Training Workshop: Training of BE Assessors Kiev, October 2009 BCS-based Biowaivers

1. Training Workshop: Training of BE Assessors • Kiev, October 2009 • BCS-based Biowaivers Dr. Henrike Potthast(h.potthast@bfarm.de) Training workshop: Training of BE Assessors, Kiev, October 2009

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; paragraph 5.1

3. 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

4. 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)

5. 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

6. 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!

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

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

9. 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

10. 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]

11. BCS-based biowaiver Pillars of the BCS SolubilityPermeabilityDissolution

12. 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?

13. 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?

14. 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)

15. BCS-based biowaiver

16. 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”

17. BCS-based biowaiver ♦„….Risk assessment: only if the risk of an incorrect biowaiver decision and an evaluation of the consequences (of an incorrect, biowaiver-based equivalence decision) in terms of public health and risks to individual patients is outweighed by the potential benefits acrued from the biowaiver approach may the biowaiver procedure be applied…“ [WHO Technical Report Series, No. 937, 2006; Annex 8]  is the concept scientifically sound?

18. 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?

19. 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?

20. 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 • ….

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

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

23. 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!

24. 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!

25. 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 or less; USP buffer; 37 °C • all: no surfactants!

26. 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. 2 of the current EU guidance; note prerequisites)

27. 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!

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

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

30. BCS-based biowaiver • 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

31. 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 should be qualitatively and quantitatively the same

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

33. 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 guidance)

34. 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.

35. 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

36. 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

37. 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

38. 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]

39. 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

40. 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

41. 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

42. BCS-based biowaiver • Current recommendation for TB drugs • no BCS-based biowaiver for RMP • ‘regular’ BCS-based biowaiver possible for levofloxacin and ofloxacin (“rapid dissolution”) • currently a BCS-based biowaiver is possible for isoniazid (cave: excipients!), ethambutol and pyrazinamide if the same “very rapid” dissolution (T and R) is demonstrated • see specific, currently published WHO guidance documents at: http://healthtech.who.int/pq/info_applicants/info_for_applicants_BE_studies.htm

43. BCS-based biowaiver Some remarks: ♦ biopharmaceutics assessment (with necessary underlying PK background!!) ≠ pure PK assessment ♦ differentiation between solubility (API) and dissolution (product performance) ♦ volume of dissolution medium (900 vs 500 ml) not relevant (no concerns regarding hydrodynamics; recent findings); sink conditions! ♦ in-vitro/in-vivo relationship rather than correlation!! ♦ note differences regarding the evaluation of excipients!!

44. BCS-based biowaiver • Becker C, Dressman JB, Amidon GL, Junginger HE, Kopp S, Midha KK, Shah VP, Stavchansky S, Barends DM: Biowaiver monographs for immediate release solid oral dosage forms: Pyrazinamide; J Pharm Sci. 2008 Feb 12; [Epub ahead of print] • Becker C, Dressman JB, Amidon GL, Junginger HE, Kopp S, Midha KK, Shah VP, Stavchansky S, Barends DM: Biowaiver monographs for immediate release solid oral dosage forms: ethambutol dihydrochloride; J Pharm Sci. 2008 Apr;97(4):1350-60. • Vogt M, Derendorf H, Krämer J, Junginger HE, Midha KK, Shah VP, Stavchansky S, Dressman JB, Barends DM: Biowaiver monographs for immediate release solid oral dosage forms: prednisone; J Pharm Sci. 2007 Jun;96(6):1480-9. • Becker C, Dressman JB, Amidon GL, Junginger HE, Kopp S, Midha KK, Shah VP, Stavchansky S, Barends DM; International Pharmaceutical Federation, Groupe BCS: Biowaiver monographs for immediate release solid oral dosage forms: isoniazid; J Pharm Sci. 2007 Mar;96(3):522-31. • Kalantzi L, Reppas C, Dressman JB, Amidon GL, Junginger HE, Midha KK, Shah VP, Stavchansky SA, Barends DM: Biowaiver monographs for immediate release solid oral dosage forms: acetaminophen (paracetamol); J Pharm Sci. 2006 Jan;95(1):4-14. • Potthast H, Dressman JB, Junginger HE, Midha KK, Oeser H, Shah VP, Vogelpoel H, Barends DM: Biowaiver monographs for immediate release solid oral dosage forms: ibuprofen; J Pharm Sci. 2005 Oct;94(10):2121-31. • Kortejärvi H, Yliperttula M, Dressman JB, Junginger HE, Midha KK, Shah VP, Barends DM: Biowaiver monographs for immediate release solid oral dosage forms: ranitidine hydrochloride; J Pharm Sci. 2005 Aug;94(8):1617-25. • Verbeeck RK, Junginger HE, Midha KK, Shah VP, Barends DM: Biowaiver monographs for immediate release solid oral dosage forms based on biopharmaceutics classification system (BCS) literature data: chloroquine phosphate, chloroquine sulfate, and chloroquine hydrochloride; J Pharm Sci. 2005 Jul;94(7):1389-95. ……….

45. BCS-based biowaiver THANK YOU FOR YOUR ATTENTION!