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本帖最后由 大傻子 于 2012-8-17 07:54 编辑
ELEVEN是何方神圣？总之也是牛人一个。
这次发布的是全英文版本，傻子看不懂，懂行的，或都有兴趣的可以拿去参考，要是论坛有牛人能翻译出来，那就更好了{:soso_e142:}。
《PDA清洁验证指南》CLEANING AND CLEANING VALIDATION ，文档已全部制成目录树，内容全部已OCR，文字可复制，方便复制出来翻译{:soso_e151:}。
网上流传的PDA的技术文件，大部分是个目录，骗人的。
这次多谢Eleven，得益于他的高清扫描，使得文字OCR识别率接近100%！
不良的书商，可以把文字复制出去出版了{:soso_e151:}。Eleven出来露个水吧，接受傻哥的加分，虽然不多{:soso_e152:}
目录：
CLEANING AND CLEANING VALIDATION 1
CONTENTS 5
INTRODUCTION 21
1PROCESS VALIDATION BASICS 27
Paul L Pluta Introduction 27
Process design — understanding the product and process 28
Process qualification — manufacturing the validation conformance lots 28
Continued process verification ——maintaining the validated state 29
The “process” of process validation 29
Lifecycle approach to process validation — organizational approach 29
Quality risk management 30
Terminology 30
Basis for the Lifecycle Approach to Process Validation 31
Expectations for Validated Processes 34
Process understanding (Pluta and Poska, 2008 ) 34
Design and development 35
Pilot scale, technology transfer, and commercial scale up 38
Identification of input variables 38
Cleaning and Cleaning Validatioi Strategy to control variables 39
Validation performance — conformance lots (Pluta et al” 2008 ) 39
Considerations prior to process performance 40
Pre process-performance documents 41
Manufacturing of conformance lots 42
Post process-performance documents 47
Maintaining the validated state (Pluta et al., 2008 ) 48
Factors supporting maintenance of the validated state 49
Activities for maintaining the validated state 52
Additional Process Validation Considerations 55
Equipment/facilities/utilities qualification 55
Analytical methods 55
Statistical methods 55
Documentation 56
Summary and Conclusions 56
References 58
About the Author 60
2CLEANING VALIDATION BASICS 61
Destin A. LeBlanc Cleaning Validation is a Type of Process Validation 61
Parts of a Formal Cleaning Validation Program 62
A Bit of History 63
Concerns with a Cleaning Process 64
Types of Residues 65
Residue Limits 66
Sampling for Residues 66
Analytical Methods 66
References 67
About the Author 69
3CLEANING VALIDATION — APPLICATION IN THE LABORATORY 71 71
Cindy Green
Introduction 71
Factors affecting cleaning in the lab 72
Case Studies in Laboratory Cleaning 73
GMP Case Study #1 : Contamination from Soap Residue 73
GMP Case Study #2 : Contamination from Soap Residue 74
GMP Case Study #3 : Contamination from Manufacturing Materials 75
GTP Case Study #4 : Product Contamination 75
GLP Case Stud/ #5 : Specimen Contamination 76
GLP Case Study #6 : Contamination from Quarantined Animals 77
GMP Case Study #7 : Contamination from Failure to Adequately Clean Work Surfaces 78
Case Study #8 : Cross Contamination of Histology Specimens 79
Key Considerations for Cleaning in the Laboratory 79
Conclusions 80
About the Author 81
4THE CLEANING VALIDATION POLICY AND THE CLEANING VALIDATION PLAN 83
yVI/gue/ A1 onto/vo introduction 83
FDA Perspective 84
The Cleaning Validation Policy 85
Develop an outline 86
Equipment design review 87
SOPs and operational cleaning procedure review 88
Matrix development 89
Worst case selection 90
Sampling plan and limits determination approach 90
Target residue identification 91
Analytical methods requirements 92
Cleaning validation documents 92
Cleaning validation maintenance 92
The Cleaning Validation Plan 93
Cleaning validation plan outline 94
Cleaning Validation Protocol 95
Execution of the Cleaning Tests 96
Summary Report 96
Summary and Key Points 96
References 97
About the Author 97
5GLOBAL REGULATORY INSPECTIONS STANDARDS 99
FOR CLEANING VALIDATION 99
Clive G. Blatchford 24
Introduction 99
Regulatory Inspections — Preparation for an Inspection 99
Preparation in the facility 100
Preparation in the meeting room 102
Global Guidance Documents 106
US FDA 106
Canada 106
Europe (and PIC/S) 106
ICH 107
