Pharmaceutical Development

Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 20071 |

Pharmaceutical DevelopmentPharmaceutical Development

Quality specifications and end-product testingQuality specifications and end-product testing

– with emphasis on the development of a with emphasis on the development of a discriminatorydiscriminatory dissolution testing method dissolution testing method

Presented by: Birgit Schmauser, pharmacist, PhDPresented by: Birgit Schmauser, pharmacist, PhD


Pharmaceutical developmentPharmaceutical development

Objectives of the presentationObjectives of the presentation

– Role of quality specificationsRole of quality specifications• Setting and justification of acceptance criteriaSetting and justification of acceptance criteria• Selection of test proceduresSelection of test procedures

– Establishment of a dissolution testing methodEstablishment of a dissolution testing methodDiscrimination of formulationsDiscrimination of formulationsDiscrimination of manufacturing performanceDiscrimination of manufacturing performanceIdentification of stability problemsIdentification of stability problems


Introduction

APIAPI– Establishing Establishing chemical equivalencechemical equivalence with Innovator API with Innovator API

• Stress stability testingStress stability testing– Identify critical chemical quality attributesIdentify critical chemical quality attributes– Developing a stability indicating analytical methodDeveloping a stability indicating analytical method

Establishing suitable acceptance criteriaEstablishing suitable acceptance criteria

FPPFPP– Establishing Establishing equivalence of performanceequivalence of performance with Innovator FPP with Innovator FPP

• Dissolution testingDissolution testing– Developing a dissolution method with discriminatory potential for changes in Developing a dissolution method with discriminatory potential for changes in

formulationformulationEstablishing discriminatory testing conditions and acceptance criteriaEstablishing discriminatory testing conditions and acceptance criteria


Discriminatory power of a dissolution method

Dissolution methods should be challenged during development to demonstrate that Dissolution methods should be challenged during development to demonstrate that change in formulation effects change in dissolution profilechange in formulation effects change in dissolution profile

Source: T.G. Dekker, E. Swanepool, A-M. Redelinghuys & E.C. van Tonder – unpublishedSource: T.G. Dekker, E. Swanepool, A-M. Redelinghuys & E.C. van Tonder – unpublished(Dissolution of Ethambutol-HCl and Isoniazid FDC)(Dissolution of Ethambutol-HCl and Isoniazid FDC)

Product A

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Withdrawal time in minutes

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Ethambutol HCl

Isoniazid

Product B

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Ethambutol HCl

Isoniazid

Product C

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Withdrawal time in minutesD

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Ethambutol HCl

Isoniazid

Product D

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Ethambutol HCl

Isoniazid


Quality specifications

SpecificationSpecification– List of List of teststests (test parameters) & reference to (test parameters) & reference to analytical proceduresanalytical procedures & &

appropriate appropriate acceptance criteriaacceptance criteria

Specifications are Specifications are critical quality standardscritical quality standards

Specifications are chosen to Specifications are chosen to confirmconfirm the quality of the the quality of theAPI / FPPAPI / FPP

Specifications are Specifications are not intended to fully characterizenot intended to fully characterize the theAPI / FPPAPI / FPP

Specifications are Specifications are one partone part of a of a quality control strategyquality control strategy of the of the API / FPPAPI / FPP


Quality of pharmaceutical products

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The quality of APIs and FPPs is determined by a The quality of APIs and FPPs is determined by a well-well-controlled, validated manufacturing processcontrolled, validated manufacturing process

– Critical quality attributes of input materialsCritical quality attributes of input materials– Critical process parametersCritical process parameters

Quality specifications are established to Quality specifications are established to ensureensure that that APIs and FPPs APIs and FPPs meet the pre-determined acceptance meet the pre-determined acceptance criteriacriteria derived from thorough product characterization derived from thorough product characterization during developmentduring development


Quality specifications of biological APIs

The quality of APIs resulting from The quality of APIs resulting from biological biological processes such as fermentationprocesses such as fermentation cannot be cannot be sufficiently ensured by quality specificationssufficiently ensured by quality specifications

PQIFPQIF– Not suitable for evaluation of biological APIsNot suitable for evaluation of biological APIs

