Guide to Microbiological Control in Pharmaceuticals and Medical Devices, Second Edition

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Guide to Microbiological Control in Pharmaceuticals and Medical Devices, SECOND EDITION......Page 2
ACKNOWLEDGMENTS......Page 4
ACKNOWLEDGEMENTS......Page 5
The Editors......Page 7
Contributors......Page 9
Contents......Page 11
CONTENTS......Page 14
Table of Contents......Page 0
1.2 THE GENERAL STRUCTURE OF A BACTERIAL AND FUNGAL CELL......Page 15
1.2.1 THE BACTERIAL CELL......Page 16
1.2.3 PROKARYOTE AND EUKARYOTE......Page 17
1.2.4.1 Bacterial Spores......Page 18
1.2.4.2 Fungal Spores......Page 19
1.3 BACTERIAL AND FUNGAL GROWTH......Page 20
1.3.1.2 Environmental Factors......Page 21
1.3.2.2 Viable Counts......Page 23
1.3.3 THE PATTERN OF GROWTH......Page 24
1.3.4.1 Genetic Exchange......Page 25
1.3.6 CHEMICAL INHIBITION AND DESTRUCTION OF MICROORGANISMS......Page 26
1.4.1 CARBOHYDRATES......Page 27
1.5 PRINCIPLES OF MICROBIAL IDENTIFICATION......Page 28
1.5.1.2 Diagnostic Media......Page 29
1.7 GENERAL PROPERTIES OF SELECTED MICROORGANISMS......Page 30
1.7.1.4 Salmonellae......Page 31
1.7.2.2 Bacillus......Page 32
1.7.3.3 Zygosaccharomyces rouxii......Page 33
FURTHER READING......Page 34
CONTENTS......Page 35
2.2 CONTAMINATION OF PHARMACEUTICAL PRODUCTS......Page 36
2.3 SOURCES OF MICROBIAL CONTAMINATION IN PHARMACEUTICAL PRODUCTS......Page 38
2.4 FACTORS THAT AFFECT SURVIVAL AND GROWTH OF ORGANISMS IN PRODUCTS......Page 41
2.5 MICROBIAL SPOILAGE OF PHARMACEUTICAL PRODUCTS......Page 42
2.5.1 BREAKDOWN OF ACTIVE INGREDIENTS......Page 43
2.5.2 PRODUCTION OF TOXINS......Page 44
2.5.3.2 Degradation of Thickening and Suspending Agents......Page 45
2.5.5 DEGRADATION OF PRESERVATIVES......Page 47
2.6.1 TYPE OF ORGANISM......Page 48
2.6.4 ROUTE OF ADMINISTRATION......Page 49
2.6.4.2 Topical Administration......Page 50
2.6.4.5 Ophthalmic Preparations......Page 51
2.6.4.7 Injections and Infusions......Page 52
2.7 CONTAMINATION OF MEDICAL DEVICES......Page 53
REFERENCES......Page 55
3.1 INTRODUCTION......Page 63
3.2 RAW MATERIALS......Page 64
3.3.1.2 Reverse Osmosis......Page 66
3.3.1.3 Deionization......Page 68
3.4 PACKAGING......Page 71
3.5.1 WAREHOUSE......Page 72
3.5.2 MANUFACTURE OF NONSTERILE DRY PRODUCTS......Page 74
3.5.3 PRODUCTION OF NONSTERILE LIQUIDS, CREAMS, AND OINTMENTS......Page 75
REFERENCES......Page 77
4.1.1 DEVELOPMENT OF ENVIRONMENTAL CONTROL......Page 80
4.1.2 CLEANROOM CLASSIFICATION......Page 81
4.2 SOURCES OF ENVIRONMENTAL CONTAMINATION......Page 83
4.3.1.1 Mechanisms of Filtration......Page 85
4.3.1.2 HEPA Filters......Page 86
4.3.1.3 HEPA Filter Installation......Page 87
4.3.2 AIRFLOW MANAGEMENT......Page 88
4.3.2.1 Conventional (Turbulent) Flow......Page 89
4.3.2.3 Unidirectional Flow Rooms (UFRs)......Page 90
4.3.3 DESIGN PRINCIPLES......Page 93
4.3.3.1 Design Features......Page 94
4.4 ISOLATOR TECHNOLOGY......Page 95
REFERENCES......Page 97
CONTENTS......Page 99
