In 2014, the Pharmaceutical Affairs Law changed its name to the “Act on Securing Quality, Effectiveness, and Safety of Pharmaceuticals and Medical Devices” (commonly known as the Pharmaceuticals and Medical Devices Act, Pharmaceutical Machinery Act). The latest major revisions were made at the end of 2019.

GMP surveys of pharmaceutical products can also be conducted on a factory-by-manufacturing basis. However, it is necessary to establish a legal compliance system for pharmaceutical products manufacturers. The GMP Ministerial Ordinance was amended in 2021 to align with international standards.

In April 2020, Kyoto Prefecture launched the "Kyoto Prefectural Pharmaceutical Affairs Support Center" to support manufacturers.

In this article, I will introduce the contents of the revised Pharmaceutical Machinery Law, the outline of the Pharmaceutical Machinery Law system, and the efforts of the Kyoto Prefectural Pharmaceutical Affairs Support Center.

A revised version of the Japanese GMP Ministerial Ordinance was issued in April 2021, and the implementation of the Pharmaceutical Quality System (PQS) was added as a new requirement. The quality system originated in the ISO9001 standard; further, ISO9001 states that quality assurance of a product consists of the manufacturing process conducted under the quality system and the quality of the product itself. The Pharmaceutical Quality System Guideline—ICH Q10—is a specified guideline, according to the concept of ISO9001, for pharmaceutical manufacturing through the product life cycle, from development to product termination. Finally, the GMP Ministerial Ordinance was established by referring to Q10 and Q10 based PIC/S -GMP. Therefore, the PQS is regarded a core quality requirement in GMP Ministerial Ordinance.

Article 3-3 of the GMP Ministerial Ordinance defines the PQS. The essential points of this article from the perspectives of ISO9001 and Q10 are summarized as follows:

First, senior management is responsible for achieving the PQS and is asked to contribute adequately to product quality. It should be noted that the responsibility of senior management has been criticized for several quality and GMP noncompliance issues in the Japanese pharmaceutical industry. Next, senior management should establish a quality policy promoting awareness among people associated with the company. Senior management should then ensure quality objectives to implement the quality policy and provide appropriate resources and training to help the manufacturer achieve them. Performance indicators (PI) that measure progress against quality objectives should be established and integrated into quality metrics. Senior management should evaluate the effectiveness of the PQS using quality metrics comprising PI. This assessment process is conducted as a management review, as evidenced by the fact that a review of past activities of the PQS where quality issues are clarified encourages continual improvements. Finally, the entire PQS process from establishing the quality policy to the management review, including daily GMP activities and periodic checks for them, can be described as a PDCA cycle. Suitable application of the PDCA cycle to the PQS introduces continual improvements. The PQS structure described above was reviewed and documented as a quality manual at a production site.

Establishing quality assurance in Japanese pharmaceutical companies advances to a new era with the PQS defined in the GMP Ministerial Ordinance. Further challenges for pharmaceutical companies are expected to ensure product quality.

In December 2020, many health damage incidents were caused by an oral antifungal drug—itraconazole 50 mg tablet—contaminated with active ingredients for sleeping pills, which was manufactured by Kobayashikako.co.,Ltd.. Subsequently, several non-conformities under the PMD Act were uncovered among other pharmaceutical manufacturers. This has led to an undermining of confidence in the quality of pharmaceuticals in Japan. The Ministry of Health, Labor, and Welfare has implemented various preventive measures for these non-conformities.

Recently, product recalls have been repeatedly reported owing to quality issues caused by critical failures of GMP control and organizational fraud. Preventing recurrence of quality issues to regain public trust in the pharmaceutical industry is a top-priority duty of marketing authorization holders, manufacturers, and regulatory authorities.

Meanwhile, the revised Act on Securing Quality, Efficacy, and Safety of Pharmaceuticals, Medical Devices, Regenerative, and Cellular Therapy Products (PMD Act) was enforced on August 1, 2021, by which the establishment of a legal compliance system was stipulated as a duty for pharmaceutical industries.

