Contents

List of Figures xxi

List of Tables xxv

About the Book xxvii

Preface xxxi

Acknowledgments xxxiii

Authors xxxv

Introduction xxxvii

Disclaimer xxxix

CLV-1 How to Establish a Cleaning Validation Program 1

1.1 Cleaning in Finished, Biopharmaceuticals, and Bulk Chemicals 1

1.1.1 Cleaning Program Norms 1

1.1.1.1 Cleaning Methods 2

1.1.1.2 Equipment 2

1.1.1.3 Product 4

1.1.1.4 Facility 4

1.1.2 Cleaning Validation 5

1.1.2.1 Cleaning Validation Program 5

1.1.2.2 Residues and Residue Removal 5

1.1.2.3 Cleaning of Equipment 6

1.1.2.4 Cycle Development 6

1.1.2.5 Sampling Techniques and Analytical Methods 7

1.1.2.6 Limits and Acceptance Criteria 7

1.1.2.7 Ongoing Monitoring of Cleaning 8

1.1.2.8 Change Control 8

CLV-2 Introduction 9

2.1 Cleaning Validation 9

2.1.1 U.S. FDA Guidelines 10

2.1.2 Health Canada Guidelines 10

2.1.3 EU-GMP Guidelines 10

2.2 Validation Master Plan 11

CLV-3 Scope and Approach 13

CLV-4 Cleaning Validation Team Members and Responsibilities 15

4.1 Specific Responsibilities 15

4.1.1 Validation Department 15

4.1.2 Production 15

4.1.3 Packaging 16

4.1.4 Utilities/Calibration/HVAC 16

4.1.5 Quality Control 16

4.1.6 Quality Assurance 16

4.1.7 Product Development Laboratory 16

CLV-5 Cleaning Validation Philosophy, Strategies, and Methodology 17

5.1 Cleaning Validation Philosophy 17

5.2 Cleaning Validation Strategies 17

5.2.1 General 17

5.2.2 Specific 17

5.3 New Products, Equipment, and Processes 18

5.4 Cleaning Validation Methodology 19

CLV-6 Planning Phase 21

6.1 Prevalidation Requirements 21

6.1.1 Equipment 21

6.1.2 Cleaning Procedures 21

6.1.3 Personnel Training 21

6.2 Worst-Case Product Selection Matrix 21

6.3 Analytical Development 22

6.4 Recovery 22

6.5 Protocol Development 23

CLV-7 Execution Phase 25

7.1 Visual Examination 25

7.1.1 Sampling 25

7.1.2 Swab Sampling 25

7.1.3 Rinse Sampling 26

CLV-8 Analytical Testing and Reporting Phase 27

8.1 Acceptance Criteria 27

8.1.1 Limits Determination 27

8.1.2 Microbial Burden 28

8.1.3 Analytical Results Reporting 28

8.1.4 Incident Investigation 28

8.1.5 Reports 29

8.1.6 Monitoring 29

8.1.7 Change Control/Revalidation 29

CLV-9 Equipment Description 31

9.1 Solid Dosage Manufacturing 31

9.1.1 Equipment Description 31

9.2 Sterile 33

9.2.1 Equipment Description (Injectables) 33

9.3 Liquid Manufacturing 34

9.3.1 Equipment Description (Soft Product) 34

9.4 Filling Lines 35

9.4.1 Equipment Description (Soft Product) 35

CLV-10 Facility Description 37

10.1 Solid Dosage Manufacturing 37

10.1.1 Facility Description 37

CLV-11 Utilities Description: DIW, WFI, Steam, and Compressed Air 39

11.1 Utilities Description 39

11.1.1 Water System 39

11.1.2 WFI System 39

11.1.3 Purified Water System 39

11.1.4 Process Chilled Water System 40

11.1.5 Steam System 40

11.1.6 Compressed Air 40

11.1.7 Compressed Air (Solid and Liquid Products) 41

11.1.8 Nitrogen System 41

CLV-12 Utilities Monitoring and Microbiological Control 43

CLV-13 Equipment Cleaning Materials/Detergent Description 45

13.1 Solid Dosage Plant 45

13.2 Sterile Plant 45

