1. ITRI Industrial Technology Research Institute The Audit Process of Medical Device GMP for Domestic Manufacturers DOH Designated Auditing Organizations Yuan-Yang Wei DOH Designated Auditing Organizations Yuan-Yang Wei

2. ITRI Industrial Technology Research Institute 2 MD Good Manufacturing Practice (GMP): The quality regulation standards mandated by the Department of Health (DOH), R.O.C. which is harmonized with ISO 13485:1996 and ISO 9001:1994 --- Pharmaceuticals Factory Establishment Standard Part 4 Medical Device GMP MD Good Manufacturing Practice (GMP): The quality regulation standards mandated by the Department of Health (DOH), R.O.C. which is harmonized with ISO 13485:1996 and ISO 9001:1994 --- Pharmaceuticals Factory Establishment Standard Part 4 Medical Device GMP 0. Definitions

3. ITRI Industrial Technology Research Institute 3 0. Definitions DOH Designated Auditing Organizations (DAO) : ETC,CMS,PIDC or MIRDC, designated by the DOH to perform MD GMP audit and QSD review. ETC: Electronics Testing Center CMS/ITRI: Center for Measurement Standards/Industrial Technology Research Institute MIRDC: Metal Industries Research & Development Center PIDC: Plastic Industry Development Center DOH Designated Auditing Organizations (DAO) : ETC,CMS,PIDC or MIRDC, designated by the DOH to perform MD GMP audit and QSD review. ETC: Electronics Testing Center CMS/ITRI: Center for Measurement Standards/Industrial Technology Research Institute MIRDC: Metal Industries Research & Development Center PIDC: Plastic Industry Development Center

4. ITRI Industrial Technology Research Institute 4 1. Purpose Independent evaluation of quality system is effectiveness and compliance with regulatory. To continuously maintain a standard method of auditing domestic medical device GMP executed by the DAO of DOH and to ensure the auditing procedure standards. A high degree of assurance for the users that only safe and effective medical devices will be provided. Independent evaluation of quality system is effectiveness and compliance with regulatory. To continuously maintain a standard method of auditing domestic medical device GMP executed by the DAO of DOH and to ensure the auditing procedure standards. A high degree of assurance for the users that only safe and effective medical devices will be provided.

5. ITRI Industrial Technology Research Institute 5 2. Scope Domestic manufacturers should apply for GMP to DOH before marketing or exporting. Manufacturers who pass the GMP audit will get the approval letter from DOH. Domestic manufacturers should apply for GMP to DOH before marketing or exporting. Manufacturers who pass the GMP audit will get the approval letter from DOH.

6. ITRI Industrial Technology Research Institute 6 GMP/Pre-market Approval GMP/Pre-market Approval ClassIIIIII Number of Items 733861128 GMP646Required 87 Not required All Required

7. ITRI Industrial Technology Research Institute 7 Independence DAO and their auditors shall be free from engagements and influences which could affect their objectivity, and in particular will not be involved in the design, construction, marketing, installation, servicing or supply of the device categories within the scope of the audit.

8. ITRI Industrial Technology Research Institute 8 Resources DAO have adequate resource in terms of competent auditors, independent financial support (nonprofit organizations), time, experience to conduct effective audits. If necessary, external expertise would be consigned to audit in order to ensure the highest reliability auditing. DAO have adequate resource in terms of competent auditors, independent financial support (nonprofit organizations), time, experience to conduct effective audits. If necessary, external expertise would be consigned to audit in order to ensure the highest reliability auditing.

