1. 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

2. 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

3. 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 ?

4. 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

5. 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

6. 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 ?

7. 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

8. 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 ?

9. 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 investigators site by trial pharmacist or maybe by trial monitor Option to allow sponsor to provide this information to investigator

10. 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

11. 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

12. 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 ?

13. 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

14. 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

15. 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 ?

16. 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 …..

17. 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 ?

18. 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 !

19. 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 ?

20. 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 ?

21. 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 ?

22. SARQA/DKG Conference 3-4 October 2002 22 Annex 13 Update Other comments - Para (6) Not clear whether the QPs 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

23. 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)

24. 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

25. 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

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

27. 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

28. 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

29. 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 ?

30. 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