WHO Workshop on Assessment of Bioequivalence Data Addis Ababa, 31. August – 3. September 2010 BCS-based Biowaivers

1. WHO Workshop on Assessment of Bioequivalence Data • Addis Ababa, 31. August – 3. September 2010 • BCS-based Biowaivers Dr. Henrike Potthast(henrike.potthast@bfarm.de) WHO Workshop on Assessment Bioequivalence Data, Addis Ababa, 31. August-3.September, 2010

2. Basis for BCS-based Biowaiver Applications/Decisions • WHO – Technical Report Series No. 937, May 2006 Annex 7: Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability Annex 8: Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate release, solid oral dosage forms • 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) • EU-guidance:“Note for Guidance on the Investigation of Bioavailability andBioequivalence” CPMP/EWP/QWP/1401/98 Rev1, Appendix 3

3. 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

4. Definitions • Bioequivalence study • in vivo comparison using humans as dissolution models • ‚biological quality control‘ • comparative evaluation of the formulation effect • Bioequivalence therapeutic equivalence

5. 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

6. 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)

7. 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!

8. BCS-based biowaiver Evaluation of drug substance and drug product Drug substance • therapeutic aspects • physicochemical aspects Drug product • in vitro dissolution

9. BCS-based biowaiver Biowaiver justification based on ”………criteria derived from the concepts underlying the Biopharmaceutics Classification System ......”

10. 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

11. 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]

12. BCS-based biowaiver Pillars of the BCS SolubilityPermeabilityDissolution Absorption

13. BCS-based biowaiver High solubility • the highest single dose is completely soluble in 250 ml or less of aqueous solution at pH 1 - 6.8 (37 °C) • generate 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?

14. BCS-based biowaiver High solubility acc. to WHO • highest dose recommended by WHO (as recommended in the WHO Model List of Essential Medicines) or • highest dose strength(if not listed s.o.) • please note the differences between guidelines!

15. BCS-based biowaiver High permeability • Revised EMA guidance: extent of absorption ≥ 85 % (absolute BA or mass balance data) or ‘known absorption’ • FDA guidance: absolute BA >90 % • WHO guidance: extent of absorption at least 85 % in humans • Human data are preferred; in-vitro data may be submitted if sufficiently justified and valid • Definition of low permeability?

16. BCS-based biowaiver Methods to investigate permeability • PK-studies (e.g. absolute BA or mass-balance studies) • Human intestinal perfusion studies • Animal models • Caco 2 cell lines or other suitable, validated cell lines (in-situ or in-vitro models for passively transported APIs only) • to be noted: the stated methods assess the fraction dose absorbed ≠ BA, which can be reduced substantially by first-pass metabolism (see e.g. Propranolol)

17. BCS-based biowaiver Supportive data to investigate permeability: • In vivo or in situ perfusion using animal models and • In vitro permeation across a monolayer of cultured epithelial cells like e.g. Caco 2 or other suitable, validated cell lines are not acceptable on a stand-alone basis (in-situ or in-vitro models for passively transported APIs only; negative as well as positive controls needed)

18. BCS-based biowaiver

19. BCS-based biowaiver Provided that ...... drug solubility is high, • permeability is limited, • excipients do not affect kinetics, • excipients do not interact ,.....

20. BCS-based biowaiver ....then very rapid dissolution (at least >85% in 15 min) of test and reference may ensure similar product characteristics because... ....absorption process is probably independent from dissolution and not product related…  limited absorption kinetics due to poor drug permeability and/or gastric emptying • Biowaiver for BCS class III drugs (see WHO and revised EMA guidance)

21. BCS-class III?! Fig. 1. Mean in vitro dissolution profiles of metformin for 500mg immediate-release tablet of Glucophage® or Glucofit® in 0.1N HCI (○,●) pH 4.6 (□,■) and pH 6.8 (∆,▲) buffer solution.

