SARQA/DKG Conference 3-4 OCTOBER 2002

1. SARQA/DKG Conference 3-4 OCTOBER 2002 Annex 13 Update An Industry Perspective Michael J Cooke Director, Global GMP QA AstraZeneca SARQA/DKG Conference 3-4 October 2002

2. Annex 13 Update • Introduction • Revision to Annex 13 • Issues and Concerns • Role of the Qualified Person • Other Challenges for the CT Directive Implementation SARQA/DKG Conference 3-4 October 2002

3. Annex 13 Update • Timings • Draft issued November 2001 • Comments submitted May 2002 • End of Year for Issue ? • As for other guidance documents ? SARQA/DKG Conference 3-4 October 2002

4. Annex 13 Update Proposed Changes : • Some are welcome ! • Removal of the 25% rule for dating of comparator products • Removal of requirement to retain unused product until after finalisation of the clinical trial SARQA/DKG Conference 3-4 October 2002

5. Annex 13 Update (1) Product Specification File (para 11) • Specifications, analytical methods • Manufacturing methods • In process testing and methods • Relevant clinical protocols and randomisation codes, as appropriate • Stability data and Storage and shipment conditions SARQA/DKG Conference 3-4 October 2002

6. Annex 13 Update (1) Product Specification File (cont) • Relevant Technical agreements with contract givers • Single File • “Approved” and referenced on the Order (para 10) • How to ensure its up to date ? • How will the Qualified Person be kept up to date with PSF ? SARQA/DKG Conference 3-4 October 2002

7. Annex 13 Update (2) Labelling Requirements (para 29) (a) Name, address, telephone number • inflexible supply for multi-national trials • Suggest name only (b) As written, implies name/identifier of the product for blinded trials SARQA/DKG Conference 3-4 October 2002

8. Annex 13 Update (2) Labelling Requirements (cont) (d) Trial subject identification number on label • May be added at time of dispensing to retain flexibility of supply • Expectation for inspections ? SARQA/DKG Conference 3-4 October 2002

9. Annex 13 Update j) “Use by” date • Product may require re-labelling (36) • Should be at manufacturing site • Alternatively, at investigator’s site by trial pharmacist or maybe by trial monitor • Option to allow sponsor to provide this information to investigator SARQA/DKG Conference 3-4 October 2002

10. Annex 13 Update (2) Labelling Requirements (cont) • Small label • Legibility and impact may be affected • Some information may be added at time of dispensing (subject/investigator identification • Provides flexibility in supply SARQA/DKG Conference 3-4 October 2002

11. Annex 13 Update (3) Role of the Qualified Person and Assessment of Batches • Article 13 of Directive 2001/20/EC requires that the Authorisation holder must have a QP at his disposal • Allows for “transitional arrangements” • Grandfather clause SARQA/DKG Conference 3-4 October 2002

12. Annex 13 Update Transitional Arrangements • “person engaged in activities as the QP for IMP…shall continue the activities in the Member State concerned” (Article 13.5) • Acceptable to other Member States ? • Movement of IMPs with EU ? SARQA/DKG Conference 3-4 October 2002

13. Annex 13 Update IMP Manufactured within EU • 91/356/EEC (GMP) • Product Specification File • Article 9(2) [Authorisation to conduct the trial] • Certify in Register SARQA/DKG Conference 3-4 October 2002

14. Annex 13 Update IMP Manufactured in a Third Country • GMP equivalent to 91/356EEC • Absence of MRA, QP must determine the equivalency • 42.c i) “normally by participation in audit” SARQA/DKG Conference 3-4 October 2002

15. Annex 13 Update Multi national organisations • Frequent transfers between sites • Same Corporate standards, possibly same QA and function management • Audit by QP not necessary ? • How to justify to inspector ? SARQA/DKG Conference 3-4 October 2002

16. Annex 13 Update Comparator Products from Third Country • Requires, for each production batch, documentation is obtained to show equivalent GMP…. • Otherwise ensure each batch has undergone all relevant tests ….. SARQA/DKG Conference 3-4 October 2002

17. Annex 13 Update Comparator Products from Third Country • Difficult to get assurance of GMP compliance ? • Accept Certificate of Analysis ? • Testing on import ? • What would be acceptable in the Application ? SARQA/DKG Conference 3-4 October 2002

18. Annex 13 Update Comparator Products from Third Country • Easiest route to source comparator product from EU with a Marketing Authorisation ! SARQA/DKG Conference 3-4 October 2002

19. Annex 13 Update Assessment of batches may include : (para 43) • Currently documents listed include many that will not be referenced routinely ? • Covered by Reference to the Product Specification File ? SARQA/DKG Conference 3-4 October 2002

20. Annex 13 Update Assessment of batches may include : (cont) • Where relevant, results of tests or analysis after importation ? • Why test at all ? • Commercial product requirements ? • Audit reports of the manufacturer ? • Stability reports ? SARQA/DKG Conference 3-4 October 2002

21. Annex 13 Update Where does the QPs responsibility end ? • Expiry date extensions ? • Re-labelling ? • Randomisation ? • Manufacture v Dispensing ? SARQA/DKG Conference 3-4 October 2002

22. Annex 13 Update Other comments - Para (6) • Not clear whether the QP’s responsibility to fulfil “these requirements” relates to all requirements of the annex or just to the training of these. • Broad knowledge of “clinical trial processes” does not include manufacture of supplies SARQA/DKG Conference 3-4 October 2002

23. Annex 13 Update Other comments – Batch release of Products • Table 1 • Confusing, “before “ and “after” clinical trial processing • (e) implies testing in EU is required for IMPs and comparators from outside of EU • Contrary to Directive 13.3 (b) and (c ) which requires the QP to confirm testing has been carried out • No mention of testing in 42c) (i) SARQA/DKG Conference 3-4 October 2002

24. Annex 13 Update Other Comments –Para 47 • Requirement for de-coding documents to be accessible before shipped to investigator site –restrictive • Propose “before dispensed” at …site SARQA/DKG Conference 3-4 October 2002

25. Annex 13 Update Other comments – Para 51 • Requirement for Investigator to understand the procedures for retrieving IMPs - not appropriate or necessary • Propose .. “investigator and monitor need to understand their obligations under the retrieval procedure” SARQA/DKG Conference 3-4 October 2002

26. Annex 13 Update Other comments –Para 55 • implies destruction at the manufacturing site… SARQA/DKG Conference 3-4 October 2002

27. Annex 13 Update Summary • Few changes in proposed draft are welcomed but …. • Further amendments/deletions necessary to simplify, clarify and ensure appropriate level of control SARQA/DKG Conference 3-4 October 2002

28. Annex 13 and GCP Directive 91/356/EEC current draft revision • Added “importer” after “manufacturer” without adequate attention to the impact of the meaning • Further amendments to simplify and clarify SARQA/DKG Conference 3-4 October 2002

29. Annex 13 and GCP Directive Requirements for Authorization referred to in Article 13, Directive 2001/20EC • Information should “high level”, not detailed • Minimise bureaucracy ? • Should not be more demanding than for commercial products • Proof of legal status ? SARQA/DKG Conference 3-4 October 2002

30. Annex 13 and GCP Directive Requirements for Authorization referred to in Article 13, Directive 2001/20EC • Alternative approach ? • information complied similar to “Plant Master File” presented to local inspectors • Mutual recognition of inspections if IMP manufactures SARQA/DKG Conference 3-4 October 2002