Preface xvii
1 Analytical Validation Within the Pharmaceutical Lifecycle 1
Phil Nethercote and Joachim Ermer
1.1 Development of Process and Analytical Validation Concepts 1
1.2 Alignments Between Process and Analytics: Three-Stage Approach 3
1.3 Predefined Objectives: ATP 5
1.4 Analytical Lifecycle 7
References 9
Part I Prerequisites 13
2 Data Governance, Data Integrity, and Data Quality 15
R.D. McDowall and C. Burgess
2.1 Terminology Used in This Chapter 15
2.2 Data Governance and Data Integrity Model 16
2.3 Interaction Between Levels 1 and 2 21
2.4 Overview of Data Integrity 21
2.5 ALCOA Criteria for Data Integrity 22
2.6 Understanding Level 3: Right Analysis for the Right Reportable Result 23
2.7 Second-Person Review 28
2.8 Summary 30
References 30
3 Analytical Instrument Qualification and System Validation Lifecycle 35
C. Burgess and R.D. McDowall
3.1 Data Integrity and Data Quality in a GMP Environment 35
3.2 AIQSV Approach as an Essential Part of the Analytical Procedure Lifecycle 37
3.3 USP General Chapter <1058> 38
3.4 Enhancement of <1058> and Harmonization of a Risk-Based Approach to Instruments and Systems with GAMP 43
3.5 Risk-Based Approaches to Analytical Instrument and System Qualification [3] 45
References 49
4 Continued HPLC Performance Qualification 51
Hermann W¤tzig and Neil J. Lander
4.1 Introduction 51
4.2 Development of the Revised OQ/PQ Parameters List 53
4.3 Transfer of Modular Parameters into the Holistic Approach 55
4.4 OQ/PQ Data in Comparison with SST Data 58
4.5 Performance Monitoring: Trending Plots/Control Charts 59
4.6 General Procedure for cPQ 61
4.7 Example 65
4.8 Concluding Remarks 66
Acknowledgment 67
References 67
Part II Establishment of Measurement Requirements 69
5 Analytical Target Profile 71
Brent Harrington
5.1 Introduction 71
5.2 Components of an ATP 72
5.3 The Probability Statements 73
5.4 Metrics for Assessment 74
5.5 Summary 76
Acknowledgments 77
References 77
6 Decision Rules and Fitness for Intended Purpose 79
Jane Weitzel
6.1 Introduction 79
6.2 Defining the Fitness for Intended Purpose 80
6.3 Decision Rules 81
6.4 Overview of Process to Develop Requirements for Procedure Performance 82
6.5 Decision Rules and Compliance 82
6.6 Calculating Target Measurement Uncertainty 83
6.7 Types of Decision Rules 86
6.8 Target Measurement Uncertainty in the ATP 88
6.9 Bias and Uncertainty in a Procedure 89
6.10 ATP and Key Performance Indicators 89
6.11 Measurement Uncertainty 90
6.12 Example 94
6.13 Conclusion 95
References 96
7 Performance Characteristics of Analytical Procedures 97
Joachim Ermer
7.1 Precision 98
7.2 Accuracy 147
7.3 Specificity/Selectivity 167
7.4 Response (Calibration Model) 175
7.5 Detection and Quantitation Limits 193
Acknowledgments 205
References 206
Part III Method Design and Understanding 217
8 ICHQ14 Analytical Procedure Development 219
Phil Borman (GSK), Peter Hamilton (AZ), and Jean-Fran§ois Dierick (GSK)
8.1 Introduction 219
8.2 The ATP 220
8.3 Connection Between Product and Analytical Procedure Understanding 222
8.4 Prior and Platform Knowledge 223
8.5 Robustness and Method Operable Design Region (MODR) 226
8.6 Link and Impact with Analytical Procedure Validation 227
8.7 Analytical Procedure Control Strategy and Ongoing Procedure Performance Verification 228
8.8 Lifecycle Strategy Including Enhanced Approaches in Submission 229
8.9 Summary 232
References 233
9 Method Selection, Development, and Optimization 237
Melissa Hanna-Brown, Roman Szucs, and Brent Harrington
9.1 Introduction 237
9.2 Method Selection 239
9.3 Method Development 240
9.4 Method Optimization 251
Acknowledgments 262
References 262
10 Multivariate Analytical Procedures 265
Wei Meng and Phil Borman
10.1 Introduction 265
10.2 Sampling and Data Quality 269
