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1、Pharmaceutical Development with Focus on Paediatric formulations,WHO/FIP Training Workshop Hyatt Regency HotelSahar Airport RoadAndheri East,Mumbai,India28 April 2008 2 May 2008,Pharmaceutical Development with Focus on Paediatric formulations,Presented by:Name:Peter YorkContact details:p.yorkbradfor
2、d.ac.uk,Pharmaceutical Development with Focus on Paediatric Formulations-Dosage form design and manufacture,In this presentation:Design of paediatric medicines underlying principlesCritical factors related to API(s)propertiesFormulation and manufacturing planFactors for formulation selection and des
3、ignChallenges for forward thinking with paediatric medicines,Medicinal Products,ACTIVE COMPOUND(API)MEDICINE(MOLECULES,QUALITYMACROMOLECULE)SAFETY EFFICACY EXCIPIENTS MANUFACTURE,Medicinal Products,PHYSICAL ADMINISTRATIONREQUIRED PATIENTFORMROUTETIME OF AGEONSET ACTION/PERIOD OF DRUG DELIVERYSOLIDSO
4、RALSECONDS PRETERM INFANTSSEMI-SOLIDSPARENTERALMINUTES TERM INFANTS(0 28 DAYS)LIQUIDSTOPICAL/RECTALHOURS INFANTS,TODDLERS(28 DAYS 23 MONTHS)RESPIRATORYDAYS CHILDREN(2 11 YRS)EYE,EARWEEKS/ADOLESCENTS(12 16/18 YRS)MONTHS ADULTS,Design of Medicines,PRIMARY FACTORS TO CONSIDERAPI properties(e.g.solubili
5、ty,absorption characteristics,BCS,stability,dose)Route of administration(linked to API pharmacology/therapeutics,pharmacokinetics,intended patient population(age etc).)Selection of type of dosage form(linked to selection of functional excipients)Awareness of manufacturing process(GMP,efficiency,expo
6、sure to manufacturing stresses.)Sourcing of quality APIs and excipients,Paediatric Medicines and Specific Dosage Forms,SOLIDSpowders,granules,pelletscapsules,DPIs,implantstablets,dispersible tablets,bilayer tabletsSEMI-SOLIDSsuppositoriesdermatologicalsLIQUIDSsyrups,solutions,suspensionspareteralsMD
7、Is,Focus Paediatric Medicines(HIV/AIDS,Malaria and TB),SOLIDSpowders,granules,pelletscapsules,DPIs,implantstablets-dispersible,bilayer,chewable,bufferedSEMI-SOLIDSsuppositoriesdermatologicalsLIQUIDSsyrups,solutions,suspensionsparenteralsMDIs,Paediatric medicines for HIV/AIDS,malaria and TB additiona
8、l issues,Continuous changes of medicine dispositional parametersDose,ADME,PK,.Dose ratios for fixed dose combinations(FDCs)Extemporaneous dispensing(eg dilutions,fractioning of adult dosage form,packaging,stability.)ComplianceStability,transport challenges for liquid formulations,WHO Model List of E
9、ssential Medicines for Children(Oct 2007),Antituberculosis medicinesethambutol:oral liquid(25mg/ml);tablet(100mg,400mg)isoniazid:oral liquid(50mg/5ml);tablet(50mg(scored),100mg,300mg)pyrazinamide:oral liquid(30mg/ml);tablet(150mg(dispersible,scored),400mg)rifampicin:oral liquid(20mg/ml);capsule and
10、tablet(150mg,300mg)rifampicin+isoniazid+pyrazinamide:tablet 60mg+30mg+150mgstreptomycin:powder for injection(1g(as sulphate)in vial),WHO Model List of Essential Medicines for Children(Oct 2007),Intended for children up to 12 years of ageCore list minimum medicine needs for a basic health care system
11、Specialized list essential medicines for priority diseases for which specialized diagnostic/monitoring,specialist medical care,and/or specialist training are neededhttp:/www.who.int/medicines/publications/essentialmedicines/en/index.html,WHO Model List of Essential Medicines for Children(October 200
12、7),AntiretroviralsSubcommittee recommends and endorses the use of fixed-dose combinations and the development of new fixed-dose combinations,including modified dosage forms,non-refrigerated products and paediatric dosage forms with assured pharmaceutical qualityNucleoside/nucleotide reverse transcri
13、ptase inhibitorseg abacavir:oral liquid(100mg/5ml(as sulphate),tablet(300mg(as sulphate)eg didanosine:buffered powder for oral liquid(100mg,167mg,250mg packets),capsule(unbuffered enteric-coated 125mg,200mg,250mg,400mg),tablet(buffered,chewable,dispersible 25mg,50mg,100mg,150mg,200mg)Non nucleotisid
14、e reverse transcriptase inhibitorseg efavirenz:capsule(50mg,100mg,200mg),oral liquid(150mg/5ml),tablet 600mgProtease inhibitorseg ritonavir:oral liquid(400mg/5ml),oral solid dosage fom(100mg),WHO Model List of Essential Medicines for Children(Oct 2007),AntiretroviralsFixed dose combinations(FDC)stav