9. ITRI Industrial Technology Research Institute 9 Consistency of procedures DAO ’ s auditors will be in accordance with defined and documented methodologies to provide consistency of audit. QSIT FDA (CAPA, production & process control, management object, sampling, design control) Training (ISO, DOH, FDA, NB Training) ISO IEC Guide 62 Periodical meeting DAO ’ s auditors will be in accordance with defined and documented methodologies to provide consistency of audit. QSIT FDA (CAPA, production & process control, management object, sampling, design control) Training (ISO, DOH, FDA, NB Training) ISO IEC Guide 62 Periodical meeting

10. ITRI Industrial Technology Research Institute 10 3. Responsibilities DAO is responsible for  the audit of domestic manufacturers to meet medical device GMP standard upon receiving documents (application) from the DOH.  recommendation and submission to the DOH DAO is responsible for  the audit of domestic manufacturers to meet medical device GMP standard upon receiving documents (application) from the DOH.  recommendation and submission to the DOH

11. ITRI Industrial Technology Research Institute 11 Important information of DOH “ In-vitro diagnostic Reagent GMP Guidance “ (Dec 26, 2003 DOH ) The major outsourcing of manufacturing shall be approved by DOH (e.g. ready for use parts) “ In-vitro diagnostic Reagent GMP Guidance “ (Dec 26, 2003 DOH ) The major outsourcing of manufacturing shall be approved by DOH (e.g. ready for use parts)

12. ITRI Industrial Technology Research Institute 12 4. Conditions for Application Domestic Medical Device manufacturers. Domestic manufacturers should have (1) plant registration license and (2) pharmaceutical permit license (s). Domestic Medical Device manufacturers. Domestic manufacturers should have (1) plant registration license and (2) pharmaceutical permit license (s).

13. ITRI Industrial Technology Research Institute 13 Domestic GMP audit flow chart ManufacturersDOH CMS/MIRDC/ETC/PIDC(DAO) Application Registration Review documents Supplement Notices Prepare On-site visit Issue the letter On-Site Audit Review Recommendation On –site Visit Audit Team Audit Plan Audit Report Final Review & Approval Surveillance Audit System Pass LA 1 Month Corrective action Plan Initial Review 3m3m Re-audit 1/2 month

14. ITRI Industrial Technology Research Institute 14 5. Application Apply to: DOH Application form (Name, Address, Product Type, Layout, Basic Information, Operation Process) Technical cooperation program Quality Manual Organization system chart Concise product chart Plant registration license Pharmaceutical permit license (s) Apply to: DOH Application form (Name, Address, Product Type, Layout, Basic Information, Operation Process) Technical cooperation program Quality Manual Organization system chart Concise product chart Plant registration license Pharmaceutical permit license (s)

15. ITRI Industrial Technology Research Institute 15 5. Application Address of submission: Bureau of Pharmaceutical Affairs, Department of Health, Executive Yuan, (#100 Ai-Kao East Rd. Taipei, Taiwan) Application may be submitted directly to DOH or by mail. The application form can be downloaded from the DOH website. http://www.doh.gov.tw/org2/b4/query1.html Address of submission: Bureau of Pharmaceutical Affairs, Department of Health, Executive Yuan, (#100 Ai-Kao East Rd. Taipei, Taiwan) Application may be submitted directly to DOH or by mail. The application form can be downloaded from the DOH website. http://www.doh.gov.tw/org2/b4/query1.html

16. ITRI Industrial Technology Research Institute 16 Receiving and returning Upon receiving the application, DOH will register and deliver all application documents to DAO. DAO will be responsible for reviewing, auditing and sending back audit report to the DOH for approval. If the manufacturer fails to be ready for the audit within 3 months without stated any reason, DAO will return the application. Upon receiving the application, DOH will register and deliver all application documents to DAO. DAO will be responsible for reviewing, auditing and sending back audit report to the DOH for approval. If the manufacturer fails to be ready for the audit within 3 months without stated any reason, DAO will return the application.

17. ITRI Industrial Technology Research Institute 17 Audit team Lead auditor Auditor(s) Expert(s) Lead auditor Auditor(s) Expert(s)

18. ITRI Industrial Technology Research Institute 18 Lead auditor Identifying the requirements of each audit assigned to the lead auditor by DAO. Previewing the manufacturer ’ s quality system documents, prior to the on-site visit (audit); Preparing the audit plan, working documents and briefing the audit team; Communicating nonconformities to the manufacturer; Preparing and presenting the audit results clearly and conclusively to the manufacturer at the closing meeting; Preparing and submitting the audit report to DAO for initial review.