10.3 Development of Multivariate Models 271
10.4 Model Optimization and Validation 286
10.5 Model Maintenance and Lifecycle Management 289
10.6 Summary 293
Acknowledgments 293
References 293
11 Case Study: Robustness Investigations 301
Gerd Kleinschmidt and Birgit Niederhaus
11.1 Introduction 301
11.2 General Considerations in the Context of Robustness Testing 302
11.3 Examples of Computer-Assisted Robustness Studies 304
Acknowledgment 337
References 337
12 Risk Assessment and Analytical Procedure Control Strategy 343
Phil Nethercote
12.1 Background 343
12.2 Risk Management Process 343
12.3 ICH Q9 344
12.4 Using Risk Management to Develop a Control Strategy 345
12.5 Analytical Procedure Control Strategy 349
References 349
Part IV Method Performance Qualification 351
13 ICH Q2(R2): Validation of Analytical Procedures 353
Joachim Ermer
13.1 How to Read This Chapter 354
13.2 Introduction 354
13.3 General Considerations for Analytical Procedure Validation 354
13.4 Validation Tests, Methodology, and Evaluation 359
13.5 Annex 2: Illustrative Examples for Analytical Techniques 367
13.6 Conclusion 370
References 371
14 Case Study: Validation of a High-performance Liquid Chromatography (HPLC) Method for Identity, Assay, and Degradation of Products 373
Gerd Kleinschmidt and Birgit Niederhaus
14.1 Introduction 373
14.2 Experimental 375
14.3 Validation Summary 377
14.4 Validation Methodology 380
14.5 Conclusion 389
References 390
15 Case Study: Design and Qualification of a Delivered Dose Uniformity Procedure for a Pressurized Metered Dose Inhaler with a Focus on Sample Preparation 391
Andy Rignall
15.1 Introduction 391
15.2 Designing a DDU Procedure that will Meet an ATP 392
15.3 Performance Characteristics of the DDU Procedure 401
15.4 Qualification of the DDU Procedure 402
15.5 Summary of the Analytical Procedure Control Strategy for a DDU Procedure 402
Acknowledgments 403
References 403
16 Case Study: Validation of a Bioassay Method 405
Andrea Sobjak
16.1 Introduction 405
16.2 Material Considerations 407
16.3 Study Design 407
16.4 Specificity/Selectivity 410
16.5 Accuracy 411
16.6 Precision 412
16.7 Range 415
16.8 Robustness 416
16.9 Conclusion 417
Acknowledgments 417
References 418
17 Implementation of Compendial/Pharmacopeia Test Procedures 419
Pauline L. McGregor
17.1 Background of Pharmacopeia Procedures 419
17.2 How Pharmacopeia Methods Are Generated and Published 420
17.3 Challenges with Compendial Procedures and the Need to Verify 420
17.4 Using Pharmacopeia Procedures in a Laboratory for the First Time 421
17.5 Verification of Pharmacopeia Procedures 422
17.6 Integration of the Verification Process and the Lifecycle Approach 423
17.7 Implementation of a Pharmacopeia Procedure Using the Lifecycle Approach 424
17.8 Performance Qualification 431
17.9 Conclusion 432
References 432
18 Transfer of Analytical Procedures 435
Christophe Agut, Marion Berger, and Hugo Zuin
18.1 Transfer Process and Strategy 435
18.2 Comparative Testing 445
References 468
19 Lifecycle Approach to Transfer of Analytical Procedures 471
Joachim Ermer
19.1 Facilitation of Transfer by Risk Assessment 472
19.2 Facilitation of Transfer by the APCS 472
19.3 âLeanâ Transfer Strategy 473
19.4 Conclusion 474
References 475
Part V Ongoing Method Performance Verification 477
20 Continuous Improvements, Adjustments, and Changes 479
Dr. Phil W. Nethercote
20.1 Drivers for Change 479
20.2 Control of Change in the Pharmaceutical Industry 480
20.3 Implementing a Change 483
References 484
21 Monitoring of Analytical Performance 487
Joachim Ermer
21.1 Sources of Performance Data and Information 488
21.2 Systematic Monitoring Program 493
21.3 Analytical Performance Evaluation Tools 495
21.4 Assessment of Analytical Performance 503
21.5 Conclusion 508
References 508
Index 511
