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235（ 15 ）Historical and hygienic aspects on roles of quality
requirements for antibiotic products in Japan:
Part 5 - Introduction of technology and knowledge
on streptomycin production fromthe United States of America
MORIMASA YAGISAWA1), PATRICK J. FOSTER2) and TATSUO KUROKAWA1,3)
1)

Division of Drug Development & Regulatory Science,
Keio University Faculty of Pharmacy
2)
Division of Basic Education in Arts & Sciences,
Keio University Faculty of Pharmacy
3)
Present afﬁliation; Japan Self-Medication Industry(Received for publication May 2, 2016)

In order to investigate the roles of quality requirements for antibiotics products inJapan, from historical and hygienic aspects, we examined how technology andknowledge in the production and quality control of streptomycin were introduced
from the United States of America.
In this study, through detailed investigations and analyses, it was conﬁrmed thatthe introduction of technology and knowledge on streptomycin was strongly
supported by Brigadier General CRAWFORD SAMS, the chief of the Public Health andWelfare Section (PHW) of the Supreme Commander for Allied Powers/General
Headquarters, via the Ministry of Welfare in Japan.
Dr. SELMAN WAKSMAN, the discoverer of streptomycin, along with scientists of
Merck & Co., also helped Japanese industries extensively, via PHW, by providing
the original streptomycin-producing strains and transferring expertise in
streptomycin production.
With the technology and knowledge being introduced from the USA, domestic
production of streptomycin preparations increased very rapidly. As noted in ourprevious report, domestic production reached amounts enough to satisfy national
demand within three years. Japanese people have a racial tendency to be highly
susceptible to tuberculosis known as an incurable national disease. Thanks to
streptomycin therapy, the tuberculosis mortality rate (per 100,000 population) had
fallen dramatically within only ﬁve years from 187.2 in 1947 to 82.2 in 1952.
Dedicated to pioneers in antibiotic research of Japan on the occasion of the 70th anniversary of Japan
Antibiotics Research Association established on the 26th August of 1946.

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Introduction
Industrial production of penicillin in Japan reached an amount sufﬁcient enough to ﬁll domestic demand within a three-year period, as described in our preceding report1), under the strong
support of Colonel CRAWFORD F. SAMS, the chief of the Public Health and Welfare Section (PHW)of the General Headquarters, along with the Supreme Commander for the Allied Powers (GHQ/
SCAP), who established the plan2) for improving the healthcare system in a devastated post-wartorn country.
Penicillin contributed greatly to the health maintenance of the Japanese people by showing
remarkable effects against life-threatening infectious diseases such as septicemia, endocarditis,
pneumonia, meningitis, and tetanus. However, it was ineffective against tuberculosis which was
the number one cause of death in Japan around 1947, with a mortality rate3) of 187.2 per 100,000of the population. Tuberculosis was known as an incurable Japanese national disease and bed rest
therapy was the sole treatment for the disease prior to 1950.
For the PHW, gaining control of tuberculosis was an important issue for reasons related tocarrying out the occupation policies of the GHQ/SCAP, as well as maintaining the health of thestationed soldiers. Measures were also undertaken to consolidate the national sanatoriums andprevent the spread of TB by use of BCG inoculations. The PHW decided to promote domestic
streptomycin production for the purpose of tuberculosis suppression, especially in light of thehigh evaluation of the prior achievement of domestic penicillin production in Japan within a shortperiod of time. The detailed involvement of the PHW in the establishment and promotion of the
penicillin industry in Japan was veriﬁed and described1) in Part 3 of our preceding report.
In this report we shall discuss the background and process of the introduction of the technology and knowledge in streptomycin production from the United States of America (USA), underthe extensive support of the PHW.

I. Methods of Investigation
The general method for resource acquisition was described in detail in the ﬁrst report4) of ourinvestigation.
The original results of Japanʼs own research in streptomycin production and the details of theimport of streptomycin preparations from the USA were obtained from the daily records of theJapan Penicillin Research Association (JPRA), published periodically in the Journal of Antibiotics.
The details of the transfer of information on streptomycin research in the USA were obtained
from the Weekly Bulletin5) of the PHW, with the permission of Professor SUGITA of Oita University who reproduced the documents.

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237（ 17 ）The acquisition of documents on the achievement of domestic production of streptomycin
was described6) in Part 2 of our preceding report.

II. Results
In the course of exploratory research on novel antibiotics produced by soil actinomycetales,
Dr. SELMAN A. WAKSMAN and his research group at Rutgers University discovered7) streptomycin
possessing activity against the tubercle bacillus in the culture broth of a strain of Streptomyces
griseus in 1944. The therapeutic effect of streptomycin on human tuberculosis was conﬁrmed
by Dr. H. CORWIN HINSHAW and his group8,9) at Mayo Clinic in 1946.
Dr. JACKSON W. FOSTER, a student of Dr. WAKSMANʼs, was well-informed about the discovery
of, and the clinical trials with, streptomycin prior to his arrival1) in Japan as a consultant on penicillin production. When Dr. FOSTER received a report that the penicillin plant at Merck & Co.,
constructed by him during wartime, was also being applied toward streptomycin production, hegave a lot of information pertaining to streptomycin research to Dr. HAMAO UMEZAWA, of the Research Institute for Infectious Diseases (RIID) of Tokyo Imperial University. At the farewell party
for Dr. FOSTER, held in March of 1947 for the occasion of his return to the USA, he informed10)
Japanese scientists about the necessity to begin preparations for the domestic production of streptomycin.
1. Attempts to produce streptomycin by Japanʼs own technology
The Division of Antibacterial Substances (DAS) was established1) in the newly organized
National Institute of Preventive Medicine and Hygiene (NIPMH) in May of 1947 and Dr.
UMEZAWA was appointed the director of the division. Exploratory research on new antibiotics produced by soil actinomycetes was conducted at the division and isolation11) of “a streptomycin-like
substance” was reported at the 10th Research Meeting of JPRA held on the 18th of July 1947. The
substance was later conﬁrmed12) to be streptomycin and the producing strain was identiﬁed13) tobe S. lavendulae, which was different at the species level from WAKSMANʼs strain (S. griseus).
From the division, some novel methods for the rapid identiﬁcation of streptomycin-producing
microorganisms were also reported13,14).
Toward the domestic production, exploratory research to isolate streptomycin-producing
strains was conducted for about two years at several laboratories in universities and pharmaceutical industries. Although some results were reported, no suitable strain for industrial production
was able to be obtained15). In those days, the patent system applicable for microbial products obtained by fermentation was a so-called “process patent” and different from todayʼs “substance patents.” Under the “process patent,” one may commercially produce a particular microbial productfrom a strain belonging to a different species of the same genus described in prior patents without