Misconceptions 107
Defects and Failures _ Where did it all go Wrong? 108
Barr Laboratories 108
Cleaning and Cleaning Validation Viracept 109
Cholestyramine resin 109
Actavis Totowa 109
Novartis Vaccines 110
Other defects 110
Conclusions 111
References 111
About the Author 111
6QUALITY BY DESIGN FOR CLEANING VALIDATION 113
Rizwan Sharnez and Martin VanTrieste Introduction to Quality by Design 113
Quality by Design Approach to Cleaning Characterization 115
Identifying Worst-Case Operating Conditions 116
Stage 丨 117
Stage II 119
Validation Strategy 120
Conclusion 122
References 122
About the Authors 123
7CLEANING AGENTS AND CLEANING CHEMISTRY 127
George Vferghese and Nancy Kaiser Introduction 127
Factors to Consider when Selecting Cleaning Agents 128
Broad-spectrum cleaning effectiveness 128
Substrate compatibility 128
Stability and shelf life 129
Analyzability 129
Disposal 129
Regulatory compliance 130
Safety 131
Toxicity 131
Foaming 131
Microbial control 133
Manufacturing quality and GMP 133
Cleaning Chemistry Mechanisms 133
Wetting 133
Emulsification 134
Dispersion 135
Solubility 136
Chelation 136
Oxidation 136
Hydrolysis 137
Cleaning Agent Options 137
Water 137
Commodity alkalis and acids 138
Organic solvents 138
Surfactants
How surfactants work 139
Surfactant types 139
Anionic surfactants 139
Cationic surfactants 140
Amphoteric surfactants
Nonionic surfactants 140
Formulated detergents 141
Components of formulated detergents 141
Surfactants 141
Alkalis 141
Acids 142
Sequestrants/chelants 142
Dispersants/anti-redeposition agents 142
Corrosion inhibitors 142
Oxidizing agents 142
Enzymes 143
Buffers/builders 143
Preservatives 143
Advantages and disadvantages of various options 143
Summary 144
References 144
About the Authors 145
8CLEANING ENGINEERING AND EQUIPMENT DESIGN 147
George Verghese and Paul Lopolito Introduction 147
Cleaning Process Parameters —TACT 149
Time 149
Action 150
Concentration 150
Temperature 151
Factors Related to the Soil or Residue 151
Soil levels 152
Soil condition 152
Case study #1 152
Hold times (dirty and clean) 153
Cleaning and Cleaning Validation Soil mixing
Cleaning Methods 154
Manual cleaning 154
Static soaking 155
Agitated immersion 155
Automated glassware and parts washing 156
Ultrasonic cleaning 156
CIP processes 157
Relationship between Parameters and Cleaning Methods 157
Case study #2 157
Equipment Design 159
Flow and coverage in process piping 160
Flow through pipes 161
Coverage in dead legs 162
Flow and coverage in vessels 163
Flow within vessels 163
Spray devices 164
Spray coverage testing 165
Vessel inserts and openings 166
Component selection 167
Surface type or materials construction 169
Case study #3 169
Surface finish or roughness 170
Drainability and Rinsing 171
System Integration and Design 171
Summary 172
References 172
About the Authors 173
9RESIDUES AND CLEANING CHEMISTRY 177
William R. Porter
Introduction 177
Factors Affecting Solubility 179
Lipophilicity and solubility 180
lonizability and solubility 181
Surfactants and solubility 182
Factors Affecting Chemical Stability 183
Kinetics of degradation of APIs and excipients 183
Reaction mechanisms and kinetics 184
Effect of temperature of reaction rates 187
Common degradation pathways 188
Hydrolysis 188
Oxidation 191
Photolysis 193
Other degradation pathways 194
Impact of chemical degradation of cleaning residues 194
Factors Affecting Physical Stability 194
Types of phase transformations 195
Conclusions 197
References 197
About the Author 199
10MICROBIAL AND ENDOTOXIN RESIDUES —PRODUCT CONTACT SURFACES 201
Jeanne Moldenhauer Introduction 201
Where do the Requirements for Cleaning and Cleaning Validation Originate 202
United States Food and Drug Administration (FDA) 21 CFR Part 211:Current GMP for Finished Pharmaceuticals 202
European Union Good Manufacturing Practices 203
International Conference on Harmonization: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients Q7 205
