DISSOLUTION TESTING OF DISSOLUTION 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 Research

Food and Drug Administration

OUTLINEOUTLINE

�� Novel dosage formsNovel dosage forms

�� Role of in vitro dissolution testsRole of in vitro dissolution tests

�� Method development considerationsMethod development considerations

�� ExamplesExamples

�� SuggestionsSuggestions

�� ConclusionsConclusions

Novel Dosage FormsNovel Dosage Forms

�� 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 stents Drug eluting stents �� Steroid eluting leads, etc.Steroid eluting leads, etc.

Novel Dosage FormsNovel Dosage Forms

� General principles of dissolution tests for conventional oral dosage forms also apply to the in vitro release tests for novel dosage forms.

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

� It is not possible to have a single test system that could be used to evaluate the release characteristics of all novel products. Rather, different apparatus and methodologies are used on a case-by-case basis.

Apparatus currently used for the Apparatus currently used for the

testing of Novel Dosage Formstesting of Novel Dosage Forms

Special apparatus, modified flow-through cell, modified reciprocating cylinder, etc.

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

Special apparatus, modified flow-through cell

Implants

Modified flow-through cell Microparticulate formulations

Flow-through cell (powder/granule sample 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 system Topicals—semisolids

Paddle over disk Transdermals—patches

Basket, paddle, or reciprocating cylinder with glass beads

Chewable tablets

Paddle Orally disintegrating tablets

Paddle Oral suspensions

Recommended

APPARATUSAPPARATUSTYPE OF DOSAGE FORM TYPE OF DOSAGE FORM

Role of Dissolution/Release TestingRole of Dissolution/Release Testing

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

��Product developmentProduct development��Investigational formulations testing (QC)Investigational formulations testing (QC)

��Product evaluationProduct evaluation��Stability program (QC)Stability program (QC)

��Establishment of product’s shelf life Establishment of product’s shelf life

��Release of commercial batches (QC)Release of commercial batches (QC)��SUPAC changes, etc.SUPAC changes, etc.

�� In certain cases, the test could be used as a In certain cases, the test could be used as a surrogate for the in vivo performance of the surrogate for the in vivo performance of the drug product.drug product.

Method Development Method Development ConsiderationsConsiderations

�� Testing Methodology Testing Methodology

�� DevelopmentDevelopment

�� ValidationValidation

�� Setting of SpecificationsSetting of Specifications

�� In vitroIn vitro--In Vivo RelationshipsIn Vivo Relationships

�� ApplicationsApplications

Method Development ConsiderationsMethod Development Considerations

�� During development the release of the drug should During 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.

�� 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.

�� Method should be sensitive enough to reject lots that Method should be sensitive enough to reject lots that

are not acceptable.are not acceptable.

�� Preferable profile should mimic the in vivo release Preferable profile should mimic the in vivo release

profileprofile

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

the release of the drug in vivo would the 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 to reliable and reproducible in order to

be used for quality control purposes.be used for quality control purposes.

Method Development ConsiderationsMethod Development Considerations

�� The proposed methodology should be adequately The proposed methodology should be adequately validated. It should provide accurate, precise, and validated. It should provide accurate, precise, and reproducible data, which ensures the productreproducible data, which ensures the product’’s s quality.quality.

�� Method validation would require lots Method validation would require lots manufactured intentionally outside the acceptable manufactured intentionally outside the acceptable specification limits of the critical manufacturing specification limits of the critical manufacturing variables (CMVs). Tvariables (CMVs). The test should be sensitive he test should be sensitive enough to detect and reject those lots with enough to detect and reject those lots with deviated manufacturing variables. deviated manufacturing variables.

�� The selected test should be able to pickThe selected test should be able to pick--up batch up batch to batch variability and reject lots with subto batch variability and reject lots with sub--optimal optimal performance.performance.

Method Validation ConsiderationsMethod Validation Considerations

�� The in vitro elution specifications should encompass the The 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 incomplete where the plateau of drug elution is reached if incomplete

elution is occurring.elution is occurring.

�� At least three specificationAt least three specification--sampling times covering the sampling times covering the

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

elution profile data should be selected. The specification elution profile data should be selected. The specification

ranges will be based on the overall elution data generated ranges will be based on the overall elution data generated

at the selected times.at the selected times.

