For Better Medicines for Children - World Health "Better Medicines for Children" ... Essential Medicines

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    ProgressmadeintheMedicinesQualityAssurance

    ProgrammeFor "Better Medicines for Children"

    Xiaoqiong ZHENG,TechnicalOfficerQualityAssuranceandSafety:Medicines

    EssentialMedicinesandPharmaceuticalPolicies

    TheThirdPartnersMeetingonBetterMedicinesforChildren,2122November2011,Geneva

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    ContributetoWHA60.20

    Developingnorms,standardsandguidelinestopromotebettermedicinesforchildrenthroughtheWHOExpertCommitteeonSpecificationsforPharmaceuticalPreparations

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    ProgressMade:20072011

    Developmentofpaediatricmedicines:pointstoconsiderinformulation

    MonographdevelopmentMonographsforpaediatricmedicinesPaediatricapproachedworkplan

    Training:2007,SouthAfrica,Estonia2008,India;2010,Beijing;2012,Singapore

    Regulatoryadvice:FirstmeetingofthePaediatricMedicinesRegulators'Network,2010PaediatricmedicinesintheWHOPrequalificationofMedicinesProgramme

    Guidelinedevelopment Otheractivities

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    ScopeofthedocumentToinformregulatoryauthoritiesandmanufacturersonissuesthatrequirespecialattentioninpharmaceuticaldevelopmentofpaediatricmedicines.

    Nottodetailinstructions,rathertomakereferencetorelevantliteratureFormulationanddosageforms

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    Historyofthedocument

    Firstdraft

    Newdraft

    Adopted

    CoordinationwithotherongoingactivitiesbothwithinandoutsideWHODiscussionatinformalconsultationsin2008(2),2010,2011Circulationforcomments,inputsandfeedbackPresentationtoExpertCommitteemeetings:43rd ,45th ,46th

    46thExpertCommitteemeeting

    42ndExpertCommitteemeeting

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    Contents

    1. Introduction

    2. Paediatricdosageforms

    3. Dosageformstobeconsideredinparticular

    4. Formulationdesign

    5. Oraladministration

    6. Rectaladministration

    7. Parenteral administration

    8. Dermalandtransdermaladministration

    9. Inhalations

    10. Packagingandlabelling

    11. Glossary

    12. References

    Developmentofpaediatricmedicines:pointstoconsiderinformulation

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    Dosageformsselectionprinciple

    Theguidingprincipleforselectingpaediatricdosageformsshouldbe asforadults thebalanceofrisk/benefit,takingintoaccountthespecificneedsofthisvulnerablepopulation.

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    Dosageformsselectionprinciple

    Acceptability&palatability

    Minimumdosingfrequency

    Acceptabilityindosageform,dosingdevice,dosevolume/size,packaging,andclearandaccuratelabelling,etc.Palatabilityinitselfwithoutanyneedforfurthermodifications

    Facilitatecompliancetodosingschemeforbothcaregiversandolderchildren

    Convenient,reliableadministration

    EnduserneedsConvenienttoproduceandaffordableRestrictionsontheapplicabledosevolume/size minimumtobeattemptedSupplychainconsiderations,e.g.easeoftransportation,storagerequirementsAccesstocleanwaterAdequateproductinformation

    Dosevolumeorsizeappropriateforthetargetagegroup/accuratedosingrequirementsDosemanipulationshouldbekepttoaminimumlevel

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    Dosageformstobeconsideredinparticular

    Technology,includingformulationandrelatedprocesses,thatcanbeusedtoobtaindifferentdosageforms,differentstrengthsand/oraccommodatedifferentAPIs.- producemultiparticulate

    solids,e.g.pellets,minitablets

    Flexiblesoliddosageformisthemostsuitabledosageform

    Considerplatformtechnologyifprecisedosemeasurementortitrationisneeded

    Adosageformthatcanbeadministeredtopatientsinmorethanonemanner,e.g.takenorallyasawholeortobedispersedordissolvedpriortoadministration.

    - e.g.orodispersibletablets,dispersibletablets,solubletablets

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    Dosageformstobeconsideredinparticular

    Dosage forms Key advantage Key considerationFlexible solid dosage forms

    Suitable for both developed and developing countriesCan be used for preparation of oral liquids suitable for very young children:

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    Formulationdesign

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    Excipients

    Useofexcipientsisdrivenbyfunctionalrequirementsandshouldbejustifiedthroughariskbasedassessment,takingintoaccountthepaediatricagegroup,frequencyofdosing,durationoftreatment,etc.

    Shouldbeminimumrequirednumberandtheirlevelinaformulation.

    Excipientsmayleadtoadversereactionsnotexperienced,ornot seentothesameextent,inadults.Adversereactionsaremostlyassociatedwithexcipientsusedforliquiddosageforms.

    Wellknownexcipientswithawelldefinedsafetyprofiletobepreferred.

    Onlyusenovelexcipientswhensafety,qualityandappropriatenessofuseinchildrenhavebeenestablished.

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    Routeofadministration

    Oraladministration

    Rectaladministration

    Parenteraladministration

    Dermalandtransdermaladministration

    Inhalations

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    PackagingandLabelling

    Containerclosuresystemsaredesignedandconstructedofmaterialsmeetingrelevantregulatoryrequirementsandtakingintoaccountthestabilityofthemedicineduringtransport,storageanduse.

    Incaseswherethepaediatricmedicineissignificantlydifferentfromasimilaradultmedicine,theproductpackagingshouldbenoticeablydifferentbetweenthetwoproducts.

    Facilitatesafeselfadministrationofmedicineinschoolchildrenandadolescents.

    Adequateinformationaboutthemedicineanditsuse;specificinstructionsabouthowtomeasureandadministeraprecisedose.

