dorantes

8/8/2019 Dorantes

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DISSOLUTION TESTING OFDISSOLUTION TESTING OF

NOVEL DOSAGE FORMS:NOVEL DOSAGE FORMS:An FDA PerspectiveAn FDA Perspective

ANGELICA DORANTES Ph.D.

Office of Clinical PharmacologyCenter for Drug Evaluation and ResearchFood and Drug Administration

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OUTLINEOUTLINE

GG Novel dosage formsNovel dosage formsGG Role of in vitro dissolution testsRole of in vitro dissolution tests

GG Method development considerationsMethod development considerations

GG ExamplesExamples

GG SuggestionsSuggestions

GG ConclusionsConclusions

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Novel Dosage FormsNovel Dosage Forms

GG Dissolution testing has widened to a variety of Dissolution testing has widened to a variety of novel or specialized dosages forms such as:novel or specialized dosages forms such as: suspensions,suspensions, Orally disintegrating tabletsOrally disintegrating tablets chewable tablets and gums,chewable tablets and gums, semisolid topical preparations,semisolid topical preparations,

suppositories,suppositories, liposomes,liposomes, Injectable microparticulate formulationsInjectable microparticulate formulations transdermal patches,transdermal patches, Subcutaneous Implants,Subcutaneous Implants, Drug eluting stentsDrug eluting stents Steroid eluting leads, etc.Steroid eluting leads, etc.

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Novel Dosage FormsNovel Dosage FormsG General principles of dissolution tests for

conventional oral dosage forms also apply to

the in vitro release tests for novel dosageforms.

G For non-oral dosage forms the test is referredas “drug release test” or “in vitro release test.For drug-device combination products thetest is also referred as “drug elution test”

G It is not possible to have a single test system

that could be used to evaluate the releasecharacteristics of all novel products. Rather,different apparatus and methodologies areused on a case-by-case basis.

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Apparatus currently used for theApparatus currently used for the

testing of Novel Dosage Formstesting of Novel Dosage Forms

Special apparatus, modified flow-throughcell, modified reciprocating cylinder, etc.

Drug-Device combination Products (i.e.Drug eluting stents and steroid elutingpacemaker-leads)

Special apparatus, modified flow-throughcell

ImplantsModified flow-through cellMicroparticulate formulations

Flow-through cell (powder/granulesample cell)

Powders and granules

Special apparatus (PhEur)Chewing gum

More work needed

Paddle, modified basket, or dual chamber flow-through cell

Suppositories

Franz cell diffusion systemTopicals—semisolids

Paddle over diskTransdermals—patches

Basket, paddle, or reciprocating cylinder with glass beads

Chewable tablets

PaddleOrally disintegrating tabletsPaddleOral suspensions

Recommended

APPARATUSAPPARATUSTYPE OF DOSAGE FORMTYPE OF DOSAGE FORM

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Role of Dissolution/Release TestingRole of Dissolution/Release Testing

Powerful and useful tool during:Powerful and useful tool during:

GGProduct developmentProduct developmentInvestigational formulations testing (QC)Investigational formulations testing (QC)

GGProduct evaluationProduct evaluationStability program (QC)Stability program (QC)

Establishment of product’s shelf lifeEstablishment of product’s shelf lifeRelease of commercial batches (QC)Release of commercial batches (QC)SUPAC changes, etc.SUPAC changes, etc.

GG In certain cases, the test could be used as aIn certain cases, the test could be used as asurrogate for the in vivo performance of thesurrogate for the in vivo performance of thedrug product.drug product.

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Method DevelopmentMethod DevelopmentConsiderationsConsiderations

GG Testing MethodologyTesting Methodology DevelopmentDevelopment

ValidationValidation

GG Setting of SpecificationsSetting of Specifications

GG In vitroIn vitro--In Vivo RelationshipsIn Vivo Relationships

GG ApplicationsApplications

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Method Development ConsiderationsMethod Development Considerations

GG During development the release of the drug shouldDuring development the release of the drug should

be evaluated under various conditions:be evaluated under various conditions: USP apparatus/special equipment, speed, dips, etc.USP apparatus/special equipment, speed, dips, etc.

Release media, pHRelease media, pH

Physical Factors, etc.Physical Factors, etc.

GG Profile should cover at least 80% release or whenever Profile should cover at least 80% release or whenever a plateau is reached.a plateau is reached.

