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Penicillin: Pharmaceutical Companies: Technical Challenges
These reasons, coupled with the improvements in the fermentation process,
culminated in the penicillin advisory committee's recommendation in
late 1945 that the OSRD terminate its contracts with the pharmaceutical
firms, the research institutions, and Great Britain. The innovations
of the NRRL, discussed in detail in The Federal Bureaucracy section,
along with the above-mentioned improvements made by the pharmaceutical
industry led to a tremendous increase in penicillin's production and
the subsequent reduction in its price. Not only was the effort to produce
penicillin synthetically a costly, large-scale endeavor, with the industry
spending $3 million and the government spending $270,000, but such efforts
yielded minimal amounts of penicillin (Helfand, et al., 48). Therefore,
"…based on the extremely low yield of synthetic penicillin,
the production of penicillin by synthesis would cost at least 50 times
more than the manufacture of natural penicillin" via fermentation
(Swann, 181). Given this monetary rationale as well as the end of wartime
penicillin needs due to the close of WWII, the OSRD cancelled its contract
with the drug companies on November 1, 1945 and with the academic institutions
on December 31, 1945. [For possible visuals on the cancellation of these
contracts, see the U.S. Federal Trade Commission, Economic Report on
Antibiotics Manufacture (Washington, D.C.: Government Printing Office,
1958), Appendix 2, "Discovery and Development of Penicillin,"
302-354 (taken from Swann, 182, note 87).] While several authors argue that the synthesis program served as an obstacle to the mass production of penicillin, others do not recognize the project as a significant impediment. As discussed in The Federal Bureaucracy section, Neushul suggests that because Richards "…remained convinced that synthesis was the key to mass production of penicillin," the CMR made minimal financial contributions to the advancement of penicillin production via fermentation despite NRRL advances (Neushul, 382). Albert Elder, the War Production Board's (WPB) "penicillin czar," believed that "…the most important deterrent [to the mass production of penicillin] was the tremendous emphasis placed on the synthesis of penicillin by Dr. A. N. Richards and his Committee on Medical Research of the [OSRD]" (Elder, 4). Neushul notes that a November 1943 progress report by James Biller, a WPB investigator, echoed Elder's concerns on Richards's focus on synthesis. The report described the reasons for Squibb's delay in opening a new plant:
Belief that synthesis of the drug may be imminent may be
contributing to a lackadaisical attitude on the part of some producers
who feel that it would be foolish to waste a lot of time and money on
a relatively inefficient method of production when large scale production
of a synthetic may be just around the Such delays compelled Elder to obtain in advance the numerous
scientific control instruments, filters, air-conditioning equipment, and
other items required for penicillin production. He also looked to the
Office of Production Research and Development (OPRD) to coordinate the
development of higher yield producing strains of penicillin, as described
in The Federal Bureaucracy section. In December 1942 the CMR refused to
enter into a contract with the Carnegie Institution's Cold Spring Harbor
Laboratory, which requested increased funds for its research on the first
isolated "super strain"-another indication, Neushul asserts,
"…that synthesis and not fermentation was Richards' preferred
method of production" (Neushul, 393). Other authors, however, suggest that while Richards and
the CMR supported penicillin synthesis, such endorsement was not in place
of fermentation. In fact, Helfand, et al. argue that "Richards was
one of those who believed originally in the fermentation process"
(Helfand, et al., 47). Moreover, although "[the] CMR decided in favor
of synthesis, and actively initiated and supported a major program,"
it simultaneously "…[watched] carefully and [encouraged] the
fermentation process…" (Helfand, et al., 47). Swann finds that
Elder's statement that Richards placed "tremendous emphasis"
on the synthesis program is a "gross overstatement" (Swann,
188). "At most," Swann asserts, "Richards helped prolong
the program when it should have been terminated, [but] he did not advocate
the pursuit of synthesis at the expense of work on fermentation"
(Swann, 188). Indeed, no fermentation plants closed in order to focus
their attention on synthesis, and the industry spent over $22 million
on fermentation plant construction compared to the $3 million on synthesis
(Swann, 188-189; Hobby, 191). Although a point of academic debate, the
simultaneous inclusion of the synthesis program, coupled with the penicillin
growth difficulties discussed above, may have slowed developments to mass-produce
penicillin. Nevertheless, the pharmaceutical industry, government, and
research science subsequently overcame these obstacles. While the NRRL
and research science developed better media and more productive penicillin
strains, in 1943 the WPB began funding and facilitating penicillin production.
The COC's successes with penicillin at Bushnell and other army hospitals
convinced the WPB to become involved in penicillin production, as described
in The Federal Bureaucracy section. The WPB, which is discussed in detail
in The War Department section, began "…an aggressive expansion
of production facilities" under the direction of Elder and Fred Stock,
the chief of the WPB's Drugs and Cosmetics Division (Richards, 443). The
allocation order on July 16, 1943 placed the penicillin supply in the
hands of the WPB, distributing it to the OSRD (CMR), the armed forces,
and the U.S. Public Health Service. In the following months, the WPB reviewed
175 companies to assist in penicillin production and it selected 21 as
"…having the [experience and scientific and technical] capacity
to justify [its] financial assistance" (Richards, 443). Pfizer's
efforts at penicillin production via submerged fermentation began to yield
results in early 1943, and by early 1944 it had successfully converted
to deep tank fermentation. Other firms followed suit, such that whereas
in June 1943, 425 million units of penicillin were produced, 646 billion
units were produced by June 1945 (Helfand, et al., 50). [Richards, 444
has a chart that reveals the increase in penicillin production within
the context of WWII events and production advances. Smith and Worthen,
186, have a picture of Pfizer receiving an "E" Award in 1943,
demonstrating the link between the pharmaceutical industry, the armed
forces, and the government.] |
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Copyright © 1997, 2002 University of Pennsylvania HSS |
The
synthesis program, while it generated scientific advances in the chemistry
of penicillin, failed to alter the commercial mass production of the
drug. There were several reasons for the program's failure. One reason
was that the penicillin molecule itself was complex and chemists lacked
the knowledge and technology to deal with it effectively (Swann, 187).
Another reason, related to this factor, was that chemists were unable
to purify synthetic penicillin adequately and "…the condensation
reaction forming the synthesis product was wholly inadequate" (Swann,
180). While U.S. and British investigators synthesized a substance identical
to natural penicillin, the quantities in which they did so were too
minute to make synthesis a commercially viable process. The synthesis
project also failed because of the design of the program itself. Specifically,
while wartime conditions required the confidential exchange of research
both within the U.S. and Great Britain as well as between the two nations,
communication across the Atlantic was often delayed. In addition, during
the program's early years, many laboratories had insufficient supplies
of penicillin for chemical research, which is not surprising given that
production did not take off until 1943. 
