Topics The 2nd Japan-Vietnam Joint Symposium was held.

Mr. Hoang Ha Phong explained the four key points of the PMDA's drug review process, including the PMDA's organizational structure, the drug review process, and the review process of documents and eCTDs (Electronic Common Technical Documents) required for approval.

The regulatory authorities in Japan include the Ministry of Health, Labour and Welfare (MHLW) and the PMDA. The PMDA is responsible for scientific review, GCP (Good Clinical Practice) and GMP (Good Manufacturing Practice) investigations, and consultation on clinical trials, etc. The MHLW is responsible for final approval and licensing, issuance of guidelines, and supervision of PMDA operations. The MHLW is responsible for final approval and licensing, issuance of guidelines, and supervision of PMDA operations.

As part of the review process from application for approval to approval by the Minister of Health, Labour and Welfare, PMDA's review team examines the application materials after receiving the application, and based on discussions with external experts, PMDA submits a review report to the MHLW. The MHLW makes the final decision on whether or not to approve the application based on the advice of the Pharmaceutical Affairs and Food Sanitation Council on whether or not to approve the application. PMDA makes every effort to ensure transparency in its review based on guidelines and other guidelines, and to conduct its review according to published timelines.

The materials that must be attached to an application for approval vary according to the 10 application categories, and applicants may consult with PMDA prior to submitting an application. The CTD to be attached to the application must meet the electronic specifications defined in the International Conference on Harmonization of Pharmaceutical Regulations (ICH) M8 guidelines, and PMDA reviewers can access the eCTD from their own PCs to view the materials, and the MHLW can also view the eCTD via a terminal server. Since 2016, we have been using an electronic system for application data, which enables centralized management of review status, product name, expected application date, application category, applicant name, indications, etc. It is also now possible to send application materials, check the review status, and send responses to inquiries.

An overview of drug registration in Vietnam was given as follows.

The total number of registered drugs as of 2020 is 15,107 (including 3,302 imported drugs). The validity period of drug registration is up to 5 years, with a maximum of 3 years for new drugs, vaccines and biologics, and those requiring safety and efficacy monitoring. In addition, according to Circular 32, a regulation on drug registration that became effective in September 2019, an application for registration extension can be filed 12 months prior to the expiration date of the registration, instead of 6 months prior to the expiration date of the registration previously. Those now specified in the said Circular include Stringent Regulatory Authorities (SRAs, e.g., ICH member authorities prior to October 2015), as well as reference countries, and the priority review system.

Requirements for certificates and other administrative documents are also new. The new requirements include: drugs for rare diseases, drugs needed in case of emergency or disaster, drugs manufactured in Vietnam within the last 18 months on production lines that comply with the Pharmaceutical Inspection Convention and the Pharmaceutical Inspection Cooperative Scheme (PIC/S) and EU-GMP, and drugs originally manufactured by foreign manufacturers but to be transferred to Vietnam. The review will be conducted in the following cases. Some generic drugs also require bioequivalence (BE) data, which will be increased in the future.

The application form for registration can be submitted using the ASEAN-CTD or ICH-CTD. Examinations will be conducted by technical examiners (affiliated with universities, research facilities, etc.) with reference to the ASEAN technical guidelines.

Finally, proposals for joint research and cooperation between the two countries were made.

After receiving an application for a GMP investigation, a risk analysis is conducted based on the information provided by the applicant, including product, manufacturing site, and previous investigation history, to determine whether a written or on-site investigation should be conducted. The COVID-19 disaster also includes an advanced desktop inspection, which is a more risk-based investigation than the conventional document-based investigation. The inspection focuses on manufacturing method risks, testing method risks, and site-specific risks. The on-site inspection of an overseas manufacturing site is basically the same as the on-site inspection of a domestic manufacturing site. The process of an on-site survey consists of the establishment of a survey team, risk identification, planning meeting, on-site survey, summary of the survey, determination of issues to be pointed out by the judgment meeting, and confirmation of improvement items submitted by the company. Information related to the investigation is accumulated in PMDA's internal database.

