International API Inspection Pilot Program Olivier Gross Scientific Administrator EMEA

1. International API Inspection Pilot ProgramOlivier GrossScientific AdministratorEMEA DIA International Conference Quality of Active Pharmaceutical Ingredients 5th – 7th September 2009 Any views expressed are those of the author and should not be understood as those of EMEA or its scientific committees

2. 27 EU Member States and 42 national authorities 3 EEA countries 5 operational MRA Partners 1 “Advanced MRA” (ACCA) partner

3. GMP Inspections within EMEA (1) No inspectors at EMEA, only coordination of inspections done by the 27 Member States Different type of inspections for APIs and FP • - Pre-authorisation Inspections • - Post-Authorisation Inspections • - Re-inspections every 2-3 years • Most of the inspections coordinated by EMEA are not in EEA

4. GMP Inspections within EMEA (2) • In EEA, EMEA relies on the inspections performed by EEA authorities of their manufacturing sites on their territories every 2-3 years • EMEA relies also on inspections carried out by MRA countries (Switzerland, Australia, New Zealand, Canada, Japan) • Quarterly meetings of GMP Inspectors Working Group

5. Main GMP inspection challenges in EU (1) • Ensure continued protection of Public Health with scarce resources and budgets • Increasing regulatory requirements and expectations with • more and more global operations. • Concerns about the supply chain in the legal and illegal sector with a growth in counterfeit activity

6. Main GMP inspection challenges in EU (2) More and more complex supply chains and a fundamental shift of the manufacturing sites of APIs outside EU leading to an increasing European and international and focus on the quality of APIs For each product a large numbers of API manufacturers involved, intermediates, API starting materials, alternative sources • Responsibility of the GMP compliance of the API manufacturer relies with the QP of the Finished Product.

7. International Collaboration activities (1) • Number of mechanisms for international partnership between EU and other countries • - EEA countries, accession countries, EDQM, WHO, PIC/S • - Mutual Recognition Agreements (MRA) • Confidentiality arrangements: FDA, Japanese MHLW, Canada, • - EU - US Transatlantic administrative simplification

8. International Collaboration activities (2) • IT exchange tools : • May 2007 launch of EudraGMP database • GMP information on inspections performed by EU and MRA partners • further release to include a module for sharing inspection plans • US FDA Compliance status database (COMSTAT)

9. Background for the project (1) • Global supply chain for APIs / Global regulatory environment (ICH) • Increasing demand for international collaboration on inspection work sharing on a risk-based approach • Quality issues in 2008 for products with API manufactured outside EU (e.g. heparin) • New EU legislative proposals expected to impact approaches to GMP API inspections

10. Background for the project (2) • Need of better use of International inspectional resources allowing an increase inspectional coverage outside participating regions • Coordination/collaboration/information between authorities on sites of common interest can contribute to risk based approaches and improve inspection efficiency.

11. The project : Starting up • Authorities performing significant number of inspections of APIs outside of their territories approached by EMEA end 2007 • EU : France, Germany, Ireland, Italy, United Kingdom • MRA : Australian TGA • Council of Europe : EDQM • US : FDA • All agreed to participate in a pilot phase to last for 18 months with recommendation for future action

12. The project : Tools of the program (1) • Objectives developed into : • Update on a pilot project to collaborate on international GMP inspection activities • http://www.emea.europa.eu/Inspections/docs/43043807enrev1.pdf • Rules of engagement and procedures for participating authorities (active pharmaceutical ingredients/active substances) • http://www.emea.europa.eu/Inspections/docs/41432308en.pdf

13. The project : Tools of the program (2) • Confidentiality agreements signed between the participating authorities to allow sharing of inspection plans • Template spreadsheet for exchange of inspection planning's, retrospective and prospective, defined. • APIs –Jurisdiction- Name of the site –Address-Zip Code- City- state/Province—Country- Last inspection- C/NC- Planned inspection-Category-Sterile- • .