5A.2 PRODUCTION OF THERAPEUTIC PROTEINS FROM CELL CULTURE FROM CELL CULTURE......Page 100
5A.3 CONSEQUENCES OF CONTAMINATION......Page 101
5A.4.1 PROCESS MATERIALS......Page 102
5A.4.3 WATER......Page 103
5A.4.5 PERSONNEL......Page 104
5A.5.1 BACTERIA AND FUNGI......Page 105
5A.5.2 ENDOTOXINS......Page 106
5A.5.3 MYCOPLASMAS......Page 107
5A.5.4 CROSS-CONTAMINATION......Page 108
5A.5.6 VIRUSES......Page 109
5A.5.7 AVOIDANCE OF BIOLOGICAL CONTAMINATION......Page 111
5A.5.7.1 Virus Clearance Validation......Page 113
ACKNOWLEDGMENT......Page 115
REFERENCES......Page 116
5B.2 THE NATURE OF MEDICAL DEVICES......Page 120
5B.3 FACTORS INFLUENCING THE MICROBIAL ECOLOGY......Page 124
5B.4 SUITABILITY OF MICROBIAL METHODS FOR MONITORING CONTAMINATION......Page 125
5B.5 USE OF INFORMATION FROM MICROBIOLOGICAL MONITORING......Page 126
5B.6 DYNAMIC MICROBIOLOGICAL QUALITY ASSURANCE FOR MEDICAL DEVICE PRODUCTION......Page 127
REFERENCES......Page 128
CONTENTS......Page 130
6.1 INTRODUCTION......Page 131
6.2.2 CLEANROOM CLASSIFICATION......Page 132
6.2.3 CLOTHING......Page 133
6.2.4 CLEANING AND DISINFECTION......Page 134
6.2.6 MOTIVATION......Page 136
6.2.8 PROCEDURES......Page 137
6.2.10 DOCUMENTATION......Page 138
6.3.1 DRY PRODUCTS......Page 139
6.3.2 LIQUIDS, CREAMS, AND OINTMENTS......Page 140
6.3.4 ASEPTIC MANUFACTURE......Page 141
6.3.5 FORM-FILL-SEAL......Page 142
6.4.1 CHEMICAL RAW MATERIALS......Page 143
6.4.3 LIQUIDS, CREAMS, AND OINTMENTS......Page 144
6.4.4.1 Water for Injection......Page 145
6.4.4.3 Filtration......Page 146
6.4.4.6 Sterilization Methods......Page 147
REFERENCES......Page 148
7.2 GENERAL MATHEMATICAL PRINCIPLES......Page 152
7.3 STILL AIR AND COMPLETELY TURBULENT MIXING AIR......Page 154
7.4 UNIDIRECTIONAL AIR FLOW......Page 157
7.5 FACTUAL SITUATIONS......Page 158
7.6 LIMITATION OF RISKS......Page 160
REFERENCES......Page 162
CONTENTS......Page 164
8.2 SAMPLING......Page 165
8.2.1 SAMPLING TECHNIQUES......Page 166
8.2.2.2 Attribute Sampling......Page 167
8.3 CULTURE MEDIA......Page 168
8.3.1 PREPARATION AND USE OF CULTURE MEDIA......Page 169
8.3.2 CULTURE METHODS......Page 170
8.4.1 CONTROL OF RAW MATERIALS......Page 171
8.4.2.1 Sterility Test......Page 173
8.4.2.2 Testing for Pyrogens......Page 176
8.4.3 MICROBIOLOGICAL TESTS ON NONSTERILE PRODUCTS......Page 177
8.4.3.1 Enumeration Methods......Page 178
8.4.3.2 Tests for Specified Microorganisms......Page 179
8.4.4 BIOBURDEN TESTING OF MEDICAL DEVICES......Page 180
8.4.5 ENVIRONMENTAL MONITORING......Page 182
8.4.5.2 Microbiological Limits......Page 183
8.4.5.3 Methodology......Page 185
8.4.5.4 Environmental Monitoring in Advanced Aseptic Processing......Page 186
8.5.3 ACTIVITIES......Page 187
REFERENCES......Page 188
9.1 INTRODUCTION......Page 192
9.2 RAPID METHODS AVAILABLE......Page 193
9.3.1 PRODUCT QUALITY ASSESSMENT......Page 195
9.3.4 STERILIZER TESTING......Page 198
9.4 OVERVIEW......Page 199
REFERENCES......Page 200
CONTENTS......Page 205