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conﬂiction. Under such circumstances, active research to obtain different strains, other than
WAKSMANʼs S. griseus, was conducted16,17) with the aim of producing streptomycin domestically.
The PHW evaluated highly the development of domestic penicillin production, which had attained a monthly output of 50 billion units within two years of the introduction1) of US technology through the lectures of Dr. FOSTER. The manufacturing of crystalline penicillin G18) with a purity of 90% or above was also noteworthy. Therefore, the PHW created a plan to promote thedomestic production of streptomycin as the second antibiotic drug in Japan.
Taking the intention of the PHW into consideration, the Pharmaceutical Affairs Bureau(PAB) of the Ministry of Health and Welfare (MHW) convened experts in penicillin production,from approximately 10 pharmaceutical companies. On the 16th of September 1948, they discussed19) the logistics for streptomycin research and conditions necessary in order to begin streptomycin manufacturing at an industrial scale at each company. Thereafter, the Preventive Medicine Bureau (PMB) of the MHW convened20) a board of scientists and physicians, under theattendance of the chief of the Bureau and directors of related Divisions, to discuss how to initiate
measures on streptomycin research. The participants involved were as follows: Drs. ROKUZOKOBAYASHI, HAMAO UMEZAWA and KEN YANAGISAWA of NIPMH, TEIJIRO YABUTA and YUSUKE SUMIKI of
the Department of Agricultural Chemistry (DAC), Faculty of Agriculture (FA), the University ofTokyo (UT), MORIZO ISHIDATE of the Pharmaceutical Institute, Medical Faculty of the UT, HAJIMETAMURA of the Department of Urology, Keio University School of Medicine, HIDEJIRO HARUKI of
the National Nakano Sanatorium, and YUKIMASA YAGISAWA of the JPRA.
Pilot production of streptomycin had been conducted, with the lead taken by NIPMH, and arequest21) given to the JPRA from the Ministry of Education, Science and Culture (MESC) to divide some portions of the Grant-in-aid for Scientiﬁc Research (GASR) provided, in the amount of¥3 million for the ﬁscal year of 1948, and apply it towards streptomycin research. The prospect
on the progress of streptomycin research was described22) in an application form to the GASR of
the MESC for the ﬁscal year of 1949. It noted that pilot production should be accomplishedwithin one yearʼs time, with an additional year necessary until the supply for commercial products by industrial processes could be reached.
While the pilot production of streptomycin at the DAS of the NIPMH progressed smoothly,some difﬁculties did occur during the production by submerged culture, utilizing steel tanks for
penicillin production, affecting the potency. Potency by submerged culture reached as low as 150
units/mL, but eventually 300 - 800 units/mL was attained via the shake-culture in glass ﬂasks.
After several repeated failures, the reason for the low productivity was elucidated23). Ferrous ions,dissolved from the penicillin tank made of steel, interrupted streptomycin formation. It was later
conﬁrmed that either rubber coating or tinning of the steel tanks, or the use of stainless steeltanks, were effective10) remedies to eventually attaining higher production potencies.

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239（ 19 ）2. Import of streptomycin preparations and establishment of the Research Council on
Streptomycin
While verifying the effects of streptomycin via the results24) of the clinical trials among
3,032 tuberculosis patients in 48 hospitals, conducted for two years since June 1946 by the US
Veterans Administration, the PHW distributed streptomycin preparations. The distributions were
included in the relief 25) supplies of the “Licensed Agencies for Relief in Asia; LARA (started
from March 1946)” to speciﬁed hospitals throughout Japan. The clinical results of the distributed
streptomycin preparations were reported26,27) at meetings of the JPRA expert committee held in
June and September of 1948, under the titles of “Clinical cases treated with the streptomycin of
the Gift-packages.”
It was described15) in the PHW Weekly Bulletin, for the period of early January 1949, thatcommercial streptomycin production was expected to reach a volume adequate to satisfy the minimum needs in Japan by the end of that year. Furthermore, in order to supply enough streptomycin until domestic preparation became available, the PHW inquired with the US Government
about the possibility of importing sufﬁcient amounts of streptomycin preparations for the treatment of Japanese tuberculosis cases. The request was approved by the US Government and theﬁrst shipment was scheduled to arrive in Japan within one month to six weeks. The PHW also
described, by means of devoting large spaces of the bulletin publication, summaries of the abovementioned clinical trials24) conducted by the US Veterans Administration, along with informationon the usefulness of chest X-rays, characteristics of tuberculosis in various organs, and the adverse effects of streptomycin.
The anticipation of the Japanese people for the efﬁcacy of streptomycin was very great. At
the Committee on Health and Welfare of the House of the Councillors of the 5th Session of theDiet, held on the 17th of March 1949, Mr. KATSUMA KOBAYASHI, a member of the House belonging
to the Democratic Party of Japan, submitted a memorandum28) of questions under the title of“regarding streptomycin - the wonder drug for tuberculosis.” It inquired about (1) reports on experiments or clinical cases concerning streptomycin efﬁcacy, (2) records of the distribution of imported streptomycin, (3) the situation of domestic streptomycin production, i.e. names offactories, their abilities and expected time frames for marketing, and (4) future intentions for thepromotion of streptomycin production. Interestingly, the written answer29) was sent under
the name of Mr. SHIGERU YOSHIDA, the Prime Minister, and not under the name of Mr. TAKEO
KUROKAWA, the Minister of the MHW. In response to the second question, it was mentioned that
streptomycin preparations in the amount of 200 kg (for 5,000 patients), slotted for import at theend of March, would be distributed in accordance with advice given by the Research Council on
Streptomycin (RCS) to national hospitals, national sanatoria, medical institutions, and general
hospitals. Beside such clinical uses, some portions for fundamental research would also be distributed to research institutes, including the DAS of the NIPMH, universities, national hospitals,

