Control of Particulate Matter Contamination in Healthcare Manufacturing

Transcription

1 Control of Particulate Matter Contamination in Healthcare Manufacturing Thomas A. Barber Interpharm Press Denver, Colorado IMHBIHHW PRESS

2 Contents iii CONTENTS PREFACE Acknowledgments xiii xv 1. INTRODUCTION AND OVERVIEW 1 Environmental Particles 2 Physiologic Effects of Environmental Particulate Matter 3 Circulatory Transport and Particle Removal 5 Particles and Patients 7 Animal Studies 9 Particle Contaminants in Manufacturing 12 Classification and Sources of Particulate Matter 12 Containers and Closures 13 The IV Therapy Process 14 Use of In-Line Filters 17 Detection and Counting of Particles 17 Subvisible Particle Detection 18 Particle Control Standards or GMP? 20 Standards for Medical Devices 21 Summary 22 References 24

3 iv Control of Particulate Matter Contamination in Healthcare Manufacturing 2. SOURCES AND CHARACTERISTICS OF CONTAMINANT PARTICLES 27 Definitions 28 Size and Classification of Particles 28 Particle Size Standards 30 Sources of Particles 33 Sources of Particles in the Controlled Environment Area 34 Personnel as Particle Sources 39 Contaminants in Device and Injectable Manufacture 42 Particle Transport, Deposition, and Adherence 48 Viable Particle Concerns 51 Particle Detection and Analysis 53 Philosophy of Contaminant Particle Control 55 Summary and Conclusion 58 References REQUIREMENTS AND TEST METHODS FOR INJECTABLE SOLUTIONS AND MEDICAL DEVICES 61 Rationales for Standards 64 Requirements for Injectable Products 67 British Pharmacopoeia, Appendix XIII Addendum Japanese Pharmacopoeia XIII 72 U.S. Pharmacopeia 23 (1995) 74 Ophthalmic Solutions 74 Stoppers Draft Amendment to ISO Requirements and Testing for Medical Devices 79 Parenteral-Type Devices 81 Device Standards Proposals 86 Syringes and Needles (Proposed USP Method) 87 Solution Administration Sets 89 Infusion Containers DIN Proposal (12/24/97) 91 ISO Draft Standard 3926 Plastic Collapsible Containers for Human Blood and Blood Components 93 USP Proposal for Blood Bags (Blood Storage Containers) 93 Summary and Conclusion 94 References 95 Standards, Compendia, and Regulatory References USP 23 <788> PARTICULATE MATTER IN INJECTIONS 97 Chapter Format 98 Excerpted Review 98 Light Obscuration Test Summary 112

4 Contents v The USP <788> Microscopic Test 114 Summary of Microscopic Test 126 Summary 127 Bibliography 129 Appendix I: Vendor and Equipment Information 130 Particle Counters 130 Calibration Materials 130 Light Microscopes 130 Microfiltration Supplies 131 Cleanroom Supplies 131 Appendix II: Manufacturers of "USP" Type Circular Area Graticule 131 Appendix III: Sampling Plans 132 Assay Variability 132 Sampling Plans ENVIRONMENTAL STANDARDS, MANUFACTURING OPERATIONS, AND GOOD MANUFACTURING PRACTICE 139 International Standards for Cleanroom Classification 139 ISO Document Levels 140 Philosophy of Compliance 143 The United Kingdom Complexities in Compliance 145 Environmental Monitoring and GMP in the United States 145 International Standards 150 International GMP Documents 151 The European Community (EC, EEC, EN) GMPs 153 Stan dards for General Application: FS-209E 157 ISO International Standard Summary and Conclusion 183 References 184 Appendix I: Good Manufacturing Practice-Related Documents 185 Appendix II: International Contamination Control Standards 186 Contamination Control Documents from the United States 186 Contamination Control Documents from Australian Agencies 187 Contamination Control Documents from Belgian Agencies 189 Contamination Control Documents from Canadian Agencies 189 Contamination Control Documents from Chinese Agencies 189 Contamination Control Documents from English Agencies 189 Contamination Control Documents from French Agencies 191 Contamination Control Documents from German Agencies 191 Contamination Control Documents from Japanese Agencies 191 Contamination Control Documents from Swedish Agencies 192 Contamination Control Documents from Swiss Agencies 192

