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Contamination
Control in
Healthcare Product
Manufacturing
Volume 5

Russell E. Madsen and Jeanne Moldenhauer

Editors

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PDA
Bethesda, MD, USA
DHI Publishing, LLC
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10 9 8 7 6 5 4 3 2 1

ISBN: 978-1-942911-28-9
Copyright © 2018 Russell E. Madsen and Jeanne Moldenhauer
All rights reserved.

All rights reserved. This book is protected by copyright. No part of it may

be reproduced, stored in a retrieval system or transmitted in any means,
electronic, mechanical, photocopying, recording, or otherwise, without
written permission from the publisher. Printed in the United States of
America.
Where a product trademark, registration mark, or other protected
mark is made in the text, ownership of the mark remains with the lawful
owner of the mark. No claim, intentional or otherwise, is made by
reference to any such marks in the book. Websites cited are current at the
time of publication. The author has made every effort to provide accurate
citations. If there are any omissions, please contact the publisher.
While every effort has been made by the publisher and the authors to
ensure the accuracy of the information expressed in this book, the
organization accepts no responsibility for errors or omissions. The views
expressed in this book are those of the editors and authors and may not
represent those of either Davis Healthcare International or the PDA, its
officers, or directors.

This book is printed on sustainable resource paper approved by the Forest Stewardship
Council. The printer, Gasch Printing, is a member of the Green Press Initiative and all paper
used is from SFI (Sustainable Forest Initiative) certified mills.

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CONTENTS

1 INTRODUCTION 1
Russell E. Madsen and Jeanne Moldenhauer
Background 1
Types of Contamination 2
Regulatory Expectations 3
Contamination Control in the Real World 4
Materials Provided 5
References 6
About the Editors 7

CONTROL STRATEGIES

2 DEVELOPING A CONTAMINATION
CONTROL STRATEGY 11
Jeanne Moldenhauer
Introduction 11
Purpose of a Contamination Control Strategy 12
A Comprehensive Written Plan 13
Design of the Plant and Process 14
Equipment and Facilities 16

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iv Contamination Control in Healthcare Product Manufacturing

Utilities 20
Raw Materials Control – Including In-Process Controls 21
Product Container and Closures 21
Vendor Approval 22
Outsourced Services 22
Process Risk Assessment 23
Preventative Maintenance 23
Cleaning and Disinfection 23
Monitoring Systems 25
Prevention 25
Trending, Investigations, CAPA and Root Cause Determination 36
Continuous Improvement 36
Conclusion 37
References 38
About the Author 39

3 CASE STUDIES ON TYPICAL MICROBIAL

DEVIATIONS THAT CAN BE AVOIDED 41
Walid El Azab and Olivier Chancel
Introduction 41
The Microbial Control Program and Continuous Improvement 43
Investigation Process and Cross-Functional Team Benefits 45
Microbial Contamination Failures and Lessons Learned 46
Case Study #1: Recurring Microbial Contamination Disrupts
The Cost-Time-Quality Balance 47
Case Study #2: Recurring Microbial Contamination in Grade A
(ISO 5) Filling Restricted Access Barrier System 61
Case Study #3: Learning Experience on Manual Diaphragm Valves 72
Case Study #4: Learning Experience on Non-Viable Particles,
Risks of False Positives 77
Case Study #5: Learning Experience on Moist Heat
Sterilization of Filters 84
Case Study #6: Learning Experience on the Risk of False
Negatives and Aseptic Process Simulations 88
Case Study #7: Learning Experience on Bioburden, Risks of False
and True Positives 90
Conclusion 94
References 94
About the Authors 101

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Contents v

4 FACTORS IN CLEANROOM DECISION MAKING 103

Sidney Backstrom and Maik Jornitz
Introduction 103
What are the Options? 105
Decision Factors to Consider 109
Cost Factors 130
Quality 132
Other Factors 136
Conclusion 138
References 138
About the Authors 141

5 DECONTAMINATION OF ITEMS
BROUGHT INTO THE CLEANROOM 143
James Polarine, Jr., Aaron Mertens and Jennifer Loughman
Introduction 143
Cleanroom Design 145
Cleaning and Disinfection 146
Contamination Prevention and Control 146
Selecting a Decontamination Chemistry 148
Laboratory Studies 149
Alcohols 149
Sporicides Comparative Efficacy 152
Sanitizers, Disinfectants and Sporicides 154
Equipment Preparation 155
General Recommendations 156
References 157
About the Authors 158

6 THE TECHNOLOGY BEHIND AND SELECTION

OF WIPERS FOR USE IN CLEANROOMS 161
Brad Lyon and Jay Postlewaite
Introduction 161
Yarn 163
Synthetic Yarns 166
Fabric Formation Processes 172
Wiper Uses 193
Using a Wiper 197
Cleanroom Wiper Manufacturing 202

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vi Contamination Control in Healthcare Product Manufacturing

Selecting a Wiper 204
Wiper Selection Examples 214
Summary 216
References 216
About the Authors 220

