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CONTENTS
Introduction xix
SECTION ONECLEANING VALIDATION
BASICS AND EXPECTATIONS
1 PROCESS VALIDATION BASICS 3Paul L. Pluta
Introduction 3Process design — understanding the product and process 4Process qualification — manufacturing the validation conformance lots 4Continued process verification — maintaining the validated state 5The “process” of process validation 5Lifecycle approach to process validation — organizational approach 5Quality risk management 6Terminology 6
Basis for the Lifecycle Approach to Process Validation 7Expectations for Validated Processes 10
Process understanding (Pluta and Poska, 2008) 10Design and development 11Pilot scale, technology transfer, and commercial scale up 14Identification of input variables 14
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Strategy to control variables 15Validation Performance — Conformance Lots (Pluta et al., 2008) 15
Considerations prior to process performance 16Pre process-performance documents 17Manufacturing of conformance lots 21Post process-performance documents 23
Maintaining theValidated State (Pluta et al., 2008) 24Factors supporting maintenance of the validated state 25Activities for maintaining the validated state 28
Additional Process Validation Considerations 31Equipment/facilities/utilities qualification 31Analytical methods 31Statistical methods 31Documentation 32
Summary and Conclusions 32References 34About the Author 36
2 CLEANING VALIDATION BASICS 37Destin A. LeBlanc
Cleaning Validation is a Type of Process Validation 37Parts of a Formal Cleaning Validation Program 38A Bit of History 39Concerns with a Cleaning Process 40Types of Residues 41Residue Limits 42Sampling for Residues 42Analytical Methods 42References 43About the Author 45
3 CLEANING VALIDATION —APPLICATION IN THE LABORATORY 47Cindy Green
Introduction 47Factors affecting cleaning in the lab 48
Case Studies in Laboratory Cleaning 49GMP Case Study #1: Contamination from Soap Residue 49GMP Case Study #2: Contamination from Soap Residue 50GMP Case Study #3: Contamination from Manufacturing Materials 51GTP Case Study #4: Product Contamination 51GLP Case Study #5: Specimen Contamination 52GLP Case Study #6: Contamination from Quarantined Animals 53GMP Case Study #7: Contamination from Failure to Adequately Clean
Work Surfaces 54Case Study #8: Cross Contamination of Histology Specimens 55
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Key Considerations for Cleaning in the Laboratory 55Conclusions 56About the Author 57
4 THE CLEANING VALIDATION POLICYAND THE CLEANINGVALIDATION PLAN 59
Miguel MontalvoIntroduction 59FDA Perspective 60The Cleaning Validation Policy 61
Develop an outline 62Equipment design review 63SOPs and operational cleaning procedure review 64Matrix development 65Worst case selection 66Sampling plan and limits determination approach 66Target residue identification 67Analytical methods requirements 68Cleaning validation documents 68Cleaning validation maintenance 68
The Cleaning Validation Plan 69Cleaning validation plan outline 70
Cleaning Validation Protocol 71Execution of the Cleaning Tests 72Summary Report 72Summary and Key Points 72References 73About the Author 73
5 GLOBAL REGULATORY INSPECTIONS STANDARDSFOR CLEANING VALIDATION 75
Clive G. BlatchfordIntroduction 75Regulatory Inspections Preparation for an Inspection 75
Preparation in the facility 76Preparation in the meeting room 78
Global Guidance Documents 82US FDA 82Canada 82Europe (and PIC/S) 82
ICH 83Misconceptions 83Defects and Failures —Where did it all goWrong? 84
Barr Laboratories 84
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Viracept 85Cholestyramine resin 85Actavis Totowa 85Novartis Vaccines 86Other defects 86
Conclusions 87References 87About the Author 87
6 QUALITY BY DESIGN FOR CLEANING VALIDATION 89Rizwan Sharnez and Martin Van Trieste
Introduction to Quality by Design 89Quality by Design Approach to Process Characterization 91IdentifyingWorst-Case Operating Conditions 92
Stage 1 93Stage II 95Validation Strategy 96
Conclusion 98References 98About the Authors 99
SECTION TWOGENERAL TECHNICAL PRINCIPLES —
CLEANING CHEMISTRY AND ENGINEERING
7 CLEANING AGENTS AND CLEANING CHEMISTRY 103George Verghese and Nancy Kaiser
Introduction 103Factors to Consider when Selecting Cleaning Agents 104
Broad-spectrum cleaning effectiveness 104Substrate compatibility 104Stability and shelf life 105Analyzability 105Disposal 105Regulatory compliance 106Safety 107Toxicity 107Foaming 107Microbial control 109Manufacturing quality and GMP 109
Cleaning Chemistry Mechanisms 109Wetting 109Emulsification 110
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Dispersion 111Solubility 112Chelation 112Oxidation 112Hydrolysis 113
