· Lifecycle approach to cleaning validation stage 1 — design and development 44 Lifecycle...

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CONTENTS

Introduction xxix

SECTION ONECLEANING VALIDATION BASICS

AND EXPECTATIONS

1 LIFECYCLE APPROACH TO CLEANING VALIDATION 3Paul L. Pluta

Introduction 3Lifecycle Approach to Process Validation 4

Stage 1 — Process design — product/process knowledgeand understanding 6Stage 2 — Process qualification — validation performance 6

Design of a facility and qualification of utilities and equipment 7PPQ 8PPQ protocol 8PPQ protocol execution and report 8

Stage 3 — Continued process verification — maintainingthe validated state 9

Documentation 10Analytical methods 10

Lifecycle Approach Strategy and Applications 10QbD and ICH 11

iii


QbD 12ICH guidances 12

Validation terminology 12Lifecycle Approach Application to Cleaning Validation 13

QbD and ICH application to cleaning and cleaning validation 15Risk management 15

Cleaning Validation Lifecycle Stage 1 — Process Design 16Cleaning method objectives, design, and development 16Product/process residue to be cleaned 17

Case Study — Cleaning Validation Failure — Unknown High-PerformanceLiquid Chromatography (HPLC) Peaks 17Introduction 17Compliance event background 18Investigation 19

Manufacturing personnel interviews 20Technical personnel evaluation 20Analytical laboratory personnel comments 20

Discussion 20Technical cleaning and the cleaning procedure 20Analytical method 21Inspection procedure 21

CAPA 21Post CAPA — verifying and maintaining validation and performance 22Other actions 23Site approach to cleaning validation 23

Analytical testing changes 23Conclusions 23

Analytical method selection and development 24Product matrix for worst-case products 24

Equipment to be cleaned 24Equipment materials with product contact 24Equipment product–contact surface areas measurement 25Equipment worst-case sampling locations 25Worst-case and equivalent equipment 25

Cleaning agent 25Cleaning process 26

Laboratory scale, pilot scale, technology transfer, andcommercial scale-up 26Cleaning equipment 26Identification and control of variables 26

Analytical methods 27Residue determination 27Recovery studies 27Sampling 27

Cleaning Validation Lifecycle Stage 2 — Process Qualification 27Considerations prior to cleaning process performance 28

Completion of stage 1 technical development work 29Master cleaning procedure record 29

Cleaning and Cleaning Validation – Volume 2iv


Pre-PPQ documents 30Cleaning procedure records for conformance lots 30Validation initiation/plan and validation protocol for specificcleaning process validation 30

PPQ cleaning performance 31Preparation for cleaning validation 31Conformance lot cleaning — execution of cleaningprocedure record 31Conformance lots sampling and testing 31

PPQ results 31Cleaning Validation Lifecycle Stage 3 — Continued Process Verification 32

Process monitoring and maintenance 32Annual product review data 33

Post-PQ special testing requirements 34Change management and control 34

Periodic management review 34Documentation 34

Scope of cleaning validation documentation 35High level policy documents 35Cleaning validation lifecycle documents 35Other applicable documents 36Documentation consistency 37

Document quality 37Document retrieval 38

Summary and Final Thoughts 38References 38About the Author 39

SECTION TWOGENERAL TECHNICAL PRINCIPLES —

CLEANING CHEMISTRY AND ENGINEERING

2 EQUIPMENT DESIGN CONSIDERATIONS FORCLEANING AND CLEANING VALIDATION 43

Gamal AmerIntroduction 32

Lifecycle approach to cleaning validation stage 1 —design and development 44

Lifecycle approach to cleaning validation stage 2 —performance qualification 44

Lifecycle approach to cleaning validation stage 3 —continued process verification 44

Equipment Types 45Off-the-shelf equipment 45Custom or unique equipment 45

Contents v


Design Issues and Considerations for Cleaning 46How toxic/potent is the residue to be cleaned? 46How difficult to clean is the residue? 47How will the equipment be cleaned? 47

Manual cleaning 47Automated cleaning 48Semi-automated cleaning 48

Where will the equipment be cleaned? 48Clean-in-place 49Clean remotely 49

General Design Considerations 50Material of construction and surface finish 50Equipment disassembly 51Access 51

