日本医疗器械质量体系法规

Quality Management System Inspection of Medical Devices and In-Vitro Diagnostics in Japan 1 2 Medical Devices/In-Vitro Diagnostics Regulation under PAL Marketing Regulation License for Marketing License for Manufacture (Accreditation for Foreign Manufacturers)  Standards of buildings and facilities  QMS Ordinance Compliance Marketing Approval  Review of quality, efficacy and safety according to product categories  QMS Compliance  GQP (Good Quality Practice)  GVP (Good Vigilance Practice) Inspection and Audit by PMDA 1 Inspection of buildings and facilities ・ License for domestic manufacturers (cell/tissue-based devices, radioactive IVDs, etc.) ・ Accreditation for foreign manufacturers 2 QMS inspection ・ Compliance inspection (domestic/foreign) ・ Inspection of medical devices for export (domestic) ・ Other Inspections 3 Authority of Inspection for Buildings and Facilities of Manufacturers Category Domestic(License) Foreign (Accreditation) IVD Radioactive PMDA PMDA Others Prefectures PMDA Medical Device Cell/Tissue- based PMDA PMDA Sterile Prefectures PMDA Others Prefectures PMDA 4 5 Flow of Foreign Manufacturer Accreditation (*) At present, accreditation is based primarily on document review [1] Application for accreditation (one original plus one copy) + Application for accreditation inspection [2] Inspection (document/on-site) (*) Questions/Comments/Requests for replacement etc. [3] Answers/Application for replacement etc. Fo re ig n m an uf ac tu rin g si te Applicant (Foreign manufacturer) PMDA (Submit application to) Office of Review Administration Office of Compliance and Standards MHLW [4] Notice of inspection result + Application for accreditation (original) [6] Grant of the certificate (M an uf ac tu re r/ D is tri bu to r) Office of Review Administration [5] Certificate 6 Prerequisite for Marketing Approval 1 Review of quality, safety and efficacy 2 QMS Compliance 3 License for marketing approval holder 4 License for manufacturer (Accreditation for foreign manufacturer) 7 Types of QMS Inspections  Compliance inspection 1 Pre-approval inspection 2 Post-approval inspection (periodic inspection)  For cause inspection Authority of Compliance Inspection Domestic establishment Foreign establishment IVD New drug PMDA PMDA Radioactive drug PMDA PMDA Others Prefectures (CB* for IVDs with certification standards) PMDA (CB for IVDs with certification standards) Medical device New device PMDA PMDA Cell/Tissue-based device PMDA PMDA Class IV PMDA PMDA Class III Prefectures PMDA Class II Prefectures (CB for medical devices with certification standards) PMDA (CB for medical devices with certification standards) Class I - - CB: Certification body registered by Ministry of Health, Labor and Welfare 8 Compliance Inspections by PMDA  Target products (Medical devices and IVDs) 1 New medical devices 2 Cell/Tissue-based medical devices 3 Class IV medical devices 4 Radioactive IVDs 5 Medical devices and IVDs manufactured in foreign manufacturing sites  Target sites Manufacturing sites (including testing laboratories, design and development Institutes) 9 Basic Principles of QMS Compliance Inspection Type of inspection Pre-approval Post-approval The 1st time The 2nd timeand after The 1st renewal The 2nd renewal and after Subject of inspection Overall Product which is applied to marketing approval. Overall Especially focused on changed parts Management ○ △ ○ ○ Design and development ○ △ △ △ Product design documentation ○ ○ ○ (Selected product) ○ (Selected product) Production process ○ △ △ △ CAPA ○ △ △ △ Purchasing controls ○ △ △ △ Documents and records ○ △ △ △ Customer related process ○ △ △ △ Findings in previous inspection ○ ○ ○ ○: Major subsystems subject to inspection △: Selective subsystems subject to inspection (can be omitted if previously inspected by PMDA, prefectures or CB) 10 Su bs ys te m 11 License/ Accreditation QMS Inspection Requirements of License/Accreditation, QMS Inspection and Description in Marketing Approval Application *1 QMS inspection is not necessary when the site’s QMS conformity has been confirmed within the past two years. *2 Institutes that conduct the main part of the design and development of high-risk devices called “Design and Development Controlled Medical Devices.” *3 Laboratories that conduct important tests for quality assurance of finished product and are not under the manufacturer’s QMS control. Important tests for quality assurance of end products include post-EOG-sterilization tests using biological indicator, coating uniformity tests for stent-coating drugs, and precious-metal-content tests for dental metals. Description in Marketing Approval Application Manufacturing sites (sterilization facilities) *1 Necessary Necessary Necessary Manufacturing sites (storage facilities) Necessary Necessary Necessary