19. ITRI Industrial Technology Research Institute 19 Auditors Planning and carrying out assigned responsibilities objectively; Assisting the manufacturer in understanding DOH policies and regulatory requirements; Co-operating with and supporting the lead auditor; Verifying that corrective actions been taken and have been effective; Complying with any effectiveness and safety or other applicable requirements of the manufacturer.

20. ITRI Industrial Technology Research Institute 20 Quality system and application documents review The responsibility of LA; If application documents haven ’ t meet the regulatory requirements, LA will not do the audit until such concerns are resolved. (License) The LA reviews every quality documents and fill out the manual review notification.manual review notification. The responsibility of LA; If application documents haven ’ t meet the regulatory requirements, LA will not do the audit until such concerns are resolved. (License) The LA reviews every quality documents and fill out the manual review notification.manual review notification.

21. ITRI Industrial Technology Research Institute 21 6. Pre-visit (On-site visit) Explanation & identification Explain the audit process and the administration work of GMP registration. Clarify the question of quality manual Clarify design control Identify the product scopes To Identify the audit site Identify the restriction Conclusion & final explanation Auditing days Visit (Pre-visit) report Explanation & identification Explain the audit process and the administration work of GMP registration. Clarify the question of quality manual Clarify design control Identify the product scopes To Identify the audit site Identify the restriction Conclusion & final explanation Auditing days Visit (Pre-visit) report

22. ITRI Industrial Technology Research Institute 22 7. Audit Process The audit plan will based on:audit plan 1. Information from the manufacturer (audit type, Information from preview of the quality system and etc.,; 2. Estimation of audit duration (auditing- days)(auditing- days) The audit plan will based on:audit plan 1. Information from the manufacturer (audit type, Information from preview of the quality system and etc.,; 2. Estimation of audit duration (auditing- days)(auditing- days)

23. ITRI Industrial Technology Research Institute 23 Opening Meeting 1.Introduction; 2.Explanation of audit scope; 3.Confirm audit plan & guides: 4.Confirm that the resources and facilities needed ; 5.Confirm the time and date for the closing meeting; 6.Sampling & Evidence; 7.Confidential & Restriction; 8.Compliments 9.Brief tour 1.Introduction; 2.Explanation of audit scope; 3.Confirm audit plan & guides: 4.Confirm that the resources and facilities needed ; 5.Confirm the time and date for the closing meeting; 6.Sampling & Evidence; 7.Confidential & Restriction; 8.Compliments 9.Brief tour

24. ITRI Industrial Technology Research Institute 24 Objectives of audit Ensuring previous corrective actions have been completed effectively. The effectiveness of the manufacturer ’ s quality system Compliance with GMP requirements; Effectiveness & safety of medical device(s); Achievement of quality objectives; Appropriate medical device regulatory requirements; Ensuring previous corrective actions have been completed effectively. The effectiveness of the manufacturer ’ s quality system Compliance with GMP requirements; Effectiveness & safety of medical device(s); Achievement of quality objectives; Appropriate medical device regulatory requirements;

25. ITRI Industrial Technology Research Institute 25 Auditing Subsystems Management Design and Development -Safety & Effectiveness (classify risk-based) Technical Files Production Process Corrective and Preventative Actions-CAPA Purchasing Control-Outsourcing manufacturing Documentation and Records Customer Requirements Sterilization validation Environment hygiene Management Design and Development -Safety & Effectiveness (classify risk-based) Technical Files Production Process Corrective and Preventative Actions-CAPA Purchasing Control-Outsourcing manufacturing Documentation and Records Customer Requirements Sterilization validation Environment hygiene

