GMP Compliance Inspection concerning Drugs and Quasi-drags of Foreign Manufacturers(Overview Guidance for Foreign Drugs Manufacturers)

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(Tentative translation　as of Sep. 26,  2023)
 

Sep. 26, 2023

Office of Manufacturing Quality for Drugs
Pharmaceuticals and Medical Devices Agency

GMP Compliance Inspection concerning Drugs and Quasi-drags (hereinafter “Drugs”) of Foreign Manufacturers
(Overview Guidance for Foreign Drugs Manufacturers)

Introduction

GMP Compliance Inspection concerning Drugs of Foreign Manufacturers is an inspection on the compliance of manufacturing control and quality control methods at the relevant manufacturing sites with Japanese GMP (“Ministerial Ordinance on Standards for Manufacturing Control and Quality Control for Drugs and Quasi-drugs”, Ordinance of Ministry of Health, Labour and Welfare, No. 179, 2004), conducted by the Pharmaceuticals and Medical Devices Agency (hereinafter “PMDA”). GMP compliance is a requirement for marketing approval.
 

Types of GMP Compliance Inspection

There are several types of GMP Compliance Inspections:

Application-based inspections

1. Inspections that are conducted upon the application for new marketing approval or the application for partial changes of approved information
2. Inspections for confirmation of Post-Approval Change Management Protocol (PACMP), which has been introduced in Aug. 2021. 
3. Periodic inspection that are conducted every five years following the obtainment of marketing approval
4. Product Category-based Inspection Inspections are conducted for each category of manufacturing process. And “GMP certificate for product category-based inspection”, which is effective for 3 years for each category of manufacturing process is issued to the manufacturer. During the effective period of the “GMP certificate for product category-based inspection”, for the products belonging to such a category, the periodic inspection may be omitted.

This system has been introduced from the viewpoint of international consistency (Aug. 2021).
See Training Materials; (7．New Approach for GMP/GCTP Compliance Inspection System Learning Videos : GxP | Pharmaceuticals and Medical Devices Agency (pmda.go.jp))
 

Inspections not based on applications

1. Normal inspections which are planned by PMDA, based on the risk analysis
2. For cause inspections

 

Manufacturing sites subject to the Inspection

1. In the cases of ‘Inspections that are conducted upon the application for new marketing approval or the application for partial changes of approved information’ and ‘Inspections for confirmation of Post-Approval Change Management Protocol (PACMP)’

Manufacturing sites and external testing laboratories listed in the application for new marketing approval or partial change approval, and whose GMP Compliance Inspection was determined to be required in the review are subject to the inspection.
Note that the following manufacturing sites do not need GMP Compliance Inspection:

1. Manufacturing sites / External testing laboratories that meet requirements, that is, in the case where GMP compliance has already been confirmed for the same product / the same active substances based on the application of GMP compliance inspection, and the applicant submits “a copy of the GMP compliance notification” and “a copy of a document by which identity of the product can be confirmed” to the responsible authority of approval for GMP compliance application.
    

2. In the cases of ‘Periodic inspections that are conducted every five years following the obtainment of marketing approval’

All manufacturing sites, including manufacturing sites for formulation, active substances, intermediates, and packaging/ labeling/ Storage, described in the application of marketing approval are subject to the GMP compliance inspection.
Note that the following manufactures do not need GMP Compliance Inspection:

1. Manufacturing sites that obtain effective “GMP certificate for product category-based inspection” for the products belonging to such a category. (The initial periodic inspection for new drugs may not be omitted.)

2. Manufacturing sites that meet requirements, that is, in the case where GMP compliance has already been confirmed for the same active substances based on the application of GMP compliance inspection, and the applicant submits “a copy of the GMP compliance notification” and “a copy of a document by which identity of the product can be confirmed” to the responsible authority of approval for GMP compliance application.

3. External testing laboratories
    

3. Others

Manufacturing sites for active substances of over-the-counter drugs (excl. new drugs) are not required to apply for GMP Compliance Inspection.
 

