1. Documentation of bioequivalence Drs. J. Welink Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009

2. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 2 |2 | http://apps.who.int/prequal/

3. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 3 |3 | Bioequivalence Bioequivalence: Two medicinal products are bioequivalents if they are pharmaceutical equivalents or alternatives and if their bioavailabilities (rate and extent) after administration in the same molar dose are similar to such degree that their effects, with respect to both efficacy and safety, will be essential the same.

4. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 4 |4 | Bioequivalence ReferenceTest Pharmaceutical Equivalent Products Possible Differences Drug particle size,.. Excipients Manufacturing process Equipment Site of manufacture Batch size …. Documented Bioequivalence = Therapeutic Equivalence

5. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 5 |5 | Bioequivalence acceptance criteria: comparative rate and extent of absorption pharmaceutical equivalence method: in principle comparative pharmacokinetics (AUC, C max )

6. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 6 |6 | Bioequivalence PD studies clinical studies in vitro methods Different approach for establishing equivalence Standard: in vivo BE studies ONLY IN EXCEPTIONAL CASE !!

7. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 7 |7 | Bioequivalence Important PK parameters AUC: area under the concentration-time curve  measure of the extent of absorption Cmax: the observed maximum concentration of a drug  measure of the rate of absorption tmax: time at which Cmax is observed  measure of the rate of absorption C max T max AUC

8. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 8 |8 | Bioequivalence IR formulations single dose, two-period, crossover Golden standard study design: Reference (comparator)/ Test (generic) healthy volunteers 90% CI AUC and Cmax: 80 – 125%

9. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 9 |9 | Bioequivalence IR formulations Bioequivalence: Linear pharmacokinetics Non narrow therapeutic drug Non highly variable drugDecision based upon parent drug data Stereochemistry not an issue Decision based upon plasma concentrations

10. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 10 | Bioequivalence IR formulations Special cases: Dose- or time dependent pharmacokinetics Specific food recommendations Active metabolitesPro-drugs Enantiomers

11. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 11 | Bioequivalence IR formulations Other study designs.. Multiple dose studies Parallel design Replicate design R T

12. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 12 | BE studies for modified release formulations MR dosage forms single unit formulations multiple unit formulations EC formulations

13. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 13 | BE studies for modified release formulations single dose, two-period, crossover, fasting Modified release (MR) oral dosage forms: Requested BE studies for enteric coated formulations: not statistical significant different 90% CI AUC and Cmax: 80 – 125% or single dose, two-period, crossover, fed 90% CI AUC and Cmax: 80 – 125% pH!

14. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 14 | BE studies for modified release formulations single dose, two-period, crossover, fasting Modified release (MR) oral dosage forms: Requested BE studies for controlled release formulations: 90% CI AUC and Cmax: 80 – 125% single dose, two-period, crossover, fed 90% CI AUC and Cmax: 80 – 125% multiple dose, two-period, crossover, fasting - steady state conditions - EU, not FDA 90% CI AUC and Cmax: 80 – 125%; Cmin and PTF! - dose dumping -- FDA guidance (Food effect bioavailability and fed bioequivalence studies; CDER, December 2002)

15. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 15 | Bioequivalence Single dose studies. Most submitted bioequivalence studies are: Crossover design. Non replicate. Fasted conditions. depends on drug substance!

16. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 16 | Special case: biowaiver PD studies clinical studies in vitro methods Different approach for establishing equivalence Standard: in vivo BE studies

17. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 17 | BCS low permeability high solubility low solubility HS/HP Class I HS/LP Class III LS/HP Class II LS/LP Class IV high permeability Biowaivers based on BCS

18. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 18 | BCS 4 variables: Rapid (and similar) Dissolution High Solubility High Permeability Therapeutic Window Candidates for Biowaivers

19. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 19 | WHO BCS-based biowaiver Active substances selected for biowaiving by WHO HIV/AIDS: Lamivudine Stavudine Zidovudine TB: Levofloxacin Ofloxacin Ethambutol Isoniazid Pyrazinamide

20. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 20 | Biowaivers normally accepted in BE Immediate release (IR) oral dosage forms: aqueous solution (incl. syrups, elixirs, but no suspensions) Possible BE exemptions: gases aqueous otic or opthalmic products (containing the same actives and excipients) nebulizer inhalation products or nasal sprays (containing the same actives and excipients)

21. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 21 | Biowaivers and dose proportionality Immediate release (IR) oral dosage forms: Bioequivalence proven for one strength If a product concerns several strengths (EU): Same manufacturer and manufacturing process Linear pharmacokinetics Same qualitative composition of different strengths (WHO) Same ratio between active substance and excipients, or same excipients in case of low concentration active substance (less than 5%) Similar dissolution profiles (WHO)

22. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 22 | Comparator Introducing the comparator: * a pharmaceutical product with which the multi-source product is intended to be interchangeable in clinical practice. * the selection of the comparator product is usually made at the national level by the drug regulatory authority.

23. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 23 | Choice of the comparator:

24. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 24 | Comparator prequalification project List of acceptable reference products for the prequalification project for reproductive health

25. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 25 | Comparator prequalification project Recommended comparator products: Reproductive Health medicines Comparator products should be obtained from a well regulated market with stringent regulatory authority i.e., from countries participating in the International Conference on Harmonization (ICH) Countries officially participating in ICH are the ICH members European Union, Japan and USA; and the ICH observers Canada and Switzerland.

26. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 26 | Comparator prequalification project

27. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 27 | Comparator prequalification project

28. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 28 | Comparator prequalification project

29. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 29 | Comparator prequalification project

30. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 30 | http://apps.who.int/prequal/

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34. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 34 | BTIF

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41. Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 41 | End Thank you for your attention