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PHARMACEUTICAL SPRAY DRYINGA Method of Choice to address Low API Solubility,Poor Bioavailability and Drug Formulation Challenges

POORLY SOLUBLE APIs INCREASINGLY FOUND AMONG NEW DRUG DEVELOPMENTS

0%

50%

100%

Marketed Drugs Pipeline Drugs

BCS II BCS IV BCS I BCS III

POORLY SOLUBLEAPIs, 40%

POORLY SOLUBLEAPIs,90%

• Low aqueous API solubility and related poor bioavailability pose a significant hurdle for an efficient drug formulation, in particular for oral delivery

• The number of APIs insoluble in water has reached very high levels among NCEs due to in-creasing drug lipophilicity for better targeting enzymes and membrane proteins or because of increasing molecular complexity

• APIs within BCS Classes II and IV (Biopharmaceutical Classification System) having poor solubility and permeability are especially problematic and frequently found among pipeline developments

POOR API SOLUBILITY PRESENTS A GROWING CHALLENGE FOR DRUG PRODUCT FORMULATION AND DRUG DELIVERY

PARTICULAR BENEFITS OF SPRAY DRYING

• Highapplicabilitycombinedwithadvantageofreducedformulationcomplexity• IncreasinglyutilizedtoimprovesolubilitypropertiesandbioavailabilityofAPIsvia anamorphoussolidAPIdispersioninasuitablematrix• Convenientone-stepprocessconvertinganAPIfromaliquidform(e.g.solution, suspension)directlyintoapowderundermildconditionsandveryshort residencetimesuitableforthermallyunstableandsheersensitivecompounds• Established,robusttechnologyoperatedatindustrialcommercialscale fordecades• Highlyversatile,reproducibleprocessthatcanbescaleduptonearlyany productionsize(batchorcontinuousmode)withlowercost(equipment, utilities,cycletime)andbetterflexibilitythanlyophilization• ModifiesvariousparticlepropertiesofAPIpowderswithgooduniformity,such assizedistribution,dispersibility,flowability;increasedsurfacearea achievablewithoutasubsequentmillingstep• Veryusefulforinhalationproductsforparticlesizecontrol• Applicableforalargevarietyofbiopharmaceuticalsfromsmallmolecules toproteins• Convenienttoconvertoilycompoundsintopowdersviaadditionofsuitable adjuvantsduringtheprocess• Utilizedforimprovingdirectcompressibility,modifiedreleaseandtastemasking formulations,particlecoatingandmicroencapsulation• ImprovementofdosevariabilityandloweringrequireddoseleadingtolessAPI consumptionandcostsavingsduringclinicalstudies

SPRAYDRYINGISAPOWERFULTECHNOLOGYTOADDRESSAPISOLUBILITYCHALLENGES

• ExtensiveexperienceinpharmaceuticalspraydryingatHaverhill/UKsite• SiteoperatesundercGMPstandardsincontrolledenvironmentandhasregularly beeninspectedbyregulatoryauthoritiesincludingFDA,EMEAandMHRA• Capacitytosupportproductrequirementsfromclinicaltrialstolargecommercial scale• Feedstock(e.g.solution,suspension)canbepreparedonsiteorreceivedinliquid form;USPgradepurifiedwateravailable• Crystallinesolutionscanbere-dissolvedandspraydried• Stirredfeedsystems• Clean-In-Place(CIP)systemavailable• Environmentalcontrols• Supplementaldryingcapabilitiesavailable,e.g.fluidbed

SANOFICEPiAOFFERSPHARMACEUTICALSPRAYDRYINGFROMCLINICALTOCOMMERCIALSCALE

LABORATORYSPRAYDRYER

o 1.5liters/hourwaterevaporationrateat250oCinlettemperatureo Samplefeedupto65ml/houro Inlettemperature40-250oCo Dryingairthroughput38-73m3/houro Automaticjetde-blocking

INTERMEDIATESCALESPRAYDRYER

o Spraydriedproductvolumes>100mt/year(productdependent)o Highpressureortwofluidatomizationo 100liters/hourliquidflowrateo Temperaturerange:200oCinlet,140oCoutleto Bagfiltero Nitrogeninertionforflammablepowders

LARGESCALESPRAYDRYER

o Spraydriedproductvolumesbetween200and>1,000mt/year (productdependent)o Highpressureatomizationo 1,500liters/hourliquidflowrateo Onlinecontrolsystemsformeasuringgasandfeedflowrateo Internalcamerastomonitorspraypatternsandproductrecoveryperformanceo Temperaturerange:250oCinlet,140oCoutleto Bagfiltero Pneumatichammersandairsweepsystemforenhancedproductrecoveryo Explosionsuppressionsystemwithfiredetectionanddelugesystemtohandle flammablepowders

ANALYTICAL CAPABILITIES

Portfolio of online and offline analytical testing:

• ProcessAnalyticalTechnology(PAT) oNIR,Raman,Mid-IR,UV• ParticleSizeDistribution(Mastersizer)• ParticleMorphology• FeedDensity&FeedConcentration• DynamicVaporSorption(DVS)• MoistureAnalysis• X-RayFluorescence(XRF)• GC,GC-MS,HS-GC,Pyrolysis-GC-MS• HPLC• MS,LC-MS• DifferentialScanningCalometry(DSC)• ThermogravimetricAnalysis(TGA),TGA-MS• SizeExclusionChromatography• IonChromatography• Rheometry• NMR• InductivelyCoupledPlasma-OpticalEmissionSpectrometry(ICP-OES)• GelElectrophoresis• Titrimetry• Conductivity• Bulk/TapDensity

SANOFICEPiAOFFERSPHARMACEUTICALSPRAYDRYINGFROMCLINICALTOCOMMERCIALSCALE

April 2016 - photo credits: SANOFI

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