Katherine A. Bakeev is Principal Scientist with GlaxoSmithKline in King of Prussia, PA where she works in the Process Analytics and Chemometrics group supporting chemical development. She has twelve years of industrial experience including work in process analytical chemistry with ISP, and as a product specialist for Foss NIRSystems. She holds a PhD in Polymer Science and Engineering from the University of Massachusetts in Amherst, and a Masters in Technology Management from Stevens Institute of Technology. She has given numerous presentations on the use of near-infrared spectroscopy (NIR), and in 2007 received the Coblentz Society Craver Award for her work in NIR and chemometrics.

Preface to the Second Edition xvii List of Contributors xix List of Abbreviations xxi 1 Overview of Process Analysis and PAT 1Jason E. Dickens 1.1 Introduction 1 1.1.1 Historical perspective 3 1.1.2 Business drivers 4 1.2 Execution of Process Analysis Projects 5 1.2.1 Wisdoms 5 1.2.2 Team structure 6 1.2.3 Project life cycle 6 1.2.4 Project scoping 9 1.2.5 Common challenges and pitfalls 10 1.3 Process Instrumentation 12 1.3.1 Process instrumentation types 12 1.3.2 Novel process instrumentation 12 1.4 Conclusions 13 1.5 Glossary of Acronyms and Terms 14 References 14 2 Implementation of Process Analytical Technologies 17Robert Guenard and Gert Thurau 2.1 Introduction to Implementation of Process Analytical Technologies (PAT) in the Industrial Setting 17 2.1.1 Definition of process analytics 18 2.1.2 Differences between process analyzers and laboratory analysis 19 2.1.3 General industrial drivers for PA 19 2.1.4 Types of applications (R&D versus manufacturing) 20 2.1.5 Organizational considerations 20 2.2 Generalized Process Analytics Work Process 23 2.2.1 Project identification and definition 24 2.2.2 Analytical application development 26 2.2.3 Design, specify and procure 26 2.2.4 Implementation in production 28 2.2.5 Routine operation 29 2.2.6 Continuous improvement 30 2.3 Considerations for PAT Implementation in the Pharmaceutical Industry 30 2.3.1 Introduction 30 2.3.2 Business model 30 2.3.3 Technical differences 31 2.3.4 Regulatory Aspects of Process Analytics in the Pharmaceutical Industry -the Concept of Quality by Design 33 2.4 Conclusions 36 References 36 3 Process Sampling: Theory of Sampling - the Missing Link in Process Analytical Technologies (PAT) 37Kim H. Esbensen and Peter Paasch-Mortensen 3.1 Introduction 37 3.2 Theory of Sampling - Introduction 39 3.2.1 Heterogeneity 41 3.2.2 Constitutional heterogeneity 41 3.2.3 Distributional heterogeneity 42 3.2.4 Structurally correct sampling 45 3.2.5 Incorrect sampling error 45 3.2.6 Increment delimitation error 45 3.2.7 Increment extraction error 46 3.2.8 Increment preparation error 46 3.2.9 Increment weighing error 47 3.2.10 Total sampling error 48 3.2.11 Global estimation error 48 3.3 Mass Reduction as a Specific Sampling Procedure 48 3.4 Fundamental Sampling Principle 51 3.5 Sampling - a Very Practical Issue 51 3.5.1 Sampling unit operations 52 3.5.2 Understanding process sampling: 0-D versus 1-D LOTS 52 3.5.3 Grab sampling - 0-D and 1-D 54 3.5.4 Correct process sampling: increment delimitation/extraction 56 3.5.5 PAT versus correct process sampling - what is required? 