22. BCS-class III?! Fig. 2. Mean in vivo plasma conentration-time profiles of metformin in 12 healthy Chinese subjects after oral administration of a 500mg immediate-release tablet of Glucophage (○) or Glucofit (●). Fig. Fig. 2

23. BCS-class III?! Fig. 1. Comparison of mean cimetidine released-time profiles obtained from dissolution testing of cimetidine tablets containing methacrylate copolymer and Tagamet® tablets in different media. Each value is the mean of six observations. Data for the Tagamet® tablet were obtained from dissolution testing in 0.01N hydrovhloric acid (HCI) and simulated intestinal fluid without pancreatin (SIFsp): (a) 0.01N HCI, pH 2; (b) phosphate buffer, pH 4.5; (c) SIFsp, pH 6.8; and (d) fasted-state simulated intestinal fluid, pH 6.5 pancreatin. Clin Pharmacokinet. Jantratid et al 2006

24. BCS-class III?! Fig. 2.Comparison of mean plasma cimetidine concentration-time profiles obtained after administration of a singel oral dose of cimetidine tablets containing methacrylyte copolymer or Tagamet® tablets. Each point represents the mean plasma cimetidine concentration (standard error) from 12 subjects. Clin Pharmacokinet. Jantratid et al 2006

25. 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; see WHO guidance]

26. 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 guidance • 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

27. BCS-based biowaiver According to the WHO guideline drug substances that belong to • BCS-class 1 and 3 • and some of BCS class 2(weak acids with high permeability) ..... are in principle eligible for the BCS-based biowaiver approach

28. BCS-based biowaiver BCS-based biowaiver approach applicable….. • pro-drugs? • effective metabolites? • instability? • polymorphic forms? • stereochemistry (enantiomer/racemate)? • wide therapeutic dose range? ..........

29. BCS-based biowaiver RISKassessment (see e.g. WHO guidance; 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”

30. 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?

31. 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 to detect possible formulation related differences?

32. 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 • ….

33. BCS-based biowaiver ‘usual’ in vitro dissolution prerequisites • reasonable, stability-indicating, validated methods • discriminative methods • reproducible methods • biorelevant methods (?) ……one fits all?!

34. BCS-based biowaiver in vitro dissolution and BCS concept • use of representative batches • meet prerequisites • ensure risk minimization • justify absence of difference • biorelevant?!

35. BCS-based biowaiver In vitro comparison of immediate release oral drug products (T and R) first option: very rapidly 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!

36. BCS-based biowaiver In vitro comparison of immediate release oral drug products (T and R) second option: rapidly 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!

37. BCS-based biowaiver Experimental conditions: • EU guidance – • usually 50 rpm (paddle) or 100 rpm (basket); 900 ml; PhEur buffer; 37 °C; sampling schedule • 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 or less; USP buffer; 37 °C • all: no surfactants!

38. 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 guidance sect. 9.2 or app. 1 of the revised EU guidance; note prerequisites)

39. 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!

40. BCS-based biowaiver • requirement: either “very rapid” or “similar” in vitro dissolution • how similar is ‘similar’? • discussion of differences usually not appropriate

41. BCS-based biowaiver BCS-based biowaiver in-vitro dissolution • no iviv correlation • no biorelevant conditions (except pH) • concept to justify absence of difference!

42. BCS-based biowaiver finally EXCIPIENTS • Evaluation of excipients(e.g., large amounts, possible interactions....; e.g. IsoniazidJ Pharm Sci 96 March 2007: “…permeability changes due to excipient interaction cannot be detected in vitro…”) • Evaluation of manufacturing processes in relation with critical physicochemical properties

43. BCS-based biowaiver Risk assessment on EXCIPIENTS acc. to WHO • i) the excipient is present in the comparator product, or the excipient is present in a number of other products which contain the same API as the multisource drug product and which have marketing authorizations in countries participating in the International Committee on Harmonisation (ICH) or associated countries; and • ii) the excipient is present in the multisource product in an amount similar to that in the comparator, or the excipient is present in the multisource drug product in an amount typically used for that type of dosage form.