Manufacturing sites (other than above two) Necessary Necessary Necessary Not necessaryDesign and development institutes *1, *2 Necessary Necessary Testing laboratories *1, *3 Not necessary Necessary Necessary 12 License/ Accreditation QMS Inspection Requirements of License/Accreditation, QMS Inspection and Description in Marketing Approval Application *4 Manufacturers of component parts should obtain a license (or accreditation) and have QMS inspection when they seek approvals for the component parts separately from the main unit of the medical device. *5 For example, the processes are heparin-coating for catheters and drug-coating for stents. *6 In principle, QMS inspection is not necessary for contracted facilities on the condition that they are under proper QMS control by the contract giver. *7 Although the name of the facility doesn’t have to be shown in the application form, conditions of important production processes should be described. If you have any question about the preparation of application forms, please ask the Office of Medical Devices, PMDA, through its consultation service. Description in Marketing Approval Application Not necessary Not necessary Not necessary Not necessary Not necessary Not necessary Not necessary Not necessary “Conditions of manufacture” should be described *7 13 Flow of QMS Compliance Inspection Manufacturing sites Testing laboratories Design and development institutes Application for compliance inspection Result of the review Inspection result (Target sites) Marketing Approval Prefectures (marketing licensing authority) Application for marketing authorization license Compliance Inspection Marketing authorization holder Marketing authorization holder PMDA Review for Compliance approval Inspection MHLW (marketing approval authority) 14 On-site Inspection and Document Review (1) On-site inspection is conducted in the order of sites’ priority, which is determined by the comprehensive evaluation of risks associated with product, manufacturing process and others. Risk Product risk Manufacturing-process risk Other risk Low ↓ High - Class II - Class III - Class IV - New medical devices - Cell/Tissue-based medical devices -Testing -Design and development -Packaging, labeling or storage -Outsourced sterilizing -Important processes such as assembly History of past inspections, etc. * “GHTF membership (Japan, US, Canada, Australia and EU) or not” can be considered. 15 On-site Inspection and Document Review (2) On-site inspection is conducted in order of priority based on: 1 Complexity of manufacturing processes; 2 Risk associated with the use of products; 3 Results of the previous on-site inspections; and 4 Previous nonconformity, recall, or the contents  Example of on-site inspection New medical devices*, cell/tissue-based medical devices, class IV medical devices * New medical devices are, as a rule, limited to ones that have new principle or new functional characteristics. Principle of QMS On-site Inspection and Document Review (Concrete Example) Facility A 1st application of QMS inspection （Product “a”） 2nd application （Product “b”） 3rd application （Product “c”) 4th application （Product “d”） On-site inspection On-site inspectionDocument review ※ Document review ※ 2 years＊ （time after the 1st notification of QMS compliance result） ※ Document review is confined to the facility not having experienced Class-1 recalls and field corrections. Major manufacturer concerned with the product for marketing approval application ※※ 16 ※※ Major manufacturer of the product : Facility A is supposed. Manufacturing sites concerned with the product for marketing approval application (Example) Assembling Contract Sterilization Packaging, Labeling or Storage Packaging, Labeling or Storage (domestic) Facility A Facility A’ (backup of Facility A) Facility B Facility C Facility D On-site inspection On-site inspection Document review Document review Document review a: PTCA Catheter b: Pacemaker c: Stent d: Defibrillator 17 1 Scheduling of inspection 2 Request of data prior to inspection 3 Notice of inspection date 4 On-site inspection 5 Notification of written observation items 6 Receipt of a report of corrective actions (plan) 7 Notification of the compliance result* to MHLW (*indicates conformance to QMS ordinance) Flow of On-site Inspection 18 QMS Inspection Schedule (Example) Date Time Item 1 AM 1. Opening Meeting (1) Greeting Confirmation on the audit schedule (2) Opening of the audit (Declaration) (3) Overview of the company and the plant (Infrastructure, Main Equipments) (4) Presentation about the product 2. Overview of Quality Management System (1) Quality Manual (2) QMS Organization, Document Structure, Seihin Hyojun Sho (Product Standard Code) (3) Agreement with MAH 3. Management Responsibility (1) Quality Policy and Quality Objectives (3) Management Review PM 4. Plant Tour 2 AM 5. Control of Design and Development (including risk management) 6. Control of Manufacture and Test/Inspection (including validation, operating procedures and records etc.) Product control (in consistency with the key specifications) 7. Control of Monitoring and Measuring Devices PM 8. Control of Nonconforming Product 9. Training 10. Purchasing Control (Control of Suppliers and Materials) 3 AM 11. Internal Audit 12. CAPA ・Recall and Adverse Event PM 13. PMDA wrap-up 14. Confirmation on findings (Site management representative and others） 15. Closing Meeting (Top management and others) ＊Timeframe and items are subject to change depending on progress. 