saq olten jan2506 - gally.ch · Bioavailability and Bioequivalence ” CPMP/EWP/QWP/1401/98; paragraph 5.1 also considered: ♦ FDA - Guidance for Industry: “Waiver of in vivo bio-equivalence

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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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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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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‘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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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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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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Biowaiver justificationparagr. 5.1.1:

”This section .........takes into considerationcriteria derived from the concepts underlyingthe Biopharmaceutics Classification System ......”


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Evaluation of drug substance anddrug product

Drug substance♦ pharmacodynamic/therapeutic aspects ♦ physicochemical aspects

Drug product♦ in vitro dissolution


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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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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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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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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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♦ Requirement: either ‘very rapid’ or “similar” in vitro dissolution

♦ how similar is ‘similar’?♦ discussion of differences usually not appropriate


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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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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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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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♦ 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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....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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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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„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!

Documents

saq olten jan2506 - gally.ch · Bioavailability and Bioequivalence ” CPMP/EWP/QWP/1401/98; paragraph 5.1 also considered: ♦ FDA - Guidance for Industry: “Waiver of in vivo bio-equivalence