14. The project : Running of the program (1) • Use of a common GMP standard = ICH Q7 • Each involved authority responsible for any follow-up actions (e.g. administrative or enforcement) • Always right to perform “own” inspections • All authorities to ensure if possible an agreed conclusion in case of joint inspection

15. The project : Running of the program (2) • Organisation of bilateral and general teleconferences to built up the program and define a strategy for the sites of common interest : • July 2008 : AFSSAPS, IMB, EDQM, EMEA, MHRA, TGA, USFDA, ZLG • September 2008 : AFSSAPS, IMB, EDQM, EMEA, MHRA, TGA, USFDA, ZLG • December 2008 : EDQM, EMEA, USFDA, • March 2009 : EMEA, USFDA • April 2009 : EMEA , TGA • April 2009 : TGA, USFDA • May 2009 : EDQM , TGA • July 2009 : AIFA, AFSSAPS, IMB, EDQM, EMEA, MHRA, TGA, USFDA

16. The project : Running of the program (3) • Main activities to be developed within the program based on the sharing of inspections planning: • - Sharing of inspection reports of passed inspections • Sharing of inspection reports of future inspections with or without scope extension • Joint inspection with or without scope extension.

17. Scenario a: inspection report sharing API manufacturer in third country INSPECTION API 1 INSPECTION API 1 EU willing to inspect and to share the report with US a: US delegates to EU US willing to inspect

18. Scenario b: inspection report sharing with expanded scope API manufacturer in third country INSPECTION API 1 INSPECTION API 2 US willing to inspect AP1 + AP2 and share the report with EU b: EU ask US to expand scope EU willing to inspect API 2

19. Scenario c: collaborative inspection API manufacturer in third country Joint inspected by EU + US Decision of joint inspection EU willing to inspect US willing to inspect

20. The project : Key Performance Indicators • Increased transparency and visibility of inspections • Decrease in “duplicate inspections” • inspections of the same product or sites carried out by more than one authority within a similar time period • Overall (pre-approval and surveillance/post-approval/GMP) increase in number of sites of API inspected relative to 2006-2008 figures • Increase in number of inspections performed of value to more than one authority • Positive assessment of the deliverables • Regulatory capacity building in countries with emerging API industry.

21. The Project : Retrospective data • Retrospective inspection data (2006-2007-2008) provided by : • EDQM (124), USFDA (215), AFSSAPS (55), TGA (47), MHRA (31), and EMEA (63) . Total 535 API manufacturing sites outside the participating countries • 91 (17 %) API manufacturing sites were inspected in the last 3 years by more than one of the above mentioned inspectorates. - 74 were inspected by two different inspectorates from which 30 sites where inspected within 6-7 month • 16 were inspected by 3different inspectorates - 1 was inspected by 4 different inspectorates

22. The project : Results in 2009 (1)

23. The project : Results in 2009 (2) • 489 sites identified and shared • 103 Sites common to at least 2 participants identified for possible cooperation

24. The project : Next steps • Regular teleconferences and e-mail exchanges for the development of the program, the organisation of joint inspections and sharing of inspection reports. • Improving process monitoring: • Gather more data on site inspections planning (all sites, APIs) • Reporting tools (e.g. feedback form) • Reliance on each other’s inspections will increase resource available to cover more sites • Enlarge the number of participants • Enlarge the scope after ending the first 18-month cycle

25. Conclusion • Working together is challenging • Need to have recognition of each other’s environments, organisation, expertise • Significant collaborative work underway • Cooperation of Regulatory authorities is in the interest of Public Health worldwide. • Communication will be the key to success

26. European Medicines Agency 7, Westferry Circus Canary Wharf London E14 4HB United Kingdom Tel: +44 (0) 20 7418 8400 Fax: +44 (0) 20 7418 8416 GMP@emea.europa.eu qdefect@emea.europa.eu GMPINS@emea.europa.eu www.emea.europa.eu

27. Abbreviations • EMEA- European Medicines Agency • CVMP - Committee for Medicinal Products for Veterinary use • CHMP - Committee for Medicinal Products for Human use • COMP - Committee for Orphan Medicinal Products • HMPC - Committee for Herbal Medicinal Products • PDCO – Committee for Paediatric Medicinal Products • MS – Member States • EU – European Union • EEA – European Economic Area • EDQM – European Directorate for the Quality of Medicines and Healthcare • MRA – Mutual Recognition Agreements • PIC/S - Pharmaceutical Inspection Cooperation Scheme • WHO - World Health Organisation • API- Active Pharmaceutical Ingredient (term active substance used in EEA) • ICH/VICH International Conference on Harmonisation/Veterinary equivalent