Other influential documents 207
Types of Cleaning Validation Studies 207
Cleaning Validation for Rooms or Areas 207
Environmental survey 208
Selection of appropriate cleaning agents 208
Developing and setting parameters for disinfection/sanitization 209
Development of cleaning procedures 213
In situ studies 214
Microbial recovery studies 214
Endotoxin removal studies 215
Product Contact Surfaces 215
Microbial issues in cleaning validation 215
The control of microbial residues 216
Reducing microbial residues 216
The concept of objectionable microorganisms 216
Setting acceptance criteria 217
Aseptic processes 218
Non-sterile processes 218
Viral and prion contamination 218
Types of product contact surfaces 218
Components 218
Glass components 219
Evaluations prior to product exposure 219
Following product exposure 219
Plastic containers 219
Cleaning and Cleaning Validation Prior to product exposure 219
Following product exposure 220
Closures 220
Prior to product exposure 220
Following product exposure 221
Equipment 221
Issues with the control of microorganisms 221
Establishing limits for microorganisms on equipment 222
Types of Equipment 223
Parts and tools 223
Prior to product exposure 223
Post product exposure 223
Clean equipment hold times 223
The Product Contact Manufacturing Lines 225
Small molecule pharmaceutical products 225
Myths regarding cleaning validation 225
Equipment design, installation, and qualification 227
Grouping of products 227
Setting limits for cleaning 227
The cleaning validation protocol 227
Biotechnology products 228
Regulatory inspectional expectations 228
Facility readiness 228
Designing a cleaning process that can be validated 229
Biofilms 233
Reasons for biofilm formation 234
Ra/stonia pickettii and Burkhoideria cepacia 234
Quorum sensors 234
How do you deal with biofilm? 235
Sanitization of biofilm 235
Pyrogens 235
Cleaning after media fills 235
Non-sterile pharmaceutical product manufacturing 236
Cleaning and sterilizing in place 236
Dealing with Adverse Trends, Media Fill Failures, Sterility Test Failures and Endotoxin Failures 236
Case Studies 237
Case study I 237
Case study 2 237
Case study 3 237
Conclusions 238
Acknowledgements 238
References 238
About the Author 243
11CLEANING OF NON-PRODUCT CONTACT SURFACES 245
Anne Mor/'e Dixon Background 245
Tools, Equipment and Supplies 244
Techniques and Methods 249
Procedures — general 249
Double bucket technique 249
Triple bucket technique 249
Procedures — specific 251
Ceilings 251
Walls and curtains 251
Floors 252
Furniture/fixtures 253
Mats 253
Waste receptacles 253
Work stations and equipment — horizontal surfaces 253
Reporting 255
Frequency 255
The “Clean” Factory 255
Zone I — critical zone 256
Zone 2 — the clean room 256
Zone 3 — personnel entrance 256
Zone 4 — controlled environment ——areas surrounding cleanrooms 256
Zone 5 — the plant 256
Zone 6 — the entrance 257
Zone 7 — the exterior 257
Testing Procedures 257
Summary 258
References 258
About the Author 258
12RESIDUE PHARMACOLOGY AND TOXICOLOGY CONSIDERATIONS 259
William H. Houser
Introduction 259
Residue Limits 260
Residue limit/residue level 260
The I /1000 of the NTD approach 261
The 10 ppm approach 262
The no visible residue approach 262
Establishing a health-based residue limit 263
Limitations of the approach 265
Cleaning Limits 266
Other General Considerations 267
Potent drugs 267
Pharmacologist perspective 268
Cleaning and Cleaning Validation Occupational toxicology perspective 268
Industrial hygiene perspective 270
Potency as a hazard 271
Containment versus cleaning 271
Cytotoxicity 272
Sensitizers 274
Proteins and peptides (nutritional, therapeutic, non-specific) 278
Nutritional proteins 279
Therapeutic proteins 279
Non-specific proteins and peptides 281
Conclusions 283
References 283
About the Author 288
13RESIDUE GROUPING STRATEGIES 289
William ￡ Hall Introduction 289
