Louis Rey, Joan C. May9780824748685, 0-8247-4868-9
Table of contents :
FREEZE-DRYING/LYOPHILIZATION OF PHARMACEUTICAL AND BIOLOGICAL PRODUCTS SECOND EDITION, REVISED AND EXPANDED……Page 1
FOREWORD……Page 10
FOREWORD……Page 13
REFERENCES……Page 12
PREFACE……Page 15
CONTRIBUTORS……Page 20
CONTENTS……Page 17
CONTENTS……Page 0
CHAPTER 1: GLIMPSES INTO THE REALM OF FREEZE-DRYING: FUNDAMENTAL ISSUES……Page 22
I. BASIC FREEZE-DRYING……Page 23
A. THERMAL AND ELECTRIC PROPERTIES……Page 27
B. GLASS AND VITREOUS TRANSFORMATIONS……Page 29
C. A NEW TOOL TO INVESTIGATE THE STRUCTURE OF LIQUIDS: LOW-TEMPERATURE THERMOLUMINESCENCE……Page 34
1. METHOD……Page 35
2. RESULTS……Page 36
III. OPERATING PRESSURE……Page 42
IV. THREE CHALLENGING WAYS TO INVESTIGATE THE FINAL DRY PRODUCT……Page 43
A. INTERNAL SURFACE: BET……Page 44
B. EQUILIBRIUM WATER VAPOR MEASUREMENT IN A SEALED VIAL……Page 46
C. LOW-TEMPERATURE THERMOLUMINESCENCE OF DRY MATERIAL……Page 50
REFERENCES……Page 52
I. INTRODUCTION……Page 54
II. THE STRUCTURE AND DYNAMICS OF LIQUID WATER: A SHORT REVIEW……Page 56
A. MODEL SYSTEMS–WATER INTERACTIONS……Page 62
B. MACROMOLECULES–WATER INTERACTIONS……Page 64
IV. DYNAMICS OF CONFINED WATER……Page 68
A. MODEL SURFACE–WATER SYSTEMS……Page 70
B. BIOPOLYMER–WATER SYSTEMS……Page 71
V. CONCLUSION……Page 79
REFERENCES……Page 80
I. INTRODUCTION……Page 84
II. STRESSES DURING FREEZE-DRYING: THERMODYNAMIC DESTABILIZATION FACTORS……Page 86
A. IN-PROCESS STABILITY: FREEZE–THAW AND FREEZE-DRY STABILITY……Page 95
B. STORAGE STABILITY……Page 98
A. PROTEIN FORMULATIONS AS AMORPHOUS SOLIDS……Page 100
B. MOLECULAR MOTION, RELAXATION, AND THE GLASS TRANSITION……Page 102
C. INSTABILITY AND THE GLASS TRANSITION: COUPLING OF REACTION MOBILITY WITH STRUCTURAL RELAXATION……Page 109
D. INSTABILITY AND THE GLASS TRANSITION: EXPERIMENTAL OBSERVATIONS……Page 111
E. STRUCTURE OF PROTEINS IN THE AMORPHOUS SOLID STATE……Page 114
A. STABILIZATION DURING FREEZING: THE ‘‘EXCLUDED SOLUTE’’ CONCEPT……Page 116
B. STABILIZATION DURING DRYING……Page 122
C. STORAGE STABILITY……Page 124
REFERENCES……Page 126
I. INTRODUCTION……Page 129
II. PROCESS PHYSICS—THE SUPPLEMENTED PHASE DIAGRAM……Page 130
III. FREEZING METHODS……Page 135
IV. MORPHOLOGY, SURFACE AREA, AND DRYING RATE……Page 136
V. NON-AQUEOUS COSOLVENT SYSTEMS……Page 145
VI. EFFECTS UPON ACTIVE INGREDIENTS……Page 146
VII. SOLUTE CRYSTALLIZATION……Page 149
VIII. MECHANISMS OF MORPHOLOGICAL CHANGE DURING ANNEALING……Page 152
IX. PRIMARY DRYING OPTIMIZATION THROUGH ANNEALING……Page 154
X. THE FUTURE……Page 156
XI. CONCLUSIONS……Page 157
REFERENCES……Page 158
I. INTRODUCTION……Page 166
II. PROTEIN STABILIZATION DURING LYOPHILIZATION/REHYDRATION……Page 168
III. MECHANISMS OF STABILIZATION OF PROTEINS BY SUGARS DURING DEHYDRATION……Page 169