15、udine+lamivudine+nevirapine:tablets(30mg+150mg+200mg)zidovudine+lamivudine:tablets(300mg+150mg)zidovudine+lamuvidine+nevirapine:tablets(300mg+150mg+200mg),WHO Model List of Essential Medicines for Children(Oct 2007),Antimalarial medicinesFor curative treatmentMedicines for the treatment of P.falcipa
16、rum malaria cases should be used in combination.The list currently recommends combinations according to treatment guidelines.The Subcommittee recognizes that not all of these FDCs exist and encourages their development and rigorous testing.The Subcommittee also encourages development and testing of
17、rectal dosage forms.eg amodiaquine:tablet(153mg or 200mg(as HCl);to be used in combination with artesunate 50mgdoxycycline:capsule(100mg(as HCl),tablet(dispersible 100mg as monohydrate);for use only in combination with quininequinine:injection(300mg(as HCl)/ml as 2 ml ampoule,tablet(300mg(as sulphat
18、e or bisulphate);used in combination with doxycycline,Critical factors related to API(s)properties,Active Pharmaceutical Ingredient(s),Sourcing patented and generic compoundsSpecifications and standardspharmacopoeial monographs(BP,USP,IP,EP);reference standardsfocus on chemical identification and pu
19、rityincreasing awareness of need to monitor physical,crystallographic and functional propertiesOther sources of information scientific literature,www,innovator product information.,API Routine Testing Good Practice,Provide assurance of quality and safetyVerification of CoA and magnitude of testing p
20、rogrammeSampling programme/isolated quarantine storage areasRetention/storage of batch samplesTraining programmes for staff,SOPs,GLP and validation of methodsConfidence in consistent quality of supply from chosen suppliers,API Properties Formulation Design and Processing(1),50%of new APIs,and many o
21、thers,have very low aqueous solubility which can constrain drug dissolution(ie rate of solution)and thereby limit bioavailabilityMany APIs exhibit polymorphism(also solvation hydration)alternative molecular packing of the same chemical in crystalline material leading to different properties such as
22、dissolution rate)Moisture content control hygroscopic material often difficult to process(eg tabletting);change in hydration state(eg during wet granulation)Respiratory drug delivery DPIs and suspension MDIs require drug particle size(aerodynamic)of 1 5 micronsAll above are also examples of QUALITY
23、issues when formulating and processing APIs;may require additional testing and/or control procedures,API Properties Formulation Design and Processing(2),Additional validated testing methods may be required to guide and direct formulation design,e.g.pH solubility profilePharmacopoeia now introducing
24、general guidance chapters,information,testing methods.Properties being introduced includeparticle sizing(laser light diffraction method)crystallinity(by x-ray powder diffraction)amorphous content(by x-ray powder diffraction)wettability(by liquid penetrating methods),API properties particle size,Many
25、 substances poorly aqueous soluble(BCS Class II and IV)Reduce particle size to maximise dissolution(also for BCS Class III)Such compounds routinely micronised potential for chemical and crystallographic damage which can compromise stability and intra-and inter-batch consistencyPotential issues for l
26、iquid suspension formulations(eg particle size changes on stability),API Properties-Polymorphism,e.g carbamazepine,ritonavir,Representation of two polymorphic forms of a crystal consisting of a molecule represented by a hockey-stick shape,Ritonavir Issue of Polymorphism,Ritonavir(originator Abbott)H
27、IV protease inhibitorNorvir product introduced in 1996 as semi-solid capsule preparation containing a solid-solution of drug in PEGSummer 1998 capsule supplies threatened as a new much less soluble crystal form of ritonavir precipitated in the capsuleDrug dissolution was slowed down,compromising bio