7 GAMMA STERILIZATION VALIDATION

OF DISPOSABLE, SINGLE-USE AND
REUSABLE CLEANROOM GARMENTS 221
Jan Eudy
Understanding Cleanroom Apparel Sterilization 221
Steam Autoclaving 223
Ethylene Oxide 223
Ionizating Radiation 224
Design Qualification 225
Installation/Operation Qualification 225
Family Grouping Assessment 227
Sample Item Portion Justification 230
Method 1 Validation 230
Verification Dose Maximum Method 232
Dose Mapping 235
Performance Qualification 235
Shelf Life Sterilization Stability 236
Routine Monitoring of Gamma Radiation 236
Certificate of Sterility 237
Documentation and Records Retention 238
References 238
About the Author 240

ENDOTOXIN RECOVERY

8 ENVIRONMENTAL ENDOTOXINS ARE

NON-STATIC STRUCTURES.WHY THE
LAL TEST CONTINUES TO BE EFFICACIOUS 243
John Dubczak and Karen Zink McCullough
Introduction 243
Purified LPS 245
Size Matters 247
Naturally Occurring Endotoxin: Environment Matters 249

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Contents vii
The Dogmatic Analytic Arguments 250
Direct Product Inoculation of an LER Matrix:
Cell Growth Matters 251
Adaption: Bacterial Physiology and Genetics Matter 254
LPS Structures in Mammalian Cell Culturing Processes 257
Conclusion 260
References 260
About the Authors 262

ENVIRONMENTAL MONITORING

9 PRACTICAL APPROACHES TO LEVERAGING

ENVIRONMENTAL MONITORING TREND
DATA TO IMPROVE PERFORMANCE 267
Michael Hodgkinson
Introduction 267
Background and Regulatory Expectations 268
Program Foundations 270
Environmental Trend Analysis 274
Leveraging Environmental Trend Data to
Improve Performance 282
Conclusion 291
References 292
About the Author 293

10 DESIGNING A RISK-BASED ENVIRONMENTAL

MONITORING PROGRAM FOR NON-STERILE
MANUFACTURING 295
Crystal Booth
Introduction 295
Overview of Environmental Monitoring 296
Establishing Where to Sample 302
A Phased Approach to EMPQ 305
Routine Environmental Monitoring 307
Establishing Alert Limits 310
Other Considerations 311
Conclusion 312
References 313
About the Author 314

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viii Contamination Control in Healthcare Product Manufacturing

11 AN ENGINEERING PERSPECTIVE ON
VALIDATING AN ENVIRONMENTAL
MONITORING SAMPLING PLAN 317
Allan Marinelli
Introduction 317
Sampling Pre-Requisite Phase 1 319
Sampling Preparation Phase 2 322
Sampling Execution Phase 3 325
Sampling to Laboratory Phase 4 335
Sampling Analysis Phase 5 336
Sampling Conclusion Phase 6 341
Conclusion 341
Appendix Detail Step Section from Sampling Pre-Requisite
Phase 1 342
References 355
About the Author 356

12 PERSONNEL MONITORING FOR

CONTROLLED ENVIRONMENTS 357
Tim Sandle
Introduction 357
Microbiome of Human Skin and Cleanroom Microbiota 358
Personnel Gowning and Behavior 372
Personnel Monitoring 384
Summary 390
References 391
About the Author 397

OBJECTIONABLE ORGANISMS

13 CLINICAL RELEVANCE OF OBJECTIONABLE

MICROORGANISMS 401
Ziva Abraham
The Challenge 401
What is Expected? 402
Knowing the Friendly and Non-Friendly Microbes 405
Bacterial Pathogens 406
Fungal Pathogens 408

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Contents ix
Infectivity vs. Pathogenicity vs.Virulence 408
Host Susceptibility 409
Infective Dose 409
Objectionable Organisms 409
Specified vs. Objectionable in Oral Dosage Forms 410
Specified vs. Objectionable in Products for Oromucosal
and Gingival Use 413
Specified vs. Objectionable in Products for Cutaneous Use
and Transdermal Patches 414
Specified vs. Objectionable in Products for Nasal Use 415
Non-invasive Fungal Sinusitis: Mycetoma (Fungus Ball) 416
Invasive Fungal Sinusitis 416
Specified vs. Objectionable in Products for Auricular Use 417
Specified vs. Objectionable in Products for Vaginal Use 418
Specified vs. Objectionable in Inhalation Use (Special
Requirements Apply to Liquid Preparations for
Nebulization) 418
Specified vs. Objectionable in Eye Products 420
Emerging Infectious Diseases 420
The General Guidance and the Dilemma 421
Research Strategy for Risk Assessment 424
Conclusion 424
References 425
About the Author 431

14 BURKHOLDERIA CEPACIA COMPLEX:

SEVERAL ABSOLUTELY-OBJECTIONABLE
BACTERIAL SPECIES 433
Arnaud Carlotti
Introduction 433
Taxonomic Overview 435
Habitats 443
Genomic, Infectivity,Virulence and Pathogenicity 446
Contaminations in the Pharmaceutical Industries 452
Laboratory Diagnosis 453
Case Study 455
Conclusion 461
References 462
About the Author 468

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x Contamination Control in Healthcare Product Manufacturing

15 BURKHOLDERIA CEPACIA COMPLEX

CASE STUDIES 469
Jeanne Moldenhauer
Introduction 469
BCC Defined 470
Regulatory Recalls Due to BCC 472
Case Study 1: Is it BCC? 473
Case Study 2: Non-Sterile Aqueous Product 476
Case Study 3: Sterile Aqueous Product 478
References 482
About the Author 486

APPENDIX 487
Contents of Volumes 1–4

INDEX 495

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