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Waivers of in-vivo BE studies

Waivers of in-vivo BE studies. Evaluation of Quality and Interchangeability of Medicinal Products 10 – 14 September 2007 Dar Es Salaam, Tanzania Dr. Henrike Potthast; Temporary Advisor to WHO. Waivers of in-vivo BE studies. ‚ If a product concerns several strengths…‘

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Waivers of in-vivo BE studies

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  1. Waivers of in-vivo BE studies 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. Waivers of in-vivo BE studies • ‚ 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

  3. Waivers of in-vivo BE studies  …the ‚sensitive‘ strength in case of non-linearity • increase more than proportional: bioequivalence testing with the highest strength • increase less than proportional : bioequivalence testing with the highest strength cave: solubility limitations… no data available… The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  4. Waivers of in-vivo BE studies  …what to do in case of… • solubility limitations: bioequivalence testing with the highest strength (or dose) even with linear kinetics • no or inconclusive data on linearity available: bioequivalence testing with the lowest and highest strength The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  5. Waivers of in-vivo BE studies  …MR products acc. to 5.1 of EU guidance (e.g. 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

  6. Basis for BCS-based Biowaiver Applications/Decisions • FDA - Guidance for Industry: “Waiver of in vivo bio-equivalence studies for immediate release solid oral dosage forms containing certain active moieties/active ingredients based on a Biopharmaceutics Classification System” (2000) • WHO – working document on multisource (generic) pharmaceutical products (QAS/04.093) • WHO – working document on a proposal to waive in vivo bioequivalence (QAS/04.109) • EU-guidance:“Note for Guidance on the Investigation of Bioavailability andBioequivalence” CPMP/EWP/QWP/1401/98; paragraph 5.1 The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  7. Definitions BCS-based ‘Biowaiver’..... .....is defined as • in vitro instead of in vivo ‘bioequivalence’ testing • comparison of test and reference ....is not defined as • no equivalence test The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  8. Definitions • 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

