List of Contributors XIII
Part I Fundamentals of Validation in Pharmaceutical Analysis 1
1 Analytical Validation within the Pharmaceutical Environment 3
Joachim Ermer
1.1 Regulatory Requirements 4
1.2 Integrated and Continuous Validation 5
1.3 General Planning and Design of Validation Studies 7
1.3.1 Always Look on the Routine’ Side of Validation 8
1.4 Evaluation and Acceptance Criteria 9
1.4.1 What does Suitability Mean? 9
1.4.2 Statistical Tests 12
1.5 Key Points 14
2 Performance Parameters, Calculations and Tests 21
2.1 Precision 21
Joachim Ermer
2.1.1 Parameters Describing the Distribution of Analytical Data 22
2.1.2 Precision Levels 30
2.1.3 Acceptable Ranges for Precisions 35
2.1.4 Sources to Obtain and Supplement Precisions 49
2.1.5 Key Points 51
2.2 Specificity 52
Joachim Ermer
2.2.1 Demonstration of Specificity by Accuracy 55
2.2.2 Chromatographic Resolution 55
2.2.3 Peak Purity (Co-elution) 57
2.2.4 Key Points 62
VII
Contents
Method Validation in Pharmaceutical Analysis. A Guide to Best Practice. Joachim Ermer, John H. McB. Miller (Eds.)
Copyright 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
ISBN: 3-527-31255-2
2.3 Accuracy 63
Joachim Ermer
2.3.1 Drug Substance 64
2.3.2 Drug Product 67
2.3.3 Impurities/Degradants and Water 71
2.3.4 Cleaning Validation Methods 74
2.3.5 Acceptance Criteria 77
2.3.6 Key Points 79
2.4 Linearity 80
Joachim Ermer
2.4.1 Unweighted Linear Regression 81
2.4.2 Weighted Linear Regression 94
2.4.3 Non-linear and Other Regression Techniques 97
2.4.4 Key Points 98
2.5 Range 99
Joachim Ermer
2.6 Detection and Quantitation Limit 101
Joachim Ermer and Christopher Burgess
2.6.1 Analytical Detector Responses 102
2.6.2 Requirements for DL/QL in Pharmaceutical Impurity Determination 104
2.6.3 Approaches Based on the Blank 108
2.6.4 Determination of DL/QL from Linearity 110
2.6.5 Precision-based Approaches 117
2.6.6 Comparison of the Various Approaches 118
2.6.7 Key Points 119
2.7 Robustness 120
Gerd Kleinschmidt
2.7.1 Terminology and Definitions 120
2.7.2 Fundamentals of Robustness Testing 122
2.7.3 Examples of Computer-assisted Robustness Studies 126
2.8 System Suitability Tests 170
John H. McB. Miller
2.8.1 Introduction 170
2.8.2 Non-chromatographic Techniques 170
2.8.3 Separation Techniques 171
3 Case Study: Validation of an HPLC-Method for Identity,
Assay, and Related Impurities 195
Gerd Kleinschmidt
3.1 Introduction 195
3.2 Experimental 197
3.3 Validation Summary 197
3.3.1 Specificity 200
3.3.2 Linearity 200
3.3.3 Precision 200
VIII Contents
3.3.4 Accuracy 200
3.3.5 Detection and Quantitation Limit 201
3.3.6 Robustness 201
3.3.7 Overall Evaluation 201
3.4 Validation Methodology 201
3.4.1 Specificity 201
3.4.2 Linearity 202
3.4.3 Accuracy 205
3.4.4 Precision 208
3.4.5 Range 210
3.4.6 Detection Limit and Quantitation Limit 210
3.4.7 Detection Limit and Quantitation Limit of DP1 212
3.4.8 Robustness 212
3.5 Conclusion 212
References Part I 213
Part II Life-cycle Approach to Analytical Validation 227
4 Qualification of Analytical Equipment 229
David Rudd
4.1 Introduction 229
4.2 Terminology 230
4.3 An Overview of the Equipment Qualification Process 231
4.4 Documentation of the EQ Process 233
4.5 Phases of Equipment Qualification 234
4.5.1 Design Qualification (DQ) 234
4.5.2 Installation Qualification (IQ) 236
4.5.3 Operational Qualification (OQ) 237
4.5.4 Performance Qualification (PQ) 237
4.6 Calibration and Traceability 238
4.7 Re-qualification 239
4.8 Accreditation and Certification 241
4.9 References 241
5 Validation During Drug Product Development – Considerations
as a Function of the Stage of Drug Development 243
Martin Bloch
5.1 Introduction 243
5.2 Validation During Early Drug Development 244
5.2.1 Simplifications During Early Development 246
5.2.2 Example 1: Assay or Content Uniformity of a Drug Product by
HPLC During Early Drug Product Development: Proposal for a
Validation Scheme 248
Contents IX
5.2.3 Variation of Example 1: More than on Strength of Drug Product 250
5.2.4 Example 2: Degradation Products from a Drug Product by HPLC During
Early Drug Product Development: Proposal for a Validation Scheme 251
5.2.5 Example 3: Residual Solvents of a Drug Product by GC During Early Drug