5 vi Control of Particulate Matter Contamination in Healthcare Manufacturing 6. REGULATORY PERSPECTIVES RELATED TO THE CONTROL OF PARTICULATE MATTER CONTAMINATION 193 The FDA FDA Concerns with Regard to Particulate Matter 196 Current Good Manufacturing Practices Current Regulatory Interests Drugs and Injectable Products 199 Current Regulatory Interests Devices 203 Environmental Monitoring 205 Visual Inspection 209 Quality Control Lab Practice in Particulate Matter Analysis 210 Preparation for FDA Inspections 213 Focus of Regulatory Inspections (Subjects for Questions) 215 Particulate Matter as a Process Indicator 215 Airborne Particulate Matter Monitoring 216 Garbing and Personnel Protection 216 Medical Devices 216 Product Complaints 216 Compliance with USP <788> for Solutions 217 Visual Inspection 217 Overall Response to In-House Particulate Matter Issues 217 Liquid Filtration 218 Facility Review 218 Record Keeping 218 Inspectional Observations 218 Manufacturing Operations 219 Personnel Protection 223 Laboratory Practice 223 Training 225 Visual Inspection 225 Filter Testing 226 Summary and Conclusions 226 References 227 Compendial Documents 228 FDA Documents VISUAL INSPECTION OF INJECTABLES AND DEVICES 229 Visible Particulate Matter as a Quality Attribute 230 General Considerations in Visual Inspection 233 Repeatability of Manual Inspection 235 Variables in Human Visual Inspection 237 The Probabilistic Detection Principle (Knapp et al.) 243 Detection of Particles in Translucent Containers 250

6 Contents vii Methods of Manual Inspection 250 Applications of Visual Inspection 254 Automated (Machine) Inspection 255 "Essentially Free" The Concept and the Compendium 261 Defining "Essentially Free" 263 Evaluation of Process Capability and Process Control 264 Compendial Allowances for Particulate Matter 264 Definition of Allowable Particulate Matter 265 Best Demonstrated Practice 266 Design of Inspection Methods 266 FDA Expectations for Visual Inspection 268 Visible Particles as Attributes Versus Variables 270 Visual Inspection of Medical Devices 271 Summary 272 References LIGHT EXTINCTION PARTICLE COUNTING OF LIQUIDS 275 The USP <788> Method 276 Light Obscuration Sensors 277 Principles of Operation 277 Sensor Construction and Function 279 Laser Versus White Light Obscuration Sensors 282 Refractive Index Dependency of the LO Measurement 286 Coincidence Counting 287 "Validation" and "Count Accuracy" 291 Resolution Effects 291 Sources of Erroneous Count Data 292 Variability Due to Sampling Effects 296 Issues Relating to Nonaqueous Vehicles, Color, and Viscositv 296 Interferences from Subcountable-Sized Particles 298 Intermittent Instrument Problems 299 Light Obscuration Count Data 300 Dry Powder Dosage Forms 300 Amorphous Material 301 Sample Pooling 302 Data Variability Versus Sample Volume 302 User Interpretation of Complex Light Obscuration Count Data 303 Changes in Calibration Points Threshold Shift 306 Error Sources Checklist 307 Laboratory Technique 308 Cleaning of Glassware 308 Sampling of Injectable Products 310

7 viii Control of Particulate Matter Contamination in Healthcare Manufacturing Using Particle Size Standards 311 Current Generation Light Obscuration Counters 313 Summary 314 References AIRBORNE PARTICLE COUNTING AND ENVIRONMENTAL MONITORING 319 Mechanisms of Airborne Particle Detection 322 Types of Scattering 323 Lower Detection Limits of Light-Scattering Instruments 326 Optical Particle Counters 327 Light Sources 331 Function of Collector Optics 331 Calibration 331 Particle Transport and Sample Acquisition 335 Transport of Particles in Tubing 337 Monitoring Methods 340 Remote Systems Analysis General 344 Cost Considerations: Manual Versus Automated Monitoring 344 Validation of Remote Sampling or Counting 344 Selection of Sampling Plans 346 Numerical Evaluation of Count Data (Bzik 1988, 1994) 349 Sampling of Compressed Gases 353 Vapors as a Source of Artifactual Counts 357 Large Particle Monitoring 357 Personnel Monitoring 357 Summary 359 References LIGHT MICROSCOPY 363 The Power of Visual Observation 365 The Light Microscope 366 Stereomicroscopes 366 The Compound Microscope 367 Microscopic Visual Descriptors (Morphology) 373 Particle Size 373 Shape 374 Particle Color 374 Refractive Index 376 Reflectivity 376 Crystals and Crystal Morphology 377 Fibers 379