�� 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

�� Specifications should be set in a way to ensure Specifications should be set in a way to ensure

consistent performance from lot to lot.consistent performance from lot to lot.

�� The chosen specifications should not allow the The chosen specifications should not allow the

release of any lots with elution profiles outside those release of any lots with elution profiles outside those

that showed clinically to be safe and effective.that showed clinically to be safe and effective.

�� Variability should not be the primary consideration Variability should not be the primary consideration

in determining the elution specificationsin determining the elution specifications

�� Ideally all lots meeting the elution specifications Ideally all lots meeting the elution specifications

should be bioequivalentshould be bioequivalent

Considerations for Setting SpecificationsConsiderations for Setting Specifications

Considerations in Developing IVIVC Considerations in Developing IVIVC

for Special Dosage Formsfor Special Dosage Forms

�� The main objective of developing and evaluating The main objective of developing and evaluating

IVIVC is to empower the in vitro release test to serve IVIVC is to empower the in vitro release test to serve

as a surrogate marker for in vivo performance.as a surrogate marker for in vivo performance.

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

�� Surrogate for bioavailability specially when Surrogate for bioavailability specially when

bioequivalence studies are difficult to perform.bioequivalence studies are difficult to perform.

�� Useful to correlate the in vitro release rate with Useful to correlate the in vitro release rate with

efficacy and safety outcomeefficacy and safety outcome..

Considerations in Developing IVIVC Considerations in Developing IVIVC

for Special Dosage Formsfor Special Dosage Forms

�� Important to determine whether release Important to determine whether release

characteristics are dependent on in vitro characteristics are dependent on in vitro

dissolution conditionsdissolution conditions

�� Choose dissolution conditions that will Choose dissolution conditions that will

result in vitro release characteristics that result in vitro release characteristics that

mimic as closely as possible the in vivo mimic as closely as possible the in vivo

release characteristicsrelease characteristics

�� If possible investigate more than one If possible investigate more than one

formulation with different release formulation with different release

characteristics in vivo.characteristics in vivo.

�� A specific value of in vitro drug release testing is its A specific value of in vitro drug release testing is its

application as a batchapplication as a batch--toto--batch quality control test batch quality control test

and its value in evaluation and approval of SUPAC and its value in evaluation and approval of SUPAC

changes.changes.

�� In vitro drug release testing is used to ensure product In 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

�� The test can also be used to grant biowaivers for the The 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.

�� The test may serve as a surrogate marker for in vivo The test may serve as a surrogate marker for in vivo

performance.performance.

ApplicationsApplications

EXAMPLESEXAMPLES

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

TRANSDERMALSTRANSDERMALS

Approved Transdermal ProductsApproved Transdermal Products

�� ClonidineClonidine

�� EstradiolEstradiol

�� Estrogen/Progestin Estrogen/Progestin

HRT combinationsHRT combinations

�� Estrogen/Progestin Estrogen/Progestin

contraceptivecontraceptive

�� FentanylFentanyl

�� NicotineNicotine

�� NitroglycerinNitroglycerin

�� OxybutyninOxybutynin

�� ScopolamineScopolamine

�� TestosteroneTestosterone

TRANSDERMALSTRANSDERMALS

�� IssuesIssues�� Transdermal products for a specific Transdermal products for a specific

drug from different manufacturers drug from different manufacturers

may differ significantly in the drug may differ significantly in the drug

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

�� Transdermal products are marketed Transdermal products are marketed

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

shapes.shapes.

Advantages of Transdermal Advantages of Transdermal

Drug DeliveryDrug Delivery

�� Preferred over other dosage forms by Preferred over other dosage forms by some patients some patients

�� Less frequent dosing may lead to Less frequent dosing may lead to improved patient complianceimproved patient compliance

�� Avoids the frequent peaks and troughs in Avoids the frequent peaks and troughs in serum concentrations seen with IR oral serum concentrations seen with IR oral drugsdrugs

�� Avoids first pass metabolismAvoids first pass metabolism

Common DesignsCommon Designs

�� Reservoir with rateReservoir with rate--limiting membranelimiting membrane

�� DrugDrug--inin--adhesive matrixadhesive matrix

�� Matrix with rateMatrix with rate--limiting membranelimiting membrane

In VitroIn Vitro Drug Release Tests forDrug Release Tests forTransdermal ProductsTransdermal Products

��Compendial MethodsCompendial Methods::– USP/PhEur Methods

��Unique MethodsUnique Methods::� Sponsors sometimes develop unique dissolution methods and apparatuses for determining the in vitro release profile of a new transdermal system.

