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.
What is Good Laboratory Practice (GLP)?
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, and that PMDA is a body which conducts the inspections regarding them.
GLP for drugs, medical devices, and regenerative medical products (hereafter, “medical products”) ensures the generation of high quality and reliable test data of nonclinical safety studies for the application of marketing authorization, re-examination and re-evaluation (hereafter, “marketing authorization etc.”).
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 etc. of medical products (see below 'Different types of inspections conducted by PMDA'). Instead, a routine GLP inspection is conducted for domestic test facilities regardless of an application of marketing authorization etc., by which a GLP Certificate will be issued, if the test facility inspected is compliant with GLP. If the submitted non-clinical safety study 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 full adherents (i.e. non-OECD members adherent to MAD, whose GLP monitoring authority is successfully evaluated by other adherents in an on-site evaluation (OSE)) 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 assessment purposes. Japan has been a member of OECD since 1964 and thus subject to the MAD system.
For the detail of MAD and OECD-GLP, see OECD Council Acts, OECD MAD website and OECD Principle of GLP.
Different 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 etc. Both a facility inspection and study audits are included in the routine inspection. If the test facility inspected is compliant with GLP, a Certificate is issued to the facility by PMDA. A GLP Certificate is valid for three years. Currently, the routine GLP inspections are open only to domestic facilities. For the detail of a routine GLP inspection conducted by PMDA, see the guideline of routine 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 etc. For the product-based inspection, GLP studies submitted with the application are inspected. If necessary, the test facility which performed the studies may be also inspected. PMDA will conduct the product-based inspection if the test facility conducted the GLP study(s) does NOT have an effective GLP Certificate issued by PMDA (for domestic facilities) or an equivalent document issued by a national GLP compliance monitoring authority of OECD members and full adherents (for overseas facilities). It should be noted that no GLP Certificate will be issued even when the nonclinical safety studies concerned are judged as ‘in-compliance’.
Fees for product-based inspections for drugs, medical devices, and regenerative medical products are 3,606,200, 3,545,600, and 4,057,000 JPY, respectively, which should include additional travel expenses of inspectors.
For the detail of a product-based GLP inspection conducted by PMDA, see the guideline of routine GLP inspections by PMDA (Japanese version only. English version is under construction.) and below 'GLP Compliance of submitted data'.
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 test facility (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 produced in domestic test facility)
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 checks whether the test facility which conducted GLP studies in dossier for an application of marketing authorization etc. 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 produced in overseas test facility)
- Data from OECD members/full adherents
A copy of GLP Certificate (or equivalent document) issued by GLP monitoring authorities of OECD members and full 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 etc., a product-based inspection may be required for the test facility (see product-based inspection).
- Data from MAD provisional adherent countries
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 as required in order to decide whether the data can be accepted (see product-based inspection)
- Data from countries outside OECD MAD
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 to the facility as required in order to decide whether the data can be accepted (see product-based inspection).
For all cases above, it should be also noted that the data may be excluded from the dossier of an application of marketing authorization etc., if the GLP compliance is not assured.
For the detail of the management of the GLP study data attached to the application of the marketing authorization etc., see the guidance on the management of GLP data for the application for the marketing authorization etc. (Japanese version only. English version is under construction.)
Legal documentation regarding GLP inspection
Ministerial Ordinance on GLP of drug, medical devices, and regenerative medical products
| Documents | Date of issue | Document number | Publisher |
|---|---|---|---|
| Ministerial Ordinance on Good Laboratory Practice for Nonclinical Safety Studies of Drugs | 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 |
Minister of Health and Welfare Minister of Health, Labour and Welfare |
| Ministerial Ordinance on Good Laboratory Practice for Nonclinical Safety Studies of Medical Devices | 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 |
Minister of Health, Labour and Welfare |
| 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 | Minister of Health, Labour and Welfare |
Public Notice on the Implimentation of GLP Ordinance
- The guideline of routine GLP inspections conducted by PMDA*
- The guidance on the management of GLP data for the application for the marketing approval*
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.