Origin of Grouping Concept for Cleaning Validation 289
Strategy or Rationale 290
Fundamental Principles of Product Grouping 291
Decision Tree Approach 292
Level I of the decision tree (sterile vs. non-sterile) 292
Level 2 of the decision tree (dosage form) 292
Level 3 of the decision tree (products) 293
Level 4 of the decision tree (equipment) 293
Level 5 of the decision tree (cleaning procedure) 295
Cleaning procedure (definition) 296
Identification of the Worst Case(s) Representative Product in each Group 297
Step I in worst case determination ~ assemble the data 297
Step 2 —“Torture the data until it confesses” 一 evaluate the data and determine the worst case product(s) 298
identification of a Worst-Case Ingredient in a Cleaning Agent Formulation 300
Case Studies
Case study I 301
Case study 2 302
Case study 3 302
Answers to case studies 303
Case study I 303
Case study 2 303
Case study 3 303
References 303
About the Author 303
14A SCIENTIFIC APPROACH TO THE SELECTION OF CLEANING VALIDATION WORST-CASE SOILS FOR BIOPHARMACEUTICAL MANUFACTURING 305
Rod J. Azadan and Alfredo J. Canhoto What is a Worst-Case Soil? 306
A Scientifically Justified Approach 306
Categorization of Soil Components 307
The Matrix Analysis Method 309
Information collection 309
Matrix design 309
Soil semi-quantitation 311
Other Considerations 314
Application of the matrix approach for process intermediates 314
Process parameter impact on soil cleanability 314
Historical experience 314
Bioburden control 315
Outstanding components 315
References 315
About the Authors 316
15VISUAL CLEANLINESS 317
Richard Forsyth Introduction 317
Parameters affecting visual observations 318
Acceptable residue limit 318
Risk management 318
Chapter objective 319
Visible Residue Limit for Cleaning Validation and its Potential Application in a Pharmaceutical Research Facility 319
Visible residue parameters 319
Experimental 321
Results and discussion 322
Conclusions — visible residues in the R&D pilot plant 333
Application of Visible Residue Limit for Cleaning Validation in a Pharmaceutical Manufacturing Facility 333
Visible residue parameters 333
Surface material 334
Solvent to prepare standards 334
Light intensity, viewing distance, and angle 334
Observers 335
Experimental 335
Results and discussion 338
Conclusions — visible residues in a commercial scale manufacturing facility 344
Ruggedness of Visible Residue Limits for Cleaning Validation 345
Methods and materials 346
Cleaning and Cleaning Validation Results and discussion 347
Initial vs. later VRL determination 347
API vs. excipient vs. formulation determinations 349
Multi-site study 350
Residue appearance 352
Conclusion 353
Risk-Management Assessment of Visible Residue Limits in Cleaning Validation 353
Risk identification 354
Risk analysis 355
Management of risks 356
Pilot plant facility uses ofVRL 357
Manufacturing facility uses ofVRL 359
Summary and Conclusions 360
References 361
About the Author 362
16PERSONNEL TRAINING —VISUAL INSPECTION OF CLEANED EQUIPMENT 363
Paul L Pluta Introduction 363
Audience 364
Development of the training content 364
Training approach 365
Trainer expertise and competence 365
Presentation as a training “update” 365
Training Objectives 366
Time allotment 367
Re-training 367
Site training internal requirements 367
Training Lecture Topics 367
Training session “icebreaker” 368
Case study #1 —Training session “icebreaker” 368
Why are we here? Why is this training needed? 370
What are we cleaning? 371
Why is clean equipment important 371
Case study #2 ~- Regulatory cleaning audit 373
Cleaning development, procedures, validation, and ongoing visual evaluation 374
What is cleaning? Cleaning is a process 375
Performance of cleaning 378
Case study #3 —“Manual cleaning — do whatever it takes” 378
What is visually clean? 381
Case study #4 _ “Clean enough” 382
Determination of visual cleanliness 384
