The challenge of scale-up
Pharmaceutical and chemical companies played an especially important role in solving the problems inherent in scaling up submerged
fermentation from a pilot plant to a manufacturing scale. As the scale of production increased, the scientists at Merck, Pfizer,
Squibb, and other companies faced new engineering challenges. Pfizer's John L. Smith captured the complexity and uncertainty facing
these companies during the scale-up process: "The mold is as temperamental as an opera singer, the yields are low, the isolation is
difficult, the extraction is murder, the purification invites disaster, and the assay is unsatisfactory." Because penicillin needs air
to grow, aerating the fermentation mixture in deep tanks presented a problem. When corn steep liquor was used as the culture medium,
bubbling sterile air through the mixture caused severe foaming. Squibb solved this problem by introducing glyceryl monoricinolate as
an anti-foaming agent. Submerged fermentation also required the design of new cooling systems for the vats and new mixing technology
to stir the penicillin mash efficiently.
Lilly was particularly successful in making the mold synthesize new types of penicillin by feeding precursors of different structure.
Once the fermentation was complete, recovery was also difficult; as much as two-thirds of the penicillin present could be lost during
purification because of its instability and heat sensitivity. Extraction was done at low temperatures: Pfizer, responding creatively
to wartime shortages, adapted an old ice cream freezer! Methods of freeze-drying under vacuum eventually gave the best results in
purifying the penicillin to a stable, sterile, and usable final form. (Journalists at the time spoke of "yellow magic," but pure
penicillin was a white powder.) The steps of fermentation, recovery, and purification and packaging quickly yielded to the cooperative
efforts of the chemical scientists and engineers working on pilot production of penicillin. On March 1, 1944, Pfizer opened the first
commercial plant for large-scale production of penicillin by submerged culture in Brooklyn, New York.
Meanwhile, clinical studies in the military and civilian sectors were confirming the therapeutic promise of penicillin. The drug was
shown to be effective in the treatment of a wide variety of infections, including streptococcal, staphylococcal, and gonococcal
infections. The United States Army established the value of penicillin in the treatment of surgical and wound infections. Clinical
studies also demonstrated its effectiveness against syphilis, and by 1944, it was the primary treatment for this disease in the armed
forces of Britain and the United States.