use and limitations of in vitro dissolution testing: topic introduction and overview
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Use and Limitations of In VitroDissolution Testing:
Topic Introduction and OverviewLawrence X. Yu, Ph. D.
Deputy Director for Science and ChemistryOffice of Generic Drugs
Food and Drug AdministrationAdvisory Committee for Pharmaceutical Science
and Clinical Pharmacology
August 8, 2012
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In VitroDissolution Testing: Objectives
Assure batch to batch qualityGuide development of new formulationsProvide process control and qualityassurance
Ascertain the need for bioequivalence studies
Different strengthsPost-approval changesMulti-source products 2
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Dissolution Testing: Issues
Dissolution testing can be non-discriminating. Dissolution testing can be over discriminating. Products that dissolve about 70% in 45 minutes oftenhave no medically relevant bioequivalence problems. Dissolution testing (especially only a single pointcriterion) is often not sufficient to assure product
quality/ bioavailability. Demonstration of in vitro-in vivocorrelation (IVIVC) isnecessary.
IVIVCs are Product Specific.3
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Desired Future State ofIn VitroDissolution Testing
Sensitive enough to detect relevant productchanges so as to ensure the quality and
consistent performance of productsPredictive of in vivoperformance of drugproducts and thus reduce unnecessary human
studies, accelerate drug development, andhasten evaluation of post-approval changes
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Uses and Limitations ofIn VitroDissolution Testing
Use and Limitations of In VitroDissolution Lawrence YuTesting: Topic Introduction and Overview
Dissolution Testing: Evolving Dissolution Cindy BuhseApparatus
Dissolution Testing: Evolving Dissolution Arzu SelenMedia for Predicting In VivoPerformance
Oral Bioperformance & 21st Century Gregory AmidonDissolution Testing
Dissolution Testing and Quality-by-Design Lawrence Yu
Followed by:
Topic Wrap-up and Future Directions
Questions to the Committee/Committee Discussion 5
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Dissolution Testing:
Evolving Dissolution ApparatusAdvisory Committee for Pharmaceutical Science and
Clinical PharmacologyAugust 8, 2012Cindy Buhse, Ph.D., Director
Zongming Gao, Ph.D., ChemistDivision of Pharmaceutical Analysis
Center for Drug Evaluation and ResearchUS Food and Drug Administration
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Dissolution Testing Evolves from Disintegration Test
Stoll-Gershberg disintegration apparatus
ERSHBERG S, STOLL FD, 1946, Apparatus, for tablet disintegration, and for shaking-
out extractions, Journal of the American Pharmaceutical Association, 35(9), 284-7.
Convenient and sensitive chemical
analyses weren't available in 1950s.
Official disintegration tests were
adopted in 1945 by the British
Pharmacopoeia and in 1950 by the
USP.
However, disintegration was
recognized as an incomplete test as
evidenced by the 1950 USP-NF
statement that "disintegration does
not imply complete solution of the
tablet or even of its active
ingredient".
G2
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A Proliferation of Designs for Dissolution Apparatusesbetween 1960 and 1970 Basket Method
Searl and Pernarowski, 1967
Belachew Desta, An evaluation of the USP dissolution apparatus, 1972, Thesis of the University of British Columbia.
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A Proliferation of Designs for Dissolution Apparatusesbetween 1960 and 1970 Paddle Method
Levy-Hayes, 1960
Belachew Desta, An evaluation of the USP dissolution apparatus, 1972, Thesis of the University of British Columbia.
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A Proliferation of Designs for Dissolution Apparatusesbetween 1960 and 1970 -- Reciprocating Cylinder Method
Vliet, 1959
Belachew Desta, An evaluation of the USP dissolution apparatus, 1972, Thesis of the University of British Columbia.
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A Proliferation of Designs for Dissolution Apparatusesbetween 1960 and 1970 Flow-through Method
Lapidus and Lordi, 1966
Belachew Desta, An evaluation of the USP dissolution apparatus, 1972, Thesis of the University of British Columbia.
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The First USP Dissolution Apparatus 1, Basket
USP Apparatus 1
A Basket
B 1000ml resin flask
C Cover
D High-torque stirring
motor
1970 - Dissolution test, apparatus 1
(basket), USP 18
1976 - Dissolution test, apparatus 2
(paddle), USP 19
Belachew Desta, An evaluation of the USP dissolution apparatus, 1972, Thesis of the University of British Columbia.
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Early Dissolution Testing in a FDA Lab in 1970s
USP rotating-basket apparatusand a centering tool
USP paddle apparatus
Pharmaceutical Technology, April, 1978, Vol 2, 16-53 8
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FDAs Definition and Views on
Dissolution Testing in 1970s
In vitro dissolution testing as applied to solid-dosage drug forms
measures the amount of drug dissolved in a known volume of
liquid medium at a predetermined time, using a specified
apparatus designed to carefully control the parameters of
dissolution testing.
In vitro dissolution testing can help pinpoint formulations that
may present potential bioequivalence problem.
Once a formulation has been shown to be bioavailable,dissolution testing is of great value in assuring lot-to-lot
bioequivalence.
Don C. Cox, Carol C. Douglas, William B. Furman, Ross D. Kirchhoefer, James W. Myrick and Clyde E.
Wells, 1978, Guidelines for dissolution testing, Pharmaceutical Technology, Vol 2, No.4, 41-53 9
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FDAs Concerns and Standpointon Dissolution Testing in 1970s
Dissolution tests are critical and difficult to carry out properly. Care andattention must be given to those aspects that have been identified as crucial.
It is our hope that other scientists will share their findings and techniques so
that dissolution testing may be advanced to a reproducible and reliable
scientific procedure.
If labs can not be expected to agree on the results of a dissolution test, then
an IVIVC obtained by one lab can not be generalized as being valid in all
labs.
Differences between dissolution results obtained in industrial labs and thoseobtained in agency labs raise problems in the making of regulatory
decisions.
