Chemical Engineering in the Pharmaceutical Industry: R&D to Manufacturing

876 Pages·2010·73.8 MB·English

CHEMICAL ENGINEERING IN THE
PHARMACEUTICAL INDUSTRY
CHEMICAL ENGINEERING IN THE
PHARMACEUTICAL INDUSTRY
R&D to Manufacturing
Editedby
DAVID J. AM ENDE
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LibraryofCongressCataloging-in-PublicationData:
Chemicalengineeringinthepharmaceuticalindustry:R&Dtomanufacturing/editedbyDavidJ.amEnde.
p.cm.
Includesindex.
ISBN978-0-470-42669-2(cloth)
1. Pharmaceuticaltechnology.2. Biochemicalengineering.3. Chemicalengineering. I.Ende,DavidJ.am.
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