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by Mary T. am Ende, David J. am Ende
Chemical Engineering in the Pharmaceutical Industry, Active Pharmaceutical Ingredients, 2nd Edition
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LIST OF CONTRIBUTORS
PREFACE
UNIT CONVERSIONS
REFERENCES
PART I: INTRODUCTION
1 CHEMICAL ENGINEERING IN THE PHARMACEUTICAL INDUSTRY: AN INTRODUCTION
1.1 GLOBAL IMPACT OF THE INDUSTRY
1.2 INVESTMENTS IN PHARMACEUTICAL R&D
1.3 BEST SELLERS
1.4 PHARMACEUTICAL RESEARCH AND DEVELOPMENT EXPENDITURES
1.5 RECENT TRENDS FOR PHARMACEUTICAL DRUG AND MANUFACTURING
1.6 CHEMICAL ENGINEERS SKILLED TO IMPACT FUTURE OF PHARMACEUTICAL INDUSTRY
REFERENCES
2 CURRENT CHALLENGES AND OPPORTUNITIES IN THE PHARMACEUTICAL INDUSTRY
2.1 INTRODUCTION
2.2 INDUSTRY‐WIDE CHALLENGES
2.3 OPPORTUNITIES FOR CHEMICAL ENGINEERS
2.4 PROSPECTS FOR CHEMICAL ENGINEERS
REFERENCES
PART II: MASS AND ENERGY BALANCES
3 PROCESS SAFETY AND REACTION HAZARD ASSESSMENT
3.1 INTRODUCTION
3.2 GENERAL CONCEPTS
3.3 STUDYING THE DESIRED SYNTHESIS REACTION AT LAB SCALE
3.4 SCALE‐UP OF THE DESIRED REACTION
3.5 STUDYING THE DECOMPOSITION REACTION AT LAB SCALE
3.6 REACTIVE WASTE
3.7 CONTINUOUS PROCESSING
3.8 OTHER POINTS TO CONSIDER
REFERENCES
4 CALORIMETRIC APPROACHES TO CHARACTERIZING UNDESIRED REACTIONS
4.1 INTRODUCTION
4.2 BACKGROUND
4.3 THERMAL STABILITY SCREENING: DIFFERENTIAL SCANNING CALORIMETRY (DSC)
4.4 PRESSURE SCREENING OF DECOMPOSITIONS: TECHNIQUES
4.5 HAZARD SCENARIOS
4.6 CASE STUDY 1: REACTION IN DIMETHYL SULFOXIDE (DMSO)
4.7 CASE STUDY 2: CONTINUOUS GAS GENERATION IN A WASTE STREAM CONTAINING CARBONATE
4.8 CASE STUDY 3: EVALUATING A FUNCTIONAL GROUP
4.9 CASE STUDY 4: USE OF THERMAL AND PRESSURE SCREENING TOOLS TO ASSESS AN mCPBA SOLUTION
4.10 NOTATIONS
ACKNOWLEDGMENTS
REFERENCES
5 CASE STUDY OF A BORANE–THF EXPLOSION
5.1 INTRODUCTION
5.2 BACKGROUND
5.3 INVESTIGATION
5.4 ARC DATA OF BTHF FROM AN ADJACENT CYLINDER
5.5 TEMPERATURE HISTORY OF THE BORANE–THF CYLINDERS
5.6 HEAT LOSS MEASUREMENTS
5.7 THERMAL STABILITY OF FRESH 2M BORANE–THF
5.8 KINETICS OF DECOMPOSITION
5.9 CONCLUSIONS
ACKNOWLEDGMENTS
5.A BORON NMR KINETIC DATA FROM FIGURE 5.13
5.B CALIBRATION FOR PHI FOR ARC ANALYSIS
REFERENCES
6 ANALYTICAL ASPECTS FOR DETERMINATION OF MASS BALANCES
6.1 INTRODUCTION
6.2 THE USE OF ANALYTICAL METHODS APPLIED TO ENGINEERING
6.3 METHODS USED AND BACKGROUND
6.4 THINGS TO WATCH OUT FOR IN LC AND GC
