WHO Training Workshop on Pharmaceutical Quality, Good Manufacturing Practice & Bioequivalence Biowaiver

1. WHO Training Workshop on Pharmaceutical Quality, Good Manufacturing Practice & Bioequivalence Biowaiver Kiev, October 3-7, 2005Dr. H. Potthast (h.potthast@bfarm.de)

2. Basis for Biowaiver Applications/Decisions • Note for Guidance on the Investigation of Bioavailability and Bioequivalence” CPMP/EWP/QWP/1401/98; paragraph 5.1 • 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) • Current scientific discussion

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. Biowaiver - Multiple Strengths • For IR oral dosage forms one BE study using (usually) the highest strength may be sufficient for all strengths if… • same manufacturer and process • linear drug input (if this is not the case…..) • same qualitative composition of different strengths • same ratio between active substance and excipients, or same excipients in case of low concentration (less than 5 %) • similar in vitro dissolution (see e.g. 5.4 of EU guidance) also valid for MR products acc. e.g. to 5.1 of EU guidance CPMP/EWP/280/96

5. Biowaiver - Multiple Strengths • in case of non-linear pharmacokinetics… • …if AUC increases more than proportional, in vivo BE testing at least of the highest dose strength • …if AUC increases less than proportional, in vivo BE testing at least of the lowest dose strength • …in case of insufficient or no information, in vivo BE testing at least of the lowestand highest dose strength

6. Biowaiver – Test vs Reference ‘Biowaiver’..... .....is defined as • in vitro instead of in vivo bioequivalence testing • comparison of test and reference ....is not defined as • no bioequivalence test

7. 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)

8. EU Note for Guidance.... In vivo bioequivalence testing is generally required but acc. to paragr. 4.2 and 5.1: ” 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!

9. EU Note for Guidance.... Biowaiver justification paragr. 5.1.1: ”This section .........takes into consideration criteria derived from the concepts underlying the Biopharmaceutics Classification System ......”

10. BCS based Biowaiver Evaluation of drug substance and drug product Drug substance • pharmacodynamic/therapeutic aspects • physicochemical aspects Drug product • in vitro dissolution

11. Drug Substance Characteristics I EU NfG paragr. 5.1.1 a)i “Risk of therapeutic failure or adverse drug reactions” (e.g., narrow therapeutic index drugs) examples: Theophylline, Carbamazepine b)ii“Risk of bioinequivalence” (i.e., bioavailability problems are evident) examples: Ciclosporine, Glibenclamide

12. Drug Substance Characteristics II Biopharmaceutics Classification System (BCS) dissolution drug product  drug substance in solution membrane transport  drug substance in the system simplified mechanistic view of bioavailability

13. BCS Assumption ♦….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?

14. BCS Assumption Pillars of the BCS SolubilityPermeabilityDissolution

15. 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]

16. Drug Substance Characteristics III High solubility (acc. to BCS) • the highest single unit dose is completely soluble in 250 ml of aqueous solution at pH 1-8 (37 °C) recommended investigations at pH 1, 4.6, 6.8 and pka cave: possible stability problems have to be considered • Discussion on ‘intermediate solubility’, i.e., pH-dependent (high) solubility • Definition of low solubility?

17. Drug Substance Characteristics IV High permeability (acc. to BCS) • EU guidance: ”Linear and complete absorption reduces the possibility of an IR dosage form influencing the bioavailability” • FDA guidance: absolute BA >90 % • Human data are preferred; in vitro data may be submitted if sufficiently justified and valid • Definition of low permeability?

18. Drug Substance Characteristics IV ♦ Methods to determine permeability • Non-clinical methods • Cell cultures (eg CaCo-2) • Animal studies (everted rat gut) Clinical methods • Intestinal perfusion • (Loc-I-gut system) • Absolute bioavailability • (mass balance)

19. Fig.2: Relation of human permeability and absorption [R. Löbenberg, G.L.Amidon/ Eur J Pharm Biopharm 50 (2000), 3-12]

20. Drug Substance Characteristics V ”More factors affect bioavailability when absorption is slow or incomplete than when it is rapid and complete,hence, slow or incomplete absorption often leads to variable therapeutic responses.” [Turner et al.Pharm Res 21(2004)68] “Dynamic character of the dissolution/uptake process”[Rinaki et al. Pharm Res 21 (2004) 1567]

21. Drug Substance Characteristics VI Absorption  Bioavailability but... High bioavailability  High absorption Low bioavailability (not necessarily)Low absorption

22. Drug Substance Characteristics VII

23. Drug Substance Characteristics VIII Additional aspects to be considered: • prodrugs • effective metabolites • instability • polymorphic forms • stereochemistry (enantiomer/racemate) • wide therapeutic dose range ..........

24. BCS Concept • 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?

25. Drug PRODUCT characteristics I In vitro comparison of immediate release oral drug products (T and R) • Not less than 85 % of labeled amount are dissolved within 15 min in each of three buffers (pH 1 – 8) – no further comparison of T and R is required • Proving similarity of dissolution profiles of T and R e.g., using f2-test, unless similarity is obvious (see app. 2 of the EU guidance; note prerequisites) • reasonable experimental conditions/methods are strongly recommended!

26. Drug product characteristics II • Evaluation of excipients (e.g., large amounts, possible interactions....) • Evaluation of manufacturing processes in relation with critical physicochemical properties

27. EU/FDA Guidance Biowaiver for immediate release drug products containing highly soluble, highly permeable drug substances only. No biowaiver for: • locally applied, systemically acting products • non-oral immediate release forms with systemic action • modified release products • transdermal products

28. Biowaiver Extensions ?! Provided that ...... • drug solubility is high, • permeability is limited, • excipients do not affect kinetics, • excipients do not interact ,.....

29. Biowaiver Extensions ?! ....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 not product related…  limited absorption kinetics due to poor drug permeability and/or gastric emptying • Biowaiver for BCS class III drugs (e.g. Atenolol)?!

30. Biowaiver Extensions ?! 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]

31. Biowaiver Extensions ?! „pH-dependant soluble, highly permeable, weak acidic, ionizable drug compounds may be handled like BCS class I drugs“ (quotation) • Current discussions on in vitro dissolution requirements?! • Probably no biowaiver for weak basic drugs (personal communication)

32. Biowaiver Extensions ?! „BDDCS - Biopharmaceutics Drug Disposition Classification System“ “Consideration of elimination criteria may expand number of class 1 drugs eligible for a waiver of in vivo BE studies and provide predictability of drug disposition profiles for classes 2, 3, and 4 compounds.” (Wu et al., Pharm Res 22 (2005) 11)

33. Biowaiver Documentation I • Evaluation of possible therapeutic risks related to bio(in)equivalence Discussion of relevant pharmacokinetic characteristics e.g.: therapeutic range metabolism kinetic linearity ‘absorption window’ variability....

34. Biowaiver Documentation II Physicochemical characterisation of the drug substance • solubility • permeability/absorption • stability Documentation of analytical method validation

35. Biowaiver Documentation III Evaluation of product characteristics • comparison of in vitro dissolution of test and reference • evaluation of excipients • evaluation manufacturing process Documentation of analytical method validation

36. Biowaiver Documentation IV • meaningful literature data may be used for drug substance characteristics (and excipients) • product related data (incl. in vitro dissolution) must always be actually generated for the particular product

37. Biowaiver Application • for generic drug applications • variations • development/new drug products (e.g., bridging studies, pilot BA batch vs production batch)

38. Biowaiver THANK YOU FOR YOUR ATTENTION!