    Stronglyrecommenddrawingsorpictogramsshowingtime,methodandrouteofadministration.

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    Coordination

    Thepreparatoryworkhasinvolvedcoordinationwithotherongoingactivities,bothwithinandoutsideWHO,especiallywiththeEuropeanMedicinesAgency,theUnitedNationsChildren'sFund,theWHOModelListofEssentialMedicinesandtheEssentialMedicinesproject.

    Reflection Paper: Formulations of Choice for the Paediatric population(2006),European Medicines Agency (EMA)First draft

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    Perspective

    Paediatricmedicinesdevelopmentislimitedinsomeareas(e.g.acceptabilityofdosageforms,safetyofexcipients),butitisalsoarapidlydevelopingfield.An updateofthedocumentmightbeneededinthenottoodistantfuture.

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    References:guideline

    1. ClinicalInvestigationofMedicinalProductsinthePaediatricPopulation,ICHTopicE11.

    2. WHOguidelineonqualityriskmanagement(workingdocumentQAS/10.376).

    3. Guidelinesforregistrationoffixeddosecombinationmedicinalproducts(2005).In:thirtyninthreportoftheWHOExpertCommitteeonSpecificationsforPharmaceuticalPreparations.Geneva,WorldHealthOrganization.WHOTechnicalReportSeries,No.929,Annex5.

    4. Pharmaceuticaldevelopmentformultisource(generic)pharmaceuticalproducts(workingdocumentQAS/08.251/Rev.1).

    5. ImpuritiesinNewDrugSubstances,ICHTopicQ3A(R2).

    6. ImpuritiesinNewDrugProducts,ICHTopicQ3B.

    7. Impurities:GuidelineforResidualSolvents,ICHTopicQ3C.

    8. GuidelineontheLimitsofGenotoxicImpurities(CPMP/SWP/5199/02).

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    References:guideline(continued)9. Q&AontheCHMPGuidelineontheLimitsofGenotoxicImpurities

    (EMEA/CHMP/SWP/431994/2007).

    10. SpecificationLimitsofResiduesofMetalCatalysts(CPMP/SWP/QWP/4446/00).

    11. ProposaltowaiveinvivobioequivalencerequirementsforWHOModelListofEssentialMedicinesimmediaterelease,soliddosageforms(2006).In:fortiethreportoftheWHOExpertCommitteeonSpecificationsforPharmaceuticalPreparations.Geneva,WorldHealthOrganization.WHOTechnicalReportSeries,No.937,Annex 8.

    12. PublicStatementonantimicrobialpreservativesinophthalmicpreparationsforhumanuse(EMEA/622721/2009).

    13. GuidelineontheInvestigationofMedicinalProductsintheTerm andPretermNeonate(EMEA/566810/2008).

    14. Multisource(generic)pharmaceuticalproducts:guidelinesonregistrationrequirementstoestablishinterchangeability(2006).In:fortiethreportoftheWHOExpertCommitteeonSpecificationsforPharmaceuticalPreparations.Geneva,WorldHealthOrganization.WHOTechnicalReportSeries,No.937,Annex7.

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    References:literature

    1. KearnsGLetal(2003).DevelopmentalPharmacology DrugDisposition,ActionandTherapyinInfantsandChildren.N.Eng.J.Med.349(12):11571167.

    2. EMEAReflectionPater:FormulationsofChoiceforthePaediatricPopulation.(EMEA/CHMP/PEG/196810/2005).

    3. ErnestTBetal(2007).DevelopingPaediatricMedicines:IdentifyingtheNeedsandRecognizingtheChallenges.J.Pharm.Pharmacol.,59:10431055.

    4. KrauseJ,BreitkreutzJ(2008).ImprovingDrugDeliveryinPaediatricMedicine.PharmaceuticalMedicine22:4150

    5. AllenLV(2008).DosageFormDesignandDevelopment.Clin.Ther.30(11):21022111.

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    References:literature(continued)6. SiewertMetal(2003).FIP/AAPSGuidelinesforDissolution/Invitro

    ReleaseTestingofNovel/SpecialDosageForms.DissolutionTechnologies,FebruaryIssue,page15.

    7. BreitkreutzJ,BoosJ(2007).PaediatricandGeriatricDrugDelivery.ExpertOpin.Drug.Deliv.4(1):3745.

    8. ShehabNetal(2009).ExposuretothePharmaceuticalExcipientsBenzylAlcoholandPropyleneGlycolamongCriticalIllNeonates.PediatricCriticalCareMedicine,10(2):256259.

    9. Inactive IngredientsinPharmaceuticalProducts:Update:http:/www.pediatrics.org/cgi/content/full/99/2/268.

    10. WHOTechnicalReportSeriesonevaluationofcertainfoodadditives.Listofpublications:http://www.who.int/ipcs/publications/jecfa/reports/en/index.html.

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    References:literature(continued)11. PollockI,YoungE,StonehamM(1989).SurveyofColoringsandPreservativesinDrugs.

    Brit.Med.J.,299:649651.

    12. PefferiG,RestaniP(2003).ThesafetyofPharmaceuticalExcipients.IlFarmaco,58:541550.

    13. MennellaJA,BeauchampGK(2008).OptimizingOralMedicationsforChildren.Clin.Ther.,30(11):21202132.

    14. StricklyRGetal(2007).PaediatricDrugs AReviewofCommerciallyAvailableOralFormulations.J.Pharm.Sci.,97(5):17311774.

    15. ThomsonSAetal(2009).Minitablets:NewModalitytoDeliverMedicinestoPreschoolagedChildren.Paediatrics,123(2):e235e238.

    16. SeagerH(1998).DrugDeliveryProductsandtheZydisFastDissolvingDosageForm.J.Pharm.Pharmacol.,50:375382.

    17. DolovichM(2000).