On the same day, the revised GMP Ministerial Ordinance (GMP-MO) was also enforced to introduce the Pharmaceutical Quality System in manufacturing sites, aiming for the international harmonization of GMP standards as well as prevention of the recurrence of quality issues.

In this paper, I outline the expected roles of the revised GMP-MO in the prevention of quality issues, focusing on its revisions and the background of the revisions, with reference to relevant notifications.

In 2013, Pharmaceutical Affairs Law (Act No. 145 of 1960) was amended and changed its name to the Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices. Then there was another amendment to the act in 2019. In those amendments, standalone software intended for medical use which is called Software as a medical device (SaMD) was subject to the medical device regulations and processes which enable patients to access earlier to the medical device with cutting-edge technology were enshrined in to law. The system to streamline the change process for medical devices including SaMD which have shorter product life cycle was also legalized.

This report describes the overview of medical device regulations in Japan and some of the review systems adopted in the amendment of the act in 2019 including“Sakigake designation system”,“priority review for specific use of medical devices”,“conditional approval system”“Post-Approval Change Management Protocol (PACMP)” (So-called IDATEN (Improvement Design within Approval for Timely Evaluation and Notice)) for early patient access. This report also overviews current efforts based on“DASH for SaMD”(DX (Digital Transformation) Action Strategies in Healthcare for SaMD) which Ministry of Health, Labour and Welfare has published in November 2020, reflecting the governmental policy to accelerate the premarket review of SaMD which is mentioned in the Basic Policy of Economic and Financial Management and Reform (decided by the Cabinet on June 18, 2021).

In March 2012, Japan has applied for entry into the Pharmaceutical Inspection Convention and the Pharmaceutical Inspection Cooperation Scheme (PIC/S), a framework for legally non-binding and informal cooperation among Good Manufacturing Practice (GMP) inspection authorities; further, it was approved as the 45th member in May 2014. Ensuring the quality of each GMP inspector was a challenge for Japan’s accession to the PIC/S. In response, the education and training programs were strengthened by the expansion of joint GMP mock inspections. In addition, the guidelines for GMP inspection have been revised to define requirements for the inspectors, and stipulate that completion of the training course conducted by the National Institute of Public Health is equivalent to one year of work experience related to GMP. This training course aims to foster inspectors who is capable of performing a GMP inspection at an international level, and has played an important role in the education and training of GMP inspectors since its inception in fiscal year 1987. This article outlines the education and training programs provided for the GMP inspectors in Japan and training course conducted by NIPH to secure quality of pharmaceuticals and medical devices.

Objectives: The purpose of this study is to confirm the secular changes in smoking rate in each prefecture and in the whole country of Japan, and to ecologically examine the associations between secular changes in smoking rate and those in death rates from selected major causes among prefectures in Japan.

Methods: Smoking rate (SR) was calculated from Comprehensive Survey of Living Conditions (the large-scale survey conducted every three years). Smoking data in 2001, 2004, 2007, 2010, 2013, 2016, and 2019 were collected from e-Stat, which is portal site of official statistics of Japan. Cause-specific death rate (CSDR) was calculated from data of Vital Statistics and Population Estimates, etc. from 2001 to 2019, which were collected from e-Stat. The age-standardized SR and CSDR (standardized to the 2015 model population of Japan by the investigation committee for revision) were calculated between 2001-2019. We investigated the average annual percent change (AAPC) of age-standardized SR and CSDR in each prefecture and in the whole country of Japan from 2001 to 2019. Then, the associations between AAPC of the age-standardized SR and the AAPCs of age-standardized CSDR from selected major causes, were examined as an ecological study with all prefectures.