6.5 USE OF MULTIPLE ANALYTICAL TECHNIQUES
6.6 CONCLUSION
REFERENCES
7 QUANTITATIVE APPLICATIONS OF NMR SPECTROSCOPY
7.1 INTRODUCTION
7.2 ONE‐DIMENSIONAL NMR METHODS
7.3 TWO‐DIMENSIONAL NMR METHODS
7.4 QUANTITATIVE NMR SPECTROSCOPY (qNMR)
REFERENCES
PART III: REACTION KINETICS AND MIXING PROCESSES
8 REACTION KINETICS AND CHARACTERIZATION
8.1 INTRODUCTION
8.2 FUNDAMENTALS OF CHEMICAL REACTION KINETICS
8.3 METHODS FOR THE CHARACTERIZATION OF CHEMICAL KINETICS
8.4 TRANSFORMING EXPERIMENTAL DATA INTO A KINETIC MODEL
8.5 EMERGING AREAS FOR INNOVATION AND IMPLEMENTATION
8.6 CONCLUSIONS
8.7 QUESTIONS
REFERENCES
9 UNDERSTANDING FUNDAMENTAL PROCESSES IN CATALYTIC HYDROGENATION REACTIONS
9.1 INTRODUCTION
9.2 SOLUTION HYDROGEN CONCENTRATION DURING HYDROGENATION REACTIONS, [H2]
9.3 IMPACT OF kLa ON REACTION KINETICS AND SELECTIVITY
9.4 CHARACTERIZATION OF GAS–LIQUID MASS TRANSFER PROCESS
9.5 CHARACTERIZATION OF CATALYST REDUCTION PROCESS
9.6 BASIC SCALE‐UP STRATEGY FOR HYDROGENATION PROCESSES
9.7 SUMMARY
ACKNOWLEDGMENTS
REFERENCES
10 CHARACTERIZATION AND FIRST PRINCIPLES PREDICTION OF API UNIT OPERATIONS
10.1 INTRODUCTION
10.2 BATCH PROCESSES WITH HOMOGENEOUS REACTIONS
10.3 MULTIPHASE BATCH PROCESSES WITH REACTIONS
10.4 FED‐BATCH PROCESSES WITH REACTIONS
10.5 APPLICATION TO CONTINUOUS FLOW SYSTEMS
10.6 EQUIPMENT CHARACTERIZATION AND ASSESSMENT
10.7 MODEL VERIFICATION STATISTICS
10.8 NOTATIONS
REFERENCES
11 SCALE‐UP OF MASS TRANSFER‐LIMITED REACTIONS: FUNDAMENTALS AND A CASE STUDY
11.1 INTRODUCTION
11.2 MASS TRANSFER IN A SOLID–LIQUID SYSTEM WITHOUT REACTION
11.3 MASS TRANSFER WITH CHEMICAL REACTION
11.4 CASE STUDY: SCALING OF A MASS TRANSFER‐LIMITED REACTION
11.5 NOTATIONS
ACKNOWLEDGMENTS
REFERENCES
12 SCALE‐UP OF MIXING PROCESSES: A PRIMER
12.1 INTRODUCTION
12.2 BASIC APPROACHES TO MIXING SCALE‐UP
12.3 OTHER CONSIDERATIONS IN MIXING SCALE‐UP
12.4 COMMON MIXING EQUIPMENT
12.5 SCALE‐UP OF CHEMICAL REACTIONS
12.6 CFD AND OTHER MODELING TECHNIQUES
12.7 NOTATIONS
REFERENCES
13 STIRRED VESSELS: COMPUTATIONAL MODELING OF MULTIPHASE FLOWS AND MIXING*
13.1 ENGINEERING OF MULTIPHASE STIRRED REACTORS
PART I: COMPUTATIONAL MODELING OF MULTIPHASE FLOWS IN STIRRED VESSELS
13.2 COMPUTATIONAL MODELING OF MULTIPHASE STIRRED REACTOR
PART II: APPLICATION TO MIXING IN STIRRED VESSELS
13.3 APPLICATION TO ENGINEERING OF STIRRED VESSELS
13.4 SUMMARY AND PATH FORWARD
13.5 NOTATIONS
REFERENCES
PART IV: CONTINUOUS PROCESSING