Lighting 51Visual inspection 52Sampling ports 52Disposable components 52Sharp corners 52Gaskets and connections 53Piping 53

Piping angles 53Slanted surfaces 53

Documentation Supporting Validation and Daily Operation 53User requirements document 54Equipment specifications 54Engineering and design drawings 54Operation and Maintenance (O&M) manual 55Cleaning procedures 55Equipment cleaning log 55Equipment certifications 55Material Safety Data Sheets (MSDS) 56

Testing of the Equipment 56Spray testing 56Leak tests 56Weld verification 56Equipment qualification 56Swab testing 57

Summary 57References 57About the Author 57Appendix: Checklist for Equipment Design Considerations for Cleaning 58

Cleaning and Cleaning Validation – Volume 2vi


3 EQUIPMENT SAMPLING LOCATIONSAND SAMPLING METHODSFOR CLEANING VALIDATION 59

Paul L. PlutaIntroduction 59Importance of Equipment Sampling Locations and Sampling Methods 60Risk Analysis for Sampling Locations and Methods 61Regulatory Requirements and Industry Expectations 62Sampling Locations on Equipment 64

Sampling locations in areas of possible non-uniform contaminationin the next product 64Sampling locations in most difficult-to-clean areas of equipment 65Sampling locations representative of entire equipment surfaces 65Sampling locations that accumulate maximum process residue 65Sampling locations that have maximum product contact 66Sampling locations for specific product–contact material 66Random sampling locations 66Sampling locations for non-product–contact surfaces 66Sampling locations most likely to be re-contaminated 67

Sampling Methods 67Swab sampling 67Rinse sampling or solvent sampling 68

Fixed volume rinse sampling 68“Grab” rinse sampling 68

Placebo sampling or product sampling 69Coupon sampling 69Direct surface sampling 69

Approach for Selection of Sampling Locations and Sampling Methods 69Equipment technical evaluation 70Observation of equipment after processing 70Equipment disassembly review 70Cleaning procedure review 71Cleaning actual experience 72

Recommendations for Sampling Locations and Sampling Methods 72Sampling locations 72

Recommended sampling locations 72Optional sampling locations 72Other sampling locations 72Special applications 72

Sampling methods 73Experimental studies 73

Visually Clean Requirements 73Documentation and Procedures 73

Procedure to evaluate sampling locations on equipment 74Equipment evaluations 74Equipment sampling procedures for cleaning validation 74

Change Control 75Summary and Conclusions 75About the Author 77

Contents vii


Appendix 1: Regulatory Guidances and Industry Expectations forCleaning Validation Sampling and Test Methods 77

Appendix 2: Cleaning Validation Equipment Sampling LocationDetermination — Cleaning Personnel Interview 84

Appendix 3: Sampling Procedure Template 85Appendix 4: Example Sampling Procedures 88

4 PROCEDURE FOR SPRAY COVERAGE TESTINGWITH RIBOFLAVIN 91

Allan Marinelli and Cor Alleblas

Introduction 91Sprayball Overview 92Testing Sprayball Coverage using Riboflavin 93Procedure for Sprayball Coverage Testing 94Sprayball Design,Acceptance, and Installation 96

Sprayball system design 96Qualification 96Pre-validation 97Riboflavin spray device 98

Equipment to be Cleaned 98Equipment design 99Identification of hard-to-clean locations 99Equipment to be cleaned by riboflavin testing 99

Riboflavin Solution Preparation and Application to Equipment Surfaces 100Riboflavin solution 100Riboflavin spray coverage 100Riboflavin solution drying 101

Rinsing/Cleaning 101Worse-case cleaning process 101Rinsing/cleaning 102

Manual method (non-CIP) 102Manual method using CIP skid 103Automated method using CIP system 105

Spray Coverage Evaluation 105Post rinsing/cleaning verification 105Action items and closure 106

Lessons Learned 107What to do when Issues are Found? How to Change/Correct? 107

Parts covered by sprayball not adequately rinsed of riboflavin 107Shadowing — all top nozzles not adequately rinsed of riboflavin 107Nozzles incompletely flushed 108Pooling in vessel — bottom of vortex breaker orbottom nozzle not free of riboflavin 108Drip locations of baffle not free of riboflavin 108Bottom-mounted agitator spindle not free of riboflavin 108

