European Medicines Agency Activities Related to API’s

1. European Medicines Agency Activities Related to API’s WHO/EDQM/SFDA Conference Quality of Pharmaceutical Ingredients March 28, 2010 Guangxi Hotel, Beijing, China Brendan CuddyScientific Administrator European Medicines Agency

2. Agenda • What is the European Medicines Agency? • API’s in the Marketing Authorisation Application • International Active Pharmaceutical Ingredients (API) Inspection Pilot Programme • Future developments • Summing Up • Questions and Discussion

3. European Medicines Agency

4. The European Union: 493 million people – 27 countries Member states of the European Union Candidate countries

5. EMEA and the Regulatory System in the EU EMEA co-exists with over 40 National Competent authorities in the EU/EEA, forming an integrated network A centralised procedure for Marketing Authorisation co-exists with procedures at national level (de-centralised procedure/mutual recognition procedure) EMEA co-ordinates the existing scientific resources in Member States and provides an interface between all parties EMEA works towards harmonisation of regulatory and technical requirements within the EU EMEA scientific guidelines apply regardless as to the marketing authorisation procedure used

6. EMEA and EU System EU institutions:Commission, Parliament and Council 42 National competent authorities 4,000 European experts Committee on Advanced Therapies (CAT) Management Board Committee for Orphan Medicinal Products (COMP) Committee for Medicinal Products for Human Use (CHMP) EMEA Paediatric Committee (PDCO) Pharmacovigilance Committee ? Committee for Veterinary Medicinal Products (CVMP) Committee for Herbal Medicinal Products (HMPC) Industry Organisations Patients and consumers organisations

7. API’s in the Marketing Authorisation

8. Marketing Authorisation Manufacturing site(s) for medicinal product Manufacturing site(s) for active substance(s) Key Terms Authorises the holder to place the medicinal product on the market Sites located in EEA including importers must hold a manufacturing/importation authorisation (MIA) Includes brokers who package, label and/or Import active substances

9. EU GMP Inspection System Collective implementation of Directives into national legislation National Manufacturing Authorisations Concept of Supervisory Authority Mutual recognition of inspection outcomes. All inspections “performed on behalf of the Community” Collective adoption of identical guidelines Harmonised practices Compilation of Community Procedures Joint audit programme Regular meetings of the GMP/GDP Inspectors Working Group

10. Marketing Authorisation Applications for marketing authorisation must specify the manufacturers of the active substance This includes: • all stages involved in manufacture - from the first use of the active substance starting materials, through to the active substance used as a starting material by the dosage form manufacturer. • all companies/sites involved in manufacture of the active substance including those (re)packaging and (re)labelling It should be noted that importers (into EEA) of active substances are also “Manufacturers” of the active substance.

11. Declarations by the Qualified Person Each application for marketing authorisation or relevant variation submission must be accompanied by a declaration signed by the QP of the manufacturing/importation authorisation holder(s) listed as manufacturer of the dosage form. • The declaration confirms that the active substance is manufactured in accordance with GMP • The declaration must cover all the manufacturing sites connected with the active substance

12. QP Declaration: responsibilities Active substance manufacturer AUDIT AUDIT Batch release site and/or importer Finished product manufacturer

13. Supervisory role of the Competent Authorities • Inspections are carried out to verify that Manufacturing Authorisation holders are fulfilling their obligations • Member States are obliged by Community legislation to conduct inspections for this purpose and on behalf of all Member States. • In addition they may inspect active substance manufacturers. These inspections are mainly triggered by specific concerns. • Some Member States issue manufacturing authorisations to active substance manufacturers

14. Conditions For Inspection Of Active Substance Manufacturers No systematic routine inspection programme is required according to Community legislation • Where there are grounds for suspicion of non-compliance • At request of Member State, EMEA or Commission • To verify data submitted in application for a CEP • At request of EDQM • At the request of a manufacturer itself

