PMDA conducts on-site inspections to test facilities which conduct non-clinical safety studies in dossier of application for marketing authorization, re-examination, and re-evaluation of drugs, medical devices, and regenerative medical products.
PMDA does not accept any applications of routine GLP inspection (see below) from test facilities outside of Japan.
What is Good Laboratory Practice
In the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics (PMD Act), it is provisioned that the data or materials shall be collected and prepared in accordance with Good Laboratory Practice (GLP), Good Clinical Practice (GCP) and Data Integrity Standards.
GLP for drugs, medical devices, and regenerative medical products (hereafter, “medical products”) ensures the generation of high quality and reliable test data of non-clinical safety studies for the application of marketing authorization.
See also below 'Legal documentation regarding GLP inspection'.
How GLP inspections are conducted?
Unlike other GXP inspections, an on-site GLP inspection is rarely conducted upon an application of marketing authorization of medical products (see below 'Types of inspections conducted by PMDA'). Instead, a routine GLP inspection is conducted for domestic test facilities regardless of an application of marketing authorization. A GLP Certificates will be issued for the test facilities successfully inspected. If the non-clinical safety study submitted in the dossier of application is conducted in a domestic test facility with the effective GLP Certificate issued by PMDA, the studies conducted in the facility will be considered to be compliant with GLP (see below 'GLP Compliance of submitted data').
Mutual Acceptance of Data (MAD) of GLP studies
Organisation for Economic Co-operation and Development (OECD) offers the system of Mutual Acceptance of Data (MAD), which avoids conflicting or duplicative national requirements, provides a common basis for co-operation among national authorities, and prevents creating non-tariff barriers to trade. The OECD member countries and non-OECD member full adherents (hereafter MAD-adherent) have agreed that a safety testing carried out in accordance with OECD Test Guidelines and OECD Principle of GLP (or their equivalents) in one country must be accepted by other countries for regulatory assessment purposes. Japan has been a member of OECD since 1964 and thus subject to the MAD system. Therefore, PMDA accepts GLP studies conducted in test facilities, which are located in MAD adherents and which are certified by the GLP Compliance Monitoring Authorities of those countries.
For the detail of MAD and OECD-GLP, see OECD MAD website.
Types of GLP inspections conducted by PMDA
Routine inspection is an inspection periodically conducted upon a request from domestic test facilities regardless of an application for the marketing authorization. Both a facility inspection and study audits are included in the routine inspection. A GLP Certificate, which is valid for three years, is issued to the test facility successfully inspected by PMDA. Currently, the routine GLP inspection is open only to domestic facilities. For the detail of the routine GLP inspection conducted by PMDA, see the guideline of GLP inspections by PMDA (Japanese version only. English version is under construction.).
Product-based inspection is an inspection conducted upon an application of marketing authorization. During product-based inspections, the studies of concerns are audited and facility is also inspected when necessary. A Product-based inspection is conducted when the GLP study(s) are conducted in the test facilities without effective GLP Certificates issued by PMDA (for domestic facilities) or in test facilities located outside of MAD adherents.
If the studies audited during a product-based inspection results in GLP non-compliance, the studies will be excluded from the application dossier and the details of the non-compliance including names of test facilities and reason of non-compliance will be reported to other OECD member countries and full adherents through the OECD.
In the Product-based inspection, PMDA verifies the GLP compliance of studies of concerns, but does not certify the test facilities. Thus a GLP certificate is not granted to the test facilities even if successfully inspected.
Fees for product-based inspections for drugs, medical devices, and regenerative medical products should be paid by the applicants of the marketing authorisation. For the detail of a product-based GLP inspection conducted by PMDA, see the guideline of GLP inspections by PMDA (Japanese version only. English version is under construction.) and below 'GLP Compliance of submitted data'.
An application for conduct of a Product-based inspection will be submitted by an applicant of marketing authorisation. After the application of product-based inspection by an applicant of marketing authorisation, test facilities to be inspected will be requested to develop the documents regarding the test facility organisation and conducts of GLP studies, which include the information of the following items and should be prepared either in English or Japanese:
1) name and location of the test facility
2) field of expertise
3) study area related to the studies of concern
4) history of test facility
5) layout of buildings and floor plans
6) organisation and personnel of the test facility (corporate organisation chart, GLP organisation chart, GLP personnel)
7) monitoring of test facility by the Test Facility Management
8) criteria to appoint study director and experiences of them
9) education and training programmes
10) organisation of Quality Assurance Unit
11) major activities of GLP-related departments and divisions
12) animal housing capacity
13) floor plans, circulation diagrammes and air condictioning diagrammes for each zone
14) handing and disposal of wastes
15) names, numbers, models of major facilities/equipment
16) animal housing facilities and their management
17) environmental control of important zones and its procedures
18) washing and disinfection procedures
19) Standard Operating Procedures (SOPs) (preparation, revision, abolishment of SOPs, list of SOPs)
20) outline of computerised systems
21) delegation of studies outside of the organisation.
Other logistic supports such as documents required for the visa application for inspectors may be requested by the applicants of the marketing authorisation.
The test facilities to be inspected are also requested to provide the inspection report from other MAD adherents if any and to translate the study plans and study reports in either English or Japanese if necessary.
