Quality Control Training Manual

Comprehensive Training Guide for API,

Finished Pharmaceutical

and Biotechnologies Laboratories

Syed Imtiaz Haider • Erfan Syed Asif

o ~Y~~F~~;~~O"P Boca Raton London New York

CRC Press is an imprint of the Taylor & Francis Group, an Informa business

• =

Contents

Preface ............................................................................................................... xvii Acknowledgements ............................................................................................ xix Authors ............................................................................................................... xxi About the Book ................................................................................................ xxiii Disclaimer ....................................................................................................... xxvii

QCr-Ol Analytical Methods, Techniques and Quality Measures for General Pharmaceutical Products ........................................... 1

QCr-01.1 Analytical Method Validation and Requirements ........................ 3

Test Methods and Standards ......................................................... 3 Test Method Validation ................................................................. 3 Test Method Transfer .................................................................... 4 Change Control ............................................................................. 4 Quality Standards Manual ............................................................ 5 Laboratory Procedures .................................................................. 5 Training ......................................................................................... 6 Testing ........................................................................................... 7 Raw Data ....................................................................................... 7 Cleaning Validation ...................................................................... 8 Raw Material ................................................................................. 8

QCT-01.2 Laboratory Equipment .................................................................. 9

Calibration and Maintenance ........................................................ 9 Documentation ............................................................................ 10 Cleaning ...................................................................................... 11 Qualification of the Equipment ................................................... 11 Columns' Records ....................................................................... 12 Columns' Evaluation ................................................................... 13 Change Control ........................................................................... 13

QCT·Ol.3 Reference Standards and Reagents ............................................. 15

USP and Other Pharmacopoeial Standards ................................ 15 Reagents, Standardized Volumetrie Solution and Buffers .......... 16 Procedure for Internal Working Standards (Secondary Reference Standards) Preparation ........................... 16 Stock Solutions, Working and Test Solution ............................... 18

viii Contents

Expiration and Retest Dates for Standards and Reagents ........... 18 Storage ........................................................................................ 18 Labelling ..................................................................................... 19

QCT-01.4 SampIe Management. .................................................................. 21

Raw Materials, Finished Products, In-Process, Validation, Swab, Water, Air, Complaint... ................................. 21

QCT-01.5 Stability Analytical Methods and Requirements ........................ 25

Written Procedures ..................................................................... 25 On Site Starts .............................................................................. 26 Time and Frequencies ................................................................. 26 Statistical Considerations ............................................................ 27 Evaluation of Stability ................................................................ 27 Specifications and Methods ........................................................ 28 Stability Methods ........................................................................ 30 Stability Methods Validation Program ....................................... 30 Technology Transfer ................................................................... 30 Change Control ........................................................................... 31 Raw Data ..................................................................................... 31 Training Effectiveness ................................................................ 31 Analyst-Specific Training ........................................................... 32 Training Documentation ............................................................. 32 Stability Chambers ..................................................................... 33 Outside Laboratories ................................................................... 33

QCT-01.6 Microbiological Methods and Analysis ...................................... 35

Microbiological Methods and Testing ........................................ 35 Microbiological Testing for Non-Sterile Products ...................... 35 Growth Promotion Testing .......................................................... 36 Media Preparation and Sterilization ........................................... 36 Outside Vendor-Supplied Media ................................................ 37 Aseptic Technique Training ........................................................ 37 Gowning ...................................................................................... 38 Sterility Testing ........................................................................... 38 Automated Identification Systems .............................................. 39 Sterility Testing Facilities ........................................................... 39 Environmental Monitoring during Sterility Testing ................... 40 Water Monitoring Data ............................................................... 40 Compressed Air for Sterile Area ................................................ 41 Nitrogen Testing for Sterile Area ................................................ 41 Oxygen Testing for Sterile Area ................................................. 41

Contents IX

Preservative Effectiveness Testing .............................................. 42 Bacterial Endotoxin Testing for Sterile Products ....................... 42

QCT-01.7 Analytical Failure Investigations ................................................ 43

Laboratory Investigations ........................................................... 43 OOS Investigations ..................................................................... 44 Training on OOS Procedure ....................................................... 47 Training Documentation ............................................................. 47

QCT-01.8 Calibration Program ................................................................... 49

QC Instruments Calibration ........................................................ 49 Calibration Procedure ................................................................. 50 Calibration Frequency ................................................................. 51 Documentation ............................................................................ 52