14 PROCESS DEVELOPMENT AND CASE STUDIES OF CONTINUOUS REACTOR SYSTEMS FOR PRODUCTION OF API AND PHARMACEUTICAL INTERMEDIATES
14.1 INTRODUCTION
14.2 BENEFITS OF CONTINUOUS PROCESSING
14.3 CONTINUOUS REACTOR AND ANCILLARY SYSTEMS CONSIDERATIONS
14.4 PROCESS DEVELOPMENT OF THE CONTINUOUS REACTION
14.5 SCALE‐UP: VOLUMETRIC VERSUS NUMBERING UP
14.6 PLANT OPERATIONS
14.7 CASE STUDY: CONTINUOUS DEPROTECTION REACTION – LAB TO KILO LAB SCALE‐UP
14.8 CASE STUDY: CONTINUOUS PRODUCTION OF A CYCLOPROPONATING REAGENT
14.9 INTEGRATED CONTINUOUS PROCESSING IN PHARMA
14.10 BARRIERS TO IMPLEMENTATION OF CONTINUOUS PROCESSING IN PHARMA
14.11 SUMMARY
REFERENCES
15 DEVELOPMENT AND APPLICATION OF CONTINUOUS PROCESSES FOR THE INTERMEDIATES AND ACTIVE PHARMACEUTICAL INGREDIENTS
15.1 INTRODUCTION
15.2 VALUE OF CONTINUOUS PROCESSES FOR THE PHARMACEUTICAL INDUSTRY
15.3 CONTINUOUS PROCESS DEVELOPMENT WORKFLOW
15.4 CONTINUOUS TECHNOLOGY
15.5 PROCESS DESIGN METHODOLOGY FOR ORGANOMETALLIC CHEMISTRY IN CONTINUOUS: FROM R&D TO MANUFACTURE
REFERENCES
16 DESIGN AND SELECTION OF CONTINUOUS REACTORS FOR PHARMACEUTICAL MANUFACTURING
16.1 DRIVERS FOR CONTINUOUS REACTIONS IN DRUG SUBSTANCE MANUFACTURING
16.2 TWO MAIN CATEGORIES OF CONTINUOUS REACTORS: PFRs AND CSTRs
16.3 EXAMPLE OF COILED TUBE PFR FOR TWO‐PHASE GAS–LIQUID REACTIONS
16.4 EXAMPLE OF CSTR FOR GRIGNARD FORMATION REACTION WITH SEQUESTERED Mg SOLIDS
16.5 NUMERICAL MODELING TO SELECT THE BEST REACTOR TYPE FOR MINIMIZING IMPURITIES
16.6 WHAT CAN BE DONE BATCH BEFORE RUNNING CONTINUOUS REACTION EXPERIMENTS?
16.7 WHAT IS DIFFICULT TO PREDICT FROM BATCH EXPERIMENTS?
ACKNOWLEDGMENTS
REFERENCES
PART V: BIOLOGICS
17 CHEMICAL ENGINEERING PRINCIPLES IN BIOLOGICS: UNIQUE CHALLENGES AND APPLICATIONS
17.1 WHY ARE BIOLOGICS UNIQUE FROM A MASS, HEAT, AND MOMENTUM TRANSFER STANDPOINT?
17.2 SCALE‐UP APPROACHES AND ASSOCIATED CHALLENGES IN BIOLOGICS MANUFACTURING
17.3 CHALLENGES IN LARGE‐SCALE PROTEIN MANUFACTURING
17.4 SPECIALIZED APPLICATIONS OF CHEMICAL ENGINEERING CONCEPTS IN BIOLOGICS MANUFACTURING
17.5 CONCLUSIONS
REFERENCES
PART VI: THERMODYNAMICS
18 APPLICATIONS OF THERMODYNAMICS TOWARD PHARMACEUTICAL PROBLEM SOLVING
18.1 INTRODUCTION
18.2 DESOLVATION OF PARECOXIB SODIUM
18.3 SOLID FORM CONTROL OF PARITAPREVIR
18.4 SCALABLE SOLUTION CYRYSTALLIZATION OF CO‐CRYSTALS
18.5 THERMODYNAMICS OF COATING PROCESS DURING THE MANUFACTURE OF DRUG‐ELUTING BIORESORBABLE VASCULAR SCAFFOLD
18.6 POLYMER–PLASTICIZER MIXING PERFORMANCE IN THE PRESENCE OF WATER