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and national sanatoria.
In reality, 209 kg streptomycin preparations were ﬁrst imported at the end of March 1949. It
was equivalent to 5,225 cases to be treated, since the total dose for one patient was 40 grams. The
price was set as low as $1.30 (¥351.-) per gram and the total cost of the import came to$271,70000, equivalent to ¥73,359,000.- (at the exchange rate of $100 ＝ ¥270.-). At that time theJapanese government did not have enough “foreign exchange allocation,” therefore payment30)
was settled by the Government Appropriation for Relief in Occupied Area (GARIOA) fund under
the discretion of GHQ/SCAP.
The MHW established the RCS for the purposes of the appropriate distribution of imported
streptomycin and the promotion of both fundamental and industrial research on streptomycin production.
A notice31), jointly signed by chiefs of the PMB and the PAB of the MHW, was issued to prefectural Governors describing the background of the imports and the purposes for the distributionof streptomycin. Also included were instructions for the methods of patient selection, regimen
creation, and the evaluation of clinical effects. In the notice, exceptionally deep gratitude was expressed to GHQ/SCAP for the courtesies of setting the price extremely low and allotting the
GARIOA fund expressly for the purchase of streptomycin preparations. These chiefs were
responsible, at that time, for the control of tuberculosis, which was the leading cause of deathnationally. Records32) showed the number of newly afﬂicted patients at 465,000 (morbidity rate of
565.7 per 100,000 population) and the number of deaths at 138,000 (mortality rate of 168.8 per
100,000) in 1949. Import of the “wonder drug - streptomycin” was very helpful in carrying out
their disease control duties.
At the inauguration ceremony of the RCS, held at the auditorium of the RIID of the UT on
the 21st of June 1949, in the presence of the Minister of the MHW, Brigadier General SAMS (promoted in April 1948) delivered a speech30). The speech revealed that the necessary amount ofstreptomycin in Japan was 15,000 kg per year and that the total amount of imported streptomycin
was 600 kg. Since this was only 1/25 of the demand, an increase in efforts to archive domestic
commercial production was necessary.
The clinical trials of the ﬁrst imported streptomycin was conducted by 31 members of the
RCS at 20 hospitals/sanatoria during May - October 1949 and the results of 679 cases were as
follows33): effective 474 [69.9%; cure 71 (10.5%) and remission 403 (59.4%)], persistence 139(20.4%), deterioration 14 (2.1%), and deaths 52 (7.6%). It should be noted that the preparation
used for the trials was streptomycin trihydrochloride-calcium chloride double salt made by Merck& Co. and the package insert for the preparations was translated into Japanese34) and distributed
to the hospitals/sanatoria involved in the trials.
A total amount of 400 kg streptomycin (equivalent to an amount adequate for 10,000 patients) arrived on the 7th of October 1949, as the second import. The exchange rate was revised toAug. 2016

