Pharmaceutical Particulate Matter

Pharmaceutical Particulate Matter Analysis and Control Thomas A. Barber Baxter Healthcare Illustrations by John G. Williams Photomicrography Section b...

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Pharmaceutical Particulate Matter Analysis and Control Thomas A. Barber Baxter Healthcare

Illustrations by John G. Williams Photomicrography Section by Damian S. Neuberger

Interpharm Press Buffalo Grove, IL

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Preface Acknowledgements

xv xvii

I. Introduction

1

GMP Principles Compendial Requirements Particle Distribution 5 Particulate Matter Control Standards 8

l 4 6

Summary References

19 19

II. Visual Inspection

22

Visual Inspection

23

Manual Inspection 24 Reproducibility of Visual Inspection

33

Automated (Machine) Inspection Application of Automated Systems

34 44

Compendial Requirements Summary References

44 46 47

III. Instrumental Particle Counting

50

The Coulter Principle Light Extinction Counting

51 54

Laser Versus White Light Extinction Sensors Error Sources 70 Recent Developments 73

Spectrex (Phototron) System Particle Size Standards Emulsion Polymerization

59

75 77 78

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Suspension Polymerization 79 Swollen Emulsion Process 80 Storage and Handling of Standard Particles 81 Use of Commercial Standards 82 USP Particle Count Reference Standard 84 Alternative Count Standards 85

Autornated Light Extinction Counting Validation of the Robotic Assay Operational Validation 92 Validation of Data Collected

93

Summary References

96 96

IV. Microscopy

100

Structure of the Compound Microscope Lens Aberrations 103 Objective Lenses 107 Working Distance of Objectives Resolving Power 110 Oculars (Eyepieces) 111 Condenser Lens 111

87 89

102

109

Reflected Illumination Dark-Field Microscopy Refractive In dex Polarized Ligh t Microscopy

112 112 114 115

Interference 116 Birefringence and Extinction 118 Refractive Index Determinations 121 Dispersion Staining 122

Isolation and Handling of Particles Hot Stage Methods Microscope Calibration Measurement of Particle Size Techniques for Microscopic Particle Counting Enumeration of Particles in Parenteral Products Summary References

123 125 126 127 129 134 139 139

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V. Instrumental Analysis for Particle Identification

143

Particle Identification—Electron Microscopy

145

Transmission Electron Microscopy 146 Electromagnetic Lenses 149 Scanning Electron Microscopy 152

Application of X-Ray Spectroscopy Elemental Composition Analysis

160 162

Infrared Microspectrophotometry Mass Spectrometry 169 LAMMA 169 Secondary Ion Mass Spectrometry

165 172

X-Ray Diffraction Crystallography Summary References

177 183 183

VI. Environmental Particulate Matter Monitoring and Control

187

Applicable Standards Principles of HEPA Filtration

189 192

HEPA Filter Particle Retention Characteristics In-Use Testing of HEPA Filters 197

197

Environmental Particle Monitoring Laser Versus White Light Counters Remote Particle Monitoring 208

201 203

Application of Federal Standard 209-D Federal Standard 209-E Isokinetic Sampling 219 Sampling of Compressed Gases 223 Tubing Transport of Particulate Matter Samples

Large Particle Monitoring Personnel Monitoring Summary References

212 215 226

229 231 232 233

VII. Process- and Product-Related Particles Packaging Materials Solution and Formulation Components 243 Dry Powder Drug Materials 246 Product-Container Interactions 248 Process Point-Generated Particulates 249 Particulate Matter Problem Solving Philosophical Considerations 255 Sampling for Large Particles 259 Summary References

VIII. Particle Population Analysis Particle Size Particle Shape Particle Size Distributions (Particle Number) Distribution of Extraneous Particle Counts 294 Average Diameters 294 Instrumentation and Methods Nephelometry 303 Laser Diffraction 306 Photon Correlation Spectroscopy 309 Microscopy and Image Analysis 312 Sieving 318 Light Extinction Counting 323 Sedimentation 328 Adsorption and Porosimetry 330 Porosimetry 334 Application of Adsorption and Porosimetry 337 Aerosol Population Analysis Summary References

237 240

253 260 261

266 268 271 281

298

338 344 345

XI

IX. Collection and Isolation of Particulate Matter

350

Filter Structure and Application Retention Ratings, Pore Size, and Porosity Mechanism of Liquid Filtration 361 Determination of Retention Ratings 364 Wettability and Refractive Index 365 Filtration Apparatus Collection of Particles for Analysis Isolation of Particles for Identification 368 Powder Sampling 371 Collection of Particles from Environmental Air 376 Microscopic Analysis of Airborne Particles 379 Monitoring of Components and Parts 385 Sampling of Clean Room Garments 386 Testing of Clean Room or Surgical Gloves 389 Summary References

352 359

366 367

390 390

X. Process Control of Particulate Matter 393 Process Design Process Control Statistical Process Control 399 Process Stability and Capability 403 Control Charting 407 Batch Sampling 420

394 398

Summary References

428 429

XL Medical Devices

431

Parenteral-Type Devices

433

Sources and Control of Particulate Matter in Devices 434 Process Design 437 Patient Concerns 440

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Analysis of Particulate Matter in Devices Autologous Transfusion Devices 448 Blood Filters 449

442

Choice of Particle Counting Methods GMP Control of Device Particulates

449 450

Current Regulatory Issues 453 Device-Related 483s 459 Device Specific Particulate Matter Issues 460 Consideration Regarding Particulate Matter Requirements 461

Safe Medical Devices Act of 1990 Summary References

463 465 466

XII. Patient Issues Related to Particulate Matter

470

Circulatory Transport Human Injury by Particles Animal Studies Liposome Research Infusion of Rlood-Related Materials Phlebitis and Particles Conclusions Regarding Patient Risk Summary References

Appendices 1. Photomicrography of Particulate Matter Sample Preparation 488 Instrumentation 489 Film 493 Light Balancing Filters 495 Color Compensating Filters 496 Polarized Light Techniques 497 Illustrations 498

471 4 73 474 476 478 479 480 480 482

487 487

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2. Vendor and Equipment Information

504

Particle Counters (Airborne and Solution) 504 Light Extinction Counter Sensors 505 Counter Calibration Software 505 Calibration Materials 505 Visual Inspection Systems 506 Image Analysis 506 Electrical Zone Sensing Counters 507 Laser Diffraction Particle Analyzers 507 Lamma Instrumentation 507 Light Microscopes 507 X-Ray Spectrometers 508 Electron Microscopes 508 Photon Correlation Spectrophotometers 509 Laser Light Scattering Liquid Counters 509 Micro (Submicron) Particle Samplers 509 Microfiltration Supplies 509 Clean Room Supplies 509 Particle Analysis Equipment (General) 510 Powder Analysis Equipment 510 Secondary Ion Mass Spectrometers 511 Laboratory Robots 511 Additional Sources of Supplemental Information and Standards 511 Software for Data Reduction 513 3. Trademarks Index

514 519

Name Subject

519 524

The color photomicrographs found near the middle of this text are described on pages 498 to 503 in Appendix I.