Flow of GMP Compliance Inspection for the foreign manufactures

1. Application for GMP Compliance inspection by foreign manufacturers shall be applied by the marketing authorization holder who apply for the application of marketing authorization, those who have obtained exceptional approval for foreign manufacturers, or those who intend to obtain exceptional approval for foreign manufacturers. Manufactures who apply for exceptional approval for foreign manufacturers must appoint marketing authorization holders.
2. In principle, GMP Compliance Inspection shall be conducted by onsite inspection by the PMDA. However, PMDA may make a decision to conduct inspection on documents only (hereinafter desk-top inspection), considering products risk, corresponding country’s GMP standard and its operation, and status of GMP conformity based on the pre-submitted documents.
3. The PMDA shall report the inspection results to the Ministry of Health, Labour and Welfare, using the form of “GMP Compliance Inspection Result Notification”. The PMDA shall issue a copy of the GMP Compliance Inspection Result Notification to the marketing approval holder that applied for the inspection, and a copy of the “GMP Compliance Inspection Result Report to the foreign manufacturer on which the onsite inspection was conducted. In the case of desk-top inspection, a copy of the GMP Compliance Inspection Result Report is not issued.
4. Examples of Flow of GMP Compliance Inspection are shown below:

     *Note that the flow differs depending on whether Master files are used or not.

 

Examples of Flow of onsite GMP Compliance Inspection

When Master files are not used.


When Master files are used.

Examples of Flow of desk-top GMP Compliance Inspection

When Master files are not used.


When Master files are used.

 

Documents to be attached to the Application of Inspection

Even applications and attached documents are concerning foreign manufacturing sites, it should be prepared in the Japanese language. If the attachment includes a large volume of documents written in a foreign language, it is acceptable to prepare only an overview of such documents in Japanese.
 

1. In the cases of ‘Inspections that are conducted at the point of application for new marketing approval or of application for partial changes of approved information’ and ‘Inspections for confirmation of Post-Approval Change Management Protocol (PACMP)’

1. Copies of Compliance Inspection Result Notifications and/or Inspection Report of GMP inspections conducted by regulatory authorities other than PMDA within two years from the date of the application for the compliance inspection (Only if an inspection has been carried out.)
2. In the case of foreign manufacturing sites, as for manufacturing sites in countries with which MRA is concluded, a copy of Compliance Certificate or GMP Inspection Report of that country based on the MRA, as for manufacturing sites in countries with which MOU is exchanged, a copy of Certificate or GMP Inspection Report of that country based on the MOU, and as for manufacturing sites in other countries, WHO Certificate, or Compliance Certificate issued by the country’s relevant authority.
3. Copy of marketing approval application for the applied products etc.
4. Documents required by the authorized compliance inspectorates

     For more information on the documents to be submitted, see the notifications^(A)(B).

 

2. In the cases of ‘Periodic inspections that are conducted every five years following the obtainment of marketing approval’

1. Copies of Compliance Inspection Result Notifications and/or Inspection Report of GMP inspections conducted by regulatory authorities other than PMDA within two years from the date of the application for the compliance inspection (Only if an inspection has been carried out.)
2. In the case of foreign manufacturing sites, as for manufacturing sites in countries with which MRA is concluded, a copy of Compliance Certificate or GMP Inspection Report of that country based on the MRA, as for manufacturing sites in countries with which MOU is exchanged, a copy of Certificate or GMP Inspection Report of that country based on the MOU, and as for manufacturing sites in other countries, WHO Certificate, or Compliance Certificate issued by the country’s relevant authority.
3. Copy of marketing approval
4. Copies of partial change approvals over the past five years
5. Copies of notification of minor changes over the past five years
6. If applications for two or more products are made simultaneously, the applicant shall categorize applications by worksite, workroom, area, equipment etc., select representative products for each category, and submit documents that show reasons for these categorization and selection. (If representative products are selected in line with these rules, documents indicated in a, b, c, d and e. may be limited to those concerning the representative products.)
7. Whether there was product recall concerning the applied products over the past five years (If there was, overview of the recall)
8. Statement (prepared by the applicant)
9. Documents required by the authorized compliance inspectorates

     For more information on the documents to be submitted, see the notifications^(A).
 

3. In the cases of ‘Product Category-based Inspection’

1. Copies of Compliance Inspection Result Notifications and/or Inspection Report of GMP inspections conducted by regulatory authorities other than PMDA within two years from the date of the application for the compliance inspection (Only if an inspection has been carried out.)
2. In the case of foreign manufacturing sites, as for manufacturing sites in countries with which MRA is concluded, a copy of Compliance Certificate or GMP Inspection Report of that country based on the MRA, as for manufacturing sites in countries with which MOU is exchanged, a copy of Certificate or GMP Inspection Report of that country based on the MOU, and as for manufacturing sites in other countries, WHO Certificate, or Compliance Certificate issued by the country’s relevant authority.
3. List of products belonging to the category of manufacturing process pertaining to the application(Notification^(C), Attachment3-1)and inspection history concerning the listed products(Notification^(C), Attachment3-2)
4. Summary of the issues which are caused by the products of the relevant manufacturing site in the past three years (including those not destined for Japan), such as recalls, non-compliance with GMP, warning letters, and import alerts (including those issued by overseas regulatory authorities).
5. Statement(Notification^(C), Attachment1-2)
6. Copy of a site master file or other document of equivalent documents g.Documents required by the authorized compliance inspectorates

     For more information on the documents to be submitted, see the notification^(A).

