1. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 1 |1 | Prequalification programme: Priority essential medicines Training programme on pharmaceutical quality, good manufacture practice and bioequivalence with a focus on TB products. Jiaxing Peoples’ Republic of China 5 – 9 November 2007

2. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 2 |2 | Training Workshop on Evaluation of quality and interchangeability of medicinal products. Regulatory requirements for BE 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 - WHO Training workshop / 5-9 November 2007 3 |3 | Guidance documents * http://mednet3.who.int/prequal * Guideline on generics - Annex 7 (Multisource (generic) pharm. products: guidelines on registration requirements to establish interchangeability) - EU “Note for Guidance on the Investigation of Bioavailability and Bioequivalence” CPMP/EWP/QWP/1401/98” - FDA “Guidance for Industry: “Bioavailability and Bioequivalence Studies for Orally Administered Drug Products – General Considerations” (Oct. 2000) – and related guidances” - CN “Guidance for Industry; Conduct and analysis of bioavailability and bioequivalence studies – Part A: Oral dosage formulations used for systemic effects (1992)

4. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 4 |4 | Bioequivalence Bioavailability means the rate and extent to which the active substance or therapeutic moiety is absorbed from a pharmaceutical form and becomes available at the site of action. Bioequivalence: = bioavailability with pre-defined criteria for the rate and extent of absorption!! Drug product characteristics

5. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 5 |5 | Bioequivalence ReferenceTest Pharmaceutical Equivalent Products Possible Differences Drug particle size,.. Excipients Manufacturing process Equipment Site of manufacture Batch size …. Documented Bioequivalence = Therapeutic Equivalence (Note: Generally, same dissolution specifications)

6. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 6 |6 | Bioequivalence PD studies clinical studies in vitro methods Different approach for establishing equivalence Standard: in vivo BE studies

7. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 7 |7 | Bioequivalence ? Bioequivalence studies:

8. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 8 |8 | Bioequivalence in vivo comparison of products by means of volunteers serving as “in-vivo dissolution model” Bioequivalence studies: comparison of product characteristics to ensure therapeutic equivalence ‘biological quality control’

9. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 9 |9 | Regulatory requirements for BE studies single dose, two-period, crossover Golden standard study design: Reference (comparator)/ Test (generic) healthy volunteers 90% CI AUC and Cmax: 80 – 125%

10. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 10 | Regulatory requirements for BE studies 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)

11. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 11 | Regulatory requirements for BE studies Particularly for IR dosage forms: BCS-based biowaiver ……which is defined as.. * in vitro instead of in vivo BE testing * comparison of Test and Reference ……which is not defined as.. * no equivalence testing Cave: different recommendations in WHO, EU and FDA!

12. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 12 | Regulatory requirements for BE studies 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

13. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 13 | Regulatory requirements for BE studies Special cases: Dose- or time dependent pharmacokinetics Specific food recommendations Active metabolitesPro-drugs Enantiomers

14. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 14 | Regulatory requirements for BE studies 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)

15. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 15 | Regulatory requirements for BE studies

16. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 16 | Regulatory requirements for BE studies Modified release (MR) oral dosage forms:

17. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 17 | Regulatory requirements for BE studies MR dosage forms single unit formulations multiple unit formulations EC formulations

18. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 18 | Regulatory requirements for BE studies 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!

19. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 19 | Regulatory requirements for BE studies 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)

20. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 20 | Regulatory requirements for BE studies Cmax,ss AUCss Cmin,ss PTF

21. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 21 | Regulatory requirements for BE studies MR oral dosage forms: Single unit formulations: –Single dose study fasted state for every strength –Multiple dose study may be waived for lower strengths If a product concerns several strengths: Multiple unit formulations: –Single and multiple dose studies may be waived for lower strengths in case of identical granules or pellets In vitro dissolution studies

22. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 22 | Regulatory requirements for BE studies Comparative in vitro dissolution… Complementary to BE studies (see e.g. section 3.7 EU guidance) Comparison of Reference products In vitro/in vivo correlation (only level A for BE decision) ‘biowaiver’ – dose proportionality ‘biowaiver’ – BCS concept Batch release and other ‘quality issues’

23. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 23 | Regulatory requirements for BE studies Fixed combination products… in vivo comparison vs. appropriate comparator combination (or separate comparator products in specific cases) general testing criteria apply to all active components bioequivalence criteria apply to all active compounds 90% CI AUC and Cmax: 80 – 125%

24. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 24 | Regulatory requirements for BE studies Bioequivalence for transdermal therapeutic systems (TTS)… in vivo in vitro

25. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 25 | Regulatory requirements for BE studies Bioequivalence for transdermal therapeutic systems (TTS)… BE single and multiple dose studies ‘BE’ regarding local tolerability dose proportionality issue: through in vitro release testing and exact proportionality (partial effective surface area!) performing a replicate design study is advisable (investigation of subject by formulation interaction)

26. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 26 | Regulatory requirements for BE studies Bioequivalence for topical dosage forms without systemic action… EU/WHO/FDA  usually therapeutic studies necessary (therapeutic equivalence, safety and tolerability usually not possible by means of blood sampling and PK data) relevant clinical studies clinical studies, efficacy/safety, PK different indication, dosing schedule different formulation generics if possible PD or local availability studies, otherwise clinical

27. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 27 | Regulatory requirements for BE studies …inhalatives..metered dose inhalers (locally acting)… usually therapeutic studies necessary in some cases PK studies in addition to in vitro (‘quality – disposition characteristics e.g. FPD) usually inpatients in some cases PK studies for safety reasons  EU guidances: CPMP/EWP/4151/00 ref. to 75/318/EEC – Council Regulation no. 594/91), CPMP/EWP/2922/01, and CPMP/EWP/239/95  FDA: Critical path opportunities for generic drugs, May 1, 2007

28. Evaluation of quality and interchangeability of medicinal products - WHO Training workshop / 5-9 November 2007 28 | End