Cleaning and Cleaning Validation – Volume 2viii


Agitator blades not free of riboflavin 108Solution drainage 108Manway cleaning 109If problems persist 109Other comments 109

References 110About the Authors 110

5 MISCELLANEOUS EQUIPMENT CLEANING TOPICS 111Destin A. LeBlanc

Introduction 111Cleaning for Dedicated Equipment 111Cleaning for Campaigns 114Cleaning After Deviations 118Cleaning After Interventions 120New Equipment Cleaning 122References 123About the Author 124

SECTION THREEGENERAL TECHNICAL PRINCIPLES — RESIDUES

6 POLYMER RESIDUE CLEANING METHODDEVELOPMENT: CASE STUDY 127

Dijana Hadziselimovic and Paul LopolitoIntroduction 127Properties of Carbomer Molecules 131Critical Parameters for Cleaning and Laboratory Studies 132Selection of Carbomers 133Laboratory Procedure 133Effect of Cleaning Agent, Concentration,Time and Temperature 137Effect of Cleaning Method, Pre-Rinse and Quality of Water 137Effect of Soil Load 139Effect of Application Condition 140Cleaning Evaluation of Various Carbomers 141Manual Cleaning Recommendations for the Various Forms of Carbomers 142Cleaning Recommendations for Various Final Dosage Forms

Containing Carbomers 143Conclusions 144References 145About the Authors 146

Contents ix


7 CLEANING AND CONTAMINATION CONTROLIN MEDICAL DEVICES 147

Barbara Kanegsberg and Edward KanegsbergIntroduction 147What Is Critical Cleaning? 148Cleaning Philosophy 149Medical Device Definitions and US Regulations 150

Class 1 devices 151Class II devices 151Class III devices 151

Challenges 151Soil Removal 151Cleaning Processes 152

Steps in the cleaning process 152Washing 153Rinsing 153Drying 153

Cleaning Agent Selection 153Why so many different cleaning agents? 153Solvency — water and isopropyl alcohol (IPA) may not be enough 154Materials compatibility 156Leachable residue 156Residue toxicity 156Surface quality 156Beneficial contamination 157

Cleaning Process Selection — Types of Cleaning Processes 158Cleaning Process Validation 161

A customized validation plan 161Surface characterization and residue determination 162

Supply Chain Quality 164Metalworking fluids 165Cleaning responsibility 165

Combination Devices — Special Challenges 166Reusable Devices 167FDA Guidance 168Conclusions 169References 169About the Authors 172

8 CHARACTERIZATION OF PROTEIN RESIDUESAFTER CLEANING 175

Alfredo J. Canhoto, Kathleen Bellorado and Michael KreuzeIntroduction 175

Proteins and relevant chemistry 176Analytical methodology 177

Experimental Approach 177

Cleaning and Cleaning Validation – Volume 2x


Materials and Methods 178Cleaning agents 178API soils 178Materials/equipment list 180SDS-PAGE solutions 181Experimental procedures 181

Working concentration determination 181Running gels 181Staining/destaining gels 182Analysis of gels in with densitometer 182

Degradation experiments 183Results 183

Effect of acidic cleaning agent 184Effect of alkaline cleaning agent 185Effect of acidic cleaning agent 186Summary of cleaning agent effects 186Discussion 188

Conclusions 189References 190About the Authors 190

9 MASTER SOILS FOR CLEANING CYCLE DEVELOPMENTAND VALIDATION: CASE STUDY 191

Rizwan SharnezIntroduction 191Criteria for Developing a Master Soil 192Case Study: Master Soil Development 192Experimental Approach 193

Acceptance criterion 194Materials and methods 194

Chemicals 194Apparatus 195

Coupons 195Soils 195Microbalance 195Oven 195

Procedure 195Pre-cleaning and soiling of coupons 195Simulated wash cycle 196Post-cleaning analysis 196

Results 196Step 1 data 196Step 2 data 197

Conclusion 198References 199About the Author 200

Contents xi


SECTION FOURSPECIFIC RESIDUES FOR CLEANING

10 CLEANING PROGRAMS FOR MANUFACTURERS FOR APIs 203William E. Hall

Introduction 203Regulatory Requirements 203The Actual “Cleaning Program” 205

Risk assessment — a good starting point 205Creation of a master plan or a “working” master plan 207Multiple-level approach to cleaning 209Campaign versus complete changeover cleanings 209