Biological APIs are not subject of this presentationBiological APIs are not subject of this presentation



General conceptsGeneral concepts Periodic testing / Periodic testing / skipskip testing testing

– Pre-selected batches / predetermined intervalsPre-selected batches / predetermined intervals• Justification / less than full schedule testing / post approvalJustification / less than full schedule testing / post approval

ReleaseRelease versus versus shelf-lifeshelf-life specification specification– Acceptance criteria / set of testsAcceptance criteria / set of tests

In-processIn-process tests tests– Conducted during manufacturing process / acceptance criteriaConducted during manufacturing process / acceptance criteria

ExclusionExclusion of tests of tests– Supported by development dataSupported by development data

• Extractables / particle size / dissolution >> disintegrationExtractables / particle size / dissolution >> disintegration

RevisionRevision of specifications based on sufficient batch data of specifications based on sufficient batch data



Pharmacopoeial standardsPharmacopoeial standards– If appropriate, pharmacopoeial test procedures If appropriate, pharmacopoeial test procedures andand acceptance acceptance

criteria should be usedcriteria should be used– Alternative test proceduresAlternative test procedures ( (andand acceptance criteria) acceptance criteria) maymay be be

used if used if comparabilitycomparability to or to or superioritysuperiority to the pharmacopoeial to the pharmacopoeial procedure is demonstratedprocedure is demonstrated

– If If pharmacopoeial finished product standardspharmacopoeial finished product standards are used are used compliance to each test parameter/procedure/acceptance compliance to each test parameter/procedure/acceptance criteria is criteria is understoodunderstood



Specifications Specifications typically not included in official compendiatypically not included in official compendia– Residual solvents Residual solvents

• API and FPP (e.g. granulation, film coating)API and FPP (e.g. granulation, film coating)– User requirementsUser requirements

• Particle sizeParticle size– Potential critical quality attribute identified during pharmaceutical Potential critical quality attribute identified during pharmaceutical

developmentdevelopment• (Polymorphic forms) (Polymorphic forms)


Verification of compendial standards

Compendial assay methodsCompendial assay methods– APIAPI

• Verification of applicability with the necessary accuracy and precisionVerification of applicability with the necessary accuracy and precision• Verification of specificity with regard to impurities/degradants identified Verification of specificity with regard to impurities/degradants identified

during stress testingduring stress testing– comparable impurity profilecomparable impurity profile

– FPPFPP• Verification of applicability with the necessary accuracy (matrix!) and Verification of applicability with the necessary accuracy (matrix!) and

precisionprecision• Verification of specificity with regard to impurities/degradants identified Verification of specificity with regard to impurities/degradants identified

during stress testing during stress testing


Verification of comparability of in-house methods with pharmacopoeial standard

Abacavir sulfate PhIntAbacavir sulfate PhInt

In-house impurity profile should In-house impurity profile should be verified by comparison with be verified by comparison with PhInt methodPhInt method

– Comparison of retention times of Comparison of retention times of PhInt impurities with PhInt impurities with chromatographic profile of chromatographic profile of samplesample

– Verification that impurities B and Verification that impurities B and D-F are not present (e.g. spike D-F are not present (e.g. spike with impurity standard)with impurity standard)

PhInt profilePhInt profile(PhInt method)(PhInt method)

In-house profile (in-In-house profile (in-house method)house method)

Impurity AImpurity AEnantiomeric impurityEnantiomeric impurity

Impurity BImpurity B--

Impurity CImpurity CAmino-impurityAmino-impurity

Impurity DImpurity D--

Impurity EImpurity E--

Impurity FImpurity F--

--Chloro-impurityChloro-impurity

--Pyrimidine-impurityPyrimidine-impurity



„„A specification establishes the A specification establishes the set of criteriaset of criteria to to which a new drug substance or new drug product which a new drug substance or new drug product should should conformconform to be considered acceptableto be considered acceptable for its for its intended useintended use“ (ICH Q6A)“ (ICH Q6A)

……JustificationJustification should be presented for each should be presented for each procedure and each acceptance criterion included procedure and each acceptance criterion included (ICH Q6A)(ICH Q6A)