GG Method should be sensitive enough to reject lots thatMethod should be sensitive enough to reject lots that

are not acceptable.are not acceptable.

GG Preferable profile should mimic the in vivo releasePreferable profile should mimic the in vivo release

profileprofile

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•• An in vitro release test that predictsAn in vitro release test that predictsthe release of the drug in vivo wouldthe release of the drug in vivo would

be optimal and highly desirable.be optimal and highly desirable.

•• The selected test should be simple,The selected test should be simple,

reliable and reproducible in order toreliable and reproducible in order tobe used for quality control purposes.be used for quality control purposes.

Method Development ConsiderationsMethod Development Considerations

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GG The proposed methodology should be adequatelyThe proposed methodology should be adequatelyvalidated. It should provide accurate, precise, andvalidated. It should provide accurate, precise, and

reproducible data, which ensures the productreproducible data, which ensures the product’’ssquality.quality.

GG Method validation would require lotsMethod validation would require lotsmanufactured intentionally outside the acceptablemanufactured intentionally outside the acceptable

specification limits of the critical manufacturingspecification limits of the critical manufacturingvariables (CMVs). Tvariables (CMVs). The test should be sensitivehe test should be sensitiveenough to detect and reject those lots withenough to detect and reject those lots withdeviated manufacturing variables.deviated manufacturing variables.

GG The selected test should be able to pickThe selected test should be able to pick--up batchup batchto batch variability and reject lots with subto batch variability and reject lots with sub--optimaloptimalperformance.performance.

Method Validation ConsiderationsMethod Validation Considerations

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GG The in vitro elution specifications should encompass theThe in vitro elution specifications should encompass the

timeframe over which at least 80% of the drug is eluted or timeframe over which at least 80% of the drug is eluted or

where the plateau of drug elution is reached if incompletewhere the plateau of drug elution is reached if incompleteelution is occurring.elution is occurring.

GG At least three specificationAt least three specification--sampling times covering thesampling times covering the

initial, middle, and terminal phases of the completeinitial, middle, and terminal phases of the complete

elution profile data should be selected. The specificationelution profile data should be selected. The specificationranges will be based on the overall elution data generatedranges will be based on the overall elution data generated

at the selected times.at the selected times.

GG Data from lots used in the clinical trials, stability studies,Data from lots used in the clinical trials, stability studies,

and toand to--bebe--marketed batches, should be used.marketed batches, should be used.

Considerations for Setting SpecificationsConsiderations for Setting Specifications

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GG Specifications should be set in a way to ensureSpecifications should be set in a way to ensureconsistent performance from lot to lot.consistent performance from lot to lot.

GG The chosen specifications should not allow theThe chosen specifications should not allow therelease of any lots with elution profiles outside thoserelease of any lots with elution profiles outside thosethat showed clinically to be safe and effective.that showed clinically to be safe and effective.

GG Variability should not be the primary considerationVariability should not be the primary considerationin determining the elution specificationsin determining the elution specifications

GG Ideally all lots meeting the elution specificationsIdeally all lots meeting the elution specificationsshould be bioequivalentshould be bioequivalent

Considerations for Setting SpecificationsConsiderations for Setting Specifications

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Considerations in Developing IVIVCConsiderations in Developing IVIVC

for Special Dosage Formsfor Special Dosage Forms

GG The main objective of developing and evaluatingThe main objective of developing and evaluatingIVIVC is to empower the in vitro release test to serveIVIVC is to empower the in vitro release test to serveas a surrogate marker for in vivo performance.as a surrogate marker for in vivo performance.

GG Great deal of utility in alleviating regulatory burdenGreat deal of utility in alleviating regulatory burden

GG Surrogate for bioavailability specially whenSurrogate for bioavailability specially whenbioequivalence studies are difficult to perform.bioequivalence studies are difficult to perform.

GG Useful to correlate the in vitro release rate withUseful to correlate the in vitro release rate withefficacy and safety outcomeefficacy and safety outcome..