IV. INFRARED SPECTROSCOPIC STUDIES OF LYOPHILIZATION-INDUCED STRUCTURAL CHANGES……Page 173
V. MECHANISM FOR STABILIZATION OF MULTIMERIC ENZYMES BY POLYMERS……Page 182
VI. EVIDENCE FOR FREEZING-INDUCED UNFOLDING DURING LYOPHILIZATION……Page 183
VII. PRACTICAL APPROACHES TO MINIMIZING FREEZING-INDUCED DAMAGE……Page 186
VIII. MECHANISMS FOR PROTEIN PROTECTION BY SURFACTANTS DURING LYOPHILIZATION AND REHYDRATION……Page 189
IX. THERMODYNAMIC MECHANISM FOR CRYOPROTECTION OF PROTEINS……Page 190
X. MECHANISMS FOR FAILURE OF DEXTRAN TO PROTECT LYOPHILIZED PROTEINS……Page 197
REFERENCES……Page 200
I. INTRODUCTION……Page 206
A. MOLECULAR MOBILITY AS DETERMINED BY SPIN–SPIN RELAXATION TIME OF PROTONS……Page 207
B. MOLECULAR MOBILITY AS DETERMINED BY THE LABORATORY AND ROTATING FRAME SPIN–LATTICE RELAXATION TIMES OF PROTONS……Page 212
C. MOLECULAR MOBILITY AS DETERMINED BY LABORATORY AND ROTATING FRAME SPIN–LATTICE RELAXATION TIMES OF CARBONS……Page 218
III. EFFECT OF MOLECULAR MOBILITY ON STORAGE STABILITY OF FREEZE-DRIED FORMULATIONS……Page 221
A. EFFECT OF MOLECULAR MOBILITY ON BIMOLECULAR REACTION DURING STORAGE OF LYOPHILIZED FORMULATIONS……Page 222
B. EFFECT OF MOLECULAR MOBILITY ON PROTEIN AGGREGATION DURING STORAGE OF LYOPHILIZED FORMULATIONS……Page 224
REFERENCES……Page 229
I. INTRODUCTION……Page 232
II. UTILIZE DSC TO CHARACTERIZE FORMULATION……Page 234
III. CONFIRM DSC RESULTS WITH A FREEZE-DRIVING MICROSCOPE……Page 238
IV. STUDY WATER SORPTION……Page 241
V. OPTIMIZE MOISTURE CONTENT……Page 243
VI. MEASURE TG OF DRY CAKES……Page 247
VII. INTERPRET DATA FOR CYCLE DEVELOPMENT……Page 249
VIII. CONFIRM THE HYPOTHESIS……Page 250
IX. CONCLUSIONS……Page 254
REFERENCES……Page 255
I. INTRODUCTION……Page 258
II. FACILITATING MANUFACTURE OF BULK SOLUTION……Page 263
III. STABILIZATION OF BULK SOLUTION……Page 264
A. EFFECT ON FREEZING……Page 266
B. ACCELERATION OF SUBLIMATION RATE……Page 271
A. POSITIVE IMPACT ON STABILITY……Page 274
VI. IMPACT ON RECONSTITUTION PROPERTIES……Page 276
VIII. CONTROL OF RESIDUAL SOLVENT LEVELS……Page 277
A. THERMAL TREATMENT (IMPACT OF ANNEALING)……Page 280
B. PURITY OF SOLVENT (IMPACT OF IMPURITIES, ETC.)……Page 281
IX. ULTRA-LOW-TEMPERATURE FREEZE-DRYING……Page 283
X. TOXICITY ISSUES……Page 284
XI. HANDLING, SAFETY, AND STORAGE ISSUES……Page 285
XII. SUPPLIER SELECTION AND QUALIFICATION……Page 288
XIV. REGULATORY CONCERNS……Page 289
XV. CONCLUSIONS……Page 290
REFERENCES……Page 291
I. INTRODUCTION……Page 296
B. REDUCTION IN THROUGHPUT……Page 297
B. BOTTOM THICKNESS……Page 298
D. BOTTOM INSIDE RADIUS……Page 299
V. LEACHING AND DISSOLUTION OF GLASS……Page 300
A. COMPOSITION AND MANUFACTURING PROCESS……Page 301
B. PHYSICAL PROPERTIES……Page 303
C. CLOSURE CONFIGURATION CONSIDERATIONS [1]……Page 304
