A guide to the lastest industry principles for optimizing the production of solid state active pharmaceutical ingredients
Solid State Development and Processing of Pharmaceutical Molecules is an authoritative guide that covers the entire pharmaceutical value chain. The authors - noted experts on the topic - examine the importance of the solid state form of chemical and biological drugs and review the development, production, quality control, formulation, and stability of medicines.
The book explores the most recent trends in the digitization and automation of the pharmaceutical production processes that reflect the need for consistent high quality. It also includes information on relevant regulatory and intellectual property considerations. This resource is aimed at professionals in the pharmaceutical industry and offers an in-depth examination of the commercially relevant issues facing developers, producers and distributors of drug substances. This important book: - Provides a guide for the effective development of solid drug forms - Compares different characterization methods for solid state APIs - Offers a resource for understanding efficient production methods for solid state forms of chemical and biological drugs - Includes information on automation, process control, and machine learning as an integral part of the development and production workflows - Covers in detail the regulatory and quality control aspects of drug development
Written for medicinal chemists, pharmaceutical industry professionals, pharma engineers, solid state chemists, chemical engineers, Solid State Development and Processing of Pharmaceutical Molecules reviews information on the solid state of active pharmaceutical ingredients for their efficient development and production.
Table of Contents
Series Editors Preface xxi
Preface xxiii
1 Aspects for Developing and Processing Solid Forms 1
Michael Gruss
1.1 Aspects for Developing and Processing Solid Forms 1
1.1.1 Introduction 1
1.1.2 Education and Personal Background 1
1.1.3 Societal Impact - Fishing in ForeignWaters 4
1.1.3.1 Motivation 4
1.1.3.2 The Personal Dimension 5
1.1.3.3 Beyond the Impact on Individuals 6
1.1.3.4 Understanding the Market - Not an Easy Task 7
1.1.3.5 Benefits of an Interdisciplinary Mindset 9
1.1.4 The Basis for Mutual Understanding 9
1.1.5 Crystallization is a Separation, Not a Separated Process 11
1.1.6 Some Early Information About Solid-state Properties 13
1.1.7 Digitalization (Not Only) in the Laboratory 13
1.1.7.1 Prerequisites - Technology and People 13
1.1.7.2 Connect Data and the Right Information from Synthesis and Analysis 15
1.1.7.3 Contributions and Choices 17
1.1.7.4 Application of Digitalization 18
1.1.7.5 Fully Digitalized Infrastructure 20
1.1.8 Basic Terms and Concepts in theWorld of Solid State 21
1.1.8.1 Crystalline and Amorphous 21
1.1.8.2 Crystallization and Precipitation 23
1.1.8.3 Understanding the Phase Diagram - Analytical Characterization of the Solid-Liquid and Solid-Solid Systems 23
1.1.8.4 Polymorphism 24
1.1.8.5 Multi-component Compounds - Salt, Cocrystal, Solvate, and Hydrate 25
1.1.8.6 Solvates, Hydrates, Non-solvated Forms, or Ansolvates 26
