Process Understanding: For Scale-Up and Manufacture of Active Ingredients

Process Understanding......Page 2
Contents......Page 6
Preface......Page 16
List of Contributors......Page 18
1.1 History......Page 20
1.2 Defining Product Design Requirements and Critical Quality Attributes......Page 22
1.3 The Role of Quality Risk Management in QbD......Page 25
1.4 Design Space and Control Strategy......Page 31
1.5 Quality Systems......Page 33
References......Page 34
2.1 Introduction......Page 36
2.2 Route Evaluation......Page 39
2.3.1 Timing......Page 43
2.3.2 Costs......Page 44
2.3.3 Safety, Health, and Environment (SHE)......Page 45
2.3.3.1 Safer Processes......Page 47
2.3.3.2 Green Chemistry......Page 52
2.3.4 Legal......Page 56
2.3.5 Other Considerations......Page 57
2.3.5.1 Throughput......Page 59
2.3.5.2 Solvents......Page 61
2.4 Route Selection......Page 62
2.4.1 Sildenafil......Page 67
2.5 Process Selection......Page 68
2.5.1 Pregabalin......Page 70
2.5.2 NK1 Receptor Antagonist......Page 72
2.5.3 Data......Page 74
2.6 Summary......Page 75
References......Page 76
3.1 Reaction Safety Concepts......Page 78
3.1.2 The Critical Effects of Scale-Up on Thermal Behavior......Page 79
3.1.3 Safety Features of a Reaction......Page 81
3.1.4 Stages of Safety Assessment......Page 83
3.2.1 Predicting Reaction Safety Characteristics......Page 84
3.2.2 Selecting Inherently Safer Processing Conditions......Page 87
3.3.1 Testing of Potentially Explosive Compounds......Page 88
3.3.2 Thermal Stability Assessment......Page 89
3.3.3 Reaction Thermodynamic, Kinetic, and Gas-Generation Quantification......Page 90
3.3.4 Developing Fault-Tolerant Processes – by Design......Page 93
3.4 Establishing a Reliable Basis of Safety for Scale-Up......Page 94
3.4.1 Hazardous Scenario Identification......Page 95
3.4.3 Experimental Simulation – Adiabatic Calorimetry......Page 96
3.4.4 Specify and Implement Safety Measures......Page 98
3.5 Flammability Hazards......Page 99
3.5.1 Assessing Pilot-Scale Flammability Hazards......Page 101
3.6 Summary......Page 103
References......Page 104
4.1 Introduction......Page 106
4.2.1 Number of Phases......Page 107
4.2.2.1 Length Scales......Page 108
4.2.2.7 Mass Transfer/Interfacial Area......Page 109
4.3 Topics for Data Acquisition......Page 110
4.4 Reaction Profiles......Page 111
4.5 Reaction Pictures......Page 112
4.6.1 Nitration......Page 114
4.6.2 Acylation......Page 115
4.7.1 Order of Reaction......Page 118
4.9 The Rate-Determining Step......Page 121
4.10 Mixing in Chemical Reactors......Page 124
4.11 Mixing Theory......Page 125
4.11.1 Mixing Regimes......Page 127
4.11.2 Micromixing......Page 128
4.11.4 Mesomixing......Page 129
4.11.6 Comments on Scalability of Mixing......Page 130
4.12 Multiphase Processes......Page 131
4.13 Mass Transfer Theory......Page 132
4.13.1.3 Solubility-Limited Reaction......Page 133
4.13.2.3 Common Ion Effect......Page 134
4.14.1 Liquid–Liquid Systems......Page 135
4.14.3 Gas–Liquid Systems......Page 137
4.14.4 Solid–Liquid–Gas Systems......Page 138
4.15.1 What Do We Mean by “Structure”?......Page 139
4.15.3 What is “Intensity”?......Page 140
4.15.4 Scales of Structure......Page 141
4.15.5 How Susceptible to Variability is the Process; When Would Different Equipment Help?......Page 142
4.16 Conclusion......Page 143
References......Page 144
5.1 Introduction......Page 146
5.2 The Process Characterization Elements of a Chemical Reaction......Page 147
5.3 The Impact of Modeling......Page 149
5.4.1 A Simple Start......Page 150
5.4.2 Getting Real Rate Parameters......Page 151
