Isolator Technology. Applications in the Pharmaceutical and Biotechnology Industries. Edited by Carmen M. Wagner James E. Akers

Transcription

1 Isolator Technology Applications in the Pharmaceutical and Biotechnology Industries Edited by Carmen M. Wagner James E. Akers Interpharm Press, Inc. Buffalo Grove, IL

2 Foreword Introduction xv xvii SECTION I. TECHNOLOGY OVERVIEW 1. Current Challenges to Isolation Technology 3 Carmen M. Wagner The Emergence of Advanced Aseptic Processing Isolators 4 Protective Barrier Systems Definitions 5 Barriers and Isolators Conceptual Differences Isolator Design 8 Functional Requirements of Isolators 11 Application Requirements Containment Pressure Requirements Isolator Function Requirements Materials of Construction 17 Key Operational Features 18 Ventilation/Filtration Manipulation Visibility Materials Transfer in

3 iv Special Challenges to Designers and Users of Isolators 26 Regulatory Compliance European GMP Guidelines Material Transfer Validation/Sterilization Sterilization Monitoring Siting of Isolators The Future of Isolation Technology 33 References Isolator Technology: Regulatory Issues and Performance Expectations 37 James E. Akers A Glossary of Terms Commonly Used in Describing Advanced Aseptic Processing Technology 38 Isolation Technology: Key Regulatory Issues 44 Sterility Assurance Summary 59 Recommended Readings Regulatory Aspects of Isolation/ Barrier Technology 63 James C. Lyda The Technology Today 64 Who Are the Regulators? 64 The First Problem Definitions 65 Definitions FDA Definitions MCA What Has Been Approved? 68 Issue The Background Environment 69

4 v Issue Monitoring of the Internal Isolator Environment 69 Issue Aseptic Processing vs. Terminal Sterilization 70 Issue Media Fills: Value and Interpretation 71 Issue Weak Links in Isolation Systems 71 Isolator Standards USP 72 Aseptic Processing Standard ISO 72 Cleanroom Standards ISO 73 The FDA and European International Standards Policies 73 Conclusions 74 References British and European Experience with Isolator Technology 77 Gordon F. Farquharson Historical Perspective 77 Market Stimulus to Use Isolators 78 Typical Applications 79 Radioactive Hazard Containment Cabinets Microbiological Safety Cabinets Laboratory Flexible Film Isolators Sterility Testing Isolators Potent Compound Dispensing Isolators Powder Handling System Isolators Small Scale Clean or Aseptic Processing Isolators Large Scale Clean or Aseptic Processing in Isolator Netxvorks Development of Standards and Monographs 83 Definitions Specification of Requirements by European Documents European Regulatory Approach 90 The Environment Surrounding Isolators 91

5 vi 5. Developing a Barrier/Isolator Implementation Plan 97 Didder Meyer Defining the Application 98 Positive Pressure Isolators Negative Pressure Isolators for Nonsterile Operations Throughput Requirements 102 Manual Operations Automated Operations Customizing Isolator Design 103 Quality Control (QC) Laboratory Sterility Testing Systems Production Environment Other Possible Applications Engineering Considerations 109 Existing Facilities Newly Designed and Built Facilities Equipment Considerations 112 Modifying Existing Equipment to Accept an Isolator Modifications for Compatibility with Sterilization Coordination of Vendor Efforts 113 Preshipment Equipment Specifications Assembly and Debugging Implementation Time Frames Lead Times Budget Considerations 115 Facility Costs Equipment Cost Operational Cost Documentation 118 Operator Training 119 Monitoring 120 Regulatory Compliance 120 Conclusion 121 References 121

6 vii SECTION II. TECHNOLOGY IMPLEMENTATION 6. Engineering and Project Management Issues for a Hydrogen Peroxide Sterilized Filling System 125 Leslie M. Edwards James R. Rickloff Communications and Project Management 126 Retrofitting Existing Equipment vs. Purchasing New Equipment 130 System Design Considerations 135 Material Selection Gas Distribution Air Handling Requirements Door, Seal, and Equipment Interface Designs Transfer Systems Automation/Control Systems Control System and Parametric Documentation Aeration Strategies and Considerations Conclusions and Future Trends in Isolator Design and Sterilization Modern Trends in Isolator Sterilization 149 James R. Rickloff Leslie M. Edwards Terminology of Antimicrobial Action Antimicrobial Agents Used in Isolators Peracetic Acid Chlorine Dioxide Hydrogen Peroxide Other Methods Material Compatibility Safety and Environmental Regulations References