1.1.8.7 Dispersed Primary Particles, Aggregates, and Agglomerates 29
1.1.8.8 Particle Size and Particle Size Distribution (PSD) 29
1.1.9 Investigating and Understanding the Polymorphic Landscape 29
1.1.10 Performing the Crystallization 31
1.1.11 Objectives for the Optimization of Crystallization Processes and Solid-State Properties 32
1.1.12 Implementation of In Silico and Simulation Techniques 32
1.1.13 Saving the Investment - Addressing Intellectual Property Rights 35
1.1.14 Concluding Remarks 36
List of Abbreviations 37
References 38
2 Determination of Current Knowledge 45
Andriy Kuzmov and Ronak Savla
2.1 Why is it Important to Search for Relevant Information Before Starting a Solid-State Project? 45
2.2 Where to Begin a Literature Search for a Solid-State Project? 47
2.2.1 Literature Search 48
2.2.1.1 Focusing Your Literature Search 49
2.2.2 Staying on Top of the Latest Publications 51
2.3 Patent Search 51
2.3.1 Types of Patent Reports 52
2.3.2 Understanding the Elements of Patents 53
2.3.3 Patent Classification 54
2.3.4 Patent Databases 56
2.3.4.1 Free Patent Databases 57
2.4 Other Useful Resources for Solid-State Projects 61
2.4.1 Cambridge Structural Database 61
2.4.2 Crystallography Open Database 62
List of Abbreviations 62
References 63
3 Systematic Screening and Investigation of Solid-State Landscapes 67
Ulrike Werthmann
3.1 Introduction 67
3.2 General Aspects of Solid-State Investigations in Early Drug Discovery Phase 68
3.3 Transition Phase from Late Stage Research to Early Stage Development 69
3.4 Solid-State Characteristics in Preclinical Formulations 70
3.5 API-crystallization Strategy in Candidate Profiling Phase 73
3.6 Selection Criteria of a Suitable Solid Form 77
3.7 Knowledge Management 79
3.8 Control of Solid Form Properties in Development 79
3.9 Exploratory Crystallization Experiments 80
List of Abbreviations 87
References 88
4.1 Solid-State Characterization Techniques: Microscopy 91
Luis Almeida e Sousa and Constança Cacela
4.1.1 Microscopy 91
4.1.1.1 Optical Microscopy 91
4.1.1.1.1 Bright-Field Microscopy 92
4.1.1.1.2 Dark-Field Microscopy 93
4.1.1.1.3 Polarized Light Microscopy 93
4.1.1.1.4 Other Optical Microscopy Variants 95
4.1.1.2 Electron Microscopy 96
4.1.1.2.1 Scanning Electron Microscopy 96
4.1.1.2.2 Transmission Electron Microscopy 100
4.1.1.3 Atomic Force Microscopy 101
4.1.1.4 Microscopy in Regulatory Documents 103
List of Abbreviations 103
References 104
4.2 Standards and Trends in Analytical Characterization - X-ray Diffraction (XRD) 107
Clemens Kühn
4.2.1 X-ray Diffraction 107
4.2.1.1 Introduction 107
4.2.1.2 Measurement Principles 108
4.2.1.2.1 The Crystal Lattice 108
4.2.1.2.2 The Space Group Symmetry 108
4.2.1.2.3 What Determines a Diffraction Peak 109
4.2.1.2.4 X-ray Scattering Technics 110
4.2.2 Technics 110
4.2.2.1 Single Crystal X-ray Diffraction 110
4.2.2.2 Powder X-ray Diffraction 111
4.2.2.2.1 Alternative Methods for Structure Determination 111
4.2.3 Instrumentation 112
4.2.3.1 X-ray Sources 112
4.2.3.2 Diffractometer Geometries 113
4.2.3.2.1 Reflection Geometry 113
4.2.3.2.2 Transmission Geometry 114
4.2.3.2.3 Benchtop Diffractometers 115
4.2.3.3 Detectors 115
4.2.3.4 Peak Asymmetry 115