QCT-01.9 Laboratory Facility ..................................................................... 53

General Requirements ................................................................ 53 Area for Handling Test and Reference Substances ..................... 54 Areas for Routine Samples after Complete Testing .................... 54 Reference Samples after Expiry ................................................. 55 Archive Room ............................................................................. 55 Storage of Bacterial Strains ........................................................ 56 Cleaning, Disinfecting and Washing Glass Apparatus ............... 56 Utilities ........................................................................................ 57 Safety Shower ............................................................................. 57

QCT-01.10 Products Annual Reviews ........................................................... 59

Annual Reviews .......................................................................... 59 Written Procedures ..................................................................... 59 Management Review ................................................................... 60 Data Reliability ........................................................................... 61 Use of Ongoing Statistics ............................................................ 61 Follow-up .................................................................................... 61

QCT-Ol.l1 Third-Party Testing ..................................................................... 63

General ........................................................................................ 64

QCT-01.12 Good Documentation Practices .................................................. 65

Documentation ............................................................................ 65 Procedure .................................................................................... 65

x Contents

QCT-Ol.13 Change Control ........................................................................... 67

Unplanned Changes .................................................................... 68 Planned Changes ......................................................................... 68 Routine Changes (Documentation) ............................................. 68

QCT-02 Analytical Methods, Techniques and Quality Measures for Biological Products ............................................................... 71

QCT-02.1 Immunoblotting .......................................................................... 73

Immunoblotting Analytical Technique ....................................... 73 Procedure .................................................................................... 74 Enhanced Chemiluminescence ................................................... 76

QCT-02.2 Gel Permeation Chromatography .. , ............................................ 79

Basic Philosophy ......................................................................... 79 Mechanism of Gel Permeation Chromatography ....................... 81 Advantages ofGPC ..................................................................... 81 Disadvantages ............................................................................. 82

QCT-02.3 Electrophoresis ............................................................................ 85

Gel Electrophoresis ..................................................................... 85 DNA Electrophoresis .................................................................. 86 One-Dimensional (lD) Electrophoresis ...................................... 87 Two-Dimensional (2D) Electrophoresis ...................................... 88 Capillary Electrophoresis ........................................................... 88 Capillary Zone Electrophoresis .................................................. 90 Capillary Gel Electrophoresis ..................................................... 90 Capillary Isoelectric Focusing .................................................... 90

QCT-02.4 Ion-Exchange Chromatography .................................................. 93

Effect of Charge on the Protein Molecule .................................. 94 Protein Separation by IEC .......................................................... 95 Anion-Exchange Chromatography ............................................. 96 Cation-Exchange Chromatography ............................................. 96

QCT-03 Laboratory Training Manual ...................................................... 99

QCT-03.1 Laboratory Safety and Good LaboratofY Practice .................... 101

Procedure ...................................................... ............................. 101 Good Laboratory Practices ....................................................... 104

Contents xi

QCT-03.2 Training of Sampling Proeedure ............................................... 107

Proeedure .................................................................................. 107

QCT-03.3.1 Training of Conventional Proeedures ........................................ 113

Proeedure ................................................................................... 113

QCT-03.3.2 Training of Basie Analytieal Teehniques .................................. 115

Weighing .................................................................................... 115 Volumetrie Teehniques .............................................................. 116 Definitions .................................................................................. 116 Use of Burette ............................................................................ 116 Temperature Measurement and Contral .................................... 117 Heating ....................................................................................... 117 Cooling ....................................................................................... 117 Meehanieal Methods of Separation ........................................... 117 Limit Tests ................................................................................. 118 Determination of Weight per Millilitre Density/Solids ............. 119 Physieal Observations ............................................................... 120

QCT-03.3.3 Training of Chromatographie Teehniques ................................ 121

Testing to Speeifieation/Praetieal Work ................................... 121 Chromatographie Teehniques ................................................... 121 HPLC Pumping System ............................................................ 122 Injeetors .................................................................................... 123 Columns .................................................................................... 123 Deteetors ................................................................................... 124 Solvents and Reagents ............................................................... 125 Data Handling and Interpretation ............................................. 125 Gas Chromatography ................................................................ 126 Sampie Injeetion ....................................................................... 126 Types of Columns ..................................................................... 126 Injeetors .................................................................................... 127 Deteetors ................................................................................... 127 Proeedure .................................................................................. 127