Don C. Cox, Carol C. Douglas, William B. Furman, Ross D. Kirchhoefer, James W. Myrick and Clyde
E. Wells, 1978, Guidelines for dissolution testing, Pharmaceutical Technology, Vol 2, No.4, 41-53 10
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USP Monographs for Dissolution TestingUSP Monographs for Dissolution Testing
Aristides Dokoumetzidis, Panos Macheras, 2006, Historical Perspectives: A century of dissolution research: From
Noyes and Whitney to the Biopharmaceutics Classification System, International Journal of Pharmaceutics, 321, 111 11
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FDAs Guidances for Dissolution Testing1978 FDA/DPA published a guideline for dissolution testing
1984 FDA/DPA published the Guidelines for dissolution testing: an addendum
1995 Guidance for Industry, SUPAC-IR: Immediate-Release Solid Oral Dosage Forms:
Scale-Up and Post-Approval Changes: Chemistry, Manufacturing and Controls, In
Vitro Dissolution Testing, and In Vivo Bioequivalence
1997 Guidance for Industry, SUPAC-MR: Modified Release Solid Oral Dosage Forms
Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; InVitro Dissolution Testing and In Vivo Bioequivalence
1997 Guidance for Industry, Dissolution Testing of Immediate Release Solid Oral Dosage
Forms
1997 Guidance for Industry, Extended Release Oral Dosage Forms: Development,Evaluation, and Application of In Vitro/In Vivo Correlations
2010 Guidance for Industry, The Use of Mechanical Calibration of Dissolution Apparatus 1
and 2 Current Good Manufacturing Practice (CGMP)
2011 Guidance for Industry, Q4B Evaluation and Recommendation of PharmacopoeialTexts for Use in the ICH Regions, Annex 7(R2) Dissolution Test General Chapter
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Current Official USP Dissolution Apparatuses
13
USP 6 (cylinder)
USP 1 (basket) USP 5 (paddle over disk)
Te perature, rotationspeed, dissolution medium
Primary use is for semi-solidtopical dosage forms but hasalso been used for drug
release and skin/membranepermeation for transdermalpatches.
Apparatus 5(Paddle overdisk)
Temperature, rotationspeed, dissolution medium
Transdermal system.Apparatus 6(Cylinder)
Temperature, rotationspeed, dissolution medium
Immediate-release, extended-release, and delayed-releasedosage forms.
Apparatus 2(Paddle)
Temperature, rotationspeed, dissolution medium
Test Parameters
Immediate-release, extended-release, and delayed-releasedosage forms.
Apparatus 1(Basket)
SamplesApparatus
mTemperature, rotationspeed, dissolution medium
Primary use is for semi-solidtopical dosage forms but hasalso been used for drug
release and skin/membranepermeation for transdermalpatches.
Apparatus 5(Paddle overdisk)
Temperature, rotationspeed, dissolution medium
Transdermal system.Apparatus 6(Cylinder)
Temperature, rotationspeed, dissolution medium
Immediate-release, extended-release, and delayed-releasedosage forms.
Apparatus 2(Paddle)
Temperature, rotationspeed, dissolution medium
Test Parameters
Immediate-release, extended-release, and delayed-releasedosage forms.
Apparatus 1(Basket)
SamplesApparatus
Pictures copied from website, http://www.protechcro.com/images/01Dissolution.pdf, accessed July 2, 2012
USP 2 (paddle)
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Current Official USP Dissolution Apparatuses
Reciprocating Apparatus is typically used for
imitating the pH changes that occur in the body and is
suited for extended and sustained release dosageforms.
Te perature, dip rate,
dissolution medium
Transdermal system,
extended-release dosageforms (coated tablet)
Apparatus 7
Temperature, dip rate,dissolution medium.
Test Parameters
Immediate-release, extended-release, and delayed-release
dosage forms.
Apparatus 3
SamplesApparatus
mTemperature, dip rate,
dissolution medium
Transdermal system,
extended-release dosageforms (coated tablet)
Apparatus 7
Temperature, dip rate,dissolution medium.
Test Parameters
Immediate-release, extended-release, and delayed-release
dosage forms.
Apparatus 3
SamplesApparatus
USP 3 - reciprocating cylinderAngled
diskDisk cylinder
Pointed
rod
spring
holder
USP 7 - reciprocating holderPictures copied from website, http://www.protechcro.com/images/01Dissolution.pdf, accessed July 2, 2012
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Current Official USP Dissolution Apparatuses
USP 4 flow through
Tablet cell12 mm
Cell forimplants
Tablet cell22.6 mm
Cell forsuppositories
and softgelatin capsules
Cell forpowders
and granulates
Temperature-Measuring Head
T st ParametersSamplesTemperature, flow rate,pulses per minute,dissolution medium
Immediate-release, extended-release, anddelayed-release dosage forms.
tablets, capsules, suppositories, powders, drugeluting stents, creams, gels, suspensions etc.
eTest ParametersSamplesTemperature, flow rate,pulses per minute,dissolution medium
Immediate-release, extended-release, anddelayed-release dosage forms.
tablets, capsules, suppositories, powders, drugeluting stents, creams, gels, suspensions etc.
Pictures copied from website, http://www.sotax.com/USP-4-Semi-automated-systems.127.0.html, accessed July 2, 2012 15
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Does Current Dissolution Method Have AnyBiological Relevance?
