1. 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

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

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

4. Criteria for „high“ solubility - FDA
Highest single dosage strength divided by the solubility of the compound over the pH range 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 – 50 rpm paddle 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:

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 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

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
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

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: ences&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