a novel continuous manufacturing system using the ...steerlife.com/assets/fractional.pdf · various...

1
NeedforContinuousProcess Significantadvancesintherapieshaveensuredthattherearesome answerstomanyofthemosttroublingdiseasestatesafflicting mankindtoday.Similardisruptionsareyettohappeninthe manufacturingofpharmaceuticalproducts.Thereisclearlya strongneedtomovethemanufacturingofpharmaceutical productsfromthecurrentbatchtocontinuousprocessing.The currentmanufacturinginvolvessingleormultistagebatch processes,comprisingofanumberofreactiveornon-reactive steps,wheresuitableconditionsforenergytransferaccompanied byestablishmentofpressureandtemperaturefieldsalongwith otherprocessingconditionsmaintainedoveraperiodoftime resultsinbuildingdesirableattributesintheproducttypically referredtoastheendpoint.Everystageoperationhastobe supportedbyconfirmingoutcomeseitherthroughtestingor validationincludingthatofcleanliness.Severalbatchprocessesare furtherlimitedbyeitherlackofclearlydefinedendpointorlackof abilitytoproducequalityattributesconsistently.Itisleftto subjectivehumandiscretionintheformofheuristicsorrulesof thumbtodecidetheendpointratherthantheoutcomebeing solelydictatedbydesign.Subjectivediscretionisalsoseenin managingtheeffectofmostinputsincludingseveral environmentalorsupplyconditionsthatchangethequalityand characteristicsofoutput.Thisleadstotheproductionofrejects, reworkandoff-specificationproducts‒theknownperilsofanon- standardoperation.Thedecisionsaregenerallyinvestigative relyingonqualitycertificationthroughpostoperativeanalytical testingratherthanassuredbydesign.Thesumofthetimespentat variousstagesinsuchbatchprocessesisoftenlargeresultingin lossofefficiency.Finally,releaseofsuchproductsinthemarket createsenormousriskstoconsumers,regulatorsandproducers. STEERLifeʼsfractionallobeprocessor(FLP)offersahugeleapover theexistingbatchprocessingequipmentandthecurrent continuousmanufacturingequipment.Therotatingmembersof theFLPmaybeconsideredascascadingarrangementof infinitesimallythinlayerswithoutanyinterruptionsor discontinuitieswiththeuniqueabilitytowipethemselvesclean. FLPprovidessignificantimprovementinbuildingbothtemporal andspatialcontrolinengineeringtheprocessthroughremovalof hotspotsanddeadzoneswhilemaintainingseamlessprocess continuity.TheseattributesofFLPmakeitnotonlydesirablebut absolutelyessentialinpharmaceuticalapplications.Theenergy transferismadeeffectiveusingthermalormechanicalmeansat widerangingmagnitudeswithminimalshearorpressurepeaks. Thisprovidesspecificadvantagesinhandlingsensitiveinput materialsthatmayormaynottolerateadverseinfluencingfactors. Themultifoldincreaseinoutputcapacityandbuilt-inprocess controlhaswide-rangingpharmaceuticalapplications. The“B2C-E”processusingtheFLPwouldreplaceHotMelt Extrusion(HME)toproduceproductwithdesirablesolid-state changes.AnotherformoftheFLPcalledMeltFragmenter,can producenon-porousparticlesofeitherlowmeltingdrugsubstance withorwithoutlipidicpharmaceuticalaids.This“B2C-F”process canreplacespraydryingorspraycongealing.Mostimportantly,the “B2C-G”processusingyetanotherformofFLPcalledActivated Granulator,mayreplaceconventionalgranulationnamelywet,dry andmeltgranulation.Thesetechnologieswithminimalhuman intervention,reducedmanufacturingfootprint,greatlyreduced wasteandenvironmentalburdenhaveimmensepotentialto design,createandmanufacturedifferenttypesofproductswith highlycontrolledphysicochemicalattributes.Additionally,product developmentbasedonthesetechnologiesismoremeaningful, seamlesslyscalableandcontinuouslyimprovingtheconsistencyof productattributesthroughbuildingknowledgedatabase throughoutproductlifecycle. A novel continuous manufacturing system using the Fractional Lobe Processor ControloverWorkinFractionalLobeProcessor