U.S. FDA Approach to Auditing Including QSIT

1. U.S. FDA Approach to Auditing Including QSIT Christine Nelson Center for Devices & Radiological Health Food & Drug Administration Frankfurt, Germany

2. FDA-Speak Terms • Inspection = Audit • Investigator = Auditor Frankfurt, Germany

3. Why does FDA inspect device manufacturers? • To evaluate compliance with the following FDA device regulations: • Quality Systems • Medical Device Reporting • Medical Device Tracking • Reports of Corrections and Removals • Registration and Listing Frankfurt, Germany

4. Who conducts inspections for FDA? • FDA investigators in 20 FDA District Offices around the U.S. • FDA-trained Auditors from Conformity Assessment Bodies in the European Union (EU) • In the future, FDA-trained auditors from independent third parties accredited by FDA Frankfurt, Germany

5. How does FDA decide who to inspect? • Registration database identifies who manufactures devices for distribution in the U.S. • Listing database identifies what devices they distribute • FDA prioritizes inspections by risk and gives higher risk devices/situations a higher priority Frankfurt, Germany

6. What is high priority for inspection? • Device manufacturers that: • Make class III devices • Make implantable devices and life supporting and life sustaining devices • Recently introduced a new device to the market • Have had significant violations in the past Frankfurt, Germany

7. Does FDA notify the manufacturer of an upcoming inspection? • FDA calls domestic manufacturers about 5 days before the inspection • FDA contacts foreign manufacturers 2 - 3 months in advance to schedule inspection • Manufacturer is requested to send Quality System Manual or equivalent for pre-inspection review Frankfurt, Germany

8. What happens when the FDA investigator arrives at the site? • The FDA investigator will: • Ask to see the top management • Present credentials (identifies person as an FDA investigator) • Issue notice of inspection explaining FDA’s legal authority to inspect (only in the U.S.) Frankfurt, Germany

9. What happens during the inspection? • Investigator may tour the facility to get an idea of layout, workflow, and areas that may need closer inspection • This helps the investigator decide how to organize the inspection Frankfurt, Germany

10. What happens next? • The investigator will: • Ask about size and structure of company, who is in charge, what products are manufactured there • Review registration and listing • Evaluate compliance with FDA regulations using the Quality System Inspection Technique (QSIT) Frankfurt, Germany

11. What is QSIT? www.fda.gov/ora/inspect_ref/igs/qsit/qsitguide.htm Frankfurt, Germany

12. What is QSIT? • Identifies 4 major subsystems to evaluate and states the purpose and importance of each subsystem • Provides flowcharts and inspectional objectives to cover during inspection • Offers advice • Provides tables for statistical sampling of records for review Frankfurt, Germany

13. What are the four main subsystems? Corrective & Preventive Actions Design Controls Production & Process Controls Management Equipment & Facility Controls MaterialControls Records, Documents, & Change Controls Frankfurt, Germany

14. What does FDA look for in the Management Subsystem? • Quality Policy established? • Management representative appointed? • Management reviews conducted? Frankfurt, Germany

15. What does FDA look for in the Management Subsystem? • Quality audit procedures established and quality audits conducted? • Quality plan established? • Quality system procedures established? Frankfurt, Germany

16. What does FDA look for in the Design Control Subsystem? • Design procedures and plan established? • Design inputs or requirements for device identified? • Design outputs or specifications for device identified? • Design verification conducted? • Design validation conducted? Frankfurt, Germany

17. What does FDA look for in the Design Control Subsystem? • Software validation completed? • Risk analysis carried out? • Design reviews conducted? • Design transfer to manufacturing completed successfully? Frankfurt, Germany

18. What does FDA look for in the Corrective and Preventive Action Subsystem? • CAPA procedures established? • Sources of data analyzed to identify nonconforming product and quality problems? • Statistical analysis across data sources? • Investigations conducted to identify root cause of failures? Frankfurt, Germany

19. What does FDA look for in the Corrective and Preventive Action Subsystem? • Nonconforming product controlled? • Appropriate corrective actions and preventive actions carried out? • Those responsible are told about CAPA activities? • Management review of CAPA activities? Frankfurt, Germany

20. What does FDA look for in the Production and Process Control Subsystem? • Processes are controlled and monitored? • Any rejects or nonconforming product? • Equipment adjusted, calibrated and maintained? Frankfurt, Germany

21. What does FDA look for in the Production and Process Control Subsystem? • Manufacturing processes validated or fully verified? • Software validated? • Production employees trained and qualified? Frankfurt, Germany