E. EXTRACTABLES/LEACHABLES……Page 307
A. MOISTURE VAPOR TRANSMISSION……Page 308
B. MOISTURE ABSORPTION……Page 309
VIII. SILICONIZATION OF CLOSURES……Page 311
A. PROCESS FOR SILICONIZATION……Page 312
C. TESTING FOR SILICONE OIL……Page 313
X. SEAL INTEGRITY METHODS……Page 314
REFERENCES……Page 315
I. THE CHALLENGE……Page 317
II. THE APPROACH……Page 318
A. REDUCTION OF STRESS IN THE FREEZE-DRYING PROCESS……Page 320
C. OPTIMIZING HEAT TRANSFER AND STRESS OF THE GLASS CONTAINER IN FREEZE-DRYING……Page 322
III. RESULTS……Page 325
REFERENCES……Page 326
I. INTRODUCTION……Page 327
B. DRYING PROPERTIES OF LYOPHILIZATION CLOSURES……Page 328
A. SILICONIZATION……Page 329
1. SILICONE OIL PARTICULATES……Page 330
B. VOLATILE SUBSTANCES……Page 331
C. MOISTURE……Page 332
1. METHODS FOR ASSESSING OCCLUDED MOISTURE……Page 333
2. METHODS FOR REMOVAL OF OCCLUDED MOISTURE……Page 334
3. KINETICS OF MOISTURE REMOVAL FROM STOPPERS……Page 336
4. VALIDATION OF MOISTURE REMOVAL FROM CLOSURES……Page 337
5. UPTAKE OF OCCLUDED MOISTURE DURING PRODUCT STORAGE……Page 338
REFERENCES……Page 340
CHAPTER 12: DEVELOPMENT OF A NEW CONCEPT FOR BULK FREEZE-DRYING: LYOGUARD FREEZE-DRY PACKAGING……Page 342
I. TESTING OF CLOSED-CONTAINMENT LYOPHILIZATION TRAYS……Page 344
1. PART 1: HEAT TRANSFER……Page 345
2. PART 2: MASS TRANSFER RESISTANCE……Page 346
3. PART 3: EFFECTIVE BARRIER OF THE GORE-TEX MEMBRANE……Page 348
4. CHEMICAL COMPATIBILITY……Page 351
4. SUMMARY OF RESULTS……Page 352
2. BIOLOGICAL REACTIVITY TESTS IN VIVO, USP 25 ……Page 353
1. PHYSICOCHEMICAL TESTS, PLASTICS, USP 25 ……Page 354
1. PARTICULATE MATTER IN INJECTIONS, USP 25 ……Page 355
2. TALC CHALLENGE TEST……Page 356
A. VARIABLE COST SAVINGS FROM PRODUCT CONTAINMENT……Page 357
1. RECOVERY SAVINGS……Page 359
3. OTHER COMPARISONS……Page 360
IV. PROCESS IMPROVEMENTS RESULTING FROM LYOGUARD TRAYS……Page 361
B. THROUGHPUT IMPROVEMENTS FROM LYOGUARD TRAYS……Page 363
V. SUMMARY: BENEFITS OF UTILIZING CLOSEDCONTAINMENT TRAYS IN LYOPHILIZATION……Page 364
A. ABOUT THE MANUFACTURER……Page 365
I. INTRODUCTION……Page 366
A. RESIDUAL MOISTURE……Page 367
B. REGULATIONS……Page 369
1. PRODUCT POTENCY AND RESIDUAL MOISTURE……Page 370
3. AGGREGATION AND RESIDUAL MOISTURE……Page 372
1. GRAVIMETRIC METHOD (LOSS ON DRYING)……Page 374
2. KARL FISCHER METHOD……Page 375
3. THERMOGRAVIMETRY……Page 379
4. THERMOGRAVIMETRY/MASS SPECTROMETRY (TG/MS)……Page 382
5. PREVENTION OF SAMPLE CONTAMINATION BY AMBIENT HUMIDITY……Page 386
6. COMPARATIVE RESULTS……Page 390
7. VAPOR PRESSURE MOISTURE METHODOLOGY……Page 391
2. KARL FISCHER METHODS……Page 394
A. TRITIUM ISOTOPE……Page 396
IV. FUTURE DEVELOPMENT……Page 397
REFERENCES……Page 398
A. BIOLOGICAL MEDICINES AND BIOLOGICAL STANDARDS……Page 402