Disintegration
Solids transfer
Dissolution
Changing pH
X
Food and drink
AbsorptionX
Clearance X
Picture copied from website,
http://www.google.com/images?q=digest+system&hl=en&gb
ju0gHx8oCYAg&start=20&sa=N,accessed July 30, 2012
v=2&tbm=isch&ei=uZQZUIT4O-
Picture copied from website,
http://www.protechcro.com/images/01Dissol
ution.pdf, accessed July 2, 2012
http://www.google.com/images?q=digest+system&hl=en&gbv=2&tbm=isch&ei=uZQZUIT4O-ju0gHx8oCYAg&start=20&sa=Nhttp://www.google.com/images?q=digest+system&hl=en&gbv=2&tbm=isch&ei=uZQZUIT4O-ju0gHx8oCYAg&start=20&sa=Nhttp://www.google.com/images?q=digest+system&hl=en&gbv=2&tbm=isch&ei=uZQZUIT4O-ju0gHx8oCYAg&start=20&sa=Nhttp://www.google.com/images?q=digest+system&hl=en&gbv=2&tbm=isch&ei=uZQZUIT4O-ju0gHx8oCYAg&start=20&sa=Nhttp://www.protechcro.com/images/01Dissolhttp://www.protechcro.com/images/01Dissolhttp://www.google.com/images?q=digest+system&hl=en&gbv=2&tbm=isch&ei=uZQZUIT4O-ju0gHx8oCYAg&start=20&sa=Nhttp://www.google.com/images?q=digest+system&hl=en&gbv=2&tbm=isch&ei=uZQZUIT4O-ju0gHx8oCYAg&start=20&sa=Nhttp://www.google.com/images?q=digest+system&hl=en&gbv=2&tbm=isch&ei=uZQZUIT4O-ju0gHx8oCYAg&start=20&sa=N -
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New Designs for Dissolution Testing
Garbacz, G. et al. Irregular absorption profiles observed from diclofenac extendedrelease tablets can be predicted using a
dissolution test apparatusthat mimics in vivo physical stresses.Eur. J. Pharm. Biopharm. 2008, 70 (2), 421428. 17
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New Designs for Dissolution Testing
Makoto KATAOKA et al. 2011,In VitroDissolution/Permeation System to Predict the Oral
Absorption of Poorly Water-Soluble Drugs: Effect of Food
and Dose Strength on It, Biol. Pharm. Bull. 34(3) 401407
M. Kobayashi et al.International Journal of Pharmaceutics 221 (2001) 8794
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New Designs for Dissolution Testing
Hanks Balanced Salts Solution (HBSS) at pH 6.8was used as the dissolution medium, in order to
accommodate the Caco-2 monolayer.
SGF and deionized water do not support Caco-2 cellviability.
The dissolution testing time is limited by Caco-2 cellsfor less than 2 hours.
Mark J. Ginski, Rajneesh Taneja, and James E. Polli, 1999, Predictionof Dissolution-Absorption Relationships from a Continuous
Dissolution/Caco-2 System,AAPS Pharmsci, 1 (3) article 3
L. Hughes et al. Dow Apparatus (FloVitro)
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New Designs for Dissolution Testing
Paul A. Dickinson, et al. An Investigation into the Utility of a Multi-compartmental, Dynamic, System of the Upper Gastrointestinal Tract
to Support Formulation Development and Establish Bioequivalence of Poorly Soluble Drugs. The AAPS Journal, Vol. 14, 196-205, 2012. 20
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New Designs for Dissolution TestingUV/vis UV/vis
DissolutionMedium
Waste
Cell 1 Cell 2
Z Gao,AAPS PharmSciTech, 10(4), 2009, 1401-1405.21
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New Designs for Dissolution Testing
USP4 as dissolution apparatus @ 4mL/min
150 mL SGF for 1 hour
Then, 500 SIF for 23 hours
BCS I, propranolol HCl
BCS II, phenazopyridine HClZ Gao,AAPS PharmSciTech, submitted, 2012.
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Advantage and Disadvantage of Newly DevelopedDissolution Method
CurrentUSP
Dissolution
Methods
X
X
X
Disintegration
Solids transfer
Dissolution
Changing pH
Food and drink
Absorption
Clearance
Standardized MethodX
NewlyDeveloped
Dissolution
Methods
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DissolutionTesting:EvolvingDissolutionMediaforPredictingInVivoPerformance
ArzuSelen,Ph.D.BiopharmaceuticsResearchLead
OfficeofNewDrugQualityAssessment/OPS/CDER/FDAAdvisoryCommitteeforPharmaceuticalScience
andClinicalPharmacologyAugust8,2012
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OutlineBackgroundDissolutiontesttorelevanceofdissolutionmedium
RecommendationsfromtheguidanceTypesandfunctionSomeexamples:productcharacterization,foodeffect,screenforalcoholdosedumpingNext
phase?
Integration
of
Quality
by
Design
(QbD)andBiopharmaceuticsandmechanisticvalue
Summary 2
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DissolutionRateLinkedwithClinicalOutcomeINARECENTstudyoffactorsaffectingtheabsorption
rate
and
gastrointestinal
irritant
effect
of
aspirin(1)itwasconcludedthat(a)absorptionratesandincidenceandseverityoflocalirritationareinterrelated,(b)bothofthesecharacteristicsareafunctionofthedissolutionrateofaspirininitsparticulardosageform,and(c)therearesignificantdifferencesininvitrodissolutionratesamongdifferentnationallydistributedbrandsofaspirintablets.GerhardLevy,ComparisonofDissolutionandAbsorptionRatesofDifferentCommercialAspirinTablets,J.Pharm.Sci.Vol.5,388392,1961
3
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FromtheBeginning2009
2006
199
198
1950s and 1960s
0s
7
Ref.1:WorkshopcosponsoredbyASCPT/DIA/APS/FDA,1987Ref.2: FromCommentaryonAAPSWorkshop,May2006,Arlington,VAC.Tong,S.S.DSouza,andT.Mirza,Pharm.Res.24(9),16031607,2007
Adissolutionmethod(andtheacceptancecriteria)shouldbedefinedtodeliverdesiredperformanceofaproductintheintendedinvivoenvironment.(Ref.2)
IVIVCisafutureobjectiveforERformulationsDissolution
testing
for
processcontrol,stability,minorformulationchangesandmanufacturingsitechanges.(Ref.1)
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OurIncreasingExpectationsinDrugDissolution/ReleaseTesting
ProvidebasiccriteriafordrugreleasefromtheproductFor
batch
to
batch
consistency/quality
(product
specification)AspotentialsurrogateforinvivoBEstudiesFor linkingtheproductanditsinvivoperformance(correlationsorrelationships:IVIVCorIVIVR) 5
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RecommendationsfromGuidanceforIndustryDissolutionTestingofImmediateReleaseSolidOralDosageForms(August1997)
Anaqueousmedium pHrange1.2to6.8(ionicstrengthofbuffersthesameasinUSP)Tosimulategastricfluid(SGF),adissolutionmediumofpH1.2(withoutenzymes)TheneedforenzymesinSGFandSIFshouldbeevaluatedonacasebycasebasisandshouldbejustified.Tosimulateintestinalfluid(SIF),adissolutionmediumofpH6.8shouldbeemployed(also,recommendedfortestingofERproducts).AhigherpHshouldbejustifiedonacasebycasebasisand,ingeneral,shouldnotexceedpH8.0.