TheFLPhastheabilitytoworkonmaterialsinsolidstatetoachieveintimateinteractionbetweentheconstituentswhileimpartingphysico-chemical changesthroughreaction,de-volatilization,shear,compression,elongation.surfacerenewal,distribution,dispersion‒eitheralonewithminimal interferingeffectsfromotheractionsorinanydesirablecombinationofactions.Workimpartedbythefractionallobeprovidestherequired uniformityinathree-dimensionalforcefieldeliminatinghotzonesthatcouldresultinmaterialdegradation.Thiscanbebeenshownby mathematicalmodelsusinganalyticalmethodsorcomputationalfluiddynamicmodelbasedonprinciplesoffiniteelementsmethod.Fractional lobeprocessorcompletelyeliminatesmeta-radialshear,thusachievingstableandimprovedprocesscontrol. ProcessAnalyticswithFeed-BackandFeed-ForwardControl Continuouspharmaceuticalprocessingwhencombinedwithprocessanalyticaltoolsallowsfurtherenhancementin controloftheproductqualityattributes.Thisisachievedbyfinelyadjustingforvariabilityininputorprocess conditions.Thesecontrolscanactuallybeprogrammedintothecontrolsalgorithmtoestablishanintelligentsystem. B2C-Extrusion Fixeddosecombination(FDC)therapyisthepreferredapproachtotreatHIVinordertominimizethevirusdeveloping resistance.ProteaseinhibitorsgiveneitheraloneorincombinationhaveanimportantroleinthetreatmentofHIV. Currentlyavailableproductsinthemarkethavebeenformulatedusinghotmeltextrusionprocesstomakesolid amorphousstatewithhydrophilicpolymerstoincreaseaqueoussolubility.Hotmeltextrusionprocessinvolves meltingofdrugsubstanceatelevatedprocessingtemperatureutilizingacombinationofthermalandmechanical energyandrequiresatightcontrolofbothquantumanduniformityofworkbeingcarriedduringtheprocessingin ordertomeetstringentcriticalqualityattributesofthefinalproduct. STEERLifeʼsexperienceofhotmeltextrusionusingFLPforshearsensitivematerialclearlydemonstratessignificant improvementinprocessefficiencyasmeasuredintermsofbothimprovedthroughputrateandqualityattributesdue tobettercontrolonfundamentalprocessingfactorssuchasresidencetime,shearpeakanduniformityofwork. B2C-Fragmentation Fractionalgeometryasaresultofuniformshearfieldsintheprevioussectionsresultsinmuchuniformsizeanda narrowerdistributionincomparisonwiththeErdmengergeometry.Plasticenergydissipationisanimportantphysical phenomenonthatoccursduringthefragmentationprocess.Asaresultoflessereffectsofdissipation,itispossibleto fragmentthematerialwithlowermeltingpointorglasstransitiontemperature. B2C-Granulation Particlesizedistributionofpharmaceuticalpowdershaveinfluenceoneverystepofmanufacturingprocessesforsolid oraldosageforms,includingpre-mixing/mixing,granulation,drying,milling,blending,coating,encapsulationor compression.ContinuousgranulationinaFLPinvolveparticleagglomerationduetovariousactivatingfactorssuchas water,moisture,mechanicalshearorheateitheraloneorincombination.Theprocessintegratesmixing,granulation, dryingandsizingstepsfollowedtypicallyinabatchprocessintoasinglecontinuousprocesstoproducefreeflowing andcompressiblegranules.STEERLifeʼsexperiencewiththisprocessclearlydemonstratesimprovedabilitytoproduce customizedgranulesmeasuredbothintermsofmeananddistributionofparticlesizewithoutneedingseparate dryingandmillingstepsasprocessdownstream. Conclusion TheFLPprovidesauniqueopportunityfortransitionfrombatchtocontinuousprocessingduetotheminimalhumanintervention,reducedmanufacturingfootprint,improvedprocesstraceabilityandcompliance,greatlyreducedwasteandenvironmentalburden.In addition,theFLPhasopenednew,hithertounexploredvistasinthefieldofmaterialtransformationowingtowiderangeofunitoperationsthatcanbeseamlesslydesignedintheFLP.ThusFLPhasimmensepotentialtodesign,createandmanufacturedifferenttypes ofproductswithhighlycontrolledphysicochemicalattributesmakingitatrueversatilecontinuousprocessorenabling“QualitybyDesign”.