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Considerations in Developing IVIVCConsiderations in Developing IVIVCfor Special Dosage Formsfor Special Dosage Forms

GG

Important to determine whether releaseImportant to determine whether releasecharacteristics are dependent on in vitrocharacteristics are dependent on in vitro

dissolution conditionsdissolution conditions

GG Choose dissolution conditions that willChoose dissolution conditions that will

result in vitro release characteristics thatresult in vitro release characteristics thatmimic as closely as possible the in vivomimic as closely as possible the in vivo

release characteristicsrelease characteristics

GG

If possible investigate more than oneIf possible investigate more than one

formulation with different releaseformulation with different release

characteristics in vivo.characteristics in vivo.

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GG A specific value of in vitro drug release testing is itsA specific value of in vitro drug release testing is itsapplication as a batchapplication as a batch--toto--batch quality control testbatch quality control test

and its value in evaluation and approval of SUPACand its value in evaluation and approval of SUPACchanges.changes.

GG In vitro drug release testing is used to ensure productIn vitro drug release testing is used to ensure product

similarity (f2 test) by profile comparison between presimilarity (f2 test) by profile comparison between pre--

change and postchange and post--change productschange products

GG The test can also be used to grant biowaivers for theThe test can also be used to grant biowaivers for the

requirement of the submission of BA/BE studies.requirement of the submission of BA/BE studies.

GG The test may serve as a surrogate marker for in vivoThe test may serve as a surrogate marker for in vivo

performance.performance.

ApplicationsApplications

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EXAMPLESEXAMPLES

-- TransdermalTransdermal Drug Delivery ProductsDrug Delivery Products-- Drug Device Combination ProductsDrug Device Combination Products

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TRANSDERMALSTRANSDERMALS

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Approved Transdermal ProductsApproved Transdermal Products

GG ClonidineClonidine

GG EstradiolEstradiol

GG Estrogen/ProgestinEstrogen/Progestin

HRT combinationsHRT combinations

GG Estrogen/ProgestinEstrogen/Progestincontraceptivecontraceptive

GG FentanylFentanyl

GG NicotineNicotine

GG NitroglycerinNitroglycerin

GG OxybutyninOxybutynin

GG ScopolamineScopolamine

GG TestosteroneTestosterone

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TRANSDERMALSTRANSDERMALS

GG IssuesIssues Transdermal products for a specificTransdermal products for a specific

drug from different manufacturersdrug from different manufacturers

may differ significantly in the drugmay differ significantly in the drug

content for a given rate of delivery.content for a given rate of delivery.

Transdermal products are marketedTransdermal products are marketed

in varying strengths, sizes, andin varying strengths, sizes, and

shapes.shapes.

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Advantages of TransdermalAdvantages of TransdermalDrug DeliveryDrug Delivery

GG

Preferred over other dosage forms byPreferred over other dosage forms bysome patientssome patients

GG Less frequent dosing may lead toLess frequent dosing may lead to

improved patient complianceimproved patient compliance

GG Avoids the frequent peaks and troughs inAvoids the frequent peaks and troughs inserum concentrations seen with IR oralserum concentrations seen with IR oral

drugsdrugs

GG Avoids first pass metabolismAvoids first pass metabolism

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Common DesignsCommon Designs

GG Reservoir with rateReservoir with rate--limiting membranelimiting membrane

GG DrugDrug--inin--adhesive matrixadhesive matrix

GG Matrix with rateMatrix with rate--limiting membranelimiting membrane

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In VitroIn Vitro Drug Release Tests for Drug Release Tests for Transdermal ProductsTransdermal Products

GGCompendial MethodsCompendial Methods:: – USP/PhEur Methods

GGUnique MethodsUnique Methods::Sponsors sometimes develop unique

dissolution methods and apparatusesfor determining the in vitro releaseprofile of a new transdermal system.

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Compendial MethodsCompendial Methods

GG

USP/PhEur Methods:USP/PhEur Methods:Paddle over disk method(USP Apparatus 5/PhEur 2.9.4.1)

Rotating cylinder method(USP Apparatus 6/PhEur 2.9.4.3)

Reciprocating disk method (Apparatus 7)

Paddle over extraction cell method(PhEur 2.9.4.2).

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USP METHODSUSP METHODSGGGeneral Procedure:General Procedure:

Methods are described in the USP <724>

GGNo. of Samples Tested:No. of Samples Tested:Six to twelve samples per test.

