Methods in Pharmacology and Toxicology Marianthi G. Ierapetritou Rohit Ramachandran Editors Process Simulation and Data Modeling in Solid Oral Drug Development and Manufacture M P ETHODS IN H A R M A C O L O G Y T A N D OXICO LOGY SeriesEditor Y. James Kang University ofLouisville School ofMedicine Prospect, Kentucky,USA For further volumes: http://www.springer.com/series/7653 Process Simulation and Data Modeling in Solid Oral Drug Development and Manufacture Edited by Marianthi G. Ierapetritou and Rohit Ramachandran Rutgers University, Piscataway, NJ, USA Editors MarianthiG.Ierapetritou RohitRamachandran RutgersUniversity RutgersUniversity Piscataway,NJ,USA Piscataway,NJ,USA ISSN1557-2153 ISSN1940-6053 (electronic) MethodsinPharmacologyandToxicology ISBN978-1-4939-2995-5 ISBN978-1-4939-2996-2 (eBook) DOI10.1007/978-1-4939-2996-2 LibraryofCongressControlNumber:2015949385 SpringerNewYorkHeidelbergDordrechtLondon #SpringerScience+BusinessMediaNewYork2016 Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpartofthematerialis concerned,specificallytherightsoftranslation,reprinting,reuseofillustrations,recitation,broadcasting,reproduction onmicrofilmsorinanyotherphysicalway,andtransmissionorinformationstorageandretrieval,electronicadaptation, computersoftware,orbysimilarordissimilarmethodologynowknownorhereafterdeveloped. Theuseofgeneraldescriptivenames,registerednames,trademarks,servicemarks,etc.inthispublicationdoesnot imply,evenintheabsenceofaspecificstatement,thatsuchnamesareexemptfromtherelevantprotectivelawsand regulationsandthereforefreeforgeneraluse. Thepublisher,theauthorsandtheeditorsaresafetoassumethattheadviceandinformationinthisbookarebelievedto betrueandaccurateatthedateofpublication.Neitherthepublishernortheauthorsortheeditorsgiveawarranty, expressorimplied,withrespecttothematerialcontainedhereinorforanyerrorsoromissionsthatmayhavebeenmade. Printedonacid-freepaper HumanaPressisabrandofSpringer SpringerScience+BusinessMediaLLCNewYorkispartofSpringerScience+BusinessMedia(www.springer.com) Preface The need for a more structured approach to process and product development has been recentlyidentifiedinthepharmaceuticalindustryinordertoconsistentlyguaranteequality and value to processes and products. This need has been formally identified by the pharmaceutical industry as the Quality by Design (QbD) initiative and has been in the center of attention over the last few years. To enable the implementation of this concept, thereisaneedforquantitativecharacterizationofprocessandproductperformance. Thegoalofthishandbookistoprovidepharmaceuticalengineerswithanintroduction tothecurrentstateoftheartinmodelingandsimulationofpharmaceuticalprocessesand to summarize a number of practical applications of such methodologies in drug product development. Chapters include reviews of the simulation and modeling methodologies, data collection and analysis, development of novel sensing techniques, development and integration of individual unit models, optimization approaches for data-based models, design space evaluation techniques, informatics-based methodologies, and emerging topicsinpharmaceuticalprocessdevelopment. The first chapter focuses on examples of more mechanistic models developed in pharmaceuticalmanufacturingandspecificallyaddressesthemodelingoffluidbedgranu- lation,tabletcoating,andspraydrying.Theimportanceoftheintegrationofsuchmodels inexistingmanufacturingworkstreamsishighlighted.Chapter2providesadetailedreview of Population Balance Models (PBM) as one of the most