– Development dataDevelopment data, pharmacopoeial standards, test data , pharmacopoeial standards, test data from preclinical and clinical studies, results from stability from preclinical and clinical studies, results from stability studiesstudies

– Range of expected Range of expected analyticalanalytical and and manufacturing variabilitymanufacturing variability


Quality specifications (FPP)

GeneralGeneral Characteristics and Tests Characteristics and Tests DescriptionDescription

– Size, shape, colourSize, shape, colour

IdentificationIdentification– Identity of API (discriminatory)Identity of API (discriminatory)

AssayAssay– Specific, stability-indicatingSpecific, stability-indicating

PurityPurity– Degradation products (single un-identified and identified; total)Degradation products (single un-identified and identified; total)– Residual solventsResidual solvents



ParticularParticular Characteristics and TestsCharacteristics and Tests

Oral solid dosage formsOral solid dosage forms– DissolutionDissolution

• Disintegration (dissolution Disintegration (dissolution 80% in 15min at pH 1.2 – 6.8) 80% in 15min at pH 1.2 – 6.8)– Hardness/friabilityHardness/friability– Uniformity of dosage unitsUniformity of dosage units– Water contentWater content– Microbial limitsMicrobial limits




Liquid dosage forms for oral useLiquid dosage forms for oral use(& powder and solution for reconstitution)(& powder and solution for reconstitution)

– Uniformity of dosage unitsUniformity of dosage units– pHpH– Microbial limitsMicrobial limits– Antimicrobial/Antioxidative preservative contentAntimicrobial/Antioxidative preservative content– Antimicrobial preservative effectivenessAntimicrobial preservative effectiveness– ExtractablesExtractables– Dissolution (suspensions)Dissolution (suspensions)– Particle size distributionParticle size distribution– Redispersibility (time required)Redispersibility (time required)– Water content (powder and solution for reconstitution)Water content (powder and solution for reconstitution)




ParenteralParenteral drug products drug products– Uniformity of dosage units (powders for reconstitution)Uniformity of dosage units (powders for reconstitution)– pHpH– SterilitySterility– EndotoxinsEndotoxins– Particulate matter (visible /subvisible particulates)Particulate matter (visible /subvisible particulates)– Water content (powders for reconstitution)Water content (powders for reconstitution)– Antimicrobial/Antioxidant presevative contentAntimicrobial/Antioxidant presevative content– Antimicrobial preservative effectivenessAntimicrobial preservative effectiveness– ExtractablesExtractables– OsmolarityOsmolarity– Particle size distribution (suspensions)Particle size distribution (suspensions)– Redispersibility (suspensions)Redispersibility (suspensions)– Reconstitution timeReconstitution time


Particular aspects – FDC-FPPs

WHO TRS 929, Annex 5, Guidelines for registration of fixed WHO TRS 929, Annex 5, Guidelines for registration of fixed dose combination medicinal productsdose combination medicinal products

– Emphasis on Emphasis on homogeneity of APIshomogeneity of APIs in dosage form (≤ 25 mg/%) in dosage form (≤ 25 mg/%)• Homogeneity of blend before compression (content uniformity, PhInt, PhEur, USP))Homogeneity of blend before compression (content uniformity, PhInt, PhEur, USP))• Homogeneity of finished dosage form (content uniformity, PhInt, PhEur, USP)Homogeneity of finished dosage form (content uniformity, PhInt, PhEur, USP)

– Emphasis on Emphasis on adequate impurity specificationsadequate impurity specifications• Calculation with reference to the parent API or API with lowest peak area percentageCalculation with reference to the parent API or API with lowest peak area percentage• Particular attention to adequate validation of analytical procedureParticular attention to adequate validation of analytical procedure• Stability testingStability testing

– Impurity specifications based on adequate stress testing (Appendix 3)Impurity specifications based on adequate stress testing (Appendix 3)– Emphasis on Emphasis on adequate dissolution testingadequate dissolution testing

• More than one dissolution medium may be necessaryMore than one dissolution medium may be necessary


Quality specifications - limitations

Quality specifications are applied to a relatively small Quality specifications are applied to a relatively small proportion of a batch and rely on proportion of a batch and rely on representativenessrepresentativeness of of samples for a batchsamples for a batch

