Transcript Waivers of in vivo BE studies

Bundesinstitut für Arzneimittel und Medizinprodukte
WHO
Training Workshop on Pharmaceutical
Quality, Good Manufacturing Practice &
Bioequivalence
Biowaiver
Kiev, October 3-7, 2005
Dr. H. Potthast ([email protected])
Pt WHO-consultant
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Bundesinstitut für Arzneimittel und Medizinprodukte
Basis for Biowaiver
Applications/Decisions
 Note for Guidance on the Investigation of
Bioavailability and Bioequivalence”
CPMP/EWP/QWP/1401/98; paragraph 5.1
 FDA - Guidance for Industry: “Waiver of in vivo bioequivalence studies for immediate release solid oral
dosage forms containing certain active
moieties/active ingredients based on a
Biopharmaceutics Classification System” (2000)
 Current scientific discussion
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Bundesinstitut für Arzneimittel und Medizinprodukte
Definitions
 Bioavailability – rate and extent at which a drug
substance... becomes available in the general system
(product characteristic!)
 Bioequivalence – equivalent bioavailability within
pre-set acceptance ranges
 Pharmaceutical equivalence  Bioequivalence
 Bioequivalence  Therapeutic equivalence
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Bundesinstitut für Arzneimittel und Medizinprodukte
Biowaiver - Multiple Strengths
♦ For IR oral dosage forms one BE study using (usually) the
highest strength may be sufficient for all strengths if…
♦
♦
♦
♦
same manufacturer and process
linear drug input (if this is not the case…..)
same qualitative composition of different strengths
same ratio between active substance and excipients, or same
excipients in case of low concentration (less than 5 %)
♦ similar in vitro dissolution
(see e.g. 5.4 of EU guidance)
 also valid for MR products acc. e.g. to 5.1 of EU guidance
CPMP/EWP/280/96
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Bundesinstitut für Arzneimittel und Medizinprodukte
Biowaiver - Multiple Strengths
♦ in case of non-linear pharmacokinetics…
♦ …if AUC increases more than proportional, in vivo
BE testing at least of the highest dose strength
♦ …if AUC increases less than proportional, in vivo
BE testing at least of the lowest dose strength
♦ …in case of insufficient or no information, in vivo BE testing
at least of the lowest and highest dose strength
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Bundesinstitut für Arzneimittel und Medizinprodukte
Biowaiver – Test vs Reference
‘Biowaiver’.....
.....is defined as
 in vitro instead of in vivo bioequivalence testing
 comparison of test and reference
....is not defined as
 no bioequivalence test
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Bundesinstitut für Arzneimittel und Medizinprodukte
Definitions
acc. to the FDA guidance:
”BCS-based biowaivers are intended only for
bioequivalence studies. They do not apply to
food effect bioavailability studies or other
pharmacokinetic studies.”
(e.g., rel. bioavailability)
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Bundesinstitut für Arzneimittel und Medizinprodukte
EU Note for Guidance....
In vivo bioequivalence testing is generally required
but
acc. to paragr. 4.2 and 5.1:
” Such studies may be exempted if the absence of
differences in the in vivo performance can be
justified by satisfactory in vitro data.”
 for oral immediate release dosage forms with
systemic action!
Pt WHO-consultant
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Bundesinstitut für Arzneimittel und Medizinprodukte
EU Note for Guidance....
Biowaiver justification
paragr. 5.1.1:
”This section .........takes into consideration
criteria derived from the concepts underlying
the Biopharmaceutics Classification System ......”
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Bundesinstitut für Arzneimittel und Medizinprodukte
BCS based Biowaiver
Evaluation of drug substance
drug product
and
Drug substance
 pharmacodynamic/therapeutic aspects
 physicochemical aspects
Drug product
 in vitro dissolution
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Bundesinstitut für Arzneimittel und Medizinprodukte
Drug Substance Characteristics I
EU NfG paragr. 5.1.1
a)i “Risk of therapeutic failure or adverse drug reactions”
(e.g., narrow therapeutic index drugs)
examples: Theophylline, Carbamazepine
b)ii “Risk of bioinequivalence”
(i.e., bioavailability problems are evident)