13.3 Antibiotic Plant 46

13.4 Liquid Dosage Plant 46

CLV-14 Microbiological Cleaning of Equipment Surface 47

CLV-15 Solubility of Active Materials in Water 49

CLV-16 Toxicity of Active Materials 55

CLV-17 Cleaning Validation Products Grouping Matrix

(Tablets, Capsules, and PPS) 61

17.1 Product Grouping Matrix (Solid Dosage) 61

17.1.1 Tablets 61

17.2 Product Grouping Matrix (Capsules) 76

17.3 Product Grouping Matrix (Granules) 78

CLV-18 Product/Equipment Train Matrix (Tab-Cap-PPS) 79

18.1 Products/Equipment Train (Tablets, Capsules, and PPS) 79

18.1.1 Wet Granulation Uncoated Tablets 79

18.1.2 Wet Granulation Coated Tablets 80

18.1.3 Dry Granulation Uncoated Tablets 80

18.1.4 Dry Granulation Coated Tablets 81

18.1.5 Sugar-Coated Tablets 81

18.2 Product/Equipment Train (Capsules) 81

18.3 Product/Equipment Train (Granules) 82

CLV-19 Worst-Case Products (Tablets, Capsules, and PPS) Matrix 83

19.1 Worst-Case Products (Tablets) 83

19.1.1 For Coating Machines Only 84

19.1.2 Sugar-Coated Products (for Conventional Coating Pans) 84

19.2 Worst-Case Products (Capsules) 84

19.2.1 For Encapsulator A 84

19.2.2 For Encapsulator B 85

19.3 Worst-Case Products (Granules) 85

CLV-20 Validation with Corresponding Cleaning Procedures 87

20.1 Protocols for Tablets Manufacturing Equipment 87

CLV-20.1 Cleaning Validation Protocol for Fluid Bed Dryer 89

20.1.1 Objective 90

20.1.2 Scope 90

20.1.3 Responsibility 90

20.1.4 Description of the Cleaning Process 91

20.1.4.1 Difficult-to-Clean Parts 92

20.1.5 Description of the Sampling Process 92

20.1.5.1 Sampling Technique 92

20.1.5.2 Sampling Precautions 92

20.1.5.3 Procedure for Sampling 92

20.1.5.3.1 Surface Swabs 92

20.1.5.4 Handling of Samples 96

20.1.6 Test Functions 96

20.1.7 Verification of Documents 97

20.1.8 Documentation 97

20.1.9 Acceptance Criteria 97

20.1.10 List of Attachments 99

CLV-20.2 Cleaning Validation Protocol for Mixer 107

20.2.1 Objective 108

20.2.2 Scope 108

20.2.3 Responsibility 108

20.2.4 Description of the Cleaning Process 109

20.2.4.1 Difficult-to-Clean Parts 109

20.2.5 Description of the Sampling Process 109

20.2.5.1 Sampling Technique 109

20.2.5.2 Sampling Precautions 110

20.2.5.3 Procedure for Sampling 110

20.2.5.4 Handling of Samples 111

20.2.6 Test Functions 111

20.2.7 Verification of Documents 111

20.2.8 Documentation 111

20.2.9 Acceptance Criteria 112

20.2.10 List of Attachments 113

CLV-20.3 Cleaning Validation Protocol for Granulation Machines (Type A) 121

20.3.1 Objective 122

20.3.2 Scope 122

20.3.3 Responsibility 122

20.3.4 Description of the Cleaning Process 123

20.3.4.1 Difficult-to-Clean Parts 123

20.3.5 Description of the Sampling Process 123

20.3.5.1 Sampling Technique 123

20.3.5.2 Sampling Precautions 124

20.3.5.3 Procedure for Sampling 124

20.3.5.4 Handling of Samples 124

20.3.6 Test Functions 124

20.3.7 Verification of Documents 126

20.3.8 Documentation 127

20.3.9 Acceptance Criteria 127

20.3.10 List of Attachments 128

CLV-20.4 Cleaning Validation Protocol for Powder Bins 137

20.4.1 Objective 138