– Well controlled manufacturing procedure (dosage forms)Well controlled manufacturing procedure (dosage forms)

Acceptance criteria of quality specifications are limited by the Acceptance criteria of quality specifications are limited by the performance/capability of the method used for testingperformance/capability of the method used for testing

– Specifications (assay, impurities) based on inadequate validationSpecifications (assay, impurities) based on inadequate validation• Impurity specifications and LOQ / responseImpurity specifications and LOQ / response

• Assay specification and peak purityAssay specification and peak purity

• Impurities not covered by an analytical methodImpurities not covered by an analytical method


Quality specifications - potential

Unravel unexpected related quality problemsUnravel unexpected related quality problems– Quality problems identified by non-conformance to organoleptic Quality problems identified by non-conformance to organoleptic

parameters/appearanceparameters/appearance• Odour (discovery of genotoxic esylates)Odour (discovery of genotoxic esylates)• Turbidity [BaTurbidity [Ba2+2+((type I-glass !type I-glass !) and SO) and SO44-containing FPP-solution]-containing FPP-solution]• Color (formation of degradation products)Color (formation of degradation products)


Pediatric formulations in PQ

Isoniazid + Pyrazinamide + Rifampicin tablet Isoniazid + Pyrazinamide + Rifampicin tablet 30mg+150mg+60mg30mg+150mg+60mg

– Uncoated dispersible tablet with break lineUncoated dispersible tablet with break line• 7th EOI, antituberculosis medicines7th EOI, antituberculosis medicines

Isoniazid + Rifampicin tabletIsoniazid + Rifampicin tablet30 mg+60mg30 mg+60mg

– Uncoated dispersible tablet with break lineUncoated dispersible tablet with break line• 7th EOI, antituberculosis medicines7th EOI, antituberculosis medicines


Quality specifications - Dissolution

Performance Testing (ICH Q8)Performance Testing (ICH Q8)– PerformancePerformance can be considered as an indicator of the can be considered as an indicator of the delivery of a drug delivery of a drug

from the dose to the target site from the dose to the target site (type of dose/route of administration)(type of dose/route of administration)– Performance monitoringPerformance monitoring of unit solid dosage forms is usually addressed as of unit solid dosage forms is usually addressed as

the the disintegrationdisintegration of the preparation of the preparation and theand the dissolutiondissolution of the active of the active substancesubstance in a suitable medium in a suitable medium

Disintegration testingDisintegration testing should demonstrate the should demonstrate the effective break up of effective break up of the solid formulationthe solid formulation after administration (performance of after administration (performance of disintegrant)disintegrant)

Routine performance of disintegration testing may not be necessary Routine performance of disintegration testing may not be necessary if if a dissolution testa dissolution test with acceptable discriminatory power with acceptable discriminatory power is is included in the finished product specificationincluded in the finished product specification


Dissolution - ICH Q8

The actual amount of The actual amount of drug liberated from the dose formdrug liberated from the dose form into an into an aqueous reservoir in vitro is intended to aqueous reservoir in vitro is intended to reflect the in-vivo behaviourreflect the in-vivo behaviour of the productof the product

In-vivo behaviour is dependent on In-vivo behaviour is dependent on several factors making in-vitro / several factors making in-vitro / in-vivo correlation difficultin-vivo correlation difficult

Investigation of dissolution characteristics Investigation of dissolution characteristics should routinely be should routinely be applied to all solid dosage forms at the development phaseapplied to all solid dosage forms at the development phase

From such studies a decision can be made as to the From such studies a decision can be made as to the relevance of relevance of the dissolution testthe dissolution test to the in-vivo behaviour to the in-vivo behaviour and its abilityand its ability to to discriminate between formulation changesdiscriminate between formulation changes


Development of Dissolution Testing

Preliminary considerationsPreliminary considerations

Physical parameters of APIs demonstrated to be Physical parameters of APIs demonstrated to be variablevariable and and criticalcritical for the quality of the product need to be for the quality of the product need to be controlledcontrolled

– Additional physical testsAdditional physical tests beyond scope of a monograph beyond scope of a monograph