10.1 INTRODUCTION......Page 206
10.2.1 MICROBIAL INACTIVATION KINETICS......Page 207
10.2.3 D VALUE......Page 209
10.2.5 NONLINEAR SURVIVOR CURVES......Page 211
10.3.1.2 Quantal Data......Page 213
10.3.2 EFFECT OF TEMPERATURE ON MICROBIAL RESISTANCE......Page 215
10.3.2.1 z Value......Page 216
10.3.2.3 Activation Energy for Microbial Inactivation......Page 217
10.4 RESISTANCE OF MICROORGANISMS TO INACTIVATION......Page 218
10.5 SELECTION OF A STERILIZATION METHOD......Page 219
10.6.1.1 Measures of Heat Sterilization Efficiency......Page 221
10.6.1.2 Integrated Lethality Determination......Page 223
10.6.1.3 Design of Optimum Autoclaving Protocols......Page 224
10.6.2 RADIATION STERILIZATION......Page 225
10.6.3.1 Alkylating Agents......Page 228
10.6.3.2 Oxidizing Agents......Page 229
10.6.4 FILTRATION STERILIZATION......Page 232
10.7 COMPARISON OF THE EFFICACY OF STERILIZATION METHODS......Page 233
FURTHER READING......Page 235
CONTENTS......Page 237
11.1 INTRODUCTION......Page 238
11.2 STERILIZATION METHODS: GENERAL ASPECTS......Page 240
11.2.4 PRODUCT RELEASE FROM STERILIZATION......Page 245
11.3 STEAM STERILIZATION......Page 246
11.3.1.1 Equipment......Page 247
11.3.1.3 Routine Tests of Performance......Page 248
11.3.2.3 Product Release......Page 250
11.3.3 BOTTLED FLUIDS STERILIZER......Page 251
11.3.3.1 Equipment......Page 252
11.3.4 STERILIZATION IN PLACE......Page 253
11.3.4.1 Equipment......Page 254
11.4.1 EQUIPMENT......Page 255
11.4.2 THE PROCESS......Page 256
11.5.1 EQUIPMENT......Page 257
11.5.2 THE PROCESS......Page 258
11.6.1 ETHYLENE OXIDE......Page 259
11.6.1.2 The Process......Page 260
11.6.2.1 Equipment......Page 262
11.6.2.2 The Process......Page 263
11.6.3.2 The Process......Page 264
11.6.3.3 Product Release......Page 265
11.7 FILTRATION STERILIZATION......Page 266
11.7.2 THE PROCESS......Page 267
11.8 LIQUID CHEMICAL STERILANTS......Page 268
11.8.3 PRODUCT RELEASE......Page 269
11.9.1 CHLORINE DIOXIDE......Page 270
11.9.3 PERACETIC ACID......Page 271
11.9.5 PULSED LIGHT......Page 272
11.9.6 MICROWAVES......Page 273
REFERENCES......Page 274
CONTENTS......Page 280
12.1 STERILITY AND ASSURANCE OF STERILITY......Page 281
12.2 REGULATORY REQUIREMENTS......Page 283
12.3.1.1 Sterilizing Principle......Page 285
12.3.1.2 Equivalent Overkill Cycles......Page 286
12.3.1.3.1 Designated Bioindicator Cycles......Page 287
12.4.1 STERILIZATION BY MOIST HEAT UNDER PRESSURE......Page 288
12.4.2.1 Gravity Displacement Cycles......Page 289
12.4.2.2 Prevacuum Cycles......Page 290
12.4.3 STERILIZATION BY DRY HEAT......Page 291
12.4.4 GASEOUS STERILIZATION......Page 292
12.4.5 STERILIZATION BY IONIZING RADIATION......Page 293
12.4.6.2 Development of the Filtration Process......Page 294
12.5.1.1 Measuring Devices for Heat......Page 295
12.5.1.3 Physical Methods for Determining Filter Integrity......Page 297
12.5.2.1 Bioindicator Preparations......Page 298
12.5.2.3 Use of Biological Indicators in the Determination of Homogeneous Conditions in an Autoclave......Page 299