4.2.3.5 Reproducibility of Diffraction Patterns: The Texture Effect (Preferred Orientation) 116
4.2.3.6 Databases of Known Diffraction Patterns 118
4.2.4 Measurement 118
4.2.4.1 Instrument Calibration 118
4.2.4.2 Sample Preparation 119
4.2.5 Data Evaluation 119
4.2.5.1 Qualitative Phase Analysis 119
4.2.5.1.1 Phase Identification or Identity Check 120
4.2.5.1.2 Amorphous Content 121
4.2.5.2 Quantification 122
4.2.5.2.1 Based on Calibration Curve 123
4.2.5.2.2 Based on Internal Standard Addition 123
4.2.5.2.3 Based on Rietveld Refinement 123
4.2.5.3 Advanced Phase Analysis 124
List of Abbreviations 125
References 125
Further Reading 127
4.3 Standards and Trends in Solid-State Characterization Techniques - Thermal Analysis 129
Juergen Thun and Nikolaus Martin
4.3.1 Introduction 129
4.3.2 Thermal Analysis in Drug Development 130
4.3.2.1 Solid form Landscape 130
4.3.2.2 Compatibility Studies 130
4.3.2.3 Other Applications 130
4.3.3 Methods 131
4.3.3.1 Differential Scanning Calorimetry 131
4.3.3.1.1 Techniques 131
4.3.3.1.2 Sample Preparation and Measuring Parameters 131
4.3.3.1.3 Evaluation 132
4.3.3.1.4 Special Applications 134
4.3.3.1.5 Detection Limits 134
4.3.3.2 Thermogravimetric Analysis 134
4.3.3.2.1 Technique 134
4.3.3.2.2 Sample Preparation and Measuring Parameters 135
4.3.3.2.3 Evaluation 135
4.3.3.2.4 Special Applications 136
4.3.4 Case Studies 136
4.3.4.1 Understanding Polymorphic Transitions 136
4.3.4.2 The Power of Ultra-fast Heating Rates 139
4.3.4.3 Understanding Amorphous Phases 141
4.3.4.4 Identification of Solvate Structures 142
4.3.5 Quality and Regulatory Aspects 144
4.3.6 Outlook 145
Acknowledgments 146
List of Abbreviations 146
Notes 146
References 146
4.4 Standards and Trends in Solid-State Characterization Techniques: Infrared (IR) Spectroscopy 151
Dagmar Lischke
4.4.1 Infrared (IR) Spectroscopy 151
4.4.1.1 Introduction 151
4.4.1.2 IR Spectroscopy as Identity Method for Drug Substances 152
4.4.1.2.1 Transmission Mode 152
4.4.1.2.2 Attenuated Total Reflectance (ATR) 152
4.4.1.2.3 Sample preparation 153
4.4.1.2.4 Analysis and Reporting 153
4.4.1.2.5 Examples and Limitations 154
4.4.1.2.6 Method Validation of IR Spectroscopy Identification and Quantification Methods 155
4.4.1.3 Application of IR Microscopy-Imaging Methods in Drug Development 156
4.4.1.3.1 Spatial Resolution 156
4.4.1.3.2 Measurement Setups 157
4.4.1.3.3 Case Studies 158
4.4.1.4 Conclusion 162
List of Abbreviations 162
References 163
4.5 Transmission Raman Spectroscopy - Implementation in Pharmaceutical Quality Control 165
Meike Römer
4.5.1 Raman Spectroscopy - From Research to Broad Applications in Industry 165
4.5.1.1 Objective 165
4.5.1.1.1 History 165
4.5.1.1.2 Introduction 165
4.5.1.1.3 The Raman Effect 166
4.5.2 Analytical use of Raman Spectroscopy for Pharmaceutical Purposes 167
4.5.2.1 Transmission Raman Spectroscopy (TRS) 167
4.5.2.1.1 Principles of Transmission Raman Spectroscopy 168
4.5.2.1.2 A Practical Guide to a Successful Business Case 171
4.5.3 Transmission Raman Spectroscopy - Another Practical Guide 173
4.5.3.1 Evaluation Phase 174
4.5.3.1.1 Prefeasibility Evaluation 174
4.5.3.1.2 Feasibility of a Product 176
4.5.3.2 Transmission Raman Method Development 177
