Introduction - Bioprocess Engineering: Kinetics, Biosystems, Sustainability and Reactor Design - page 13

for penicillin, if it could be made in sufficient amount. To make large amounts of penicillin
would require a process, and for such a process development, engineers would be needed,
in addition to microbial physiologists and other life scientists.
The war further complicated the situation. Great Britain's industrial facilities were already
totally devoted to the war. Florey and his associates approached pharmaceutical firms in the
United States to persuade them to develop the capacity to produce penicillin, since the
United States was not at war at that time. Many companies and government laboratories,
assisted by many universities, took up the challenge. Particularly prominent were Merck,
Pfizer, Squibb, and the USDA Northern Regional Research Laboratory in Peoria, Illinois.
The first efforts with fermentation were modest. A large effort went into attempts to chem-
ically synthesize penicillin. This effort involved hundreds of chemists. Consequently, many
companies were at first reluctant to commit to the fermentation process, beyond the pilot
plant stage. It was thought that the pilot plant fermentation system could produce sufficient
penicillin to meet the needs of clinical testing, but large-scale production would soon be done
by chemical synthesis. At that time, U.S. companies had achieved a great deal of success with
chemical synthesis of other drugs, which gave the companies a great deal of control over the
drug's production. The chemical synthesis of penicillin proved to be exceedingly difficult.
(It was accomplished in the 1950s, and the synthesis route is still not competitive with
fermentation.) However, in 1940, fermentation for the production of a pharmaceutical was
an unproved approach, and most companies were betting on chemical synthesis to ulti-
mately dominate.
The early clinical successes were so dramatic that in 1943 the War Production Board
appointed A. L. Elder to coordinate the activities of producers to greatly increase the supply
of penicillin. The fermentation route was chosen. As Elder recalls, “I was ridiculed by some of
my closest scientific friends for allowing myself to become associated with what obviously
was to be a flop-namely, the commercial production of penicillin by a fermentation process”
(from Elder, 1970). The problems facing the fermentation process were indeed very
formidable.
The problem was typical of most new fermentation processes: a valuable product made at
very low levels. The low rate of production per unit volume would necessitate very large and
inefficient reactors, and the low concentration (titer) made product recovery and purification
very difficult. In 1939, the final concentration in a typical penicillin fermentation broth was
one part per million (ca. 0.001 g/L); gold is more plentiful in seawater. Furthermore, peni-
cillin is a fragile and unstable product, which places significant constraints on the approaches
used for recovery and purification.
Life scientists at the Northern Regional Research Laboratory made many major contribu-
tions to the penicillin program. One was the development of a corn steep liquor-lactose-based
medium. Andrew J. Moyer succeeded to increase productivity about tenfold with this
medium in November 26, 1941. A worldwide search by the laboratory for better producer
strains of Penicillium led to the isolation of a Penicillium chrysogenum strain. This strain, iso-
lated from a moldy cantaloupe at a Peoria fruit market, proved superior to hundreds of other
isolates tested. Its progeny have been used in almost all commercial penicillin fermentations.
The other hurdle was to decide on a manufacturing process. One method involved the
growth of the mold on the surface of moist bran. This bran method was discarded because
of difficulties in temperature control, sterilization, and equipment size. The surface method