Pharmaceutical Development with Focus on Paediatric ulations[与专注于儿科剂型药物开发](PPT35).ppt

pharmaceuticaldevelopmentwithfocusonpaediatricformulations who fiptrainingworkshophyattregencyhotelsaharairportroadandherieast mumbai india28april2008 2may2008 pharmaceuticaldevelopmentwithfocusonpaediatricformulations presentedby name peteryorkcontactdetails p york bradford ac uk pharmaceuticaldevelopmentwithfocusonpaediatricformulations dosageformdesignandmanufacture inthispresentation designofpaediatricmedicines underlyingprinciplescriticalfactorsrelatedtoapi s propertiesformulationandmanufacturingplanfactorsforformulationselectionanddesignchallengesfor forwardthinking withpaediatricmedicines medicinalproducts activecompound api medicine molecules qualitymacromolecule safety efficacyexcipientsmanufacture medicinalproducts physicaladministrationrequiredpatientformroutetimeofageonsetaction periodofdrugdeliverysolidsoralsecondspreterminfantssemi solidsparenteralminutesterminfants 0 28days liquidstopical rectalhoursinfants toddlers 28days 23months respiratorydayschildren 2 11yrs eye earweeks adolescents 12 16 18yrs monthsadults designofmedicines primaryfactorstoconsiderapiproperties e g solubility absorptioncharacteristics bcs stability dose routeofadministration linkedtoapipharmacology therapeutics pharmacokinetics intendedpatientpopulation ageetc selectionoftypeofdosageform linkedtoselectionoffunctionalexcipients awarenessofmanufacturingprocess gmp efficiency exposuretomanufacturing stresses sourcingofqualityapisandexcipients paediatricmedicinesandspecificdosageforms solidspowders granules pelletscapsules dpis implantstablets dispersibletablets bilayertabletssemi solidssuppositoriesdermatologicalsliquidssyrups solutions suspensionspareteralsmdis focus paediatricmedicines hiv aids malariaandtb solidspowders granules pelletscapsules dpis implantstablets dispersible bilayer chewable bufferedsemi solidssuppositoriesdermatologicalsliquidssyrups solutions suspensionsparenteralsmdis paediatricmedicinesforhiv aids malariaandtb additionalissues continuouschangesofmedicinedispositionalparametersdose adme pk doseratiosforfixeddosecombinations fdcs extemporaneous dispensing egdilutions fractioning ofadultdosageform packaging stability compliancestability transportchallengesforliquidformulations whomodellistofessentialmedicinesforchildren oct2007 antituberculosismedicinesethambutol oralliquid 25mg ml tablet 100mg 400mg isoniazid oralliquid 50mg 5ml tablet 50mg scored 100mg 300mg pyrazinamide oralliquid 30mg ml tablet 150mg dispersible scored 400mg rifampicin oralliquid 20mg ml capsuleandtablet 150mg 300mg rifampicin isoniazid pyrazinamide tablet60mg 30mg 150mgstreptomycin powderforinjection 1g assulphate invial whomodellistofessentialmedicinesforchildren oct2007 intendedforchildrenupto12yearsofagecorelist minimummedicineneedsforabasichealthcaresystemspecializedlist essentialmedicinesforprioritydiseasesforwhichspecializeddiagnostic monitoring specialistmedicalcare and orspecialisttrainingareneededhttp www who int medicines publications essentialmedicines en index html whomodellistofessentialmedicinesforchildren october2007 antiretrovirals subcommitteerecommendsandendorsestheuseoffixed dosecombinationsandthedevelopmentofnewfixed dosecombinations includingmodifieddosageforms non refrigeratedproductsandpaediatricdosageformswithassuredpharmaceuticalquality nucleoside nucleotidereversetranscriptaseinhibitorsegabacavir oralliquid 100mg 5ml assulphate tablet 300mg assulphate egdidanosine bufferedpowderfororalliquid 100mg 167mg 250mgpackets capsule unbufferedenteric coated125mg 200mg 250mg 400mg tablet buffered chewable dispersible25mg 50mg 100mg 150mg 200mg nonnucleotisidereversetranscriptaseinhibitorsegefavirenz capsule 50mg 100mg 200mg oralliquid 150mg 5ml tablet600mgproteaseinhibitorsegritonavir oralliquid 400mg 5ml oralsoliddosagefom 100mg whomodellistofessentialmedicinesforchildren oct2007 antiretroviralsfixeddosecombinations fdc stavudine lamivudine nevirapine tablets 30mg 150mg 200mg zidovudine lamivudine tablets 300mg 150mg zidovudine lamuvidine nevirapine tablets 300mg 150mg 200mg whomodellistofessentialmedicinesforchildren oct2007 antimalarialmedicinesforcurativetreatment medicinesforthetreatmentofp falciparummalariacasesshouldbeusedincombination thelistcurrentlyrecommendscombinationsaccordingtotreatmentguidelines thesubcommitteerecognizesthatnotallofthesefdcsexistandencouragestheirdevelopmentandrigoroustesting thesubcommitteealsoencouragesdevelopmentandtestingofrectaldosageforms egamodiaquine tablet 153mgor200mg ashcl tobeusedincombinationwithartesunate50mgdoxycycline capsule 100mg ashcl tablet dispersible100mgasmonohydrate foruseonlyincombinationwithquininequinine injection 300mg ashcl mlas2mlampoule tablet 300mg assulphateorbisulphate usedincombinationwithdoxycycline criticalfactorsrelatedtoapi s properties activepharmaceuticalingredient s sourcing patentedandgenericcompoundsspecificationsandstandardspharmacopoeialmonographs bp usp ip ep referencestandardsfocusonchemicalidentificationandpurityincreasingawarenessofneedtomonitorphysical