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241（ 21 ）be ﬁxed at $100 ＝ ¥360.- starting from the 1st of April 1949 and the price of streptomycin for thesecond import was $194 (¥700.-) per gram. Therefore, the sum came to ¥280 million, which was
equivalent to 0.04% of the general account budget of Japan (¥699.4 billion) for the ﬁscal year of
1949.
The imported streptomycin preparations were stored at the warehouses of 12 pharmaceuticalcompanies35) responsible for distribution (100 kg at Takeda Chemicals, 50 kg at Shionogi, 30 kg
each at Tanabe Pharmaceutical, Fujisawa Pharmaceutical, Yamanouchi Pharmaceutical, Dainippon Pharmaceutical, and Daiichi Pharmaceutical, and 20 kg each at Sankyo, Torii Pharmaceutical,
Tokyo Tanabe, Banyu Pharmaceutical, and Nakamura-Taki Pharmaceutical). These streptomycin
preparations were scheduled to be distributed to 9,200 patients throughout Japan (e.g., Tokyo
911, Osaka 490, Fukuoka 469, Kanagawa 390, Aichi 370, Chiba 322, and Kyoto 315 patients).
Facilities (national sanatoria, national hospitals, and university hospitals) to accommodate thesepatients, along with the number of patients for each prefecture and speciﬁc facility sites depending on the number of available tuberculosis therapy experts, were designated by a notice36) issued
by the chief of the PAB of the MHW.
3. Initiation of streptomycin production with the support of the PHW
The plan listed for 1949, by the PHW, to produce streptomycin on an industrial scale was approved by GHQ/SCAP and the MHW recognized the usefulness of streptomycin for tuberculosis
treatment. A target was set to produce streptomycin domestically in sufﬁcient amounts to ﬁll minimum demands by the end of 1949.
However, it was described15) in the PHW Weekly Bulletin that there existed no appropriate
strain for the use of commercial streptomycin production, despite extensive research on streptomycin having been conducted for approximately two years at several laboratories in Japan. Under
such circumstances, the PHW obtained two S. griseus strains for producing streptomycin from
Dr. WAKSMAN and passed them on to the NIPMH on the 28th of December 1948. It was also mentioned that the provided strains were patent protected property of the Rutgers Research and Endowment Foundation (RREF), being used throughout the world for the commercial production of
streptomycin. Therefore, a license agreement would be necessary between any company involved
and the RREF, when commercial production commenced under the supervision of the NIPMH.
In the same PHW Weekly Bulletin, it was mentioned15) that the supply of these strains was inresponse to a request by the Japanese Government to GHQ/SCAP and not at the suggestion of thePHW. Such an approach by the PHW, to state independent status from the Japanese Government,
was consistent with the expectations of the initial invitations of Dr. FOSTER for penicillin production and suggests the basic idea of the occupation policy of GHQ/SCAP.
In the early stages in Japan, research on the production and clinical applications of streptomycin was promoted by the GASR of the MESC and remarkable accomplishments were ob-242（ 22 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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tained. In the ﬁscal year of 1949, ¥6.2 million, out of a total of ¥7.0 million allotted to antibiotic
research37), was divided up for different categories of streptomycin research: ¥4.5 million for production, including ¥2.0 million for running costs of the pilot plant, ¥1.5 million for clinical investigations, and ¥0.2 million for administrative purposes.
At the ﬁrst meeting30) of the Production Division of the RCS (PD-RCS), scheduling perspectives were sought for the start of tank-fermentation and prospective yields for domestic commercial production by March of 1950. Research subjects were categorized into 1) collection ofstrains, 2) cultivation, 3) puriﬁcation, 4) facilities for culture and puriﬁcation, and 5) assay. A notable discussion took place at this meeting regarding the US strains S. griseus 18-16 (strain No.
R4-3463) and its progeny strain No. R4-3475, both of which originated from WAKSMANʼs laboratory10,38). The maximum amount of streptomycin production was as low as 100-200 units/mL.
Subsequently, the PD-RCS requested that the PHW, through the MHW, provide better quality
strains enabling higher streptomycin productivity. The request made with GHQ/SCAP and the research institutes in the USA (i.e., WAKSMANʼs laboratory at Rutgers University and the researchlaboratory of Merck & Co.), recognized that the Japanese research group already possessed13, 23)
the necessary techniques and requisite knowledge to produce streptomycin on a large scale.
At the second meeting39) of the PD-RCS, held on the 22nd of July 1949, the DAS of the
NIPMH requested that 40 g of the imported streptomycin be provided monthly in order to establish a national certiﬁcation procedure and the “Minimum Requirement of Streptomycin.” The latter was under preparation by referring to the provisions on streptomycin drugs described in the
Code of Federal Regulations Title 21, issued by the U.S. Food and Drug Administration (FDA).
It was also decided, at the same meeting, to provide a considerable part of the experimentally produced streptomycin to Dr. MORIZO ISHIDATE for his research on the synthesis of streptomycin derivatives. The initiation of the derivative synthesis at such an early stage might be due inpart to the tradition of the “creation of novel drugs” in Japanese pharmaceutical sciences (since
the time of Dr. NAGAYOSHI NAGAI40), the ﬁrst president of the Pharmaceutical Society of Japan)
and by a desire to avoid already known adverse reactions to streptomycin.
At the third meeting41) held on the 17th of September 1949, it was decided among the sevenlaboratories in charge of the improvement of the strains and culture methods, to compare the twostrains from WAKSMANʼs laboratory and the thirteen strains isolated domestically by use of theculture media invented by Dr. WAKSMAN and the media created at the individual laboratories. As
an interim report on the isolation of the producing strains from over 1,000 soil isolates, one strain
was found to produce 300 units/mL or more streptomycin by a shaking culture method. A successful strain improvement was also reported on the WAKSMAN strains by the UV-right irradiationand mono-spore isolation techniques. Regarding puriﬁcation, it was reported that the applicationof ion-exchange resin was promising. Additionally, a chemical conversion of streptomycin into
dihydrostreptomycin by a novel catalytic reduction under normal pressure was reported.

