1. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 1 |1 | Prequalification programme: Priority essential medicines Training Workshop for evaluators from National Medicines Regulatory Authorities in the East African Community: Evaluation of quality and interchangeability of medicinal products. Dar Es Salaam United Republic of Tanzania 10 – 14 September 2007

2. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 2 |2 | Training Workshop on Evaluation of quality and interchangeability of medicinal products. Innovator versus generic Presenter: Drs. J. Welink Senior pharmacokineticist Medicines Evaluation Board, NL WHO adviser E-mail: j.welink@cbg-meb.nl

3. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 3 |3 | Innovator Innovator dossier QUALITY CLINICAL PRE-CLIN. PHARMACOVIGILANCE

4. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 4 |4 | Innovator QUALITY

5. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 5 |5 | Innovator QUALITY Manufacture: active substance specifications starting materials process conditions

6. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 6 |6 | Innovator QUALITY Characterisation structure: active substance spectroscopic impurities process solvents/reagents control of drug substance (specifications) degradation products

7. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 7 |7 | Innovator QUALITY Stability: active substance accelerated (i.e. 40°C/75% RH) Iong term storage conditions extreme humidity thermal photolytic oxidative stress basic acidic conditions

8. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 8 |8 | Innovator Pharmaceutical development: manufacturing process control excipients control critical steps validation manufact. process - conform requirements USP/NF and Pharm. EU - excipients human/animal origin (risk of TSE) control drug product - release specifications - shelf-life specifications QUALITY drug product

9. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 9 |9 | Innovator Characterisation structure: justification specifications characterisation impurities appearance potency/degradates identity dose uniformity by weight dissolution tests moisture specifications microbiol. limits test QUALITY drug product

10. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 10 | Innovator Container closure system: package safety compatibility stability QUALITY drug product

11. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 11 | Innovator PRE-CLINICAL

12. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 12 | Innovator PRE-CLIN. Pharmacology: primary/secondary pharmacodynamics safety pharmacology pharmacodynamic drug interactions QT

13. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 13 | Innovator PRE-CLIN. Pharmacokinetics:

14. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 14 | Innovator PRE-CLIN. Pharmacokinetics: ABSORPTION IV/PO BIOAVAILABILITY DOSE DEPENDENCY

15. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 15 | Innovator PRE-CLIN. Pharmacokinetics: DISTRIBUTION

16. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 16 | Innovator PRE-CLIN. Pharmacokinetics: METABOLISM IN VITRO hepatocytes/microsomes incubation drug recovery

17. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 17 | Innovator PRE-CLIN. Pharmacokinetics: METABOLISM IN VIVO

18. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 18 | Innovator PRE-CLIN. Pharmacokinetics: METABOLISM Interspecies extrapolation ?

19. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 19 | Innovator PRE-CLIN. Pharmacokinetics: EXCRETION INPUT OUTPUT

20. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 20 | Innovator PRE-CLIN. TOXICOLOGY: genotoxicity single/repeat dose carcinogenicity reproductive/ developmental local tolerance ecotox.

21. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 21 | Innovator CLINICAL

22. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 22 | Innovator CLINICAL Pharmacokinetics: ABSORPTION DISTRIBUTION METABOLISM EXCRETION

23. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 23 | Innovator CLINICAL Pharmacokinetics: ABSORPTION BIOAVAILABILITY FOOD EFFECT BIOEQVALENCE TRIAL FORMULATIONS absolute relative + -

24. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 24 | Innovator CLINICAL Pharmacokinetics: DISTRIBUTION Vd PROTEINBINDING ANIMAL DATA TISSUE albumin AAG

25. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 25 | Innovator CLINICAL Pharmacokinetics: METABOLISM IN VITRO hepatocytes/ microsomes human liver microsomal preparations recombinant enzymes (cloned CYP enzymes)

26. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 26 | Innovator CLINICAL Pharmacokinetics: METABOLISM IN VIVO 14 C - interconversion - PK metabolites

27. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 27 | Innovator CLINICAL Pharmacokinetics: EXCRETION

28. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 28 | Innovator CLINICAL PHARMACOKINETICS: elderly gender race paediatrics liver/renal impairment interactions

29. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 29 | Innovator CLINICAL EFFICACY PATIENT STUDIES SAFETY DOSE RESPONSE AEs DRUG RESISTANCE OVERDOSE IMMUNOLOGICAL pharmacovigilance

30. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 30 | Innovator OVERVIEW

31. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 31 | Generic WHAT IS THE DIFFERENCE BETWEEN INNOVATOR AND GENERIC?

32. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 32 | Generic WHAT IS THE RELATION BETWEEN INNOVATOR AND GENERIC? INNOVATOR GENERIC BE

33. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 33 | Generic GENERIC DOSSIER QUALITY PART: IN LINE INNOVATOR PRE-CLINICAL PART: ONLY REFERENCE CLINICAL PART: PHARMACOKINETICS: bioequivalence studies EFFICACY/SAFETY: only reference

34. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 34 | End