15. Conditions For Inspection Of Active Substance Manufacturers Biologicals The quality of biological medicinal products are highly dependent on the manufacturing process and are usually characterised by it. GMP has therefore always been applied to the biological substance. Sterile active substances The sterilisation step in the production of a sterile active substance, where the active substance is to be incorporated aseptically in the manufacture of the medicinal product, is a manufacturing step of the medicinal product and has always been subject to GMP. Therefore subject to routine inspections

16. Possible Triggers Possible Grounds for suspicion: • Unsatisfactory evidence of audit by manufacturer of medicinal product • Competent authority not satisfied with measures taken by medicinal product manufacturer • Concerns about distribution chain • Previous unsatisfactory inspection history • Concerns raised through CEP scheme • When disagreement on the conclusions of an inspection • Non compliance with specifications • Suspicions relating to authenticity of data

17. International API Inspection Pilot Programme

18. Background of the project • 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)

19. Justification of the project • Better use of International inspectional resources allowing an increase inspectional coverage outside participating regions Better coordination/collaboration/information between authorities on sites of common interest can contribute to risk based inspection approaches and improve inspection efficiency.

20. Justification of the project • Information from the retrospective data : • Out of 85 sites which were inspected by more than 2 participants between 2005 and 2008 and for which the last inspection dates were known : • 8 sites were inspected during the same month • 7 sites were inspected within 3 month • 11 sites were inspected within 6 month • 20 sites were inspected within 12 month • 14 sites inspected within 2 years • 25 sites inspected within more than 2 years

21. Organisation of the Pilot Program Authorities performing significant number of inspections of APIs outside of their territories approached by European Medicines Agency end 2007 • EU : France AFSSAPS, Germany ZLG, Ireland IMB, Italy AIFA, United Kingdom MHRA • MRA : Australian TGA • Council of Europe : EDQM • USA : US FDA All agreed to participate in a pilot phase to last for 18 months with recommendation for future action.

22. Organisation of the Pilot Program Always right to perform “own” inspections Use of a common GMP standard = ICH Q7 All authorities to ensure if possible an agreed conclusion in case of joint inspection Each involved authority responsible for any follow-up actions (e.g. administrative or enforcement) Possible joint follow-up actions in case of GMP non- compliance

23. Tools of the Pilot Program (1) • Objectives developed into : • Update on a pilot project to collaborate on international GMP inspection activities • Rules of engagement and procedures for participating authorities (active pharmaceutical ingredients/active substances) • Organisation of bilateral and general teleconferences to built up the program and define a strategy for the sites of common interest

24. Tools of the Pilot Program (2) 4. Confidentiality Agreements signed between the participating authorities to allow sharing of inspection plans 5. Template spreadsheet for exchange of inspection planning's, retrospective and prospective, defined. 6. Creation of a master list of common sites • http://www.ema.europa.eu/Inspections

25. Sites for cooperation in 2009/2010 • 920 sites (entries) identified and shared • 350 sites not shared • Total of : 213 common sites • sites common to 2 participants : 118 sites • sites common to 3 participants : 57 sites • sites common to 4 participants : 32 sites • sites common to 5 participants : 6

26. Geographic distribution of the API manufacturers • China : 104 sites from which 43 are not shared • 39 shared by 2 • 14 shared by 3 • 6 shared by 4 • 2 shared by 5 • 58 % of the sites in China are shared

27. Activities within the Pilot Program • 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 planned inspections with or without scope extension Joint inspection with or without scope extension.

28. Scenario a: inspection report sharingpassed or future inspection API manufacturer in third country API 1 API 1 is used in medicinal products in EU (CAP) & US. EU/US both interested in the inspection and agree to delegate the inspection to one of them and to share the inspection report. Possible for the same scope or overall GMP compliance

29. Scenario b: sharingof inspectionreports of plannedinspections with extension of the scope API manufacturer in third country API 1 API 2 API 1 is used in medicinal products marketed in EU (CAP) and a CEP was granted by EDQM. API 2 is used in a product in Australia EDQM/European Medicines Agency/TGA are interested in the inspection and agree to delegate the inspection to one of them, extending the scope of the inspection to cover API 1/2 and to share the inspection report.

