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Classification of the Essential Medicines List (EML) according to BCS

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Classification of the Essential Medicines List (EML) according to BCS
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
Class II
Highly soluble
Poorly soluble
Highly permeable
Class III
Highly permeable
Class IV
Highly soluble
Poorly soluble
Poorly permeable
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
D:S ratio above 250
ml at any pH value
(1-7.5) based on
literature data?
yes
solubility
no
Determine
solubility
experimentally
WHO Prequalification Programme
Dependent
on D:S ratio
and pKa
value „high“
solubility was
assumed
Potential
„high“
solubility
D:S ratio < 250 ml
at pH 1–7.5 at 37
°C -> „high“
solubility
„Low“
Solubility
deemed
uncertain
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
BCS Class
III
Solubility
Minimum solubility at pH 1-8:
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
BCS Class
IV
Solubility
Permeability
Minimum solubility at pH 1-8:
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%
38%
37%
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%
43%
32%
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
BCS Class
II
Permeability
pH 1.2: 0.04 mg/ml
BA 100%
pH 5.5: 0.09 mg/ml
“High” permeability in Caco II
cells
pH 6.8: 2.47 mg/ml
D/SpH 6.8: 162 ml
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
BCS Class
III
Solubility
800
Solubility > 700 mg/ml
700
D/s ratio
600
400mg
500
< 0.7 ml
 60-80% Urinary excretion after
144 h
 12-19% recovery in the feces
400
300
 Dose-proportional absorption
4-50 mg/kg
200
100
Biowaiver
0
With specific indications
for monitoring of vision
120
100
dissolution [%]
Permeability
80
60
“Very rapidly
dissolving”
40
20
 Indication: Long-term
treatment of TB
 Toxicity: Ocular
 Monitoring of vision
0
0
USP SGF pH 1.2
10
20
time [min]
phosphate buffer pH 4.5
30
USP SIFsp pH 6.8
 400 mg
pure substance
Dissolution
WHO Prequalification Programme
Risks
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
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