examples: Ciclosporine, Glibenclamide
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Bundesinstitut für Arzneimittel und Medizinprodukte
Drug Substance Characteristics II
Biopharmaceutics Classification System (BCS)
dissolution
drug product  drug substance in solution
membrane transport
 drug substance in the system
simplified mechanistic view of bioavailability
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Bundesinstitut für Arzneimittel und Medizinprodukte
BCS Assumption
♦ ….if the fraction of the dose absorbed is the same,
the human body should always do the same with the
absorbed compound …Even in a disease state, this
argument is still a valid statement.
[Faassen et al. Clin Pharmacokinet 43 (2004)1117]
 what does the product do to the drug substance?
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Bundesinstitut für Arzneimittel und Medizinprodukte
BCS Assumption
Pillars of the
BCS
Solubility
Permeability
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Dissolution
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Bundesinstitut für Arzneimittel und Medizinprodukte
Melting point
Charge
Solubility
Size
Ionisation
Shape
H-bonding
Charge
Distribution
Lipophilicity
Amphiphilicity
Fig.1: Physicochemical properties that affect absorption (after oral
administration)
[H. van de Waterbeemd/ Eur J Pharm Sci 7 (1998), 1-3]
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Bundesinstitut für Arzneimittel und Medizinprodukte
Drug Substance Characteristics III
High solubility (acc. to BCS)
 the highest single unit dose is completely soluble in
250 ml of aqueous solution at pH 1-8 (37 °C)
recommended investigations at pH 1, 4.6, 6.8 and pka
cave: possible stability problems have to be considered
• Discussion on ‘intermediate solubility’, i.e.,
pH-dependent (high) solubility
• Definition of low solubility?
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Bundesinstitut für Arzneimittel und Medizinprodukte
Drug Substance Characteristics IV
High permeability (acc. to BCS)
 EU guidance: ”Linear and complete absorption reduces
the possibility of an IR dosage form influencing the
bioavailability”
• FDA guidance: absolute BA >90 %
• Human data are preferred; in vitro data may be
submitted if sufficiently justified and valid
• Definition of low permeability?
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Bundesinstitut für Arzneimittel und Medizinprodukte
Drug Substance Characteristics IV
♦ Methods to determine permeability
Non-clinical methods
♦ Cell cultures (eg CaCo-2)
♦ Animal studies (everted rat gut)
Clinical methods
♦ Intestinal perfusion
(Loc-I-gut system)
♦ Absolute bioavailability
(mass balance)
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Bundesinstitut für Arzneimittel und Medizinprodukte
Fig.2: Relation of human permeability and absorption [R. Löbenberg,
G.L.Amidon/ Eur J Pharm Biopharm 50 (2000), 3-12]
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Bundesinstitut für Arzneimittel und Medizinprodukte
Drug Substance Characteristics V
”More factors affect bioavailability when
absorption is slow or incomplete than when it is
rapid and complete,hence, slow or incomplete
absorption often leads to variable therapeutic
responses.” [Turner et al. Pharm Res 21(2004)68]
“Dynamic character of the dissolution/uptake
process” [Rinaki et al. Pharm Res 21 (2004) 1567]
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Bundesinstitut für Arzneimittel und Medizinprodukte
Drug Substance Characteristics VI
Absorption  Bioavailability
but...
High bioavailability  High absorption
Low bioavailability  (not necessarily) Low
absorption
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Bundesinstitut für Arzneimittel und Medizinprodukte
Drug Substance Characteristics VII
Solubility
high
low
high
low
Permeability
high
high
low
low
Pt WHO-consultant
BCS classification
I (e.g. Propranolol)
II (e.g. Glibenclamide)
III
(e.g. Atenolol)
IV(e.g. Acetazolamide)
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Bundesinstitut für Arzneimittel und Medizinprodukte
Drug Substance Characteristics VIII
Additional aspects to be considered:
 prodrugs
 effective metabolites
 instability
 polymorphic forms
 stereochemistry (enantiomer/racemate)
 wide therapeutic dose range
..........
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Bundesinstitut für Arzneimittel und Medizinprodukte
BCS Concept

