CHEMICAL ENGINEERING IN THE PHARMACEUTICAL INDUSTRY CHEMICAL ENGINEERING IN THE PHARMACEUTICAL INDUSTRY R&D to Manufacturing Editedby DAVID J. AM ENDE Copyright(cid:1)2011JohnWiley&Sons,Inc.Allrightsreserved. PublishedbyJohnWiley&Sons,Inc.,Hoboken,NewJersey PublishedsimultaneouslyinCanada Nopartofthispublicationmaybereproduced,storedinaretrievalsystem,ortransmittedinanyformorbyanymeans,electronic,mechanical, photocopying,recording,scanning,orotherwise,exceptaspermittedunderSection107or108ofthe1976UnitedStatesCopyrightAct,withouteither thepriorwrittenpermissionofthePublisher,orauthorizationthroughpaymentoftheappropriateper-copyfeetotheCopyrightClearanceCenter,Inc., 222RosewoodDrive,Danvers,MA01923,(978)750-8400,fax(978)750-4470,oronthewebatwww.copyright.com.RequeststothePublisherfor permissionshouldbeaddressedtothePermissionsDepartment,JohnWiley&Sons,Inc.,111RiverStreet,Hoboken,NJ07030,(201)748-6011, fax(201)748-6008,oronlineathttp://www.wiley.com/go/permission. 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RS192.C5252010 6150.19–dc22 2010013146 PrintedintheUnitedStatesofAmerica 10 9 8 7 6 5 4 3 2 1 CONTENTS PREFACE ix CONTRIBUTORS xi CONVERSIONTABLE xv PART I INTRODUCTION 1 1 ChemicalEngineering inthe Pharmaceutical Industry:An Introduction 3 DavidJ.amEnde 2 Current Challenges and Opportunities inthe Pharmaceutical Industry 21 JosephL.KukuraandMichaelPaulThien 3 ChemicalEngineering Principles in Biologics:Unique Challenges and Applications 29 SouravKundu,VivekBhatnagar,NaveenPathak,andCenkUndey 4 Designing a Sustainable Pharmaceutical Industry:The Role of Chemical Engineers 57 Concepcio´nJim(cid:1)enez-Gonz(cid:1)alez,CeliaS.Ponder,RobertE.Hannah,andJamesR.Hagan 5 Scientific OpportunitiesThrough Quality by Design 67 TimothyJ.WatsonandRogerNosal PART II ACTIVE PHARMACEUTICAL INGREDIENT (API) 71 6 The Role of Chemical Engineering in Pharmaceutical API Process R&D 73 EdwardL.Paul 7 Reaction Kinetics and Characterization 79 UtpalK.SinghandCharlesJ.Orella v vi CONTENTS 8 Understanding Rate Processes inCatalytic Hydrogenation Reactions 101 YongkuiSunandCarlLeBlond 9 Characterization and FirstPrinciples Prediction of API Reaction Systems 113 JoeHannon 10 Modeling, Optimization, and Applicationsof Kinetic Mechanisms with OpenChem 137 JohnE.Tolsma,BrianSimpson,TaeshinPark,andJasonMustakis 11 ProcessSafetyandReaction Hazard Assessment 155 WimDermaut 12 Design ofDistillation and Extraction Operations 183 EricM.Cordi 13 CrystallizationDesignand Scale-Up 213 RobertRahnMcKeown,JamesT.Wertman,andPhilipC.Dell’Orco 14 Scale-Upof Mixing Processes: APrimer 249 FrancisX.McConvilleandStephenB.Kessler 15 Stirred Vessels: Computational Modeling ofMultiphase Flows and Mixing 269 AvinashR.KhopkarandVivekV.Ranade 16 Membrane Systems for Pharmaceutical Applications 299 DimitriosZarkadasandKamaleshK.Sirkar 17 Design ofFiltrationand DryingOperations 315 SaravanababuMurugesan,PraveenK.Sharma,andJoseE.Tabora 18 The Design and Economicsof Large-Scale ChromatographicSeparations 347 FirozD.Antia 19 Milling Operationsin the Pharmaceutical Industry 365 KevinD.Seibert,PaulC.Collins,andElizabethFisher 20 ProcessScale-Up and Assessment 379 AlanD.Braem,JasonT.Sweeney,andJeanW.Tom 21 Scale-UpDos and Don’ts 407 FrancisX.McConville 22 Kilo Lab and Pilot Plant Manufacturing 417 JasonC.Hamm,MelanieM.Miller,ThomasRamsey,RichardL.Schild,AndrewStewart,andJeanW.Tom 23 ProcessDevelopment and Case Studies ofContinuous Reactor Systems for Production ofAPI and Pharmaceutical Intermediates 437 ThomasL.LaPorte,ChenchiWang,andG.ScottJones 