B. CANDIDATE BIOLOGICAL STANDARDS AND REFERENCE MATERIALS PROCESSED AT NIBSC……Page 403
A. REQUIREMENTS FOR PROCESSING—ACCEPTANCE CRITERIA……Page 404
1. EQUIPMENT USED*……Page 414
4. PILOT-SCALE WORK (SEE SECTION III)……Page 415
6. DISPENSING……Page 416
8. FREEZE-DRYING……Page 417
12. LABELING……Page 419
C. STORAGE AND DISPATCH……Page 420
1. FREEZING……Page 421
2. PRIMARY DRYING……Page 423
3. SECONDARY DRYING AND FURTHER DESICCATION……Page 424
B. USE OF PRODUCT TEMPERATURE PROBES……Page 426
1. DIFFERENTIAL SCANNING CALORIMETRY (DSC)……Page 428
3. FREEZE-DRYING MICROSCOPY (FDM)……Page 430
D. RESIDUAL MOISTURE DETERMINATION……Page 431
E. PRODUCT STABILITY……Page 432
B. TYPICAL TESTING PROTOCOL……Page 433
D. CONFIDENCE LIMITS OF PREDICTION……Page 434
2. DISCONTINUITY IN THE RELATIONSHIP BETWEEN DEGRADATION RATE AND TEMPERATURE……Page 435
4. TEMPERATURE EFFECTS ON THE INTEGRITY OF THE CONTAINER……Page 436
F. EXAMPLE OF ACCELERATED DEGRADATION STUDIES ON A BIOLOGICAL STANDARD……Page 437
V. FUTURE DEVELOPMENTS……Page 438
REFERENCES……Page 439
I. INTRODUCTION……Page 442
A. LEAK TEST……Page 443
B. LOADING AND FREEZING……Page 444
C. MAIN DRYING……Page 447
D. CHANGE FROM MD TO SD……Page 450
E. SECONDARY DRYING AND IN-PROCESS MOISTURE DETERMINATION……Page 451
F. PACKING AND STORAGE……Page 453
B. MEASURING METHODS AND TOLERANCES……Page 455
C. LOADING, HEAT TREATMENT, AND FREEZING……Page 457
D. MAIN DRYING, SECONDARY DRYING, AND RESIDUAL MOISTURE CONTENT……Page 459
E. UNIFORMITY WITHIN ONE CHARGE AND BETWEEN CHARGES……Page 463
IV. SPECIFICATION OF THE PRODUCTION EQUIPMENT FOR AN AUTOMATED PROCESS DEVELOPED IN SECTIONS II AND III……Page 467
A. LOADING AND UNLOADING OF VIALS, DRYING CHAMBER, STOPPERING OF VIALS……Page 468
C. COOLING SYSTEMS FOR CONDENSERS AND SHELVES……Page 471
D. WATER VAPOR TRANSPORT FROM THE VIALS TO THE CONDENSER……Page 474
E. VACUUM PUMPS, VENTING SYSTEM……Page 478
F. PROCESS CONTROL, VACUUM MEASURING, LEAK TESTING SYSTEMS……Page 480
G. CLEANING AND STERILIZATION……Page 482
H. UNIFORMITY AND RELIABILITY CONSIDERATION……Page 485
A. PROLONGED EVACUATION TIME……Page 488
D. SLOW INCREASE OF THE CHAMBER PRESSURE DURING MAIN DRYING……Page 489
E. TRACES OF HIGHLY VOLATILE COMPONENTS……Page 490
REFERENCES……Page 491
I. INTRODUCTION……Page 493
A. FREEZING……Page 495
1. TICE AS A FUNCTION OF THE OPERATION PRESSURE PC AND THE SHELF TEMPERATURE TSH……Page 496
2. CHANGE FROM MD TO SECONDARY DRYING (SD)……Page 498
A. SPECIFICATIONS FOR THE PILOT PLANT……Page 499
A. QUALIFICATION TESTS……Page 503
B. WATER VAPOR FLOW IN THE PILOT PLANT……Page 510
ABBREVIATIONS……Page 512
REFERENCES……Page 513
A. PRINCIPLE……Page 514
1. CLEANING……Page 517
F. CIP SKID……Page 518
1. CHAMBER AND CONDENSER……Page 519
3. VACUUM PUMP……Page 520
C. OPERATION……Page 521