19 1 Request for the document 2 Review of the document 3 Request for additional document, as necessary 4 Receipt of additional document 5 Notification of the compliance result* to MHLW (*indicates conformance to QMS ordinance) Flow of Document Review 20 Points to Consider in the Application of QMS Inspection 1 Application should be made for every facility that needs to be inspected. 2 Submission Timing; Application should be made at least six months prior to the day on which standard administrative process time of the Marketing Approval Application expires. In case the process time is less than six months, the application should be made at the same time as the Marketing Approval Application. 3 Inspection will be conducted after quality specifications and manufacturing methods are finalized in the Marketing Approval Application. 4 Facilities should be well prepared for the inspection. Note) In principle, application of QMS inspection is not required for the application of pre-approval for partial changes regarding addition of component parts and change of product specifications → The partial changes are subjected to upcoming QMS periodic (renewal) inspection etc. 21 1 Copies of result notifications or reports of QMS inspections conducted on other products in last two years 2 For foreign manufacturing sites, copies of certificates or inspection reports issued in the country, certificates issued by WHO, certificates of ISO 13485 or certificates issued by the local authorities 3 Copy of the marketing approval (or approval of partial changes) application form 4 Other materials required by the inspecting organization (submission may be made after the application) Data Required for the Application of Pre-approval Inspection 1 Outline of the sites (fill in a provided format) 2 Floor plan (including: layout drawings, dimensions of working area, material and personal flow, location or list of main manufacturing and testing equipments, and for devices that require sterilization, environment condition and pressure difference in each part of the building) 3 Organization structure for QMS • Organization chart of the sites : include a contact window with GQP organization of the marketing authorization holder • Agreement with outsourcing sites on important processes (For example, sterilization process) 4 Quality policies and summary of Quality Management System Standard Code (Quality Manual) • A copy of Quality Manual • In case of ISO 13485 certification holder, it is acceptable to submit only Introduction, Scope and QMS general requirements included in the Quality Manual. 22 The Materials Required by PMDA In the case of pre-approval inspection (1/4) Items to be stipulated Documents containing the information 1. Generic Name and Selling Product Name N/A for foreign facilities 2. Approval Date and Number N/A for foreign facilities 3. Specifications of the product DHF XXXXX 4. Design and Drawings DHF XXXXX 5. Manufacturing Method and Procedure DHF XXXXX, WI XXX And so on 23 The Materials Required by PMDA In the case of pre-approval inspection (2/4) 5 Structure of QMS documents on the manufacturing site including Seihin Hyojun Sho (Seihin Hyojun Sho can be substituted by a list of documents that contain required information as shown in the next slide.) Example of Seihin Hyojun Sho (The following table is acceptable with description of document numbers containing the information required in the Notice PFSB-CND No. 0330001. In case of ‘Not Applicable’ for the item, ‘N/A’ can be put in the column.) 6 Outline of the products (products’ package inserts will be acceptable) 7 Outline of manufacturing process (based on the flow chart described in the marketing approval document) and important control points 8 Specifications of the products (For example, specifications of the raw materials that contact with blood/body fluid, or important specifications regarding functional characteristics of the medical devices) 9 In case of foreign manufacturing sites, list of countries other than Japan to which the product is exported and its brand names in each country, if any. 24 The Materials Required by PMDA In the case of pre-approval inspection (3/4) The Materials Required by PMDA In the case of pre-approval inspection (4/4) 10 Outline of validation on production processes (Ex. sterilization and other processes) Not requested to submit validation procedures and records of the product, but summary of organized systems/operational methods for validation (Initial validation ,and re-validation etc.) and mechanism of the assessment. If there is no validation in the production processes, describe it in the document. 