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Describes the methodologies and best practices of the sterile manufacture of drug productsThoroughly trained personnel and carefully designed, operated, and maintained facilities and equipment are vital for the sterile manufacture of medicinal products using aseptic processing. Professionals in pharmaceutical and biopharmaceutical manufacturing facilities must have a clear understanding of current good manufacturing practice (cGMP) and preapproval inspection (PAI) requirements.Sterile Processing of Pharmaceutical Products: Engineering Practice, Validation, and Compliance in Regulated Environments provides up-to-date coverage of aseptic processing techniques and sterilization methods. Written by a recognized expert with more than 20 years of industry experience in aseptic manufacturing, this practical resource illustrates a comprehensive approach to sterile manufacturing engineering that can achieve drug manufacturing objectives and goals. Topics include sanitary piping and equipment, cleaning and manufacturing process validation, computerized automated systems, personal protective equipment (PPE), clean-in-place (CIP) systems, barriers and isolators, and guidelines for statistical procedure. Offering authoritative guidance on the key aspects of sterile manufacturing engineering, this volume:* Covers fundamentals of aseptic techniques, quality by design, risk assessment and management, and operational requirements* Addresses various regulations and guidelines instituted by the FDA, ISPE, EMA, MHRA, and ICH* Provides techniques for systematic process optimization and good manufacturing practice* Emphasizes the importance of attention to detail in process development and validation* Features real-world examples highlighting different aspects of drug manufacturingSterile Processing of Pharmaceutical Products: Engineering Practice, Validation, and Compliance in Regulated Environments is an indispensable reference and guide for all chemists, chemical engineers, pharmaceutical professionals and engineers, and other professionals working in pharmaceutical sciences and manufacturing.

Sterile Processing of Pharmaceutical Products: Engineering Practice, Validation, and Compliance in Regulated Environments

Preface xiiiAcknowledgments xvii1 Introduction 12 Sterilization 4Steam Sterilization 5Flash Sterilization 5Low-Temperature Sterilization Technologies 6Ethylene Oxide Gas Sterilization 6Hydrogen Peroxide Gas Plasma 7Disinfection and Surface Sterilization Using Peracetic Acid 7Ionizing Radiation 8Dry-Heat Sterilizers 8Filtration 9Microwave 9Vaporized Hydrogen Peroxide (VHP(r)) 9Ozone 9Formaldehyde Steam 10Gaseous Chlorine Dioxide 10Vaporized Peracetic Acid 10Infrared Radiation 10Sterilization Cycle Verification 11Monitoring 113 Sterile Manufacturing Facilities 154 Sanitary Process Piping and Equipment 17QA Procedures 18Standard Operating Procedures - cGMP Installations 19Heat Exchangers 19Sanitary Pumps 20Sanitary Tanks 20Instruments 21Pressure Transmitter (Various Sources) 21Temperature Transmitter (Various Sources) 21Standard Operating Procedures - cGMP Installations 25Surface Finish 30Welding 32Applicability 33Process/Procedure 39Records (General) 41Records 44Automatic Orbital Welding 47Weld Acceptance Criteria for Automatic Orbital Weld Qualifications 475 Passivation 49In-house Passivation Using Vats 51Spot Passivation 53Astro Pak UltraPass Gel Passivation 53Alternative Process 54Control of Passivated Items 57Preparing, Testing, and Adjusting Cleaning and Passivation Chemicals (Passivation in Vats) 586 Chilled Water System 63Process Description 65Commissioning of HVAC 75Installation Verification - X Ton Chiller System 78SystemStartup - X Ton Chiller 81Functional Testing - X Ton Chiller 827 Clean-In-Place (CIP) Systems 84Life Cycle Requirements 86Product and Process User Requirements 86Process Quality Requirements 86Process Parameter Requirements 87Installation User Requirements 87Operational Requirements 918 Computerized Automated Systems 95Functional Requirement Specification 95Process Automation System 95EMS User Requirement Specification 96Automation Overview 96Software 97Hardware 97SCADA 97Control Panels 97Main Control Panel 97Remote I/O Panels 98Power Distribution Panels 98Instrumentation Panels 98System Functions 98System Overview 98Control Modules 99Interfaces 99User Interface (SCADA) 99PAS System Overview 99Graphical Screen Navigation 99Client EMS Area Graphical Screens 99Graphical Control Screens 99Interfaces to Equipment 101Interfaces to Other Systems 101Ethernet Network 101Nonfunctional Attributes 101Power Failure Recovery 101PLC Only Failure 101HMI Only