PROCEDURE FOR THE PRODUCATION OF A STERILE DEXMEDETOMIDINE HYDROCHLORIDE FORMULATION FOR INTRAVENOUS ADMINISTRATION AND APPLICATIONS THEREOF

BE1033145B1Active Publication Date: 2026-07-01A FORALL DEVELOPMENT NV
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Authority / Receiving Office
BE · BE
Patent Type
Patents
Current Assignee / Owner
A FORALL DEVELOPMENT NV
Filing Date
2024-11-21
Publication Date
2026-07-01
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Abstract

The present invention relates to a method for the production of a liquid formulation suitable for intravenous administration in a glass vial with a rubber stopper, where the formulation is dexmedetomidine hydrochloride in water for injection (WFI). The method comprises steps of introducing WFI into a preparation vessel, passing an inert gas through the WFI until a dissolved oxygen content of 1 ppm or less is obtained, adding and dissolving a quantity of sodium chloride and dexmedetomidine hydrochloride, filtering the dexmedetomidine hydrochloride solution, and filling one or more glass vials with the liquid dexmedetomidine hydrochloride-in-WFI formulation before closing said vials with a rubber stopper and sealing the vials. The invention also relates to a sterile liquid formulation of dexmedetomidine hydrochloride in WFI, and its applications.
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Description

2 Inparticular,themethodinvolvesaseriesofstepsthatincludeheatingWFI,using inertgastoreducethedissolvedoxygencontent,addinganddissolvingsodium chlorideanddexmedetomidinehydrochloride,andfilteringtheresultantsolution. Themethodensuresstringentsterilitycontrolmeasures,improvedstability,anda ready-to-useformulation.Theformulationisfilledincontainer,preferablyaglass5 vials,whicharestoppered,andsubsequentlysealed.Themethodalsoincludes specificconditionsforvarioussteps,suchasstirringspeeds,temperatureranges, andtheuseofspecificmaterialsforthecompoundingvesselandfilters,allofwhich contributetothefinalproduct'ssafety,efficacy,andstability. Inasecondaspect,thepresentinventionrelatestosterileliquidformulationof10 dexmedetomidinehydrochlorideinwaterforinjection(WFI),suitableforintravenous administrationaccordingtoclaim12.Preferably,thesterileliquidformulationis producedaccordingtothemethodofanyoneofclaims1to11. Thedetailedandcarefullystagedproductionmethodoutlinedbelowcanminimizeoxidationpotential,therebyleadingtoenhancedstabilityandshelf-lifeofthefinal15 dexmedetomidinehydrochloridesterileformulation. Inathirdaspectthepresentinventionalsocoverstheuseofthesterileformulation. Inparticular,itrelatestoauseofthesterileformulationaccordingtoclaim14,asa sedativeagent,asananalgesicagentforreducingpaininpatients,orasan anxiolyticagentforreducinganxietyinpatients.20 DESCRIPTIONOFFIGURES Figure1showstheresultsoftheHPLCAssaydescribedintheExamplesection, includingthechromatogramofthedexmedetomidinesolution(A),ofthemobile phase(B),excipientsodiumchloride(C),hydroxymedetomidine(D),25 dexmedetomidinespikedwithhydroxymedetomidine(E),asystemsuitability solution(F),asensitivitysolution(G),andfinallythelinearity(H). Figure2showsSEMimagesofthefiltersurfaceoftheGlassVialDelaminationStudy intheExamplesection. Figure3showsSEMimagesoftheinternalsurfacesofthevialsoftheGlassVial30 DelaminationStudyoftheExamplesectionatvariousareasofthevials:shoulderarea(A),wallarea(B),5mmarea(C),andbottomarea(D). DETAILEDDESCRIPTIONOFTHEINVENTION Thepresentinventionconcernsamethodfortheproductionofaliquidformulation35 suitableforintravenousadministrationinacontainer,preferablyaglassvialwitha rubberstopper,whereintheformulationisdexmedetomidinehydrochlorideinwater BE2024 / 5807 3 forinjection(WFI).Theinventionalsocoverstheuseofthesterileformulationasa sedative,analgesic,andanxiolyticagent. Themethodensuresstringentsterilitycontrolmeasures,improvedstability,anda ready-to-useformulation.Theformulationisfilledinoneormorecontainers,such5 asglassvialswhicharestopperedandsubsequentlysealed.Themethodalso includesspecificconditionsforvarioussteps,suchasstirringspeeds,temperature ranges,andtheuseofspecificmaterialsforthecompoundingvesselandfilters,all ofwhichcontributetothefinalproduct'ssafety,efficacy,andstability. 10 Definitions Unlessotherwisedefined,alltermsusedindisclosingtheinvention,includingtechnicalandscientificterms,havethemeaningascommonlyunderstoodbyoneof ordinaryskillinthearttowhichthisinventionbelongs.Bymeansoffurtherguidance, termdefinitionsareincludedtobetterappreciatetheteachingofthepresent15 invention. Asusedherein,thefollowingtermshavethefollowingmeanings: “A”,“an”,and“the”asusedhereinreferstobothsingularandpluralreferentsunless20 thecontextclearlydictatesotherwise.Bywayofexample,“acompartment”refers tooneormorethanonecompartment. “About”asusedhereinreferringtoameasurablevaluesuchasaparameter,an amount,atemporalduration,andthelike,ismeanttoencompassvariationsof+ / -25 20%orless,preferably+ / -10%orless,morepreferably+ / -5%orless,evenmore preferably+ / -1%orless,andstillmorepreferably+ / -0.1%orlessofandfromthe specifiedvalue,insofarsuchvariationsareappropriatetoperforminthedisclosed invention.However,itistobeunderstoodthatthevaluetowhichthemodifier “about”refersisitselfalsospecificallydisclosed.30 “Comprise”,“comprising”,and“comprises”and“comprisedof”asusedhereinaresynonymouswith“include”,“including”,“includes”or“contain”,“containing”, “contains”andareinclusiveoropen-endedtermsthatspecifiesthepresenceofwhat followse.g.componentanddonotexcludeorprecludethepresenceofadditional,35 non-recitedcomponents,features,element,members,steps,knownintheartor disclosedtherein. BE2024 / 5807 4 Furthermore,thetermsfirst,second,thirdandthelikeinthedescriptionandinthe claims,areusedfordistinguishingbetweensimilarelementsandnotnecessarilyfor describingasequentialorchronologicalorder,unlessspecified.Itistobeunderstood thatthetermssousedareinterchangeableunderappropriatecircumstancesand thattheembodimentsoftheinventiondescribedhereinarecapableofoperationin5 othersequencesthandescribedorillustratedherein. Therecitationofnumericalrangesbyendpointsincludesallnumbersandfractions subsumedwithinthatrange,aswellastherecitedendpoints. 10 Theexpression“%byweight”,“weightpercent”,“%wt”or“wt%”,hereand throughoutthedescriptionunlessotherwisedefined,referstotherelativeweightoftherespectivecomponentbasedontheoverallweightoftheformulation. Whereastheterms“oneormore”or“atleastone”,suchasoneormoreoratleast15 onemember(s)ofagroupofmembers,isclearperse,bymeansoffurther exemplification,thetermencompassesinteraliaareferencetoanyoneofsaid members,ortoanytwoormoreofsaidmembers,suchas,e.g.,any≥3,≥4,≥5, ≥6or≥7etc.ofsaidmembers,anduptoallsaidmembers. 20 Unlessotherwisedefined,alltermsusedindisclosingtheinvention,including technicalandscientificterms,havethemeaningascommonlyunderstoodbyoneof ordinaryskillinthearttowhichthisinventionbelongs.Bymeansoffurtherguidance, definitionsforthetermsusedinthedescriptionareincludedtobetterappreciatethe teachingofthepresentinvention.Thetermsordefinitionsusedhereinareprovided25 solelytoaidintheunderstandingoftheinvention. Referencethroughoutthisspecificationto"oneembodiment"or"anembodiment" meansthataparticularfeature,structureorcharacteristicdescribedinconnection withtheembodimentisincludedinatleastoneembodimentofthepresentinvention.30Thus,appearancesofthephrases"inoneembodiment"or"inanembodiment"in variousplacesthroughoutthisspecificationarenotnecessarilyallreferringtothe sameembodiment,butmay.Furthermore,theparticularfeatures,structuresor characteristicsmaybecombinedinanysuitablemanner,aswouldbeapparenttoa personskilledintheartfromthisdisclosure,inoneormoreembodiments.35 Furthermore,whilesomeembodimentsdescribedhereinincludesomebutnotother featuresincludedinotherembodiments,combinationsoffeaturesofdifferent embodimentsaremeanttobewithinthescopeoftheinvention,andformdifferent BE2024 / 5807 5 embodiments,aswouldbeunderstoodbythoseintheart.Forexample,inthe followingclaims,anyoftheclaimedembodimentscanbeusedinanycombination. Inthepresentcontext,"dexmedetomidine"referstoapharmaceuticalcompound thatbelongstotheclassofdrugsknownasalpha-2adrenergicagonists.5 Dexmedetomidineactsprimarilyonalpha-2adrenergicreceptorsinthecentral nervoussystem,producingsedative,analgesic,andanxiolyticeffects.Itisgenerallyusedinmedicalsettings,particularlyinintensivecareunitsandduringsurgical procedures.Dexmedetomidineisknownforitsabilitytoinduceastateofsedation andcalmnesswithoutcausingsignificantrespiratorydepression,makingitsuitable10 foruseinpatientsrequiringconscioussedationorproceduralsedation.Itisalso usedforitsanalgesicproperties,providingpainreliefduringandaftersurgical procedures,andforitsanxiolyticeffects,helpingtoalleviateanxietyandagitation inpatients. 