Preface xiii Acknowledgments xvii 1 Introduction 1 2 Sterilization 4 Steam Sterilization 5 Flash Sterilization 5 Low-Temperature Sterilization Technologies 6 Ethylene Oxide Gas Sterilization 6 Hydrogen Peroxide Gas Plasma 7 Disinfection and Surface Sterilization Using Peracetic Acid 7 Ionizing Radiation 8 Dry-Heat Sterilizers 8 Filtration 9 Microwave 9 Vaporized Hydrogen Peroxide (VHP®) 9 Ozone 9 Formaldehyde Steam 10 Gaseous Chlorine Dioxide 10 Vaporized Peracetic Acid 10 Infrared Radiation 10 Sterilization Cycle Verification 11 Monitoring 11 3 Sterile Manufacturing Facilities 15 4 Sanitary Process Piping and Equipment 17 QA Procedures 18 Standard Operating Procedures - cGMP Installations 19 Heat Exchangers 19 Sanitary Pumps 20 Sanitary Tanks 20 Instruments 21 Pressure Transmitter (Various Sources) 21 Temperature Transmitter (Various Sources) 21 Standard Operating Procedures - cGMP Installations 25 Surface Finish 30 Welding 32 Applicability 33 Process/Procedure 39 Records (General) 41 Records 44 Automatic Orbital Welding 47 Weld Acceptance Criteria for Automatic Orbital Weld Qualifications 47 5 Passivation 49 In-house Passivation Using Vats 51 Spot Passivation 53 Astro Pak UltraPass Gel Passivation 53 Alternative Process 54 Control of Passivated Items 57 Preparing, Testing, and Adjusting Cleaning and Passivation Chemicals (Passivation in Vats) 58 6 Chilled Water System 63 Process Description 65 Commissioning of HVAC 75 Installation Verification - X Ton Chiller System 78 SystemStartup - X Ton Chiller 81 Functional Testing - X Ton Chiller 82 7 Clean-In-Place (CIP) Systems 84 Life Cycle Requirements 86 Product and Process User Requirements 86 Process Quality Requirements 86 Process Parameter Requirements 87 Installation User Requirements 87 Operational Requirements 91 8 Computerized Automated Systems 95 Functional Requirement Specification 95 Process Automation System 95 EMS User Requirement Specification 96 Automation Overview 96 Software 97 Hardware 97 SCADA 97 Control Panels 97 Main Control Panel 97 Remote I/O Panels 98 Power Distribution Panels 98 Instrumentation Panels 98 System Functions 98 System Overview 98 Control Modules 99 Interfaces 99 User Interface (SCADA) 99 PAS System Overview 99 Graphical Screen Navigation 99 Client EMS Area Graphical Screens 99 Graphical Control Screens 99 Interfaces to Equipment 101 Interfaces to Other Systems 101 Ethernet Network 101 Nonfunctional Attributes 101 Power Failure Recovery 101 PLC Only Failure 101 HMI Only Failure 101 Network Only Failure 101 Maintainability 102 Backup and Recovery 102 Functional Requirement Specification 102 GLC Environmental Monitoring System 102 Automation Overview 103 System Components 104 Software 104 Hardware 104 Control Panels 104 Gateways 105 System Functions 105 System Overview 105 Control Modules 105 Interfaces 105 User Interface (SCADA) 105 GLC EMS Area Graphical Screen 105 Global Logistics Center (GLC) Environmental Monitoring System 105 Interfaces to Equipment 105 Interfaces to Other Systems 106 Ethernet Network 106 Wireless Connections 106 Nonfunctional Attributes 106 Power Failure Recovery 106 PLC Only Failure 106 HMI Only Failure 106 Network Only Failure 106 Maintainability 107 Backup and Recovery 107 Software Module Design Specification 107 Functional Requirement Specification 108 Process Automation System 108 Automation Overview 109 System Components 109 Software 109 Hardware 110 Control Panels 110 System Functions 111 System Overview 111 Control Modules 111 Interfaces 111 User Interface (SCADA) 111 PAS System Overview Screen 112 Graphical Screen Navigation 112 Graphical Control Screens 112 Interfaces to Equipment 113 Interfaces to Other