Unique Nature of Active Pharmaceutical Ingredients 210Nature of contaminants 210Sources of information 211Sources of contamination — two examples 213

Viracept 213Cholestyramine resin 213

Cleaning Agents 214Traditional cleaning agents 214Solvents as cleaning agents 214

Calculation of Scientifically Acceptable Maximum Allowable Residues 214Therapeutic dose approach 214No Observed Effect Level (NOEL) approach 215

Highly Potent APIs and the Concept of Containment 215Sampling and Analytical Considerations 216

Analytical methods 217Difficult to clean areas, surfaces, and recovery studies 217

Documentation of Cleaning in an API Facility 217Basic routine documentation 217Validation documentation 218Quality system documentation 218Training records 218

References 219Case Study # 1: Understanding Residue Chemistry 220Case Study # 2: Inadequate Cleaning in Campaigns 221Case Study # 3: Manual Cleaning Problems 221About the Author 222

11 VACCINE RESIDUES — CELL CULTURE MANUFACTURINGAND CLEANING 223

VivienneYankahTypes of Vaccines 224

Mechanism of action of vaccines 225Active immunization vaccines 225

Cleaning and Cleaning Validation – Volume 2xii


Passive immunization vaccines 225Vaccine Processing Technologies 227

Cell culture vaccines 227Cell bank 227Cell growth propagation and harvesting 228Inactivation 228Detoxification 228Purification 228Stability processing 229

Animal source for cell propagation 229Adenovirus 230Others 230

DNA vaccines 230Plant-based vaccines 230

Vaccine Formulation Ingredients 231Characteristics for selection of vaccine ingredients 231Stabilizing agents 233Preservatives 233Adjuvants 233

Adjuvant mechanism of action 234Residues in Typical Manufacturing Processes 235

Fermentation residues 236Purification residues 236Formulation residues 236

Typical Equipment and Manufacturing Processes 236Equipment design 237Equipment procurement 237Cleaning equipment 238

Automated CIP systems 238Semi-automated cleaning stations 238Manual cleaning 238

Cleaning equipment qualification 239Factory Acceptance Testing 239Installation Qualification 239Operational Qualification 239Performance Qualification 239

Coupon studies 240Cleaning Agents and Equipment Cleaning Procedures 240

Basic operations of the cleaning process 241Cleaning validation 242Planning validation strategy for cleaning design based onmanufacturing process 242Setting limits for acceptance criteria 243Soil categories and the cleaning process 243

Live soil cleaning process 243Non-live soil cleaning process 244

Identifying sampling locations 244Equipment hold times 244

Contents xiii


Dirty hold time 245Clean hold time 245Sterile hold 245Overcoming hold time excursions 245

Challenges of Cleaning Equipment Types 246Chromatography systems 246Bioreactor 247Centrifuges 247Tangential Flow Filtration 247Small equipment parts and hoses 248

Quality Attributes and Acceptance Criteria 248Sampling 248

Swab samples 249Rinse samples 249Visual inspection 249

Analytical test markers 251Total Organic Carbon 251Bacterial Endotoxin Test 251Protein 251Conductivity 251pH 252

Test method validation 252Recovery studies 252

Documentation 253Documentation for cleaning validation 253Documentation for routine cleaning 253

Training for Cleaning Validation 253Continuous Improvement 254

Quality by Design 254Process Analytical Technology 254Continuous monitoring 255Validation maintenance 255

Summary 255References 256About the Author 258

12 BIOTECH MANUFACTURING CLEANINGVALIDATION: CASE STUDIES 259

Michael Parks and Brian J. LloydIntroduction 259Case Study #1: Atypical Product Residue 260

Background 261Residue analysis 261Cleaning cycle analysis 261Laboratory studies 262Cleaning process changes — short term and long term 262

Cleaning and Cleaning Validation – Volume 2xiv


Overcoming process variation 263Summary 263

Case Study #2: Vessel Visual Inspection for a White Precipitate 264Background 264

Residue analysis 265Cleaning cycle analysis and problem solution 265

Summary 265Case Study #3: Bioburden Within a Non-sterile Purification Process 266