15 Theterm"inertgas"isusedtorefertoachemicallynon-reactivegascharacterized byitsstabilityandlackofchemicalreactivityundernormalconditions.Examplesof inertgasesincludenitrogen,carbondioxide,andelementsofgroup18oftheperiodic tablewhichincludeargon,helium,neon,argon,krypton,xenon,andradon.In certainindustrialprocesses,inertgasesareemployedtocreateaninertatmosphere,20 preventoxidationorcombustion,ormaintainspecificenvironmentalconditions conducivetodesiredreactionsoroutcomessuchasinpurgingoxygenfromvessels,asablanketinggasinfoodpackagingtopreventoxidation,andasacarriergasin gaschromatography. 25 Theterm"dissolvedoxygencontent",orshortly“oxygencontent”or“oxygenlevel” referstotheconcentrationofoxygenmoleculesthataredissolvedinaliquid, typicallymeasuredinpartspermillion(ppm)ormilligramsperliter(mg / L).This parameterisimportantinvariousindustries,includingpharmaceutical manufacturing,wherethepresenceofoxygencanaffectthestability,quality,and30 safetyofliquidformulations.Controllingthedissolvedoxygencontentiscrucialin pharmaceuticalformulationstopreventoxidativedegradationofactiveingredients, maintainproductefficacy,andensurecompliancewithregulatorystandards.High levelsofdissolvedoxygencanpromotechemicalreactionsthatdegradesensitive compounds,whilelowlevelsmayindicateinadequateoxygenation,whichcould35 affecttheviabilityofaerobicmicroorganismsorcellularcultures. BE2024 / 5807 6 Theterm"waterforinjection"(WFI)referstoahighlypurifiedformofwaterthatmeetsspecificqualitystandardssetbyregulatoryagencies,suchastheUnited StatesPharmacopeia(USP)ortheEuropeanPharmacopoeia(Ph.Eur.).WFIisused asasolventordiluentinpharmaceuticalmanufacturingprocesses,particularlyfor thepreparationofinjectablemedications,parenteralsolutions,andothersterile5 productsthatcomeintodirectcontactwiththebloodstreamortissuesofpatients. WFImustundergorigorouspurificationprocessestoremoveimpurities, contaminants,andmicrobialorganismstoensureitssuitabilityforusein pharmaceuticalapplications.Thesepurificationprocessestypicallyincludemultiple stagesoffiltration,distillation,and / orreverseosmosistoachievethedesiredlevel10 ofpurity.WFImustalsomeetstringentmicrobialqualityrequirements,including limitsontotalviablemicroorganisms,endotoxinlevels,andothermicrobial contaminants. Theterm"0.2µmfilter"or“0.22µmfilter”referstoafilterwithaporesizeof0.215 or0.22micrometersrespectively.Thisspecificationindicatesthesizeoftheopeningsorporeswithinthefiltermembrane,whichdeterminesthetypesandsizesof particlesthatcanpassthroughorberetainedbythefilter.Inpharmaceutical manufacturing,forexample,a0.2µmor0.22µmfiltermaybeemployedtoremove bacteria,fungi,othermicroorganisms,aswellasparticulatematter,fromliquids,20 ensuringtheproductionofsterilepharmaceuticalproducts. Theterm"hydrophilicmembrane"referstoatypeoffiltermembranethathasan affinityforwateroraqueoussolutions.Hydrophilicmembranesaredesignedtoallow thepassageofwatermoleculeswhileblockingthepassageofnon-aqueous25 substances,suchasoilsororganicsolvents.Hydrophilicmembranesaregenerally usedinfiltrationprocesseswherewater-basedsolutionsneedtobeclarified, purified,orsterilized.Non-limitingpreferredexamplesofmembranesthatmaybe hydrophilicarepolyvinylidenefluoride(PVDF)membraneandpolyethersulfone(PES) membrane.Furtherexamplesarecelluloseacetate(CA)membrane,regenerated30 cellulose(RC)membrane,nylon(polyamide)membrane,polytetrafluoroethylene(PTFE)membrane(hydrophilictreated),polypropylene(PP)membrane(hydrophilic treated),andpolysulfone(PS)membrane.A"polyvinylidenefluoride(PVDF) membranefilter"maybeatypeofhydrophilicmembrane.PVDFisasynthetic polymerthatmaypossessinherenthydrophilicproperties,meaningithasanaffinity35 forwater.WhenPVDFisfabricatedintoamembranefilter,itretainsitshydrophilic nature,allowingittoreadilywetwithwaterandpermitthepassageofaqueous solutionswhileblockingthepassageofnon-aqueoussubstances.Theyofferexcellent BE2024 / 5807 7 chemicalresistance,thermalstability,andmechanicalstrength,makingthem suitableforawiderangeoffiltrationprocesses. Bytheterm“container”ismeantanysuitablevesselorpackagingusedtoenclose, store,andmaintaintheliquidformulationofdexmedetomidineinwaterforinjection5 (WFI).Thisincludes,butisnotlimitedto,(glass)vials,ampules,intravenousbags, syringes,bottles,andothersterilepackagingdesignedtoensuretheprotection, preservation,andappropriateadministrationoftheformulation.Thecontainerisselectedtomaintaintheintegrityandsterilityoftheformulationduringstorage, handling,andtransportation.10 Bytheterm"glassvial"ismeantinthepresentinventionaglasscontainerusedto storeliquidformulations.TheglassvialsmentionedarepreferablyneutralglassType Ivials,whichareknownfortheirchemicalresistanceandsuitabilityforstoring pharmaceuticalpreparations.15 Inthecontextofthepresentinvention,theterm"rubberstopper"referstoatype ofclosureusedtosealglassvials,ensuringtheircontentsaresecurelyenclosed. Non-limitingexamplesincludebromobutylandchlorobutylstoppers.Theserubber stoppersprovideexcellentbarrierstogasesandmoisture,therebypreservingthe20 stabilityandintegrityoftheformulation.Bromobutylstoppersoffersuperior resistancetopermeationandarecommonlyusedfortheirexcellentsealing propertiesandcompatibilitywithvariousformulations.Chlorobutylstoppersarealso utilizedfortheireffectivebarrierpropertiesandchemicalresistance.Bothtypesof stoppersareselectedtomaintainthequalityandeffectivenessoftheformulation25throughoutstorageanduse. Theterm"bioburden"referstothetotalpopulationofviablemicroorganismspresent onorwithinaproduct,material,orenvironmentpriortosterilizationorother microbialcontrolmeasures.Thesemicroorganismsencompassbacteria,fungi,30 yeast,andmoldsandaretypicallyquantifiedintermsofcolony-formingunits(CFU) perunitofvolumeorsurfacearea.Bioburdenassessmentisintegraltoquality controlprocessesinindustriessuchaspharmaceuticalmanufacturing,whereitis crucialtoensurethesafetyandefficacyofproductsintendedformedicaluse. Controllingbioburdenlevelshelpsmitigatetheriskofmicrobialcontaminationand35 associatedadverseeffectsinend-users. BE2024 / 5807 8 Theterm"endotoxins"referstotoxinsthatarepartoftheoutermembraneofcertain typesofbacteria,particularlyGram-negativebacteria.Endotoxinsare lipopolysaccharides(LPS)foundinthecellwallofthesebacteriaandarereleased whenthebacteriaaredestroyedorundergolysis.Endotoxinscancauseadverse effectswhentheyenterthebloodstreamortissuesofhumansoranimals.Theycan5triggerimmuneresponses,inflammation,fever,andpotentiallyseverereactions, includingsepticshock.Therefore,controllingendotoxinlevelsiscrucialinindustries suchaspharmaceuticalmanufacturing,whereproductsintendedforinjectionor implantationmustmeetstrictqualityandsafetystandards. 10 Theterm"compoundingvessel"referstoacontainerorvesselusedin pharmaceuticalmanufacturingprocessesforcompounding,mixing,andpreparing liquidformulationsofpharmaceuticalproducts.Thecompoundingvesselplaysa crucialroleintheproductionofsterilesolutions,suspensions,oremulsions, particularlyforinjectablemedicationsorparenteralformulations.Thecompounding15 vesselistypicallyconstructedfrommaterialsthatarecompatiblewith pharmaceuticalmanufacturingrequirements,suchasstainlesssteelorglass,to ensurecleanliness,durability,andchemicalcompatibilitywiththeformulationbeing processed.Thevesselmayhavefeaturessuchasastirringmechanism,temperature controlsystems,portsfortheadditionofingredientsorsampling,andconnections20forinertgaspurgingorfiltration.Duringthecompoundingprocess,thenecessary ingredients,suchasactivepharmaceuticalingredients(APIs),excipients,and solventslikewaterforinjection(WFI),areaddedtothecompoundingvessel accordingtoapredeterminedformulationrecipeorbatchformula.Theingredients aremixed,dissolved,ordispersedwithinthevesselundercontrolledconditions,such25 astemperature,agitation,andinertgasatmosphere,toensureuniformityand homogeneityofthefinalproduct. Theterm"stainlesssteel316Lgradematerial"referstoaspecifictypeofstainless steelalloythatconformstotheASTM(AmericanSocietyforTestingandMaterials)30 designation316L.Thisdesignationindicatesthecompositionandpropertiesofthe stainlesssteel,with"316"referringtotheseriesofstainlesssteelalloysand"L" indicatingthelowcarboncontentofthealloy.Stainlesssteel316Lisahighly corrosion-resistantanddurablematerialcommonlyusedinvariousindustries, includingpharmaceuticalmanufacturing,medicaldevices,andfoodprocessing.It35offersexcellentresistancetocorrosioninawiderangeofenvironments,including thosecontainingchloridesandothercorrosiveagents.The"316L"gradedesignation signifiesthatthestainlesssteelalloycontainslowcarboncontent,typicallylessthan BE2024 / 5807 9 0.03%,whichimprovesitsweldabilityandresistancetosensitization-induced corrosion.Thismakesitparticularlysuitableforapplicationswhereexposureto corrosiveenvironmentsorhightemperaturesisaconcern. Theterm"ready-to-useproduct"referstoreferstoafinalproductorformulation5 thatispreparedandpackagedinamannerthatallowsittobeuseddirectlywithout theneedforadditionalprocessingorpreparationstepsbytheend-user.Aready-to- useproductistypicallydesignedtobeconvenientanduser-friendly,eliminatingthe needforfurthermanipulationorassemblybeforeitcanfulfillitsintendedpurpose. Thistermisoftenusedinindustriessuchaspharmaceuticals,biotechnology,and10 foodandbeverage,whereeaseofuseandconvenienceareimportantconsiderationsforend-users.Thisfeaturemayprovideadvantagessuchastimesavings,reduced riskoferrors,andimprovedefficiencyinvariousapplications. Theterm"sedativeagent"referstoasubstanceorcompoundthatinducessedation,15 astateofcalmness,relaxation,andreducedanxiety.Sedativeagentsarecommonly usedinmedicalpracticetopromotesleep,alleviateanxiety,andinduceacalming effectonpatients.Theymaybeadministeredorally,intravenously,orviaother routesofadministrationdependingonthespecificapplication. 