Prequalification programme: Priority essential medicines

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. 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. 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. 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. Bioequivalence Pharmaceutical Equivalent Products Reference Test Possible Differences Drug particle size, .. Excipients Manufacturing process Equipment Site of manufacture Batch size …. Documented Bioequivalence = Therapeutic Equivalence (Note: Generally, same dissolution specifications)

6. Bioequivalence Different approach for establishing equivalence Standard: in vivo BE studies in vitro methods clinical studies PD studies

7. Bioequivalence Bioequivalence studies: ?

8. Bioequivalence Bioequivalence studies: in vivo comparison of products by means of volunteers serving as “in-vivo dissolution model” ‘biological quality control’ comparison of product characteristics to ensure therapeutic equivalence

9. Regulatory requirements for BE studies Golden standard study design: single dose, two-period, crossover healthy volunteers Reference (comparator)/ Test (generic) 90% CI AUC and Cmax: 80 – 125%

10. Regulatory requirements for BE studies Immediate release (IR) oral dosage forms: Possible BE exemptions: • aqueous solution (incl. syrups, elixirs, but no suspensions) • 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. 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. Regulatory requirements for BE studies Linear pharmacokinetics Non narrow therapeutic drug Non highly variable drug Decision based upon parent drug data Decision based upon plasma concentrations Stereochemistry not an issue Bioequivalence:

13. Regulatory requirements for BE studies Dose- or time dependent pharmacokinetics Specific food recommendations Active metabolites Pro-drugs Enantiomers Special cases:

14. Regulatory requirements for BE studies Immediate release (IR) oral dosage forms: If a product concerns several strengths (EU): • Bioequivalence proven for one strength • 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. Regulatory requirements for BE studies

16. Regulatory requirements for BE studies Modified release (MR) oral dosage forms:

17. Regulatory requirements for BE studies MR dosage forms multiple unit formulations EC formulations single unit formulations

18. Regulatory requirements for BE studies Modified release (MR) oral dosage forms: Requested BE studies for enteric coated formulations: single dose, two-period, crossover, fed single dose, two-period, crossover, fasting pH! 90% CI AUC and Cmax: 80 – 125% 90% CI AUC and Cmax: 80 – 125% or not statistical significant different

19. Regulatory requirements for BE studies Modified release (MR) oral dosage forms: Requested BE studies for controlled release formulations: multiple dose, two-period, crossover, fasting single dose, two-period, crossover, fasting single dose, two-period, crossover, fed 90% CI AUC and Cmax: 80 – 125% 90% CI AUC and Cmax: 80 – 125% 90% CI AUC and Cmax: 80 – 125%; Cmin and PTF! • - dose dumping • - FDA guidance (Food effect bioavailability and fed bioequivalence studies; CDER, December 2002) - steady state conditions - EU, not FDA

20. Regulatory requirements for BE studies Cmax,ss AUCss Cmin,ss PTF

21. Regulatory requirements for BE studies MR oral dosage forms: If a product concerns several strengths: • Single unit formulations: • Single dose study fasted state for every strength • Multiple dose study may be waived for lower 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. 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. 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 90% CI AUC and Cmax: 80 – 125% • bioequivalence criteria apply to all active compounds

24. Regulatory requirements for BE studies Bioequivalence for transdermal therapeutic systems (TTS)… in vivo in vitro

25. Regulatory requirements for BE studies Bioequivalence for transdermal therapeutic systems (TTS)… • BE single and multiple dose studies • performing a replicate design study is advisable (investigation of subject by formulation interaction) • ‘BE’ regarding local tolerability • dose proportionality issue: through in vitro release testing and exact proportionality (partial effective surface area!)

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) different indication, dosing schedule different formulation generics if possible PD or local availability studies, otherwise clinical relevant clinical studies clinical studies, efficacy/safety, PK

27. Regulatory requirements for BE studies …inhalatives..metered dose inhalers (locally acting)… • usually therapeutic studies necessary • in some cases PK studies for safety reasons • in some cases PK studies in addition to in vitro (‘quality – disposition characteristics e.g. FPD) • usually inpatients  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

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