20.4.2 Scope 138

20.4.3 Responsibility 138

20.4.4 Description of the Cleaning Process 140

20.4.4.1 Difficult-to-Clean Parts 140

20.4.5 Description of the Sampling Process 140

20.4.5.1 Sampling Technique 140

20.4.5.2 Sampling Precautions 140

20.4.5.3 Procedure for Sampling 140

20.4.5.4 Handling of Samples 140

20.4.6 Test Functions 141

20.4.7 Verification of Documents 142

20.4.8 Documentation 143

20.4.9 Acceptance Criteria 143

20.4.10 List of Attachments 144

CLV-20.5 Cleaning Validation Protocol for Tablet Press 153

20.5.1 Cleaning Validation Protocol for Tablet

Press Type A 154

20.5.1.1 Objective 154

20.5.1.2 Scope 154

20.5.1.3 Responsibility 154

20.5.1.4 Description of the Cleaning Process 154

20.5.1.5 Difficult-to-Clean Parts 156

20.5.1.6 Description of the Sampling Process 156

20.5.1.6.1 Sampling Technique 156

20.5.1.6.2 Sampling Precautions 157

20.5.1.6.3 Surface Swabs 157

20.5.1.7 Test Functions 157

20.5.1.8 Verification of Documents 161

20.5.1.9 Documentation 161

20.5.1.10 Acceptance Criteria 161

20.5.1.11 List of Attachments 162

20.5.2 Cleaning Validation Protocol for Tablet Press Type B (Figure 20.5.2.1) 170

20.5.3 Cleaning Validation Protocol for Tablet Press Type C (Figure 20.5.3.1) 180

20.5.3.1 List of Attachments 180

CLV-20.6 Cleaning Validation Protocol for Sieve 193

20.6.1 Objective 194

20.6.2 Scope 194

20.6.3 Responsibility 194

20.6.4 Description of the Cleaning Process 194

20.6.4.1 Difficult-to-Clean Parts 196

20.6.5 Description of the Sampling Process 196

20.6.5.1 Sampling Technique 196

20.6.5.2 Sampling Precautions 196

20.6.5.3 Procedure for Sampling 196

20.6.5.4 Handling of Samples 196

20.6.6 Test Functions 197

20.6.7 Verification of Documents 198

20.6.8 Documentation 198

20.6.9 Acceptance Criteria 198

20.6.10 List of Attachments 199

CLV-20.7 Cleaning Validation Protocol for Powder-Filling Machine 207

20.7.1 Objective 208

20.7.2 Scope 208

20.7.3 Responsibility 208

20.7.4 Description of the Cleaning Process 209

20.7.4.1 Difficult-to-Clean Parts 209

20.7.5 Description of the Sampling Process 210

20.7.5.1 Sampling Technique 210

20.7.5.2 Procedure for Sampling 210

20.7.5.3 Sampling Precautions 210

20.7.5.4 Handling of Samples 210

20.7.6 Test Functions 210

20.7.7 Verification of Documents 213

20.7.8 Documentation 213

20.7.9 Acceptance Criteria 213

20.7.10 List of Attachments 214

CLV-20.8 Cleaning Validation Protocol for Encapsulation Machine 223

20.8.1 Cleaning Validation Protocol for Encapsulation Machine (Type A) 223

20.8.1.1 Objective 223

20.8.1.2 Scope 223

20.8.1.3 Responsibility 224

20.8.1.4 Description of the Cleaning Process 225

20.8.1.5 Description of the Sampling Process 225

20.8.1.5.1 Sampling Technique 225

20.8.1.5.2 Sampling Precautions 226

20.8.1.5.3 Procedure for Sampling 226

20.8.1.5.4 Handling of Samples 226

20.8.1.6 Test Functions 229

20.8.1.7 Verification of Documents 229

20.8.1.8 Documentation 229

20.8.1.9 Acceptance Criteria 229

20.8.1.10 List of Attachments 231

20.8.2 Cleaning Validation Protocol for Encapsulation Machine (Type B) 239