20 Theterm"analgesicagent"referstoasubstanceorcompoundthatrelievespain withoutcausinglossofconsciousness.Analgesicagentsworkbyblockingorreducing theperceptionofpainsignalsinthenervoussystem.Theyareusedtomanagepain ofvaryingintensity,rangingfrommildtosevere,andcanbeadministeredinvarious forms,includingorally,topically,orviainjection.25 Theterm"anxiolyticagent"referstoasubstanceorcompoundthatreducesanxiety andpromotesastateofrelaxationandcalmness.Anxiolyticagentsarecommonlyprescribedforthetreatmentofanxietydisorders,panicattacks,andotherconditions characterizedbyexcessiveworryorfear.Theyworkbymodulatingneurotransmitter30 activityinthebrain,particularlygamma-aminobutyricacid(GABA),whichhas inhibitoryeffectsonthecentralnervoussystem.Anxiolyticagentsmaybe administeredorally,intravenously,orthroughotherroutesofadministration dependingonthespecificneedsofthepatient. 35 Description Inanaspectofthepresentdisclosure,amethodfortheproductionofaliquid formulationsuitableforintravenousadministrationisprovided.Theformulationis BE2024 / 5807 10 dexmedetomidinehydrochlorideinwaterforinjection(WFI).Theliquidformulation isprovidedinacontainerasdescribedabove,preferablyaglassvialwithrubber stopper.Thismethodcomprisesseveralstepswhicharecarefullydesignedtoensure thestabilityandlongevityoftheresultantformulation.Thestepsofthemethodare interlinkedandworkinharmonytocreateaformulationthatisnotonlysafefor5 intravenous(IV)administrationbutalsodisplaysenhancedstabilityandaprolongedshelflife.Inparticular,themethodcomprisesthestepsof: a)introducinglessthan100%ofadesiredbatchvolumeoftheliquidformulation ofWFIinacompoundingvessel,whereintheWFIinthevesselismaintainedat atemperatureofnotlessthan75°C,10 b)wheretheWFIhasadissolvedoxygencontentofover1ppm,passinganinert gas,preferablynitrogengas,throughtheWFIuntiladissolvedoxygencontent of1ppmorlessisobtained;andallowingtheWFItocooldowntoatemperature ofmaximally40°C, c)addinganddissolvinganamountofsodiumchlorideinpowderedforminsaid15 cooleddownWFIwhilestirringatleastuntilcompletedissolutionofthe powderedsodiumchloride,whilepassingsaidinertgasthroughtheWFI,thereby obtainingasodiumchloridesolution, d)addinganddissolvinganamountofdexmedetomidinehydrochlorideinsaid sodiumchloridesolutionofstepc)whilestirringatleastuntilcomplete20 dissolutionofthedexmedetomidinehydrochloride,whilepassingsaidinertgas throughsaidsodiumchloridesolution,therebyobtainingadexmedetomidine hydrochloridesolution,e)addingfurtherWFItosaiddexmedetomidinehydrochloridesolutionofstepd) toobtain100%ofthedesiredbatchvolume,whilepassingsaidinertgas25 throughsaiddexmedetomidinehydrochloridesolutionuntiladissolvedoxygen contentofmaximum1ppmisobtained, f)filteringthedexmedetomidinehydrochloridesolutionhavingadissolvedoxygen contentofmaximum1ppmusingafilter,preferablya0.2µm,therebyobtaining theliquiddexmedetomidinehydrochlorideinWFIformulation,30 g)fillingoneormorecontainers,preferablyglassvials,withtheliquid dexmedetomidinehydrochlorideinWFIformulation,beforeclosingsaid containersorstopperingsaidvialswitharubberstopperandsubsequently sealingthevials. 35 Thefirststepofthemethodinvolvesintroducinglessthan100%ofadesiredbatch volumeoftheliquidformulationofWFIinacompoundingvessel.TheWFIinthe vesselismaintainedatatemperatureofnotlessthan75°C.Thistemperatureis BE2024 / 5807 11 morepreferablynotlessthan80°C,evenmorepreferablynotlessthan85°C,and ornotlessthan90°C.Thetemperaturecouldforinstancebebetween75°Cand100°C,suchasbetween75°Cand85°C.ThehightemperatureoftheWFInotonly ensuresthesterilityoftheformulationbutalsoreducestheamountofdissolved oxygenintheWFI,therebyreducingtheriskofoxidation-relateddegradationof5 dexmedetomidinehydrochloridelateronintheprocess. Inanembodiment,said‘lessthan100%ofadesiredbatchvolumeoftheliquid formulationofWFI’preferablyreferstoavolumeofbetween80%and99%, preferably85%to95%,morepreferably87%to93%,mostpreferablyabout90%10 ofthedesiredbatchquantityoftheliquidformulationisintroducedinsaid compoundingvessel. Inanextstep,stepb)iftheWFIhasadissolvedoxygencontentofover1ppm,an inertgas,preferablynitrogengas,ispassedthroughtheWFIuntiladissolvedoxygen15 contentof1ppmorlessisobtained.Examplesofinertgasesincludenitrogen,carbon dioxide,andelementsofgroup18oftheperiodictablewhichincludeargon,helium, neon,argon,krypton,xenon,andradon.Thisprocessofpassingsaidinertgas throughtheWFI,commonlyknownas(nitrogen)bubblingorpurging,involvesthecontinuousflowofinert(nitrogen)gasthroughtheWFI,creatingbubblesasthegas20 (nitrogen)dispersesthroughouttheliquid.Thenitrogengas,oranyotherinertgas used,servestodisplacetheoxygenpresentintheWFI,effectivelyloweringits concentrationtothedesiredlevel.Thedissolvedoxygencontentcouldbereduced tobepreferablylessthan0.5ppm.Theuseofaninertgassuchasnitrogengas effectivelyremovesoxygenfromtheformulation,therebypreventingtheoxidation25 ofdexmedetomidineandenhancingthestabilityoftheformulation. Atthesametimeorsubsequently,theWFIis,then,allowedtocooldowntoa temperatureofmaximally40°C.Thetemperaturecouldbecooleddowntobetween 40°Cand30°C,morepreferablybetween40°Cand35°C,mostpreferablybetween30 38°Cand40°C.ThecoolingoftheWFInotonlypreparesitforthesubsequent additionofsodiumchlorideanddexmedetomidinehydrochloridebutalsohelpsin maintainingthedesiredphysicalandchemicalpropertiesoftheresultant formulation.CoolingtheWFIwithinthistemperaturerangeensuresoptimalsolubilityoftheaddedingredientsandpromotesuniformmixingwithoutcompromisingthe35 stabilityorintegrityoftheformulation.Moreover,coolingtheWFItotemperatures below30°C,35°C,or38°Cmayintroduceunnecessarydelaysinthemanufacturing processwithoutprovidingsignificantadditionalbenefits.Whilefurthercoolingis BE2024 / 5807 12 technicallyfeasible,itwouldextendtheprocessingtimewithoutofferingsubstantial advantagesforthesubsequentsteps,whicharenottemperature-sensitive. Therefore,maintainingtheWFItemperaturewithinthespecifiedrangeoptimizes manufacturingefficiencywhileensuringthequalityandconsistencyofthefinal product.5 Next,accordingtostepc)anamountofsodiumchlorideinpowderedformisadded anddissolvedinthecooleddownWFI.Thestirringcontinuesatleastuntilcomplete dissolutionofthepowderedsodiumchloride,whilepassingtheinertgasthroughthe WFI,therebyobtainingasodiumchloridesolution.Thesodiumchlorideispreferably10 presentinthefinalformulationataconcentrationof0.81wt%to0.99wt%,preferablyabout0.9wt%.Theadditionofsodiumchloridenotonlyaidsinthe solubilityofdexmedetomidinehydrochloride,butalsohelpsinmaintainingthe isotonicityoftheformulation,makingitsafeforintravenousadministration. Preferably,aftercompletedissolution,stirringiscontinuedatleastforanother5,10,15 or15minutes,toensureoptimalhomogeneity. Inthepresentcontext,wherereferenceismadeto‘about0.9%’,‘about’preferably referstoaconcentrationrangewithin±10%ofthespecifiedvalue,morepreferably within±5%.For‘about0.9%’,thiscorrespondstoarangeof0.81%to0.99%20 (±10%)or0.855%to0.945%(±5%). Accordingtostepd)anamountofdexmedetomidinehydrochlorideisaddedand dissolvedinsaidsodiumchloridesolutionofstepc).Thestirringcontinuesatleast untilcompletedissolutionofthedexmedetomidinehydrochloride,whilepassingthe25 inertgasthroughsaidsodiumchloridesolutionuntiladissolvedoxygencontentof maximum1ppm,preferablymaximum0.5ppmorless,isobtained,thereby obtainingadexmedetomidinehydrochloridesolution.Preferably,aftercompletedissolution,stirringiscontinuedforatleastanother5,10,or15minutes,toensure optimalhomogeneity.Whereneeded,thepassingoftheinertgascanbecontinued30 afterstirring,toensuretherequiredmaximumdissolvedoxygencontentisreached. Accordingtostepe),andthusoncetherequiredamountsofsodiumchlorideand dexmedetomidinehydrochloridehavebeenaddedtothe‘lessthan100%ofthe desiredbatchvolumeofWFI’,furtherWFIisaddedtothedexmedetomidine hydrochloridesolutiontoobtain100%ofthedesiredbatchvolume.Thepassingof35 theinertgasthroughthesolutioncontinuesuntiladissolvedoxygencontentof maximum1ppmisobtained.Thisoxygencontentismorepreferablyamaximumof 0.9ppm,evenmorepreferablyamaximumof0.8ppm,morepreferablyamaximum BE2024 / 5807 13 of0.7ppmmorepreferablyamaximumof0.6ppmandmostpreferablyamaximum of0.5ppm. Thedexmedetomidinehydrochloridesolutionissubsequentlyfilteredusingafilter, preferablya0.2µm,toobtaintheliquiddexmedetomidinehydrochlorideinWFI5 formulation.Thisformulationisthenfilledintooneormorecontainerswhicharesubsequentlyclosed.Saidcontainermaybeanysuitablevesselorpackagingused toenclose,store,andmaintaintheliquidformulationofdexmedetomidineinwater forinjection(WFI).Thisincludes,butisnotlimitedto,(glass)vials,ampules, intravenousbags,syringes,bottles,andothersterilepackagingdesignedtoensure10 theprotection,preservation,andappropriateadministrationoftheformulation. Preferably,saidcontainersareglassvialswhicharesubsequentlystopperedwitha rubberstopperandsubsequentlysealed.Thismethodenablesanefficientand streamlinedproductionprocessforfillingglassvialswiththeformulation. 