GGDissolution Medium/Temperature & pH:Dissolution Medium/Temperature & pH:As stated in the individual monograph at 32oC

Ideally, pH should be 5 to 6, reflecting skin conditions

GGTest Duration:Test Duration:

Until 85% of total drug is released, or Until treatment duration, or

Until a plateau is reached

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Paddle Over Disk MethodPaddle Over Disk MethodGG Advantages:Advantages:

Simple, reliable, reproducible,

stability indicating test. Applicable to all sizes and

shapes. Ruggedness and flexibility

have been well documented.

Can be used for batch to batchuniformity.

GG Limitations:Limitations: Difficult to have same release

specifications for all brands of a given drug. Cannot detect changes in

adhesive properties.

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Specifications for Specifications for TransdermalsTransdermals

GG For NDAs, the setting of drug release rateFor NDAs, the setting of drug release rate

specifications is based on drug releasespecifications is based on drug releasedata from the biodata from the bio--lot(s).lot(s).

GG To set the specification ranges, aTo set the specification ranges, a

minimum of three to four time points tominimum of three to four time points to

describe the complete release profile aredescribe the complete release profile are

selected.selected.

GG The mean value (MV) for each time point isThe mean value (MV) for each time point is

estimated and the specification ranges areestimated and the specification ranges areset to MV+10%.set to MV+10%.

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Is There an In VitroIs There an In Vitro--In VivoIn VivoCorrelation for Transdermals ?Correlation for Transdermals ?

GG Correlation:Correlation:In vitro release - In vitro skin permeation

In vitro release - In vivo bioavailability

In vitro skin permeation - In vivo bioavailability

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TransdermalTransdermal

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TransdermalsTransdermals

GG

Low success in developing meaningful IVIVCLow success in developing meaningful IVIVCfor matrix type patchesfor matrix type patches

GG Rate limiting step is due to absorption fromRate limiting step is due to absorption from

the skin and not release from the patchthe skin and not release from the patch

GG Possibility of correlation between in vitroPossibility of correlation between in vitro

permeation and in vivo performance for permeation and in vivo performance for

reservoir type patchesreservoir type patches

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DrugDrug--DeviceDeviceCombination ProductsCombination Products-- Drug ElutingDrug Eluting StentsStents

-- Steroid Eluting LeadsSteroid Eluting Leads

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Product DescriptionProduct Description

GG DeviceDevice--Polymer/DrugPolymer/Drug

GG DeviceDevice--Biodegradable polymer/DrugBiodegradable polymer/Drug

GG DeviceDevice--DrugDrug

Drug ElutingDrug Eluting

StentStent

Stent

D r u g C

a r r i e r ?

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Drug Eluting Stents (DES):Drug Eluting Stents (DES):Where are we today?Where are we today?

Two DES ApprovedTwo DES ApprovedGG Cordis Cypher SirolimusCordis Cypher Sirolimus--Eluting Coronary StentEluting Coronary Stent

– – April 2003April 2003 – – expedited reviewexpedited review

GG Taxus ExpressTaxus Express22 PaclitaxelPaclitaxel--Eluting Coronary StentEluting Coronary Stent

– – March 2004March 2004

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CYPHERCYPHER

CYPHERCYPHER ™™ SirolimusSirolimus--Eluting StentEluting Stent

Drug: SirolimusDrug: Sirolimus Polymers: PEVA and PBMAPolymers: PEVA and PBMA

Devices: RAPTORDevices: RAPTOR ™™ & RAPTORRAIL& RAPTORRAIL®®

(316L Stainless Steel)(316L Stainless Steel)

Sponsor: Johnson & JohnsonSponsor: Johnson & Johnson

Approved: April 2003Approved: April 2003

Retail Price: $3,195Retail Price: $3,195

Use: indicatedUse: indicated for improving coronaryfor improving coronaryluminal diameter in patients withluminal diameter in patients with

symptomatic ischemic disease due tosymptomatic ischemic disease due todiscretediscrete dede novo lesionsnovo lesions << 30 mm in30 mm inlength in native coronary arterieslength in native coronary arteries >> 2.5 to2.5 to<< 3.5 mm in diameter.3.5 mm in diameter.