REFERENCES
19 A GENERAL FRAMEWORK FOR SOLID–LIQUID EQUILIBRIA IN PHARMACEUTICAL SYSTEMS
19.1 INTRODUCTION
19.2 THERMODYNAMIC FUNDAMENTALS FOR SOLUBILITY CALCULATIONS
19.3 THE SAFT‐γ MIE GROUP CONTRIBUTION EoS
19.4 SYSTEM CHARACTERIZATION FOR SOLUBILITY CALCULATIONS
19.5 ILLUSTRATIVE EXAMPLES
19.6 DISCUSSION
19.7 CONCLUSIONS
19.A USING FORMATION PROPERTIES IN THE INFINITE DILUTION STATE
19.B SAFT‐γ MIE FUNCTIONAL GROUP DECOMPOSITION
REFERENCES
20 DRUG SOLUBILITY, REACTION THERMODYNAMICS, AND CO‐CRYSTAL SCREENING
20.1 INTRODUCTION
20.2 SOLUBILITY PREDICTION WITH COSMO‐RS
20.3 CHEMICAL REACTIONS IN SOLUTION
20.4 SCREENING OF CO‐CRYSTALS
20.5 CONCLUSION AND OUTLOOK
20.A DETAILS OF COSMO AND GAS‐ PHASE CALCULATIONS
20.B STEPS FOR CALCULATING THE FREE ENERGY OR ENTHALPY OF A COMPOUND
ABBREVIATIONS
SYMBOLS
REFERENCES
21 THERMODYNAMIC MODELING OF AQUEOUS AND MIXED SOLVENT ELECTROLYTE SYSTEMS
21.1 INTRODUCTION
21.2 MODELING THERMODYNAMIC PROPERTIES OF ELECTROLYTE SOLUTIONS
21.3 ELECTROLYTE THERMODYNAMIC MODELS
21.4 EXAMPLES: MODELING WITH eNRTL
21.5 ONGOING DEVELOPMENTS
21.6 CONCLUDING REMARKS
REFERENCES
22 THERMODYNAMICS AND RELATIVE SOLUBILITY PREDICTION OF POLYMORPHIC SYSTEMS
22.1 INTRODUCTION
22.2 METHODS
22.3 RESULTS AND DISCUSSION
22.4 APPLICATION TO AN ESTIMATION OF LIKELY IMPACT ON DRUG SOLUBILITY BY UNKNOWN MORE STABLE FORM
22.5 CONCLUSION
22.A PROPAGATION OF ERRORS OF THE SOLUBILITY RATIO MEASUREMENTS
22.B SUMMARY OF EXPLICIT EQUATIONS USED FOR THE SOLUBILITY RATIO PREDICTIONS
ACKNOWLEDGMENTS
REFERENCES
23 TOWARD A RATIONAL SOLVENT SELECTION FOR CONFORMATIONAL POLYMORPH SCREENING
23.1 INTRODUCTION
23.2 METHODS
23.3 RESULTS AND DISCUSSION
23.4 CONCLUSIONS
ACKNOWLEDGMENTS
REFERENCES
PART VII: CRYSTALLIZATION AND FINAL FORM
24 CRYSTALLIZATION DESIGN AND SCALE‐UP
24.1 INTRODUCTION
24.2 CRYSTALLIZATION DESIGN OBJECTIVES AND CONSTRAINTS
24.3 SOLUBILITY ASSESSMENT AND PRELIMINARY SOLVENT SELECTION
24.4 CRYSTALLIZATION KINETICS AND PROCESS SELECTION
24.5 APPLICATION OF SOLUBILITY AND KINETICS DATA TO CRYSTALLIZATION MODES
24.6 ADVANCED TOPICS
REFERENCES
25 INTRODUCTION TO CHIRAL CRYSTALLIZATION IN PHARMACEUTICAL DEVELOPMENT AND MANUFACTURING
25.1 TERNARY PHASE DIAGRAMS
25.2 TERNARY PHASE DIAGRAMS OF CHIRAL SYSTEMS CONTAINING SOLIDS
25.3 EXPERIMENTAL CHARACTERIZATION OF CHIRAL SYSTEMS
25.4 CHIRAL ANALYTICAL METHODS IN PHARMACEUTICAL DEVELOPMENT
25.5 PROCESS DESIGN OF CHIRAL CRYSTALLIZATIONS