5.4.3 Introduction of Temperature Dependence......Page 154
5.4.4 Including Reaction Heats......Page 156
5.4.5 Putting Elements Together: Large-Scale Simulations......Page 157
5.4.6 Thermal Process Safety Simulations......Page 160
5.5 Physical Rates (the Elements of Mass Transfer)......Page 163
5.5.1 Gas/Liquid Mass Transfer......Page 164
5.5.2 Solid/Liquid Mass Transfer......Page 168
5.6 Summary and Outlook......Page 171
References......Page 172
6.1 Introduction......Page 174
6.2 Case Study – Batch Hydrogenation......Page 175
6.3 Scale-Up of Stirred Tank Reactors (STRs)......Page 178
6.3.1 Fundamentals of Flow Regimes, Turbulence, and Turbulent Mixing......Page 179
6.3.1.1 Mixing Mechanisms in Laminar Flows......Page 180
6.3.1.2 Mixing Mechanisms in Turbulent Flows......Page 181
6.3.1.3 Estimating Energy Dissipation and Mixing Length Scales from Turbulent Flow Fields......Page 183
6.3.2 Stirred Vessel Design and Scale-Up......Page 185
6.3.2.2 Power Input and Specific Energy Dissipation Rate......Page 186
6.3.2.3 Mixing Times......Page 189
6.4.1.1 Constant Mixing Time (Constant N)......Page 190
6.4.2 Heat Transfer......Page 191
6.4.3 Multiphase Systems: Solid–Liquid Systems......Page 193
6.4.3.1 Particle Suspension and Flow Patterns......Page 194
6.4.4 Multiphase Systems: Gas–Liquid Systems......Page 196
6.4.4.2 Gas Hold-Up and Flow Patterns......Page 197
6.4.4.3 Mass Transfer......Page 198
6.4.5 Summary......Page 199
6.5.1 “Fed-Batch” Liquid-Phase Reactions......Page 200
6.5.2 Liquid–Solid Reactions......Page 201
6.5.3.2 Gaseous Product......Page 202
6.6 Achieving Process Understanding for Reactor Scale-Up......Page 203
6.6.1 Chemistry Scale-Up Sensitivity......Page 204
6.6.2 On the Acquisition of Relevant Chemical Information......Page 205
6.6.3 On the Acquisition of Relevant Reactor Design Information......Page 206
6.7.1 So Which Reactor Can I Use?......Page 207
6.7.3 Characterizing Mixing Rate......Page 208
6.7.5 Characterizing Heat Transfer......Page 209
6.8 Exploiting Process Understanding in Scale-Up......Page 210
6.8.1 Mixing Rate-Limited Reactions......Page 211
6.8.3 Heat-Transfer-Limited Reactions......Page 212
6.9 Conclusions......Page 213
References......Page 214
7.1 Introduction......Page 218
7.1.1 Crystal Definition and Structure – Crystal Defects and Basics of Crystal Growth......Page 219
7.1.2 Thermodynamics of Crystallization......Page 221
7.1.3 Kinetics of Crystal Growth, Nucleation......Page 223
7.1.4.1 Supersaturation and Metastable Zone Width......Page 225
7.2.1.1 The Bridgman Method......Page 227
7.2.2.1 Single Solvent Crystallization......Page 228
7.2.2.2 Multiple Solvent Crystallization......Page 230
7.2.3 Crystallization from Vapor......Page 231
7.3.1 Tank Crystallizers......Page 232
7.3.2 Continuous (Flow) Crystallizers......Page 233
7.3.2.1 Continuous Oscillatory Baffled Crystallizer......Page 234
7.4 Process Control of Crystallization......Page 235
7.4.2 Particle and Crystal Size......Page 236
7.4.4 Composition Control (Cocrystallization)......Page 237
7.5 Analytical Techniques for Product Characterization......Page 238
7.5.1 Focused Beam Reflectance Measurements and Attenuated Total Reflectance Ultra Violet......Page 239
7.5.4 X-Ray Methods......Page 240
7.5.5 DSC/TGA......Page 242
References......Page 244
8.1.1 The Drug Substance–Drug Product Interface......Page 248
8.1.2 Physical Characteristics and Bioavailability......Page 250
8.2 Opportunities for Innovation......Page 252
8.3 Crystallization......Page 253
8.3.1 Spherical Crystallization......Page 254
8.3.2 Ultrasonic Crystallization......Page 255
