1. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 1 Regulatory Requirements for BE Evaluation of Quality and Interchangeability of Medicinal Products 10 – 14 September 2007 Dar Es Salaam, Tanzania Dr. Henrike Potthast; Temporary Advisor to WHO

2. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 2 Regulatory Requirements for BE  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  WHO – Multisource (generic) pharmaceutical products: Guidelines on registration requirements to establish interchangeability (2005)  CN – Guidance for Industry; Conduct and analysis of bioavailability and bioequivalence studies – Part A: Oral dosage formulations used for systemic effects (1992)  ….and others

3. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 3 Regulatory Requirements for BE  Bioavailability – rate and extent at which a drug substance... becomes available in the general system (product characteristic!)  Bioequivalence – equivalent bioavailability within pre-set acceptance ranges  Pharmaceutical equivalence  Bioequivalence  Bioequivalence  Therapeutic equivalence

4. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 4 Regulatory Requirements for BE  Bioequivalence Studies Fin vivo comparison of products by means of volunteers serving as “in-vivo dissolution model” F‘biological quality control’  comparison of product characteristics in order to ensure therapeutic equivalence

5. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 5 Regulatory Requirements for BE  Immediate and Modified Release Dosage Forms FBE is generally required and can be investigated by means of ♦pharmacokinetic (BE) studies (preferred as most sensitive) ♦comparative pharmacodynamic studies ♦comparative clinical trials ♦comparative in vitro trials

6. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 6 Regulatory Requirements for BE  Immediate Release (IR) Dosage Forms Fpossible BE exemptions ♦aqueous solution (incl. syrups, elixirs, but no suspensions) ♦gases ♦aqueous otic or ophthalmic products (contg. the same actives and excipients) ♦nebulizer inhalation products or nasal sprays (contg. the same actives and excipients)

7. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 7 Regulatory Requirements for BE Particularity for IR dosage forms ‘BCS-based Biowaiver’..........which is defined as  in vitro instead of in vivo bioequivalence testing  comparison of test and reference....is not defined as  no equivalence testing cave: different recommendations in WHO, EU, and FDA!

8. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 8 Regulatory Requirements for BE  Bioequivalence for Immediate Release Dosage Forms by means of… F…the ‘parent’ drug substance within a single dose 2-period crossover design is usually appropriate Fnote – special cases ♦dose- or time-dependent kinetics ♦specific food recommendations in the SPC ♦active metabolites ♦pro-drugs ♦enantiomers……

9. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 9 Regulatory Requirements for BE  Modified Release (MR) Dosage Forms Fcontrolled (extended, sustained) release Fdelayed release ♦single unit formulations ♦multiple unit formulations

10. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 10 Regulatory Requirements for BE  Modified Release (MR) Dosage Forms Fgenerally BE under specific conditions ♦single dose study (fasting) ♦multiple dose study (steady state conditions – EU, not FDA) ♦food-effect study (“dose-dumping” under high-fat conditions; note: FDA guidance on ‘Food-Effect Bioavailability and Fed Bioequivalence Studies’, CDER; December 2002 )

11. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 11 Regulatory Requirements for BE ♦ ‚ If a product concerns several strengths…‘ (see e.g. 5.4 EU guidance) ♦ bioequivalence proven for one strength ♦ same manufacturer and manufacturing process ♦ linear drug input (if this is not the case…..) ♦ same qualitative composition of different strengths (WHO) ♦ same ratio between active substance and excipients, or same excipients in case of low concentration (less than 5 % API) ♦ similar in vitro dissolution (WHO)  see also guidance for MR products, 5.1 of EU guidance CPMP/EWP/280/96…

12. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 12 Regulatory Requirements for BE  … MR products acc. to 5.1 of EU guidance (CPMP/EWP/280/96) …however, there is a possibility for ♦ single-unit forms: single dose study in the fasted state for every strength, multiple dose study may be waived for lower strengths ♦ multiple-unit forms: single and multiple dose studies may be waived for lower strengths in case of identical beeds or pellets cave: in vitro dissolution studies……..

13. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 13 Regulatory Requirements for BE ♦ Comparative in vitro dissolution …. ♦ complementary to BE studies (see e.g. 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‘….

14. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 14 Regulatory Requirements for BE  Fixed combination products Fin vivo comparison vs appropriate comparator combination (or separate comparator products in specific cases) Fgeneral testing criteria apply to all active components  bioequivalence criteria apply to all active components

15. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 15 Regulatory Requirements for BE  Bioequivalence for transdermal therapeutic systems (TTS) FBE by means of single and multiple dose studies Fperforming a replicate design study is advisable (investigation of subject by formulation interaction) F‘BE’ regarding local tolerability  dose proportionality issue: thorough in vitro release testing and exact proportionality (partial effective surface area!)

16. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 16 Regulatory Requirements for BE  Bioequivalence for topical dosage forms without systemic action EU/WHO  usually therapeutic studies necessary (therapeutic equivalence, safety and tolerability usually not possible by means of blood sampling and PK data) FDA  usually therapeutic studies necessary (specific FDA guidance for corticosteroids…..)  possibilities are e.g. skin stripping, microdialysis, NIR…

17. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 17 Regulatory Requirements for BE ♦..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‘ - deposition characteristics e.g. FPD) ♦ usually in patients  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

18. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 18 Regulatory Requirements for BE THANK YOU FOR YOUR ATTENTION