4.5.3.2.1 Transmission Raman Spectroscopic Method Development 177
4.5.3.2.2 Risk Analysis 179
4.5.3.2.3 Transmission Raman Model Development, Calibration, and Validation 180
4.5.4 Regulatory Assessment and Guidelines 180
List of Abbreviations 181
References 182
4.6 Solid-state Characterization Techniques: Particle Size 185
Maria Paisana and Constança Cacela
4.6.1 Introduction 185
4.6.2 Analytical Methodologies Used to Measure Particle Size 187
4.6.2.1 Sedimentation 187
4.6.2.2 Electrozone Sensing 187
4.6.2.3 Sieving 188
4.6.2.4 Microscopy 188
4.6.2.5 Dynamic Light Scattering 188
4.6.2.6 Laser Diffraction 189
4.6.3 Method Development for Precise Particle-size Measurements by Laser Diffraction 189
4.6.3.1 Instrumentation and Measurement 189
4.6.3.2 Selection of an Appropriate Optical Model 190
4.6.3.3 Sample Dispersion 191
4.6.3.3.1 Wet Dispersion 192
4.6.3.3.2 Dry Dispersion 194
4.6.3.4 Sample Representativeness and Obscuration 195
4.6.3.5 Readiness for Method Validation 196
4.6.4 Unexpected Results and Troubleshooting in Laser Diffraction Measurement 197
4.6.4.1 Inconsistent Disconnected Peaks 197
4.6.4.2 Repeatable Artifact Peaks 199
List of Abbreviations 199
References 200
4.7 Micro Computational Tomography 203
Susana Campos and Constança Cacela
4.7.1 Tomography Imaging Techniques 203
4.7.2 Micro X-ray Computed Tomography Scan 203
4.7.2.1 The Use of CT in the Pharmaceutical Industry 204
4.7.2.1.1 μCT Applied to Density Distribution and Porous Characterization 205
4.7.2.1.2 μCT Applied for Characterization of Structural Features: Size, Shape, and Dimensions and Interfaces 207
4.7.2.1.3 μCT Applied to Coating Characterization 207
4.7.2.1.4 μCT Applied to Performance Evaluation 209
4.7.2.1.5 Foreign Matter Detection by μCT 210
List of Abbreviations 211
Notes 211
References 211
4.8 In Situ Methods for Monitoring Solid-State Processes in Molecular Materials 215
Adam A. L. Michalchuk, Anke Kabelitz, and Franziska Emmerling
4.8.1 In Situ Methods for Monitoring Solid-State Processes in Molecular Materials 215
4.8.1.1 The Complexity of Solid Materials 215
4.8.1.2 Methods to Consider 216
4.8.1.3 Methods to Monitor Crystallization Kinetics from Solution 218
4.8.1.3.1 UV-Vis Spectroscopy 218
4.8.1.3.2 Infrared Spectroscopy 219
4.8.1.4 Monitoring Crystallization from Solution: Following Solid Product Formation 221
4.8.1.4.1 Light Scattering 221
4.8.1.5 Methods to Monitor Extrinsic Solid Properties 224
4.8.1.5.1 Acoustic Emission 224
4.8.1.5.2 Thermography 226
4.8.1.6 Methods to Monitor Intrinsic Solid Properties 228
4.8.1.6.1 X-ray Diffraction 228
4.8.1.6.2 Raman Spectroscopy 232
4.8.1.7 Benefits of Combining Methods for In Situ Monitoring 236
4.8.1.8 Summary 240
List of Abbreviations 242
References 243
4.9 Application of Process Monitoring and Modeling 249
Jochen Schoell and Roberto Irizarry
4.9.1 In-process Solid Form Monitoring Techniques 249
4.9.1.1 Direct Characterization Techniques 250
4.9.1.1.1 Raman Spectroscopy 250
4.9.1.1.2 Near Infrared Spectroscopy 252
4.9.1.2 Indirect Monitoring Tools 254
4.9.1.2.1 Focused Beam Reflectance Measurement (FBRM) 254
4.9.1.2.2 Monitoring Particle Shape Using In-process Microscopy 256
4.9.1.2.3 Monitoring Solute Concentration 256