25.6 SUMMARY AND CONCLUSIONS
ACKNOWLEDGMENT
REFERENCES
26 MEASUREMENT OF SOLUBILITY AND ESTIMATION OF CRYSTAL NUCLEATION AND GROWTH KINETICS
26.1 INTRODUCTION
26.2 SOLUBILITY
26.3 ESTIMATION OF NUCLEATION AND GROWTH KINETICS
26.4 SUMMARY
ACKNOWLEDGMENT
REFERENCES
27 CASE STUDIES ON CRYSTALLIZATION SCALE‐UP
27.1 INTRODUCTION
27.2 CASE STUDY I: DESIGNING SHEAR EXPOSURE TO ACHIEVE SIMILAR BREAKAGE/ATTRITION ACROSS SCALES
27.3 CASE STUDY II: TAILORING MIXING TO ACHIEVE DESIRED CRYSTAL FORM AND PARTICLE SIZE DISTRIBUTION
27.4 CASE STUDY III: SCALE‐UP CONSIDERATIONS FOR ANTISOLVENT ADDITION INTO A RECIRCULATION LOOP
27.5 CASE STUDY IV: MORPHOLOGY CONTROL IN A REACTIVE CRYSTALLIZATION
ACKNOWLEDGMENT
REFERENCES
28 POPULATION BALANCE‐ENABLED MODEL FOR BATCH AND CONTINUOUS CRYSTALLIZATION PROCESSES
28.1 INTRODUCTION
28.2 POPULATION BALANCE FRAMEWORK FOR CRYSTALLIZATION
28.3 A GENERALIZED MODEL FOR BATCH AND CONTINUOUS CRYSTALLIZATION PROCESSES
28.4 CASE I: PARACETAMOL–ETHANOL SYSTEM
28.5 CASE II: SODIUM NITRITE–WATER CRYSTALLIZATION
28.6 SUMMARY AND RECOMMENDATIONS
28.A APPENDIX
ACKNOWLEDGMENT
NOTATIONS
REFERENCES
29 SOLID FORM DEVELOPMENT FOR POORLY SOLUBLE COMPOUNDS
29.1 INTRODUCTION
29.2 PERSPECTIVE ON SOLID FORM SCREENING IN DRUG DEVELOPMENT
29.3 SOLID FORM CONTROL OF LINIFANIB
29.4 SOLID FORM CONTROL OF DASABUVIR
ACKNOWLEDGMENTS
REFERENCES
30 MULTISCALE ASSESSMENT OF API PHYSICAL PROPERTIES IN THE CONTEXT OF MATERIALS SCIENCE TETRAHEDRON CONCEPT
30.1 INTRODUCTION
30.2 STRUCTURAL, SURFACE, BULK, AND MECHANICAL CHARACTERIZATION TOOLS
30.3 MODELING POWDER FLOWABILITY FROM FUNDAMENTAL PHYSICAL PROPERTIES
30.4 IMPACT OF API INTRINSIC MECHANICAL PROPERTIES ON PROCESS‐INDUCED DISORDER
ACKNOWLEDGMENTS
REFERENCES
PART VIII: SEPARATIONS, FILTRATION, DRYING AND MILLING
31 THE DESIGN AND ECONOMICS OF LARGE‐SCALE CHROMATOGRAPHIC SEPARATIONS
31.1 INTRODUCTION
31.2 KEY DESIGN ELEMENTS
31.3 FUNDAMENTAL CHROMATOGRAPHIC RELATIONSHIPS
31.4 CHROMATOGRAPHIC ADSORBENT CHEMISTRIES AND BASIS OF RETENTION
31.5 OPERATIONAL ASPECTS
31.6 EQUIPMENT
31.7 SCALE‐UP
31.8 DESIGN SPACE
31.9 ECONOMICS
31.10 CONCLUSIONS
ACKNOWLEDGMENTS
REFERENCES
32 MEMBRANE SYSTEMS FOR PHARMACEUTICAL APPLICATIONS
32.1 INTRODUCTION
32.2 PERVAPORATION IN THE PHARMACEUTICAL INDUSTRY
32.3 OSN IN PHARMACEUTICAL INDUSTRY
32.4 NONDISPERSIVE MEMBRANE SOLVENT EXTRACTION
32.5 CONCLUDING REMARKS
REFERENCES
33 DESIGN OF DISTILLATION AND EXTRACTION OPERATIONS