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Sirolimus is released in a controlled manner from a

polymer matrix bound to the stent Topcoat

StentStent

Basecoat

Basecoat = polymer/sirolimus

+Topcoat = diffusion barrier

Controlled Elution from CYPHERControlled Elution from CYPHERTMTM

In Vivo Sirolimus Release in Pig Coronary Arteries

0.0

0.2

0.4

0.6

0.8

1.0

0 7 14 21 28 35

Time (days)

F r a c t i o n a l R e l e a s e

Fast

Slow

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Cypher StentCypher Stent

BiopharmaceuticBiopharmaceutic Issues:Issues: Low percentage of the drug was releasedLow percentage of the drug was released

in vitroin vitro

Less than optimal in vitro elution methodLess than optimal in vitro elution method

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Cypher StentCypher Stent

Ongoing Biopharmaceutic Issues:Ongoing Biopharmaceutic Issues:

GG The proposed elution method and elutionThe proposed elution method and elution

rate specification were accepted on anrate specification were accepted on an

interim basisinterim basis

GG Currently, the sponsor still is continuingCurrently, the sponsor still is continuing

with the development of an optimal in vitrowith the development of an optimal in vitro

elution test for the Cypher stent.elution test for the Cypher stent.

STOP

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Lessons LearnedLessons LearnedCYPHER StentCYPHER Stent

•• To have a better understanding of the factors thatTo have a better understanding of the factors thatmay affect the elution/release characteristics of themay affect the elution/release characteristics of thedrug will help to:drug will help to:

Develop an optimal in vitro elution methodDevelop an optimal in vitro elution method

Better control the quality of the productBetter control the quality of the product

Decrease variability from lot to lotDecrease variability from lot to lot

Setting of appropriate specificationsSetting of appropriate specifications

•• It is crucial to have interaction with the AgencyIt is crucial to have interaction with the Agencyduring method development/validation.during method development/validation.

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TAXUSTAXUSTAXUSTAXUS™™ ExpressExpress22™™ PaclitaxelPaclitaxel--

Eluting Coronary Stent SystemEluting Coronary Stent System

(Monorail and Over (Monorail and Over --thethe--Wire)Wire)

Drug:Drug: Paclitaxel (1 mcg/mmPaclitaxel (1 mcg/mm22))

Polymer: TranslutePolymer: Translute™™ (SIBS)(SIBS)

Device: ExpressDevice: Express22 (313L Stainless(313L Stainless

Steel stent)Steel stent)

Sponsor: Boston Scientific,Sponsor: Boston Scientific,

Approved March 2004Approved March 2004

Retail Price: $2,700Retail Price: $2,700

Use:Use: indicated for improving luminalindicated for improving luminal

diameter for the treatment of diameter for the treatment of dede novonovolesionslesions << 28 mm in length in native28 mm in length in nativecoronary arteriescoronary arteries >> 2.5 to2.5 to << 3.75 mm in3.75 mm indiameter.diameter.

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Controlled Elution from TAXUSControlled Elution from TAXUS

0

5

10

1520

25

30

35

0 20 40 60 80 100Time, Days

C u m u l a t i v e % P a c l i t a x e l

R e l e a s

e d

In Vitro Release of Taxus Stents Using

the Commercial KDR Method

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TAXUSTAXUS – –

In Vitro Elution Test DevelopmentIn Vitro Elution Test Development

GGApparatusApparatus

Special equipment andSpecial equipment and

USP Apparatus 1 to 7 were testedUSP Apparatus 1 to 7 were tested

GGIn vitro Release MediaIn vitro Release Media >50>50 elutionelution mediamedia werewere studiedstudied

GGPhysical FactorsPhysical Factors DifferentDifferent temperaturetemperature conditionsconditions werewere testedtested

SonicationSonication waswas evaluatedevaluated

GGProduct DiscriminationProduct Discrimination

CoatingCoating formulationformulation changeschanges werewere testedtested

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Lessons LearnedLessons Learned

TAXUS StentsTAXUS Stents

GG Early and continuous communicationEarly and continuous communicationwith the sponsor helped on thewith the sponsor helped on thedevelopment of the optimal testingdevelopment of the optimal testing

conditions and help to solve all theconditions and help to solve all theissues before the product was approved.issues before the product was approved.

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Where are we going with theWhere are we going with theDES under development ?DES under development ?

GG

New & approved drugs (NMEs)New & approved drugs (NMEs)GG New polymersNew polymersGG Biodegradable polymersBiodegradable polymersGG No polymersNo polymersGG New stent designsNew stent designs

– – New materials; new strut configurationsNew materials; new strut configurations

GG New implantation sitesNew implantation sites – – Cardiovascular, renal, neurovascular, etc.Cardiovascular, renal, neurovascular, etc.