Background 267Initial study 267Expanded study 268

Problem-solving approach 268Process improvements 269Summary 270

About the Authors 270

13 CLEANING OF FERMENTATIONTANKS FORMANUFACTURE OF A SMALL MOLECULE API:CASE STUDY 273

Michael J. Egan and Thomas J. PaulusIntroduction 273

Cleaning objective 274Fermentor Equipment Component and Process 274Fermentation Process Residue 274Fermentor Steam Sterilization 274Fermentor Chemical Cleaning 275

Raw material assessment 275Typical Fermentor Cleaning Process 275Summary 276About the Authors 276

14 ASEPTIC PARENTERAL PRODUCTS —RESIDUES AND CLEANING 279

ValerieWelterIntroduction 279Product Types 280Formulation Ingredients 280

Typical ingredients 281Equipment and Manufacturing Process 282

Equipment 282Equipment terminology 283Cleaning of dedicated/captive product contact equipment 284Cleaning of direct product contact equipment 284

Cleaning of tanks/vessels 284

Contents xv


Cleaning of mixing equipment 285Cleaning of filtration equipment 285Cleaning of miscellaneous small parts 285Cleaning of permeable materials 285Cleaning of advanced aseptic processing environments (isolators) 286

Typical manufacturing process 286Dispensing of formulation ingredients 286Solution formulation 288Transfer to aseptic filling suite 288Lypholization 289Capping 289

Equipment considerations and the impact on cleaning 290Critical sites 290Difficult to clean sites 290Representative sites 290

Residues in a Typical Aseptic Manufacturing Process 291Microbial considerations for aseptic formulations 291

Cleaning Agents and Cleaning Procedures 292Acceptance Criteria for Aseptic Parenteral Products 292Case Studies 295

Case study #1: Inadequate characterization of “clean” 295Problem 295Discussion 295Corrective actions 295

Case study #2: Recovery techniques not adequately defined 296Problem 296Discussion 296Corrective actions 296

Case study #3: Calculated acceptance criteria below the LOQof the analytical method 296

Problem 296Investigation 296Corrective actions 296

References 297About the Author 297

15 CLEANING PROCESS AND VALIDATION FOR MDIs 299Michael Taylor, Paul Sullivan, Jay Holt and Li Li Bovet

Introduction 299MDI Composition and Formulation 300Production Processes and Equipment 300

Manufacturing scale 302Product development scale production 302Small scale production 302Medium scale production 302Large scale production 302

Cleaning and Cleaning Validation – Volume 2xvi


Cleaning Considerations 303Cleaning agents 303Equipment considerations 303Specific equipment considerations 305

Tanks 305Impellers 306Recirculation pumps, valves, and lines 306Canister and valve hoppers/guide tracks 306Small equipment 307Valves and gaskets 307

Cleaning Validation 308Cleaning process 308

Methanol rinse 308HFA-134a rinses 308Additional cleaning for comprehensive clean cycles 308

Cleaning validation process 309Background 309Purpose 309Process description 309Cleaning approach 309Review of active drug residual limits 309Sampling methodology 309Data analysis 310Acceptance criteria for cleaning verification 310Test results 310Conclusion 310Approval signatory 310

Acceptance criteria 310Case Studies 311

Case study #1: DH Autocart — an automated solution to enabledynamic off-line cleaning in a GMP environment 311

Problem 311Investigation 311Action 311Conclusion 312

Case study #2:Test equipment 312Case study #3: Process equipment 312

About the Authors 313

16 TRANSDERMAL PATCHES — RESIDUESAND CLEANING 315T.J.Woody and Rashmi S. Upasani

Introduction 315Transdermal Patch Design, Configurations, and Components 316

Transdermal patch configurations 316Transdermal patch components 317

Manufacturing Process and Equipment 318

Contents xvii


Residues from Manufacturing Process 319Cleaning Agents and Cleaning Procedures 319

Cleaning process considerations 320Dirty hold time 320Cans and tanks 320Pumps 320Equipment disassembly 320Manual cleaning process 321Cleaning time 321Safety — solvent flammability and explosivity 321

General cleaning process 321Cleaning Quality Attributes and Acceptance Criteria 322

