Process Engineering Applications

Transcription

1 u ' SterUe Pharmaceutical Products Process Engineering Applications Drug Manufacturing Technology Series Kenneth E. Avis, Editor Interpharm Press, Inc. Buffalo Grove, IL

2 CONTENTS Foreword xi 1. Introduction 1 Kenneth E. Avis Chapter Contents 2 2. Engineering Control of the Aseptic Filling Environment 7 Howard R. Leary Objective and Introduction 7 Creating and Maintaining Aseptic Environments for Pharmaceutical Filling 9 The Enclosure 10 Particulate Control 11 Ingress to and Egress from the Controlled Environment 11 Machine Design Issues in Aseptic Packaging 13 Asepsis: A Hostile Environment for Filling Equipment 13 Designing to Protect the Machinery 16 Designing to Enhance Bioburden Control 23 Designing for Particulate Control 32 Conclusion 34 References 35 ui

3 iv Contents 3. Air Handling Systems for Cleanroom Control 37 Brian D. Moore General Design Guidelines 37 Cost Effectiveness 38 Characteristics of Pharmaceutical Clean Rooms 39 Air Qualify Standards and Guidelines 40 Cleanroom Attributes 43 Operational Cleanroom Classifications 46 Air Distribution to the Clean Room 46 Terminal HEPA Filters 46 Cleanroom Return Air 49 Air Distribution to Product Exposure Areas 54 General Cleanroom HVAC System Concepts 58 System Configuration 59 Equipment Sizing and Selection 65 Aseptic Area Pressurization 66 Mechanical Space Location 66 Air Handling Units 71 Air Handling Unit Construction 71 Air Handling Unit Design 72 Ductwork Design and Construction 74 Ductwork Design 74 Ductwork Construction 75 HVAC System Controls 77 Temperature and Humidify Control 77 Pressure Control 78 Details 83 System Testing, Commissioning, and Validation 83 Testing 84 Commissioning 84 Validation 85 The Future 86 References 87

4 Contents 4. High Speed, Automated Filling of Sterile Liquids and Powders 89 R William Rahe Scope 89 High Speed, Automated Filling 89 Aseptic Processing 90 Containers 90 Small Volume Liquids and Powders 90 Trends 90 General Machine Features 91 Common Design Issues 92 Dose Control 92 Cleanliness 94 Sterilizable Parts 94 Materials of Construction 95 Validation 95 Machine Capacity Sizing 97 Liquid Filling 99 Metering 99 Container Handling 111 Powder Filling 113 Why Powder Filling? 113 Pneumatic Cylinder and Piston Wheel 113 Totally Enclosed Pneumatic Pump 119 Volumetric Compression 123 Auger Filling 126 Future Developments 131 Recommended Readings Engineering Considerations for CIP/SIP Systems 135 Dale A. Seiberling Alfred]. Ratz Historical Review, Evolution, and Applicable Criteria 135

5 vi Contents CIP Pharmaceutical Processes 136 CIP and SIP Technology Defined 136 Types of Equipment That Are CIP Candidates 136 Criteria for the Design of CIP Equipment 137 The CIP Procedure 139 Additional Components and Criteria for Incorporating SIP 140 Design Overview of a CIP Process 141 CIP Systems Defined 144 CIP System Components 144 CIP Recirculating Units 144 Engineering Considerations 144 Single-Use Versus Reuse Operation 148 Desirable Criteria for Pharmaceutical and Biotech CIP Systems 152 Location of CIP Recirculating Units and Chemical Feed Equipment 156 CIP Program Control Systems 158 CIP Program Data Acquisition 162 CIP Data Logger Capability 162 Summary Reports 164 Spray Device Selection and Application 164 Design of the Pharmaceutical Tank for Effective Spray Cleaning 166 An Example of a CIP Dry Drug Process 169 CIP Supply/Return System Criteria 172 CIP Supply/Return Piping Concepts 174 CIP Supply/Return Engineering 176 Return Flow Motivation 179 Return Pump Selection 181 Eductor Return Systems 181 Uniform Flow Rates 182 Automation of the Pharmaceutical or Biotech Process 182 CIP Air-Operated Values 182 Automated Process Piping Design 186 Air-Operated Valve Pulsing and Sequencing 188 U-Bend Transfer Panels 190 Integrated Pro cess/cip Piping with U-Bend Transfer Panels in a Hypothetical Process 196 Integrated Process/CIP Piping in a Biotech Process 199 Integrated Process/CIP Piping with Transfer Panels in the Pharmaceutical Process 200