QCT-03.3.4 Speetroseopie Techniques .......................................................... 131

UV Absorption and Colorimetry ............................................... 131 Infrared Speetrophotometry ..................................................... 132 Atomic Absorption Speetrometry ............................................. 132 Instrumentation ......................................................................... 133 Sampie Preparation and Vaporization ...................................... 134

xii Contents

Interferences and Quantitative Measurements .......................... 134 Trainee Assessment .................................................................. 135 Flame Emission Spectrometry.................................................. 135 SampIe Preparation and Vaporization ...................................... 136 Interference and Quantitative Measurements ........................... 136 Trainee Assessment .................................................................. 137

QCT-03.3.5 Electrochemical Techniques ..................................................... 139

pH Measurement and Ion-Selective E1ectrodes ........................ 139 Potentiometer Titrations, if Availab1e ....................................... 140 Biamperometrie Titrations ........................................................ 140 Kar! Fischer Titrations .............................................................. 140 Automatie Titrations .................................................................. 141

QCT-03.3.6 Dissolution Test. ......................................................................... 143

QCT-03.3.7 Miseellaneous Teehniques ........................................................ 145

Polarimetry ............................................................................... 145 Particle Size Analysis ............................................................... 146 Suppository Penetration Tester ................................................. 146 Viscometry ................................................................................. 147 Other Analytieal Teehniques ..................................................... 147

QCT-04 Assessment of Training ............................................................. 149

QCT-04.1 Assessment Proeedure for Chemical Testing ........................... 151

Procedure .................................... " ................................. , .......... 151 Use of Balance and Volumetrie Techniques ............................. 151 Titration with 1.0 M Hydrochlorie Acid ................................... 151 Quantitative Transfer of Sodium Hydroxide ............................. 152 Temperature Measurement and Control ................................... 152 Solvent Extraetion Exereise ...................................................... 153 Exereise for Limit Tests ............................................................ 153 Determination ofWeight per mL and Density of Solid ............ 155 Physieal Observation ................................................................. 155 Testing to Specifieation/Praetieal Work ................................... 155 Chromatographie Teehniques ................................................... 155 Assessment Proeedures for GC and HPLC ............ " ...... " ........ 156 Test Procedure ............................... " ................ """"""""""""" 157 Criteria for Assessment ............................................................. 159

Contents xiii

QCT-04.2 Assessment Pracedure for Microbiologist ................................. 161

Procedure ................................................................................... 161 Use of Balance and Volumetrie Techniques .............................. 161 Temperature Measurement and Contral .................................... 161 Media Preparation ..................................................................... 162 Glassware Preparation .............................................................. 162 Aseptic Technique ..................................................................... 162 Autoclaves ................................................................................. 162 Testing to Specification/Practical Work ................................... 163 M icrabiologicaI Assays ............................................................. 163 pH Measurement ....................................................................... 164 Environmental Monitoring ....................................................... 164 Aerobic MicrabiaI Counts Organism Identification ................. 164 Maintenance of Cultures and Organism Identification ............. 165

QCT-05 Training Assessment with Quiz and Answers .......................... 167

QCT-05.1 Assessment for Analytical Methods Validation and Requirements ............................................................................ 169

QCT-05.1.1 Answers to Quiz for Analytical Methods Validation and Requirements ............................................................................. 173

QCT-05.2 Assessment for Analytical Equipment... ................................... 177

QCT-05.2.1 Answers to Quiz for Analytical Equipment ............................. 183

QCT-05.3 Assessment for Reference Standards and Reagents .................. 187

QCT-05.3.1 Answers to Quiz for Reference Standards and Reagents ......... 193

QCT-05.4 Assessment for Sampie Management ....................................... 197

QCT-05.4.1 Answers to Quiz for Sampie Management ............................... 201

QCT-05.5 Assessment for Stability Analytical Methods and Requirements ............................................................................ 205

QCT-05.5.1 Answers to Quiz for Stability Analytical Methods and Requirements ............................................................................. 211

xiv Contents

QCT-05.6 Assessment for Microbiological Methods and Testing ............... 215

QCT-05.6.1 Answers to Quiz for Microbiological Methods and Testing ...... 219

QCT-05.7 Assessment for Laboratory Investigations ................................ 223

QCT-05.7.1 Answers to Quiz for Laboratory Investigations ........................ 229

