| Slide 1 of 25 Dr Rägo 28 April – 2 May 2008 Pharmaceutical Development with Focus on Paediatric formulations WHO/FIP Training Workshop Hyatt Regency Hotel Sahar Airport Road Andheri East, Mumbai, India 28 April 2008 – 2 May 2008

| Slide 2 of 25 Dr Rägo 28 April – 2 May 2008 Biopharmaceutical Classification System (BCS) Presented by: Lembit Rägo MD, PhD Contact details: Dr Lembit Rägo Coordinator, Quality Assurance and Safety: Medicines Medicines Policy and Standards World Health Organization Geneva Switzerland

| Slide 3 of 25 Dr Rägo 28 April – 2 May 2008 Biopharmaceutical Classification System (BCS) Background What is a problem? What is WHO doing and planning to do? What resources are available? Conclusions

| Slide 4 of 25 Dr Rägo 28 April – 2 May 2008 What is the key for multisource (generic) pharmaceutical products? New medicines – applicant has to prove quality, safety and efficacy Multisource (generic) pharmaceutical products – applicant has to prove quality, in case of safety and efficacy it refers to the originator product The key is THERAPEUTIC INTERCHANGEABILITY –It is assumed that if the concentration pattern in the blood is essentially the same then the safety and efficacy profile must be essentially the same

| Slide 5 of 25 Dr Rägo 28 April – 2 May 2008 Therapeutic interchangeability: prerequisites Constant and reproducible quality of MPPs –Manufactured under GMP –Compliance with all quality specifications Variations control No constant and reproducible quality, no need for proving interchangeability as it is meaningless (all batches different anyhow…)

| Slide 6 of 25 Dr Rägo 28 April – 2 May 2008 Options to show therapeutic interchangeability of multisource pharmaceutical products (MPP) Experimental settingSensitivity/use Comparative pharmacokinetic studies in humans – evaluation of systemic exposure by means of pharmacokinetic measures like e.g. AUC and Cmax (and Tmax) Generally regarded as most sensitive Comparative in vitro tests – BCS-based biowaiver Prerequisites should be noted Comparative pharmacodynamic studies in humans – evaluation of relevant pharmacodynamic endpoints like e.g., lowered blood pressure in mm Hg Sensitivity may not be optimal, rarely used comparative clinical trials – evaluation of e.g., non-inferiority trials Rarely used for oral MPP formulations with systemic actions

| Slide 7 of 25 Dr Rägo 28 April – 2 May 2008 The in vitro approach refers to the Biopharmaceutics Classification System (BCS) PermeabilitySolubilityBCS classification High BCS class I HighLowBCS class II LowHighBCS class III Low BCS class IV Drug substance classification according to the BCS. Active pharmaceutical ingredients (APIs) are classified into classes based on their aqueous solubility and permeability characteristics

| Slide 8 of 25 Dr Rägo 28 April – 2 May 2008 In Vitro Approaches/Biowaiver options The possibility of ‘in vitro documentation of bioequivalence’ for ‘certain medicines and dosage forms’ is specified in Section 9 of the WHO guidance document [1]. If the drug substance in question is highly soluble and highly permeable (BCS class I) and is manufactured as an immediate release dosage form, exemption from an in vivo pharmacokinetic bioequivalence study may be considered provided that relevant dissolution requirements are fulfilled.

| Slide 9 of 25 Dr Rägo 28 April – 2 May 2008 Principles The solubility is not meant to be the absolute solubility here. In contrast high solubility refers to the highest single unit dose to be completely soluble in 250 ml aqueous buffer medium within the pH range of 1.2 to 6.8 without any stability problems. As another related physicochemical characteristic high permeability should be demonstrated for the particular API demonstrating that the fraction dose absorbed amounts to at least 85 %. Accordingly, high permeability would stand for almost complete absorption of the compound in humans. Physicochemical measures needed for BCS classification purposes may be taken from sound literature. The WHO Model List of Essential Medicines has been reviewed based on the BCS concept and active compounds are classified accordingly in the appendix of respective WHO document [1].

| Slide 10 of 25 Dr Rägo 28 April – 2 May 2008 A theoretical risk assessment is mandatory to minimize risk for falsely waiving a necessary in vivo study Formulation related considerationsImmediate release dosage forms with intended systemic action - non-oral, non-parenteral products with systemic action (e.g. transdermal therapeutic systems (TTS), suppositories, etc.) - critical use medicines (e.g. hormones) - modified release products with systemic action - narrow therapeutic range (steep dose- response curve) drugs - fixed combination products with at least one API requiring an in vivo study i.e., this API is not eligible for the BCS based biowaiver approach - where there are documented evidence of bioavailability problems (or bio-inequivalence - non-solution products with non-systemic action (and without systemic absorption*), e.g., topical, locally acting emulsions - polymorphs, certain excipients, or a manufacturing process which may have implications for bioavailability Situations where BCS-based biowaivers are not applicable

| Slide 11 of 25 Dr Rägo 28 April – 2 May 2008 Assessment of risks – practical points In practice some of the criteria listed in the table for risk assessment are difficult to assess e.g., the meaning of ‘critical use’ or ‘bioavailability problems’, and are probably not easy to be defined. However, published literature provides valuable examples of how to evaluate the applicability of the BCS based biowaiver approach (see biowaiver monographs on the following slide).

