World Health Organization Multisource (generic) products and Interchangeability 15 April, 2017 Training Workshop on Dissolution, Pharmaceutical Product Interchangeability and Biopharmaceutical Classification System. Hotel Bratislava 1 Malyshko Street Kyiv, Ukraine Date: 25 to 27 June 2007

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

What does BCS stand for? Biopharmaceutics Classification System Highly soluble Highly permeable Class II Poorly soluble Class III Poorly permeable Class IV

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

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

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

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)

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

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

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

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

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?

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

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

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

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

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

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

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

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)

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)

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

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

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

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)

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

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

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_sci ences&pharmacy_sciences=sciences_bioavail_groupbcs

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