in Washington, D.C., on October 8, 1941, to exchange information on company and government research and to plan a collaborative research program to expedite penicillin production. In addition to representatives of the CMR, the National Research Council and the U.S. Department of Agriculture, participants included research directors Randolph T. Harrop of the Squibb Institute for Medical Research; Jasper Kane of Pfizer; and Y. The next CMR penicillin conference, held in New York in December, ten days after Pearl Harbor and U.S.

entry into the Second World War, was more decisive.

At this meeting, which was attended by the heads of Merck, Squibb, Pfizer and Lederle, as well as the company research directors, Robert Coghill's report on the success at the NRRL with corn steep liquor was encouraging to the industry leaders present. Merck, who had been pessimistic about the possibility of producing adequate quantities of penicillin given the constraints of available fermentation techniques and

yields

immediately spoke up, saying that if these results could be confirmed in their laboratories, it was possible to produce the kilo of material for Florey, and industry would do it!". It was agreed that

although

Although there was some concern that investments in fermentation processes might be wasted if a commercially-viable synthesis of penicillin were developed, other companies also began to show an interest in the drug.