saq olten jan2506 - gally.ch · bioavailability and bioequivalence ” cpmp/ewp/qwp/1401/98;...
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Bundesinstitut für Arzneimittel und Medizinprodukte
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Dissolution Testing Dissolution Testing Analytik,MethodenentwicklungAnalytik,Methodenentwicklung,,
BioäquivalenzBioäquivalenz
SAQ Olten, 25. Januar 2006
Dr. H. Potthast ([email protected])
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Bundesinstitut für Arzneimittel und Medizinprodukte
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Basis for Biowaiver Basis for Biowaiver Applications/DecisionsApplications/Decisions
“Note for Guidance on the Investigation of Bioavailability and Bioequivalence”
CPMP/EWP/QWP/1401/98; paragraph 5.1
also considered:♦ FDA - Guidance for Industry: “Waiver of in vivo bio-equivalence
studies for immediate release solid oral dosage forms containing certain active moieties/active ingredients based on aBiopharmaceutics Classification System” (2000)
♦ Current scientific discussion on biowaiver extensions
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Bundesinstitut für Arzneimittel und Medizinprodukte
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Definitions 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 (“biological quality control”)
♦ Pharmaceutical equivalence ≠ Bioequivalence
♦ Bioequivalence ⇒ Therapeutic equivalence
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Bundesinstitut für Arzneimittel und Medizinprodukte
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Definitions Definitions
‘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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Definitions Definitions
acc. to the FDA guidance:
”BCS-based biowaivers are intended only for bioequivalence studies. They do not apply tofood effect bioavailability studies or otherpharmacokinetic studies.” (e.g., rel. bioavailability)
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Bundesinstitut für Arzneimittel und Medizinprodukte
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EU Note for Guidance....EU Note for Guidance....
In vivo bioequivalence testing is generally requiredbut
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!
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EU Note for Guidance....EU Note for Guidance....
Biowaiver justificationparagr. 5.1.1:
”This section .........takes into considerationcriteria derived from the concepts underlyingthe Biopharmaceutics Classification System ......”
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EU Note for Guidance....EU Note for Guidance....
Evaluation of drug substance anddrug product
Drug substance♦ pharmacodynamic/therapeutic aspects ♦ physicochemical aspects
Drug product♦ in vitro dissolution
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EU Note for Guidance....EU Note for Guidance....
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, Lithium…
b)ii “Risk of bioinequivalence”(i.e., bioavailability problems are evident)
examples: Ciclosporine, Glibenclamide…
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BCS ConceptBCS Concept
Biopharmaceutics Classification System (BCS)
dissolutiondrug product ⇒ drug substance in solution
membrane transport⇒ drug substance in the system
- simplified mechanistic view of bioavailability -
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BCS BCS AssumptionAssumption
Solubility Permeability Dissolution
Pillars of theBCS
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Solubility Permeability BCS classificationhigh high I (e.g. Propranolol)low high II (e.g. Glibenclamide)high low III (e.g. Atenolol)low low IV(e.g. Acetazolamide)
Drug Substance CharacteristicsDrug Substance Characteristics
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BCS BCS AssumptionAssumption
? ….if the fraction of the dose absorbed is the same, the human body should always do the same with theabsorbed compound …Even in a disease state, thisargument is still a valid statement.
[Faassen et al. Clin Pharmacokinet 43 (2004)1117]
F what does the product do to the drug substance?F rate aspects?
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DissolutionDissolution
in vitro dissolution objectives
♦ quality control♦ justification of minor variations ♦ iviv-correlation (e.g. major variations; bridging)♦ additiv to BE studies♦ proportionality based biowaiver♦ BCS based biowaiver♦ ….
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DissolutionDissolution
in vitro dissolution prerequisites
♦ reasonable, validated methods♦ discriminative methods ♦ reproducible methods♦ biorelevant methods (?)
♦ ……one fits all?!
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BCS based BiowaiverBCS based Biowaiver
u When are in vitro results sufficient for bioequivalence evaluation?
u When is in vitro instead of in vivo bioequivalence testing scientifically justified (or even more restrictive)?
u Minimizing risk by means of ‘worst case’ investigation?
u Which in vitro investigations may be sufficient?