4.9.1.3 Advantages and Challenges of In Situ Solid Form Monitoring Techniques 257
4.9.2 Quantification Methods and Application to Solid Form Transformation Modeling 258
4.9.2.1 Multivariate Data Analysis 259
4.9.2.2 Data-driven Model for CLD-PSD Prediction 260
4.9.2.3 Process Modeling of Polymorph Transformation Processes 262
List of Abbreviations 265
References 266
4.10 Photon Density Wave (PDW) Spectroscopy for Nano- and Microparticle Sizing 271
Lena Bressel and Roland Hass
4.10.1 Classification of Particle Sizing Technologies 271
4.10.2 Particle Size and Solid Fraction Ranges 272
4.10.3 Photon DensityWave (PDW) Spectroscopy - Theory, Instrumentation, and Application Examples 275
4.10.4 Particle Sizing by PDWSpectroscopy 277
4.10.5 Sample Versus Process Measurements 280
4.10.6 Technical Implementation and Data Access 281
4.10.7 Examples for Process Analysis with PDWSpectroscopy 282
4.10.7.1 Crystallization of Lactose 283
4.10.7.2 Precipitation of Barium Sulfate 284
4.10.8 Summary 285
List of Abbreviations 286
References 287
5 Impact of Solid Forms on API Scale-Up 289
Sophie Janbon, Clare Mayes, and Amy L. Robertson
5.1 Introduction 289
5.2 Background 290
5.3 Small-Scale Crystallization Development 291
5.3.1 Form Selection 291
5.3.2 Solvent Selection 293
5.3.2.1 Solvent Screening 293
5.3.2.2 Solubility Diagram 294
5.3.2.3 Solubility Measurement 295
5.3.3 Crystallization Process Selection 298
5.3.3.1 Process Outline Selection 298
5.3.3.2 Process Outline Evaluation 299
5.3.3.3 Process Exploration 300
5.3.4 Process Development Conclusions 302
5.4 Crystallization Scale-Up 302
5.4.1 Crystallization Process Accommodation 303
5.4.1.1 Vessel Size and MoC 304
5.4.1.2 Agitation 304
5.4.1.3 Heat Transfer 305
5.4.1.4 Solution Addition 305
5.4.1.5 Solid Addition 305
5.4.1.6 Alternative Technologies 306
5.4.2 Risks and Common Problems 307
5.4.2.1 Metastable Forms 307
5.4.2.2 Amorphous 307
5.4.2.3 Salt Stoichiometry 308
5.4.2.4 Oiling and Phase Separations 308
5.4.3 Isolation and Drying 308
5.4.3.1 Isolation 309
5.4.3.2 Drying 311
5.4.4 Agglomeration 314
5.4.5 Particle Size Reduction 314
5.4.5.1 Delumping 314
5.4.5.2 Milling and Micronization 314
5.4.5.3 Storage and Packing 315
5.4.6 Scale-up Conclusions 315
5.5 People and Skill Requirements 315
5.6 Regulatory Requirements 315
5.6.1 Process Documentation 316
5.6.2 Safety 316
5.6.3 Quality and Manufacturability 316
5.7 Closing Remarks 317
List of Abbreviations 318
References 318
6 Impact on Drug Development and Drug Product Processing 325
Susanne Page and Anikó Szepes
6.1 Introduction 325
6.2 Pharmaceutical Profiling 327
6.3 Formulation Development 330
6.3.1 Liquid Formulations: Solutions and Suspensions 332
6.3.2 Solid Dosage Forms 335
6.3.3 Solubility Enhanced Formulations 339
6.3.3.1 Lipid-Based Formulations and Drug Delivery Systems 339
6.3.3.2 Solid Solutions and Amorphous Solid Dispersions 343
6.4 Process Development and Transfer to Commercial Manufacturing 344
6.4.1 Particle Size Reduction 345
6.4.2 Blending 345
6.4.3 Granulation 345
6.4.3.1 Wet Granulation and Drying 346
6.4.3.2 Dry Granulation/Roller Compaction 347
6.4.4 Tablet Compression 347
6.4.5 Film Coating 348
6.5 Control Strategy 348
6.6 Regulatory Submissions 349