28、availabilityProduct was withdrawn and reformulated in soft elastic capsule form with new form of ritonavir(Baur et al,Pharm Res 18(6)859-866(2001),API Properties Formulation Design and Processing(3),Alternative pre-treatment and processing of APIs(eg alternative final solvent used during final cryst
29、allisation step during synthesis of API;use of crystallisation rather than milling process for particle size reduction)can lead to different surface properties of particles,such as interparticle cohesion and surface chargeThese phenomena can lead to different secondary processing behaviour and poten
30、tially variation in product performance,API Properties Characteristics to be considered when formulating medicines,API Property Classification inter-dependencies between groupings,Formulation and manufacturing plan(Development pharmaceutics),Design of a Paediatric Dosage Form(1),Define API(s)and dos
31、age regimeConsider route of administration-suitable dosage formWhat are pharmacokinetic Determine relevant properties of characteristics of API(s)?)API(s)-t50,Cmax,AUC-physicochemical,crystallographicBCS(for oral products-stability under stress conditionsBA/BD issue-compatibility with second API and
32、/or common excipientSelect dosage form and strength,Development pharmaceutics;formulation and manufacturing plan,Design of a Paediatric Dosage Form(2),Selection dosage form and strengthConsider suitable formulations and manufacturing processesPrototype formulations andmanufacturing route,and prototy
33、pe packagingOptimisation techniquesValidation(formulation andManufacturing process)Selection final formulation,Define design space,process control,Sources of informationInnovator literatureCompany experienceOther literature sources,TestingPhys/chem stability(Dissolution)Relevant product tests(Pilot
34、BE study),DoE AI tools,Design of a Paediatric Dosage Form,Select final formulation,manufacturing processand packagingProcess scale-up studies/batchesConfirmatory stability(dissolution)studies(BE study)Documentation for prequalification/registration dossiers,Factors influencing formulation selection
35、and design,Paediatric medicines-liquid formulations,Solutions,syrups-preferably avoid sugar and alcohol in formulations-drug solubility(dose/volume),stability,pH,-API(s)compatibility with vehicle/liquid diluents-taste(taste masking),colour,flavour-single dose vs multidose(preservatives etc)Suspensio
36、ns(and liquids products reconstituted from powders/granules)-as above-viscosity,API(s)particle sedimentation volume/redispersion-suspending/flocculating agents-particle size/crystallinity changes on storage/shelf life,Paediatric medicines solid formulations,API(s)compatibility with excipients/other
37、active(s)(need to separate APIs?)Selection of appropriate functional excipientsAPI dose and/or physicochemical properties may direct selection of manufacturing route(eg direct compression for low dose products,heat/light sensitive APIs)Key product performance test is dissolution of drug(s)QC test(me
38、et specification,batch reproducibility)Potential surrogate test for in vivo performance,but ivivc(in vitro/in vivo correlations)remain challenging for most solid dosage formsCritical test for BE waivers(BCS Class I and III),Paediatric medicines-all dosage forms,Stability indicating assay for shelf-l
39、ife testingEstablish sensitivity of API(s)to applied stresses during selected manufacturing processesPacking is an integral component of the medicinal product,Challenges,Quality,safe and efficacious medicines,appropriately designed medicines for childrenClinical pharmacology;dose versus age;clinical
40、 trial evidence aiding dose and design criteriaADME/PK/pharmacogenetics knowledge/data base for APIsElimination of dose-risk at point of delivery(administration)of medicineInnovative yet pragmatic solutions to dose dilution,and dose ratio options for FDC products,Pharmaceutical Development with Focus on Paediatric formulations,In this presentation:Design of paediatric medicines underlying principlesCritical factors related to API(s)propertiesFormulation and manufacturing planFactors influencing formulation selection and designChallenges for forward thinking with paediatric medicines,