promising alternatives to represent particulate systems. The distributed nature of the PBM makes it an appropriate modelingframeworkforpharmaceuticalpowder-baseddrugmanufacturing. Materialpropertiesandhowtheyaffectproductandprocessperformancearediscussed in Chap. 3. In particular, specific properties of raw materials and the techniques used to measurethemaredescribed,andthestateoftheartofapplyingthisinformationtodefine productformulationisalsopresented. Chapter 4 reviews one of the most commonlyused mechanistic approaches to model particularsystems,whichisDiscreteElementMethod(DEM).Themainadvantageofthis approachisthatitcancapturemechanistic,particle-scaleinformationsuchasvelocityand collisionprofiles. In pharmaceutical manufacturing, it is important to establish the right procedures to guaranteetheconsistencyinprocessperformance.Chapter5reviewstheproceduresused forthedevelopmentofnearinfrared(NIR)spectroscopicmethodsanddescribesexamples ofthemostrecentlydevelopedapproachesbasedonpartialleastsquares(PLS)calibration methodsthatminimizethenumberofsamplesused.Followingtheideasonlatent-variable modeling techniques, Chap. 6 presents how those approaches can be used to support pharmaceuticaldevelopmentandmanufacturingactivities. Chapter7isdedicatedtocontrolstrategiesrequiredtosupporttheswitchfrombatch to continuous models of operations for the production of pharmaceutical products. A general methodology required to design and implement a control system is presented together withtherequiredsoftwareandhardwareofthecontrolplatform.Chapters8and 9focusontheimportanceofmathematicalmodelingforprocesssimulation,optimization, andthedevelopmentofthedesignspaceforpharmaceuticalprocessoperations.Inpartic- ular, Chap. 8 reviews the approaches that are used to define process feasibility and how v vi Preface those are applied for pharmaceutical manufacturing. Chapter 9 provides a review of the optimization methodologies that have been applied to achieve better performance in pharmaceutical manufacturing. Finally, Chapter 10 provides a very detailed step-by-step descriptionofthemanufacturingstagesinvolvedintheproductionofsoliddosageforms. Process analytical technology (PAT) devoted to the continuous manufacturing of solid- baseddrugsisalsodescribed. It is hoped that the collection of these papers will promote research into the process systemsmethodologiesandtheirapplicationinpharmaceuticalproductandprocessdevel- opment,whichwillundoubtedlybecomeanincreasinglyimportantareainthefuture. Piscataway,NJ,USA MarianthiG.Ierapetritou RohitRamachandran Contents Preface.................................................................... v Contributors............................................................... ix 1 ApplicationsofModelinginOralSolidDosageFormDevelopment andManufacturing .................................................... 1 OlavLyngberg,LieveBijnens,JeroenGeens,AlexMarchut, SteveMehrman,andElisabethSchafer 2 PopulationBalanceModelsforPharmaceuticalProcesses................... 43 AnweshaChaudhury,MaitrayeSen,DanaBarrasso, andRohitRamachandran 3 AQuantitativeApproachtoUnderstandRawMaterialVariability ........... 85 SaraKoynovandFernandoJ.Muzzio 4 DiscreteElementModelingofSolidDosageManufacturingProcesses....... 105 DanaBarrassoandRohitRamachandran 5 AProcedureforDevelopingQuantitativeNearInfrared(NIR) MethodsforPharmaceuticalProducts ................................... 133 RodolfoJ.Roman˜ach,Andre´sD.Roma´n-Ospino,andManelAlcala` 6 AdvancedProcessDecisionMakingUsingMultivariateLatent VariableMethods...................................................... 