List of Abbreviations 352
References 353
7 Workflow Management 365
Christian Große
7.1 Motivation 365
7.2 Workflow Management 365
7.3 Organization of Solid-State Development by Project Management 366
7.3.1 Stakeholders 366
7.3.2 CMC Project Management 367
7.3.3 Substance Requirement Plan 368
7.3.4 Pre-CMC Data 369
7.4 Workflows in the Environment of the Crystallization Laboratory 369
7.4.1 Micro-Project Management 369
7.4.2 Dependencies 370
7.4.3 Material Flow 371
7.4.4 Designations and Code Assignment 371
7.4.5 Analytic Database System 373
7.4.6 Physical Sample Transfer 375
7.4.7 Analytic Transfer Tool 375
7.4.8 Analytical Processes - Timely Measurement 376
7.4.9 Sample Storage Processes 377
7.4.10 Documentation 378
7.4.11 Review Process for ELN Documents 379
7.4.11.1 Document Status 379
7.4.11.2 Manual ELN Review Process 380
7.4.11.3 Archive Process 381
7.4.12 Communication with CROs 381
7.4.13 Fundamental Lab Processes 382
7.5 Processes in the Solid-State Lab 382
7.5.1 Initial Testing 382
7.5.2 Solubility Estimation 384
7.5.3 Manual Screening 384
7.5.4 High-Throughput Screening 385
7.5.5 Processes for Replica Experiments and Scale-Up of Solid Forms 387
7.6 Development of Crystallization Processes 387
7.7 Support Processes 388
7.7.1 Route Scouting Process 389
7.7.2 Crystallization of Impurities and Intermediates 389
7.7.3 Downstream Processes 389
7.7.4 Scale-Up and Technology Transfer Process 390
7.7.5 Analytical Development 390
7.7.6 Preformulation 391
7.7.7 Formulation 391
7.8 Conclusion 392
List of Abbreviations 393
References 393
8 Digitalization in Laboratories of the Pharmaceutical Industry 397
Tanja S. Picker
8.1 Introduction 397
8.2 Motivation of Digitalization in the Laboratory 398
8.2.1 Expectations of the Staff 398
8.2.2 Increasing Throughput 400
8.2.3 Repeatability 400
8.2.4 Enhanced Requirements on Data Integrity 400
8.2.5 Centralized Archiving 401
8.2.6 Ad Hoc Analysis 401
8.2.7 The Value of Data 402
8.3 Categories of Laboratory IT Systems 403
8.3.1 Devices 403
8.3.2 Lab Execution Systems (LES) and Scientific Data Management Systems (SDMS) 404
8.3.3 Lab Data Systems 404
8.3.4 Enterprise Resource Planning (ERP) 405
8.3.5 Further Use of Data 405
8.3.5.1 Data Analysis and Reporting 405
8.3.5.2 Big Data Analytics and Artificial Intelligence 406
8.4 System Interfaces for Data Exchange 406
8.4.1 Adapters 407
8.4.1.1 Serial Port (RS232) 407
8.4.1.2 Universal Series Bus (USB) 407
8.4.1.3 Ethernet 407
8.4.1.4 Cable Less Connections 407
8.4.2 Communication Medium and Protocols 408
8.4.2.1 File-Based Communication 408
8.4.2.2 ANSI/ISA-88 Batch Control (S-88) 408
8.4.2.3 Open Platform Communications Unified Architecture (OPC UA) 408
8.4.2.4 Standards in Lab Automation (SiLA) 408
8.4.3 Data Formats 409
8.4.3.1 Common Data Formats (e.g. TXT, XML, JSON) 409
8.4.3.2 Analytical Information Markup Language (AnIML) 409
8.4.3.3 Allotrope Data Format (ADF) 410
8.5 Implementation of IT Solutions 411
8.5.1 Identification of Digital Gaps in the Lab Processes 411
8.5.1.1 Contextual Inquiry 411
8.5.1.2 Interaction Room 411
8.5.2 Implementation Approach 412
8.5.2.1 Design 413
8.5.2.2 Realization 415
8.5.2.3 Verification 415
8.5.2.4 Rollout 416