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243（ 23 ）At the fourth meeting42) held on the 16th of December 1949, the results comparing the 15
strains distributed at the previous meeting were reported to have attained a production of 500 1,100 units/mL streptomycin, but became unstable upon reaching 1,200 units/mL or above. Furthermore, some of the newly isolated strains from the soil were found to produce 460 - 900 units/mL streptomycin. Such results were comparable to those published during the period from 1947
to 1949 by the US Pharmaceutical companies (i.e., Drs. ALFRED R. STANLEY43) of Commercial Solvent, GEORGE M. SAVAGE44) of Upjohn, and MAX TISHLER45) of Merck & Co.). It could be said thatthe bleeding technology for antibiotic producers in Japan had already reached a comparable levelto that of the USA at the time. On the other hand, in the experimental production at the pilot
plant, strain Y-41 yielded 300 units/mL streptomycin in submerged culture using a stainless or
tinning tank.
At the sixth meeting of the PD-RCS46) held on the 26th of June 1950, the production yields
were reported to be approximately 990 units/mL by shaken culture in ﬂasks and constantly
around 500 units/mL by submerged culture in tanks. Regarding puriﬁcation, while the crude powder obtained by the charcoal absorption method possessed a potency of 180-280 units/mg, thoseobtained by the method of combination of charcoal absorption and solvent extraction possessed
340-490 units/mg. Those obtained solely by the method of solvent extraction possessed 460-530
units/mg; those by the ion-exchange method possessed 538-819 units/mg. In particular, in theion-exchange method, the carboxylic cation exchange resin developed by Mitsui Chemical
showed remarkable efﬁcacy when compared to the usual sulfonic cation exchange resin in the puriﬁcation of streptomycin.
4. Governmental purchasing of the domestically produced streptomycin
Having a strong conviction that the manufacturing technology of streptomycin had been adequately established and that domestic commercial production was close at hand, the 3rd YOSHIDA
Cabinet decided47), on the 22nd of September 1949, that 1) it was necessary to establish a way forthe domestic production of streptomycin to proceed in order to secure a stable supply, 2) in taking
measures in preparation for domestic production, advanced technology and appropriate facilities
would be introduced from the USA with the Government supporting costs and material procurements, and 3) the budget to purchase domestically produced streptomycin be duly appropriated.
Responding to the cabinet decision, the MHW took budgetary steps to purchase the domestically produced streptomycin. Meanwhile, several companies belonging to the PD-RCS conductedpilot production of streptomycin by tank fermenters and submitted applications for the approvalof commercial production to the MHW. In April of 1950, the MHW gave approval to ﬁve companies, Meiji Seika, Kyowa Fermentation, Kaken, Nikken Chemical, and Shimane Chemical, forthe commercial manufacture of streptomycin and eagerly encouraged domestic production.
Meiji Seika began fundamental studies on streptomycin48) in September of 1947, initiated244（ 24 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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test production by pilot tanks in July of 1948, requested the formulation of governmental policy
to promote domestic production at a hearing by the MHW held in September of that same year,
and played important roles in the PD-RCS since its establishment in September of 1949. At thiscompany, two sets of 46-ton tanks for the production of streptomycin were operated in 1950.
Kyowa Fermentation had substantial experience in penicillin production by use of Japanʼslargest tank, 4 tons in size, since September of 1947; attainment of a monthly penicillin manufacture of 1,000 vials of 30,000-unit preparations was reached in April and 14,000 vials of 100,000unit preparations in December of 1948. This company began fundamental studies on streptomycin in September of 1948 and aimed to initiate commercial production by three 2-ton tanks with aproducing strain supplied from Dr. TOSHINOBU ASAI of the DAC-FA-UT. In 1950, three 8-ton tanks
began operations producing streptomycin (reported by Dr. SHUKURO KINOSHITA, in personal communications).
Kaken initiated their fundamental studies on streptomycin in April of 1948, began test production by a 200-liter tank in November of the same year, and sent leading scientists of that time(Drs. TEIJIRO YABUTA, KINICHIRO SAKAGUCHI, and YOSHITOSHI OYAMA) to the PD-RCS as core committee members. Independent from the RCS plan to establish a pilot plant, Kaken built its own
pilot plant equipped with three 600-liter tanks and started their operation in October of 1949. Thisinitiative took place under the presidential leadership of Dr. YOSHIO NISHINA. Commercial production using these tanks started on the 1st of May 1950. During the ﬁrst-half of 1950, the total production of streptomycin was only 200 g, but when operation of the three 6-ton tanks was started
in October 1950, the total production for the second-half of the year reached 71.4 kg. Three 60ton tanks were constructed and began operation on the 27th of September 1951; maximum production of these tanks was recorded to have reached 2,300 units/mL using the producing strain
Ku-M11-106 (as reported by Dr. SHIGEO FUJITA, in personal communications).
The ceremony49) for the ﬁrst governmental purchasing of domestically produced streptomycin was held on the 18th of July 1950, in the Ministerʼs room at the MHW. In attendance were the
Minister, chiefs and directors of the responsible Bureaus and Divisions of the MHW, Brigadier
General SAMS and Dr. BAND of the PHW, and representatives of the ﬁve companies who produced
the streptomycin. A total of 1,160 vials containing 1.0 g (potency) of streptomycin trihydrochloride were purchased; 1,000 vials produced by Meiji Seika and 40 vials each by Kyowa Fermentation, Nikken Chemical, Kaken, and Shimane Chemical.
An outline of the purchasing process was noted50) by the PAB of the MHW, on the 6th ofOctober 1950. It was indicated by the buying plan as outlined in Table 1A. The actual results ofthe domestic production and purchase, by the end of September of 1950, were also noted (Table
1B). In addition, the plan to import streptomycin preparations for three quarters, from July 1950
to March 1951, was referenced (Table 1C). The reported ratios of the amounts of domestic production (Table 1A) to that of the imported preparations (Table 1C) were at 1/80 (Quarter 1) - 1/9

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245（ 25 ）Table 1. Outline of the purchasing of domestically produced streptomycin(Quarter 3). As reference information, the transition51) of streptomycin production in these ﬁvecompanies during the second-half of 1950, along with the size of the equipped tanks, was also
published (Table 2).
5. The introduction of US technology under contracts
The PHW convened a conference52) on streptomycin, on the 10th of March 1950. Responsible ofﬁcers of the MHW and representatives of the RCS and pharmaceutical companies were inattendance. Brigadier General SAMS explained, in detail, the results of the search for and negotia-246（ 26 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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Table 2. Monthly production of streptomycin (second-half of 1950)