58 3.6 Reactors and Vessels - Identical Process Sampling Issues 60 3.6.1 Correct process sampling with existing process technology 62 3.6.2 Upward flux - representative colocated PAT sampling 62 3.6.3 Upstream colocated PAT sampler 64 3.7 Heterogeneity Characterization of 1-D lots: Variography 66 3.7.1 Process sampling modes 67 3.7.2 The experimental variogram 67 3.7.3 Sampling plan simulation and estimation of TSE 71 3.7.4 TSE estimation for 0-D lots - batch sampling 72 3.7.5 Corporate QC benefits of variographic analysis 73 3.8 Data Quality - New Insight from the TOS 75 3.9 Validation in Chemometrics and PAT 76 3.10 Summary 78 References 79 4 UV-visible Spectroscopy for On-line Analysis 81Marcel A. Liauw, Lewis C. Baylor and Patrick E. O'Rourke 4.1 Introduction 81 4.2 Theory 82 4.2.1 Chemical concentration 82 4.2.2 Color 84 4.2.3 Film thickness 85 4.2.4 Turbidity 85 4.2.5 Plasmons/nanoparticles 85 4.3 Instrumentation 85 4.4 Sample Interface 86 4.4.1 Cuvette/vial 87 4.4.2 Flow cells 87 4.4.3 Insertion probe 87 4.4.4 Reflectance probe 89 4.5 Implementation 89 4.5.1 A complete process analyzer 89 4.5.2 Troubleshooting 89 4.6 Applications 91 4.6.1 Gas and vapor analysis 92 4.6.2 Liquid analysis 92 4.6.3 Solid analysis 96 4.6.4 Other applications 99 4.7 Detailed Application Notes 100 4.7.1 Gas and vapor analysis: toluene 100 4.7.2 Liquid analysis: breakthrough curves 101 4.7.3 Solids analysis: extruded plastic color 101 4.7.4 Film thickness determination: polymer 103 4.8 Conclusion 104 References 104 5 Near-infrared Spectroscopy for Process Analytical Technology: Theory, Technology and Implementation 107Michael B. Simpson 5.1 Introduction 107 5.2 Theory of Near-infrared Spectroscopy 112 5.3 Analyser Technologies in the Near-infrared 114 5.3.1 Light sources and detectors for near-infrared analyzers 114 5.3.2 The scanning grating monochromator and polychromator diode-array 119 5.3.3 The acousto-optic tunable filter (AOTF) analyzer 123 5.3.4 Fourier transform near-infrared analyzers 127 5.3.5 Emerging technologies in process NIR analyzers 134 5.4 The Sampling Interface 136 5.4.1 Introduction 136 5.4.2 Problem samples: liquids, slurries and solids 142 5.4.3 The use of fiber optics 145 5.5 Practical Examples of Near-infrared Analytical Applications 147 5.5.1 Refinery hydrocarbon streams 148 5.5.2 Polyols, ethoxylated derivatives, ethylene oxide/propylene oxide polyether polyols 149 5.5.3 Oleochemicals, fatty acids, fatty amines and biodiesel 151 5.6 Conclusion 152 References 153 6 Infrared Spectroscopy for Process Analytical Applications 157John P. Coates 6.1 Introduction 157 6.2 Practical Aspects of IR Spectroscopy 161 6.3 Instrumentation Design and Technology 163 6.4 Process IR Instrumentation 166 6.4.1 Commercially available IR instruments 167 6.4.2 Important IR component technologies 172 6.4.3 New technologies for IR components and instruments 176 6.4.4 Requirements for process infrared analyzers 178 6.4.5 Sample handling for IR process analyzers 185 6.4.6 Issues for consideration in the implementation of process IR 187 6.5 Applications of Process IR Analyzers 189 6.6 Process IR Analyzers: a Review 191 6.7 Trends and Directions 192 References 193 7 Raman Spectroscopy 195Nancy L. Jestel 7.1 Attractive Features of Raman Spectroscopy 195 7.1.1 Quantitative information 195 7.1.2 Flexible sample forms and sizes used as accessed without damage 196 7.1.3 Flexible sample interfaces 196 7.1.4 Attractive spectral properties and advantageous selection rules 197 7.1.5 High sampling rate 197 7.1.6 Stable and robust equipment 198 7.2 Potential Issues with Raman Spectroscopy 198 7.2.1 High background signals 198 7.2.2 Stability 198 7.2.3 Too much and still too little sensitivity 199 7.2.4 Personnel experience 199 7.2.5 Cost 200 7.3 Fundamentals of Raman Spectroscopy 200 7.4 Raman Instrumentation 203 