6 Contents vii Typical Cleaning Programs and Water Requirements 202 Steam-in-Place 204 The Application of Single-Use Eductor-Assisted CIP Systems to Automate COP Operations 208 Installation of CIP Systems in the Gean Room 209 Evaluation of Results 215 Advantages and Disadvantages of CIP 216 Summary 217 References 218 Suggested Additional Reading Engineering Aspects of WFI Systems Design 221 Henry Kuhlman Drew Coleman Definition of Water for Injection 222 Uses of Water for Injection 222 Historical Background and General Engineering Practices 223 Pretreatment Requirements 224 Why Water Pretreatment Is Required 224 The Standard System Design Components 224 Contemporary Feedivater Systems Design Components 226 Design Considerations 228 Production Equipment 228 Equipment Sizing and Selection 229 Storage and Distribution System Design Components 238 Piping Design 242 Construction Standards and Procedures 243 Acceptance Criteria 243 Welding Procedures 244 Slope Verification 244 Validation Requirements 244 WFI System Description 244 Validation Master Plan 246

7 viii Contents Outside Validation Resources 248 Document Handling and Storage 250 The Start-Up and Validation Sequence-An Example 250 Start-Up Concerns and Case Histories 259 System Preventive Maintenance 259 Conclusion 266 References Engineering Considerations in Sterile Powder Processes 269 Alpaslan Yaman Sterilization of the Bulk Drug Substance 270 Packaging of the Bulk Drug Substance 273 Container Considerations 273 Characterization of the Bulk Drug Process 274 Powder Density 275 Angle of Repose 276 Particle Size Distribution 277 Crystal History 280 Aseptic Transfer of Raw Material to the Filling Room 281 Factors Affecting Filling Rate 281 Single Versus Double Stroke Filling 281 Multiple Powder Fill 286 Aseptic Milling and Blending 287 Double Shot Filling 292 Environmental Concerns and Their Effects on Finished Product Characteristics 295 Humidity 296 Electrostatic Discharge 296 Oxygen Control 297 Dust Containment 298 Particulate Matter 298 Acknowledgements 302 References 304

8 Contents ix 8. Engineering Considerations in Sterile Filtration Processes 305 Holly Haughney Introduction to Membrane Filters Used in Sterile Filtration Processes 305 Filtration Mechanisms 305 Membrane Filter Ratings for Particulate Removal Filters 306 Sterilizing Grade Membrane Filter Ratings and Integrity Tests 307 Membrane Filter Construction 308 Filter Assemblies Used in Processes 311 Sterile Liquid Filtration Design and Operational Considerations 312 Design Considerations for a Filtration Process 312 Operational Considerations for a Filtration Process 329 Integrity Testing Design and Operation Considerations 338 Sterile Gas Filtration Process Design and Operational Considerations 348 Considerations for Sterile Filtration offermenter Air 348 Considerations for Sterile Tank Vent Filters 349 Summary 353 References The Development of Integrated, Automated Filling and Packaging Equipment Using Hybrid Robotics 357 Hans W. Trechsel Understanding Integrated, Automated Manufacturing: The Integration Process 359 The Challenges of Designing a Processing System 360 Processing Requirements 360 Machine Design 361 Robotic Design 362

9 Contents Processing a Product 365 Batch Processing 365 Index Motion Processing-Single or Multiple Stations 367 Continuous Motion Flow Processing 368 Process Layout-Rotary, In-Line, or Reverse In-Line 369 Row Advance Processing 373 The Handling of Parts (Bottles, Syringes, Stoppers, Caps, Etc.) 373 An Integrated, Automated Liquid Filling Processing Line User Requirements for the Representative System Design Approach Integration of Processes Prefeeding Washing Sterilization and Depyrogenation Accumulating/Down-Bottle Reject In-Feed Line Conveyor and Starwheel/ No Vial-No Fill Tare Weighing Nitrogen Flushing Filling/Checkweighing Stoppering Nitrogen Purging and Seating of Stoppers Capping/Sealing Reject of Bad Parts Trayloading (Lyophilizing) Labeling/Final Inspection/Packaging Material Selection Product Contact Areas Exposed Areas Enclosed Areas Name Index Subject Index