Regarding the "subject of GMP" and "subject of GMP investigation" in Japan, in the case of ethical drugs, APIs and drug products including starting materials and API intermediates are subject to GMP and require a GMP investigation. For OTC drugs and quasi-drugs, APIs including starting materials and drug intermediates are subject to GMP but do not require investigation, while drug formulations are subject to GMP and also require investigation. Additives are subject to "voluntary" standards that refer to international standards and do not require a GMP investigation.

Finally, the process of issuing a GMP certificate is explained below. After receiving the application, the PMDA conducts an on-site inspection, confirms that there are no problems, including the results of the on-site inspection, and reports the results to the MHLW, which issues the GMP Certificate. The GMP certificate is issued based on the results of the on-site survey, which is a survey conducted within the past two years on the product in question or other products that are considered to be in the same process as the product in question. The investigation is shared by PMDA and the 47 prefectures. For the manufacture of new drugs, biological products, and radiopharmaceuticals, both domestic and overseas, PMDA conducts the investigation, while for other pharmaceutical products, domestic manufacturing sites are investigated by the 47 prefectures and overseas manufacturing sites are investigated by PMDA.

Regulations and the actual situation regarding GMP inspections in Vietnam were explained.

The legal basis for GMP assessment is Decree No. 54 of 2017 and Notification No. 35 of 2018 of the Ministry of Health. A country-specific evaluation process is used, and GMP evaluations by the respective authorities are accepted for manufacturers from SRA or mutual recognition signatory countries such as the US, EU, Japan, and Australia. Documents submitted for evaluation include a consular GMP certificate (or manufacturing license, GMP inspection report, etc.) and the site master file (SMF) of the manufacturing site in question. For foreign manufacturers in other countries, a written survey will be conducted if necessary. In this case, in addition to the GMP certificate and SMF, the GMP inspection report, a list of GMP inspection results for the last three years, and, in the case of a sterile preparation, a product quality verification are required. If there are any doubts during the document inspection, DAV may conduct an on-site inspection. All domestic manufacturers are subject to GMP inspections and GMP assessment results are posted on the Vietnamese authorities' GMP website. The inspection team is led by the DAV and consists of one or two members each from the DAV, the National Institute for Vaccine and Biological Products Control or the National Institute for Drug Research, and local health authorities.

The GMP inspection process is described as follows: DAV receives the application, evaluates the application materials, and requests additional materials from the applicant if necessary. Upon completion of the document evaluation, an inspection plan is developed and the GMP inspection team inspects the manufacturer. DAV evaluates the improvement report, and if necessary, requests additional materials or conducts another inspection. If improvement cannot be made within 180 days of the inspection, the inspection becomes invalid. The inspection plan is developed based on the PIC/S risk-based inspection planning model.

DAV conducts about 70 on-site inspections per year and has 215 domestic factories certified as GMP compliant at this time. GMP evaluations of overseas manufacturers began in 2018, with 1,726 in 2020; since September 2020, domestic manufacturing facilities have been required to apply for GMP evaluations online. In the future, we intend to expand the online application to overseas manufactures.

The status of drug safety information and e-labeling in Japan was explained.

In order to ensure the safe use of pharmaceutical products, it is important to provide patients and healthcare professionals with new information on adverse drug reactions and other information in a timely manner after the product is put on the market. Under Japanese law, any changes in information such as precautions for use in the package insert must be immediately and widely disseminated, and information can now be provided electronically via the Internet or other means. However, the law has been legally obligated to provide information in paper form on each product package. e-Labeling (electronic labeling of the package insert) will be officially introduced with the amendment of the law at the end of 2019, and this will become effective from August 2021. In the future, we will create a system whereby the attached document information can be viewed via the Internet or other means using the QR code on the drug packaging. We believe that it will no longer be necessary to attach all paper to each product package, and that it will be possible to deliver the latest information electronically and promptly to medical institutions and patients.

The benefits of e-labeling are Accessibility (easy access to information), Arrangeability (easy modification and arrangement), and Searchability (easy search). Using XML format for the attached documents, which is convenient for handling on computers, makes it easier to convert and search for terms. By preparing a dictionary of side-effect terms, it would be possible to replace terms for specialists with easy-to-understand terms for patients. For example, if there is a dictionary of side-effects in Vietnamese, it would be possible to convert the attached document information in Japanese into Vietnamese.