20.8.2.1 Objective 239

20.8.2.2 Scope 239

20.8.2.3 Responsibility 240

20.8.2.4 Description of the Cleaning Process 240

20.8.2.4.1 Cleaning Agent/Disinfectant 240

20.8.2.5 Description of the Sampling Process 240

20.8.2.5.1 Sampling Technique 240

20.8.2.5.2 Sampling Precautions 241

20.8.2.5.3 Surface Swab 241

20.8.2.5.4 Handling of Samples 242

20.8.2.6 Test Functions 242

20.8.2.7 Verification of Documents 242

20.8.2.8 Documentation 242

20.8.2.9 Acceptance Criteria 243

20.8.2.10 List of Attachments 243

CLV-20.9 Cleaning Validation Protocol for Film-Coating Pan 259

20.9.1 Objective 259

20.9.2 Scope 259

20.9.3 Responsibility 261

20.9.4 Description of the Cleaning Process 261

20.9.4.1 Difficult-to-Clean Parts 261

20.9.5 Description of the Sampling Process 262

20.9.5.1 Sampling Technique 262

20.9.5.2 Sampling Precautions 262

20.9.5.3 Handling of Samples 262

20.9.5.4 Surface Swabs 262

20.9.5.4.1 Procedure for Sampling 262

20.9.6 Test Functions 264

20.9.7 Verification of Documents 264

20.9.8 Documentation 264

20.9.9 Acceptance Criteria 264

20.9.10 List of Attachments 266

CLV-20.10 Cleaning Validation Protocol for Sugar-Coating Pan 275

20.10.1 Objective 275

20.10.2 Scope 275

20.10.3 Responsibility 276

20.10.4 Description of the Cleaning Process 276

20.10.4.1 Difficult-to-Clean Parts 277

20.10.5 Description of the Sampling Process 277

20.10.5.1 Sampling Technique 277

20.10.5.2 Handling of Samples 277

20.10.5.3 Surface Swabs 278

20.10.5.3.1 Procedure for Sampling 278

20.10.6 Test Functions 280

20.10.7 Verification of Documents 280

20.10.8 Documentation 280

20.10.9 Acceptance Criteria 281

20.10.10 List of Attachments 282

CLV-21 Cleaning Validation Product Grouping Matrix (Syrup) 291

CLV-22 Cleaning Validation Product/Equipment Train (Syrup) 293

CLV-23 Worst-Case Products (Syrup) 295

CLV-24 Cleaning Validation Product Grouping Matrix (Suspension) 297

CLV-25 Product Grouping/Equipment Train Matrix (Suspension) 299

CLV-26 Worst-Case Products (Suspension) 301

CLV-27 Product Grouping Matrix (Drops) 303

CLV-28 Product/Equipment Train (Drops) 305

CLV-29 Worst-Case Products (Drops) 307

CLV-30 Cleaning Validation Product Grouping Matrix (Cream/Ointment) 309

30.1 Ointments 310

CLV-31 Product/Equipment Train (Cream and Ointment) 311

31.1 Cream Products 312

CLV-32 Worst-Case Products (Ointment and Cream) 313

32.1 Ointments 313

32.1 Creams 313

CLV-33 Product Grouping Matrix (Suppositories) 315

CLV-34 Cleaning Validation Product/Equipment Train (Suppositories) 317

CLV-35 Worst-Case Products (Suppositories) 319

CLV-36 Cleaning Validation Protocols Products (Suppositories) 321

CLV-36.1 Protocol for Manufacturing Vessel 323

36.1.1 Objective 324

36.1.2 Scope 324

36.1.3 Responsibilities 326

36.1.4 Description of the Cleaning Process 327

36.1.5 Identification of Critical Parameters 327

36.1.6 Description of the Sampling Process 328

36.1.6.1 Sampling Technique 328

36.1.6.1.1 Surface Swabs 328

36.1.7 Test Functions 331

36.1.7.1 Visual Inspection 331

36.1.8 Verification of Documents 331

36.1.9 Documentation 331