22. What about the other subsystems? • The other three subsystems are covered through links with the four main subsystems: • Records, documents and change control • Facility and equipment control • Material control Frankfurt, Germany

23. What happens at the end of the inspection? • The investigator will: • Meet with management to discuss the inspection • Present the FDA 483 list of observations of any significant deficiencies • Discuss the deficiencies Frankfurt, Germany

24. What should the manufacturer do after the inspection? • Send a letter to FDA identifying how they have corrected deficiencies or will correct them • Provide documentation of any corrections that have been completed • Provide a timetable or estimated completion date for future corrections Frankfurt, Germany

25. Where should I send the letter? Office of Compliance Center for Devices and Radiological Health (CDRH) Food and Drug Administration 2094 Gaither Road, HFZ-300 Rockville, Maryland 20850 U.S.A. Frankfurt, Germany

26. Center for Devices & Radiological Health Frankfurt, Germany

27. Division of Enforcement A Dental, ENT & Ophthalmic Devices OB/GYN, Gastro & Urology Devices General Hospital Devices General Surgery Devices Division of Enforcement B Cardiovascular & Neurological Devices Diagnostic X-ray Devices Electronic Products & Devices Orthopedic, Physical Medicine & Anesthesiology Devices Office of Compliance Frankfurt, Germany

28. What happens next? • Investigator writes an “Establishment Inspection Report” or EIR • EIR is sent to the Office of Compliance, Center for Devices and Radiological Health (CDRH) • Inspection is classified based on inspectional findings • Office of Compliance reviewer writes Warning Letter for inspection classified “OAI” Frankfurt, Germany

29. How does FDA classify inspection reports? • NAI – No action indicated • VAI – Voluntary action indicated – some deficiencies identified but not serious • OAI – Official action indicated – serious deficiencies identified, and FDA must take action to assure correction Frankfurt, Germany

30. What actions can FDA take to address OAI inspections? • For device manufacturers outside the U.S.: • Warning Letter • Warning Letter + Automatic Detention Frankfurt, Germany

31. Warning Letter • FDA sends “Warning Letter” describing manufacturer’s violations of FDA regulations and requesting a reply within 15 days Frankfurt, Germany

32. Warning Letter + Automatic Detention • FDA sends “Warning Letter” describing manufacturer’s violations of FDA regulations and requesting a reply within 15 days • Manufacturer’s products are put on automatic detention to prevent them from entering the U.S. Frankfurt, Germany

33. What will the Warning Letter say about Automatic Detention? • Given the serious nature of these violations of the Act, all products manufactured at this facility may be detained without physical examination upon entry into the United States. In order to prevent your devices from being detained without physical exam, your firm will need to respond to this Warning Letter (as set forth below) and correct the violations noted in this letter. In addition, the agency usually needs to conduct a follow-up inspection to verify that the appropriate corrections have been implemented. Frankfurt, Germany

34. How do I get my devices off automatic detention? • Submit documentation to FDA showing that deficiencies have been corrected • FDA will inspect you to confirm that corrections are adequate before lifting automatic detention Frankfurt, Germany

35. Where can I get more information about FDA inspections and regulations? • QSIT: • http://www.fda.gov/ora/inspect_ref/igs/qsit/QSITGUIDE.PDF • http://www.fda.gov/ora/inspect_ref/igs/qsit/qsitguide.htm • Inspections of Medical Device Manufacturers Compliance Program 7382.845: http://www.fda.gov/ora/cpgm/default.htm#devicesMore . . . Frankfurt, Germany

36. Where can I get more information about FDA inspections and regulations? • Quality system regulation: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=820 • General quality system info: http://www.fda.gov/cdrh/devadvice/32.html • Investigations Operations Manual: http://www.fda.gov/ora/inspect_ref/iom/default.htmMore . . . Frankfurt, Germany

37. Where can I get more information about FDA inspections and regulations? • Other medical device regulations: http://www.fda.gov/cdrh/devadvice/ • Division of Small Manufacturers, International and Consumer Assistance - E-mail: dsma@cdrh.fda.gov • Christine Nelson – E-mail: mcn@cdrh.fda.gov Frankfurt, Germany

38. Summary • Quality System Inspection Technique (QSIT) • How FDA conducts inspections • What should a manufacturer do after an inspection • Warning Letter or Warning Letter + Automatic Detention • Where to go for more information Frankfurt, Germany