| | Contents | |
| | | |
| |
| | Preface | V |
| | List of Contributors | XIII |
| | | |
| Part I | Fundamentals of Validation in Pharmaceutical Analysis | 1 |
| | | |
| 1 | Analytical Validation within the Pharmaceutical Environment
Joachim Ermer | 3 |
| 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
Joachim Ermer | 21 |
| 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
Joachim Ermer | 52 |
| 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 |
| 2.3 | Accuracy
Joachim Ermer | 63 |
| 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
Joachim Ermer | 80 |
| 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
Joachim Ermer | 99 |
| 2.6 | Detection and Quantitation Limit
Joachim Ermer and Christopher Burgess | 101 |
| 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
Gerd Kleinschmidt | 120 |
| 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
John H. McB. Miller | 170 |
| 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
Gerd Kleinschmidt | 195 |
| 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 |
| 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
David Rudd | 229 |
| 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
Martin Bloch | 243 |
| 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 |
| 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
Hermann Wätzig | 265 |
| 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
Mark Broughton and Joachim Ermer (Section 7.3) | 281 |
| 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 |
| 7.4 | Conclusion | 299 |
| 7.5 | References | 300 |
| 8 | Validation of Pharmacopoeial Methods
John H. McB. Miller | 301 |
| 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
Raymond A. Cox | 337 |
| 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 |
| 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
Christopher Burgess | 355 |
| 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
David Rudd | 387 |
| 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 |
| | Index | 399 |