Safety-based method 322Minimum or normal therapeutic dose method 32310 ppm carryover method 323Disposables 324

Case StudiesCase study #1:Absence of active failure 324

Problem 324Background information and investigation 324Corrective actions 324Conclusion 324

Case study #2: Mixer cleaning 325Problem 325Investigation 325Corrective actions 325Conclusion 326

Summary 326References 326About the Authors 327

17 MEDICAL DEVICE REAGENT PRODUCTRESIDUESAND CLEANING 329

RobertW. MarshmanIntroduction 329Product Types 329

Assay foundation 330Products 330

Production Processes and Equipment 330Active ingredient synthesis 330Active ingredient isolation 331Formulation of bulk active ingredient 331Kit preparation 331

Active Ingredient Synthesis 332Cell culture 332

Fermentation vessels 332


Hollow fiber cartridges 333

Spinner flasks and roller bottles 333Organic synthesis 333

Active Ingredient Isolation 334Homogenization 334

Homogenization equipment 334Column chromatography and purification equipment 334Dialysis 335Diafiltration and concentration 335

Stirred cell 335Hollow fiber 335Plate and frame 336

Plasma processing 336Formulation of Bulk Active Ingredient 336

Particle coating 337Equipment and process residues 337

Bulk reagent formulation 337Equipment and process residues 337

Kit Preparation 338Equipment and process residues 338

Acceptance Criteria for Medical Device Reagents 339Establishment of limits for cleaning 339Specific equipment limits 339

Cleaning Agents, Cleaning Methods, and Other Variables 340Cleaning agents 341Cleaning options 341

Example: cleaning of homogenizers 342CIP systems 342Cabinet washers 343COP systems 346Equipment-specific procedures 346Manual procedures 346Dedicated equipment 347Disposable equipment 347

Case Studies 347Case Study #1: Microbial load reduction 347

Issue 347Approach 347Challenges 348Results 348

Case Study #2:Tangential flow filter — concentration 348Issue 348Approach 348Challenges 348Results 348

Case Study #3: Detergent discontinuation 348Issue 348

Contents xix


Approach 348Challenges 349Results 349

Reference 349About the Author 349

SECTION FIVEANALYSIS OF RESIDUES

18 PROCESSANALYTICALTECHNOLOGYFOR CLEANING SYSTEMS 353

Keith Bader and PeterWatlerOverview 353Cleaning System Processes 353Cleaning Process Parameters and Critical Quality Attributes 354

Concentration 355Cleaning solution temperature 355External energy 356Time — cleaning duration and contact time 357

Cleaning rate for laminar flow 358Cleaning rate in turbulent flow 359Turbulent vs. laminar cleaning rates 360

Analytical Methods and Sensors 361Temperature 361Flowrate 361Conductivity and pH 361

Total Organic Carbon 362TOC operating principles 362

Interference, pressure, and temperature 362Oxidation and measurement 363

Oxidation 363Advanced oxidation 364Thermal oxidation 364Chemically-assisted oxidation 365

Measurement and detection 365Conductivity 366Membrane conductometric 367Serial conductometric 368Spectrophotometric detection 369

Rapid Microbial Methods 371Bacterial Endotoxin Testing (BET) 371Adenosin Triphosphate (ATP) bioluminescence 372Optical and spectrophotometric detection methodologies 372Summary 374

Installation and Placement 374

Cleaning and Cleaning Validation – Volume 2xx


Location and sample residence time 374Case studies 376

PAT for chromatography column cleaning 376Column integrity test as PAT forward processing criteria 378Column pressure drop as PAT forward processing criteria 381Product peak HETP as PAT critical quality attribute and forward

processing criteria 383Product peak asymmetry factor as a PAT critical quality attribute 385Product peak retention — resin capacity 386

References and Further Reading 387About the Authors 390

19 SWAB SAMPLING FOR CLEANING VALIDATION 393Sandeep Kalekar and Jay Postlewaite

Introduction — Why Validate Cleaning? 393The importance of sampling 394

Sampling Methods 394Swab and rinse sampling 394

Swab Sampling 395Selection of the swab 395Proper swabbing procedure 396

Training for Swab Sampling 396Case Studies 398

Case study #1: False negative cleaning data 398Introduction 398Background 398Investigation 399Discussion 399CAPA 401Cleaning validation of modified cleaning process 401Summary 401