Product Development: Proposal for a Validation Scheme 257
5.2.6 Example 4: Analytical Method Verification’ for GLP Toxicology
Study 258
5.2.7 Example 5: Dissolution Rate of a Drug Product During Early Drug
Product Development: Proposal for Validation Schemes 259
5.2.8 Validation of other Tests (Early Development) 263
5.3 References 264
6 Acceptance Criteria and Analytical Variability 265
Hermann Watzig
6.1 Introduction 265
6.2 Analytical Variability 266
6.2.1 Uncertainty of the Uncertainty 266
6.2.2 Estimating the Analytical Uncertainty 269
6.3 Acceptance Criteria 274
6.3.1 Assay of Drug Substances 274
6.3.2 Assay of Active Ingredients in Drug Products 274
6.3.3 Dissolution Testing 276
6.3.4 Stability Testing 276
6.3.5 Impurities 277
6.4 Conclusions 277
6.5 References 278
7 Transfer of Analytical Procedures 281
Mark Broughton and Joachim Ermer (Section 7.3)
7.1 Overview 281
7.1.1 Transfer Process 282
7.2 Process Description 283
7.2.1 Method Selection 283
7.2.2 Early Review of the Analytical Procedure 285
7.2.3 Transfer Strategy 286
7.2.4 Receiving Laboratory Readiness 287
7.2.5 Self-qualification 290
7.2.6 Comparative Studies 290
7.3 Comparative Studies 291
7.3.1 General Design and Acceptance Criteria 291
7.3.2 Assay 293
7.3.3 Content Uniformity 297
7.3.4 Dissolution 297
7.3.5 Minor Components 298
X Contents
7.4 Conclusion 299
7.5 References 300
8 Validation of Pharmacopoeial Methods 301
John H. McB. Miller
8.1 Introduction 301
8.2 Identification 304
8.3 Purity 307
8.3.1 Appearance of Solution 308
8.3.2 pH or Acidity/Alkalinity 308
8.3.3 Specific Optical Rotation 310
8.3.4 Ultraviolet Spectrophotometry 310
8.3.5 Limit test for Anions/Cations 310
8.3.6 Atomic Absorption Spectrometry 312
8.3.7 Separation Techniques (Organic Impurities) 313
8.3.8 Loss on Drying 319
8.3.9 Determination of Water 319
8.3.10 Residual Solvents or Organic Volatile Impurities 322
8.4 Assay 326
8.4.1 Volumetric Titration 327
8.4.2 Spectrophotometric Methods 329
8.5 Conclusions 332
8.6 References 332
9 Analytical Procedures in a Quality Control Environment 337
Raymond A. Cox
9.1 Monitoring the Performance of the Analytical Procedure 337
9.1.1 Utilization of Blanks 337
9.1.2 System Suitability Test Parameters and Acceptance Criteria 338
9.1.3 Use of Check or Control Samples 339
9.1.4 Analyst Performance 341
9.1.5 Instrumental Performance 342
9.1.6 Reagent Stability and Performance 343
9.1.7 Internal Limits and Specifications 343
9.2 Use of Control Charts 344
9.2.1 Examples of Control Charts 344
9.2.2 Population in Control Charts 347
9.2.3 Cost of Control Charts 347
9.3 Change Control 348
9.3.1 Basic Elements of Test Procedure Change Control 348
9.3.2 Change Control for Calibration and Preventative Maintenance 349
9.3.3 Future Calibration and Preventative Maintenance 350
9.4 When is an Adjustment Really a Change? 350
9.4.1 Chromatographic Adjustments versus Changes 351
Contents XI
9.5 Statistical Process Control (SPC) 351
9.5.1 Purpose of Control Charts 352
9.5.2 Advantages of Statistical Process Control 352
9.6 Revalidation 352
9.6.1 Revalidation Summary 354
9.7 References 354
10 Aberrant or Atypical Results 355
Christopher Burgess
10.1 Laboratory Failure Investigation 355
10.2 Basic Concepts of Measurement Performance 357
10.3 Measurements, Results and Reportable Values 359
10.4 Sources of Variability in Analytical Methods and Procedures 361
10.5 Analytical Process Capability 362
10.6 Classification of Atypical or Aberrant Results 366
10.7 Statistical Outlier Tests for Out-of-Expectation Results 371
10.8 Trend Analysis for Quality Control 378
10.9 CuSum Analysis of System Suitability Data 380
10.10 Summary 385
10.11 References 385
11 Future Trends in Analytical Method Validation 387
David Rudd
11.1 Introduction 387
11.2 Real Time’ Analytical Methodologies 389
11.3 Validation Consequences of Real Time’ Analytical Methodologies 390
11.4 Additional Validation Factors 393
11.4.1 To Calibrate or not to Calibrate? 393
11.5 Validation of Analytically-based Control Systems 394
11.5.1 What is the Basis for the Decision-Making Process? 394
11.5.2 What are the Acceptable Operating Ranges? 395
11.5.3 Robustness of Process Signature 395
11.6 Continuous Validation 395
11.7 Conclusion 396
11.8 References 396