Compendial MethodsCompendial Methods

��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).

USP METHODSUSP METHODS

��General Procedure:General Procedure:�Methods are described in the USP <724>

��No. of Samples Tested:No. of Samples Tested:

�Six to twelve samples per test.

��Dissolution 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

��Test Duration:Test Duration:�Until 85% of total drug is released, or

�Until treatment duration, or

�Until a plateau is reached

Paddle Over Disk MethodPaddle Over Disk Method

�� 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 batch uniformity.

�� Limitations:Limitations:� Difficult to have same release specifications for all brands of a given drug.

� Cannot detect changes in adhesive properties.

Specifications forSpecifications for TransdermalsTransdermals

�� For NDAs, the setting of drug release rate For NDAs, the setting of drug release rate

specifications is based on drug release specifications is based on drug release

data from the biodata from the bio--lot(s).lot(s).

�� To set the specification ranges, a To set the specification ranges, a

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

describe the complete release profile are describe the complete release profile are

selected.selected.

�� The mean value (MV) for each time point is The mean value (MV) for each time point is

estimated and the specification ranges are estimated and the specification ranges are

set to MV+10%.set to MV+10%.

Is There an In VitroIs There an In Vitro--In Vivo In Vivo

Correlation for Transdermals ?Correlation for Transdermals ?

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

�In vitro release - In vivo bioavailability

�In vitro skin permeation - In vivo bioavailability

TransdermalTransdermal

TransdermalsTransdermals

�� Low success in developing meaningful IVIVC Low success in developing meaningful IVIVC

for matrix type patchesfor matrix type patches

�� Rate limiting step is due to absorption from Rate limiting step is due to absorption from

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

�� Possibility of correlation between in vitro Possibility of correlation between in vitro

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

reservoir type patchesreservoir type patches

DrugDrug--Device Device Combination ProductsCombination Products

-- Drug Eluting Drug Eluting StentsStents

-- Steroid Eluting LeadsSteroid Eluting Leads

Product DescriptionProduct Description

�� DeviceDevice--Polymer/DrugPolymer/Drug

�� DeviceDevice--Biodegradable polymer/Drug Biodegradable polymer/Drug

�� DeviceDevice--DrugDrug

Drug ElutingDrug Eluting

StentStent

Stent

Drug

Carrier?

Drug Eluting Stents (DES):Drug Eluting Stents (DES):

Where are we today?Where are we today?

Two DES ApprovedTwo DES Approved�� Cordis Cypher SirolimusCordis Cypher Sirolimus--Eluting Coronary Stent Eluting Coronary Stent

–– April 2003April 2003 –– expedited reviewexpedited review

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

–– March 2004March 2004

CYPHERCYPHER

CYPHER CYPHER ™™ SirolimusSirolimus--Eluting StentEluting Stent�� Drug: SirolimusDrug: Sirolimus

�� Polymers: PEVA and PBMAPolymers: PEVA and PBMA

�� Devices: RAPTOR Devices: RAPTOR ™™ & RAPTORRAIL& RAPTORRAIL®®

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

�� Sponsor: Johnson & JohnsonSponsor: Johnson & Johnson

�� Approved: April 2003Approved: April 2003

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

�� Use: indicated Use: indicated for improving coronary for improving coronary luminal diameter in patients with luminal diameter in patients with symptomatic ischemic disease due to symptomatic ischemic disease due to discrete discrete de de novo lesions novo lesions << 30 mm in 30 mm in length in native coronary arteries length in native coronary arteries >> 2.5 to 2.5 to << 3.5 mm in diameter.3.5 mm in diameter.