7.4.1 Safety 203 7.4.2 Laser wavelength selection 204 7.4.3 Laser power and stability 204 7.4.4 Spectrometer 205 7.4.5 Sample interface (probes) 206 7.4.6 Communications 208 7.4.7 Maintenance 209 7.5 Quantitative Raman 209 7.6 Applications 212 7.6.1 Acylation, alkylation, catalytic cracking, and transesterification 213 7.6.2 Bioreactors 213 7.6.3 Blending 214 7.6.4 Calcination 214 7.6.5 Catalysis 215 7.6.6 Chlorination 216 7.6.7 Counterfeit pharmaceuticals 217 7.6.8 Extrusion 218 7.6.9 Forensics 218 7.6.10 Hydrogenation 218 7.6.11 Hydrolysis 219 7.6.12 Medical diagnostics 219 7.6.13 Microwave-assisted organic synthesis 219 7.6.14 Mobile or field uses 220 7.6.15 Natural products 220 7.6.16 Orientation, stress, or strain 221 7.6.17 Ozonolysis 222 7.6.18 Polymerization 222 7.6.19 Polymer curing 224 7.6.20 Polymorphs (crystal forms) 225 7.6.21 Product properties 228 7.6.22 Purification: distillation, filtration, drying 229 7.6.23 Thin films or coatings 229 7.7 Current State of Process Raman Spectroscopy 230 References 231 8 Near-infrared Chemical Imaging for Product and Process Understanding 245E. Neil Lewis, Joseph W. Schoppelrei, Lisa Makein, Linda H. Kidder and Eunah Lee 8.1 The PAT Initiative 245 8.2 The Role of Near-infrared Chemical Imaging (NIR-CI) in the Pharmaceutical Industry 246 8.2.1 Characterization of solid dosage forms 246 8.2.2 'A picture is worth a thousand words' 247 8.3 Evolution of NIR Imaging Instrumentation 247 8.3.1 Spatially resolved spectroscopy - mapping 247 8.3.2 The infrared focal-plane array 247 8.3.3 Wavelength selection 248 8.3.4 The benefits of NIR spectroscopy 248 8.3.5 NIR imaging instrumentation 249 8.4 Chemical Imaging Principles 251 8.4.1 The hypercube 251 8.4.2 Data analysis 251 8.4.3 Spectral correction 252 8.4.4 Spectral preprocessing 253 8.4.5 Classification 253 8.4.6 Image processing - statistical 255 8.4.7 Image processing - morphology 257 8.5 PAT Applications 257 8.5.1 Content uniformity measurements - 'self calibrating' 258 8.5.2 Quality assurance - imaging an intact blister pack 260 8.5.3 Contaminant detection 261 8.5.4 Imaging of coatings - advanced design delivery systems 263 8.6 Processing Case Study: Estimating 'Abundance' of Sample Components 267 8.6.1 Experimental 268 8.6.2 Spectral correction and preprocessing 268 8.6.3 Analysis 268 8.6.4 Conclusions 273 8.7 Processing Case Study: Determining Blend Homogeneity Through Statistical Analysis 273 8.7.1 Experimental 273 8.7.2 Observing visual contrast in the image 274 8.7.3 Statistical analysis of the image 274 8.7.4 Blend uniformity measurement 276 8.7.5 Conclusions 276 8.8 Final Thoughts 277 Acknowledgements 278 References 278 9 Acoustic Chemometric Monitoring of Industrial Production Processes 281Maths Halstensen and Kim H. Esbensen 9.1 What is Acoustic Chemometrics? 281 9.2 How Acoustic Chemometrics Works 282 9.2.1 Acoustic sensors 282 9.2.2 Mounting acoustic sensors (accelerometers) 283 9.2.3 Signal processing 284 9.2.4 Chemometric data analysis 284 9.2.5 Acoustic chemometrics as a PAT tool 284 9.3 Industrial Production Process Monitoring 285 9.3.1 Fluidized bed granulation monitoring 285 9.3.2 Pilot scale studies 286 9.3.3 Monitoring of a start-up sequence of a continuous fluidized bed granulator 291 9.3.4 Process monitoring as an early warning of critical shutdown situations 295 9.3.5 Acoustic chemometrics for fluid flow quantification 296 9.4 Available On-line Acoustic Chemometric Equipment 299 9.5 Discussion 301 9.5.1 Granulator monitoring 301 9.5.2 Process state monitoring 301 9.5.3 Ammonia...