QCT-05.8 Assessment for Calibration Programme ................................... 233

QCT-05.8.1 Answers to Quiz for Calibration Programme ........................... 239

QCT-05.9 Assessment for Laboratory Facility .......................................... 243

QCT-05.9.1 Answers to Quiz for Laboratory Facility .................................. 249

QCT-05.10 Assessment for Annual Reviews ............................................... 253

QCT-05.10.1 Answers to Quiz for Annual Reviews ...................................... 257

QCT-05.11 Assessment for Third-Party Testing ......................................... 259

QCT-05.11.1 Answers to Quiz for Third-Party Testing ................................. 263

QCT-05.12 Assessment for Good Documentation Practices ....................... 265

QCT-05.12.1 Answers to Quiz for Good Documentation Practices ............... 269

QCT-05.13 Assessment for Change Control.. .............................................. 271

QCT-05.13.1 Answers to Quiz for Change Contro1... ..................................... 275

QCT-05.14 Assessment for Immunoblotting ............................................... 277

QCT-05.14.1 Answers to Quiz for Immunoblotting ....................................... 281

QCT-05.15 Assessment for Gel Permeation Chromatography .................... 283

QCT-05.15.1 Answers to Quiz for Gel Permeation Chromatography ............ 289

QCT-05.16 Assessment for Electrophoresis ................................................ 293

QCT-05.16.1 Answers to Quiz for Electrophoresis ........................................ 299

Contents xv

QCT-05.17 Assessment for Ion-Exchange Chromatography ....................... 303

QCT-05.17.1 Answers to Quiz for Ion-Exchange Chromatography ............... 307

QCT-06 Training Log ............................................................................. 309

QCT-06.1 General Introduction Training Log ............................................ 311

General Introduction of Company and Department .................. 311

QCT-06.2 Good Housekeeping and Good Laboratory Practice ................. 3l3

Good Housekeeping Safety and GLP ........................................ 313

QCT-06.3 Sampling Procedure Training Log ............................................ 315

Training of Sampling Procedure ................................................ 315

QCT-06.4 Chemical Testing Training Log ................................................. 317

Training of Chemical Testing .................................................... 317

QCT-06.5 Training Log for Microbiology ................................................. 323

QCT-07 Analytical Method Validation Master Plan .............................. 327

Purpose ..................................................................................... 328 Introduction ............................................................................... 328 Scope and Approach ................................................................. 329 Method Validation Team Responsibilities ................................ 333 Method Validation Strategies .................................................... 334 New Products, Methods and Instruments ................................. 335 Revalidation .............................................................................. 336 Protocol Development Phase ................................................... , 336 Selectivity and Specificity ......................................................... 337 Precision and Reproducibility ................................................... 338 Accuracy and Recovery ............................................................ 339 Linearity and Calibration Curve ............................................... 339 Range ........................................................................................ 340 Limit of Detection and Quantitation ......................................... 340 Robustness ................................................................................ 340 Acceptance Criteria .................................................................. 341 Analytical Results Reporting .................................................... 341 Incident Investigation ................................................................ 341

xvi Contents

Validation Reports .................................................................... 3·+1 Change ControlIRevalidation ................................................... 342

QCT-08 Analytical Methods Validation Protocol .................................. 3 .. ß

Purpose ..................................................................................... 344 Introduction ............................................................................... 344 Materials and Equipment .......................................................... 344 Responsibilities ......................................................................... 345 Definitions ................................................................................. 345 Procedure .................................................................................. 346

QCT-09 SOP for Annual Re .. Qualification of HPLC Units .................... 349

Purpose ..................................................................................... 349 Scope ......................................................................................... 349 Responsibilities ......................................................................... 349 HPLC Qualification .................................................................. 349 Attachment ................................................................................ 350 Procedure .................................................................................. 350 Form No. I ................................................................................ 355

QCT-IO SOP for Annual Re-Qualification of GC Units ........................ 357

Purpose ..................................................................................... 357 Scope ......................................................................................... 357 Responsibilities ......................................................................... 357 HPLC Qualification .................................................................. 357 Attachment ................................................................................ 358 Procedure .................................................................................. 358 Form No. 1 ................................................................................ 363

QCT-ll ABC Pharmaceutical Company ................................................ 365

Good Laboratory Practices ....................................................... 365

QCT-12 Regulations ............................................................................... 371

Index ................................................................................................................. 449