Sirolimus is released in a controlled manner from a

polymer matrix bound to the stentTopcoat

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)

Fractional Release

Fast

Slow

Cypher StentCypher Stent

BiopharmaceuticBiopharmaceutic Issues:Issues:

�� Low percentage of the drug was released Low percentage of the drug was released

in vitro in vitro

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

Cypher StentCypher Stent

Ongoing Biopharmaceutic Issues:Ongoing Biopharmaceutic Issues:

�� The proposed elution method and elution The proposed elution method and elution

rate specification were accepted on an rate specification were accepted on an

interim basisinterim basis

�� Currently, the sponsor still is continuing Currently, the sponsor still is continuing

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

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

STOP

Lessons LearnedLessons Learned

CYPHER StentCYPHER Stent

•• To have a better understanding of the factors that To have a better understanding of the factors that may affect the elution/release characteristics of the may affect the elution/release characteristics of the drug 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 Agency It is crucial to have interaction with the Agency during method development/validation. during method development/validation.

TAXUS TAXUS

TAXUSTAXUS™™ 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: Express2 2 (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 luminal indicated for improving luminal

diameter for the treatment of diameter for the treatment of de de novo novo

lesions lesions << 28 mm in length in native 28 mm in length in native

coronary arteries coronary arteries >> 2.5 to 2.5 to << 3.75 mm in 3.75 mm in

diameter.diameter.

Controlled Elution from TAXUSControlled Elution from TAXUS

0

5

10

15

20

25

30

35

0 20 40 60 80 100

Time, Days

Cumulative % Paclitaxel

Released

In Vitro Release of Taxus Stents Using

the Commercial KDR Method

TAXUS TAXUS ––

In Vitro Elution Test DevelopmentIn Vitro Elution Test Development

��ApparatusApparatus

�� Special equipment andSpecial equipment and

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

��In vitro Release MediaIn vitro Release Media�� >50 >50 elutionelution media media werewere studiedstudied

��Physical FactorsPhysical Factors�� DifferentDifferent temperaturetemperature conditionsconditions werewere testedtested

�� SonicationSonication waswas evaluatedevaluated

��Product DiscriminationProduct Discrimination

�� CoatingCoating formulationformulation changeschanges werewere testedtested

Lessons LearnedLessons Learned

TAXUS StentsTAXUS Stents

�� Early and continuous communication Early and continuous communication with the sponsor helped on the with the sponsor helped on the

development of the optimal testing development of the optimal testing conditions and help to solve all the conditions and help to solve all the

issues before the product was approved.issues before the product was approved.

Where are we going with the Where are we going with the

DES under development ?DES under development ?

�� New & approved drugs (NMEs)New & approved drugs (NMEs)�� New polymersNew polymers�� Biodegradable polymers Biodegradable polymers �� No polymersNo polymers�� New stent designsNew stent designs

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

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

In Vitro Elution/Release MethodIn Vitro Elution/Release Method

IssuesIssues� Currently, an official FDA or USP in vitrorelease method for DES products, is not available

� Manufacturers have use modified compendial equipment and also have developed unique methods for determining the in vitro release profile of their DES products.

DRUGDRUG--DEVICE PRODUCTDEVICE PRODUCT

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

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

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

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

RELEASE PROFILERELEASE PROFILE

�� 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 products device products

((learning as we golearning as we go))

TESTING METHODOLOGYTESTING METHODOLOGY

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

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

�� Use of nonUse of non--physiological media physiological media

�� Aggressive handling/battering of stentsAggressive handling/battering of stents

�� High variability of elution data High variability of elution data

�� Development of highly sensitive analytical methods Development of highly sensitive analytical methods

�� Proper validation of elution test methodsProper validation of elution test methods

�� Testing lengthTesting length

SPECIFICATIONSSPECIFICATIONS

�� Appropriate specification settingAppropriate specification setting

Challenges with DESChallenges with DES

Challenges with DESChallenges with DES

IVIVC DEVELOPMENTIVIVC DEVELOPMENT

�� For some DES, it may not be possible to For some DES, it may not be possible to

determine the systemic levels of drugdetermine the systemic levels of drug

�� Difficulty in measuring the drug at the site of Difficulty in measuring the drug at the site of

action action

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

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

�� Difficulty in conducting in vivo studiesDifficulty in conducting in vivo studies

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

Regulatory Concerns for the DES Regulatory Concerns for the DES

under Developmentunder Development

�� Some sponsors are proposing very fast in vitro elution Some sponsors are proposing very fast in vitro elution

tests. Are these fast tests able to pick up and reject lots tests. Are these fast tests able to pick up and reject lots

with bad performance? with bad performance?