12.5.2.4 Value of Bioindicator Use in Routine Sterilization Processes......Page 300
12.5.2.7 Bioindicators for Dry Heat Sterilization......Page 301
12.5.2.9 Bioindicator Validation of Isolator Sterilization (Decontamination)......Page 302
12.5.2.11 Biological Indicators for Microorganism-Retentive Filters......Page 303
12.6 VALIDATION PLANS FOR STERILIZERS......Page 304
12.6.1.3 Development of the Sterilization Procedure......Page 305
12.6.2.3 Performance Qualification and Performance Validation......Page 306
12.6.3.1 Specification of Data to Be Routinely Collected and Evaluated......Page 307
REFERENCES......Page 312
13.1 INTRODUCTION......Page 315
13.2.1 THE NEED FOR PRESERVATION OF PHARMACEUTICAL PRODUCTS......Page 316
13.2.3 MICROBIAL ADAPTATION......Page 318
13.3 RECOGNITION OF THE PRESERVATIVE SYSTEM CONCEPT......Page 320
13.4 THE IDEAL PRESERVATIVE......Page 321
13.6 RATIONAL DEVELOPMENT OF A PRODUCT PRESERVATIVE SYSTEM......Page 322
13.7 CROSS-RESISTANCE OF PRESERVATIVES WITH OTHER ANTIMICROBIAL AGENTS......Page 323
REFERENCES......Page 324
CONTENTS......Page 328
14.2 FACTORS AFFECTING PRESERVATIVE ACTIVITY......Page 329
14.2.1 CONCENTRATION......Page 330
14.2.2 EFFECT OF PH......Page 332
14.2.3 EFFECT OF TEMPERATURE......Page 333
14.2.4 EFFECT OF PARTITIONING IN MULTIPLE-PHASE SYSTEMS......Page 334
14.3.1 SPECTRUM OF ACTIVITY......Page 336
14.4 POTENTIATION AND SYNERGY......Page 338
14.5 TOXICITY......Page 339
14.6 PRESERVATIVE MONOGRAPHS......Page 340
14.6.3 BENZOIC ACID (AND SALTS)......Page 341
14.6.6 BUTYLATED HYDROXYANISOLE......Page 342
14.6.9 CHLORHEXIDINE......Page 343
14.6.12 DIAZOLIDINYL UREA......Page 344
14.6.15 IMIDUREA......Page 345
14.6.17 PHENOL......Page 346
14.6.21 PROPIONIC ACID (AND SALTS)......Page 347
14.6.24 SULPHITES, INORGANIC......Page 348
REFERENCES......Page 349
15.1 INTRODUCTION......Page 354
15.2.1 THE EFFECT OF CONCENTRATION......Page 356
15.2.3 ADSORPTION BY SOLIDS......Page 357
15.2.4 INTERACTION WITH GEL-FORMING AND SUSPENDING AGENTS......Page 358
15.2.5 INTERACTION WITH EMULSIFIERS......Page 359
15.2.6 INTERACTION WITH MISCELLANEOUS COMPOUNDS......Page 360
15.3.1 METABOLIC STATE......Page 361
15.3.3 INTERACTION WITH INGREDIENTS......Page 362
15.4.2 WATER AS AN EXTRINSIC FACTOR......Page 363
15.5.2 ESSENTIAL OILS......Page 364
15.5.6 MISCELLANEOUS COMPOUNDS......Page 365
REFERENCES......Page 366
16.1 INTRODUCTION......Page 372
16.2 PACKAGE INTEGRITY QUALITY ASSURANCE......Page 374
16.3 LEAKAGE THEORY......Page 375
16.3.1 ESTABLISHING A CRITICAL LEAKAGE RATE......Page 377
16.4 INTEGRITY TESTING METHOD SELECTION......Page 380
16.4.1.3 Liquid Tracer Immersion......Page 382
16.4.1.5 Vacuum Decay Testing......Page 383
16.4.1.8 Helium Leakage Rate Testing......Page 384
16.5 CONCLUSION......Page 385
REFERENCES......Page 386
CONTENTS......Page 387
17.2 MATHEMATICAL APPROACH TO PRESERVATIVE EVALUATION......Page 388
17.3.1 CHOICE OF CHALLENGE ORGANISMS......Page 390