33.1 INTRODUCTION TO SEPARATION DESIGN BY DISTILLATION AND EXTRACTION
33.2 DESIGN OF DISTILLATION OPERATIONS
33.3 DESIGN OF EXTRACTION OPERATIONS
33.A GUIDE TO GENERATION OF BINARY INTERACTION PARAMETERS FOR SOLVENT PAIRS
REFERENCES
34 CASE STUDIES ON THE USE OF DISTILLATION IN THE PHARMACEUTICAL INDUSTRY
34.1 INTRODUCTION
34.2 INTRODUCTION TO DISTILLATION
34.3 DISTILLATION MODELING
34.4 CASE STUDIES ON THE USE OF DISTILLATION MODELS
ACKNOWLEDGMENTS
REFERENCES
35 DESIGN OF FILTRATION AND DRYING OPERATIONS
35.1 INTRODUCTION
35.2 FILTRATION
35.3 DRYING
REFERENCES
36 FILTRATION CASE STUDIES
36.1 INTRODUCTION
36.2 FILTRATION DECISION TREE
36.3 LOW TO MODERATE CAKE RESISTANCE
36.4 MODERATE TO HIGH CAKE RESISTANCE
36.5 REDESIGN OF SOLID‐STATE PROPERTIES FOR IMPROVED FILTRATION
36.6 CUMULATIVE PLUGGING OF AGITATED FILTER DRYER PLATE
REFERENCES
37 DRYING CASE STUDIES
37.1 INTRODUCTION
37.2 PROCESS TRANSFER TO ALTERNATE EQUIPMENT TRAIN
37.3 OPTIMIZATION OF SOLVATE DRYING THROUGH HEAT TRANSFER MODELING
37.4 DRYING WITH HUMIDIFIED NITROGEN
37.5 DISTILLATIVE DRYING IN AN AGITATED FILTER DRYER
37.6 CONCLUDING REMARKS
ACKNOWLEDGMENTS
REFERENCES
38 MILLING OPERATIONS IN THE PHARMACEUTICAL INDUSTRY
38.1 INTRODUCTION
38.2 SAFETY AND QUALITY CONCERNS
38.3 TYPES OF MILLING AND MILL EQUIPMENT
38.4 MECHANISTIC MODELS
38.5 CASE STUDIES
38.6 CONCLUSIONS
38.7 NOMENCLATURE
REFERENCES
PART IX: STATISTICAL MODELS, PAT, AND PROCESS MODELING APPLICATIONS
39 EXPERIMENTAL DESIGN FOR PHARMACEUTICAL DEVELOPMENT
39.1 INTRODUCTION
39.2 THE TWO‐LEVEL FACTORIAL DESIGN
39.3 BLOCKING
39.4 FRACTIONAL FACTORIALS
39.5 DESIGN PROJECTION
39.6 STEEPEST ASCENT
39.7 CENTER RUNS
39.8 RESPONSE SURFACE DESIGNS
39.9 COMPUTER‐GENERATED DESIGNS
39.10 MULTIPLE RESPONSES
39.11 ADVANCED TOPICS
REFERENCES
40 MULTIVARIATE ANALYSIS IN API DEVELOPMENT
40.1 INTRODUCTION
40.2 APPROACHES TO MODEL DEVELOPMENT
40.3 BUILDING THE CALIBRATION MODEL
40.4 CASE STUDY
ACKNOWLEDGMENTS
REFERENCES
41 PROBABILISTIC MODELS FOR FORECASTING PROCESS ROBUSTNESS
41.1 INTRODUCTION
41.2 MEASURING PROCESS ROBUSTNESS
41.3 REGULATORY REQUIREMENTS FOR PROCESS ROBUSTNESS
41.4 MODELING PROCESS ROBUSTNESS
41.5 PROCESS UNCERTAINTY
41.6 BRIEF OVERVIEW OF PROBABILISTIC GRAPHICAL MODELS
41.7 SIMULATION TOOLS FOR BAYESIAN STATISTICS
41.8 EXAMPLE OF MODELING PROCESS ROBUSTNESS
SUMMARY
SUPPORTING INFORMATION
REFERENCES
42 USE OF PROCESS ANALYTICAL TECHNOLOGY (PAT) IN SMALL MOLECULE DRUG SUBSTANCE REACTION DEVELOPMENT