24 Drug Solubilityand Reaction Thermodynamics 457 KarinWichmannandAndreasKlamt CONTENTS vii 25 Thermodynamics and Relative SolubilityPrediction ofPolymorphic Systems 477 YuriyA.AbramovandKlimentinaPencheva 26 Toward a RationalSolvent Selection for Conformational Polymorph Screening 491 YuriyA.Abramov,MarkZell,andJosephF.Krzyzaniak 27 MolecularThermodynamics for Pharmaceutical ProcessModelingandSimulation 505 Chau-ChyunChen 28 The Role of Simulation andScheduling Tools inthe Development and Manufacturing ofActivePharmaceutical Ingredients 521 DemetriPetrides,AlexandrosKoulouris,CharlesSiletti,Jos(cid:1)eO.Jim(cid:1)enez,andPericlesT.Lagonikos PART III ANALYTICAL METHODS AND APPLIEDSTATISTICS 543 29 Quality by Design for Analytical Methods 545 TimothyW.Graul,KimberL.Barnett,SimonJ.Bale,ImogenGill,andMelissaHanna-Brown 30 Analytical Chemistry for API ProcessEngineering 563 MatthewL.Jorgensen 31 QuantitativeApplicationsof NMR Spectroscopy 581 BrianL.MarquezandR.ThomasWilliamson 32 ExperimentalDesign for Pharmaceutical Development 597 GregoryS.Steeno 33 Multivariate Analysisfor Pharmaceutical Development 621 FrederickH.Long PART IV DRUGPRODUCTS 633 34 Process Modeling Techniques and Applications for Solid OralDrug Products 635 MaryT.amEnde,RahulBharadwaj,SalvadorGarc´ıa-Mun˜oz,WilliamKetterhagen,AndrewPrpich, andPankajDoshi 35 Process Design and Development for NovelPharmaceutical Dosage Forms 663 LeahAppel,JoshuaShockey,MatthewShaffer,andJenniferChu 36 Design of Solid DosageFormulations 673 KevinJ.Bittorf,TapanSanghvi,andJeffreyP.Katstra 37 Controlled Release Technology and Design ofOralControlled ReleaseDosage Forms 703 AvinashG.Thombre,MaryT.amEnde,andXiaoYu(Shirley)Wu 38 Design and Scale-Up of Dry Granulation Processes 727 OmarL.SprockelandHowardJ.Stamato 39 Wet Granulation Processes 757 KarenP.HapgoodandJamesD.Litster viii CONTENTS 40 Spray AtomizationModelingfor Tablet Film Coating Processes 781 AlbertoAliseda,AlfredBerchielli,PankajDoshi,andJuanC.Lasheras 41 The Freeze-Drying Process:The Use of MathematicalModelingin ProcessDesign, Understanding, and Scale-Up 801 VenkatKoganti,SumitLuthra,andMichaelJ.Pikal 42 Achievinga Hot Melt Extrusion DesignSpace for the Productionof Solid Solutions 819 LukeSchenck,GregoryM.Troup,MikeLowinger,LiLi,andCraigMcKelvey 43 Continuous Processing in Secondary Production 837 MartinWarman 44 Pharmaceutical Manufacturing:The Role ofMultivariate Analysisin Design Space, Control Strategy, Process Understanding, Troubleshooting,and Optimization 853 TheodoraKourti INDEX 879 PREFACE Chemical Engineering in the Pharmaceutical Industry is including API and DP process design, scale-up assessment uniqueinmanywaystowhatistraditionallytaughtinschools from laboratory to plant, process modeling, process under- ofchemicalengineering.Thisbookisthereforeintendedto standing, and general process development that ultimately covermanyimportantconceptsandapplicationsofchemical reduces cost and ensures safe, robust, and environmentally engineering science that are particularly important to the friendly processes are transferred to manufacturing. How PharmaceuticalIndustry.Therehavebeenseveralexcellent effective the teams leverage each of the various skill sets bookswrittenrecentlyonthesubjectsofprocesschemistryin (i.e.,viaresourceallocation)toarriveatanoptimalprocess the pharmaceutical industry and separately on formulation depends in part on the roles and responsibilities as deter- development,butrelativelylittlehasbeenpublishedspecif- minedwithineachorganizationandcompany.Ingeneral,itis