Cleaning Agent Options 113Water 113Commodity alkalis and acids 114Organic solvents 114Surfactants 114How surfactants work 115Surfactant types 115
Anionic surfactants 115Cationic surfactants 116Amphoteric surfactants 116Nonionic surfactants 116
Formulated detergents 117Components of formulated detergents 117
Surfactants 117Alkalis 117Acids 118Sequestrants/chelants 118Dispersants/anti-redeposition agents 118Corrosion inhibitors 118Oxidizing agents 118Enzymes 119Buffers/builders 119Preservatives 119
Advantages and disadvantages of various options 119Summary 120References 120About the Authors 121
8 CLEANING ENGINEERING AND EQUIPMENT DESIGN 123George Verghese and Paul Lopolito
Introduction 123Cleaning Process Parameters —TACT 125
Time 125Action 126Concentration 126Temperature 127
Factors Related to the Soil or Residue 127Soil levels 128Soil condition 128
Case study #1 128Hold times (dirty and clean) 129
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Soil mixing 129Water quality and residue 129
Cleaning Methods 130Manual cleaning 130Static soaking 131Agitated immersion 131Automated glassware and parts washing 132Ultrasonic cleaning 132CIP processes 133
Relationship between Parameters and Cleaning Methods 133Case study #2 133
Equipment Design 135Flow and coverage in process piping 136
Flow through pipes 137Coverage in dead legs 138
Flow and coverage in vessels 139Flow within vessels 139Spray devices 140Spray coverage testing 141Vessel inserts and openings 142
Component selection 143Surface type or materials construction 145
Case study #3 145Surface finish or roughness 146
Drainability and Rinsing 147System Integration and Design 147Summary 148References 148About the Authors 149
SECTION THREEGENERAL TECHNICAL PRINCIPLES — RESIDUES
9 RESIDUESAND CLEANING CHEMISTRY 153William R. Porter
Introduction 153Factors Affecting Solubility 155
Lipophilicity and solubility 156Ionizability and solubility 157Surfactants and solubility 158
Factors Affecting Chemical Stability 159Kinetics of degradation of APIs and excipients 159
Reaction mechanisms and kinetics 160Effect of temperature of reaction rates 163
Common degradation pathways 164
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Hydrolysis 164Oxidation 167Photolysis 169Other degradation pathways 170Impact of chemical degradation of cleaning residues 170
Factors Affecting Physical Stability 170Types of phase transformations 171
Conclusions 173References 173About the Author 175
10 MICROBIAL AND ENDOTOXIN RESIDUES —PRODUCT CONTACT SURFACES 177
Jeanne MoldenhauerIntroduction 177Where do the Requirements for Cleaning and Cleaning Validation Originate? 178
United States Food and Drug Administration (FDA) 21 CFR Part 211:Current GMP for Finished Pharmaceuticals 178
European Union Good Manufacturing Practices 179International Conference on Harmonization: Good Manufacturing
Practice Guide for Active Pharmaceutical Ingredients Q7 181Other influential documents 183
Types of Cleaning Validation Studies 183Cleaning Validation for Rooms or Areas 183
Environmental survey 184Selection of appropriate cleaning agents 184Developing and setting parameters for disinfection/sanitization 185Development of cleaning procedures 189In situ studies 190Microbial recovery studies 190Endotoxin removal studies 191
Product Contact Surfaces 191Microbial issues in cleaning validation 191
The control of microbial residues 192Reducing microbial residues 192The concept of objectionable microorganisms 192Setting acceptance criteria 193Aseptic processes 194Non-sterile processes 194Viral and prion contamination 194Types of product contact surfaces 194
Components 194Glass components 195
Evaluations prior to product exposure 195Following product exposure 195
Plastic containers 195
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Prior to product exposure 195Following product exposure 196
Closures 196Prior to product exposure 196Following product exposure 197
Equipment 197Issues with the control of microorganisms 197Establishing limits for microorganisms on equipment 198
Types of Equipment 199Parts and tools 199
Prior to product exposure 199Post product exposure 199Clean equipment hold times 199
The Product Contact Manufacturing Lines 201Small molecule pharmaceutical products 201
Myths regarding cleaning validation 201Equipment design, installation, and qualification 203Grouping of products 203Setting limits for cleaning 203The cleaning validation protocol 203
Biotechnology products 204Regulatory inspectional expectations 204Facility readiness 204
Designing a cleaning process that can be validated 205Biofilms 209
Reasons for biofilm formation 210Ralstonia pickettii and Burkholderia cepacia 210Quorum sensors 210How do you deal with biofilm? 211Sanitization of biofilm 211Pyrogens 211Cleaning after media fills 211
Non-sterile pharmaceutical product manufacturing 212Cleaning and sterilizing in place 212