III. CONCLUSION……Page 523
I. INTRODUCTION……Page 524
B. SUBLIMATION……Page 525
A. SHELF FREEZING AND HEATING……Page 526
C. CONDENSER COOLING……Page 527
IV. FREEZE-DRYING USING INTEGRAL HTF SYSTEM……Page 528
V. CONCLUSION……Page 529
I. INTRODUCTION……Page 532
A. INSTALLATION QUALIFICATION……Page 533
B. OPERATIONAL QUALIFICATION……Page 535
2. EQUIPMENT OPERATIONAL QUALIFICATION……Page 537
3. RESULTS……Page 545
C. FINAL REPORT……Page 547
BIBLIOGRAPHY……Page 548
I. INTRODUCTION……Page 549
1. THERMODYNAMIC REQUIREMENTS……Page 550
2. STRUCTURAL REQUIREMENTS……Page 551
3. THERMAL TREATMENT……Page 552
1. THERMODYNAMIC REQUIREMENTS……Page 553
2. DETERMINATION OF PRODUCT PRIMARY DRYING TIME AND MAXIMUM TEMPERATURE……Page 554
III. INDEPENDENT VERSUS DEPENDENT PROCESS PARAMETERS……Page 556
1. CONDENSER TEMPERATURE……Page 557
3. PRODUCT TEMPERATURE……Page 558
6. SHELF TEMPERATURE AND PRESSURE VERSUS PRODUCT PRIMARY DRYING TIME……Page 559
7. MAXIMUM VACUUM VERSUS PRESSURE-CONTROLLED LYOPHILIZATION……Page 560
B. SHELF AND PRODUCT FREEZING RATES……Page 561
H. PRESSURE DURING PRIMARY DRYING……Page 562
J. TERMINAL DRYING AND CYCLE TOTAL DURATION……Page 563
K. PARTIAL BATCH SIZE……Page 564
L. CONDENSER TEMPERATURE……Page 565
B. CHOICE OF PROCESS LIMITS……Page 566
C. PRACTICAL CONSIDERATIONS……Page 567
D. VALIDATION PROGRAM……Page 568
A. DEFINITION AND AIMS……Page 570
1. CONTROL OF THE FREEZE-DRYING PARAMETERS……Page 571
5. EXTENSIVE ANALYTICAL TESTING OF THE PRODUCT FOR UNIFORMITY……Page 572
7. ANALYTICAL TESTING OF IN-PROCESS SAMPLES……Page 573
A. DEFINITION AND AIMS……Page 575
1. FREEZE-DRYING DATA……Page 576
2. QC RELEASE DATA AND VISUAL INSPECTION……Page 577
A. DEFINITION AND AIMS……Page 578
B. TESTING OF PRODUCT UNIFORMITY ACROSS THE SHELVES……Page 579
C. TESTING OF THE EQUIVALENCE OF THE PRODUCT FROM ALL AREAS WITHIN THE LYOPHILIZER……Page 581
IX. CONCLUSIONS……Page 585
REFERENCES……Page 586
I. INTRODUCTION……Page 588
B. MOLECULAR SIZING AND POTENCY ASSAYS……Page 589
2. FREEZE-DRIED HAEMOPHILUS B CONJUGATE VACCINE (TETANUS TOXOID CONJUGATE)……Page 590
3. ACELLULAR PERTUSSIS COMPONENT OF DIPHTHERIA AND TETANUS TOXOIDS AND PERTUSSIS VACCINE ADSORBED (LIQUID)……Page 591
5. 7-VALENT PNEUMOCOCCAL CONJUGATE VACCINE (LIQUID)……Page 595
II. FUTURE DEVELOPMENTS……Page 596
REFERENCES……Page 597
A. SOME BASIC ISSUES……Page 599
1. INERT CARRIERS……Page 602
2. SOFT-ICE……Page 603
3. CONTINUOUS FREEZE-DRYING……Page 604
4. IRRADIATION TECHNOLOGY……Page 607
II. CHEMICALS AND NON-AQUEOUS SOLVENTS……Page 611
B. COMPLEX FREEZE-DRYING……Page 612
2. SUCCESSIVE FREEZE-DRYING……Page 613
1. AMMONIA……Page 614
2. CARBON DIOXIDE……Page 615
D. FREEZE-DRYING AND THE MAJOR CHEMICAL INDUSTRY……Page 617
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