36.1.10 Acceptance Criteria 332

36.1.11 List of Attachments 333

CLV-36.2 Protocol for Bin-Washing Station 339

36.2.1 Objective 340

36.2.2 Scope 340

36.2.3 Responsibilities 340

36.2.4 Description of the Process 341

36.2.5 Identification of Critical Parameters 341

36.2.6 Description of the Sampling Process 341

36.2.6.1 Sampling Technique 341

36.2.6.1.1 Surface Swabs (Sterile Cotton Swabs

Wetted with WFI) 342

36.2.7 Test Functions 342

36.2.8 Verification of Documents 343

36.2.9 Documentation 343

36.2.10 Acceptance Criteria 343

36.2.11 List of Attachments 344

CLV-36.3 Cleaning Validation Protocol for Syrup-Holding Tank 355

36.3.1 Objective 356

36.3.2 Scope 356

36.3.3 Validation Approach 356

36.3.4 Responsibility 356

36.3.5 Procedure 356

36.3.6 Description of the Cleaning Process 357

36.3.6.1 Procedure 357

36.3.7 Identification of Critical Parameters 358

36.3.8 Description of the Sampling Process 358

36.3.8.1 Sampling Technique 358

36.3.8.2 Sampling Precautions 358

36.3.8.3 Rinse Sample 358

36.3.8.4 Handling of Sample 358

36.3.9 Test Functions 359

36.3.9.1 Visual Inspection 359

36.3.10 Verification of Documents 360

36.3.11 Documentation 360

36.3.12 Acceptance Criteria 360

36.3.13 List of Attachments 361

CLV-36.4 Protocol for Filling Station and Filter Assembly 367

36.4.1 Protocol for Filling Machine (Type A) 368

36.4.1.1 Objective 368

36.4.1.2 Scope 368

36.4.1.3 Cleaning Validation Approach 368

36.4.1.4 Responsibilities 368

36.4.1.5 Description of the Cleaning Process 368

36.4.1.6 Identification of Critical Parameters 369

36.4.1.7 Description of the Sampling Process 370

36.4.1.7.1 Sampling Technique 370

36.4.1.7.2 Surface Swabs 372

36.4.1.8 Test Functions 373

36.4.1.8.1 Visual Inspection 373

36.4.1.9 Verification of Documents 373

36.4.1.10 Documentation 373

36.4.1.11 Acceptance Criteria 374

36.4.1.12 List of Attachments 374

36.4.2 Protocol for Filling Station (Type B) 380

36.4.2.1 Objective 380

36.4.2.2 Scope 380

36.4.2.3 Validation Approach 380

36.4.2.4 Responsibilities 381

36.4.2.5 Description of the Cleaning Process 381

36.4.2.6 Identification of Critical Parameters 382

36.4.2.7 Description of the Sampling Process 382

36.4.2.7.1 Surface Swabs 383

36.4.2.8 Test Functions 384

36.4.2.8.1 Visual Inspection 384

36.4.2.9 Verification of Documents 384

36.4.2.10 Documentation 384

36.4.2.11 Acceptance Criteria 385

36.4.1.12 List of Attachments 385

36.4.3 Protocol for Filling Station (Type C) 391

36.4.3.1 Test Functions 392

36.4.3.1.1 Visual Inspection 392

36.4.3.1.2 Verification of Documents 394

36.4.3.2 Documentation 394

36.4.3.3 Acceptance Criteria 394

36.4.3.4 List of Attachments 395

CLV-37 Cleaning Validation Product Grouping Matrix (Sterile) 401

CLV-38 Cleaning Validation Product/Equipment Train Matrix (Sterile) 403

CLV-39 Validation Protocols Biological and Sterile Products 405

CLV-39.1 Cleaning Validation Protocol for Freeze Dryer 407

39.1.1 Objective 408

39.1.2 Scope 408

39.1.2.1 Cleaning Validation Program 408

39.1.3 Responsibility 410

39.1.4 Description of the Cleaning Process 410