15 Moreparticularly,accordingtostepf),thedexmedetomidinehydrochloridesolution isfilteredusinga0.2µmfilter,therebyobtainingtheliquiddexmedetomidine hydrochlorideinWFIformulation.Thefiltrationstepensurestheremovalof particulatematterandmicrobialloadfromtheformulation,therebyensuringits safetyforintravenousadministration.20 Finally,asmentionedinstepg),oneormorecontainers,preferablyglassvialsarefilledwiththeliquiddexmedetomidinehydrochlorideinWFIformulationbefore closingsaidcontainersorstopperingsaidvialswitharubberstopperand subsequentlysealingthevials.25 Themethoddescribedhereinthusprovidesarobustandefficientwayofproducing adexmedetomidinehydrochlorideinWFIformulationthatisnotonlysafefor intravenousadministrationbutalsodisplaysenhancedstabilityandaprolongedshelf life,thankstothecarefulmanagementoftheoxygencontentduringtheproduction30 process. Asindicatedabove,inapreferredembodiment,theformulationcontainssodium chlorideataconcentrationof0.81wt%to0.99wt%,preferablyabout0.9wt%. Sodiumchlorideisacommonlyusedexcipientinpharmaceuticalformulations,and35 itspresenceintheformulationimprovesthecompatibilityoftheformulationwith thebody'sfluidenvironment.Sodiumchlorideisatonicityadjuster,whichmodifies theosmoticpressure,makingtheformulationisotonictothesurroundingfluidsafter BE2024 / 5807 14 administration.Thisisotonicityiscrucialasitenhancestheefficiencyofdrugaction,byensuringthatthedrugisdeliveredtothebody'scellsinamannerthatdoesnot disruptthecells'normalfunctioning,asasodiumchlorideconcentrationthatistoo highortoolowcouldpotentiallydisruptthesolubilityoftheactiveingredientand thusaffecttheefficacyoftheformulation.Theconcentrationofsodiumchloridemay5 alsovarywithincertainlimits.Preferably,theconcentrationisbetween0.5and1.5 wt%,morepreferablybetween0.7and1.1wt%,morepreferablyaround0.81wt% to0.99wt%,preferablyabout0.9wt%.Theserangesareprovidedasexamplesof preferredembodimentsandarenotintendedtobelimiting. 10 Inanembodiment,thestepofaddinganddissolvingthesodiumchlorideinthewater forinjection(WFI)isperformedwhilestirringtheWFI.Thisstirringactionhelpsto distributethesodiumchlorideevenlythroughouttheWFI,ensuringthatthesodium chlorideisfullydissolvedandthattheresultingsolutionhasauniformtonicity. Preferably,thestirringisperformedataspeedofatleast50rpm,morepreferably15 ataspeedofatleast75rpm,mostpreferablyataspeedofabout100rpm,andpreferablyataspeedofnotmorethan150rpm.Thisrangeofstirringspeedsis chosentoensureathoroughmixingofthesodiumchlorideintheWFI,whileavoiding excessiveagitationthatcouldpotentiallyleadtotheformationofbubblesorfoamin thesolution.20 Inanembodiment,thestepofaddinganddissolvingthedexmedetomidine hydrochlorideinsaidsodiumchloridesolutionisperformedwhilestirring.This stirringhelpstodistributethedexmedetomidinehydrochlorideevenlythroughout thesodiumchloridesolution.Preferably,thestirringisperformedataspeedofat25 least50rpm,morepreferablyataspeedofatleast75rpm,mostpreferablyata speedofabout100rpm,andpreferablyataspeedofnotmorethan150rpm.This rangeofstirringspeedsischosentoensureathoroughandhomogeneousmixingof dexmedetomidinehydrochloridethroughoutthesodiumchloridesolution,while avoidingexcessiveagitationthatcouldpotentiallyleadtotheformationofbubbles30 orfoaminthesolution.Ahigherdegreeofhomogeneityimprovestheeffectiveness oftheintravenousformulationwhenadministeredtoapatient,asitensuresthattheactiveingredient,dexmedetomidinehydrochloride,isuniformlydistributedwithin thesolution.Thisuniformdistributioncanimprovethebioavailabilityoftheactive ingredient,therebyenhancingthetherapeuticeffectoftheformulation.35 Inapreferredembodiment,theformulationcomprisesdexmedetomidine hydrochlorideataconcentrationof4.2to5.2µg / mL,preferablyabout4.72µg / mL, BE2024 / 5807 15 thelatterwhichcorrespondstoadexmedetomidineconcentrationof4µg / mL. Dexmedetomidinehydrochlorideisknownforitssedativeproperties,andits inclusionintheformulationisintendedtoenhancethesedativeeffectivenessin patientsreceivingtheformulation.Itisanticipatedthatthiswillleadtoimproved patientcomfortandeaseofadministration.Moreover,dexmedetomidine5 hydrochlorideisalsousedasananalgesicagentforreducingpaininpatients,and asananxiolyticagentforreducinganxietyinpatients,suchasthosebeinganxious fortreatmentorsurgery.Therefore,thepresenceofdexmedetomidinehydrochloride intheformulationmaycontributetoamorecomprehensivemanagementofpatientdiscomfort,potentiallyreducingtheneedforadditionalmedications.10 Theconcentrationofdexmedetomidinehydrochlorideintheformulationmayvary withincertainlimits.Preferably,theconcentrationisbetween2and10µg / mL,more preferablybetween3and8µg / mL,morepreferablybetween4and6µg / mL,or4.2 to5.2µg / mL,andmostpreferablyaround4.72µg / mL.Theserangesareprovided15 asexamplesofpreferredembodimentsandarenotintendedtobelimiting. Inthepresentcontext,wherereferenceismadeto‘around4.72µg / mL’or‘about 4.72µg / mL’,‘about’or‘around’preferablyreferstoaconcentrationrangewithin ±10%ofthespecifiedvalue,morepreferablywithin±5%.For‘about4.72µg / mL’,20 thiscorrespondstoarangeof4.248to5.192µg / mL(±10%)or4.484to4.956 µg / mL(±5%);or4.2to5.2µg / mLor4.4to5.0µg / mL. Inapreferredembodiment,instepf),thedexmedetomidinehydrochloridesolution ispressurizedfromthecompoundingvesseltoanintermediatevesseloverthe,25 preferably0.2µm,filter,whereintheinertgasofthecompoundingvesselisusedaspressurizinggas.Thispreferredembodimentprovidesanumberofadvantagesin theproductionprocess.Notably,theuseoftheinertgasfromthecompounding vesselasthepressurizinggasfacilitatesanefficient,contaminant-free,andcost- effectiveproductionprocess.Additionally,usingtheinertgasfromthecompounding30 vesselasthepressurizinggaseliminatestheneedforanadditionalsourceof pressurizinggas,therebyreducingtheoverallcostandcomplexityoftheproduction process.Moreover,theuseoftheinertgasasthepressurizinggasmayhelpto furtherreducethedissolvedoxygencontentofthedexmedetomidinehydrochloride solution,therebyenhancingthestabilityofthesolution.Thepressurizinggasis35 preferablyintroducedintothecompoundingvesselatapressureofbetween0.5and 2bar,morepreferablybetween0.7and1.5bar,morepreferablybetween0.8and 1.2bar,mostpreferablyatabout1bar.Theintermediatevesselispreferablylinked BE2024 / 5807 16 toafillingmachine,configuredforfillingtheglassvials.Inthisway,thepressurizeddexmedetomidinehydrochloridesolutioncanbeefficientlytransferredfromthe compoundingvesseltotheglassvials,therebyfurtherenhancingtheefficiencyand cost-effectivenessoftheproductionprocess. 5 Inapreferredembodiment,thefilterusedinstepf)ispreferablyahydrophilic membrane.Examplesarementionedabove.Morepreferablythefilterisahydrophilic polyvinylidenefluoride(PVDF)membranefilter.Thechoiceofthisparticulartypeof filtercontributestotheeffectivesterilizationofthedexmedetomidineformulation, enhancingtheoverallqualityandsafetyofthefinalproduct.Thisisparticularly10 advantageousasitreducestheriskofcontamination,ensuringtheformulationis safeforintravenousadministration.Furthermore,thehydrophilicnatureofthefilter isbeneficialinreducingpotentialabsorptionbythefilter,therebyensuringthe maximumamountoftheactiveingredient,dexmedetomidinehydrochloride,is presentinthefinalformulation.SuchfilteralsomeetstheUnitedStates15 Pharmacopeia(USP)BiologicalreactivitytestinvivoforclassVI-121°Cplastics.Thisindicatesthatthefilterhasbeentestedandfoundtobebiologicallycompatible, ensuringthatitdoesnotintroduceanyharmfulsubstancesintotheformulation duringthefiltrationprocess. 