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RecommendationsforDissolutionMedium(Continued)
Withgelatincapsuleproductsmediumcontainingenzymes(pepsinwithSGFandpancreatinwithSIF)maybeusedtodissolvepellicles.Useofwateraloneasadissolutionmediumisdiscouraged(watersourcemayaffecttestconditionssuchaspHandsurfacetension,andmaychangeduringthedissolutiontestduetotheinfluenceoftheactiveandinactiveingredients)Forwaterinsolubleorsparinglywatersolubledrugproducts,useofasurfactantsuchassodiumlaurylsulfateisrecommended(Shah1989,1995). Theneedforandtheamountofthesurfactantshouldbejustified.
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AShortListofDissolutionMediaStandardCompendial(inUSP):
SimulatedGastricFluid(withandwithoutpepsin)SimulatedIntestinalFluid(withandwithoutpancreatin)WaterTheirmodifications(mediawithsurfactants)AdditionalMedia(includingpatentedBiorelevantmedia)
FastedStateSimulatedGastricFluid(FaSSGF)FedStateSimulatedGastricFluid(FeSSGF)FastedStateSimulatedIntestinalFluid(FaSSIF)FedStateSimulatedIntestinalFluid(FeSSIF)BlankFastedandFed(GF)and(IF)Andothers(suchasEnsurePlusforforecastingfoodeffect)
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Composition ofFaSSGFand FeSSGF
Reference:Jantratidetal.,Europ.JofPharm.andBiopharm.69,776785,2008 9
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Last20 30years:Dissolution/releaseTesting
Linksdrugproducttoitsinvivoperformance
Qualitycontrol
tool
Andrecently:Can/shouldQbDmergethetwopaths?Does
it
help
if
single
and/or
multiple
media
are
used? 10
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Desired State for
Drug Release/Dissolution Method
Reliable,reproducible,wellcharacterizedmethod
InfluencedbyCriticalQualityAttributes
Hasinvivorelevance
Supportslinkingprocess,product
and
patient
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Desired State forDrug Release/Dissolution Media
Standardized,wellcharacterized,easytoprepareandstableduringtesting
FacilitatesAssessmentof CriticalQualityAttributes hasproductrelevance
Hasinvivorelevance
Supports
linkingprocess,productandpatient
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ConsiderationsforSelectionofDissolutionMedium
Consistentwithrouteofdrugadministrationandinvivoenvironment(Relevance)Physiologicalandconditionalsimilarity(suchasfed/fasted)Function(mechanisticunderstanding,exploratoryvs.predictive)Possiblealternates(suchassimplifiedmedia)Easeofpreparation(reliablemethod)Standardized(reproducibleandstableduringtesting) 13
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InVitroTestsforProductCharacterization(usingcompendialand/ornoncompendialmethods)
USPApparatusandcompendialmedia(and/ormodifications)Assessingsolubility,dispersionandconditionsleadingtoprecipitation
BilesaltsolubilityExploringinvivosolubilizingcapacityofgutlumenFormulationdispersion,dissolutionanddrugprecipitationFormulationdevelopmentTestingchangesinformulationandproductandenvironmentinteractions(foodeffect,alcoholdosedumping)
Invitrodigestion/lipolysistestsaspossiblepredictorsforfoodeffect(effectofthedigestionproducts) 14
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EffectofLikelyComponentsintheGutLumenonRateandExtentofDissolution
MeanDissolutionProfilesofRomazinTablets(Troglitazone)inVariousMedia
References:Nicolaides,Galia,Efthymiopoulos,Dressman,andReppas.Pharm.Res.16:18771883,1999andC.W.Pouton,Europ.J.ofPharm.Sci.29,278287,2006 15
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FurosemideSolubilityinSimulatedGastricMedia1:1milk:BlankFeSSGF
FaSSGF(FastedStateSimulatedGastricFluid,pH1.6)andFeSSGF(FedStateSimulatedGastricFluid,pH5),andcorrespondingblankbuffers(withoutsurfactant)
Reference:Fromthe2011AAPSposterpresentationofSarahGordon, AnetteMuellertzandothers16
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ExploringFoodEffectandPossibleUseofSimplifiedBiorelevantMediaKetoconazoleReleasefromNizoralTabletsinBiorelevantMediaandRespectiveBlankBuffers
Time (min)
%R
elease
Reference:T.ZoellerandS.Klein,Dissol.Technol. 813,November2007 17
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KetoconazoleReleasefromNizoralTabletsinSimplifiedBiorelevantDissolutionMedia(Continued)
Time (min.)
%R
elease
18
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SingleMediumvs.pHGradientMethodDiclofenacreleasefromdiclofenacsodiummodifiedreleasepellets
(E.Jantratid,V.DeMaio.E.Rondaetal.Eur.J.Pharm.Sci.37,434441,2009)
19
Single Medium
900 mL pH 6.8Phosphate buffer
Biorelevant pH Gradient Method
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InvitroresultsfromthebiorelevantpHgradientmethodpredictfoodeffect
Plasmadiclofenacconcentrationsafterasingleoraldoseofmodifiedreleasediclofenacsodiumpellets(n=16healthyvolunteers,fastedandfedstates).
20
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InVitroReleaseofOpioidsfromOralProlongedreleasePreparationsinSimulatedGastricFluidandSimulatedGastricFluidwithEthanol
Hydrom
orphoneRe
leased(%) 40% ethanol
20%
15%
10%
5%
control
10 20 30 40 50 60
10203040
9080706050
100
00
Time(min)Reference:Waldenetal,DrugDev.AndIndust.Pharm.33:11011111,2007 21
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ScreeningforAlcoholEffectonDrugProductIntegrityCorrelationBetweenHydromorphoneCmaxandInVitroReleaseat30min.and60min.
