Historical and Hygienic Aspects on Roles of Quality Requirements for Antibiotic Products in Japan : Part 3-Introduction of Technology and Knowledge in the Production Process and Quality Control of Penicillin from the United States of America.

In order to investigate the roles of quality requirements for antibiotic products in Japan, from historical and hygienic aspects, we examined and analyzed how technology and knowledge in the production and quality control of penicillin were introduced from the United States of America, applied, and further developed. Owing to the strong support of Colonel Crawford Sams, the chief of the Public Health and Welfare Section of the Supreme Commander for Allied Power/General Headquarters, via the Ministry of Welfare in Japan, the technology and knowledge were acquired from an experienced leader, Dr. Jackson W. Foster, and as a result, domestic production of penicillin was successfully achieved in amounts required to meet national demands sufficiently within three years in a devastated post-war-torn Japan. Based on the consensus that penicillin should be dealt with as "biological products" similar to vaccines and antisera, the quality standards for penicillin were enacted as the "Minimum Requirements for Penicillin (MRP)" on the 1st of May 1947. Due to the development of penicillin production technology, the quality standards of penicillin provided by the MRP were revised often to higher levels ; content of the active element from no less than 60 units/mg (purity 3.8%) to no less than 1,430 units/mg (purity 89.7%). Regarding the penicillin preparations, the content of the active ingredient per vial was changed from 30,000 units at the beginning, to 100,000 units in January 1948, to 3,000,000 units in December 1950, and two preparations containing 200,000 units and 1,000,000 units per vial are currently available, according to clinical convenience.

Historical and hygienic aspects on roles of quality requirements for antibiotic products in Japan: Part 4 - Enactment of requirements for individual antibiotic products.

Supplies of high quality antibiotic products to clinics contributed greatly to the health maintenance of the citizens of Japan. In this report, we describe the results of our investigation and analyses on the establishment and amendments of 'he quality standards for individual antibiotic products, which were regarded as the guidelines for quality control in the production processes. "The minimum requirements of penicillin" enacted in May of 1947 was at a relatively moderate standard level, due to considerations for domestic technical levels. However, after several amendments, in response to the rapid development of manufacturing technologies and new penicillin preparations, standards became increasingly stricter. "The minimum requirements of streptomycin" enacted in December of 1949 was prepared by the use of streptomycin preparations imported from the USA. The 3rd and 4th standards, "the minimum requirements of dihydrostreptomycin" and "the minimum requirements of chloramphenicol", were prepared by applying provisions described in the rules for certification of the U.S. Food and Drug Administration. In accordance with an increase in the varieties of antibiotic products, "the minimum requirements of antibacterial products" was enacted by the integration of previously existing standards and newly enacted ones. Thereafter, in response to the innovation of scientific technologies and the globalization of antibiotic products, "the minimum requirements for antibiotic products in Japan" was further developed and became the basis for supplying high quality antibiotic preparations.

[Historical and Hygienic Aspects on Roles of Quality Requirements for Antibiotic Products in Japan: Part 1--Development of Antibiotic Products].

Antibiotic products have contributed greatly to keep Japanese people healthy by controlling lethal infections. In the early days, antibiotics such as penicillin and streptomycin were produced using microbial fermentation processes. Therefore, the component ratio of the active element and related substances varied lot by lot. For the purpose of efficacy and assuring safety, minimum requirements for penicillin and streptomycin products were enacted. Both variations and the number of clinically available antibiotic products have increased due to the pharmaceutical development of novel natural antibiotics. In addition, semi-synthetic derivatives of various antibiotics have been developed for the purpose of enhancing antimicrobial activity or improving pharmacological properties. As a result, 202 entities of antibiotic products have been approved and used clinically as of 2012. We conducted a detailed investigation of the progress made in the field of antibiotic products, and analyzed the characteristics of those belonging to each class of antibiotics by means of setting up a system of classification that reflects clinical applications. This report is intended to serve as an introduction to our series of investigations into the role and influence of quality requirements on development of antibacterial antibiotic products in Japan. As described here, the general view of antibacterial antibiotic products spanning a time frame of 67 years in Japan might serve as an ideal reference for future reports.

[Historical and Hygienic Aspects on Roles of Quality Requirements for Antibiotic Products in Japan: Part 2--Achievements of Domestic Production of Penicillin and Streptomycin].

Domestic production of penicillin was initiated in 1946 and that of streptomycin in 1950. In the early days, however, the quality of products was considerably lower and the capacity of production small. Surprisingly, there was a sufficient amount of penicillin preparations, with a purity of 85% or more, satisfying domestic demand within three years (1949). In the case of streptomycin, within three years (1953), preparations with a purity two-fold higher than initially available were produced in amounts sufficient to meet both domestic demand and create a surplus availability for exporting purposes. Such increases in quality and production were considered to be made possible by strict quality control of penicillin and streptomycin preparations, based on "Minimum Requirements for Penicillin" established in May 1947 and "Minimum Requirements for Streptomycin" established in December 1949. These requirements were also amended over time in order to provide even higher quality standards in response to the evolving improvements in production processes. Life-threatening diseases such as septicemia and pneumonia were controlled by the sufficient supply of high-quality penicillin preparations and the mortality rate of tuberculosis, regarded as a national disease at the time, markedly decreased by that of streptomycin preparations. Achievements of domestic production of penicillin and streptomycin were considered important factors that contributed greatly to the maintenance of public health in Japan.