Regulatory Requirements for BE

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 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 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 The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

4. Regulatory Requirements for BE • Bioequivalence Studies • in vivo comparison of products by means of volunteers serving as “in-vivo dissolution model” • ‘biological quality control’ comparison of product characteristics in order to ensure therapeutic equivalence 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 • BE 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 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 • possible 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) 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! 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… • …the ‘parent’ drug substance within a single dose 2-period crossover design is usually appropriate • note – special cases • dose- or time-dependent kinetics • specific food recommendations in the SPC • active metabolites • pro-drugs • enantiomers…… 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 • controlled (extended, sustained) release • delayed release • single unit formulations • multiple unit formulations 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 • generally 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) 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… 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…….. 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‘…. The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

14. Regulatory Requirements for BE • 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 components 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) • BE by means of 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: thorough in vitro release testing and exact proportionality (partial effective surface area!) 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… 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 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 The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health