PalladoneXLwasgivenwith240mLwaterandalsowith4%,20%and40%alcoholicbeverage
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Reference: Lennernas,Molec.Pharma.6(5),14291440,2009
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IntegrationofQbDandBiopharmaceutics
23
June2009workshopofQbDandBiopharmaceuticsRockville,MDRef.:AAPSJ,12(3),465472,September2010
PatientBenefit
QTPPdrivenspecification
BiopharmaceuticsRiskAssessmentRoadMap
MechanisticUnderstanding(invivoandinvitro)
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Summary:TowardsDevelopinganInVitroTestMimickingInVivoConditions(Mechanistic/PredictiveMethods)
Dissolution/releasetestmethodshouldbewellcharacterized(sourcesofvariabilityandtheimpactofchangesshouldbeknown).Dissolutiontestmediashouldbephysiologicallymeaningful.Dissolution/releasetestconditions(e.g.agitation),durationandsamplecollectiontimesshouldbeconsistentwithitsintendedreleasepattern/environment,anduse(asinQualityTargetProductProfile). 24
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Oral Bioperformance
&21st Century Dissolution Testing
Gregory E. AmidonResearch Professor of Pharmaceutical Sciences
College of PharmacyUniversity of Michigan
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What is it that we cant do today, but if we
could, it would revolutionize our business?Joel Barker
Futurist
Comprehensive computational tools and
meaningful in vitro test methods that accuratelyreflect and predict oral bioperformance wouldrevolutionize oral formulation development.
2
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Topics
Where are we now?What opportunities are there? There are many!
GI physiology
Fluid volumeHydrodynamics
Buffer (bicarbonate)
Advanced dissolution methods
Two phase systems (simulating dissolution and absorption)
Two compartment systems (simulating stomach and intestine)
Computational Tools
Fluid Dynamics
Dissolution
Absorption Modeling
3
USP C di l T f O l Bi f
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USP Compendial Tests for Oral Bioperformance
1950: Disintegration Test1970: Dissolution Apparatus 1 (rotating basket)
1980: Dissolution Apparatus 2 (paddle)
. .
USPDisintegrationTest
USPDissolutionTest(basket)USPDissolutionTest(paddle)
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Dissolution Testing is what links the dosage form
to the proven efficacy (eg: typically the clinicallot used in the Phase 3 pivotal efficacy study)!
..
Dissolution testing is what links every lot of the
dosage form from every manufacturer to thelabeling (proven efficacy and safety)! This canbe 100s or 1000s of lots separated by years or
decades as well as continents from the pivotalefficacy lot.
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Some areas of success (1970-2012)
Dissolution Testing as an analytical measure of:
Product consistency
Product quality
Manufacturing process controlIVIVC, IVIVR, IVIVE
BCS
Intestinal media simulation
FaSSIF
FeSSIF
Physiologically relevant solubilityImproved understanding of GI environment
Application of computational tools
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Some weaknesses (1970-2012)
IVIVC, IVIVR, IVIVE
Application of oral physiology understanding to drug and
drug product testingDissolution Testing as in vivo simulation
Application of advanced computational tools
Application of comprehensive physicochemicalprinciples to oral absorption
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The price of less than ideal in vitro methods is:
Over-discriminatory in vitro test methodsResult is wasted resources and delays in the development of newproducts to meet unmet medical needsChasing down unimportant problems
Spending unnecessary development and analytical resources
Slowing development of innovative dosage forms for difficult
to deliver drugs
Conducting unnecessary clinical or animal testing
Under-discriminatory in vitro test methods Result in a lack of meaningful product quality control
Difficulty comparing innovator and generic products Product failure (eg: efficacy and/or safety) in patients!
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A b tt di l ti t t!
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A better dissolution test!Rube Goldberg
More Accurate Oral Bioperformance Prediction would help:
Formulation finding/screening (early development)Define meaningful in vitro performance requirements such asdisintegration, dissolution, supersaturation extent and time,functional excipient impact (solubilizer, precipitation inhibitor) etc.
Optimize dosage form delivery rate
Enhance material and process understanding (Quality by Design)Facilitate meaningful in vitro testing of varying in vivo conditions
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Topics
Where are we now?What opportunities are there (there are many)?
GI physiology
Fluid volumeHydrodynamics
Buffer (bicarbonate)
Advanced dissolution methods
Two phase systems (simulating dissolution and absorption)
Two compartment systems (simulating stomach and intestine)
BCS Advances
Computational Tools
Fluid Dynamics
Dissolution
Absorption Modeling
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What have we learned about human physiology that
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at a e e ea ed about u a p ys o ogy t atmight related to dissolution testing?
Key considerations include:
Fluid volumeIntestinal surface area
Buffer (bicarbonate)pH (average, range)Ionic strengthSurfactants (bile acids)
Carbonic anhydraseHydrodynamicsResidence timeStomach emptying rate
.
Intestinal ContentsBicarbonate (mEq L-1)Bile salts (mM)Lipids (mg/mL)Phospholipids (mM)Pepsin (mg/mL)LipasePotassium (mM)Sodium (mM)Chloride (mM)Calcium (mM)Buffer capacity (mmol L-1 pH-1)Osmolality (mOsm kg-1)Surface tension (mN m-1)ViscosityVolumeShearpH
11
Physiology: What volume of liquid is the dosage form exposed to?
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Physiology: What volume of liquid is the dosage form exposed to?
Average aqueous volume in the fasted small intestine is ~100 ml (Refs: multiple)Total volume in the small intestine
Fasted Mean
Range
Fed Mean
Range
86, 81, 11227, 109 36, 16522, 10572 ~ 100 mL34-46, 37-130, 45-319
47, 381, 59073, 5441
18-78, 343-491, 20-156
Evidence of liquid pockets Schiller et al. Aliment Pharmacol .Ther. 22:971-979 (2005).
Fasted Fed
Number of liquid
pockets
Mean 4 6
Individual(approx.)