39.1.5 Description of the Sampling Process 410

39.1.5.1 Sampling Technique 410

39.1.5.2 Surface Swabs 410

39.1.5.3 Rinse Sampling 410

39.1.5.4 Sampling Precautions 411

39.1.6 Test Functions 411

39.1.7 Verification of Documents 412

39.1.8 Documentation 412

39.1.9 Acceptance Criteria 412

39.1.10 List of Attachments 413

CLV-39.2 Cleaning Validation Protocol for Glass-Lined Mobile Tank 421

39.2.1 Objective 422

39.2.2 Scope 422

39.2.2.1 Cleaning Validation Program 422

39.2.3 Responsibilities 422

39.2.4 Description of the Cleaning Process 422

39.2.5 Identification of Critical Parameters 423

39.2.6 Description of the Sampling Process 423

39.2.6.1 Sampling Technique 423

39.2.6.2 Surface Swabs 424

39.2.6.2.1 Procedure for Sampling 424

39.2.6.3 Water Rinses 424

39.2.6.3.1 Procedure for the Sample 424

39.2.6.4 Sampling Precautions 425

39.2.7 Test Functions 425

39.2.8 Verification of Documents 426

39.2.9 Documentation 426

39.2.10 Acceptance Criteria 427

39.2.11 List of Attachments 427

CLV-39.3 Protocol for Preparation and Holding Vessel for Egg Protein 435

39.3.1 Objective 435

39.3.2 Scope 435

39.3.3 Cleaning Validation Approach 436

39.3.4 Responsibilities 436

39.3.5 Description of the Cleaning Process 436

39.3.6 Description of the Sampling Process 436

39.3.6.1 Sampling Technique 436

39.3.6.2 Procedure for Sample 437

39.3.6.3 Surface Swabs 437

39.3.6.4 Sampling Precautions 437

39.3.6.5 Sampling and Testing Plan 438

39.3.6.6 Preparation Vessel (Swab Sample) 439

39.3.6.7 Sampling and Testing Plan 439

39.3.6.8 Holding Vessel (Swab Sample) 440

39.3.7 Test Functions 440

39.3.7.1 Visual Inspection 440

39.3.8 Verification of Document 440

39.3.9 Documentation 440

39.3.10 Acceptance Criteria 441

39.3.11 List of Attachments 441

CLV-39.4 Protocol for Filtration Assembly 447

39.4.1 Objective 447

39.4.2 Scope 447

39.4.3 Responsibility 449

39.4.4 Description of the Cleaning Process 449

39.4.4.1 Sampling Technique 449

39.4.4.2 Procedure for Sampling 450

39.4.4.2.1 Surface Swabs 450

39.4.4.2.2 Water Rinses 451

39.4.4.3 Sampling Precautions 451

39.4.5 Test Functions 451

39.4.5.1 Vancomycin HCl 452

39.4.5.2 Bacitracin Injection, USP 452

39.4.6 Verification of Documents 453

39.4.7 Documentation 453

39.4.8 Acceptance Criteria 453

39.4.9 List of Attachments 454

CLV-39.5 Protocol for Preparation and Holding Vessels for Biological Products 465

39.5.1 Objective 465

39.5.2 Scope 465

39.5.3 Responsibilities 466

39.5.4 Description of the Cleaning Process 466

39.5.5 Identification of Critical Parameters 466

39.5.6 Documentation 467

39.5.6.1 Documents Required 467

39.5.6.2 Documents Attached/Checking 467

39.5.7 Verification of Document 467

39.5.8 Test Functions 467

39.5.9 Acceptance Criteria 468

39.5.10 Description of the Sampling Process 469

39.5.10.1 Sampling Technique 469

39.5.10.2 Procedure for Sample 469

39.5.10.3 Surface Swabs 473

39.5.10.4 Sampling Precautions 473

CLV-39.6 Protocol for Filtration Assembly and Filling Machine for Biologica

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