7 viii 8. Microbiological Monitoring and Control in Isolator Systems 173 Michael C. Carroll Air Monitoring 174 Special Concerns for Isolator Systems Surface Monitoring 180 Process Validation 181 External Environment 182 Sterility Hold 184 Sterility Testing Isolators Production/Manufacturing Barriers Conclusion 186 References Introduction to the Validation of Sterile Processing Using Isolation Technology 189 Richard M. Johnson Materials Sterilization 192 Primary Packaging Product Gases Isolation Technology 193 Isolator Design References Guideline to the Validation of Isolation Technology 197 Richard M. Johnson Isolator Integrity 197 Isolator Sterilization 198 Isolator Validation 199

8 ix Installation Qualification Operational Qualification Performance Qualification References Points to Consider in the Use of Sterility Testing Isolators 205 Richard T. Wood Sterility Test Limitations 206 Isolator Technology 208 Advantages of an Isolator Laboratory Disadvantages of an Isolator Laboratory Designing an Isolator Laboratory 211 Location Size Material Flow Integrated Systems Utilities Methods of Sterilization Monitoring Instruments Environmental Monitoring Test Incubators Validation Conclusions 227 References 228 SECTION III. APPLICATIONS: THE INDUSTRY EXPERIENCE AND PERSPECTIVE 12. Barrier Isolation Technology: A Systems Approach 231 Jack P. Lysfjord Paul J. Haas Hans L. Melgaard Irving J. Pflug The System 240

9 Filler Design 240 The Barrier Isolator 243 Materials Selection and Compatibility Interface Issues Handling of Freeze-Dried Products Particulate Control Considerations Barrier Isolator Internal Condition Control and Monitoring Clean-in-Place of Barrier Isolators 262 Sterilization of Barrier Isolators 263 Atmospheric Steam/Hydrogen Peroxide Sterilization System Validation Considerations 271 Overview 272 Recommended Readings The History and Future of Barrier Isolation Technology at Merck & Co., West Point, PA 281 Michael E. Porter Leslie M. Edwards 14. Use of Isolation Technology for Production of a Sterile Anti- Cancer Drug 283 Paul Martin Objectives 283 To Protect the People To Ensure Product Sterility To Protect the Environment Meeting the Objectives 286 The Facilities Environment Classification

10 xi Validation of Isolators Sterility 289 Methodology Monitoring Conclusion Aseptic Filling in a Rigid Isolator at Evans Medical 293 Julian Wilkins Project Requirements 295 The Traditional Approach 295 Isolator Network 296 Detailed Development 296 Ergonomic Modelling 297 Separated Operations 297 Control and Instrumentation 299 Building Integration 299 Reduced Work Volume Isolation Technology for Sterility Testing at Burroughs Wellcome, Greenville, NC 303 John Shirtz 17. Experience in the Design and Use of Isolator Systems for Sterility Testing 309 James E. Akers James P. Agalloco Colleen M. Kennedy Specific Validation Testing 314 Sterilization 314

11 xii Sterilization Cycle Development 315 Temperature Mapping 316 Determination of VHP Concentration 317 Biological Indicator Challenge Studies 318 Other Validation Issues 319 Conclusion 321 Recommended Readings Isolation Technology: A Consultant's Perspective James Agalloco History Definitions Advantages Limitations and Obstacles Application Sterility Testing Filling Manufacturing Clinical Manufacturing Manual Procedures Sterilization Regulatory Perspectives Other Subjects 331 Retrofitting Isolation Technology toexisting Facilities Environmental Monitoring Process Validation Conclusion 333 References

12 xiii 19. Isolation Technology Issues from an Engineering Company Viewpoint 335 Dimitri P. Wirchansky SECTION IV. RESOURCES Glossary 343 Appendix. List of Resources 357 Barrier/Isolator Manufacturers 357 Filling Machine Manufacturers 359 Validation Support and Consulting Services 361 Engineering Companies and Consulting Services 362 Sterilization Equipment 364 Manufacturers of Accessory Equipment or Services 364 Association, Institutes, and Laboratories Information Resources 366 Name/Company Index 369 Subject Index 374