icallywithafocus onchemical engineering. clear that with increased cost pressures facing the pharma- The intention of the book is to highlight the importance ceuticalindustry,includingR&Dandmanufacturing,oppor- and value of chemical engineering to the development and tunitiestoleveragethefieldofchemicalengineeringscience commercializationofpharmaceuticalscoveringactivephar- continue to increase. Indeed I have observed a significant maceuticalingredient(API)anddrugproduct(DP)aswellas increase in chemical engineering emphasis in API process analytical methods. It should serve as a resource for prac- developmentwithinPfizeroverthe15yearssinceIjoinedthe ticingchemical engineersaswell asfor chemists,analysts, companyand especiallyin the past 5years. technologists, and operations and management team This book is divided into four main parts: members—all those who partner to bring pharmaceuticals successfully to market. The latter will benefit through an (1) Introduction exposure to the mathematical and predictive approach and (2) ActivePharmaceutical Ingredient (API) thebroadercapabilitiesofchemicalengineersandalsobythe (3) Analytical Methods and Applied Statistics illustrationofchemicalengineeringscienceasappliedspe- (4) Drug Product(DP) cificallytopharmaceuticalproblems.Thisbookemphasizes boththeneedforscientificintegrationofchemicalengineers The introductory chapters span roles and opportunities withsyntheticorganicchemistswithinprocessR&Dandthe for chemical engineering in small-molecule API, biologi- importance of the interface between R&D engineers and cals, drug products,as well asenvironmental sustainability manufacturingengineers.Theimportanceofanalyticalche- and quality by design (QbD) concepts. The Active Phar- mists and other scientific disciplines necessary to deliver maceuticalIngredient partconsists of23chapterscovering pharmaceuticalstothemarketplaceisalsoemphasizedwith chemical engineering principles applied to pharmaceutical chapters dedicatedtoselected topics. specific unit operations (reaction engineering, crystalliza- Although specific workflows for engineers in R&D de- tion, chromatography, filtration, drying, etc.) as well as pendoneachcompany’sspecificorganization,ingeneralit pilot plant and scale-up manufacturing assessment chap- is clear that, as part of a multidisciplinary team in R&D, ters, including process safety. Process modeling promises chemicalengineeringpractitionersoffervalueinmanyways ix x PREFACE to have significant payback as more in silico screening There are many people to thank who made this work enables process design to be performed with fewer possible. First, I would like to thank all the contributors of resources (for selection process conditions/optimization, thisbook.IalsowouldliketothankmycolleaguesatPfizer solubility, distillation, and extraction design, etc.). Several for writing many of the chapters and for my management chapters are devoted to process modeling with emphasis (past and present) who encouraged and made this effort on several of the software tools currently available. The possible and who continue to encourage the role of chem- section on drug product includes formulation chapters as ical engineering in chemical R&D and pharmaceutical well as chapters highlighting unit operations specific to sciences. drug product (wet granulation, dry granulation, extrusion, Special thanks to my family (Mary, Nathan, Noah, and controlled release, and lyophilization). In addition, process