8.4 Selected Manufacturing Technologies at the Drug Substance–Drug Product Interface......Page 256
8.4.1.1 Jet Milling......Page 257
8.4.1.3 Contrast between Jet Milled and In situ Micronized Material......Page 258
8.4.2 Nanonization......Page 259
8.4.2.1 Contrasting Performance of Micro- and Nanoparticles......Page 260
8.4.3 Blending......Page 261
8.5 Analytical Techniques......Page 262
8.5.1.3 Focussed Ion Beam (FIB)......Page 263
8.5.1.5 Particle Size......Page 264
8.5.2 Bulk......Page 266
8.5.2.1 Angle of Repose, Carr’s Index, and Hausner Ratio......Page 267
8.5.2.3 Dry Powder Rheology and Dynamic Avalanching......Page 268
8.5.3.3 Laser Light Scattering......Page 270
References......Page 271
9.1 Introduction......Page 274
9.2 The Status Quo......Page 275
9.3 Risk and Reward......Page 276
9.4.2 Process Understanding, Critical Quality Attributes, and Critical Process Parameters......Page 277
9.4.6 Fitness for Purpose......Page 278
9.4.11 Continuous Quality Verification......Page 279
9.5.1 Start with the End in Mind......Page 280
9.5.2.3 R&D/Engineering......Page 281
9.5.3.1 Phases of Operation......Page 282
9.5.4 Measurable Variation in a Process......Page 283
9.5.5.1 Analyzer Design......Page 284
9.5.5.4 Sampling Frequency......Page 285
9.5.6.1 Lag......Page 286
9.5.7 Failure Modes and Effects Analysis (FMEA)......Page 287
9.6.2 Starting in the Lab......Page 288
9.6.3.2 Complex......Page 289
9.7 Statistical Process Control......Page 290
9.7.2 2D Plots......Page 291
9.7.3 Parallel Coordinate Geometry......Page 292
9.7.5 The Analysis of Noise......Page 293
9.8.1.2 More Consistent Quality......Page 294
9.8.2 The Control Philosophy......Page 295
9.8.4 Univariate Control......Page 296
9.9 Conclusion......Page 298
References......Page 299
10.1 Introduction......Page 302
10.1.1 CAPEX Project Phases......Page 303
10.1.2 Starting Plant Design......Page 305
10.1.3 Equipment Selection......Page 306
10.1.4 Assets (Existing or New)......Page 308
10.2.1 Process Information......Page 309
10.2.2 Physical Properties......Page 311
10.2.5 Combining and Splitting Tasks......Page 312
10.2.6 Batch versus Continuous Processing......Page 314
10.2.7 Sustainability......Page 316
10.3 Regulations......Page 317
10.3.2 Industry Standards......Page 318
10.3.4 Quality Control......Page 319
10.4.1 Plug‘N’Play......Page 320
10.5 Portfolio Analysis and Asset Planning......Page 321
10.5.2 Agile and/or Lean Manufacturing......Page 322
10.5.3 Asset Planning Options......Page 323
10.5.4 The Contract Manufacturer......Page 324
11.2 Why Contract?......Page 326
11.3 The Contractor......Page 327
11.4.1 Scope Required by a Client......Page 328
11.5.1 Prior to Winning the Contract......Page 330
11.5.2 After Winning the Contract......Page 331
11.6 What Makes a Good Technical Package?......Page 332
11.7 Client Process Understanding......Page 333
11.8 Case Studies......Page 334
11.9.1 Winning the Business......Page 335
11.9.2 Delivering the Scope......Page 337
11.10 Project Timing......Page 339
11.11 Challenges of Multiproduct Plant Scheduling against an Uncertain Background......Page 340
11.12 Conclusion......Page 341
12.1 Process Understanding for Whole Process Design......Page 342
12.1.1 Process Complexity and Its Impact on Data Needs for Understanding......Page 346
12.2 Process Outcomes......Page 349
12.3 Organization of the Design Activity......Page 350
12.4 Risk and Uncertainty in WPD......Page 352
12.5 Whole Process Representations......Page 354
12.6.1 Decisions about the Design Activity......Page 356
12.6.2 Decisions in Process Development......Page 357
References......Page 359
Index......Page 362