Dealing with Adverse Trends, Media Fill Failures, Sterility Test Failures andEndotoxin Failures 212
Case Studies 213Case study 1 213Case study 2 213Case study 3 213
Conclusions 214Acknowledgements 214References 214About the Author 219
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11 CLEANING OF NON-PRODUCT CONTACT SURFACES 221Anne Marie Dixon
Background 221Tools, Equipment and Supplies 220Techniques and Methods 225
Procedures — general 225Double bucket technique 225Triple bucket technique 225
Procedures — specific 227Ceilings 227Walls and curtains 227Floors 228Furniture/fixtures 229Mats 229Waste receptacles 229Work stations and equpiment — horizontal surfaces 229
Reporting 231Frequency 231The “Clean” Factory 231
Zone 1 — critical zone 232Zone 2 — the cleanroom 232Zone 3 — personnel entrance 232Zone 4 — controlled environment — areas surrounding cleanrooms 232Zone 5 — the plant 232Zone 6 — the entrance 233Zone 7 — the exterior 233
Testing Procedures 233Summary 234References 234About the Author 234
12 RESIDUE PHARMACOLOGY ANDTOXICOLOGY CONSIDERATIONS 235
William H. HouserIntroduction 235Residue Limits 236
Residue limit/residue level 236The 1/1000 of the NTD approach 237The 10 ppm approach 238The no visible residue approach 238
Establishing a health-based residue limit 239Limitations of the approach 241
Cleaning Limits 242Other General Considerations 243
Potent drugs 243Pharmacologist perspective 244
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Occupational toxicology perspective 244Industrial hygiene perspective 246Potency as a hazard 247Containment versus cleaning 247
Cytotoxicity 248Sensitizers 250
Proteins and peptides (nutritional, therapeutic, non-specific) 254Nutritional proteins 255Therapeutic proteins 255Non-specific proteins and peptides 257
Conclusions 259References 259
13 RESIDUE GROUPING STRATEGIES 265William E. Hall
Introduction 265Origin of Grouping Concept for Cleaning Validation 265Strategy or Rationale 266Fundamental Principles of Product Grouping 267Decision Tree Approach 268
Level 1 of the decision tree (sterile vs. non-sterile) 268Level 2 of the decision tree (dosage form) 268Level 3 of the decision tree (products) 269Level 4 of the decision tree (equipment) 269Level 5 of the decision tree (cleaning procedure) 271Cleaning procedure (definition) 272
Identification of theWorst Case(s) Representative Product in each Group 273Step 1 in worst case determination — assemble the data 273Step 2 — “Torture the data until it confesses” — evaluate the data
and determine the worst case product(s) 274Identification of aWorst-Case Ingredient in a Cleaning Agent Formulation 276Case Studies
Case study 1 277Case study 2 278Case study 3 278Answers top case studies 279
Case study 1 279Case study 2 279Case study 3 279
References 279About the Author 279
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14 A SCIENTIFIC APPROACH TO THE SELECTION OFCLEANINGVALIDATIONWORST-CASE SOILS FORBIOPHARMACEUTICAL MANUFACTURING 281
Rod J. Azadan and Alfredo J. CanhotoWhat is aWorst-Case Soil? 282A Scientifically Justified Approach 282Categorization of Soil Components 283The Matrix Analysis Method 285
Information collection 285Matrix design 285Soil semi-quantitation 287
Other Considerations 290Application of the matrix approach for process intermediates 290Process parameter impact on soil cleanability 290Historical experience 290Bioburden control 291Outstanding components 291
References 291About the Authors 292
15 VISUAL CLEANLINESS 293Richard Forsyth
Introduction 293Parameters affecting visual observations 294Acceptable residue limit 294Risk management 294Chapter objective 295
Visible Residue Limit for Cleaning Validation and its Potential Applicationin a Pharmaceutical Research Facility 295Visible residue parameters 295Experimental 297Results and discussion 298Conclusions — visible residues in the R&D pilot plant 309
Application of Visible Residue Limit for Cleaning Validation in a PharmaceuticalManufacturing Facility 309Visible residue parameters 309
Surface material 310Solvent to prepare standards 310Light intensity, viewing distance, and angle 310Observers 311
Experimental 311Results and discussion 314Conclusions — visible residues in a commercial scale
manufacturing facility 320Ruggedness of Visible Residue Limits for Cleaning Validation 321
Methods and materials 322
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Results and discussion 323Initial vs. later VRL determination 323API vs. excipient vs. formulation determinations 325Multi-site study 326Residue appearance 328
Conclusion 329Risk-Management Assessment of Visible Residue Limits in Cleaning Validation 329
Risk identification 330Risk analysis 331
Management of risks 332Pilot plant facility uses of VRL 333Manufacturing facility uses of VRL 335
Summary and Conclusions 336References 337About the Author 338