Upload: ngodieu

Post on 23-Jul-2018

212 views

Category:

Documents


0 download

TRANSCRIPT

Need�for�Continuous�ProcessSignificant�advances�in�therapies�have�ensured�that�there�are�some�answers�to�many��of�the�most�troubling�disease�states�afflicting�mankind�today.�Similar�disruptions�are�yet�to�happen�in�the�manufacturing�of�pharmaceutical�products.�There�is�clearly�a�strong�need�to�move�the�manufacturing�of�pharmaceutical�products�from�the�current�batch�to�continuous�processing.�The�current�manufacturing�involves�single�or�multistage�batch�processes,�comprising�of�a�number�of�reactive�or�non-reactive�steps,�where�suitable�conditions�for�energy�transfer�accompanied�by�establishment�of�pressure�and�temperature�fields�along�with�other�processing�conditions�maintained�over�a�period�of�time�results�in�building�desirable�attributes�in�the�product�typically�referred�to�as�the�end�point.�Every�stage�operation�has�to�be�supported�by�confirming�outcomes�either�through�testing�or�validation�including�that�of�cleanliness.�Several�batch�processes�are�further�limited�by�either�lack�of�clearly�defined�end�point�or�lack�of�ability�to�produce�quality�attributes�consistently.�It�is�left�to�subjective�human�discretion�in�the�form�of�heuristics�or�rules�of�thumb�to�decide�the�end�point�rather�than�the�outcome�being�solely�dictated�by�design.�Subjective�discretion�is�also�seen�in�managing�the�effect�of�most�inputs�including�several�environmental�or�supply�conditions�that�change�the�quality�and�characteristics�of�output.�This�leads�to�the�production�of�rejects,�rework�and�off-specification�products�‒�the�known�perils�of�a�non-standard�operation.�The�decisions�are�generally�investigative�relying�on�quality�certification�through�postoperative�analytical�testing�rather�than�assured�by�design.�The�sum�of�the�time�spent�at�various�stages�in�such�batch�processes�is�often�large�resulting�in�loss�of�efficiency.�Finally,�release�of�such�products�in�the�market�creates�enormous�risks�to�consumers,�regulators�and�producers.

STEERLifeʼs�fractional�lobe�processor�(FLP)�offers�a�huge�leap�over�the�existing�batch�processing�equipment�and�the�current�continuous�manufacturing�equipment.�The�rotating�members�of�the�FLP�may�be�considered�as�cascading�arrangement�of�infinitesimally�thin�layers�without�any�interruptions�or�discontinuities�with�the�unique�ability�to�wipe�themselves�clean.�FLP�provides�significant�improvement�in�building�both�temporal�and�spatial�control�in�engineering�the�process�through�removal�of�hot�spots�and�dead�zones�while�maintaining�seamless�process�continuity.�These�attributes�of�FLP�make�it�not�only�desirable�but�absolutely�essential�in�pharmaceutical�applications.�The�energy�transfer�is�made�effective�using�thermal�or��mechanical�means�at�wide�ranging�magnitudes�with�minimal�shear�or�pressure�peaks.�This�provides�specific�advantages�in�handling�sensitive�input�materials�that�may�or�may��not�tolerate�adverse�influencing�factors.�The�multifold�increase�in�output�capacity��and�built-in�process�control�has�wide-ranging�pharmaceutical�applications.

The�“B2C-E”�process�using�the�FLP�would�replace�Hot�Melt�Extrusion�(HME)�to�produce�product�with�desirable�solid-state�changes.�Another�form�of�the�FLP�called�Melt�Fragmenter,�can�produce�non-porous�particles�of�either�low�melting�drug�substance�with�or�without�lipidic�pharmaceutical�aids.�This�“B2C-F”�process�can�replace�spray�drying�or�spray�congealing.�Most�importantly,�the�“B2C-G”�process�using�yet�another�form�of�FLP�called�Activated�Granulator,�may�replace�conventional�granulation�namely�wet,�dry�and�melt�granulation.�These�technologies�with�minimal�human�intervention,�reduced�manufacturing�footprint,�greatly�reduced�waste�and�environmental�burden�have�immense�potential�to�design,�create�and�manufacture�different�types�of�products�with�highly�controlled�physicochemical�attributes.�Additionally,�product�development�based�on�these�technologies�is�more�meaningful,�seamlessly�scalable�and�continuously�improving�the�consistency�of�product�attributes�through�building�knowledge�data�base�throughout�product�life�cycle.