crystallographicand functional propertiesothersourcesofinformation scientificliterature www innovatorproductinformation apiroutinetesting goodpractice provideassuranceofqualityandsafetyverificationofcoaandmagnitudeoftestingprogrammesamplingprogramme isolatedquarantinestorageareasretention storageofbatchsamplestrainingprogrammesforstaff sops glpandvalidationofmethods confidence inconsistentqualityofsupplyfromchosensuppliers apiproperties formulationdesignandprocessing 1 50 ofnewapis andmanyothers haveverylowaqueoussolubilitywhichcanconstraindrugdissolution ierateofsolution andtherebylimitbioavailabilitymanyapisexhibitpolymorphism alsosolvation hydration alternativemolecularpackingofthesamechemicalincrystallinematerialleadingtodifferentpropertiessuchasdissolutionrate moisturecontentcontrol hygroscopicmaterialoftendifficulttoprocess egtabletting changeinhydrationstate egduringwetgranulation respiratorydrugdelivery dpisandsuspensionmdisrequiredrugparticlesize aerodynamic of1 5micronsallabovearealsoexamplesofqualityissueswhenformulatingandprocessingapis mayrequireadditionaltestingand orcontrolprocedures apiproperties formulationdesignandprocessing 2 additionalvalidatedtestingmethodsmayberequiredtoguideanddirectformulationdesign e g phsolubilityprofilepharmacopoeianowintroducinggeneralguidancechapters information testingmethods propertiesbeingintroducedincludeparticlesizing laserlightdiffractionmethod crystallinity byx raypowderdiffraction amorphouscontent byx raypowderdiffraction wettability byliquidpenetratingmethods apiproperties particlesize manysubstancespoorlyaqueoussoluble bcsclassiiandiv reduceparticlesizetomaximisedissolution alsoforbcsclassiii suchcompoundsroutinelymicronised potentialforchemicalandcrystallographicdamagewhichcancompromisestabilityandintra andinter batchconsistencypotentialissuesforliquidsuspensionformulations egparticlesizechangesonstability apiproperties polymorphism e gcarbamazepine ritonavir representationoftwopolymorphicformsofacrystalconsistingofamoleculerepresentedbya hockey stick shape ritonavir issueofpolymorphism ritonavir originatorabbott hivproteaseinhibitornorvirproductintroducedin1996as semi solid capsulepreparationcontaininga solid solution ofdruginpegsummer1998 capsulesuppliesthreatenedasanewmuchlesssolublecrystalformofritonavirprecipitatedinthecapsuledrugdissolutionwassloweddown compromisingbioavailabilityproductwaswithdrawnandreformulatedinsoftelasticcapsuleformwithnewformofritonavir bauretal pharmres18 6 859 866 2001 apiproperties formulationdesignandprocessing 3 alternativepre treatmentandprocessingofapis egalternativefinalsolventusedduringfinalcrystallisationstepduringsynthesisofapi useofcrystallisationratherthanmillingprocessforparticlesizereduction canleadtodifferentsurfacepropertiesofparticles suchasinterparticlecohesionandsurface charge thesephenomenacanleadtodifferentsecondaryprocessingbehaviourandpotentiallyvariationinproductperformance apiproperties characteristicstobeconsideredwhenformulatingmedicines apipropertyclassification inter dependenciesbetween groupings formulationandmanufacturingplan developmentpharmaceutics designofapaediatricdosageform 1 defineapi s anddosageregimeconsider routeofadministration suitabledosageformwhatarepharmacokineticdeterminerelevantpropertiesofcharacteristicsofapi s api s t50 cmax auc physicochemical crystallographicbcs fororalproducts stabilityunder stress conditionsba bdissue compatibilitywithsecondapiand orcommonexcipientselectdosageformandstrength developmentpharmaceutics formulationandmanufacturingplan designofapaediatricdosageform 2 selectiondosageformandstrengthconsidersuitableformulationsandmanufacturingprocessesprototypeformulationsandmanufacturingroute andprototypepackagingoptimisationtechniquesvalidation formulationandmanufacturingprocess selectionfinalformulation define designspace processcontrol sourcesofinformationinnovatorliteraturecompanyexperienceotherliteraturesources testingphys chemstability dissolution relevantproducttests pilotbestudy doeaitools designofapaediatricdosageform selectfinalformulation manufacturingprocessandpackagingprocessscale upstudies batchesconfirmatorystability dissolution studies bestudy documentationforprequalification registrationdossiers factorsinfluencingformulationselectionanddesign paediatricmedicines liquidformulations solutions syrups preferablyavoidsugarandalcoholinformulations drugsolubility dose volume stability ph api s compatibilitywithvehicle liquiddiluents taste tastemasking colour flavour singledosevsmultidose preservativesetc suspensions andliquidsproductsreconstitutedfrompowders granules asabove viscosity api s particlesedimentationvolume redispersion suspending flocculatingagents particlesize crystallinitychangesonstorage shelflife paediatricmedicines solidformulations api s compatibilitywithexcipients otheractive s needtoseparateapis selectionof appropriate functionalexcipientsapidoseand orphysicochemicalpropertiesmaydirectselectionofmanufacturingroute egdirectcompressionforlowdoseproducts heat lightsensitiveapis keyproductperfo