17.3.4 TEMPERATURE RECOMMENDATIONS IN THE PRESERVATIVE EFFICACY TEST......Page 391
17.3.5.4 Methods of Sampling from Products......Page 392
17.4.1 CHOICE OF MICROORGANISMS......Page 393
17.4.2 INOCULATION CONDITIONS......Page 394
17.4.3 INTERPRETATION OF RESULTS......Page 395
17.5 COSMETIC, FOOD AND TOILETRY ASSOCIATION GUIDELINES FOR PRESERVATIVE EFFICACY TESTING......Page 396
17.7 PRACTICAL CONSIDERATIONS OF PRESERVATIVE EFFICACY TESTING IN COMPLEX FORMULATIONS......Page 397
REFERENCES......Page 398
18.1 INTRODUCTION......Page 401
18.2 LINEAR REGRESSION METHOD......Page 402
18.2.2 MATHEMATICAL DETERMINATION OF D VALUES......Page 403
18.2.4 STATISTICAL QUALITY CONTROL OF THE LINEAR REGRESSION METHOD......Page 405
18.2.6 PRESERVATIVE EFFICACY TESTING WITHOUT COUNTING COLONIES......Page 407
18.3.1 RATIONAL DEVELOPMENT OF A PRESERVATIVE SYSTEM......Page 408
18.3.2 MAXIMUM ALLOWABLE D VALUES FOR GRAM-NEGATIVE BACTERIA......Page 410
18.3.3 THE REQUIRED D VALUE......Page 411
18.3.4 INTERFERENCES: INACTIVATION OF PRESERVATIVES BY SURFACTANTS......Page 412
18.3.6 ACCEPTANCE CRITERIA......Page 413
REFERENCES......Page 414
CONTENTS......Page 416
19.1 INTRODUCTION......Page 417
19.2 DEFINING REGULATORY AFFAIRS AND REGISTRATION......Page 418
19.3.2 PURPOSES OF REGULATORY PROCEDURES......Page 419
19.3.3 TYPES OF EC LEGISLATIVE INSTRUMENTS......Page 423
19.4.1 THE CENTRALIZED PROCEDURE......Page 424
19.4.2 THE MUTUAL RECOGNITION PROCEDURE......Page 425
19.4.3 THE ICH PROCESS......Page 426
19.5 PRESERVATIVES, ANTIMICROBIALS, AND ANTIOXIDANTS IN FORMULATED PRODUCTS: LEGISLATIVE CONSIDERATIONS......Page 428
19.5.1 TESTS USED TO DETERMINE THE EFFECTIVENESS OF A PRESERVATIVE SYSTEM......Page 429
19.5.3 TYPICAL PROBLEM AREAS FOR REGISTRATION......Page 431
19.5.3.3 Type of Container......Page 432
19.5.3.6 Volatility......Page 433
19.5.3.10 Odor......Page 434
19.5.3.14 Scale-Up and Production......Page 435
19.5.3.16 Analytical Methods......Page 436
19.6 CONCLUSIONS......Page 437
REFERENCES......Page 438
20.1 INTRODUCTION......Page 440
20.2.1 STERILE PHARMACEUTICALS......Page 441
20.2.2 NONSTERILE PHARMACEUTICALS......Page 443
20.2.3 WATER......Page 447
REFERENCES......Page 448
CONTENTS......Page 450
21.3 APPROACHES TO RISK ASSESSMENT......Page 451
21.3.1 FAILURE MODE AND EFFECT ANALYSIS......Page 452
21.3.2.1 Applicability to the Pharmaceutical Industry......Page 453
21.4.2 IDENTIFICATION OF POTENTIAL HAZARDS AND POTENTIAL CONTROL MEASURES......Page 454
21.4.3 DETERMINATION OF CRITICAL CONTROL POINTS......Page 455
21.4.7 ESTABLISHMENT OF VERIFICATION PROCEDURES TO DEMONSTRATE COMPLIANCE......Page 456
21.5 USING RISK ANALYSIS TO ENHANCE THE EFFECTIVENESS OF MICROBIOLOGICAL AUDITING......Page 457
21.5.2.1 Tablet Manufacture......Page 458
21.5.2.2 Small Volume Parenteral Manufacture by Aseptic Processing......Page 459
21.5.2.3 The Microbiological Quality Control Laboratory......Page 460
21.6 OVERVIEW......Page 461
REFERENCES......Page 462