What if equipment is not visually clean after cleaning? 389
Aids to determine visually clean 390
Non product-contact surfaces 390
Documentation 390
Site-specific considerations 391
Demonstrations and Participatory Activities 393
“Water-break” test 394
Cleaning agent residue — solution foam 395
Visual evaluation of wet and dry residues 395
Swab sampling in cleaning validation 396
Dried residue examples: no cleaning，partial cleaning, completed cleaning 396
Known dried residue concentrations on stainless steel plates 397
Known dried residue concentrations — evaluations at various distances 398
Known dried residue concentrations — evaluation at different lighting levels 398
Aids for visual examination 399
Key Points for Visual Evaluation of Surfaces 399
Review of trainee expectations and questions 400
Training Summary 400
Appendix 401
References 403
About the Author 404
17BIOTECH RESIDUES AND CLEANING 407
Jennifer Carlson Introduction 407
Production Processes 408
Recominbant protein produced through a mammalian cell line 408
Cell culture 409
Harvest 410
Purification 411
Formulation, freezing, and aseptic filling 411
Protein produced through bacterial fermentation 412
Fermentation 412
Initial recovery process 413
Purification 413
Formulation, freezing, and aseptic filling 414
Process Ingredients 414
Equipment 415
Impact of material of construction 415
Tanks 415
Design considerations 415
Cleaning considerations 417
Cleaning cycle considerations 419
Cleaning and Cleaning Validatioi Passivation cycles (or maintenance cycles) 420
Filter housings 420
Cleaning considerations 421
Process lines and chromatography skids 421
Design considerations 422
Centrifuges and homogenizers 423
Design considerations 423
Filler 424
Lyophilizer and stopper bowl 424
Small equipment 425
Residue in a Typical Manufacturing Process 426
Cell culture or fermentation fluid 426
Pluronic F-68 and antifoams 427
Medium preparations solutions 427
Cleaning Agents and Cleaning Procedures 428
CIP cleaning 428
Pre-rinse 429
Caustic wash 429
Post caustic rinse 429
Acid wash 429
Intermediate rinse or post acid rinse 430
Final rinse 430
Parts washers 430
Manual cleaning 431
Acceptance Criteria for Biological APIs 431
Residual active product 431
Cleaning agent 432
Bioburden 433
Endotoxin 433
Visual inspection 433
Case Studies 433
Case study # I — the case of revalidation failing TOC and conductivity 433
Problem 433
Investigation 433
Results 434
Corrective actions due to investigation 434
Conclusion 435
Case study #2 _ cell culture CIP failure 435
Problem 435
investigation 435
Corrective actions due to investigation 436
Conclusion 436
References 436
Acknowledgements 437
About the Author 437
18CASE STUDY — CLEANING PROCESS OPTIMIZATION 439
FOR A MANUFACTURING PROCESS CHANGE 439
Soren Damkjaer and Pernille L Johansen Introduction 439
Problem 439
Physical Examination of Equipment 440
Laboratory Studies 440
Testing the Original Cleaning Process 441
Developing the New Cleaning Process 441
Test Procedure 441
Test Data 441
Cleaning Procedures 444
Original cleaning procedure 444
New cleaning procedure 444
Results and Conclusions 444
About the Authors 445
19MANUAL CLEANING PROCESSES AND PROCEDURES 447
Valerie Welter Yes ...You Can Validate Manual Cleaning Processes 447
Getting Started 448
Process Evaluation — Eliminating Unnecessary Processes 449
Required Framework 449
Process equipment train 449
Product contact materials of construction 450
Cleaning procedure(s) 451
Allowable equipment holding times 459
Product formulations and product cleaning test methods 460
Cleaning Validation Master Plan (VMP) 461
The Validation Protocol and Report 462
Summary Report 464
Routine Monitoring and Control 464
Revalidation/Change Control 464
Audit Checklist for Manual Cleaning 465
About the Author 466
Index 467
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发表于 2012-8-17 07:30:01
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