8.6 Conclusion 416
List of Abbreviations 416
References 417
9.1 Polymorphs and Patents - the US Perspective 421
Kristi McIntyre
9.1.1 Introduction 421
9.1.2 What is a Patent? 421
9.1.3 How Are Patents Obtained? 422
9.1.4 United States Patent Law 422
9.1.4.1 Tapentadol Hydrochloride 423
9.1.4.1.1 Tapentadol Hydrochloride Form A Held Not Obvious 423
9.1.4.1.2 Tapentadol Hydrochloride Form AWas Found to Have Utility 424
9.1.4.2 Paroxetine Hydrochloride Hemihydrate 424
9.1.4.2.1 PHC Hemihydrate History 425
9.1.4.2.2 Meaning of “Crystalline Paroxetine Hydrochloride Hemihydrate” 425
9.1.4.2.3 PHC Hemihydrate: Infringed, But Invalid for Anticipation 426
9.1.4.3 Ranitidine Hydrochloride 426
9.1.4.3.1 History of RHCl Form 2 426
9.1.4.3.2 RHCl Form 2 Not Anticipated by Example 32 427
9.1.4.4 Cefdinir 427
9.1.4.5 Amlodipine Besylate 428
9.1.4.5.1 History of Amlodipine Besylate 428
9.1.4.5.2 Amlodipine Besylate Found Obvious 428
9.1.4.6 Concluding Remarks 429
Notes 429
References 430
9.2 Polymorphs and Patents - The EU Perspective 431
Oliver Brosch
9.2.1 European Patent Applications and European Patents 431
9.2.1.1 Introduction 431
9.2.1.2 Summary of the Processing of Applications and Patents Before the European Patent Office (EPO) 431
9.2.1.3 Economic Factors 432
9.2.1.4 Unitary Patents 433
9.2.1.5 Protection of Polymorphs and Solid Forms in General 433
9.2.1.6 Polymorph Screening 434
9.2.2 Decisions of Technical Boards of Appeal of the EPO 435
9.2.2.1 Decision T 777/08 of 24 May 2011 435
9.2.2.2 Decision T 1555/12 Dated 29 April 2015 435
9.2.2.3 Decision T 2114/13 Dated 12 October 2016 442
9.2.2.4 Decision T 2397/12 Dated 12 March 2018 442
9.2.2.5 Decision T 246/15 Dated 13 November 2018 442
9.2.3 Jurisdiction of the Federal Patent Court and the German Federal Supreme Court 443
9.2.3.1 Decision “Kristallformen” German Federal Court 443
9.2.3.2 Decision X ZR 58/08 Dated 15 March 15 2011 443
9.2.3.3 Decision X ZR 98/09 Dated 15 May 2012 444
9.2.3.4 Decision X ZR 110/16 Dated 7 August 2018 444
9.2.4 Assessing Validity of a Patent or the Chances of Success 445
9.2.5 Interaction with Patent Professionals 446
List of Abbreviations 447
References 447
10 Regulatory Frameworks Affecting Solid-State Development 449
Christoph Saal
10.1 Introduction - The Need for Regulation in Pharmaceutical Industry 449
10.2 Solid-State Forms to Be Used for Drugs 451
10.3 General Regulatory Considerations for Pharmaceutical Solid-State Forms 453
10.4 Regulatory Framework for Pharmaceutical Salts 454
10.4.1 Pharmaceutical Equivalence and Pharmaceutical Alternatives 454
10.4.2 Bioequivalence 456
10.4.3 Therapeutic Equivalence 458
10.4.4 Biowaivers 458
10.4.5 Regulatory Approval for Pharmaceutical Salts 460
10.4.5.1 Regulatory Approval Pathways in the United States 460
10.4.5.2 Regulatory Approval Pathways in the European Union 461
10.4.6 Regulatory Approval for Polymorphs 463
10.4.7 Polymorphism in Pharmacopoeias 469
10.5 Regulatory Framework for Co-crystals 471
10.6 Summary 476
List of Abbreviations 476
References 477
11 Opportunities and Challenges for Generic Development from a Solid-state Perspective 481
Judith Aronhime and Mike Teiler
11.1 The Birth of a New Drug and the Generic Siblings that Will Follow - Two Different Mindsets 481