Results: Age-standardized SR in the whole country significantly decreased after 2001 in both genders, with AAPC of -2.8% (95% confidence interval: -2.9, -2.6) in men and -2.3% (-2.7, -1.9) in women. Age-standardized SR significantly decreased after 2001 in all prefectures in men, however in women it significantly decreased in prefectures excluding Aomori, Tottori, Saga and Kagoshima prefectures. The associations of age-standardized SR and CSDR among the prefectures were different according to the causes of death and genders. We confirmed that the correlations between AAPC of age-standardized SR and the AAPCs of age-standardized CSDR from all-cause (Pearson’s correlation coefficient: men 0.456, women 0.439), malignant neoplasms (men 0.359, women 0.431), and cerebrovascular diseases (men 0.460, women 0.331) were statistically significant in both genders. These correlations mean that the larger the average annual decreasing rates of age-standardized SR, the larger the average annual decreasing rates of age-standardized death rates from all-cause, malignant neoplasms, and cerebrovascular diseases in both genders.

Conclusion: The AAPC of age-standardized SR and AAPCs of the age-standardized death rates from all-cause, malignant neoplasms, and cerebrovascular diseases were significantly positively correlated among prefectures in both genders. Our analysis method would be one of the methods to confirm the association between secular changes in cause and result.

Objectives: To clarify the general relationships between meteorological factors and musty odor production, nationwide musty odor occurrence cases in drinking water sources reported in literatures, and long term monitoring data at Takataki dam reservoir are investigated.

Methods: Average temperature, precipitation, and sunshine duration in the week before the detection date of the maximum concentration of geosmin or 2-MIB, which are musty odor causing compounds, in each case were calculated.

Results: About the temperature in the nationwide cases, all the geosmin cases caused by Anabaena spp. were higher than 17℃, most of the 2-MIB cases caused by Oscillatoria spp. were under the range of 20-28℃, and most of the 2-MIB cases caused by Phormidium spp. were under the range of 11-20℃. In the high-concentration cases observed in Takataki Dam reservoir, all the geosmin cases caused by Anabaena spp. were higher than 16℃. And 2-MIB cases were under the range of 8-28℃, however, it was suggested that the cases at higher than 20℃ were caused by Oscillatoria spp., and the cases at lower than 10℃ were caused by Phormidium spp.. In addition, it was considered that low precipitation, which prolongs the hydraulic retention time, was one of the important conditions, however the sunshine duration was not sufficient as an index for predicting the musty odor occurrence.

Conclusion: It was concluded that the temperature at which each cyanobacteria genus can grow, and the low precipitation were important conditions of the musty odor occurrence. This study might be useful for drinking water source monitoring.

Objectives: The objectives are to confirm the secular changes in smoking rate in each prefecture and in the whole country of Japan, and to ecologically examine the associations between secular changes in smoking rate and those in death rates from selected major causes among prefectures in Japan.

Methods: The data of smoking rate (SR) and cause-specific death rate (CSDR) were collected from e-Stat, which is a portal site of official statistics of Japan. The age-standardized SR and CSDR (standardized to the 2015 model population) were calculated between 2001-2019. The average annual percent changes (AAPCs) of age-standardized SR and CSDR in each prefecture and in the whole country of Japan were investigated from 2001 to 2019. Then, the associations between AAPC of the age-standardized SR and the AAPCs of age-standardized CSDR from selected major causes, were examined as an ecological study with all prefectures.

Results: Age-standardized SR in the whole country significantly decreased after 2001 in both genders. Age-standardized SR significantly decreased after 2001 in all prefectures in men, however in women it significantly decreased in prefectures excluding Aomori, Tottori, Saga, and Kagoshima prefectures. The associations between the age-standardized SR and CSDR among the prefectures were that the larger the average annual decreasing rates of age-standardized SR, the larger the average annual decreasing rates of age-standardized death rates from all-cause, malignant neoplasms, and cerebrovascular diseases in both genders.

Conclusion: The AAPC of age-standardized SR and AAPCs of the age-standardized death rates from all-cause, malignant neoplasms, and cerebrovascular diseases were significantly positively correlated among prefectures in both genders. Our analysis method would be one of the methods to confirm the association between secular changes in cause and result.