Case study #2: Cleaning validation sampling with an extension pole 402Background 402Investigation 403Discussion 403Summary 403

Analytical Methods 404Total Organic Carbon 405High performance liquid chromatography 405Residue recovery studies 407

Residue affinity for product–contact surface 408Summary 409References 409About the Authors 410

Contents xxi


20 SWAB SAMPLING TRAINING AND SAMPLINGPERSON QUALIFICATION 411

Brian P. HueyIntroduction 411Swab Sampling Overview 412Personnel Sampling Skills 413Approach to Sampling Person Training and Qualification 414

Worse-case approach 414Review of site sampling and analytical methods 414Sampling technique 414Sampling testing 415Atypical sampling 415Acceptance criteria 415

Sampling Person Qualification (Certification) 415Failing Sampling Qualification 416Sampling Person Requalification 416Key Points for Sampling Programs and Sampling Person Training 417Documentation 418Conclusions 418Reference 419About the Author 419

SECTION SIXCLEANING AND CLEANING

VALIDATION QUALITY SYSTEMS

21 QUALITY SYSTEMSAPPROACHTO CLEANINGAND CLEANINGVALIDATION 423

Timothy J. FieldsIntroduction 423Management Role in Cleaning 424

Policies and procedures 425Personnel 425Test facilities 425Facilities and equipment 426Cleaning agents 426Periodic review 426Cleaning and cleaning validation at contract facilities 426Management communication 427

Continuous Improvement 427Quality System Enablers 428

Knowledge management 428Key information for cleaning 428Applications of knowledge management 430External sources of knowledge 431

Cleaning and Cleaning Validation – Volume 2xxii


Quality risk management 431Applications of quality risk management 431

Quality System Elements 434Process performance and product quality monitoring system 434CAPA system 434Change management system 435Management review of process performance and product quality 435

Plan-Do-Check-Act 436Summary 436References 436About the Author 437

22 CHANGE MANAGEMENT IN CLEANINGAND CLEANING VALIDATION 439

David E. JonesIntroduction 439Change Management Overview 440

Definition 441Background and evolution 441Regulations and risk management 442

Validation and Change Control — A Maintenance Activity 444Change Management Programs 445

Establishing a change management program 445Change control procedures 446

Who may initiate changes? 447Change judgments — quality risk management 448Change control documentation 451One-size does not fit all 451

Training In Cleaning Validation 452Change Management in Cleaning and Cleaning Validation 453

Cleaning process 453Case Study: Change to the Cleaning Agent 454

Cleaning agent lack of control 454Inadequate cleaning agent incoming specifications 455

Case Study: Changes to the Cleaning Process — Vague InexplicitProcess Directions 456Cleaning liquid concentration 456Cleaning process rinsing 456

Case Study: Changes to the Cleaning Process 457Manual cleaning — “Do whatever it takes” 457“Clean enough” 457Formulation or process residue 458

Case Study: Changes to the Residue 458Red tablet formulation 458Dirty hold time 459

Contents xxiii


Clean hold time 459Equipment surface 460

Case Study: Changes to the Equipment Surface 460New product–contact material 460Sampling and analytical procedure 460

Case Study: Sampling and Analytical 461Sampling with extension pole 461New sampling person — false negative results 462

Summary 463References 465About the Author 466

23 CONTROL CHARTING FUNDAMENTALS 467Bernard M. McGarvey

Introduction 467Variation and Control Charting — A Personal Application 468Shewhart Steps In! 471Individual’s Control Chart 473Moving Range (mR) Control Chart 476

Combination XmR control charts 478Significance of Statistical Control for Variability Reduction

and Process Improvement 479Control vs.Analysis with Control Charts 482What Parameters should be Monitored via a Control Chart? 483Run Rules for Control Charts 485

Run rules fundamentals 485Run rules practical advice 486

Sensitivity to Key Assumptions? 486Other Types of Control Charts 489

X/R, X/s Charts 489Control charts for count data 491

Defective units and defects 491Constructing an np chart 492Constructing a p chart 493Constructing a c chart 494Constructing a u chart 494LCL in count charts 495

A warning on the use of count control charts 496Case Study — Implementing Control Charts 496Exercise — Using Control Charts 500References 502About the Author 503Answers to Control Chart Exercise Questions 503