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Dissolution and BiowaiverDissolution and Biowaiver
in vitro dissolution and BCS concept
♦ prerequisites ♦ risk minimization ♦ justification of absence of difference♦ biorelevant?!
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Dissolution and BiowaiverDissolution and Biowaiver
In vitro comparison of immediate release oraldrug 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 Re.g., using f2-test, unless similarity is obvious(see app. 2 of the EU guidance; note prerequisites)
F reasonable, validated experimental conditions/methodsare strongly recommended!
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Bundesinstitut für Arzneimittel und Medizinprodukte
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Dissolution and BiowaiverDissolution and Biowaiver
Experimental conditions:
t EU guidance – no specific information
t US-FDA guidance – ‚USP‘-conditions♦ 50 rpm (paddle) or 100 rpm (basket); 900 ml; USP buffer; 37 °C♦ no surfactants!
F recommendations?!
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Dissolution and BiowaiverDissolution and Biowaiver
Experimental conditions:
t agitation: 75 rpm?! t volume: less than 900/500 ml?!t rapid dissolution: 15 or 30 min?!
t very rapid: 15 min or less?!
t rapid: 30 min or less?!
♦ recommendations?!
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Dissolution and BiowaiverDissolution and Biowaiver
♦ Requirement: either ‘very rapid’ or “similar” in vitro dissolution
♦ how similar is ‘similar’?♦ discussion of differences usually not appropriate
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Dissolution and BiowaiverDissolution and Biowaiver
f2-test (see app. 2 of the EU guidance)
♦ at least 3 sampling points (excl. zero)♦ n=12♦ not more than one mean result > 85%♦ mean SD < 10 %
F must be carefully used!
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Dissolution and BiowaiverDissolution and Biowaiver
f2-test (see app. 2 of the EU guidance)
t acceptance value based on 10 % difference betweenprofiles
t „identical“ profiles: f2 =100„similar“ profiles: f2 between 50 and 100 (?!)
F any other reasonable/justified test possible!
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Dissolution and BiowaiverDissolution and Biowaiver
BCS based biowaiver in vitro dissolution
t no iviv correlation
t no biorelevant conditions (except pH)
F concept to justify absence of difference?!
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Dissolution and BiowaiverDissolution and Biowaiver
♦ Evaluation of excipients (e.g., large amounts, possible interactions....)
♦ Evaluation of manufacturing processes in relation with critical physicochemical properties
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EU (FDA) GuidanceEU (FDA) Guidance
Biowaiver for immediate release drug products containing highly soluble, highly permeable drugsubstances only.
No BCS-based biowaiver for:
u locally applied, systemically acting productsu non-oral immediate release forms with systemic actionu modified release productsu transdermal products
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Biowaiver Extensions ?!Biowaiver Extensions ?!
Provided that ......
u drug solubility is high, u permeability is limited,u excipients do not affect kinetics,u excipients do not interact ,.....
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Biowaiver Extensions ?!Biowaiver Extensions ?!
....then very rapid dissolution (e.g.>85% in 15 min) of testand reference may ensure similar product characteristics because.......absorption process is probably independent fromdissolution and not product related…
F limited absorption kinetics due to poor drugpermeability and/or gastric emptying
♦ Biowaiver for BCS class III drugs?!
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Biowaiver Extensions ?!Biowaiver Extensions ?!
For drugs showing ....
u ‘very’ high permeability
u 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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Biowaiver Extensions ?!Biowaiver Extensions ?!
„pH-dependant soluble, highly permeable, weakacidic, ionizable drug compounds may be handledlike BCS class I drugs“ (quotation)
♦ current discussions on in vitro dissolution requirements?!
♦ at least 85% within 30 min at pH 6.8 and f2 testing for pH 1.2 and 4.5 profiles
♦ probably no biowaiver for weak basic drugs (personal communication)
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BCS Based BiowaiverBCS Based Biowaiver
umeaningful literature data may be used for drug substance characteristics (and excipients)
u product related data must always be actually generated for the particular product
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BCS Based BiowaiverBCS Based Biowaiver
THANK YOU FOR YOUR ATTENTION!