Penicillin: Pharmaceutical Companies: Technical Challenges

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.

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
corner (Neushul, 387). [Taken from Memorandum from James C. Biller to Robinson Newcomb, 27 November 1943, National Archives, WPB, Record Group 179, 533.81405 (Neushul, 387, note 54).]

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.]