20 Inapreferredembodiment,thedissolvedoxygencontentduringanyofthesteps b),e)andg)ismaintainedatamaximumof0.5ppm.Theoxygencontentinthe solutionispreferablykeptatalevelthatsignificantlyreducestheriskofoxidation ofdexmedetomidinehydrochloridetohydroxymedetomidine.Thisisparticularly advantageousasitimprovesthestabilityofthedexmedetomidinehydrochloride,25 therebyavoidingproductionofunwantedby-productsandimpurities,inadditionto increasingtheshelflifeofthefinalproduct. Theprocessofmaintainingalowoxygencontent,preferablyatamaximumof0.5 ppm,involvespassinganinertgas,preferablynitrogengas,throughthesolution.30 Thisisdoneuntilthedesiredoxygencontentisobtained.Inafurtherpreferred embodiment,thedissolvedoxygencontentismaintainedatamaximumof0.5ppm throughouttheentireproductionprocess,asfromstepb)inthecompoundingvesseltothefinalsealingofthevials.Thiscontinuouscontroloftheoxygencontentensures thatthedexmedetomidinehydrochlorideremainsstableanditstherapeuticefficacy35 ispreservedthroughouttheshelflifeoftheproduct.Theprocessofmaintaininga lowoxygencontent,therefore,notonlyimprovesthestabilityofthe BE2024 / 5807 17 dexmedetomidinehydrochloridebutalsoensuresthatthefinalproductisofhigh qualityandsafeforuseinpatients. Inapreferredembodiment,theinertgas,preferablyasusedthroughoutthewhole method,hasbeenfilteredthrougha0.22µmfilter.Thisparticularfilteringprocess5 servesasapurificationstep,eliminatingpotentialparticulatecontaminantsfromthe inertgas.Theprocessmayrelatetotheuseofanyinertgas,butmorepreferably, itrelatestotheuseofnitrogengas.Thepurityoftheinertgasisofsignificant importanceasitcontributestotheoverallsafetyoftheformulationintendedfor intravenousadministration.Themorepurifiedtheinertgas,thesafertheformulation10 becomes.Intermsofthefilter,a0.22µmfilterispreferred.However,filterswithdifferentporesizesmayalsobeused.Forexample,filterswithporesizesof0.25 µmor0.20µmmayalsobeused.Morepreferably,theporesizeofthefilteris between0.20µmand0.25µm,mostpreferablyaround0.22µm.Thechoiceofthe filtersizeisimportantasitdeterminestheextenttowhichtheinertgasispurified.15 Asmallerporesizewouldresultinahigherdegreeofpurification,butitmayalso slowdowntherateoffiltration.Therefore,abalancebetweenthedegreeof purificationandtherateoffiltrationneedstobestruck. Inapreferredembodiment,thedexmedetomidinehydrochloridesolutioninstepe),20 beforefiltering,hasabioburdenoflessthan20cfu / mLforeachofbacteriaand fungi,andamaximumbacterialendotoxinlevelof2.8IU / mL.Thisensuresthatthe formulationmaintainsahighstandardofmicrobialcleanlinessandmeetsregulatory requirementsforpharmaceuticalproductsintendedforintravenousadministration. Inanotherorfurtherpreferredembodiment,theliquiddexmedetomidine25 hydrochlorideinWFIformulationafterfilteringinstepf)anbeforeanoptionalsterilizationstephasabioburdenoflessthan10cfu / mLforeachofbacteriaand fungi.Thisenhancedmicrobialcontrolfurtherensuresthesafetyandefficacyofthe finalproductforintravenousadministration.Thisalsoallowsfullsterilizationina next,optional,terminalsterilizationstep(seefurther).30 Byadheringtothesestringentmicrobiallimitsthroughoutthemanufacturing process,theresultingliquidformulationofdexmedetomidinehydrochlorideinWFI meetsthehigheststandardsofquality,makingitsuitableforintravenous administrationwithouttheriskofbacterialorendotoxincontamination.These35 preferredembodimentsensurethatthefinalformulationhashighsafetymargins, minimizingtheriskofcontaminationandensuringpatientsafetyduringintravenous administration. BE2024 / 5807 18 Inapreferredembodiment,theliquiddexmedetomidinehydrochlorideinWFI formulationinthecontainers,preferablyglassvials,isterminallysterilizedby autoclavingbeforeclosingthecontainersorstopperingthevials,preferablyatatemperatureof121°Cfor20min.Thisverificationofsterilityviaautoclaving5 enhancesthesafetyoftheproductbyeliminatingpotentialmicrobialcontamination andendotoxinpresence.Theautoclavingprocessmaybeperformedatarangeof temperatures,preferablybetween100and150°C,morepreferablybetween110 and140°C,morepreferablybetween115and135°C,morepreferablybetween120 and130°C,andmostpreferablyat121°C.Thedurationofthisprocesscanalsovary,10 preferablybetween10and30minutes,morepreferablybetween15and25minutes, morepreferablybetween18and22minutes,morepreferablybetween19and21 minutes,andmostpreferablyfor20minutes.Theautoclavingprocessservesto sterilizetheformulationandtheinteriorofthevials,ensuringthatthefinalproduct isfreefrom,oratleastverylowin,anymicrobialcontamination.Thisisanessential15 stepinensuringthesafetyandefficacyofthefinalproduct.Theuseofautoclaving asasterilizationmethodisadvantageousasitisawell-established,reliable,and efficientmethodforthesterilizationofmedicalproducts.Inapreferredembodiment,theliquiddexmedetomidinehydrochlorideinWFI20 formulation,preferablyafterautoclaving,hasapHofbetween4.5and7.0, preferablybetween5.8and6.3.ThisspecificpHrangeenhancesthestabilityofthe solutionandreducespotentialharmandirritationduringadministration.ThispH rangeispreferablybetween4.5and7.0,preferablybetween5and7,more preferablybetween5.5and6.5,morepreferablybetween5.6and6.4,more25 preferablybetween5.7and6.3,morepreferablybetween5.8and6.2,more preferablybetween5.9and6.2,mostpreferablybetween6.0and6.2. Theautoclavingprocessisfollowedbytheclosingofthecontainers,preferablythe stopperingofthevialswitharubberstopper,whichisdesignedtomaintainthe30 sterilityoftheformulationandpreventanypotentialcontamination.Thestoppering processispreferablycarriedoutinacontrolledenvironmenttofurtherensurethe sterilityofthefinalproduct. Preferredbutnon-limitingexamplesincludebromobutylandchlorobutylstoppers.35 Theserubberstoppersprovideexcellentbarrierstogasesandmoisture,therebypreservingthestabilityandintegrityoftheformulation.Bromobutylstoppersoffer superiorresistancetopermeationandarecommonlyusedfortheirexcellentsealing BE2024 / 5807 19 propertiesandcompatibilitywithvariousformulations.Chlorobutylstoppersarealso utilizedfortheireffectivebarrierpropertiesandchemicalresistance.Bothtypesof stoppersaresuitabletomaintainthequalityandeffectivenessoftheformulation throughoutstorageanduse. 5 Thesterilizedandclosedcontainers,preferablystopperedvials,arethenreadyfor subsequentsealing,andpreferablylabelingandpackagingprocesses,leadingtoa ready-to-useproductthatdoesnotrequireanyfurtherdilutionorpreparationbefore administeringtoapatient.Thispreferredembodimentthusprovidesasafe,efficient, andconvenientmethodfortheproductionofasterileliquidformulationof10 dexmedetomidinehydrochlorideinWFI,suitableforintravenousadministration. Inapreferredembodiment,thelabelingprocessmayincorporatebarcodesorQR codesonthelabelsforeasyscanningandtrackingoftheproduct.Theinsert,ontheotherhand,maycontaindetailedinstructionsontheuse,dosage,andstorageofthe15 medication,aswellasanypotentialsideeffectsandcontraindications.This informationispreferablyprovidedinmultiplelanguagestocatertoaglobalmarket. Inapreferredembodiment,themethodofproductionutilizesspecificmaterialsfor packagingthedexmedetomidinehydrochlorideformulation.Thesematerials,which includeTypeIglassvials,chlorobutylorbromobutylstoppers,and / oraluminum20 caps,contributetotheimprovedstoragestabilityoftheformulation. TheTypeIglassvialsarepreferredasthistypeofglassiswellknownforitsexcellent chemicalresistanceproperties,andsuchvialsdonotdelaminatewhenincontact withtheformulation,ensuringthesafetyoftheproduct.Thisensuresthatthe25 formulationremainsstableandeffectiveoveralongperiodoftime. Inaddition,bothtypesofstoppers,bromobutylandchlorobutylstoppers,havebeen selectedastheinventorsexperimentallydeterminedthattheydonot(orbelowan acceptablepresetthreshold)releaseextractablesintothepresentformulation,30maintainingthepurityandintegrityoftheformulation.TheneutralityoftheTypeI glassandchlorobutylorbromobutylstopperswithrespecttotheactiveingredient, dexmedetomidineHCl,isofparticularimportance.Thesematerialsdonotallow adsorptionorabsorptionoftheactiveingredient,oratleastnotoverapredefined threshold,thusmaintainingtheintegrityandefficacyoftheformulation.35 Theuseofaluminumcapsinconjunctionwiththestoppersisalsopreferredasthis combinationeffectivelypreventsmicrobialcontamination.Thisiscrucialin BE2024 / 5807 20 maintainingthesterilityoftheformulation,particularlyasitisintendedfor intravenousadministration,preferablyIVinjection.Theuseofchlorobutylor bromobutylstoppersandaluminumcapsfurtheralsoenhancesthestoragestability oftheformulation,asthesematerialsprovideaneffectivebarrieragainst environmentalfactorssuchasmoistureandoxygen.5 Inamostpreferredembodiment,thedexmedetomidinehydrochlorideformulationis packagedinacontainer,suchas50mLor100mLcontainers,preferablyglassvialsandmorepreferablyTypeIglassvials.Thesevialsarethenstopperedwith