Training Workshop on Dissolution, Pharmaceutical Product Interchangeability and Biopharmaceutical Classification System.

1. Multisource (generic) products and Interchangeability Training Workshop on Dissolution, Pharmaceutical Product Interchangeability and Biopharmaceutical Classification System. Hotel Bratislava 1 Malyshko Street Kyiv, Ukraine Date: 25 to 27 June 2007

2. Pharmaceutical Development Classification of the Essential Medicines List (EML) according to BCS Presenter: Marc Lindenberg Analytical Development (PTDF-A) F. Hoffmann-La Roche Ltd. Basel, Switzerland E-mail: marc.lindenberg@roche.com

3. What does BCS stand for? • Biopharmaceutics Classification System

4. Criteria for „high“ solubility - FDA • Highest single dosage strength divided by the solubility of the compound over the pH range 1-7.5 at 37°C • <250 ml „highly“ soluble • 250 ml: Amount of fluid present in the upper GI-tract when administering the drug in the fasted state • Method of choice: saturation shake-flask method • Other methods are accepted if shown to produce similar results to the shake-flask method

5. Criteria for „high“ permeability - FDA • Permeability > 90% „highly“ permeable • Measured in humans, animals or suitable cell lines (Caco II cells) • Determination in Caco II cells only applicable to passively absorbed substances • Traning set to validate the cell experiments required

6. Biowaiver - FDA • Approval of SUPAC changes or of a generic product on the basis on in vitro tests alone • Requires: • Class I compound • >85% dissolved within 30 minutes in media which mimic physiological pH values (pH 1.2 – 6.8) @ 50 rpm paddle or @ 100 rpm basket • No addition of lecithin, bile salts or enzyme

7. BCS – WHO classification • Differences to FDA requirements: • Solubility determination at pH 1.2 – 6.8 • Permeability > 85 % leads to a „highly“ permeable classification • Biowaiver: Class III copmound are eligible biowaiver if they dissolve within 15 minutes in buffer media pH 1.2 –6.8 (75 rpm) • Biowaiver: Class II acids with D:S ratio < 250 ml in at pH 6.8 and > 85 % dissolved within 30 minutes at pH 6.8 (75 rpm)

8. WHO Essential Medicines List (EML) • Minimum medicine needs for a basic health system (core list) • Complementary list includes medicines which require specialized equipment (e.g. for monitoring) or specialist training • Selected by relevance, safety and cost-effectiveness • Newest version may be downloaded here: • http://www.who.int/medicines/publications/EssMedList15.pdf

9. Methods • Literature search for suitable solubility and permeability data • Missing or insufficient solubility data was supplemented by experimental determination

10. Solubility determination: Sources • Literature: Martindale, Merck Index, Florey`s Analytical Drug Profiles,… • Internet: Medline with different keywords (e.g. aqueous, solubility…) • Experiments: Saturation shake-flask method

11. Solubility determination: Experiments • Excess of substance is weighed into a vessel (2-3 times expected solubility) • Exact amount of buffer medium is added • Put on an orbital shaker for a specified amount of time at 37°C • Measure concentration at specific time points • Ensure that no degradation occurs or that degradation is detected via analytical method

12. Solubility determination: Problems with literature data • Solubility only tested in water • Solubility tested only at room temperature • Only one pH value tested • Was the pH value kept constant throughout the whole experiment? • Was the pH value measured in a buffered medium or only adjusted by addition of acid or base?

