The supply problem
By 1941, the Oxford researchers had shown that purified penicillin could protect infected animals and help at least some patients. The next obstacle was entirely practical: the mold produced very little of it. The early material was scarce enough that the team collected it from patients’ urine to use again. A drug that worked but could not be made in quantity would help almost nobody. This page covers how that was changed. It is a history of manufacturing, not medical advice.
Oxford’s improvised production
In the early 1940s, the Oxford group grew the mold in whatever containers could be adapted: bedpans, biscuit tins, flat dishes and later purpose-built ceramic vessels, in which the mold grew in a thin layer on the surface of liquid. Norman Heatley designed much of the apparatus and the extraction process. The system worked, but yields were small. British industry was stretched by the war and, partly because of the risk of bombing, firms were reluctant to commit.
The move to the United States
In mid-1941 Howard Florey and Heatley traveled to the United States and visited laboratories that could help. The visit led to work at the US Department of Agriculture’s Northern Regional Research Laboratory in Peoria, Illinois, a center for studying fermentation of farm products. Three changes are especially associated with it.
- Corn steep liquor. This is a by-product of corn starch manufacturing, and adding it to the nutrient broth sharply increased the amount of penicillin produced.
- A better mold. Researchers collected and tested molds from many sources. One strain that was often reported to have come from a moldy cantaloupe in a Peoria market, a Penicillium now called chrysogenum, produced much more than Fleming’s original. Later, X-rays and other treatments were used to produce mutant strains with higher yields, in a program involving several universities and companies.
- Submerged culture. Instead of letting mold grow on top of a liquid, the mold was grown throughout large tanks of broth that were stirred and supplied with sterile air. This is called deep-tank fermentation, and it greatly raised the volume that could be made.
Industry and government
The United States entered the war in December 1941, and penicillin was soon treated as a military priority. A government body, the War Production Board, worked to coordinate which companies would produce it and share technical information, and the pharmaceutical firms involved were asked to exchange findings instead of competing. British and American groups also exchanged materials and staff. Several American drug companies built large fermentation plants, and a number of firms entered production.
The engineering work was substantial. Tanks had to be kept clean of other microbes, since a single contaminant could ruin a batch. Air supply, temperature and acidity needed careful control. Extracting the drug from the broth was another challenge, and drying the product by freeze drying, a method also used for blood plasma in the war years, helped keep some preparations stable. The drug breaks down easily, so it was recovered in stages using solvents and acidity changes, and the final product had to be tested for strength and purity.
From scarcity to supply
The amounts increased dramatically during the war. In 1942, supplies were so small that they were allocated by committee and used for a handful of cases. By 1943 they were being tested in military hospitals, and by mid-1944, around the time of the Allied landings in Normandy, there was enough for the treatment of wounded soldiers. After the war, further improvements brought prices down, and civilian supplies became more common. Exact production figures differ between sources, so the numbers are better left out of a short history.
Chemistry and attempts to synthesize
During the war, British and American chemists studied the structure of penicillin, and Dorothy Hodgkin determined it in 1945 with X-ray methods. Many hoped to make the drug entirely from chemicals instead of from mold, which seemed possible once the structure was known. Fermentation remained more practical, but later work in the 1950s found how to alter the molecule and produce modified forms, starting from material made by the mold. That produced the wide family of penicillin-type antibiotics.
Questions of credit and patents
The scale-up was a collective effort, and attention in popular accounts tends to go to a few names. The researchers at Peoria, the staff of the companies and the engineers who designed the tanks are less famous than Fleming, Florey and Chain. Patents were also contentious. The Oxford team has been described as having faced difficulties in claiming protection in Britain, while American companies filed patents on processes and strains. Historians still discuss how these arrangements affected the later pharmaceutical industry.
What this part of the story shows
Penicillin demonstrates that an invention is not complete when it works in a laboratory. The 1940s effort involved biology, chemistry, agricultural science, engineering and government planning. The result is one of the earliest examples of a large coordinated program to bring a medicine into production, and it set a pattern that later drug development often followed. Fleming’s original dish and the Oxford experiments are told elsewhere, and what is described here is the factory work that came afterward.