11.1.1 Generics 481
11.1.2 Proprietary Products 482
11.1.3 API and Solid State 483
11.1.3.1 Generics 483
11.1.3.2 Proprietary 483
11.2 Portfolio Management - How is a Portfolio Constructed and Maintained? 484
11.2.1 Activities and Timelines 484
11.2.1.1 Strategy 484
11.2.1.2 Value 484
11.2.1.3 Factors Impacting on Timing - When and How Does a Product Show Up on a Generic Company’s Radar Screen? 485
11.2.2 Timing 487
11.2.2.1 When is “On-time?” 487
11.2.3 Market-specific Considerations Based on Local Legislation and Administration (OB, PIV, Various Exclusivities - US, EU, JP, etc.) 489
11.2.3.1 Patents Through the Eyes of the Regulatory Authorities 489
11.2.3.2 Data Exclusivity (Data Protection) 489
11.2.3.3 Salts and Esters 490
11.2.3.4 Think Global, Act Local 490
11.2.4 Sources to Evaluate a Project 491
11.2.4.1 Government and Regulatory Agencies 491
11.2.4.2 Analyst Reports and Company Financial Reports 492
11.2.4.3 Pay Data Sources 492
11.2.5 Evaluation Tools 493
11.2.5.1 Business Case 493
11.2.5.2 Quality Target Project Profile (QTPP) 493
11.2.6 Criteria for Identifying Promising Projects 493
11.2.7 Criteria for Building a Robust Portfolio 494
11.3 Challenges in Developing a Generic Product from the Solid-state Perspective 495
11.3.1 Implications in Developing Formulation with a Metastable API 496
11.3.2 The Stability Question 497
11.3.2.1 Polymorphic Stability in Dry Conditions 497
11.3.2.2 Polymorphic Stability inWet Conditions (Slurry) 498
11.4 Generic Solid-state Development 498
11.4.1 General 498
11.4.2 Predevelopment Phase: Solid-state Strategy 499
11.4.2.1 Review of the Solid State, Especially the Polymorph Patent Landscape 499
11.4.2.2 Design-around Considerations 500
11.4.3 Crystal Forms Discovery 503
11.4.3.1 Importance of the Crystal Forms Discovery Stage 503
11.4.3.2 New Crystal Forms Unpredictability 503
11.4.3.3 Pragmatic Questions About Crystal Forms Search 504
11.4.3.4 Late-appearing Polymorphs 505
11.4.3.5 Irreproducibility of Procedures 506
11.4.3.6 Analytical Focus 507
11.4.4 Target Selection 507
11.4.4.1 Solubility 508
11.4.4.2 Morphology 509
11.4.4.3 Solid-state Stability 509
11.4.4.4 Additional Factors 509
11.4.5 Process Development in the Laboratory Scale 510
11.4.5.1 Process Development 510
11.4.5.2 Thermodynamic Stability Relationships 510
11.4.5.3 Solubility Curves 510
11.4.5.4 API Target 511
11.4.5.5 Analytical Methods for Polymorphic Purity 512
11.4.6 Scale-up Challenges 512
11.4.6.1 Control of Crystal Form 512
11.4.6.2 Control of Particle Size and Morphology 513
11.4.6.3 Lot-to-Lot Variability 513
11.4.6.4 Analytical Focus 514
11.4.7 Pharma Development 515
11.4.7.1 The Tetrahedron Principle and Consistency Among Lots 516
11.4.7.2 The Effect of Micronization on Amorphous Content in Crystalline APIs 516
11.4.7.3 Solid-state Stability upon Storage 517
11.4.8 Impact on Formulation 517
11.4.9 Summary of Timelines for Solid-state Activity 518
11.4.10 Intellectual Property (IP) Strategies and Activities 519
11.5 Success Factors 520
11.5.1 Successful Biostudy 520
11.5.2 Successful Launch 521
11.5.3 Generic Commercial Success 522
List of Abbreviations 523
References 524
Index 531
