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
WHO Prequalification Programme 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
WHO Prequalification Programme June 2007

What does BCS stand for?
 Biopharmaceutics Classification System
Class I
Highly soluble
Highly permeable
Class III
Highly soluble
Poorly permeable
Class II
Poorly soluble
Highly permeable
Class IV
Poorly soluble
Poorly permeable
WHO Prequalification Programme June 2007

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
WHO Prequalification Programme June 2007

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
WHO Prequalification Programme June 2007

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
WHO Prequalification Programme June 2007

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 Prequalification Programme June 2007

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
WHO Prequalification Programme June 2007

Methods
 Literature search for suitable solubility and permeability data
 Missing or insufficient solubility data was supplemented by experimental determination
WHO Prequalification Programme June 2007

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
WHO Prequalification Programme June 2007

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
WHO Prequalification Programme June 2007

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?
WHO Prequalification Programme June 2007

Solubility determination: Flow Chart
Determine solubility experimentally
D:S ratio above 250 ml at any pH value
(1-7.5) based on literature data?
yes
„
Low“ solubility no
Potential
„high“ solubility
Dependent on D:S ratio and pKa value „high“ solubility was assumed
D:S ratio < 250 ml at pH 1 –7.5 at 37
°C -> „high“ solubility
Solubility deemed uncertain
WHO Prequalification Programme June 2007

Permeability determination: Sources
 Literature: Martindale, Merck Index, Florey`s Analytical
Drug Profiles,…
 Internet: Medline with different keywords (e.g. permeability, bioavailability…)
WHO Prequalification Programme June 2007

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
WHO Prequalification Programme June 2007

Human permeability data
 Bioavailability studies
 Urin recovery
 Radioactively marked substances
 Perfusion studies in humans
WHO Prequalification Programme June 2007

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
WHO Prequalification Programme June 2007

Human permeability data - problems
 Bioavailability below 90 %
 Possible reasons:
 Degradation in GI-tract
 First pass effect
 Solubility limited bioavailability
 Poor absorption
WHO Prequalification Programme June 2007

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
WHO Prequalification Programme June 2007

Example of a reliable classification
Solubility
Minimum solubility at pH 1-8:
BCS Class
III
Permeability
“Low” permeability in human perfusion studies
6 mg/ml at 37 °C absolute BA 61% (oral vs iv)
D:S < 34 ml
Paracellular transport
Cimetidine
(200 mg)
WHO Prequalification Programme June 2007

Example of an uncertain classification
Solubility
Minimum solubility at pH 1-8:
BCS Class
IV
Permeability absolute BA 25% (oral vs iv)
0.8 mg/ml at 37 °C
BA study conducted in horses (!)
D:S > 312 ml
Acetazolamide
(250 mg)
WHO Prequalification Programme June 2007

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
WHO Prequalification Programme June 2007

Results – Classification according to FDA requirements
9%
37%
38%
Class I
Class II
Class III
Class IV
16%
 38 % could be classified as class I and are therefore potential biowaivers
 75 % of the compounds show „high“ solubility
WHO Prequalification Programme June 2007

Results – Classification according to WHO requirements
9%
32%
43% Class I
Class II
Class III
Class IV
16%
 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
WHO Prequalification Programme June 2007

Potential biowaiver according to WHO criteria
Solubility pH 1.2: 0.04 mg/ml pH 5.5: 0.09 mg/ml pH 6.8: 2.47 mg/ml
D/S pH 6.8
: 162 ml
BCS Class
II
Permeability
BA 100%
“High” permeability in Caco II cells
Ibuprofen
(400 mg)
WHO Prequalification Programme June 2007

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 Prequalification Programme June 2007

WHO Biowaiver monograph –
Ethambutol hydrochloride
Solubility
BCS Class
III
800
700
600
500
400
300
200
100
0
Solubility > 700 mg/ml
D/s ratio
400mg
< 0.7 ml
Biowaiver
With specific indications for monitoring of vision
120
100
80
60
40
20
0
0
USP SGF pH 1.2
10 time [min] phosphate buffer pH 4.5
20 30
USP SIFsp pH 6.8
“Very rapidly dissolving”
 400 mg pure substance
Dissolution
Permeability
 60-80% Urinary excretion after
144 h
 12-19% recovery in the feces
 Dose-proportional absorption
4-50 mg/kg
 Indication: Long-term treatment of TB

Toxicity: Ocular
 Monitoring of vision
Risks
WHO Prequalification Programme June 2007

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
WHO Prequalification Programme June 2007

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
WHO Prequalification Programme June 2007