44. BCS-based biowaiver Excipients – generally • Should be ‘well-known’ • Used in ‘usual amounts’ • Without relevant impact on the absorption process Preferred for class I drugs and requested for class III: • same excipients in • similar amounts as the reference ‘Critical’ excipients (e.g. surfactants, mannitol, sorbitol…) should be qualitatively and quantitatively the same

45. BCS-based biowaiver Summary Requirements - BCS class 1 • „Dosage forms of APIs which are highly soluble, highly permeable (BCS Class 1), and are rapidly dissolving are eligible for a biowaiver based on the BCS provided: • (i) the dosage form is rapidly dissolving(as defined in section 9.1.2.2) and the dissolution profile of the multisource product is similar to that of the comparator product at pH 1.2, pH 4.5 and pH 6.8 buffer using the paddle method at 75 rpm or the basket method at 100 rpm (as described in section 9.2) and meets the criteria of dissolution profile similarity, f2 > 50 (or equivalent statistical criterion); • (ii) if both the comparator and the multisource dosage forms are very rapidly dissolving (as defined in section 9.1.2.1) the two products are deemed equivalent and a profile comparison is not necessary.“ (see WHO technical Report Series, No. 937, 2006 Annex 7 and 8)

46. BCS-based biowaiver Summary Requirements - BCS class 3 • „Dosage forms of APIs which are highly soluble and have low permeability (BCS Class 3) are eligible for biowaivers provided all the criteria (a–d) listed in section 9.2 are met and the risk–benefit is additionally addressed in terms of extent, site and mechanism of absorption.“ • Very rapidly dissolving (release of >85 % within 15 min) in standard media pH 1.2, 4.5, and 6.8; 75 rpm (paddle) or 100 rpm (basket) applies to IR products containing class III APIs. (see WHO technical Report Series, No. 937, 2006 Annex 7 and 8)

47. BCS-based biowaiver Summary Requirements - BCS class 3 ctd. - criteria (a–d) listed in section 9.2: • A biowaiver based on the BCS considers: (a) the solubility and permeability of the API (see section 9.1); (b) the similarity of the dissolution profiles of the multisource and comparator products in pH 1.2, 4.5 and 6.8 media (see below); (c) the excipients used in the formulation (see below); and (d) the risks of an incorrect biowaiver decision in terms of the therapeutic index of, and clinical indications for, the API (see section 5.1 for cases where an in vivo study would be required to demonstrate bioequivalence). (see WHO technical Report Series, No. 937, 2006 Annex 7)

48. BCS-based biowaiver Summary Requirements - BCS class 2 • „Dosage forms of APIs with high solubility at pH 6.8 but not at pH 1.2 or 4.5 and with high permeability (by definition, some but not all BCS Class 2 compounds with weak acidic properties) are eligible for a biowaiver based on BCS provided that criteria (b), (c) and (d) described in section 9.2. are met, that the API has high permeability (i.e. the fraction absorbed is 85% or greater) and a dose:solubility ratio of 250 ml or less at pH 6.8, and that the multisource product:…. (see WHO technical Report Series, No. 937, 2006 Annex 7)

49. BCS-based biowaiver Summary Requirements - BCS class 2 ctd….. • „is rapidly dissolving (85% in 30 minutes or less) in pH 6.8 buffer using the test procedure conforming to section 9.2; and • (ii) the multisource product exhibits similar dissolution profiles, as determined with the f2 value or equivalent statistical evaluation, to those of the comparator product at the three pH values (pH 1.2, 4.5 and 6.8).“ (see WHO technical Report Series, No. 937, 2006 Annex 7)

50. BCS-based biowaiver Summary Requirements - BCS class 2 ctd…. • „For multisource products containing Class 2 APIs with dose:solubility ratios of 250 ml or less at pH 6.8, the excipients should additionally be critically evaluated in terms of type and amounts, e.g. of surfactants, in the formulation. Further, if the Cmax is critical to the therapeutic efficacy of the API, the risk of reaching an inappropriate biowaiver decision and its associated risks to public health and for individual patients may be deemed unacceptable.“ (see WHO technical Report Series, No. 937, 2006 Annex 7)