tions on the introduction of technology for streptomycin production from the USA to Japan. In
the USA, six companies were manufacturing streptomycin under individual patents and there
were three ways to introduce the technology: (1) purchase and subdivide the bulk, (2) purchase
inexpensive crude material and purify it, or (3) enter into a special contract with a US company,
under the supervision of GHQ/SCAP, to transfer the expertise on streptomycin production. For
the third option, it was thought to be possible to invite a technical expert from a US company as
an advisor to the PHW and, depending on the results of site visits by the expert, make a special
contract with the company.
Another conference52) on streptomycin, organized by the MHW, was held on the 14th ofMarch 1950. In attendance, were the Administrative Vice-Minister and chiefs of the responsible
Bureaus of the MHW, Drs. BAND, PAYNE, and BOZEMAN of the PHW, Drs. SUMIKI, UMEZAWA andYAGISAWA of the RCS, and representatives of various pharmaceutical companies (Meiji Seika,
Kyowa Fermentation, Kaken, Nikken Chemical, Takeda Chemicals, and Shionogi). Mr. EULER,
the Vice-President of Merck & Co., received a special invitation in order to share the current stateof streptomycin manufacturing in the USA and to take questions pertaining to the subject area ofspecial contracts. Merck & Co. had several advantages in streptomycin production. Among them:patented expertise on the crystallization of streptomycin trihydrochloride-calcium chloride double
salt (SM-HCl-CaCl2), removal of histamine-like depressants with phenol, puriﬁcation of streptomycin by carboxylic cation exchange resin (Amberlite IRC-50), and synthesis of dihydrostreptomycin by reduction with platinum catalysts.
The MHW, the RCS, and representatives from various pharmaceutical companies reached aAug. 2016

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247（ 27 ）consensus on how to introduce the know-how on streptomycin production from a US company
under special contract and Merck & Co. was selected to be the candidate partner. Responding to
the request of the PHW, Dr. ADDINALL (Foreign Scientiﬁc Manager) and Dr. COLIN, (director of
Pilot Plant Division) of Merck & Co. came to Japan on the 3rd of May 1950. They visited53) andinspected prospective counterparty factories and other related companies through the 23rd of May.
Related companies included Mitsui Chemical, Kaken, Meiji Seika, Mitsubishi Kako Instrument,
Nikken Chemical, Takeda Chemicals, Tokunaga Glass, Shionogi and Kyowa Fermentation (in theorder of visitation).
The second conference54) on streptomycin convened by the PHW was held on the same day
as the 6th meeting of the PD-RCS. Brigadier General SAMS elaborated on the opinions of Drs.
ADDINALL and COLIN, stating that they were very much impressed by the progress of the Japanesecompanies. It was speciﬁed that Merck & Co. would be able to make a contract with only one or
two companies, not with all companies, because of prohibitions under antitrust laws. Brigadier
General SAMS also mentioned that all companies were encouraged to make their own efforts to
produce streptomycin commercially by a process other than the patented method of Merck &Company.
The reason why it was necessary to make a special contract with Merck & Co. and introduce
their patented process, was that the domestically produced streptomycin trihydrochloride manifested many problems in terms of its quality and applicability for injection. Firstly, there was low
crystallinity and, consequently, low purity. It was also quite hygroscopic and yellow colored.
Administration via injection was also found to be very painful.
In contrast, SM-HCl-CaCl2 showed high crystallinity, high purity, no coloration, and wasless painful than streptomycin trihydrochloride for injection purposes. The production processesof SM-HCl-CaCl2 were covered and monopolized by the patents of Merck & Company. Therefore, a Japanese company who wished to produce the complex salt had to make a special contract
in order to gain exclusive license. The contracting party was also able to use the carboxylic cationexchange resin, Amberlite IRC-50, in the puriﬁcation steps of streptomycin and commercially
produce the synthetic derivative dihydrostreptomycin.
In the “Minimum Requirements of Streptomycin”55) released on the 20th of December 1949,
the standards for streptomycin trihydrochloride were speciﬁed to 1) contain not less than 300 μg(potency)/mg, 2) be sterile, 3) be non-toxic, 4) be non-pyrogenic, 5) be free from histamine orhistamine-like depressants, 6) contain not over 3% moisture, 7) have a pH between 4.5-7.0, and
8) be transparent in aqueous solution at 0.2 g/mL. Thus, the purity of streptomycin trihydrochloride salt was set to be equivalent to 35.6% or above (when calculated based on 842 μg (potency)/
mg being equal to a theoretical purity of 100%). The imported SM-HCl-CaCl2 made by Merck &Co. contained approximately 650 μg (potency)/mg, equivalent to a purity of around 83.4% (with779 μg(potency)/mg being equal to a theoretical purity of 100%).

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Fig. 1. A variety of streptomycin preparations

Front row from left to right: streptomycin trihydrochloride-calcium chloride double salt, streptomycin trihydrochloride,
streptomycin sesquisulfate, dihydrostreptomycin sesquisulfate, dihydrodesoxystreptomycin sesquisulfate, and a
combination of sesquisulfate of streptomycin with dihydrostreptomycin.
Back row: a box containing 10 vials of streptomycin sesquisulfate for injection.
[Properties of the Japan Antibiotics Research Association]