26. ITRI Industrial Technology Research Institute 26 Closing meeting 1.Compliment; 2.Explanation of the audit scope, objective and area. 3.Sampling; 4.Any complain; 5.Non-conformity report; 6.Conclusions; 7.Final report, Signature & Copy; 8.A corrective action plan (10 days) 1.Compliment; 2.Explanation of the audit scope, objective and area. 3.Sampling; 4.Any complain; 5.Non-conformity report; 6.Conclusions; 7.Final report, Signature & Copy; 8.A corrective action plan (10 days)

27. ITRI Industrial Technology Research Institute 27 Working documents MD management system manual; Observation report; Observation report Nonconformity report; Nonconformity report Final report. Final report. MD management system manual; Observation report; Observation report Nonconformity report; Nonconformity report Final report. Final report.

28. ITRI Industrial Technology Research Institute 28 Application restriction Manufacturers fail to comply with the GMP regulations and are unable to amend within 3 months before the formal audit, will not be approved for registration.

29. ITRI Industrial Technology Research Institute 29 Audit team members Members in the audit team includes: (1) LA and A(s) (2) Observers (if necessary) (3) Technical specialist: experts with relevant area of expertise will be invited to join the audit if necessary (e.g. IVD, sterilization).

30. ITRI Industrial Technology Research Institute 30 Preparations before audit Communicate with team members before audit (meeting): Checklist (if necessary) Scale & process complexity, Sterilized operations (sterilization and validation) Designated external manufacturer/inspectors Expert(s)

31. ITRI Industrial Technology Research Institute 31 Preparations of Closing meeting 1. Final audit report; 2. Nonconformity reports and observation reports; 3. Audit plan; 4. Opening and closing meeting attendance sheet; 5. QA manual, QA manual notification; pre-visit report

32. ITRI Industrial Technology Research Institute 32 8. Administration process DAO collecting the audit reports and corrective action plans; DAO do the initial review. DOH do the final review and approval. Relevant documents shall be maintained. DAO collecting the audit reports and corrective action plans; DAO do the initial review. DOH do the final review and approval. Relevant documents shall be maintained.

33. ITRI Industrial Technology Research Institute 33 Approval and registration DAO will continue to conduct follow-up surveillance manufacturers at least every three years. ~ Pharmaceutical Affairs Act

34. ITRI Industrial Technology Research Institute 34 Re-audit While received DOH unapproved notice, the manufacturer could apply for re-audit within 2 months. If manufacturers apply re-audit to DOH, it will be completed in 4 months after applying. Auditors will check the whole elements of quality system, especially nonconformities in last audit. While received DOH unapproved notice, the manufacturer could apply for re-audit within 2 months. If manufacturers apply re-audit to DOH, it will be completed in 4 months after applying. Auditors will check the whole elements of quality system, especially nonconformities in last audit.

35. ITRI Industrial Technology Research Institute 35 9. References Medical Device of Good Manufacture Practice (GMP) GHTF.SG4.(99)28-Guidelines for Regulatory Auditing of Quality Systems of Medical Device Manufacturers-Part 1 GHTF.SG4./N30 R6- Guidelines for Regulatory Auditing of Quality System of Medical Device Manufacturers- Part 2 ISO/IEC Guide 62 Guide to Inspections of Quality System (QSIT); FDA Aug. 1999 ISO 13485 2003 ISO 19011:2002 Medical Device of Good Manufacture Practice (GMP) GHTF.SG4.(99)28-Guidelines for Regulatory Auditing of Quality Systems of Medical Device Manufacturers-Part 1 GHTF.SG4./N30 R6- Guidelines for Regulatory Auditing of Quality System of Medical Device Manufacturers- Part 2 ISO/IEC Guide 62 Guide to Inspections of Quality System (QSIT); FDA Aug. 1999 ISO 13485 2003 ISO 19011:2002

36. ITRI Industrial Technology Research Institute 36 Thank you for your attention