2, 3, 4, 5, 8 2, 5, 6, 7, 11
Volume of liquidpocket (mL)
Median 12 4
Ref: D.M. Mudie, G.L. Amidon, and G.E. Amidon. Physiological Parameters for OralDelivery and In Vitro Testing. Mol Pharmaceutics. 7:1388-1405 (2010).
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Physiology is complex
13
Some physiological dissolution systems
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Some physiological dissolution systems
Artificial Dynamic GI System, TIM-1 (TNO)
Stress test apparatus
Dissolution/Permeation system (uses Caco-2 cells)
Two-compartment apparatus:
Artificial Stomach and Duodenum (ASD)
FloVitro Technology (Rohm and Haas)Two-phase dissolution apparatus
Simultaneous dissolution and partitioning in singlecompartment containing two phases (water:organic)
1-octanol
water
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In vivo Intestinal Fluid Flow Rates
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In-vivo Intestinal Fluid Flow Rates
Time (s)Gutzeit A, Patak MA, Weymarn Cv, Graf N, Doert A, Willemse E, Binkert CA, Froehlich JM 2010. Feasibility of SmallBowel Flow Rate Measurement With MRI. Journal of Magnetic Resonance Imaging 32:345-351.
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Hydrodynamics of dissolution apparatus: USP
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y y ppApparatus 2 - Velocity & Shear Profiles meters/s
Highest velocities occur at the tip ofthe paddle (~20 cm/sec)The lowest velocities are directlybeneath the centerline of the
impeller and around the shaft of theimpeller.
The Reynolds numbers (Re) vary depending onthe rotational speed and location(Re ~ 104).
The shear rates throughout the vessel are
heterogeneous.Maximum shear rates: 92s-1 at 50 RPMAverage shear rates: ~ 20s-1 at 50 RPM
Ref: Bai G, Wang Y, Armenante PM 2011. Velocity Profiles and Shear Strain Rate Variability in theUSP Dissolution Testing Apparatus 2 at Different Impeller Agitation Speeds. International Journal ofPharmaceutics 403:1-14.
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Fl Th h C ll
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Flow Through Cell
May allow for testing at more physiologically relevant Reynoldsnumber (5 300) and flow rates (0.1 0.6 cm/sec).Velocity Profiles in a 12mm Cell
Ref: Schematic of a flow through cell: Kakhi (2009). Mathematical Modeling of the Fluid Dynamics in the FlowThrough Cell. International Journal of Pharmaceutics. Vol 376, pg 25.
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Impact of Fluid Shear on Particle Dissolution (h ):
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Impact of Fluid Shear on Particle Dissolution (happ):High Performance Computational Analysis
Hintz, Johnson (1989)
Predicted based on
Ref: (1) JJSheng, etal. JPharmSci.
97:4815-4829 (2008). human intestinal shear(2) Wang, Brasseur, Penn State University (unpublished) rates
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Importance of physical chemistry and
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Importance of physical chemistry andphysiologic buffer (bicarbonate)
Drug Properties:
Solubility
pKa
Diffusion coefficient
Particle size
Physiological Properties:
pH
Buffer species and concentration
Fluid hydrodynamics
Intestinal motilityBulk concentration
Volume and temperature etc.
19
Bicarbonate Buffer Physiological
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Bicarbonate Buffer Physiological
Relevance Bicarbonate is secreted by the pancreas and
epithelial cells throughout the GI lumen.
GI Lumen
Blood Ref: Sly WS, Hu PY 1995.Human Carbonic Anhydrasesand Carbonic Anhydrase
Deficiencies. Annu RevBiochem 64:375 - 401
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Dissolution (37oC) of Ibuprofen in bicarbonate
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( ) pbuffer compared to phosphate buffer (rotating disk)
Bicarbonate buffer, pH=6.5
Phosphate buffer pH=6.5
Dissolution in 50 mM phosphatebuffer @ pH=7.2 (USP test)
is 0.7 mg/cm2/min
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op cs
Where are we now?
What opportunities are there (there are many)?
GI physiology
Fluid volumeHydrodynamics
Buffer (bicarbonate)
Advanced dissolution methods
Two phase systems (simulating dissolution and absorption)
Two compartment systems (simulating stomach and intestine)
BCS Advances
Computational Tools
Fluid Dynamics
Dissolution
Absorption Modeling
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Combining dissolution and
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Combining dissolution and
absorption (two phase model)
1-octanol
water
Ten + systems described in literature
Being used in industryOvercome difficulties in maintainingsink conditions for poorly-solubledrugs (BCS 2, 4), super-saturablesystems, and controlled-release
Circumvent analytical difficultiesassociated with lipid-based capsuleformulations
Simultaneously study impact offormulation changes (e.g.
surfactants) on dissolution andabsorption processes!
Can potentially be scaled to moreaccurately reflect in vivo conditions!
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Two phase IVIVR: Nifedipine GITS tablets
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Two-phase IVIVR: Nifedipine GITS tablets
BCS IIc
Log P = 2 - 4
Sol. FaSSIF = 0.024mg/ml Two-phase
Single-phase
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Two phase physiologic dissolution model
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p p y gPm= 5 x 10
-4 cm/sec, particle radius = 50 m100 BCS Class II
90Sol=100g/mL Dose= 25 mg
80(Dose number = 1)
70 A/V = 2.360 Vw = 100 mL
50%
% in buffer - two phase40
% in 1-octanol% dissolved - two phase30 % in buffer (% dissolved) - single phase
% saturation in buffer - two phase20 % saturation in buffer - single phase
10
00 50 100 150 200 250 300 350
time, min
25
Two phase physiologic dissolution model
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p p y gPm= 2 x 10
-4 cm/sec, particle radius = 50 m
%
100908070605040302010
00 50 100 150 200 250 300 350
time, min
BCS Class IISol=100g/mL Dose= 25 mg(Dose number = 1)
A/V = 2.3Vw = 100 mL
% in buffer - two phase
% in 1-octanol% dissolved - two phase
% in buffer (% dissolved) - single phase
% saturation in buffer - two phase
% saturation in buffer - single phase
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Two phase physiologic dissolution model
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Pm= 1 x 10-4 cm/sec, particle radius = 50 m
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%
100908070605040302010
00 50 100 150 200 250 300 350
time, min
BCS Class IISol=100g/mL Dose= 25 mg(Dose number = 1)
A/V = 2.3Vw = 100 mL
% in buffer - two phase
% in 1-octanol% dissolved - two phase
% in buffer (% dissolved) - single phase
% saturation in buffer - two phase
% saturation in buffer - single phase
Two phase physiologic dissolution model
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p p y gPm=1x10
-4 cm/sec, particle radius = 5 m
%
100908070605040302010
00 20 40 60 80 100 120 140 160
time, min
BCS Class IISol=100g/mL Dose= 25 mg(Dose number = 1)
A/V = 2.3Vw = 100 mL
% in buffer - two phase
% in 1-octanol% dissolved - two phase
% in buffer (% dissolved) - single phase
% saturation in buffer - two phase
% saturation in buffer - single phase
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Stomach and intestine: Two-compartment
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Sto ac a d test e o co pa t e tdissolution apparatus
Several publications inliterature describing
Artificial Stomach-Duodenum (ASD)
Used in pharmaceuticalindustry
Used to compare ASDperformance with in vivobioavailability values
Relative bioavailability estimationof carbamazepine crystal forms
CmaxAUC
SRCarino, DCSperry, MHawley. JPharmSci 95:116-125 (2006).