25 26 Outline of Manufacturing Site of Medical Devices as of (date) Name of the site: Location of the site: License (accreditation) number Date of the first license (accreditation) _＿＿＿_______ License (accreditation) categories Expiry date of license (accreditation) ___＿＿＿_____ Number of employees (those involved in production , those involved in testing ) Name and position of a person in charge Annual production output of the site by value in the year (may be left blank in case of non- disclosure) Class I Class II Class III Class IV Total Number of manufacturing products Name of the principal product (the principal product for export to Japan, in case of foreign manufactures) Name of products exported and destinations for export (for domestic manufacturing sites only) Area of the manufacturing site m2 Warehouse area m2 Area of production facility m2 Area of testing laboratory m2 Area of design and management institute m2 (if appropriate) Inspected by the government or ISO certification bodies? (If yes, fill in the target items and timing of inspection) (Attachment) For medical devices Breakdown of manufacturing items (that is; items for export to Japan, in case of foreign manufactures) *The above information is acceptable, if it was obtained during the last 1 year. Data of Products 6 Outline of the products A4 size： 1 to 3 sheets 7 Outline of manufacturing process and important control points A4 size： 1 to 3 sheets 8 Specifications of the products A4 size： 1 to 3 sheets 9 In case of foreign manufacturing sites, list of countries other than Japan to which the product is exported and its brand names in each country, if any A4 size： 1 to 5 sheets 10 Outline of validation on production processes A4 size： 3 to 10 sheets 27 Data on QMS 3 Organization structure for QMS A4 size： 2 to 3 sheets 4 Quality policies and summary of Quality Management System Standard Code (Quality Manual) A4 size： 10 sheets 5 Structure of QMS documents on the manufacturing site including Seihin Hyojun Sho A4 size： 3 to 5 sheets Data on Manufacturing Sites 1 Outline of the sites (fill in a provided format) A4 size： 1 sheet 2 Floor plan A4 or A3 size： 1 to 5 sheets The Materials Required by PMDA In the case of pre-approval inspection * A rough idea as to the number of sheets, some increase or decrease can be acceptable. 28 Required data Points to consider 1. Data on manufacturing sites (1) Outline of the sites (2) Floor plan (1) Fill in a provided format (2) Shows the location of sterilizers 2. Data on QMS (3) Organizational structure for QMS (including outsourcing contracts) (4) Summary of the Quality Manual *1 (5) QMS document architecture *1 (3) Submission of the QMS organization chart of the contract sterilization facility is not necessary when it is attached to the organization chart of the contract giver as a document showing a relationship between the contract giver and the contract sterilization facility. (4) Example: Quality policies and table of contents of the Quality Manual (5) Example: Documentation pyramid shown in the Quality Manual Example: List of top-level documents shown in the Quality Manual Example: List of Standard Operating Procedures required by ISO 13485 3. Data on products (including Seihin Hyojun Sho) Not necessary because the same information will appear in the contract giver’s data *2 Data Required for QMS Document Review of Contract Sterilization Facilities *1 Not necessary when it was already submitted at the last QMS inspection conducted within the past two years and no change has been made since then. *2 Parameters of sterilization will be shown in the outsourcer’s data. 29 Outline of Manufacturing Site of Medical Devices as of (date) Name of the site: Location of the site: License (accreditation) number Date of the first license (accreditation) _＿＿＿_______ License (accreditation) categories Expiry date of license (accreditation) ___＿＿＿_____ Number of employees (those involved in production , those involved in testing ) Name and position of a person in charge Annual production output of the site by value in the year (may be left blank in case of non- disclosure) Class I Class II Class III Class IV Total Number of manufacturing products Name of the principal product (the principal product for export to Japan, in case of foreign