Special inspection is a GLP inspection conducted to the domestic test facilities which have a valid GLP Certificate issued by PMDA, whatever needed (such as a request from the Review Offices of PMDA and whistleblowing).
| Type | Timing | Performance | Certificate |
|---|---|---|---|
| Routine | Upon request from domestic test facilities (regardless of the application of marketing authorization) |
Voluntary | Issued |
| Product-based | Upon application of marketing authorization | Mandatory | not issued |
| Special | Whenever needed - request from regulatory authority - any problems |
Mandatory, if needed |
not issued |
GLP Compliance of submitted data
Data generated in domestic test facilities
If a domestic test facility has an effective GLP Certificate issued by PMDA, a product-based GLP inspection of the study is able to be exempted. When an application of marketing authorization is submitted to PMDA, the Office of Non-clinical and Clinical Compliance II checks whether the test facility which conducted GLP studies in dossier for an application of marketing authorization has an effective GLP Certificate at the time of the study performed. In principle, if a test facility does not have an effective GLP Certificate at the time of the study, PMDA will inspect the study (see above product-based inspection).
Data generated in overseas test facilities
Data from OECD members/full adherents
A copy of GLP Certificate (or equivalent documents such as inspection reports) issued by GLP monitoring authorities of MAD adherents should also be submitted when an application of the marketing authorization etc. are made. If such documents are not confirmed after an application of marketing authorization, study audits will be requested to the GLP compliance monitoring authorities of MAD adherents.
Data from MAD provisional adherents
MAD provisional adherents are countries which adhere to relevant OECD Acts on MAD but has not yet undergone a successful evaluation. They must accept data from OECD members and full adherents, while OECD members and full adherents do not have to accept the data generated by the test facilities located in the provisional adherents. Thus, PMDA will either refuse to accept the data from the test facility located in the provisional adherent or conduct a product-based inspection to the facility (see product-based inspection).
Data from economies outside of OECD MAD framework
If an overseas test facility is located in countries outside the framework of OECD MAD, PMDA will either refuse to accept the data from the overseas test facility, or conduct a product-based inspection (i.e. verification of GLP compliance of studies of concern) as required in order to decide whether the data can be accepted (see product-based inspection). The same rule is applied to the test facilities successfully inspected by other MAD adherents. A Product-based inspection is also required to accept the data from such test facilities.
Likewise, the studies successfully audited by PMDA are not obligated to be accepted by other MAD adherents. The acceptance of such data is prerogative for each MAD adherent.
For all cases, it should be also noted that the data may be excluded from the dossier of an application of marketing authorization, if the GLP compliance is not assured.
Legal documentation regarding GLP inspection
Ministerial Ordinance on GLP of drug, medical devices, and regenerative medical products
Ministerial Ordinance on Good Laboratory Practice for Nonclinical Safety Studies of Drugs[74KB]March 26, 1997 (Amended on June 13, 2008), Ordinance of the Ministry of Health and Welfare No.21
Ordinance of the Ministry of Health, Labour and Welfare No.114
Ministerial Ordinance on Good Laboratory Practice for Nonclinical Safety Studies of Medical Devices[74KB]
March 23, 2005 (Amended on June 13, 2008), Ordinance of the Ministry of Health, Labour and Welfare No.37
Ordinance of the Ministry of Health, Labour and Welfare No.115
Ministerial Ordinance on Good Laboratory Practice for Nonclinical Safety Studies of Regenerative Medical Products*
July 30, 2014, Ordinance of the Ministry of Health, Labour and Welfare No.88
Public Notice on the Implementation of GLP Ordinance
Guidance on the Implementation of the Ministerial Ordinance on the Good Laboratory Practice for Nonclinical Safety Studies of Drugs as Revised by the Ministerial Ordinance for Partial Revision of the Ministerial Ordinance on the Good Laboratory Practice for Nonclinical Safety Studies of Drugs [83KB]June 13, 2008, PFSB Notification No.0613007
Guidance on the Implementation of the Ministerial Ordinance on the Good Laboratory Practice for Nonclinical Safety Studies of Medical Devices as Revised by the Ministerial Ordinance for Partial Revision of the Ministerial Ordinance on the Good Laboratory Practice for Nonclinical Safety Studies of Medical Devices [84KB]
June 13, 2008, PFSB Notification No.0613010
Guidance on the Implementation of the Ministerial Ordinance on the Good Laboratory Practice for Nonclinical Safety Studies of Regenerative Medicine Products*
August 12, 2014, PFSB Notification No.081220
The guideline of routine GLP inspections conducted by PMDA*
The guidance on the management of GLP data for the application for the marketing approval*
*Japanese version only. English version is under construction.
Other GLP Programmes in Japan
There are six GLP programmes for nonclinical safety studies for chemicals including medical products in Japan, and four ministries have a jurisdiction over them (see table below). GLP programmes for chemicals other than medical products, see websites of corresponding ministries and organizations.
| Chemicals | Ministry | Related Organization |
|---|---|---|
| Medical Products (Drugs, Medical Devices, Regenerative Medical Products) |
MHLW | PMDA |
| Workplace Chemicals | MHLW | NIOSH |
| 1) Pesticides 2) Feed Additives 3) Veterinary Drugs |
MAFF | 1), 2) FAMIC |
| 3) NVAL | ||
| Industrial Chemicals 1) Health Effect 2) Bioaccumulation/Biodegradation 3) Ecotoxicity |
1) MHLW | NIHS |
| 2) METI | NITE | |
| 3) ME | NIES |
MHLW: Ministry of Health, Labour, and Welfare, MAFF: Ministry of Agriculture, Forestry, and Fisheries, METI: Ministry of Economy, Trade, and Industry, ME: Ministry of Environment, NIOSH: National Institute of Occupational Safety and Health, FAMIC: Food and Agricultural Materials Inspection Centre, NVAL: National Veterinary Assay Laboratory, NIHS: National Institute of Health Sciences, NITE: National Institute of Technology and Evaluation, NIES: National Institute for Environmental Studies
For any questions, contact GLP team (PMDA-GLP “at” pmda.go.jp*) in Office of Non-clinical and Clinical Compliance, PMDA. *When you send e-mail, please change “at” to “@” in the e-mail address.