�� What would be the most adequate approach to set What would be the most adequate approach to set

elution specifications for DES?elution specifications for DES?

�� Should the setting of in vitro release specifications be Should 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

�� Development of acceptable IVIVC to support:Development of acceptable IVIVC to support:

�� Pre/post formulation changesPre/post formulation changes

Possible SolutionsPossible Solutions

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

�� In VitroIn Vitro--In Vivo RelationshipsIn Vivo Relationships

�� Setting of Release SpecificationsSetting of Release Specifications

Possible SolutionsPossible Solutions

Method Development:Method Development:

�� Modifications to the compendial testing equipment Modifications to the compendial testing equipment

is acceptableis acceptable

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

�� Development of more sensitive stateDevelopment of more sensitive state--ofof--the art the art

analytical methods (best effort) is needed analytical methods (best effort) is needed

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

�� Use of animal data to better understand the in vivo Use of animal data to better understand the in vivo

release characteristics of the product.release characteristics of the product.

�� Use of the in vivo release data for the development Use of the in vivo release data for the development

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

Possible Solutions Possible Solutions (cont.)(cont.)

Setting of Elution SpecificationsSetting of Elution Specifications

�� Evaluation of different approachesEvaluation of different approaches

��Using DESUsing DES--data from clinical, stability, data from clinical, stability,

and production batchesand production batches

�� Propose the best approachPropose the best approach

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

ensure consistent performance from lot ensure consistent performance from lot to lot.to lot.

Possible Solutions Possible Solutions (cont.)(cont.)

In Vitro In Vivo RelationshipsIn Vitro In Vivo Relationships

�� 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 using Determine in vivo release rate using deconvolutiondeconvolution

�� Confirm using human data: Confirm using human data:

�� Measure drug using noninvasive methodsMeasure drug using noninvasive methods [i.e., X[i.e., X--ray ray

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 using Determine in vivo release using deconvolutiondeconvolution

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

SUGGESTIONSSUGGESTIONS

SuggestionsSuggestions

�� Benefit from other relevant (successful) Benefit from other relevant (successful)

technology examples.technology examples.

�� Invest the necessary effort, EARLY ON, Invest the necessary effort, EARLY ON,

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

elution method.elution method.

�� Share ALL you efforts and data with Share ALL you efforts and data with

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

Suggestions Suggestions (cont.)(cont.)

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

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

submission of your application.submission of your application.

�� Resolve the issues; donResolve the issues; don’’t ignore the advice.t ignore the advice.

�� Request specific meeting if necessary to Request 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.)

CONCLUSIONSCONCLUSIONS

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

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

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

systemic or nonsystemic or non--systemic.systemic.

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

during product development and to support during product development and to support

AgencyAgency’’s requirements during the stability s requirements during the stability

program, shelfprogram, shelf--life, productlife, product’’s release, SUPAC s release, SUPAC

changes, etc.changes, etc.

•• Selected test should be simple, reliable and Selected test should be simple, reliable and

reproducible in order to be used for quality reproducible in order to be used for quality

control purposes.control purposes.

Conclusions Conclusions (cont.)(cont.)

•• The selected test should be able to pickThe selected test should be able to pick--

up batch to batch variability and to reject up batch to batch variability and to reject

formulations with subformulations with sub--optimal optimal

performance.performance.

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

release of the drug in vivo would be release of the drug in vivo would be

optimal.optimal.

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

the development of the development of IVIVCsIVIVCs for special for special

dosage formsdosage forms

Conclusions Conclusions (cont.)(cont.)

•• Early and continuous communication Early and continuous communication

between the sponsor and the Agency between the sponsor and the Agency

will help to solve all the issues, before will help to solve all the issues, before

the product is approved.the product is approved.

AcknowledgmentsAcknowledgments

•• Dr. Patrick Dr. Patrick MarroumMarroum

•• Dr. Dr. MehulMehul MehtaMehta