30. Scenario c: joint inspection API manufacturer in third country API 1 API 2 API 3 API 1 and API 2 are used in medicinal products marketed in EU(CAP) , in US and in Australia. API 2 and API 3 were granted a CEP by EDQM. EDQM/European Medicines Agency/FDA/TGA are interested in the inspection and agree to organise a joint inspection done by two of them, covering API 1/2/3 and share the inspection report with all.

31. Joint inspections Feb. 2010 EDQM , 5 joint inspections : 3 TGA - 1 MHRA - 1 European Medicines Agency European Medicines Agency, 2 joint inspections 1 FDA - 1 EDQM FDA, 2 joint inspections 1 European Medicines Agency – 1 TGA TGA, 5 joint inspections 3 EDQM - 1 FDA - 1 MHRA

32. Key Performance Indicators Increased transparency and visibility of participants inspections planning Decrease in “duplicate inspections” i.e inspections of the same product or sites carried out by more than one authority within a similar time period Increase in number of inspections of value to more than one authority performed Positive assessment of the deliverables

33. Next steps Regular teleconferences and e-mail exchanges for the development of the program. Improving the knowledge of each other’s organisation and constraints Improve the exchange of information by gathering and sharing more data on site inspections planning (all sites, APIs inspections schedules and reporting tools (e.g. feedback forms) Reliance on each other’s inspections will increase resource available to cover more sites.

34. Future Developments Legal proposal to combat counterfeit medicines Pedigree of API Supply Chain Security

35. EC envisages a combination of tightened requirements in the API area Notification requirements Tightened GMP standards Enhanced inspections

36. Notification requirements Mandatory notification for manufacturers/importers of APIs Present Proposed • API manufacture • & import to mandatory notification procedure • Information on notified parties • available in a Community database • (EudraGMP database extension) • legal framework for APIs only on • manufacture • activities of distributors, traders, • agents and brokers outside • scope of Community legislation • should be subject to the relevant GMP

37. Audit and enforceability of GMP Enhancing audit and enforceability of GMP Present Proposed • Make regular audits of API suppliers on GMP compliance mandatory • auditors sufficiently qualified • third-party audits by accredited companies • Control of APIs via discriminating analytical techniques • Principles of GMP for APIs into a legal act of Community law • obligation of the MIA holder to source from GMP compliant API manufacturers • in practice auditing by the MIA holder (EU FP manufacturer or importer) • FP manufacturers test APIs supplied to them • other sites / other processes as declared

38. API GMP inspections Enhancing API GMP inspections Present Proposed • inspections by competent authorities restricted to suspected non-compliance with GMP • Particular concerns for manufacturing in third countries (TC): • GMP not equivalent to EU • inspection and control mechanisms insufficient • Need to continue cooperation with TC • bilateral arrangements • international synergies in performing inspections • Legal basis for any GMP API inspection • competent authorities (EU inspectorates) shall carry out API inspections if suspicion of non-compliance with GMP • The competent authority shall carry out repeated inspections in the exporting country (TC) if • GMP in TC not at least equivalent to EU • mechanisms for supervision and inspections not at least equivalent to EC

39. Pedigree of API Supply Chain Proposal for amendment of GMP Guide to introduce a pedigree concept for API’s. Proposal still very much in draft form Work anticipated to continue on the proposal throughout 2010.

40. To sum up • Overview of API’s in Marketing Authorisation • Inspections of active substance manufacturers • International Pilot Programme • New initiatives e.g EC proposals

41. Questions and Discussion 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 www.ema.europa.eu/Inspections/index.html gmp@ema.europa.eu