• Water contentWater content (crystal properties/particle size/stability) (crystal properties/particle size/stability)

• Particle sizeParticle size (bioavailability/content uniformity/solubility/stability) (bioavailability/content uniformity/solubility/stability)

• Crystal propertiesCrystal properties and and polymorphismpolymorphism (solubility / bioavailability / stability) (solubility / bioavailability / stability)



Consideration of physicochemical characteristics of the API in Consideration of physicochemical characteristics of the API in formulationformulation

– Solubility of API (at 37°C)Solubility of API (at 37°C)• choice of formulationchoice of formulation/choice of analytical method/choice of analytical method

– Physical properties of Physical properties of APIs and excipientsAPIs and excipients• Differing properties may lead to uneven distribution/alteration in drug deliveryDiffering properties may lead to uneven distribution/alteration in drug delivery

To be addressed in development studiesTo be addressed in development studies(WHO TRS 929, Annex 5, (6.3.2.3, 6.3.2.5, 6.3.3, Appendix 3)(WHO TRS 929, Annex 5, (6.3.2.3, 6.3.2.5, 6.3.3, Appendix 3)

– HomogeneityHomogeneity– Performance characteristicsPerformance characteristics (e.g. (e.g. dissolution testing)dissolution testing)

• Establishing pharmaceutical equivalence to innovatorEstablishing pharmaceutical equivalence to innovator



Establish a dissolution methodEstablish a dissolution method– ApparatusApparatus– Dissolution mediumDissolution medium– Test conditionsTest conditions

ExpectationsExpectations– discriminating discriminating sufficiently ruggedsufficiently rugged– Reproducible for day-to-day operationReproducible for day-to-day operation– Capable to be transferred between laboratoriesCapable to be transferred between laboratories– Acceptance criteria representative of multiple batchesAcceptance criteria representative of multiple batches

• Same composition, same manufacturing procedure including key Same composition, same manufacturing procedure including key batches (clinical studies/stability studies)batches (clinical studies/stability studies)



Discrimination (balance)Discrimination (balance) Distinguishing significant changes in a composition or a manufacturing Distinguishing significant changes in a composition or a manufacturing

process – process – likely to affect bioavailabilitylikely to affect bioavailability

Distinguishing between batches - Distinguishing between batches - without significant difference observed in without significant difference observed in vivovivo

Reflect relevant Reflect relevant changes in drug product over timechanges in drug product over time (by temperature / (by temperature / humidity / photosensitivity and other stresses)humidity / photosensitivity and other stresses)

Characterize discriminatory power of the procedureCharacterize discriminatory power of the procedure

– Assessing results from multiple batches (typical variability in composition Assessing results from multiple batches (typical variability in composition and manufacturing parameters)and manufacturing parameters)

– Intentional variation of manufacturing parameters (e.g. lubrication, blend Intentional variation of manufacturing parameters (e.g. lubrication, blend time, compression force) or drying parameterstime, compression force) or drying parameters


Development of Dissolution Testing Separate development of

different dissolution methodsfor different purposes

Discrimination betweendifferent concentrations of a functional excipient (sodium laurylsulfate) in preformulation experiments

Source: Bansal, A.K. Criticality of functional excipients and decoding methods during generic product development, Pharmaceutical Technology Europe, 01 June 2006



Variability of dissolution data is discouragedVariability of dissolution data is discouragedbecause it is difficult to identify trends or effects of formulation changes on because it is difficult to identify trends or effects of formulation changes on highly variable datahighly variable data

• RSD ≥ 20% at ≤ 10 min, RSD ≥ 10% at RSD ≥ 20% at ≤ 10 min, RSD ≥ 10% at 10 min 10 min

Root cause investigation on variability (prerequisite)Root cause investigation on variability (prerequisite)– Variability of formulation itselfVariability of formulation itself

• Content uniformity, process inconsistency, excipient interactions, film coating capsule Content uniformity, process inconsistency, excipient interactions, film coating capsule shell aging, hardening/softening of dosage form (stability)shell aging, hardening/softening of dosage form (stability)

– Artifacts associated with test procedure (coning, sticking)Artifacts associated with test procedure (coning, sticking)– No free dispersing of contents throughout vesselNo free dispersing of contents throughout vessel