Systems 113 Ethernet Network 113 Nonfunctional Attributes 114 Power Failure Recovery 114 PLC Only Failure 114 HMI Only Failure 114 Network Only Failure 114 Maintainability 114 Backup and Recovery 114 Software Design Specification 115 Prosoft Configuration 115 Enabling and Disabling of the Gateway Default Server Interface 115 Temperature Sensor Settings 116 Humidity Sensor Settings 116 Software Design Specification 116 Continuous Logic 116 Module Classes and Control Modules 116 Virtual Differential Pressure Alarm Disable 116 Room Condition Indication 117 Navigation Links 117 Alarm Daily Report 118 WFI Still Equipment Module Class 118 WFI Silo Equipment Module Class 126 EM_SILO 126 WFI Primary Loop Equipment Module Class 143 EM_PRIM_LOOP 143 WFI Supply Header Equipment Module Class 155 EM_HEADER 155 Electrical - Controls Equipment Specifications 162 Documentation 165 Drives/Motors 165 9 Personal Protective Equipment (PPE) and Process Flow 170 10 Sterile Aseptic Processing 172 11 Integrated Facility Design 174 Case Study 178 Issue 178 Root Cause 178 Corrective Action 179 Preventive Actions 179 12 Barriers and Isolators 180 Isolator Design Considerations 181 13 Guidelines for Statistical Procedure 183 Process Capability Analysis 184 Long-term Studies 186 Acceptance Sampling 187 Attribute and Variable Sampling Plans 187 Variable Sampling Plans - ANSI Z1.9 188 Normality 188 Transformation of Non-normal Data (Normalization) 190 Protocol Sampling 190 Failure Mode and Effect Analysis (FMEA) 191 Calculating or Recalculating Control Limits 193 14 Calibration 194 Contingency Plan/Disaster Recovery 204 15 Cleaning Validation 205 New Products and Product Changes 208 Cleaning Processes and Changes 208 Risk Assessment/Matrix Approach 209 Matrix Development 209 Cleaning Processes (Manual and Automated) 210 CPP/CQA 210 Cleaning Validation Life Cycle - Cleaning Method Development 211 Strategy for Process Controls 211 Worst-Case Identification - Product/Component 211 Equipment 212 Validation Tests/Inspections - Visual Inspection 212 Chemical Testing 212 Microbiological Testing 213 Endotoxin Testing 213 Sampling Methods 213 Direct Swab Sampling 214 Rinse Sampling 214 Coupon Testing 214 Sampling Sites 214 Acceptance Criteria 214 Residual Levels 214 Endotoxin Levels 215 Microbiological Levels 215 Cleaning Agents/Sanitizer Validation Studies 215 Hold Time Development 216 Dirty Hold Time 216 Clean Hold Time 217 Additional Hold Times/Cleaning Frequencies 217 Continuous Process Verification 217 Failure Investigations 217 16 Validation of Filling Equipment 218 Technical References 223 17 Manufacturing Process Validation 224 Stage 2 - Process Qualification 229 Appendix A Installation Test Plans 232 Appendix B Operational Tests Plans 235 Appendix C WFI Turbulence Flow Requirements 238 Appendix D Water For Injection (WFI) - Design Requirements 239 Process Description 240 Specifications 241 Life Cycle Requirements 241 Product and Process User Requirements 241 Product Description 241 Operating Ranges 243 Material of Construction 244 Metallics 244 Plastics 244 Elastomers 244 Glass 244 Welding Requirements 245 Construction Requirements 246 Lubrication Requirements 247 Electrical Requirements 247 Safety Requirements 247 Operational Requirements 248 Process Constraints and Limitations 248 Process Control System 248 Operator Interface 249 Power Loss and Recovery 250 Cleaning and Sanitizing 250 Maintenance Requirements 250 Training and Documentation Requirements 250 Appendix E Solution Transfer System (STS) - Design Requirements 252 System Description 253 Bulk Powder Handling System 255 Glossary 259 Nomenclature 261 References 263 Further Reading 267 Index 335.