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).