Notification^(A)

• ”Documents to be submitted for the application for GMP compliance inspection" Notification from PMDA, Office of Manufacturing Quality for Drugs, August 2, 2023. (English version is under preparation)

Notification^(B)

• “Documents to be submitted for the application for new GMP compliance inspection”, Notification form PMDA, Office of Manufacturing Quality for Drugs, August 2, 2023. (English version is under preparation)

Notification^(C)

• “Enactment and revision of cabinet orders and ministerial ordinances in accordance with partial enforcement of the act on partial amendments to the Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices etc.”,　PSEHB/CND Notification No. 0713/12 from the Manager of the Compliance and Narcotic Division, PFSB, MHLW, July 13, 2021

 

Reference Information

Scope of Drugs subject to GMP Compliance Inspection

Drugs and APIs (the products showed below a. ~ g. and APIs for over-the-counter drugs do not require GMP compliance Inspection.)

1. Drugs that are intended to be used for the extermination or prevention of rats, flies, mosquitoes, fleas and other similar creatures, which are not used directly on human bodies.
2. Drugs that are intended to be used mainly for disinfection and sanitization, which are not used directly on human bodies.
3. Drugs that are, APIs, intended to be mainly used for the manufacturing of drugs indicated in a. or b.
4. Drugs that are manufactured at manufacturing sites that only conduct processes of powdering and/or cutting crude drugs.
5. Drugs that are manufactured and/or marketed by pharmacies.
6. Of gases used for medical purposes, 1) nitrous oxide, 2) oxygen, 3) nitrogen, 4) carbon dioxide, 5) compound of nitrous oxide and oxygen.
7. In addition to a. through f., drugs included in the Japanese Pharmacopoeia, which are designated by the Minister of Health, Labour and Welfare as causing mild action to human bodies (110 items including gum arabic).

 

Sources

• “Handling of Application for GMP Compliance Inspection”, PFSB/ELD Notification No 0713-1 and PFSB/CND Notification No, 0713-8 from the Managers of the Evaluation and Licensing Division and the Compliance and Narcotic Division, PFSB, MHLW,　July 13, 2021
• “Enactment of GMP inspection guidelines”, PFSB/CND Notification No, 0317-5 from the Managers the Compliance and Narcotic Division, PFSB, MHLW, March 17, 2022　(English version is under preparation)

 

GMP Inspection Report form

Report date:yyyy,mm,dd

GMP Inspection Report

To: Chief Executive, Pharmaceuticals and Medical Devices Agency

Principal Inspector
Co-Inspector

 

1. Reference Number

 

2. Brief report of the inspection activities undertaken
   1. (1) Inspection dates
   2. (2) Name of the manufacturer inspected
   3. (3) Address of the manufacturer inspected
   4. (4) Name of the site inspected
   5. (5) Address of the site inspected
   6. (6) Category, number and date of Manufacturing License of the site inspected
   7. (7) Activities carried out by the site
      • Manufacture of Active Ingredient
      • Manufacture of Finished Medicinal Product
      • Manufacture of Intermediate or bulk
      • Subdivision, Packaging, Labeling
      • External Testing Institution
      • Batch Control and Batch release
      • Other ()
   8. (8) Scope of inspection
   9. (9) Name, title and contact information of the authorized person in the inspected site
   10. (10) Results of previous inspection

 

3. Content of Inspection
   1. (1) Purpose of inspection
   2. (2) Kind of inspection【Compliance inspection【On-site・Desktop・Exploratory Inspection 】
   3. (3) Details on inspection
      1. A)Description of the site and the products inspected
      2. B)Quality System
      3. C)Equipment and facilities system
      4. D)Products and Materials Holding System
      5. E)Manufacturing System
      6. F)Packaging and Labeling System
      7. G)Laboratory Control System
      8. H)Conformity with the Standard for Biological Ingredients
      9. I)Discrepancy between NDA file and MF for API

 

4. reference information

 

5. Observations
   1. (1) Contents
      1. A)Critical deficiency
      2. B)Major deficiency
      3. C)Minor deficiency
   2. (2) Corrective action and review of report Issue date of observation:
      Receipt date of corrective action plan/report :
      1. A)Corrective action plan/report against critical deficiency
      2. B)Corrective action plan/report against major deficiency
      3. C)Corrective action plan/report against minor deficiency

 

6. Synthetic judgment ：yyyy,mm,dd

End