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In Vitro Elution/Release MethodIn Vitro Elution/Release Method

IssuesIssues Currently, an official FDA or USP in vitro

release method for DES products, is notavailable

Manufacturers have use modified compendialequipment and also have developed uniquemethods for determining the in vitro releaseprofile of their DES products.

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DRUGDRUG--DEVICE PRODUCTDEVICE PRODUCT

GG Very low amounts of drug in the finished productVery low amounts of drug in the finished product

GG Most drugs are insoluble in aqueous mediaMost drugs are insoluble in aqueous media

GG Stability of the drug can be an issueStability of the drug can be an issue

GG High Cost (up to $3,500 eachHigh Cost (up to $3,500 each))

RELEASE PROFILERELEASE PROFILE

GG Difference in the time frames of drug release; in vivo vs.Difference in the time frames of drug release; in vivo vs.in vitro (hours/days vs. weeks/months)in vitro (hours/days vs. weeks/months)

Challenges with DESChallenges with DESNew field involving combination drugsNew field involving combination drugs--device productsdevice products

((learning as we golearning as we go))

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TESTING METHODOLOGYTESTING METHODOLOGY

GG Lack of specialized equipment for the in vitro testLack of specialized equipment for the in vitro test

GG Development of optimal testing equipments for DES.Development of optimal testing equipments for DES.

GG Use of nonUse of non--physiological mediaphysiological media

GG Aggressive handling/battering of stentsAggressive handling/battering of stents

GG High variability of elution dataHigh variability of elution data

GG Development of highly sensitive analytical methodsDevelopment of highly sensitive analytical methods

GG Proper validation of elution test methodsProper validation of elution test methods

GG Testing lengthTesting length

SPECIFICATIONSSPECIFICATIONS

GG Appropriate specification settingAppropriate specification setting

Challenges with DESChallenges with DES

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Challenges with DESChallenges with DES

IVIVC DEVELOPMENTIVIVC DEVELOPMENT

GG For some DES, it may not be possible toFor some DES, it may not be possible todetermine the systemic levels of drugdetermine the systemic levels of drug

GG Difficulty in measuring the drug at the site of Difficulty in measuring the drug at the site of actionaction

GG Collection of data at the site of actionCollection of data at the site of action

GG Long term Duration (months to years)Long term Duration (months to years)

GG Difficulty in conducting in vivo studiesDifficulty in conducting in vivo studies

GG In vitro methods reflecting the in vivo behavior.In vitro methods reflecting the in vivo behavior.

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Regulatory Concerns for the DESRegulatory Concerns for the DES

under Developmentunder Development

GG Some sponsors are proposing very fast in vitro elutionSome sponsors are proposing very fast in vitro elution

tests. Are these fast tests able to pick up and reject lotstests. Are these fast tests able to pick up and reject lotswith bad performance?with bad performance?

GG What would be the most adequate approach to setWhat would be the most adequate approach to set

elution specifications for DES?elution specifications for DES? Should the setting of in vitro release specifications beShould the setting of in vitro release specifications be

similar to CR products or,similar to CR products or,

DES specifications should be set on a different wayDES specifications should be set on a different way

GG Development of acceptable IVIVC to support:Development of acceptable IVIVC to support:

Pre/post formulation changesPre/post formulation changes

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Possible SolutionsPossible Solutions

GG InIn--Vitro Elution/Release MethodVitro Elution/Release Method

GG In VitroIn Vitro--In Vivo RelationshipsIn Vivo Relationships

GG Setting of Release SpecificationsSetting of Release Specifications

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Possible SolutionsPossible Solutions

Method Development:Method Development:

GG Modifications to the compendial testing equipmentModifications to the compendial testing equipment

is acceptableis acceptable

GG Use of nonUse of non--conventional elution media is acceptedconventional elution media is accepted

GG Development of more sensitive stateDevelopment of more sensitive state--of of --the artthe artanalytical methods (best effort) is neededanalytical methods (best effort) is needed

(LC/MS/MS)(LC/MS/MS)

GG Use of animal data to better understand the in vivoUse of animal data to better understand the in vivo

release characteristics of the product.release characteristics of the product.GG Use of the in vivo release data for the developmentUse of the in vivo release data for the development

of optimal in vitro release methodology.of optimal in vitro release methodology.