A novel continuous manufacturing system using the Fractional Lobe Processor

Control�over�Work�in�Fractional�Lobe�ProcessorThe�FLP�has�the�ability�to�work�on�materials�in�solid�state�to�achieve�intimate�interaction�between�the�constituents�while�imparting�physico-chemical�changes�through�reaction,�de-volatilization,�shear,�compression,�elongation.�surface�renewal,�distribution,�dispersion�‒�either�alone�with�minimal�interfering�effects�from�other�actions�or�in�any�desirable�combination�of�actions.�Work�imparted�by�the�fractional�lobe�provides�the�required�uniformity�in�a�three-dimensional�force�field�eliminating�hot�zones�that�could�result�in�material�degradation.�This�can�be�been�shown�by�mathematical�models�using�analytical�methods�or�computational�fluid�dynamic�model�based�on�principles�of�finite�elements�method.�Fractional�lobe�processor�completely�eliminates�meta-radial�shear,�thus�achieving�stable�and�improved�process�control.

Process�Analytics�with�Feed-Back�and�Feed-Forward�ControlContinuous�pharmaceutical�processing�when�combined�with�process�analytical�tools�allows�further�enhancement�in�control�of�the�product�quality�attributes.�This�is�achieved�by�finely�adjusting�for�variability�in�input�or�process�conditions.�These�controls�can�actually�be�programmed�into�the�controls�algorithm�to�establish�an�intelligent�system.

B2C-�ExtrusionFixed�dose�combination�(FDC)�therapy�is�the�preferred�approach�to�treat�HIV�in�order�to�minimize�the�virus�developing�resistance.�Protease�inhibitors�given�either�alone�or�in�combination�have�an�important�role�in�the�treatment�of�HIV.�Currently�available�products�in�the�market�have�been�formulated�using�hot�melt�extrusion�process�to��make�solid�amorphous�state�with�hydrophilic�polymers�to�increase�aqueous�solubility.�Hot�melt�extrusion�process�involves�melting�of�drug�substance�at�elevated�processingtemperature�utilizing�a�combination�of�thermal�and�mechanical�energy�and�requires�a�tight�control�of�both�quantum�and�uniformity�of�work�being�carried�during�the�processing�in�order�to�meet�stringent�critical�quality�attributes�of�the�final�product.

STEERLifeʼs�experience�of�hot�melt�extrusion�using�FLP�for�shear�sensitive�material�clearly�demonstrates�significant�improvement�in�process�efficiency�as�measured�in�terms�of�both�improved�throughput�rate�and�quality�attributes�due�to�better�control�on�fundamental�processing�factors�such�as�residence�time,�shear�peak�and�uniformity�of�work.

B2C�-�FragmentationFractional�geometry�as�a�result�of�uniform�shear�fields�in�the�previous�sections�results�in�much�uniform�size�and�a�narrower�distribution�in�comparison�with�the�Erdmenger�geometry.�Plastic�energy�dissipation�is�an�important�physical�phenomenon�that�occurs�during�the�fragmentation�process.�As�a�result�of�lesser�effects�of�dissipation,�it�is�possible�to�fragment�the�material�with�lower�melting�point�or�glass�transition�temperature.

B2C�-�GranulationParticle�size�distribution�of�pharmaceutical�powders�have�influence�on�every�step�of�manufacturing�processes�for�solid�oral�dosage�forms,�including�pre-mixing/mixing,�granulation,�drying,�milling,�blending,�coating,�encapsulation�or�compression.�Continuous�granulation�in�a�FLP�involve�particle�agglomeration�due�to�various�activating�factors�such�as�water,�moisture,�mechanical�shear�or�heat�either�alone�or�in�combination.�The�process�integrates�mixing,�granulation,�drying�and�sizing�steps�followed�typically�in�a�batch�process�into�a�single�continuous�process�to�produce�free�flowing�and�compressible�granules.�STEERLifeʼs�experience�with�this�process�clearly�demonstrates�improved�ability�to�produce�customized�granules�measured�both�in�terms�of�mean�and�distribution�of�particle�size�without�needing�separate�drying�and�milling�steps�as�process�downstream.

ConclusionThe�FLP�provides�a�unique�opportunity�for�transition�from�batch�to�continuous�processing�due�to�the�minimal�human�intervention,�reduced�manufacturing�footprint,�improved�process�traceability�and�compliance,�greatly�reduced�waste�and�environmental�burden.�In�addition,�the�FLP�has�opened�new,�hitherto��unexplored�vistas�in�the�field�of�material�transformation�owing�to�wide�range�of�unit�operations�that�can�be�seamlessly�designed�in�the�FLP.�Thus�FLP�has�immense�potential�to�design,�create�and�manufacture�different�types�of�products�with�highly�controlled�physicochemical�attributes�making�it�a�true�versatile�continuous�processor�enabling�“Quality�by�Design”.