29
Impact of stomach pH on Oral Absorption ofA i A
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Anticancer Agents
Ref: N.R. Budha, A. Frymoyer, G.S. Smelick, J.Y. Jin, M.R. Yago, M.J. Dresser, S.N. Holden, L.Z. Benet, and J.A.Ware. Clinical Pharmacology & Therapeutics (2012).
30
Advantages & disadvantages of two-
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Advantages & disadvantages of two
compartment systemsAdvantages
Sequentially exposes drug to gastric followed by intestinalmedia Differing media properties in stomach and intestine (e.g. pH,
lipid & bile salt concentrations) can affect dissolution
Captures in vivogastric-emptying rates and flow rates
Can vary to simulate effect on dissolutionPotential to integrate peristaltic motion
Disadvantages
Does not contain separate phase/chamber for absorption Assumes dissolved drug proportional to drug in plasma
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p
Where are we now?
What opportunities are there (there are many)?
GI physiology
Fluid volumeHydrodynamics
Buffer (bicarbonate)
Advanced dissolution methods
Two phase systems (simulating dissolution and absorption)
Two compartment systems (simulating stomach and intestine)
Computational Tools
Fluid Dynamics
Dissolution
Absorption Modeling
a particle path32
Exciting research is going on.
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c t g esea c s go g o
Motility and Absorption in the Small Intestine
Quantification of Small Bowel Water/Physiology
Coupling Biorelevant Dissolution Testing with PBPK Modeling
Modeling Hydrodynamics in the Intestine
Bicarbonate Buffer and Surface pH
In Vitro Dynamic Lipolysis Model
Precipitation Kinetics of Poorly Soluble Drugs under Supersaturated State and PrecipitationInhibitorsRotating Disk as a Dissolution ToolArtificial Stomach Duodenum (2 compartment dissolution)Miniscale Dissolution-membrane Partitioning System
Two Phase Dissolution SystemTwo Compartment Caco2 model /Mini-scale Dissolution
In vivo and computational biopharmaceutical aspects of precipitation and intestinal permeability
Dynamic Dissolution (TIM-1)
Methods for Estimation of Biorelevant Drug Solubility
Combining Experimental and Computational Approaches for Predicting Oral Bioperformance
33
Future Direction and Research Needs
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Enhanced Understanding In Vivo environment (human, animal)
HydrodynamicsVolumeGastric EmptyingFluid content, buffer
Development of Relevant In Vitro Methodologies
Likely not one-size-fits-allAddress/simulate dissolution and absorption kineticsPrecipitation assessment / inhibition
Modified / Delayed Release optimizationDevelopment of Advanced Computational Tools (In Vitro & InVivo)HydrodynamicsDissolutionAbsorptionMetabolism
Application of physicochemical principles to dissolution
34
Questions/discussion
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Questions/discussion
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Dissolution Testing and
Quality-by-Design
Lawrence X. Yu, Ph. D.Deputy Director for Science and ChemistryOffice of Generic Drugs
Food and Drug Administration
Advisory Committee for Pharmaceutical Scienceand Clinical Pharmacology
August 8, 2012 1
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Quality-by-Design
ICH Q8(R2)Pharmaceutical Quality-by-Design (QbD) is a
systematic approach to development that begins withpredefined objectives and emphasizes product and
process understanding and process control, based onsound science and quality risk management
Quality-by-Design Tools
Prior knowledgeRisk assessment
Design of experiments and data analysis
Process analytical technology (PAT) tools 2
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QbD: Linking Process/Product /PatientPatient
Product
Quality Target
Product Profile
Critical QualityAttributes
ProcessMaterial Attributes &Process Parameters
3
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Quality Target Product Profile (QTPP)
QTPP
A prospective summary of the qualitycharacteristics of a drug product that ideally
will be achieved to ensure the desired quality(performance)
Guide to establish product design strategyand keep product development effort
focused and efficient
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What Does QTPP Include?
