Table Of ContentControl of Particulate
Matter Contamination in
Healthcare Manufacturing
Thomas A. Barber
~CRC Press
~ Taylor & Francis Group
Boca Raton London New York
CRC Press is an imprint of the
Taylor & Francis Group, an informa business
Published in 2000 by
CRC Press
Taylor & Francis Group
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' 2000 by Taylor & Francis Group, LLC
CRC Press is an imprint of Taylor & Francis Group
No claim to original U.S. Government works
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10 9 8 7 6 5 4 3 2
International Standard Book Number-10: 1-57491-072-8 (Hardcover)
International Standard Book Number-13: 968-1-57491-072-8 (Hardcover)
Library of Congress catalog number: 99-18307
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Contents Hi
PREFACE xm
Acknowledgments 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
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 58
3. REQUIREMENTS AND TEST METHODS FOR INJECTABLE SOLUTIONS
AND MEDICAL DEVICES 61
Rationales for Standards 64
Requirements for Injectable Products 67
Bhtish Pharmacopoeia, Appendix XIII Addendum 1996 68
Japanese Pharmacopoeia XIII 72
U.S. Pharmacopeia 23 (1995) 74
Ophthalmic Solutions 74
Stoppers-Draft Amendment to ISO 8871 77
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 58363-15 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 95
4. USP 23 <788> PARTICULATE MATTER IN INJECTIONS 97
Chapter Format 98
Excerpted Review 98
Light Obscuration Test Summary 112
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 134
5. 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
Standards for Geneml Application: FS-209E 157
ISO International Standard 14644-1 167
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
vi Control of Particulate Matter Contamination in Healthcare Manufacturing
6. REGULATORY PERSPECTIVES RELATED TO THE
CONTROL OF PARTICULATE MATTER CONTAMINATION 193
TheFDA 195
FDA Concerns with Regard to Particulate Matter 196
Current Good Manufacturing Practices 198
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
Inspcctional Observations 218
Manufacturing Operations 219
Personnel Protection 223
Labomtory Practice 223
Training 225
Visual Inspection 225
Filter Testing 226
Summary and Conclusions 226
References 227
Compendia! Documents 228
FDA Documents 228
7. VISUAL INSPECTION OF INJECTA BLES 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
Contents vn
Methods of Manual Inspection 250
Applicotions of Visuol Inspection 254
Automated (Machine) Inspection 255
"Essentially Free"-The Concept and the Compendium 2G1
Defining "Essentially Free" 2fi3
Evaluation of Process Capability and Process Control 264
Compendia] Allowances for Particulate Motter 264
Definition of Allowable Particulate Motter 265
Best Demonstmted Pmctice 266
Design of Inspection Methods 26G
FDA Expectations for Visual Inspection 268
Visible Particles as Attributes Versus Variables 270
Visual Inspection of Medical Devices 271
Summary 272
References 273
8. LIGHT EXTINCTION PARTICLE COUNTING OF LIQUIDS 275
The USP <788> Method 276
Light Obscuration Sensors 277
Principles of Opemtion 277
Sensor Construction and Function 279
Loser Versus White Light Obscuration Sensors 282
Fiefroctive Index Dependency of the LO Meosurement 286
Coincidence Counting 287
"Validation" and "Count Accuracy" 291
Resolution Effects 291
Sources of Erroneous Count Dolo 292
Variability Due to Sampling Ejji;cts 296
Issues Relating to Nonaqueous Vehicles, Color, and Viscosity 296
Interferences ji'Oln Subcountable-Sized ParUcles 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
viii Control of Particulate Matter Contamination in Healthcare Manufacturing
Using Particle Size Standards 311
Current Generation Light Obscuration Counters 313
Summary 314
References 315
9. 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 1\!Ionitoring 344
Validation of Remote Sampling or Counting 344
Selection of Sampling Plans 346
Numerical Evaluation of Count Data (Ezik 1988, 1994) 349
Sampling of Compressed Gases 353
Vapors as a Source of Artifactua! Counts 357
Large Particle Monitoring 357
Personnel Monitoring 357
Summary 359
References 360
10. 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 C1ystal Morphology 377
Fibers 379
Contents lX
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
Pmticle Identification with Polarized Light Microscopy 387
Definitions 389
Morphology and Particle Identification 390
Anisotropic Substances 390
Identification by Refructive 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 402
1. Insect Parts 402
2. Ilust (Iron Oxide) 403
3. Cosmetic Residue: Talc (J'vfagnesium Aluminum Silicate) and Skin Cells 403
4. Storch 403
5. Popcr Frogments 403
6. Teflon® (DuPont) Flakes 403
7. Stopper Frugmcnts (Black Chlorobutyl Rubber) 404
8. Stainless Steel 404
9. Polyethylene (cutting frogment) 404
10. Calcium Carbonate 404
11. Magnesium Phopshate 404
12. Corn Starch 404
13. Filter lvfcmbrane Fragments 404
14. Dandruff 405
15. Drug Residue 405
16. Diatoms 405
17. Fungal Hyphae 405
18. Amorphous Moteriol (Drug Residue) 405
19. Hair (Human, Caucasian) 405
20. Rat Hair 406
21. Paper (Coarse, Hardwood) 406
22. Cotton 406
23. Paper and Cotton Mixed 406