After intense negotiations, two companies, Meiji Seika and Kyowa Fermentation, reachedagreements for the establishment of individual contracts with Merck & Co. in February. Their introduction of foreign technology was approved56) by the Japanese Government on the 12th ofApril 1951. In Meiji Seika, both quality and productivity of streptomycin were remarkably improved48) by the processes covered in the contract. The company started production of dihydrostreptomycin in April of 1953, to replace the market use of SM-HCl-CaCl2. As the result of suchcontracts, collaborative research on streptomycin conducted among pharmaceutical companies in
the PD-RCS was terminated. The companies excluded from the contract with Merck & Co.,
namely Kaken, Nikken Chemical and Shimane Chemical (merged to Sanyo Pulp in June of1951), continued streptomycin production by means of their own independent processes.
With the technology and knowledge being introduced from the USA, the production of
streptomycin preparations at Meiji Seika and Kyowa Fermentation increased very rapidly. As
noted in our previous report6), domestic production reached amounts enough to satisfy national
demand. As a result, the import of streptomycin from the USA was discontinued in 1953 and thatof dihydrostreptomycin in 1954.
As seen in Fig. 1, a variety of preparations, namely streptomycin trihydrochloride, SM-HClCaCl2, sesquisulfate salts of streptomycin, dihydrostreptomycin, dihydrodesoxystreptomycin, anda combination of streptomycin and dihydrostreptomycin, were used clinically in Japan. However,
only streptomycin sesquisulfate remains currently in use, due to adverse reactions associated with

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249（ 29 ）the other compounds.
6. Exemption from royalties on the streptomycin patent
Following a request by Dr. WAKSMAN in 1946, Merck & Co. transferred basic patent rights on
streptomycin to the RREF. The rights had been in possession of the company under a 1939 agreement. However, Dr. SCHATZ, the co-discoverer of streptomycin, in March of 1950, brought a lawsuit against Dr. WAKSMAN and the RREF for receipt of some portion of the royalties. The case wassettled57) in December of 1950, but Dr. WAKSMAN and the RREF had a very difﬁcult time throughout the year defending against the lawsuit. It was uncertain as to why the RREF did not request
royalties on the patent for ﬁve Japanese companies who were involved in streptomycin production. Hence, it is unknown whether or not the lawsuit or courtesies from Dr. WAKSMAN played any
contributing roles.
In the midst of such confusion, around the end of September 1950, Dr. YUSUKE SUMIKI, aboard member director of the JPRA, visited Rutgers University and asked Dr. WAKSMAN to support the Japanese microbiologists in their research efforts and studies abroad. Responding to therequest, Dr. WAKSMAN proposed58) that his share (10%) of the royalty on streptomycin be waived
with the hope of promoting antibiotic research in Japan. Upon his return from the USA, Dr.
SUMIKI negotiated59) intensely with the Directors Board of the JPRA, the MHW, the Science
Council of Japan, and GHQ/SCAP to establish a research organization to manage the funds to beraised as a portion of the royalties from streptomycin in Japan.
Dr. WAKSMAN visited Japan in December of 1952 on his return home from Stockholm, where
he had just received the 1952 Nobel Prize in Physiology or Medicine. The purpose of his visit toJapan was to deliver a lecture for the centennial celebration of Dr. SHIBASABURO KITASATOʼs birth,in response to an invitation by the Kitasato Institute in cooperation with Keio University Schoolof Medicine (established by Dr. KITASATO, in 1917). During his stay, Dr. WAKSMAN also visitedseveral microbiology laboratories throughout Japan and strengthened his intentions to support capable researchers that may be hampered by ﬁnancial constraints. Building on the momentum of
this visit, the Waksman Foundation of Japan was established60) in November of 1957, with theaim of supporting and encouraging academic research on microbiology and medicine. Word washanded down that Dr. WAKSMAN was very much impressed with the quality of the domestically
produced streptomycin in Japan, containing not less than 650μg (potency)/mg (81.5% pure or
higher). This was as stipulated in the “Minimum Requirements for Antibiotic Preparations” enacted61) in March of 1952, nine months before WAKSMANʼs visit (taken from Dr. HAMAO UMEZAWAʼspersonal communications).

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III. Discussion
Japanese people have a racial tendency to be highly susceptible to tuberculosis, irrespectiveof average lifespan. Based on the WHO global tuberculosis database62), incidences per 100,000
population in 2014 were 3.1 in the USA, 5.2 in Canada, 6.0 in Italy, 6.2 in Germany, 8.7 inFrance, and 12.0 in the UK (including North Ireland). In Japan, however, it stands at 18.0. Even
now, among developed countries, the extraordinarily high incidence of those suffering from tuberculosis in Japan is widely recognized.
Thanks to streptomycin therapy, the tuberculosis mortality rate (per 100,000 population) had
fallen3) dramatically within only ﬁve years, from 187.2 in 1947 to 82.2 in 1952. Although several
cases of original Japanese research on streptomycin progressed since 1947, the support of the
PHW and GHQ/SCAP was necessary in order to achieve production of sufﬁcient amounts to ﬁlldomestic demand and control the much-feared national disease tuberculosis.
In this study, the authors investigated and analyzed (based on the documents of the PHW and
JPRA and other sources) the details of the actions taken by the PHW, under cooperation with
GHQ/SCAP and the US Government, to introduce advanced US technology for streptomycin
production in Japan. It was also conﬁrmed that the PHW extensively helped Japanese industries
in ways that would be inconceivable today. Such examples are the provision of the original streptomycin-producing strains obtained from Dr. WAKSMAN and transfer of expertise in streptomycin
production from the principal manufacturer, Merck & Company.
Additionally, the PHW intended to periodically import high quality streptomycin preparations from the USA and distribute them throughout Japan, until domestic production was satisfactory. Best efforts were also made to allot the GARIOA fund for such purchases.
In our previous report6), the achievement of domestic streptomycin production was described, along with the scope of the production transitions, production amounts, and quality standards. As a result of this study, it is possible to grasp a much larger perspective regarding the support of the PHW as related to streptomycin production in Japan.
It might be worthwhile, in the research of the history of pharmacy, to know the backgroundof such a rapid achievement of domestic streptomycin production and how the existence of PHW
policies greatly inﬂuenced the improvement of hygienic conditions in war-torn, occupied Japan.
Dr. JACKSON FOSTER, who contributed1) greatly to the achievement of domestic penicillin production in Japan, had plenty of experience with industrial scale production of antibiotics produced by soil actinomycetales, at Merck & Co. in collaboration with WAKSMANʼs laboratory at
Rutgers University. Therefore, it was inevitable that Dr. HAMAO UMEZAWA obtained, as early as
1947, a streptomycin-like substance11) from a strain of Streptomyces, after learning about promising prospects of soil actinomycetales and antibiotics produced by Dr. FOSTER.
Dr. SELMAN WAKSMAN visited, during his stay in 1952, several microbiology laboratories