• Change of apparatus, agitation speed, deaerationChange of apparatus, agitation speed, deaeration• Sinker type, composition of mediumSinker type, composition of medium



Selecting a suitable dissolution mediumSelecting a suitable dissolution medium– Solubility of drugSolubility of drug– Solution state stabilitySolution state stability– SINK conditionsSINK conditions

• Dissolution volume 3 – 10 times saturation volume (PhEur; USP)Dissolution volume 3 – 10 times saturation volume (PhEur; USP)– Physiologic pH range 1.2 – 6.8, aqueousPhysiologic pH range 1.2 – 6.8, aqueous

Selection of appropriate conditions for routine testingSelection of appropriate conditions for routine testingdiscriminatory capabilitydiscriminatory capabilitystability of the analytestability of the analyterelevance to the in-vivo performancerelevance to the in-vivo performance

As a function of pH



Typical mediaTypical media– Dilute HCl, buffers in the pH range 1.2 – 6.8, simulated gastric/intestinal Dilute HCl, buffers in the pH range 1.2 – 6.8, simulated gastric/intestinal

fluid, waterfluid, water

VolumeVolume– 500 – 1000 ml (500 – 1000 ml (900 ml900 ml))

• Extendable to 2 – 4 L (sink conditions) Extendable to 2 – 4 L (sink conditions) with justification, validationwith justification, validation

ApparatusApparatus– Basket or paddle (most frequently for solid oral dosage forms)Basket or paddle (most frequently for solid oral dosage forms)– Reciprocating cylinder or Flow through cell (special dosage forms)Reciprocating cylinder or Flow through cell (special dosage forms)

AgitationAgitation– Baskets: 100 rpm / Paddles: 50 – 75 rpmBaskets: 100 rpm / Paddles: 50 – 75 rpm

• Decreasing or increasing (25 – 150 rpm) justified Decreasing or increasing (25 – 150 rpm) justified if supported by data/profiles/resultsif supported by data/profiles/results



Design of dissolution studiesDesign of dissolution studies

Immediate release dosage formsImmediate release dosage forms– For routine release purposeFor routine release purpose

• Single time point specificationSingle time point specification– For product For product comparabilitycomparability//performanceperformance

• Profiles with NLT 5 time pointsProfiles with NLT 5 time points– Characterise ascending and plateau phaseCharacterise ascending and plateau phase– Calulation of similarity factorsCalulation of similarity factors

• ExceptionException– Release of more than 85% of API within 15 minRelease of more than 85% of API within 15 min



AssayAssay– Spectrometric determination (fast/simple/no solvents)Spectrometric determination (fast/simple/no solvents)– HPLCHPLC

• no interference from excipients, stability indicating, specificno interference from excipients, stability indicating, specific

Validation of assayValidation of assay– Specificity / Linearity and Range / Accuracy/Recovery / Specificity / Linearity and Range / Accuracy/Recovery /

Precision / Robustness / Solution stabilityPrecision / Robustness / Solution stability



Acceptance criteria (see also ICH Q6A)Acceptance criteria (see also ICH Q6A)– Typical range Q=75 – 80%Typical range Q=75 – 80%

• Assay and content uniformity ranges are consideredAssay and content uniformity ranges are considered– To be established on the basis of To be established on the basis of evaluation of profile dataevaluation of profile data– ConsistencyConsistency with historical data with historical data

• AcceptableAcceptable batches will fall within the acceptance criteria batches will fall within the acceptance criteria– No significant differences in No significant differences in in vivoin vivo performance, composition, performance, composition,

manufacturing proceduremanufacturing procedure• „„UnacceptableUnacceptable“ batches should be outside the acceptance criteria“ batches should be outside the acceptance criteria

– Batches from the development phase that showed poor Batches from the development phase that showed poor bioavailability, different composition, difference in manufacturing bioavailability, different composition, difference in manufacturing procedureprocedure


Acceptance criteria IIAcceptance criteria II– Discriminating stability problemsDiscriminating stability problems

• Disintegration rate affected by change in hardness, friabilityDisintegration rate affected by change in hardness, friabilityDissolution rate subsequently revealing changeDissolution rate subsequently revealing change