13. Solubility determination: Flow Chart D:S ratio above 250 ml at any pH value (1-7.5) based on literature data? yes „Low“ solubility Dependent on D:S ratio and pKa value „high“ solubility was assumed no Determine solubility experimentally Potential „high“ solubility D:S ratio < 250 ml at pH 1–7.5 at 37 °C -> „high“ solubility Solubility deemed uncertain

14. Permeability determination: Sources • Literature: Martindale, Merck Index, Florey`s Analytical Drug Profiles,… • Internet: Medline with different keywords (e.g. permeability, bioavailability…)

15. Determination of permeability data from literature • Permeability data from humans was prefered • Data from Caco II cells was only used as additional confirmation • Animal data was only used if no other data could be found • Computer simluated data (clogP...) was not used as the FDA currently does not accept this data for biowaiver decisions

16. Human permeability data • Bioavailability studies • Urin recovery • Radioactively marked substances • Perfusion studies in humans

17. Human permeability data • Bioavailability studies showing absolute bioavailability > 90% • Urin recovery of the compound and its metabolites > 90 % • Human perfusion studies providing direct permeability data • These data led to a reliable classification

18. Human permeability data - problems • Bioavailability below 90 % • Possible reasons: • Degradation in GI-tract • First pass effect • Solubility limited bioavailability • Poor absorption

19. Human permeability data - problems • Urinary recovery below 90 % • Possible reasons: • Biliar excretion • Solubility limited bioavailability • Poor absorption • Missing i.v. comparison or missing metabolite assessment

20. Example of a reliable classification BCS Class Solubility Permeability III Minimum solubility at pH 1-8: 6 mg/ml at 37°C D:S < 34 ml “Low” permeability in human perfusion studies absolute BA 61% (oral vs iv) Paracellular transport Cimetidine (200 mg)

21. Example of an uncertain classification BCS Class Solubility Permeability IV Minimum solubility at pH 1-8: 0.8 mg/ml at 37°C D:S > 312 ml absolute BA 25% (oral vs iv) BA study conducted in horses (!) Acetazolamide (250 mg)

22. Results – Classification according to FDA requirements • Of the 130 orally available medicines on the EML (April, 2002): • 64 could be classified reliably • 25 could be classified provisionally • 41 could not be classified unambiguously, but could be narrowed down on two classes

23. Results – Classification according to FDA requirements • 38 % could be classified as class I and are therefore potential biowaivers • 75 % of the compounds show „high“ solubility

24. Results – Classification according to WHO requirements • Allopurinol, ascorbic acid, promethazine among others move from class III to class I (6 substances in total) • 75 % of the compounds show „high“ solubility and are potential biowaiver • Weak acids in class II are also potential biowaiver

25. Potential biowaiver according to WHO criteria BCS Class Solubility Permeability II pH 1.2: 0.04 mg/ml pH 5.5: 0.09 mg/ml pH 6.8: 2.47 mg/ml D/SpH 6.8: 162 ml BA 100% “High” permeability in Caco II cells Ibuprofen (400 mg)

26. Biowaiver decision • Additional parameters for selecting compounds as biowaivers not covered by the list : • Excipients used in the formulation (surfactants..) • Excipient interaction with the compound • Therapeutic index • Therapeutic indication • Risk assessment

27. WHO Biowaiver monograph – Ethambutol hydrochloride Solubility > 700 mg/ml D/s ratio < 0.7 ml 400mg • “Very rapidly • dissolving” • 400 mg pure substance BCS Class Solubility Permeability III • 60-80% Urinary excretion after 144 h • 12-19% recovery in the feces • Dose-proportional absorption 4-50 mg/kg Biowaiver Withspecific indications for monitoring of vision • Indication: Long-term treatment of TB • Toxicity: Ocular • Monitoring of vision Dissolution Risks

28. Biowaiver decision • Detailed biowaiver monographs are available for various substances from the FIP • Monographs cover solubility, permeability, food and excipient interaction and pharmacokinetic behavior among others • Give advice on how to design meaningful dissolution tests • Published in Journal of Pharmaceutical Sciences • Or available from: http://www.fip.org/www2/sciences/index.php?page=pharmacy_sciences&pharmacy_sciences=sciences_bioavail_groupbcs

29. References • Lindenberg et al. „Classification of orally administered drugs on the World Health Organization Model list of Essential Medicines according to the biopharmaceutics classification system. EJPB; 2004 Sep; 58(2):265-78