chlorobutylorbromobutylstoppersandsealedwithaluminumcaps.Thispreferred10 embodimentprovidesaready-to-useproductthatdoesnotrequiredilutionpriorto administrationtoapatient,thusenhancingtheconvenienceandeaseofuseofthe product. Inapreferredembodiment,themethodprovidesaliquidformulationof15 dexmedetomidinehydrochloridepackedindifferentvolumeoptions,whichmay includebutnotlimitedto50mLor100mLglassvials.Thisembodimentoffers flexibilityindosageandeaseofuseforhealthcareproviders.Itisideallysuitedfor scenarioswheredifferentdosagesarerequiredfordifferentpatients,orforthesame patientatdifferenttimes.20 Theformulationispreferablyaready-to-useproduct,eliminatingtheneedforfurther dilutionpriortoadministration.Thiscanpotentiallyreducetheriskofdosingerrors, savetimeforhealthcareproviders,andimprovepatientsafety.Theavailabilityof differentvolumeoptionsalsoallowsforoptimalvolumestobeprovidedtopatients,25enhancingtheefficiencyofthetreatmentprocess. Inapreferredembodiment,thecompoundingvessel,andfurtherpreferablyany connectingtubing,vessels,syringes,pumps,andvalvescomingintocontactwith anyoneofthesolutionsformedinthemethod,aremadeofstainlesssteelof316L30 gradematerial.Thismaterialisparticularlysuitableforthemanufactureofmedical products.Theuseofhigh-gradestainlesssteelinthemanufacturingprocess minimizestheriskofsolutioncontamination,leadingtoincreasedproductsafetyand efficacy.Thestainlesssteelof316Lgradematerialispreferablyusedduetoits excellentcorrosionresistanceproperties,especiallyinchlorideenvironments,and35 itsexceptionalmechanicalpropertiesathightemperatures.Itisalsopreferreddue toitsenhancedresistancetopittingandcrevicecorrosioninchlorideenvironments. Inamorepreferredembodiment,thestainlesssteelof316Lgradematerialisused BE2024 / 5807 21 forthecompoundingvessel,connectingtubing,vessels,syringes,pumps,andvalves duetoitssuperiorcleanlinessanditsabilitytobeeasilysterilized,whichfurtherreducestheriskofcontamination.Inapreferredembodiment,thestainlesssteelof 316Lgradematerialisusedforallcomponentscomingintocontactwiththesolutions formedinthemethod,andthesecomponentsaresterilizedpriortouse.Thisensures5 thattheentiremanufacturingprocessisconductedinacleanandsterile environment,furtherenhancingthesafetyandefficacyofthefinalproduct. Inanotherorfurtheraspect,thepresentinventionrelatestoasterileliquid formulationofdexmedetomidinehydrochlorideinwaterforinjection(WFI),suitable10 forintravenousadministration,preferablyIVinjection,whereindexmedetomidine hydrochlorideispresentintheformulationataconcentrationof4.2to5.2µg / mL, preferablyabout4.72µg / mL,andsodiumchlorideataconcentrationof0.81wt% to0.99wt%,preferablyabout0.9wt%,wheretheliquidformulationhasapHof between4.5and7.0,preferablybetween5.8and6.3,andpackedinacontainer,15 preferablyneutralTypeIglassvial,stopperedwitharubberstoppersuchas bromobutylorchlorobutylstopperandsealedusinganaluminumcappreferablywhereinsaidcontainersorvialsare50mLor100mLvials. Apersonofordinaryskillintheartwillappreciatethatelementsoftheaspectofthe20 methodasdescribedabovereturnintheaspectofthesterileliquidformulationof theinvention,andintheaspectoftheusesoftheformulationasdescribedfurther below.Consequently,allaspectsofthepresentinventionarerelated.Allfeaturesas describedinoneoftheaspects,asdescribedaboveaswellasbelow,canrelateto anyoftheseaspects,eveniftheyaredescribedinconjunctionwithaspecificaspect.25 Inanembodiment,theformulationcomprisesamaximumof2.5endotoxinspermL. Thisensuresthattheformulationmaintainsahighstandardofmicrobialcleanliness andmeetsregulatoryrequirementsforpharmaceuticalproductsintendedfor intravenousadministration. 30 Inanembodiment,theformulationisproducedaccordingtothemethodasdescribed aboveinanyoneoftheembodiments. Inanotherorfurtheraspect,thepresentinventionrelatestoauseofasterile formulationasdescribeaboveinanyoneoftheembodimentsasasedativeagent.35Preferably,theformulation,whenadministeredtoa,preferablyhuman,patient, inducessedation,astateofcalmness,relaxation,and / orreducedanxiety.Sedative agentsarecommonlyusedinmedicalpracticetopromotesleep,alleviateanxiety, BE2024 / 5807 22 andinduceacalmingeffectonpatients.Theymaybeadministeredorally, intravenously,orviaotherroutesofadministrationdependingonthespecific application. Inanotherorfurtheraspect,thepresentinventionrelatestoauseofasterile5 formulationasdescribeaboveinanyoneoftheembodimentsasananalgesicagent forreducingpaininpatients. Preferably,theformulation,whenadministeredtoa,preferablyhuman,patient, relievespainwithoutcausinglossofconsciousness.Analgesicagentsworkby10 blockingorreducingtheperceptionofpainsignalsinthenervoussystem.Theyare usedtomanagepainofvaryingintensity,rangingfrommildtosevere,andcanbe administeredinvariousforms,includingorally,topically,orviainjection. Inanotherorfurtheraspect,thepresentinventionrelatestoauseofasterile15formulationasdescribeaboveinanyoneoftheembodimentsasananxiolyticagent forreducinganxietyinpatients. Preferably,theformulation,whenadministeredtoa,preferablyhuman,patient, reducesanxietyandpromotesastateofrelaxationandcalmness.Anxiolyticagents20 arecommonlyprescribedforthetreatmentofanxietydisorders,panicattacks,and otherconditionscharacterizedbyexcessiveworryorfear.Theyworkbymodulating neurotransmitteractivityinthebrain,particularlygamma-aminobutyricacid (GABA),whichhasinhibitoryeffectsonthecentralnervoussystem.Anxiolyticagents maybeadministeredorally,intravenously,orthroughotherroutesofadministration25 dependingonthespecificneedsofthepatient. Inapreferredembodiment,oftheusesofthesterileformulationassedativeagent, asananalgesicagent,and / orasananxiolyticagent,isintravenouslyadministered toapatient.Inafurtherpreferredembodiment,saidpatientisahumanpatient.30 SaidintravenousadministrationwhichcanbeachievedthroughIVinjectionorinfusion,involvesthedirectdeliveryofthesterileformulationintothepatient's bloodstream.‘IVinjection’referstotherapidadministrationofabolusdoseofthe formulationdirectlyintoaveinusingasyringe,providinganimmediatetherapeutic35 effect.Ontheotherhand,‘IVinfusion’involvesthegradualadministrationofthe formulationoveraperiodoftime,typicallyusinganIVdriporinfusionpump.This methodallowsforacontrolledandcontinuousdeliveryoftheformulation.Both BE2024 / 5807 23 methodsofIVadministrationaimtorapidlyfunctionassedativeagent,asanalgesic agent,and / orasanxiolyticagent. EXAMPLES Thepresentinventionwillnowbefurtherexemplifiedwithreferencetothefollowing5 examples.Thepresentinventionisinnowaylimitedtothegivenexamplesortothe embodimentspresentedinthefigures. Example1:methodaccordingtothepresentinvention Aliquidformulationofdexmedetomidinehydrochloridewaspreparedusingthe10 methodasdescribedintheclaims: a)90%ofwaterforinjectionofbatchformulaareaddedintoastainlesssteel316Lgradecompoundingvesselwithstainlesssteel316Lstirreratwhereits temperatureinthevesselisnotlessthan75°C, b)0.2μmfilterednitrogenisbubbleduntiladissolvedoxygenlevelofmaximum15 0.5ppmandtemperatureof38-40°Cisobtained, c)Undernitrogenbubblingandstirring,sodiumchlorideofbatchformula(final concentrationof0.9wt%totalweightofformulation)isaddeduntilcomplete dissolution+undernitrogenbubbling,stirringisperformedfor15minutesto ensuredissolutionofsodiumchloride,20 d)Undernitrogenbubblingandstirring,DexmedetomidineHClofbatchformula (finalconcentrationof4.72µg / mLinformulation)aisaddeduntilcomplete dissolution+undernitrogenbubbling,stirringisperformedfor15minutesto ensuredissolutionofDexmedetomidineHCl, e)Undernitrogenbubblingandstirring,finalvolumeisbroughtwithwaterfor25 injection+Oxygenlevelischecked:itshouldbeatmaximum0.5ppm.If not,nitrogenisbubbleduntilachievemaximum0.5ppm, f)Thesolutionisfilteredbythe0.2μmPVDFfilter.Thesolutiongoesthroughoutthefilterby0.2or0.22μmfilterednitrogenpressurefromthe compoundingvesselanditisreceivedintheintermediatevesselthatison30 thefillingmachine, g)Thesolutionistakenfromtheintermediatevesselbythefillingmachinein ordertobefilledintothevials,andthesolutionisfilledintothevials.The fillingspeedisintherangeof6000–9000vials / hour,thesameforboth50 mLand100mLvials(for100mLvials:volumebetween102mLand10635 mL;for50mLvials:volumebetween51mLand53mL).Sterilizationofthe solutionfilledinthevialsisperformed,immediatelyafterendoffilling,in autoclavebysuper-heatedwaterat121°Cfor20minutes.Vialsareclosed BE2024 / 5807 24 bythestoppers.Closedvialsonthefillingmachinearesealedbyaluminum capsusingasealingmachine(crimpingmachine). Theresultingformulationwasfoundtobestableandsuitableforintravenous injection,demonstratingtheenhancedproductsafetyandstabilityoftheinvention.5 Example2:Compoundingresults –Dexmedetomidinehydrochloridecanbeeasilydissolvedat4.72μg / mlin90%volumeof0.9%sodiumchloridesolutionwithoutparticularissue. –DexmedetomidinehydrochlorideissolubleatdifferentpHs3,5,6,8and9.10 –DissolutionofDexmedetomidinehydrochlorideismaintainedatdifferentpHs 3,5,6,8and9solutionsdespitetemperaturechange. –ObtainedsolutionsofDexmedetomidinehydrochlorideat4.72μg / mlare clear,colorlessandparticlefreebyvisualinspection. –Noparticularissueisobservedinrelationwithstirringspeedfordissolution.15 Mediumstirringspeedof100rpmisenoughforthedissolution. –DissolutionofDexmedetomidinehydrochlorideisensuredatthe concentrationof4.72mg / mlindrugproduct. –WFIiscirculatingatmorethan80°Cintheloop.RequiredtimeforWFIto cooldownto38°C-40°Cincompoundingvesselisrelativelyquickerthanto20 cooldowntotemperaturesofabout22°C–25°C.DexmedetomidineHClin solutionisnotsensitivetotemperature(seebelow).Therefore,inorderto minimizethemanufacturingdurations,SodiumChloridefollowedby dexmedetomidineadditiontoWFIisinitiatedattemperatureof38°C-40°C.Afterthecompoundingprocessisinitiated,temperatureofthesolutiongoes25 downslowlyalongthecompoundingprocess. – Example3:impuritytesting Possibleknownimpurities: -duetooxidationofdexmedetomidine:hydroxymedetomidine30 -duetoinversionofenantiomerDexintoLevo:levomedetomidine Specificationsofimpurities:Basedonamaximumdailydose(MDD)of Dexmedetomidineof1068mcg / day,thespecificationof: -eachknownimpurityis1.0%,whichcouldbetightenedto0.5%ifstability35 resultsallowto,and -ofeachunknownimpurityis0.5%. BE2024 / 5807 25 RationalofchoiceofanalyticalmethodsusedforassayofDexmedetomidine,assay ofimpuritiesandenantiomerpurityintheproductisbasedontheHPLCmethods describedintheUSPmonographsforDexmedetomidineHydrochlorideand DexmedetomidineInjection.Chromatographicconditionsofthemethodsareapplied onDexmedetomidineHydrochloridein0.9%SodiumChlorideInjectionbecause5 excipientsarewaterforinjection,sodiumchlorideandnitrogenthatdonotinterfere inHPLCanalysis.Nevertheless,analysisconcentrationsofsampleandstandardsolutionsarestudiedandadaptedtotheproductconcentrationof4µg / mL Dexmedetomidineandtoestablishedimpuritiesspecifications. 10 AssayMethodAndRational-Chromatographicconditions: –Column:C18,150x4.6mm,5µ –Columntemperature:30°C –Detection:UV220nm –Flowrate:1.0ml / min15 –Injectionvolume:50µl –Runtime:20minutes –Mobilephase:MethanolandbuffersolutionpH7.8intheratioof600:400v / v respectively. –Buffer:1.5gofdisodiumhydrogenphosphatedihydrateand0.14gof20 monobasicsodiumphosphatemonohydratein1000mlofwater.pHadjusted to7.8±0.02with0.1Northo-phosphoricacidsolutionor0.1Nsodium hydroxide. –Standardsolution:24mgofDexmedetomidinehydrochloridestandardand transferinto100mlofvolumetricflask.Addabout60mlofmobilephase,25 sonicatetodissolveandmakeupvolumeuptothemarkwithdiluentandmix well.Furtherdilute5mlofabovesolutionto250mlwithmobilephase. (ConcentrationDexmedetomidinehydrochlorideStandardsolution:4.8 µg / ml). –Samplesolution:DexmedetomidineInjectionsolutionassuch.30–SinceDexmedetomidinehydrochlorideconcentrationintheFinishedDrug Productis4.72µg / ml(4µg / mldexmedetomidine),aboveUSPmethodis appliedforassayofDexmedetomidineintheFinishedDrugProduct. AssayOfImpuritiesMethodAndRational-Chromatographicconditions:35 –Column:C18,150x4.6mm,5µ –Columntemperature:30°C –Detection:UV210nm BE2024 / 5807 26 –Flowrate:1.0ml / min –Injectionvolume:100µl –Runtime:45minutes –Mobilephase:sameasinassay. –Samplesolution:TheUSPdescribessamplesolutioninDexmedetomidine5 ImpuritiesHPLCassaymethodasfollows:Usetheneatinjectionasis.The solutionofthedrugproductisat4µg / mlofDexmedetomidine,therefore, limitofdetectionandquantificationoftheknowndegradationsubstance Hydroxymedetomidineisstudiedaswellaslimitofdetectionand quantificationofDexmedetomidineforunknownimpurities.10 ProgressivesmallamountsofHydroxymedetomidineandof DexmedetomidinehavebeentestedbytheabovedescribedHPLCanalytical method.ReferencestandardsofDexmedetomidineHClUSPRSisusedandHydroxymedetomidineisacquiredfromtheCompanyTLCinCanada. Certificatesofanalysisforthereferencestandardsareprovidedin15 attachments: Itturnsouttobe0.012µg / mLofbothsubstancestobedetected.This amountis0.3%ofthe4µg / mlofDexmedetomidineofthedrugproduct. Sincereportinglimitshouldbe0.1%ofconcentrationofthesolutiontobe20 analysed,the0.3%ishighandtherefore,the4µg / mlsolution Dexmedetomidineofthedrugproductshouldbeconcentrated.Theabove encountered0.012µg / mliscorrespondingto0.1%of12µg / ml,sotest solution4µg / mlsolutionDexmedetomidineofthedrugproductis concentratedto12µg / mlasfollows:3mlofthesolutionoftheFinishedDrug25 Producttobeexaminedaretakenandtheliquidisevaporatedinnitrogen atmosphere:4µg / mlx3=12µg / ml.Theresidueisdissolvedin1mlof water:12µg / mlDexmedetomidine,equivalentto14.16µg / ml DexmedetomidineHCl. -Standardsolution:Sinceconformitylimitis0.5%.Standardsolutionis0.5%30 of12µg / mltestsolution=0.06µg / mlDexmedetomidine,equivalentto 0.0708µg / mlDexmedetomidineHCl.EnantiomerPurityandRational-DescriptionOfHPLCAssayMethodForEnantiomer PurityOfTheUSP:35 EnantiomerpurityisnotlistedinDexmedetomidineInjectionUSPmonograph; Nevertheless,thisdeterminationisperformedinpharmaceuticaldevelopmentto studyifinversionofDexmedetomidineintoLevomedetomidinecanbeproducedin BE2024 / 5807 27 theFinishedDrugProductinstressconditions.Decisiontoincludeornotenantiomer purityinspecificationsofFinishedDrugProductwillbetakenonbasisofobtained results.Therefore,enantiomerpuritytestisdeveloped. RationalofchoiceofanalyticalmethodforenantiomerpurityofDexmedetomidinein5 theFinishedDrugProductistheHPLCmethodofthisdeterminationthatisdescribed inDexmedetomidineHClUSPmonograph(drugsubstance).Themethodisapplicable ontheFinishedDrugProductsinceexcipientsaresodiumchloride,waterand nitrogenthatdonotinterfereinHPLC. 10 Chromatographicconditions: –Column:4-mm×10-cm;5-μmpackingL41 –Columntemperature:ambient –Detection:UV220nm –Flowrate:1.0ml / min15 –Injectionvolume:20µl –Mobilephase:–Buffer:To1Lof5.34g / Ldibasicsodiumphosphatedihydratesolution,adjust withasuitableamount(about700–800mL)of4.08g / Lmonobasicpotassium phosphatesolutiontoapHof7.0.20 –Mobilephase:AcetonitrileandBuffer(35:165). –Sensitivitysolution:0.05μg / mlofUSPLevomedetomidineRSinMobile phase. –Samplesolution: –TheUSPdescribessamplesolutionas50μg / mlwhilethesolutionofthe25 genericdrugproductis4µg / mlofDexmedetomidine,therefore,sameabove samplesolutionof12µg / mlDexmedetomidineforassayofimpuritiesisalso usedforenantiomerpurity. –Standardsolution:StudyofeventualinversionofDexmedetomidineinto LevomedetomidinethatcanbeproducedintheFinishedDrugProductin30 stressconditionswillbeperformedbytheobservationofareacorresponding toLevomedetomidineinthechromatogramofDexmedetomidineHClsolution notsubmittedtoanystressconditionandareacorrespondingto LevomedetomidineinthechromatogramDexmedetomidineHClsolutions submittedtostressconditions.Incaseofobservationofincreaseof35LevomedetomidineareainDexmedetomidineHClsolutionssubmittedto stressconditions,thiswillmeanthatLevomedetomidineshouldbepartof BE2024 / 5807 28 specificationoftheFinishedDrugProductandconcentrationofstandard solutionforquantificationwillbethendevelopedandestablished. HPLCchromatogramsfromanalyticaldevelopmentoftestmethodsareprovidedin Figure1.Figure1Ashowsthechromatogramofthedexmedetomidinesolution.5 Figures1Bto1Hfurthershowthechromatogramofthemobilephase(B),excipient sodiumchloride(C),hydroxymedetomidine(D),dexmedetomidinespikedwith hydroxymedetomidine(E),asystemsuitabilitysolution(F),asensitivitysolution (G),andfinallythelinearity(H). 10 Figure1NameRetentiontimeArea AHydroxymedetomidine Butilparabene dexmedetomidine 5.913 7.557 17.100 23150 100631 113287867 BHydroxymedetomidine Butilparabene Dexmedetomidine / / / / / / CHydroxymedetomidine Butilparabene Dexmedetomidine / / / / / / DHydroxymedetomidine Butilparabene Dexmedetomidine 6.033 / / 355759 / / EHydroxymedetomidine ButilparabeneDexmedetomidine 6.070 7.567 17.133 500880 62024 112803715 F Butilparabene Dexmedetomidine 3.473 8.040 10.953 342921 1976997 2894565 G Butilparabene Dexmedetomidine 3.427 / 10.420 347499 / 4102 HHydroxymedetomidine Butilparabene Dexmedetomidine 5.777 / 16.127 624684 / 676712 BE2024 / 5807 29 PeakofHydroxymedetomidine,theimpuritybyoxidationofDexmedetomidine,has aRelativeRetentionTime(RRT)ofabout0.4inrelationwiththepeakof Dexmedetomidineinthechromatograms. Example4:stressdegradationstudies5 Stressdegradationstudiesareperformedontheformulation,(4.72mgof Dexmedetomidinehydrochlorideisdissolvedin900.0mlofwaterforinjectionand finalvolumeisbroughtto1000mlwithwaterforinjection(4.72µg / ml))asdescribed above,beforefillingaccordingtothefollowingstudies: –Sensitivitytolight:100mlofthesolutionareintroducedin100mlvolumetric10 flaskandsubmittedtoartificiallaboratorylightfor5days. –SensitivitytoUV:100mlofthesolutionareintroducedin100mlvolumetric flaskandsubmittedto100-wattUVlampat365nmfor5days.