Penicillin: Pharmaceutical Companies: Cooperation & Competition

Even with the growing interest of the pharmaceutical industry and U.S. government alike, several obstacles still stood in the way of the mass production of penicillin. Penicillin, a naturally occurring substance, posed several production difficulties. For instance, Fleming and subsequent penicillin researchers recognized the compound's temporal and pH-dependent instability (Wainwright, 1996, 15). In 1939-1940, Heatley, in addition to his improvised culture vessels and back-extraction technique, developed a quantitative assay procedure-the "cylinder plate" or "penicillinder" (Moberg, 734). This method, despite penicillin's instability, facilitated the production of enough of the substance to initiate clinical trials at Oxford. The assay procedure, as well as Heatley's "…introduction of a defined unit of penicillin activity," contributed significantly the eventual development of penicillin-innovations that he shared with the NRRL and Merck upon his visit to the U.S. in 1941 and that subsequently spread throughout the industry (Hobby, 82; Helfand, et al., 42). [Moberg does not include visuals of Heatley's innovations. Where might we locate these?]

Nonetheless, penicillin remained a problematic compound. Penicillin cultures sometimes became contaminated. Moreover, there was the problem of insufficient yields, as reflected in the high cost of penicillin (Swann, 159). As noted above, the NRRL's efforts to overcome these production difficulties lent it a pivotal role in the movement towards the mass production of penicillin. Its development of more productive strains, a more effective growth medium, and more efficient submerged fermentation methods complemented advances made by private industry. For instance, as noted earlier, Pfizer had experience with submerged fermentation. Specifically, in 1929, James Currie and several other researchers working at Pfizer evaluated submerged versus surface fermentation in the production of gluconic acid (Hobby, 178, 183). The submerged process proved a success. From 1941 on, Pfizer, due in part to the knowledge gained from this earlier development, concentrated on developing means of penicillin production in large tanks or vats to work in combination with the production improvements made by the NRRL (Hobby, 96). Merck subsequently began converting its cylindrical steel vessels, in which flat pans had been placed for surface culture growth, into deep fermentation tanks with a 750-gallon capacity (Helfand, et al., 43). [I believe Erin has pictures of these tanks from several articles and advertisements (speak with her for citations). Have they already been scanned?]

Although Pfizer and other pharmaceutical companies recognized that in order for production to be possible economically they must pursue submerged growth methods, they nevertheless continued to produce the substance via surface fermentation in flasks, bottles, and trays. Though this stationary surface process demanded vast amounts of media surface area as well as high capital and labor costs, it allowed them to fulfill at least some of the immediate needs the medical profession and armed forces while they developed effective submerged technology (Helfand, et al., 43; Hobby, 183). Despite the advances of the NRRL and Pfizer's research group over a decade earlier, it seems that these contributions did not have "immediate industrial applicability" (Swann, 159).
The persisting penicillin growth difficulties, particularly those associated with fermentation, as well as the growing civilian and military pressures for the drug led Richards and the CMR to look elsewhere for a production solution-namely, to synthesis (Helfand, et al., 47). The study of the chemistry of penicillin began soon after its discovery, and by 1943, Great Britain and the U.S. realized that each possessed a distinct form of penicillin (Swann, 169). After this key observation, American and British scientists were able to isolate three major degradations products of penicillin and had synthesized two of these by the end of 1943 (Swann, 171). Encouraged by these results, by Squibb's crystallization of the sodium salt of penicillin, by the promising clinical findings of the NRC's Committee on Chemotherapeutic and Other Agents (COC), and by the fear that natural fermentation would not be able to provide for penicillin needs, the U.S. and British governments initiated collaboration on a synthesis project (Richards, 445; Helfand, et al., 47). [For a document reflecting the CMR's recommendation to move ahead with synthesis, see letter, A. N. Richards to Vannevar Bush, 14 August 1943, National Archives, Record Group 227, OSRD, Office of the Director, Special Subject File, Penicillin, February-September 1943 (taken from Helfand, et al., 47, note 73).]