8 Contents ix Biologicals 380 Other Morphologically Distinct Particles 382 Polarized Light Microscopy 383 Polarization 383 Interference 383 Construction of the Polarizing Light Microscope 383 Illumination in Polarized Light Microscopy 386 Particle Identification with Polarized Light Microscopy 387 Definitions 389 Morphology and Particle Identification 390 Anisotropic Substances 390 Identification by Refractive Index 390 Dispersion Staining 392 Microchemical and Microphysical Tests 393 Characterization and Sourcing of Mixed Particle Populations 397 Microscope Calibration 398 Isolation and Handling of Particles 399 Summary 399 References 399 Specifications and Standards 401 Appendix: Descriptions of Photomicrographs of Commonly Encountered Particulate Matter Insect Parts Rust (Iron Oxide) Cosmetic Residue: Talc (Magnesium Aluminum Silicate) and Skin Cells Starch Paper Fragments Teflon (DuPont) Flakes Stopper Fragments (Black Chlorohutyl Rubber) Stainless Steel Polyethylene (cutting fragment) Calcium Carbonate Magnesium Phopshate Corn Starch Filter Membrane Fragments Dandruff Drug Residue Diatoms Fungal Hyphae Amorphous Material (Drug Residue) Hair (Human, Caucasian) Rat Hair Paper (Coarse, Hardwood) Cotton Paper and Cotton Mixed 406

9 x Control of Particulate Matter Contamination in Healthcare Manufacturing 24. Glass Fibers Asbestos Acrylic Fiber (Orion, Delustered) Polyester (Dacron ) Bulk Powder Drug Residue Talc Calcium Oxalate Skin Cells Glass Balloons (Cenospheres) VALIDATION AND ITS APPLICATION TO PARTICLE COUNTING INSTRUMENT SYSTEMS 409 The Terminology 410 Validation: The Compendial Information 412 The Literature 413 To Validate or Not to Validate 415 FDA Perspectives and Enforcement Activity 416 The Process of Validation (Chamberlain 1991) 417 Timing of Validation Activity 418 The Components of Validation 418 Risk Assessment (Validation Rationale) 419 Requirements Definition 419 Vendor Qualification 419 Design Qualification 421 Installation Qualification 421 Validation Plan (Test Plan) 422 System Suitability Testing 422 Execution of System Testing 423 Maintenance/Change Control 424 System Security 425 The Validation Report Certification 427 Extent of Validation 427 How Much Validation Is Enough? 428 Regulatory Inspections 428 Specific Considerations in Light Obscuration Counting 432 System Validation for Particle Counting Systems 434 Vendor Support for Validation Activities 436 Application of In-Use Standards and Operational/Performance Qualification Tests 436 Data Integrity 437 Analyst Training 438 Requirements Definition 438 System Testing 438 System-Specific Validation Approaches 438 User Testing of APSS 200 and 9703 Systems 445

10 Contents xi Validation Report 447 Retesting and Particle Count Data 450 Summary 452 References 453 Bibliography SAMPLING AND COLLECTION OF PARTICULATE MATTER FOR ANALYSIS 457 Theory of Particle Sampling and Collection 457 Sampling Guidelines 459 Sample Protection 460 Sample Container Cleaning 461 Methods of Collection/Isolation 461 Direct Isolation and Manipulation of Particles 463 Filtration 466 Collection of Particles from Surfaces 473 Adhesion and Entrainment 476 Sedimentation Techniques 477 Inertial Collection 479 Sieving 480 Chemical Isolation Technique 481 Sampling of Device Parts or Container Components 483 Sampling of Cleanroom Garments 484 On-line Sampling 486 Powder Sampling 487 Summary 490 References 491 Specifications and System Standards APPLICATION AND IN-USE TESTING OF HEPA FILTERS 493 Principles of HEPA Filtration 496 Definitions of a "Leak" 501 In-Use Testing of HEPA Filters 502 Testing with Polydisperse Dioctyl Phthalate and Other Oils 502 Photometer Technology 507 Additional Considerations in the Use of Cold DOP Challenge 508 Potential Safety Hazards of DOP 510 Test Aerosol Concentration 511 Variables in Leak Detection (McDonald 1993, 1994a, 1994b) 511 Alternate Means of Filter Testing in the Pharmaceutical Industry 515 Laser Submicrometer Particle Counters in Leak Testing 516 Substitute Oil Challenge Materials 516

11 xii Control of Particulate Matter Contamination in Healthcare Manufacturing Monodisperse Latex Aerosols 518 Ambient Aerosol Challenge Method 520 Smaller Particle Test Aerosols 521 Monodisperse Sodium Chloride Solid Aerosols 523 Silica Test Dust 524 Average Downstream In-Place Testing 524 Pulsed Aerosol 525 Uranine Fluorescent Dye Method 525 Sources of Leaks Patching of Leaks Current Developments in HEPA Testing Summary Acknowledgments References Standards and Sources APPENDIX 1: SOURCES OF STANDARDS AND DOCUMENTS APPENDIX 2: TRADEMARKS INDEX The color micrographs found near the middle of this text are described in the appendix to Chapter 10