Cleaning and Cleaning Validation – Volume 2xxiv


24 ANALYTICAL CLEANING LABORATORY GAP ANALYSIS 505Brian P. Huey

Introduction 505Self-audit Questions 506

Laboratory organization 506Sample collection 506Sample handling in the laboratory 507Analytical method development 507Testing performance 508Data treatment 509Reporting of results 509Data storage 510

Communicating with Auditors 510The Audit Process 510Case Study: Cleaning Validation Laboratory Audit 511Document Retrieval 513Conclusions 513References 513About the Author 514

EPILOGUEPROBLEMS IN CLEANING

AND CLEANING VALIDATION

25 CLEANING AND CLEANING VALIDATIONGENERAL PROBLEMS 517

Paul L. Pluta, Rizwan Sharnez, Cormac Dalton and Kevin O’DonnellIntroduction 517Product Residue Considerations 519

Physical and chemical properties of residue as a basis for cleaning 520Case Study #1: Cleaning of a Basic API 520Case Study #2: Cleaning of a Highly Insoluble API 521

Regulatory considerations 522Residue solubility in most difficult-to-clean residue matrix 523

Regulatory considerations 526“Cleanability” in determining the most difficult-to-clean residue 527

Equipment Considerations 528Non-uniform contamination transfer 529Most difficult-to-clean locations in equipment 531

Equipment technical analysis 532Observation of equipment after processing 532Equipment disassembly review 532Cleaning procedure review 532Operator interviews 532Analysis and evaluation of above information 532

Contents xxv


Preparation of sampling documents for cleaning validation 533Documentation of above 533

Cleaning Process Considerations 536Case Study #3: Manual Cleaning — Reality 536

Manual cleaning qualification 537Stage 1 — Manual cleaning process development 537Stage 2 — Manual cleaning performance 538Equipment inspection 538Stage 3 — Maintaining and monitoring manualcleaning performance 538Regulatory assessment of manual cleaning processes 539

Cleaning procedure documentation 541Laboratory Considerations 542

Residue stability in cleaning residue analysis 542Residue recovery studies 543Swab sampling technique, reliability, and training 544

Conclusions 545References 545About the Authors 547

Index 549

Cleaning and Cleaning Validation – Volume 2xxvi


CASE STUDIES

Cleaning Validation Failure — Unknown High-PerformanceLiquid Chromatography (HPLC) Peaks 17

Polymer Residue Cleaning Method Development 127Master Soils for Cleaning Cycle Development andValidation 192Understanding Residue Chemistry 220Inadequate Cleaning in Campaigns 221Manual Cleaning Problems 221Biotech Manufacturing Cleaning Validation 259Atypical Product Residue 260Vessel Visual Inspection for aWhite Precipitate 264BioburdenWithin a Non-sterile Purification Process 266Cleaning of Fermentation Tanks for Manufacture of a Small Molecule API 273Inadequate Characterization of “Clean” 295Recovery Techniques Not Adequately Defined 296Calculated Acceptance Criteria Below the Loq of the Analytical Method 296Dh Autocart — An Automated Solution to Enable

Dynamic Off-Line Cleaning in a GMP Environment 311Test Equipment 312Process Equipment 312Absence of Active Failure 324Mixer Cleaning 325Microbial Load Reduction 347Tangential Flow Filter — Concentration 348

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Detergent Discontinuation 348PAT for Chromatography Column Cleaning 376Column Integrity Test as PAT Forward Processing Criteria 378Column Pressure Drop as PAT Forward Processing Criteria 381Product Peak HETP as PAT Critical Quality Attribute and Forward Processing Criteria 383Product Peak Asymmetry Factor as a PAT Critical Quality Attribute 385Product Peak Retention — Resin Capacity 386False Negative Cleaning Data 398Cleaning Validation Sampling with an Extension Pole 402Change to the Cleaning Agent 454Changes to the Cleaning Process —Vague Inexplicit 456Changes to the Cleaning Process 457Changes to the Residue 458Changes to the Equipment Surface 460Sampling and Analytical 461Implementing Control Charts 496Cleaning of a Basic API 520Cleaning of a Highly Insoluble API 521Manual Cleaning — Reality 536

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