42.1 INTRODUCTION
42.2 PAT METHODS
42.3 PAT APPLICATION IN PHARMACEUTICAL REACTION ENGINEERING
42.4 CASE STUDIES
42.5 SUMMARY
ACKNOWLEDGMENTS
REFERENCES
43 PROCESS MODELING APPLICATIONS TOWARD ENABLING DEVELOPMENT AND SCALE‐UP: CHEMICAL REACTIONS
43.1 INTRODUCTION
43.2 PREDICTIVE SCALE‐UP OF A HIGHLY EXOTHERMIC REACTION
43.3 EFFICIENT SCALE‐UP OF A MULTIPHASE EXOTHERMIC NITRATION REACTION
43.4 KINETIC JUSTIFICATION‐BASED CONTROL FOR POTENTIAL MUTAGENIC IMPURITIES
ACKNOWLEDGMENTS
LIST OF SYMBOLS
REFERENCES
PART X: MANUFACTURING
44 PROCESS SCALE‐UP AND ASSESSMENT
44.1 INTRODUCTION
44.2 DRIVERS FOR DEVELOPMENT/RISK ASSESSMENT
44.3 UNIT OPERATIONS
SUMMARY
REFERENCES
45 SCALE‐UP DO'S AND DON'TS
45.1 INTRODUCTION
45.2 LEARNING THE HARD WAY
45.3 TYPICAL SCALE‐UP ISSUES
45.4 PURPOSE OF THIS CHAPTER
45.5 THINGS TO DO DURING SCALE‐UP
45.6 THINGS TO AVOID DURING SCALE‐UP
45.7 CONCLUSIONS AND FINAL THOUGHTS
REFERENCES
46 KILO LAB AND PILOT PLANT MANUFACTURING
46.1 INTRODUCTION
46.2 KILO LAB AND PILOT PLANT FACILITY DESIGN AND UNIT OPERATIONS
46.3 OPERATING PRINCIPLES AND REGULATORY DRIVERS
46.4 SUMMARY
46.5 EXERCISE
REFERENCES
47 THE ROLE OF SIMULATION AND SCHEDULING TOOLS IN THE DEVELOPMENT AND MANUFACTURING OF ACTIVE PHARMACEUTICAL INGREDIENTS
47.1 INTRODUCTION
47.2 COMMERCIALLY AVAILABLE SIMULATION AND SCHEDULING TOOLS
47.3 MODELING AND ANALYSIS OF AN API MANUFACTURING PROCESS
47.4 UNCERTAINTY AND VARIABILITY ANALYSIS
47.5 PRODUCTION SCHEDULING
47.6 CAPACITY ANALYSIS AND PRODUCTION PLANNING
47.7 SUMMARY
REFERENCES
PART XI: QUALITY BY DESIGN AND REGULATORY
48 SCIENTIFIC OPPORTUNITIES THROUGH QUALITY BY DESIGN
ACKNOWLEDGMENT
REFERENCE
49 APPLICATIONS OF QUALITY RISK ASSESSMENT IN QUALITY BY DESIGN (QbD) DRUG SUBSTANCE PROCESS DEVELOPMENT
49.1 WHY RISK ASSESSMENT IS USED IN THE PHARMACEUTICAL INDUSTRY
49.2 OVERVIEW OF RISK ASSESSMENT PROCESS
49.3 RISK ASSESSMENT TYPES
49.4 RISK ASSESSMENT TOOLS
49.5 RISK ASSESSMENT BEST PRACTICES
49.6 RISK ASSESSMENTS THROUGH THE PRODUCT LIFE CYCLE
49.7 CONCLUDING REMARKS
REFERENCES
50 DEVELOPMENT OF DESIGN SPACE FOR REACTION STEPS: APPROACHES AND CASE STUDIES FOR IMPURITY CONTROL
50.1 INTRODUCTION
50.2 ELEMENTS OF PHARMACEUTICAL DEVELOPMENT
50.3 REACTION DESIGN SPACE DEVELOPMENT
50.4 DEFINING THE DESIGN SPACE
50.5 VERIFICATION OF THE DESIGN SPACE
50.6 CASE STUDIES
50.7 CONCLUSIONS
50.8 GLOSSARY OF TERMS
REFERENCES
INDEX
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