–Sensitivitytooxidation:75mlofthesolutionareintroducedin100ml volumetricflask.25mlofhydrogenperoxideat30%areaddedandmixed.15 Thesolutioniskept5daysat20-22°Cprotectedfromlight. –Sensitivitytoheat:100mlofthesolutionareintroducedin100mlvolumetric flask,convenientlyclosedandautoclavedat121°Cfor20minutes. –SolutionatpH3.0:pHof100mlofthesolutionisadjustedto3.0by hydrochloricacid0.1Mandiskept5daysat20-22°Cprotectedfromlight.20 –SolutionatpH6.0:pHof100mlofthesolutionisadjustedto6.0bysodium hydroxideacid0.1Mandiskept5daysat20-22°Cprotectedfromlight. –SolutionatpH8.0:pHof100mlofthesolutionisadjustedto8.0bysodium hydroxideacid0.1Mandiskept5daysat20-22°Cprotectedfromlight. –100mlofthesolutionareintroducedin100mlvolumetricflaskandkept525 daysat20-22°Cprotectedfromlightwithoutanysubmission(Control). Degradedsolutionsaretestedforthefollowingstabilityindicatingtestsusingthe followinganalyticalmethods: –Appearanceofthesolutionistestedbyvisualinspection30–ClarityofthesolutionistestedaccordingtothetestoftheUSP –ColourofthesolutionistestedaccordingtothetestoftheUSP shouldbeclearliquidfreeof(visual)particles –Assay(contentinDexmedetomidine)istestedbytheHPLCmethodforassay35 thatisdescribedintheprevioussectionofanalyticaldevelopment Shouldbe95.0-105%oflabelclaim BE2024 / 5807 30 –AssayofimpuritiesistestedbytheHPLCmethodforassayofimpuritiesthat isdescribedabove –EnantiomerpurityistestedbytheHPLCmethodforenantiomerpuritythatis describedabove ShouldmeetICHrequirements(USPmonographsforDexmedetomidine5 HydrochlorideandDexmedetomidineInjection) –pHshouldbetested shouldbebetween4.5and7.0 10 Resultsofthestressdegradationstudy: TestControl solution Sensi- tivity to light Sensi- tivity toUV light Sensi- tivityto Oxidation 30% H2O2 Sensi- tivityto Oxidation 3% H2O2 Sensi- tivity to heat pH 3.0 pH 6.0 pH 8.0 Appear- ance CfCfCfCfCfCfCfCfCf ClarityCfCfCfCfCfCfCfCfCf ColourCfCfCfCfCfCfCfCfCf Assay99.599.799.782.889.099.799.499.698.9 Hydroxy medeto-midine NONO0.050.930.09NO0.04NONO Individual specified Impurity NONONO2.80.23NONONONO Any unspecified Impurity 0.10.09NO2.90.29NO0.10.080.2 Total impurities 0.10.170.0514.53.10.00.20.10.3 Mass balance 99.699.999.897.392.199.799.699.799.2 Cf-Conform Appearance-Cf:Clearliquidandparticlesfreebyvisualinspection Colour-Cf:colourless NO-Notobservedinchromatogram.Consideredbelowdetectionlimit15 Acceptancecriteria: -massbalanceNLT95.0%fromthecontrolsample(94.5-104.5%). 20 Observationofresultsofstressdegradationstudyshowthat: BE2024 / 5807 31 –Exceptforoxidation,noimpactofanystressdegradationconditionon stabilityofDexmedetomidineHClinsolutionwhereallparametersarein conformity. –Dexmedetomidinehydrochlorideinsolutionishighlysensitivetooxidation. Assayresultis82.5%,Hydroxymedetomidinetheoxidationproductisat5 10.1%andtotalimpuritiesat18.2%. –Noimpactofanystressconditiononappearance,clarityandcolorof Dexmedetomidinehydrochloridesolution.–Noimpactoflight,UVandheatonDexmedetomidinehydrochloridesolution. –EnantiomerLevomedetomidineisnotobservedincontrolsolutionneitherin10 anyofstressdegradedsolutions. FindingsOfStressDegradationStudy –Dexmedetomidineishighlysensitivetooxidation,thereforeitshouldbe protectedbyreducingoxygenleveltobelow1ppm,preferablybelow0.515 ppm.Thisisachievedbybubblingnitrogen,theinertgasinthesolution duringmanufacturing. –Dexmedetomidinesolutionisstabletoheatanditcanbesterilizedby autoclavingwithoutparticularissue. –Noparticulateissueistobetakeninrelationtolight.20 –EnantiomerLevomedetomidineisnotobservedinanyofstressdegraded solutions,sotheconclusionisthatnoinversionofDexmedetomidineinto Levomedetomidineenantiomeroccurs,therefore;enantiomerpuritytestis notdeemednecessaryinspecificationofthegenericFinishedDrugProduct. –HPLCanalyticalmethodforassayofDexmedetomidineandforassayof25 impuritiesisstabilityindicatingthatiscapabletodetectandquantifydegradationproductwithoutcoelution.Massbalanceofdegradedsolutionsis suitable. ImpurityProfile30 –ImpurityprofileisestablishedforDexmedetomidineinsolution.Impurities maybepresentintheFinishedDrugProductmainlyduetotheoxidationof dexmedetomidineresultinginformationoftheknownimpurity Hydroxymedetomidineandunknownimpurities. 35 Example4:usedcompoundingvessels / pumps / tubing / …,filters,vials,stoppersand seals BE2024 / 5807 32 Compoundingvessel,andfurtherpreferablyanyconnectingtubing,vessels, syringes,pumps,andvalvescomingintocontactwithanyoneofthesolutions formedinthemethod,arestainlesssteel316Lgradematerialsuitablefor manufactureofmedicalproducts. 5 Componentsofdrugproductsolutionhavenoparticularaggressivepropertyagainst stainlesssteel316L,wheretheyhaveneitherchemicalincompatibilitywiththis materialandpHofthesolutionisratherneutral.Stainlesssteel316Lmaterialhas noadsorptionnorabsorptionproperties.Propertiesofdrugproductsolutionhavenoparticularissuethatmayconducttoincompatibilitywithstainlesssteel316L.10 Stainlesssteel316gradehashighcorrosionresistance,particularlytopitting corrosioninchlorideenvironmentsandhighalkalinepHsolutions.Thisisanextreme situationversusthestainlesssteel316gradehascorrosionresistanceinawide rangeofmedia.Itresistsordinaryrustinginmostpackagingapplications.Itisalso resistanttomostpharmaceuticals,cosmeticsandfoodprocessingenvironments.It15 canbereadilycleaned,andresistsorganicchemicals,dyestuffsandawidevariety ofinorganicchemicals.Stainlesssteel316gradeisnon-magneticintheannealed condition(ie.verylowmagneticpermeability).Onbasisoftheevaluationofthe stainlesssteel316Lmaterialpropertiesandofdrugproductsolutionproperties,no corrosionofthestainlesssteel316Lmaterialcanbeattributedtothecontactwith20 drugproductsolution.Noreleaseofmetallicparticlesbythestainlesssteel316L materialintothegenericdrugproductsolutionisobserved.Nocleaningagentsareusedforcleaningofequipmentatthefinisheddrugproductmanufacturingsiteat SMF.Equipmentiscleanedonlywithwaterforinjection. 25 Asitisrequiredforparenteralproductsmanufacturedbyterminalsterilization,the solutionshouldbefilteredpriortofillingtoreducetheparticulatematterand microbialload.BecauseofthelowconcentrationofDexmedetomidineHClinthe formulation,hydrophilicmembraneissuitableinordertoreduceeventualabsorption bythefilter,therefore;chosenfilteristhehydrophilic0.2μmmembrane30 polyvinylidenefluoride(PVDF)suchasFluorodyne®EXfromPALLorsimilar.The filtershouldalsomeettheUSPBiologicalReactivitytestinvivoforclassVI-121°C plastics. Findings:Inexaggeratedworst-casesituations,extractableresultsof1.70μg(vial35 50ml)andof1.17μg(vial100ml)arelargelybelowtheacceptabledailyintakeof 120μgoftreatmentcontinuouslyforonemonth,whilethetreatmentwithgeneric drugproductDexmedetomidine4μg / mldoesnotexceed5-7days.Safetyofthe BE2024 / 5807 33 filtereveninworst-casesituationisdemonstrated.SafetyofthePVDFfilterisdemonstratedsuitabilityforthefiltrationofDexmedetomidineHydrochloridein0.9% sodiumchlorideinjection,4mcg / mL(dexmedetomidine). Therationaleforselectionofthecontainerclosuresystemforthedrugproductisas5 follows: –Neutralityofglassthatisincontactwiththesolutionisachievedbyusing TypeIglass –complyingwithUSP:GlassContainer<660>;therebyensuringneutrality withrespecttothestabilityofthedrugproduct.10 –Neutralityofstopperthatisincontactwiththesolutionisachievedbyusing achlorobutylstoppercomplyingwithUSP:ElastomerClosureforInjections <381>,therebyensuringneutralitywithrespecttothestabilityofthedrug product. –Sealingwithaluminumcaps.15 GlassVialDelaminationStudy Thepotentialfortheformationofglassparticlesanddelaminationwasevaluated. ThestudywasperformedonexhibitbatchDEX06ofDexmedetomidineHClin0.9% sodiumchlorideinjection,100mLTypeIglassVial,after28monthsstorageat40°C20 +2°C / RH75%+5%. Thefindingsofthestudywere: –Suspendedparticles:noflatand / orcurledparticles(glassflakes)werefoundonthesurfaceofthefilter. –Internalsurfaces:Inalltheinvestigatedareasoftheglassbottlestheinternal25 surfacesdidn’tshowsignificantsignsofalterationand / ormarksattributable toglassscalesdetachment(flaking). –Extractableanalysis:thechemicalanalysisbyICP-OESofSilicon(Si),Boron (B)andAluminum(Al)intheliquiddrugrecoveredfromthefiltrationofthe bottlesprovidedquitelowresults,lowerthanthetypicalconcentrations30 expectedincaseofglasscorrosion(Figure2). –ThechemicalanalysisbyICP-OESofSilicon(Si),Boron(B)andAluminum (Al)contentsintheliquiddrugrecoveredfromthefiltrationoftheN.8bottles providedthefollowingresults: Si<0.5ppm35 B<1.0ppm Al<1.0ppm. BE2024 / 5807 34 Suchconcentrationscanbeconsideredquitelow,lowerthanthetypical valuesexpectedincaseofglasscorrosion. ScanningElectronMicroscopy: Figure2showsSEMimagesofthefiltersurfaceoftheGlassVialDelaminationStudy5 intheExamplesection.