– Discriminating manufacturing problemsDiscriminating manufacturing problems• Dissolution affected by alternative manufacturing procedure/alternative Dissolution affected by alternative manufacturing procedure/alternative

manufacturing site?manufacturing site?Variation No. 5, Doc. No. 9Variation No. 5, Doc. No. 9(Supplement I, Generic Guideline)(Supplement I, Generic Guideline)


Formulation investigation by dissolution ObjectiveObjective: : Develop a formulation which is pharmaceutically equivalent to the Develop a formulation which is pharmaceutically equivalent to the

innovator (capsules)innovator (capsules) Direct fillingDirect filling

– Improper flow, poor uniformity of contentImproper flow, poor uniformity of content Wet granulation (with water)Wet granulation (with water)

– Dissolution inferior to innovatorDissolution inferior to innovator Sieving at different mesh size, disintegrant partly extragranularySieving at different mesh size, disintegrant partly extragranulary

– Dissolution higher than innovatorDissolution higher than innovator Decreasing the quantity of disintegrantDecreasing the quantity of disintegrant

– Dissolution slightly faster than innovatorDissolution slightly faster than innovator Adding binder intragranularlyAdding binder intragranularly

– Dissolution still slightly faster than innovatorDissolution still slightly faster than innovator Decreasing disintegrantDecreasing disintegrant

– Final formulation; dissolution performed without sinkerFinal formulation; dissolution performed without sinker

APIAPIFillerFillerBinderBinderDisintegrantDisintegrantLubricantLubricant


Dissolution Testing and in-vivo performance

Dissolution and potential in vitro / in vivo correlationDissolution and potential in vitro / in vivo correlation– Biorelevant medium (USP; Medium with some relevance on the Biorelevant medium (USP; Medium with some relevance on the

in vivo-performance)in vivo-performance)• Absorption site (if known)Absorption site (if known)• Rate-limiting step to absorptionRate-limiting step to absorption

Dissolution or permeability?Dissolution or permeability?• Case A: quick dissolution in the stomach, high permeabilityCase A: quick dissolution in the stomach, high permeability

• Rate limiting step to absorption may be gastric emptying time → acidic Rate limiting step to absorption may be gastric emptying time → acidic dissolution mediumdissolution medium

• Case B: poorly soluble drug, weak acidCase B: poorly soluble drug, weak acid• dissolution mainly in the intestine → pH 6.8 dissolution mediumdissolution mainly in the intestine → pH 6.8 dissolution medium


Dissolution Testing and in-vivo performance

Cynthia Brown et al. (2004) Acceptable Analytical Practices for Poorly Soluble Cynthia Brown et al. (2004) Acceptable Analytical Practices for Poorly Soluble Compounds. Compounds. Pharmaceutical TechnologyPharmaceutical Technology

– Relationship of Relationship of rate of disintegrationrate of disintegration versus versus rate of dissolutionrate of dissolution


Dissolution testing and in-vivo performance

Discriminatory potential of dissolution test conditions Discriminatory potential of dissolution test conditions and acceptance criteriaand acceptance criteria

– Physical characteristicsPhysical characteristics of the APIs of the APIs• Relation between Relation between solubilitysolubility and permeability of the drugs and permeability of the drugs

– Influence ofInfluence of formulationformulation on performanceon performance

Dissolution test conditions and acceptance criteria Dissolution test conditions and acceptance criteria must be developed individually for each particular must be developed individually for each particular formulationformulation


Summary

A well controlled manufacturing process is the essential A well controlled manufacturing process is the essential prerequisite for FPPsprerequisite for FPPs

Quality specifications will help to ensure that manufacturing Quality specifications will help to ensure that manufacturing has been performed under well-controlled conditions to meet has been performed under well-controlled conditions to meet predetermined acceptance criteriapredetermined acceptance criteria

Dissolution testing can help to develop a suitable formulation Dissolution testing can help to develop a suitable formulation and manufacturing process during developmentand manufacturing process during development

Established discriminatory dissolution testing will Established discriminatory dissolution testing will consequently identify FPP-problems consequently identify FPP-problems


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