Failure 101Network Only Failure 101Maintainability 102Backup and Recovery 102Functional Requirement Specification 102GLC Environmental Monitoring System 102Automation Overview 103System Components 104Software 104Hardware 104Control Panels 104Gateways 105System Functions 105System Overview 105Control Modules 105Interfaces 105User Interface (SCADA) 105GLC EMS Area Graphical Screen 105Global Logistics Center (GLC) Environmental Monitoring System 105Interfaces to Equipment 105Interfaces to Other Systems 106Ethernet Network 106Wireless Connections 106Nonfunctional Attributes 106Power Failure Recovery 106PLC Only Failure 106HMI Only Failure 106Network Only Failure 106Maintainability 107Backup and Recovery 107Software Module Design Specification 107Functional Requirement Specification 108Process Automation System 108Automation Overview 109System Components 109Software 109Hardware 110Control Panels 110System Functions 111System Overview 111Control Modules 111Interfaces 111User Interface (SCADA) 111PAS System Overview Screen 112Graphical Screen Navigation 112Graphical Control Screens 112Interfaces to Equipment 113Interfaces to Other Systems 113Ethernet Network 113Nonfunctional Attributes 114Power Failure Recovery 114PLC Only Failure 114HMI Only Failure 114Network Only Failure 114Maintainability 114Backup and Recovery 114Software Design Specification 115Prosoft Configuration 115Enabling and Disabling of the Gateway Default Server Interface 115Temperature Sensor Settings 116Humidity Sensor Settings 116Software Design Specification 116Continuous Logic 116Module Classes and Control Modules 116Virtual Differential Pressure Alarm Disable 116Room Condition Indication 117Navigation Links 117Alarm Daily Report 118WFI Still Equipment Module Class 118WFI Silo Equipment Module Class 126EM_SILO 126WFI Primary Loop Equipment Module Class 143EM_PRIM_LOOP 143WFI Supply Header Equipment Module Class 155EM_HEADER 155Electrical - Controls Equipment Specifications 162Documentation 165Drives/Motors 1659 Personal Protective Equipment (PPE) and Process Flow 17010 Sterile Aseptic Processing 17211 Integrated Facility Design 174Case Study 178Issue 178Root Cause 178Corrective Action 179Preventive Actions 17912 Barriers and Isolators 180Isolator Design Considerations 18113 Guidelines for Statistical Procedure 183Process Capability Analysis 184Long-term Studies 186Acceptance Sampling 187Attribute and Variable Sampling Plans 187Variable Sampling Plans - ANSI Z1.9 188Normality 188Transformation of Non-normal Data (Normalization) 190Protocol Sampling 190Failure Mode and Effect Analysis (FMEA) 191Calculating or Recalculating Control Limits 19314 Calibration 194Contingency Plan/Disaster Recovery 20415 Cleaning Validation 205New Products and Product Changes 208Cleaning Processes and Changes 208Risk Assessment/Matrix Approach 209Matrix Development 209Cleaning Processes (Manual and Automated) 210CPP/CQA 210Cleaning Validation Life Cycle - Cleaning Method Development 211Strategy for Process Controls 211Worst-Case Identification - Product/Component 211Equipment 212Validation Tests/Inspections - Visual Inspection 212Chemical Testing 212Microbiological Testing 213Endotoxin Testing 213Sampling Methods 213Direct Swab Sampling 214Rinse Sampling 214Coupon Testing 214Sampling Sites 214Acceptance Criteria 214Residual Levels 214Endotoxin Levels 215Microbiological Levels 215Cleaning Agents/Sanitizer Validation Studies 215Hold Time Development 216Dirty Hold Time 216Clean Hold Time 217Additional Hold Times/Cleaning Frequencies 217Continuous Process Verification 217Failure Investigations 21716 Validation of Filling Equipment 218Technical References 22317 Manufacturing Process Validation 224Stage 2 - Process Qualification 229Appendix A Installation Test Plans 232Appendix B Operational Tests Plans 235Appendix C WFI Turbulence Flow Requirements 238Appendix D Water For Injection (WFI) - Design Requirements 239Process Description 240Specifications 241Life Cycle Requirements 241Product and Process User Requirements 241Product Description 241Operating Ranges 243Material of Construction 244Metallics 244Plastics 244Elastomers 244Glass 244Welding Requirements 245Construction Requirements 246Lubrication Requirements 247Electrical Requirements 247Safety Requirements 247Operational Requirements 248Process Constraints and Limitations 248Process Control System 248Operator Interface 249Power Loss and Recovery 250Cleaning and Sanitizing 250Maintenance Requirements 250Training and Documentation Requirements 250Appendix E Solution Transfer System (STS) - Design Requirements 252System Description 253Bulk Powder Handling System 255Glossary 259Nomenclature 261References 263Further Reading 267Index 335