On Richards's recommendation, Bush appointed a penicillin advisory committee on November 17, 1943 to examine which organizations and companies within the U.S. should be selected to partake in the penicillin synthesis project. In a response to an October 2, 1943 letter from Richards, George Merck, speaking for his company as well as for Squibb and Pfizer, agreed to continue research at their own expense and to collaborate among themselves and with British researchers. He did, however, suggest that building new facilities and involving too many companies, especially those without proven scientific capacity, would be unwise (Helfand, et al., 47). Richards, without waiting for Merck's response, contacted fourteen additional companies. The advisory committee, which consisted of Hans T. Clarke, a Columbia University biochemist, Coghill, and Roger Adams, a University of Illinois organic chemist, selected ten of the seventeen suggested companies (Swann, 163). In addition, the synthesis program involved several unaffiliated companies, five British firms, and several government agencies, universities, and research foundations on both sides of the Atlantic (Swann, 164; Helfand, et al., 48).

The advisory committee selected the ten pharmaceutical companies based on three criteria. The company must have been in "…possession of personnel and facilities especially appropriate for research on synthetic methods, [it must have had] interest in the development of penicillin demonstrated by having engaged in extensive studies of production methods [or] chemistry during the early days of the problem, [and it must have had] experience and demonstrated success in the manufacture of synthetic chemicals, especially for pharmaceutical purposes" (Swann, 163-164). Despite George Merck's opinion that involving companies that lacked the experience of firms such as Merck, Pfizer, and Squibb would prove a waste of resources, newcomers were included in the synthesis project and thus "[the] perceived needs of the total effort and the national effort won out" (Helfand, et al., 48). [The criteria for selection-Swann, 163-164, note 28-are taken from H. T. Clarke, Roger Adams, and R. D. Coghill to the Director of the OSRD (memorandum), 19 November 1943, National Archives, Record Group 227, OSRD, Office of the Director, Special Subject File, Penicillin, October-December, 1943-copy in Kremers Reference Files (KRF), F. B. Power Pharmaceutical Library, University of Wisconsin, Madison, Wisconsin.]

Given the involvement of pharmaceutical companies, government agencies, and research organizations, a means of coordinating the exchange of information proved necessary. According to the contracts formed in December 1943-January 1944 between the government and these companies and research foundations, who were referred to as "Contractors," the OSRD assumed the task of facilitating information exchange in addition to its other responsibilities discussed in The Federal Bureaucracy section (Swann, 165). The companies, agencies, and foundations working on the problem of synthesis forwarded monthly reports to the OSRD, including "[all] information obtained on the purification, structure, and synthesis of penicillin or a therapeutic equivalent…" (Swann, 166). At its discretion, the OSRD then "…[passed these] reports on in such a way as to advance the problem of synthesis" while simultaneously protecting all interests (Swann, 164; Helfand, et al., 47). [With regard to the contracts referred to in Swann, 165, note 34, an untitled, unsigned copy of the contract between the government and Squibb can be found in the National Archives, Record Group 227, OSRD, Office of the Director, Special Subject File, Penicillin, October-December 1943, copy in KRF. This contract is similar to the contracts with other firms-see Irvin Stewart, Organizing Scientific Research for War, 339-346, Appendix Two (we have this). The above-mentioned National Archives citation also contains correspondence that may be relevant, such as a 19 November 1943 letter from J. T. Connor to A. B. Hastings and a 16 December 1943 letter from J. T. Connor to H. T. Clarke (see Helfand, et al., 55, note 75).]

The contracts also included patent provisions. First, "…the OSRD had the right to require the Contractor to grant non-exclusive licenses to other contracting organizations for its patentable discoveries. [These] licenses were subject to reasonable royalties, which could not exceed five percent of the lowest net wholesale price the licensee charged for the product" (Swann, 166). Second, in times of threat to national defense, the Contractor was obligated to provide non-exclusive, royalty-free licenses to the government. Lastly, the contracts "…contained the extraordinary provision that the determination of ownership of patent rights, originating from inventions in the United States, should be made by the director of the OSRD" (Richards, 445). Bush "…assured the firms that he could appreciate the resources invested by both the ultimately successful inventors and the organizations that had already uncovered much relevant information" (Swann, 166). Despite the central role played by commerce and academic research in penicillin synthesis, the government nonetheless retained considerable authority, as evident in the OSRD's information exchange and patent determination responsibilities. [For Bush's perspective towards patent granting, see Vannevar Bush, [Transmittal Letter Accompanying Each Penicillin Synthesis Contract], 2-3, National Archives, Record Group 227, OSRD, Office of the Director, Special Subject File, Penicillin, October-December 1943, copy in KRF (taken from Swann, 166, note 38-in addition to the contract citation above).]