159 MatteoOttavian,EmanueleTomba,andMassimilianoBarolo 7 AdvancedControlofContinuousPharmaceuticalTablet ManufacturingProcesses ............................................... 191 RavendraSingh,CarlosVelazquez,AbhishekSahay, KriziaM.Karry,FernandoJ.Muzzio,MarianthiG.Ierapetritou, andRohitRamachandran 8 MathematicalToolsfor theQuantitativeDefinitionofaDesignSpace....... 225 AmandaRogersandMarianthiG.Ierapetritou 9 OptimizationMethodologiesfor theProductionofPharmaceutical Products ............................................................. 281 M.SebastianEscotet-Espinoza,AmandaRogers, andMarianthiG.Ierapetritou 10 AnOverviewofPharmaceuticalManufacturingforSolidDosageForms ..... 311 StephanSacherandJohannesG.Khinast Index..................................................................... 385 vii Contributors MANELALCALA` (cid:1) GrupdeQuimiometrı´aAplicada,DepartamentdeQuı´mica,Unitatde Quı´micaAnalı´tica,UniversitatAuto`nomadeBarcelona,Bellaterra,Barcelona,Spain MASSIMILIANO BAROLO (cid:1) Computer-AidedProcessEngineeringLaboratory(CAPE-Lab), DepartmentofIndustrialEngineering,UniversityofPadova,Padova,PD,Italy DANABARRASSO (cid:1) DepartmentofChemicalandBiochemicalEngineering,Rutgers,The StateUniversityofNewJersey,Piscataway,NJ,USA LIEVEBIJNENS (cid:1) PharmaceuticalDevelopmentandManufacturingSciences,Janssen Pharmaceuticals,Beerse,Belgium ANWESHACHAUDHURY (cid:1) DepartmentofChemicalandBiochemicalEngineering,Rutgers, TheStateUniversityofNewJersey,Piscataway,NJ,USA M.SEBASTIANESCOTET-ESPINOZA (cid:1) DepartmentofChemicalandBiochemicalEngineering, Rutgers,TheStateUniversityofNewJersey,Piscataway,NJ,USA JEROENGEENS (cid:1) PharmaceuticalDevelopmentandManufacturingSciences,Janssen Pharmaceuticals,Beerse,Belgium MARIANTHIG.IERAPETRITOU (cid:1) DepartmentofChemicalandBiochemicalEngineering, EngineeringResearchCenter forStructuredOrganicParticulateSystems(ERC-SOPS), Rutgers,TheStateUniversityofNewJersey,Piscataway,NJ,USA KRIZIAM.KARRY (cid:1) DepartmentofChemicalandBiochemicalEngineering,Engineering ResearchCenter forStructuredOrganicParticulateSystems(ERC-SOPS),Rutgers,The StateUniversityofNewJersey,Piscataway,NJ,USA JOHANNESG.KHINAST (cid:1) ResearchCenter forPharmaceuticalEngineering(RCPE),Graz, Austria;InstituteforProcessandParticleEngineering,GrazUniversityofTechnology, Graz,Austria SARAKOYNOV (cid:1) DepartmentofChemicalandBiochemicalEngineering,Engineering ResearchCenter forStructuredOrganicParticulateSystems(ERC-SOPS),Rutgers,The StateUniversityofNewJersey,Piscataway,NJ,USA OLAVLYNGBERG (cid:1) JanssenSupplyChain,TechnicalOperations,JanssenPharmaceuticals, Raritan,NJ,USA ALEXMARCHUT (cid:1) JanssenSupplyChain,TechnicalOperations,JanssenPharmaceuticals, Raritan,NJ,USA STEVE MEHRMAN (cid:1) PharmaceuticalDevelopmentandManufacturingSciences,Janssen Pharmaceuticals,Beerse,Belgium FERNANDOJ.MUZZIO (cid:1) DepartmentofChemicalandBiochemicalEngineering, EngineeringResearchCenter forStructuredOrganicParticulateSystems(ERC-SOPS), Rutgers,TheStateUniversityofNewJersey,Piscataway,NJ,USA MATTEOOTTAVIAN (cid:1) ManufacturingScience&Technology,SandozIndustrialProducts S.p.A.,Rovereto,TN,Italy ROHITRAMACHANDRAN (cid:1) DepartmentofChemicalandBiochemicalEngineering, EngineeringResearchCenter forStructuredOrganicParticulateSystems(ERC-SOPS), Rutgers,TheStateUniversityofNewJersey,Piscataway,NJ,USA AMANDAROGERS (cid:1) DepartmentofChemicalandBiochemicalEngineering,Rutgers,The StateUniversityofNewJersey,Piscataway,NJ,USA ix