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Possible SolutionsPossible Solutions (cont.)(cont.)

Setting of Elution SpecificationsSetting of Elution Specifications

GG Evaluation of different approachesEvaluation of different approachesUsing DESUsing DES--data from clinical, stability,data from clinical, stability,

and production batchesand production batches

GG Propose the best approachPropose the best approach

Specifications should be set in a way toSpecifications should be set in a way to

ensure consistent performance from lotensure consistent performance from lotto lot.to lot.

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Possible SolutionsPossible Solutions (cont.)(cont.)

In Vitro In Vivo RelationshipsIn Vitro In Vivo Relationships

GG

Evaluate using animal data:Evaluate using animal data: Measure % of drug remaining to be releasedMeasure % of drug remaining to be released

Determine in vivo release rate usingDetermine in vivo release rate using deconvolutiondeconvolution

GG Confirm using human data:Confirm using human data: Measure drug using noninvasive methodsMeasure drug using noninvasive methods [i.e., X[i.e., X--rayray

computed tomography, positron emission tomography (PET),computed tomography, positron emission tomography (PET),

single photon emission computed tomography (SPECT),single photon emission computed tomography (SPECT),

magnetic resonance spectroscopy (MRS), etc.]magnetic resonance spectroscopy (MRS), etc.] Determine in vivo release usingDetermine in vivo release using deconvolutiondeconvolution

A validated animal model also can be usedA validated animal model also can be used

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SUGGESTIONSSUGGESTIONS

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SuggestionsSuggestions

GG Benefit from other relevant (successful)Benefit from other relevant (successful)

technology examples.technology examples.

GG Invest the necessary effort, EARLY ON,Invest the necessary effort, EARLY ON,

to come up with a meaningful in vitroto come up with a meaningful in vitro

elution method.elution method.

GG Share ALL you efforts and data withShare ALL you efforts and data with

FDA in a timely manner.FDA in a timely manner.

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SuggestionsSuggestions (cont.)(cont.)

GG Come to resolution on in vitro method,Come to resolution on in vitro method,

specs and data needed prior to thespecs and data needed prior to the

submission of your application.submission of your application.

GG

Resolve the issues; donResolve the issues; don’’t ignore the advice.t ignore the advice.GG Request specific meeting if necessary toRequest specific meeting if necessary to

resolve important issues (clear questions,resolve important issues (clear questions,

all the relevant data in the package, etc.)all the relevant data in the package, etc.)

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CONCLUSIONSCONCLUSIONS

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ConclusionsConclusions•• An in vitro dissolution/release test is expectedAn in vitro dissolution/release test is expected

for each novel/specialized dosage formfor each novel/specialized dosage form

regardless of whether the intended effect isregardless of whether the intended effect is

systemic or nonsystemic or non--systemic.systemic.

•• Elution/release tests are used to monitor QCElution/release tests are used to monitor QC

during product development and to supportduring product development and to support

AgencyAgency’’s requirements during the stabilitys requirements during the stabilityprogram, shelf program, shelf --life, productlife, product’’s release, SUPACs release, SUPAC

changes, etc.changes, etc.

•• Selected test should be simple, reliable andSelected test should be simple, reliable andreproducible in order to be used for qualityreproducible in order to be used for quality

control purposes.control purposes.

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ConclusionsConclusions (cont.)(cont.)

•• The selected test should be able to pickThe selected test should be able to pick--up batch to batch variability and to rejectup batch to batch variability and to reject

formulations with subformulations with sub--optimaloptimalperformance.performance.

•• An in vitro release test that predicts theAn in vitro release test that predicts the

release of the drug in vivo would berelease of the drug in vivo would beoptimal.optimal.

•• Firms are strongly encouraged to exploreFirms are strongly encouraged to explore

the development of the development of IVIVCsIVIVCs for specialfor specialdosage formsdosage forms

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ConclusionsConclusions (cont.)(cont.)

•• Early and continuous communicationEarly and continuous communication

between the sponsor and the Agencybetween the sponsor and the Agencywill help to solve all the issues, beforewill help to solve all the issues, beforethe product is approved.the product is approved.

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AcknowledgmentsAcknowledgments•• Dr. PatrickDr. Patrick MarroumMarroum

•• Dr.Dr. MehulMehul MehtaMehta

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