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251（ 31 ）throughout Japan63) and gave guidance on how to isolate, cultivate, and identify actinomycetes
strains. Using it as an opportunity, extensive exploratory research was conducted at many laboratories and it resulted in many novel antibiotics being discovered. This time period, the 1950ʼs 1960ʼs, later became known as “The Golden Era” of antibiotic discovery. Among the antibiotics, amacrolide leucomycin (complex) 64), discovered in 1953 by Dr. TOJU HATA of the Kitasato Institute, and an aminoglycoside kanamycin65), discovered in 1957 by Dr. UMEZAWA of the NIPMH,
have been particularly regarded as masterpieces of the era.
Dr. SATOSHI ŌMURA of the Kitasato Institute elucidated66) the macrolide structure of the leucomycin components in 1967 and, thereafter, continued to expand research on macrolide antibiotics. In collaborative research between the Kitasato Institute and Merck Research Laboratories, anepoch-making macrolide compound, avermectin, and its dihydroderivative, ivermectin, were discovered67). By 2014, the antiprotozoal activity of ivermectin, particularly against ﬁlarial worms
causing river blindness (onchocerciasis) and elephantiasis (lymphatic ﬁlariasis), has protected
over 480 million African people from suffering from these diseases. For the discovery concerning
a novel therapy against infections caused by roundworm parasites, the 2015 Nobel Prize in Physiology or Medicine was awarded68) to Dr. SATOSHI ŌMURA, jointly with Dr. WILLIAM CAMPBELL of
Merck Research Laboratory (currently Drew University, New Jersey, USA).
One may recognize the legacy of antibiotic research that began with Dr. WAKSMAN and eventually continued through many succeeding scientists, like Drs. FOSTER, UMEZAWA, TISHLER, and
BOYD WOODRUFF, to Dr. ŌMURA and his colleagues67,69).

IV. Conclusion
As described in our previous report6), the commercial production of streptomycin in Japan
was achieved within a short period of time, following that of penicillin. In the background ofsuch success, the active support of the PHW, based on their policies to improve the hygienic status of occupied countries, also existed. In this study, through detailed investigations and analyses,
it was conﬁrmed that the introduction of technology and knowledge on streptomycin production
from the USA contributed greatly to the achievement of successful commercial manufacturing ofstreptomycin in Japan.
It is widely known that the domestic penicillin production was successfully initiated by the
introduction1) of the US technology through the guidance of Dr. FOSTER. However, no appropriate
document existed displaying the entire perspective of the active support given by Brigadier General SAMS for the establishment of commercial streptomycin production in Japan. In particular, his
actions to import streptomycin preparations from the USA until domestic production reached anamount satisfactory enough to ﬁll national demand, might be regarded as a form of humanitarianassistance. In fact, it is conﬁrmable from the statistical data3) that streptomycin exerted a great hy-252（ 32 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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gienic contribution toward dramatically decreasing the mortality rate of tuberculosis within avery short period of time in Japan.
Acknowledgments
The authors are grateful to Dr. SATOSHI ŌMURA, Distinguished Emeritus Professor of theKitasato Institute for Life Sciences, Kitasato University, 2015 Nobel Laureate in Physiology
or Medicine, for his encouragements throughout this investigation.

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我が国において抗生物質医薬品の品質基準の果たした役割に関する薬史学的・公衆衛生学的考察：
第5報

米国からのストレプトマイシン製造に関する技術と知識の移入†
八木澤守正 1），PATRICK J. FOSTER2），黒川達夫 1,3）
慶應義塾大学薬学部医薬品開発規制科学講座

1）

慶應義塾大学薬学部基礎教育講座

2）

現所属：日本 OTC 医薬品協会

3）

我が国において抗生物質医薬品に係る品質基準が果たした役割を，薬史学的に検証し公衆衛生学的に解析するために，ストレプトマイシンの製造に関する技術と知識を米国より移入した経緯を調べた。本研究により，それらの移入は連合国軍総司令部の公衆衛生局長であったクロフォード・サムス准将が，厚生省を通じて行った強力な支援によることが確認された。ストレプトマイシンの発見者であるセルマン・
ワックスマン博士も，メルク社の研究者たちと協力し，同局を通じて日本の企業にス
トレプトマイシンのオリジナルの生産菌株を供与し，ストレプトマイシン製造に関する専門的知識や技術を移転するなどの援助を与えている。
米国より導入した技術と知識により，国内のストレプトマイシン製品の製造は急速に増加した。前報に記述したように，国内生産量は 3 年間のうちに，国内需要を十分に満たすまでに達している。日本国民は民族的に，不治の国民病として知られていた結核に対して感受性が高い傾向がある。ストレプトマイシンの導入により，1947
年には人口 10 万対 187.2 であった結核死亡率が，1952 年には 82.2 へと急速に低下した。

本論文を，1946 年（昭和 21 年）8 月 26 日に設立された「日本ペニシリン学術協議会（財団法人日本抗生物質学術協議†会を経て，現在は公益財団法人日本感染症医薬品協会）」の 70 周年に際して，我が国における抗生物質研究の先駆者に捧げます。