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

2. 2 EMEA and the Regulatory System in the EU -The European medicines Agency (EMEA) co-exists with over 40 National Competent authorities and works towards harmonisation of regulatory and technical requirements within the EU. -A centralised procedure for Marketing Authorisation co- exists with procedures at national level and the EMEA co-ordinates the existing scientific resources (assessors, inspectors, quality control laboratories) in the Member States.

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

4. 4 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

5. 5 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

6. 6 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

7. 7 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.

8. 8 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

9. 9 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)

10. 10 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

11. 11 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.

12. 12 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

13. 13 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

14. 14 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-.

15. 15 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

16. 16 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

17. 17 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.

18. 18 Scenario a: inspection report sharing API manufacturer in third country EU willing to inspect and to share the report with US US willing to inspect INSPECTION API 1 INSPECTION API 1 a: US delegates to EU

19. 19 Scenario b: inspection report sharing with expanded scope API manufacturer in third country US willing to inspect AP1 + AP2 and share the report with EU EU willing to inspect API 2 INSPECTION API 1 INSPECTION API 2 b: EU ask US to expand scope

20. 20 Scenario c: collaborative inspection API manufacturer in third country Joint inspected by EU + US EU willing to inspect US willing to inspect Decision of joint inspection

21. 21 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.

22. 22 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

23. 23 The project : Results in 2009 (1) EMEA 99 EDQM125 FDA42 TGA174 AFSSAPS9 AIFA4 ZLG3 IMB2 MHRA31 Total 489 sites shared 489 Inspection ReportsDone6 Requested14 Proposed12 Total 32 Joint InspectionsDone6 Confirmed2 Asked10 Proposed2 Total 20

24. 24 The project : Results in 2009 (2) 489 sites identified and shared 103 Sites common to at least 2 participants identified for possible cooperation NCANb of SitesNb of Hits%Collaboration EMEA995350 %10 IR + 11 JI EDQM1254536 %9 IR + 6 JI TGA1478760 %15 IR + 13 JI FDA422866 %8 IR + 8 JI

25. 25 The project : N ext 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

26. 26 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

27. 27 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

28. 28 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