Intended use in clinical setting
Route of administration, dosage form (deliverysystems), and container closure system
Quality attributes of drug productAppearance, Identity, Strength, Assay, Uniformity,Purity/Impurity, Stability, and others
Active pharmaceutical ingredient release ordelivery and attributes affecting pharmacokineticcharacteristics (safety and efficacy)
Dissolution, aerodynamic performance, etc. 5
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Dissolution and QbD
Dissolution can be used to help relate the
Product to the Patient in the QbD paradigm
Relate in vivoperformance of a drug to in vitromeasurements
Enable development of clinically relevantspecificationsUnderstand the impact of formulation andmanufacturing process variations
Clinically meaningful dissolution specificationsthat assure consistent therapeutic benefit can
aid manufacturing control strategy development 6
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Roles of Dissolution Testing
A quality control tool
Batch-to-batch consistencyProvide quality assurance
An in vitrosurrogate for productperformance
Formulation developmentBioequivalence studies7
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Dissolution for Quality Control A product specific quality control test
The hydrodynamics and medium for this testare chosen for reproducibility and detection of
product changes
The design of this test is not constrained by a
desire to mimic in vivoconditionsAcceptance criteria for consistency of batches
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Dissolution for In VivoPerformance A biorelevant dissolution testCorrelates with in vivodissolution
The hydrodynamics and medium for this test
are chosen to reflect in vivo
Biorelevant dissolution test is a one-time test
to provide a baseline for product performance
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Predictive Dissolution EnablesEfficient Product Development
It is unrealistic to conduct in vivobioequivalencestudies for every formulation and manufacturing
change during pharmaceutical development orfor every post-approval change
Predictive dissolution can streamline productdevelopment and lead to time and cost savingsduring product development while enhancing
the significance of in vitrotesting 10
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FDA IVIVC Guidance
IVIVC = in vitro-in vivo
correlation
Contents
Data/formulationrequirementsPredictability evaluationApplication in waivers of in
vivo bioequivalence studiesand dissolution specifications(pre- and post-approval)
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Oral Drug Absorption Process
Transit
PermeationDissolution
Metabolism
Gastric
Emptying
DisintegrationDissolution
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Limits to Oral Drug Absorption
Gastric emptying
DissolutionDS dissolution rate = D *S/h (Cs - Cl)
D - diffusion coefficientS - dissolution surface area : Drug substance
h - Aqueous boundary thickness
Cs - Solubility: Drug substance
Cl - Concentration in dissolution media
Permeability: Drug substance
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In Vitroand In VivoRelationship Limits to oral drug absorption
Dissolution-limited
dM D= S (CS - C )ldt hSolubility-limited
Permeability-limited
Dissolution Permeation
Concentration Solubility 14
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The CAT ModelSmall InteKttinal Tracts
15
Plasma
KaKa Ka
M0 Mexit
Liver
Dissolution
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Predicting Oral Absorption
0.2
0.4
0.6
0.8
1.0
PredictedExperimental
0.0
Human Permeability (cm/hr)
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
Fraction
ofDose
Absorbed
1.0
0 20 40 60 80 1000.0
Particle Diameter ( m)
Fraction
ofDose
Absorbed
0.8
0.6
0.4
0.2
1.0
Dose = 250 mg
Dose = 500 mgDose = 1000 mg
0 10 20 30 40 50 60
0.8
0.6
0.4
0.2
0.0
Diameter of Particle ( m)
Fraction
ofDoseAbsorbed
Permeability-limitedDissolution-limitedSolubility-limited
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Biopharmaceutics Classification SystemAmidon, et al., Pharm. Res., 1995
The Biopharmaceutics Classification System (BCS) is a
scientific framework for classifying drugs based on theiraqueous solubility and intestinal permeability.Biopharm. Class Solubility Permeability
I High High
II Low High
III High Low
IV Low Low
The understanding of drugs based on BCS can aid informulation and manufacturing development in a QbD
paradigm. 17
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BCS Class I and III DrugsRapid dissolution for BCS Class I drugsand very rapid dissolution for BCS ClassIII drugs ensure that in vivo dissolution isnot the rate limiting step. Bioequivalenceis assured provided no effect of excipient
on absorption and similar dissolutionprofiles
18
Transit Permeation
Metabolism
GastricEmptying
DisintegrationDissolution
Dissolution
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BCS Class II and IV DrugsIVIVR possible for BCS Class II drugsand difficult for BCS Class IV drugs. Inreality, it is often not attempted todevelop in vitrodissolution that is
predictive of in vivo
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Transit Permeation
Metabolism
GastricEmptying
DisintegrationDissolution
Dissolution
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BCS Class I BCS Class I drugs formulated in an
immediate release dosage forms
No bioequivalence studies may be needed for
developing predictive dissolutionRapid dissolution may be used for formulation
development and establishment of design space
Rapid dissolution for BCS Class I drugs inimmediate release dosage forms may be used to
justify formulation and manufacturing changes
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BCS Class II BCS Class III drugs formulated in an
immediate release dosage forms
No bioequivalence studies may be neededVery rapid dissolution may be used forformulation development and establishment ofdesign space
Very rapid dissolution for BCS Class III drugsin immediate release dosage forms may beused to justify manufacturing changes
Excipient effect needs to be furtherinvestigated 21
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BCS Class II and IV BCS Class II and IV drugs formulated in
an immediate release dosage forms
Bioequivalence studies are most likelyneeded to develop predictive dissolution
Predictability of biorelevant dissolution should
be further explored and investigated
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Extended-release Dosage Forms
Extended-release Dosage Forms
Bioequivalence studies are likely needed toestablish IVIVC/IVIVR and develop predictive
dissolutionPredictive dissolution can then be used tosupport establishment of a design spaceIVIVC/IVIVR can be used to supportmanufacturing changes
23
Dissolution for a BCS Class I Drugs
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g
%
DR U
GRE
LE
ASE D
110
100
90 ANDA1
ANDA280ANDA3
ANDA470
ANDA5
ANDA660ANDA7
ANDA850ANDA9
74-21740UMAB-SLOW
UMAB-MEDIUM30UMAB-FAST
20
10
00 5 10 15 20 25 30 35
TIME IN MINUTES 24
In Vitrovs. In VivoDissolution
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IR suspension IR tablet
XR tablet XR capsule
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Future Directions
Application of the QbD approach has the
potential to bridge the gaps between in vitromeasurements and in vivoperformance
A science based approach incorporating studies both
in the laboratory and clinicUtilization of advanced dissolution methodologies forpredictive dissolution
Other approaches other than IVIVC/IVIVR arepossible that provide increased product andprocess understanding
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Conclusions
There are many tools related to dissolution
that can aid in implementation of QbD
Biorelevant dissolution methods, which mayutilized advanced apparatus and/or mediaPredictive dissolution modelingIVIVC or IVIVR studies
All of these tools can aid product qualityEnhanced product and process understanding
Cli i ll l t ifi ti
top related