Brianna) for their support during the preparation of this modeling within drug product chapter describes the var- book. Special thanks to Mary, not only for contributing ious modeling approaches used to understand and predict two chapters to this book but also for her assistance in all performance of powder blending, mixing, tablet presses, phases of the project including the cover art. Finally, a tablet coating, and so on. The Analytical Methods and special thanks to my parents for their encouragement to Applied Statistics part describes important topics on pursue chemical engineering in 1983 and their support chemometrics, statistics, and analytical methods applied throughmyattendanceattheUniversityofIowaandPurdue toward chemical engineering problems (e.g., material bal- University. ance, kinetics, design of experiments, or quality by design for analytical methods). DAVIDJ. AMENDE, PH.D. Thecontributorswereencouragedtoprovideworkedout examples—so in most chapters a quantitative example is ChemicalR&D offered to illustrate key concepts and problem-solving Pfizer,Inc. Groton,CT approaches.Inthisway,thechapterswillservetohelpothers January2010 solvesimilar problems. CONTRIBUTORS Yuriy A. Abramov, Pfizer Global Research & Develop- Jennifer Chu, Pharmaceutical Sciences, Neurogen Corp- ment,Pharmaceutical Sciences, Groton, CT, USA oration, Branford,CT, USA Alberto Aliseda, Department of Mechanical Engineering, PaulC. Collins, Eli Lilly & Co., Indianapolis, IN, USA Universityof Washington,Seattle, WA, USA Eric M. Cordi, Chemical Research and Development, David J. am Ende, Chemical R&D, Pfizer, Inc., Groton, Pfizer Inc., Groton,CT, USA CT, USA Philip C. Dell’Orco, Chemical Development, Glaxo- Mary T. am Ende, Pharmaceutical Development, Pfizer SmithKline, King ofPrussia, PA, USA Global Research &Development, Groton, CT,USA WimDermaut, ProcessSafetyCenter,APISmallMolecule Firoz D. Antia, Product Development, Palatin Techno- Development, Johnson and Johnson Pharmaceutical logies,Inc., Cranbury, NJ, USA Research and Development, Beerse, Belgium Leah Appel, Green Ridge Consulting, Bend, OR, USA PankajDoshi, ChemicalEngineeringandProcessDivision, National Chemical Laboratory,Pune,India Simon J. Bale, Pfizer Global Research & Development, Sandwich, Kent, UK Elizabeth Fisher, Merck& Co., Inc., Rahway, NJ, USA Kimber L. Barnett, Pfizer Global Research & Develop- Salvador Garc´ıa-Mun˜oz, Pharmaceutical Development, ment,Groton, CT,USA PfizerGlobalResearch&Development,Groton,CT,USA Alfred Berchielli, Pharmaceutical Development, Pfizer Imogen Gill, Pfizer Global Research & Development, worldwide Research &Development,Groton, CT, USA Sandwich, Kent, UK Rahul Bharadwaj, Pharmaceutical Development, Pfizer Timothy W. Graul, Pfizer Global Research & Develop- Global Research &Development, Groton, CT,USA ment, Groton, CT, USA VivekBhatnagar, ProcessDevelopment,AmgenInc.,West James R. Hagan, GlaxoSmithKline, Sustainability and Greenwich, RI, USA Environment, 1 FranklinPlaza, Philadelphia, PA,USA Kevin J. Bittorf, Formulation Development, Vertex Jason Hamm, Process Research & Development, Bristol- Pharmaceuticals Inc., Cambridge,MA, USA Myers Squibb Co., New Brunswick,NJ, USA AlanD.Braem, ProcessResearch&Development,Bristol- Melissa Hanna-Brown, Pfizer Global Research & Devel- Myers Squibb Co.,NewBrunswick, NJ, USA opment, Sandwich,Kent, UK Chau-Chyun Chen, Aspen Technology, Inc., Burlington, Robert E. Hannah, GlaxoSmithKline, Sustainability and MA, USA Environment, Philadelphia,PA,USA xi