  9. Definitions acc. to the FDA guidance: ”BCS-based biowaivers are intended only for bioequivalence studies. They do not apply to food effect bioavailability studies or other pharmacokinetic studies.” (e.g., rel. bioavailability) The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  10. BCS-based biowaiver In vivo bioequivalence testing is generally required but ” Such studies may be exempted if the absence of differences in the in vivo performance can be justified by satisfactory in vitro data.” • for oral immediate release dosage forms with systemic action! The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  11. BCS-based biowaiver Evaluation of drug substance and drug product Drug substance • pharmacodynamic/therapeutic aspects • physicochemical aspects Drug product • in vitro dissolution The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  12. BCS-based biowaiver RISKassessment (see e.g. WHO QAS/04/093/rev4) sect. 9.2 and 5.1.(a)) • “critical use medicines” • “narrow therapeutic index drugs” • “documented evidence for BA or BE problems • “scientific evidence that API polymorphs, excipients or the manufacturing process affects BE” The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  13. BCS-based biowaiver Biowaiver justification based on ”……… criteria derived from the concepts underlying the Biopharmaceutics Classification System ......” The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  14. BCS-based biowaiver Biopharmaceutics Classification System (BCS) dissolution drug product  drug substance in solution membrane transport  drug substance in the system simplified mechanistic view of bioavailability The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  15. BCS-based biowaiver The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  16. Melting point Charge Solubility Size Shape Ionisa-tion H-bonding Charge Distribution Lipophilicity Amphiphilicity Fig.1: Physicochemical properties that affect absorption (after oral administration) [H. van de Waterbeemd/ Eur J Pharm Sci 7 (1998), 1-3] The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  17. BCS-based biowaiver Pillars of the BCS SolubilityPermeabilityDissolution The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  18. BCS-based biowaiver High solubility • the highest single unit dose is completely soluble in 250 ml or less of aqueous solution at pH 1 - 6.8 (37 °C) • create a pH-solubility profile cave: possible stability problems have to be considered • Discussion on ‘intermediate solubility’, i.e., pH-dependent (high) solubility • Definition of low solubility? The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  19. BCS-based biowaiver High permeability • EU guidance: ”Linear and complete absorption reduces the possibility of an IR dosage form influencing the bioavailability” • FDA guidance: absolute BA >90 % • WHO guidance: at least 85 % absorption in humans • Human data are preferred; in vitro data may be submitted if sufficiently justified and valid • Definition of low permeability? The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  20. BCS-based biowaiver The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  21. BCS-based biowaiver ♦….if the fraction of the dose absorbed is the same, the human body should always do the same with the absorbed compound …Even in a disease state, this argument is still a valid statement. [Faassen et al. Clin Pharmacokinet 43 (2004)1117]  what does the product do to the drug substance? The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  22. BCS-based biowaiver • When are in vitro results sufficient for bioequivalence evaluation? • When is in vitro instead of in vivo bioequivalence testing scientifically justified (or even more restrictive)? • Minimizing risk by means of ‘worst case’ investigation? • Which in vitro investigations may be sufficient? The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  23. BCS-based biowaiver in vitro dissolution objectives • quality control • justification of minor variations • iviv-correlation (e.g. major variations; bridging) • additional to BE studies • proportionality based biowaiver • BCS based biowaiver • …. The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  24. BCS-based biowaiver in vitro dissolution prerequisites • reasonable, stability-indicating, validated methods • discriminative methods • reproducible methods • biorelevant methods (?) • ……one fits all?! The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  25. BCS-based biowaiver in vitro dissolution and BCS concept • meet prerequisites • ensure risk minimization • justify absence of difference • biorelevant?! The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  26. BCS-based biowaiver In vitro comparison of immediate release oral drug products (T and R) first option: very rapidely dissolving products • Not less than 85 % of labeled amount are dissolved within 15 min in each of three buffers (pH 1.2, pH 4.5 acetate buffer, pH 6.8 phosphate buffer) – no further profile comparison of T and R is required • reasonable, validated experimental conditions/methods are strongly recommended! The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  27. BCS-based biowaiver In vitro comparison of immediate release oral drug products (T and R) second option: rapidely dissolving products • Not less than 85 % of labeled amount are dissolved within 30 min in each of three buffers (pH 1.2, pH 4.5 acetate buffer, pH 6.8 phosphate buffer) • reasonable, validated experimental conditions/methods are strongly recommended! The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  28. BCS-based biowaiver Experimental conditions: • EU guidance – no specific information yet • US-FDA guidance – ‚USP‘-conditions • 50 rpm (paddle) or 100 rpm (basket); 900 ml; USP buffer; 37 °C • WHO – • 75 rpm (paddle) or 100 rpm (basket); 900 ml; USP buffer; 37 °C • no surfactants! The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  29. BCS-based biowaiver In vitro comparison of immediate release oral drug products (T and R) • Proving similarity of dissolution profiles of T and R e.g., using f2-test, unless similarity is obvious (see e.g. WHO QAS/04.093 sect. 9.2 or app. 2 of the EU guidance; note prerequisites) The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  30. BCS-based biowaiver f2-test • acceptance value based on 10 % difference between profiles • „identical“ profiles: f2 =100 „similar“ profiles: f2 between 50 and 100 (?!) • any other reasonable/justified test possible! The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  31. BCS-based biowaiver • Requirement: either very rapid or “similar” in vitro dissolution • how similar is ‘similar’? • discussion of differences usually not appropriate The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  32. BCS-based biowaiver BCS based biowaiver in vitro dissolution • no iviv correlation • no biorelevant conditions (except pH) • concept to justify absence of difference! The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  33. BCS-based biowaiver • Evaluation of excipients (e.g., large amounts, possible interactions....; e.g. Isoniazid J Pharm Sci 96 March 07: “…permeability changes due to excipient interaction cannot be detected in vitro…”) • Evaluation of manufacturing processes in relation with critical physicochemical properties The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  34. BCS-based biowaiver BCS-based Biowaiver for immediate release drug products containing highly soluble, highly permeable drug substances. No BCS-based biowaiver for: • locally applied, systemically acting products • non-oral immediate release forms with systemic action • modified release products • transdermal products The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  35. BCS-based biowaiver Provided that ...... • drug solubility is high, • permeability is limited, • excipients do not affect kinetics, • excipients do not interact ,..... The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  36. BCS-based biowaiver ....then very rapid dissolution (e.g.>85% in 15 min) of test and reference may ensure similar product characteristics because... ....absorption process is probably independent from dissolution and almost not product related…  limited absorption kinetics due to poor drug permeability and/or gastric emptying • Biowaiver for BCS class III drugs The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  37. BCS-based biowaiver For drugs showing .... • ‘very’ high permeability • pH-dependent solubility within the physiologically relevant pH range .....an ‘intermediate solubility’ class is suggested [Polli et al. J Pharm Sci 93 (2004) 1375] The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  38. BCS-based biowaiver pH-dependent soluble, highly permeable, weak acidic, ionizable drug compounds may be handled like BCS class I drugs(e.g. chpt 8 in: Drug Bioavailability, van de Waterbeemd, Lennernäs, Artursson (edts) 2003 Wiley-VCH) • in vitro dissolution requirements acc. to WHO doc • at least 85% within 30 min at pH 6.8 and f2 testing for pH 1.2 and 4.5 profiles • but no biowaiver for weak basic drugs The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  39. BCS-based biowaiver • meaningful literature data may be used for drug substance characteristics (and excipients) • product related data must always be actually generated for the particular product The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  40. BCS-based biowaiver • BCS-based biowaiver are not just in-vitro dissolution, but in-vitro dissolution is meant to be an important part of BCS-based biowaiver applications The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

  41. BCS-based biowaiver THANK YOU FOR YOUR ATTENTION! The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

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