When are in vitro results sufficient for bioequivalence
evaluation?

When is in vitro instead of in vivo bioequivalence testing
scientifically justified (or even more restrictive)?

Minimizing risk by means of ‘worst case’ investigation?

Which in vitro investigations may be sufficient?
Pt WHO-consultant
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Bundesinstitut für Arzneimittel und Medizinprodukte
Drug PRODUCT characteristics I
In vitro comparison of immediate release oral
drug products (T and R)
 Not less than 85 % of labeled amount are dissolved
within 15 min in each of three buffers (pH 1 – 8) – no
further comparison of T and R is required
 Proving similarity of dissolution profiles of T and R e.g.,
using f2-test, unless similarity is obvious
(see app. 2 of the EU guidance; note prerequisites)
 reasonable experimental conditions/methods are
strongly recommended!
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Bundesinstitut für Arzneimittel und Medizinprodukte
Drug product characteristics II
 Evaluation of excipients (e.g., large amounts,
possible interactions....)
 Evaluation of manufacturing processes in
relation with critical physicochemical
properties
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Bundesinstitut für Arzneimittel und Medizinprodukte
EU/FDA Guidance
Biowaiver for immediate release drug products
containing highly soluble, highly permeable drug
substances only.
No biowaiver for:

locally applied, systemically acting products
 non-oral immediate release forms with systemic
action
 modified release products
 transdermal products
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Bundesinstitut für Arzneimittel und Medizinprodukte
Biowaiver Extensions ?!
Provided that ......

drug solubility is high,
 permeability is limited,
 excipients do not affect kinetics,
 excipients do not interact ,.....
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Bundesinstitut für Arzneimittel und Medizinprodukte
Biowaiver Extensions ?!
....then very rapid dissolution (e.g.>85% in 15 min) of test
and reference may ensure similar product characteristics
because...
....absorption process is probably independent from
dissolution and not product related…
 limited absorption kinetics due to poor drug
permeability and/or gastric emptying
 Biowaiver for BCS class III drugs (e.g. Atenolol)?!
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Bundesinstitut für Arzneimittel und Medizinprodukte
Biowaiver Extensions ?!
For drugs showing ....

‘very’ high permeability

pH-dependent solubility within the physiologically
relevant pH range
.....an ‘intermediate solubility’ class is suggested
[Polli et al. J Pharm Sci 93 (2004) 1375]
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Bundesinstitut für Arzneimittel und Medizinprodukte
Biowaiver Extensions ?!
„pH-dependant soluble, highly permeable, weak
acidic, ionizable drug compounds may be handled
like BCS class I drugs“ (quotation)
 Current discussions on in vitro dissolution
requirements?!
 Probably no biowaiver for weak basic drugs
(personal communication)
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Bundesinstitut für Arzneimittel und Medizinprodukte
Biowaiver Extensions ?!
„BDDCS - Biopharmaceutics Drug Disposition
Classification System“
“Consideration of elimination criteria may expand number
of class 1 drugs eligible for a waiver of in vivo BE studies
and provide predictability of drug disposition profiles for
classes 2, 3, and 4 compounds.”
(Wu et al., Pharm Res 22 (2005) 11)
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Bundesinstitut für Arzneimittel und Medizinprodukte
Biowaiver Documentation I

Evaluation of possible therapeutic risks related to
bio(in)equivalence
Discussion of relevant pharmacokinetic characteristics
e.g.:
therapeutic range
metabolism
kinetic linearity
‘absorption window’
variability....
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Bundesinstitut für Arzneimittel und Medizinprodukte
Biowaiver Documentation II
Physicochemical characterisation of
the drug substance
 solubility
 permeability/absorption
 stability
Documentation of analytical method validation
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Bundesinstitut für Arzneimittel und Medizinprodukte
Biowaiver Documentation III
Evaluation of product characteristics
 comparison
of in vitro dissolution of test
and reference
 evaluation of excipients
 evaluation manufacturing process
Documentation of analytical method validation
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Bundesinstitut für Arzneimittel und Medizinprodukte
Biowaiver Documentation IV
 meaningful
literature data may be used for
drug substance characteristics (and excipients)
 product
related data (incl. in vitro dissolution)
must always be actually generated for the
particular product
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Biowaiver Application
 for
generic drug applications
 variations
 development/new
drug products
(e.g., bridging studies, pilot BA batch vs
production batch)
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Bundesinstitut für Arzneimittel und Medizinprodukte
Biowaiver
THANK YOU FOR YOUR
ATTENTION!
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