16 PERSONNEL TRAINING —VISUAL INSPECTIONOF CLEANED EQUIPMENT 339
Paul L. PlutaIntroduction 339
Audience 340Development of the training content 340Training approach 341Trainer expertise and competence 341Presentation as a training “update” 341
Training Objectives 342Time allotment 343Re-training 343Site training internal requirements 343
Training Lecture Topics 343Training session “icebreaker” 344
Case study #1 —Training session “icebreaker” 344Why are we here?Why is this training needed? 346What are we cleaning? 347Why is clean equipment important 347
Case study #2 — Regulatory cleaning audit 349Cleaning development, procedures, validation, and ongoing
visual evaluation 350What is cleaning? Cleaning is a process 351Performance of cleaning 354
Case study #3 — “Manual cleaning — do whatever it takes” 354What is visually clean? 357
Case study #4 — “Clean enough” 358Determination of visual cleanliness 360What if equipment is not visually clean after cleaning? 365Aids to determine visually clean 366
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Non product-contact surfaces 366Documentation 366Site-specific considerations 367
Demonstrations and Participatory Activities 369“Water-break” test 370Cleaning agent residue — solution foam 371Visual evaluation of wet and dry residues 371Swab sampling in cleaning validation 372Dried residue examples: no cleaning, partial cleaning, completed cleaning 372Known dried residue concentrations on stainless steel plates 373Known dried residue concentrations — evaluations at various distances 374Known dried residue concenttrations — evaluation at different
lighting levels 374Aids for visual examination 375
Key Points for Visual Evaluation of Surfaces 375Review of trainee expectations and questions 376
Training Summary 376Appendix 377References 379About the Author 380
SECTION FOURSPECIFIC RESIDUES FOR CLEANING — PART 1
17 BIOTECH RESIDUES AND CLEANING 383Jennifer Carlson
Introduction 383Production Processes 384
Recominbant protein produced through a mammalian cell line 384Cell culture 385Harvest 386Purification 387Formulation, freezing, and aseptic filling 387
Protein produced through bacterial fermentation 388Fermentation 388Initial recovery process 389Purification 389Formulation, freezing, and aseptic filling 390
Process Ingredients 390Equipment 391
Impact of material of construction 391Tanks 391
Design considerations 391Cleaning considerations 393Cleaning cycle considerations 395
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Passivation cycles (or maintenance cycles) 396Filter housings 396
Cleaning considerations 397Process lines and chromatography skids 397
Design considerations 398Centrifuges and homogenizers 399
Design considerations 399Filler 400Lyophilizer and stopper bowl 400Small equipment 401
Residue in a Typical Manufacturing Process 402Cell culture or fermentation fluid 402Pluronic F-68 and antifoams 403Medium preparations solutions 403
Cleaning Agents and Cleaning Procedures 404CIP cleaning 404
Pre-rinse 405Caustic wash 405Post caustic rinse 405Acid wash 405Intermediate rinse or post acid rinse 406Final rinse 406
Parts washers 406Manual cleaning 407
Acceptance Criteria for Biological APIs 407Residual active product 407Cleaning agent 408Bioburden 409Endotoxin 409Visual inspection 409
Case Studies 409Case study #1 — the case of revalidation failing TOC and conductivity 409
Problem 409Investigation 409Results 410Corrective actions due to investigation 410Conclusion 411
Case study #2 — cell culture CIP failure 411Problem 411Investigation 411Corrective actions due to investigation 412Conclusion 412
References 412About the Author 413
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18 CASE STUDY — CLEANING PROCESS OPTIMIZATIONFORA MANUFACTURING PROCESS CHANGE 415
Søren Damkjaer and Pernille L. JohansenIntroduction 415Problem 415Physical Examination of Equipment 416Laboratory Studies 416Testing the Original Cleaning Process 417Developing the New Cleaning Process 417Test Procedure 417Test Data 417Cleaning Procedures 420
Original cleaning procedure 420New cleaning procedure 420
Results and Conclusions 420About the Authors 421
19 MANUAL CLEANING PROCESSES AND PROCEDURES 423Valerie Welter
Yes ...You CanValidate Manual Cleaning Processes 423Getting Started 424Process Evaluation — Eliminating Unnecessary Processes 425Required Framework 425
Process equipment train 425Product contact materials of construction 426Cleaning procedure(s) 427Allowable equipment holding times 435Product formulations and product cleaning test methods 436
Cleaning Validation Master Plan (VMP) 437TheValidation Protocol and Report 438Summary Report 440Routine Monitoring and Control 440Revalidation/Change Control 440Audit Checklist for Manual Cleaning 441About the Author 442
Index 443
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