| Slide 12 of 25 Dr Rägo 28 April – 2 May 2008 Available resources: Biowaiver Monographs Biowaiver monographs are worked out by group of well established scientists linked to FIP and published in Journal of Pharmaceutical Sciences These can be useful scientific material for manufacturers when considering applications for biowaiver based on BCS The monographs as such have no "regulatory authority" – decisions will be made by regulators who may or may not accept biowaiver depending on their national legislation and requirements

| Slide 13 of 25 Dr Rägo 28 April – 2 May 2008 Biowaiver monographs published Stosik A.G., Junginger H.E., Kopp S., Midha K.K., Shah V.P., Stavchansky S., Dressman J.B., Barends D.M.: Biowaiver monographs for immediate release solid oral dosage forms: metoclopramide hydrochloride. J Pharm Sci Feb 12 (2008) Becker C., Dressman J.B., Amidon G.L, Junginger H.E., Kopp S., Midha K.K., Shah V.P., Stavchansky S., Barends D.M.: Biowaiver monographs for immediate release solid oral dosage forms: Pyrazinamide. J Pharm Sci Feb 12 (2008) Becker C., Dressman J.B., Amidon G.L, Junginger H.E., Kopp S., Midha K.K., Shah V.P., Stavchansky S., Barends D.M.: Biowaiver monographs for immediate release solid oral dosage forms: ethambutol dihydrochloride. J Pharm Sci Aug 21 (2007) Becker C., Dressman J.B., Amidon G.L, Junginger H.E., Kopp S., Midha K.K., Shah V.P., Stavchansky S., Barends D.M.:Biowaiver monographs for immediate release solid oral dosage forms: isoniazid. J Pharm Sci 96 (2007)

| Slide 14 of 25 Dr Rägo 28 April – 2 May 2008 WHO Guidance (1) The in vitro dissolution investigations including experimental conditions and characteristics are outlined in Section 9 of the WHO guideline [1]. It is of utmost importance to note that it is not sufficient to demonstrate the in vitro dissolution characteristics for the particular multisource product, but to ensure ‘the similarity of dissolution profiles between the test and comparator products’ [1].

| Slide 15 of 25 Dr Rägo 28 April – 2 May 2008 WHO guidance (2) The WHO guidance in basic aspects is similar to the US FDA guidance on the biowaiver approach (August 2000) In addition, the current scientific discussions in terms of so called ‘biowaiver extensions’ are also considered. Accordingly, BCS based biowaivers may be acceptable for drugs containing BCS class 2 and 3 drug substances manufactured as immediate release dosage forms. As an example, a biowaiver may be possible for BCS class 3 drug products that are ‘very rapidly’ (i.e. at least 85 % dissolution within 15 min in all required media) dissolving. The relevant dissolution criteria are outlined in section of the WHO guideline [1].

| Slide 16 of 25 Dr Rägo 28 April – 2 May 2008 Regulators guidance for industry US FDA relevant to biowaiver guidelines: nl.pdf

| Slide 17 of 25 Dr Rägo 28 April – 2 May 2008 Conclusions Biowaiver concept is a developing concept and new guidance documents and scientific data are appearing Proper comparator products are also crucial for biowaiver Regulatory acceptance and practice of biowaivers needs to catch up the concept development WHO will soon issue more practical implementation guidelines for PQ programme WHO PQ programme starts accepting biowaivers, as appropriate

| Slide 18 of 25 Dr Rägo 28 April – 2 May 2008 Some useful references (1) Multisource (generic) pharmaceutical products: Guidelines on registration requirements to establish interchangeability. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations, Fortieth Report. Geneva, World Health Organization, 2006, WHO Technical Report Series, No. 937, Annex 7: (2) van Faassen F., Vromans H. et al. Biowaivers for oral immediate-release products: implications of linear pharmacokinetics. Clin Pharmacokinet 43 (2004) (3) Note to Applicants on the Choice of Comparator Products for the Prequalification Project. Located on the World Health Organization (WHO) Prequalification of Medicines web site, Guidance on selection of comparator product. Web page: (4) Shah, V.P. et al. Bioanalytical method validation – a revisit with a decade of progress. Pharmaceutical Reseach, 17 (2000) (5) Schuirmann, D.J. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. Journal of Pharmacokinetics and Biopharmaceutics, 15 (1987) (6) Westlake, W.J. Bioavailability and bioequivalence of pharmaceutical formulations. In: Peace, K.E. ed. Biopharmaceutical statistics for drug development. New York, Marcel Dekker, Inc., 1988: (7) Guidelines for registration of fixed-dose combination medicinal products. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations, Thirty-ninth report. Geneva, World Health Organization, 2005 (WHO Technical Report Series, No. 929, Annex 5):