Penicillin: Pharmaceutical Companies: Cooperation & Competition
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 "
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
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
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).
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 "
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,
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, "
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 "
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 "
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).]
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