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ContaminationControl in

Healthcare ProductManufacturing

Volume 3

Russell E. Madsen and Jeanne MoldenhauerEditors

PDABethesda, MD, USA

DHI Publishing, LLCRiver Grove, IL, USA

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ISBN: 1-933722-81-9Copyright © 2014 Russell E. Madsen and Jeanne MoldenhauerAll rights reserved.

All rights reserved. This book is protected by copyright. No part of it maybe reproduced, stored in a retrieval system or transmitted in any means,electronic, mechanical, photocopying, recording, or otherwise, withoutwritten permission from the publisher. Printed in the United States ofAmerica.

Where a product trademark, registration mark, or other protectedmark is made in the text, ownership of the mark remains with the lawfulowner of the mark. No claim, intentional or otherwise, is made byreference to any such marks in the book. Websites cited are current at thetime of publication. The author has made every effort to provide accuratecitations. If there are any omissions, please contact the publisher.

While every effort has been made by the publisher and the authors toensure the accuracy of the information expressed in this book, theorganization accepts no responsibility for errors or omissions. The viewsexpressed in this book are those of the editors and authors and may notrepresent those of either Davis Healthcare International or the PDA, itsofficers, or directors.

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

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CONTENTS

1 INTRODUCTION 1Russell E. Madsen and Jeanne Moldenhauer

2 DESIGN AND SANITIZATION OFWATERSYSTEMS TO PREVENT CONTAMINATION 13Teri C. SoliIntroduction 13Ongoing Control Designs 13Materials of Construction for Ongoing Control 14Other General Design Features 16

Tank level controls, vent filters, and rupture disks 16Loops 17Dead legs 18Points of use valves 19Points of use connectors 20Sampling ports 21Flush water disposal 22

Unit Operations 24UV units 24Micro-retentive filters 26

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Ultrafilters and nanofilters 28Polishing deionizers 30Operational controls 30

Routine Maintenance 30Multi-media or sand filters 31Softeners 32Activated carbon beds 32UV lights 33Filters 35RO units 37Deionizers 39Ultrafilters 43In-line/on-line instrumentation 44

Routine Sanitization 44Sanitization Approaches — Mechanisms, Use Conditions,

Advantages and Disadvantages 46Challenges of Penetration 46Heat Sanitization 47

Hot water 47Steam 50Chemical sanitization 52Oxidizing sanitants 55Chlorine 57Ozone 60Peracetic acid 64Hydrogen peroxide 65Chlorine dioxide 67Proprietary mixtures 68Hydrogen peroxide + peracetic acid + acetic acid 68Alkaline peroxide + quat + chelator 70

Little Used, Specialized and Ineffective Approaches 72Cleanroom environmental disinfectants 72Acids and caustics 73Passivating/derouging agents 74Non-chlorine halogens 74

Overview of Keys to Effective Sanitization 74Sanitize frequently 75Kill and remove biofilm 75Use an effective sanitizer 75Use an effective procedure 76Minimize recolonization 76In-line UV sanitizers 77In-line UV sanitizers + downstream filter 79

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In-line filter(s) 79Heating/”pasteurization” of water before entering the tank 80Continuous tank ozonation 80Ultra-pure water 81

Conclusion 82References 82About the Author 84

3 REAL TIME MICROBIAL ANALYZER FORWATER 85J.P. JiangTechnical Description of RMS-Water Analyzer 86Validation Test of RMS-W using BioBall® 89

BioBall quantitative samples 90Validation Test Data and Method Descriptions 92

Ruggedness test procedure 97Miscellaneous suggestions for conducting

feasibility study of RMS-W instrument 98Application Example: OnlineWater Monitoring Using RMS-W 99

Example 1: RMS-W online monitoring of a high puritywater line 99

Example 2: RMS-W online monitoring at a mineral waterbottling plant 101

Application Example: Surface Sampling and Cleaning Validation 104Example 1: Surface sampling using RMS-W and Quantiswab® 105Example 2: Cleaning validation using RMS-W and

Quantiswab® 106Summary 107References 108About the Author 110

4 USE OF OZONATEDWATER AS AN AIDTOCONTAMINATIONAND BIOFILM CONTROL 111Bruce Hinkle and Brian G. HubkaIntroduction 111Formation of Ozone 113What is Ozone? “Natures Proven Solution” 113How PureQuest Duplicates Nature 113How itWorks: Pathogenic Disinfection/Sterilization 114The Final Result: A Clean Organic Process 115

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Advantages of OzonatedWater 116The Effect of OzonatedWater on Biofilm 117Oxidation by OzonatedWater 119OzonatedWater System Technologies 119Efficacy of OzonatedWater 122PharmaceuticalWater Systems Assessment 124References 128About the Authors 129

5 TESTINGANDVERIFICATION OFVENTILATIONSYSTEMS FOR BIOSAFETY LEVEL 3 (BSL-3)ANDANIMAL BIOSAFETY LEVEL 3 (ABSL-3)FACILITIES 131Farhad Memarzadeh and Louis DiBerardinisIntroduction 131Definitions 134What is Laboratory Biocontainment? 135History of ANSI/ASSE Z9.14 139What Is ANSI/ASSE Z9.14? 142Findings of the Gap and Needs Analysis 144

National US and local laws, standards and guidelines 147National initiatives outside the US 151International initiatives 153

ANSI/ASSE Z9.14:The Standard 154How to read the standard 154Purpose 154Scope 155Definitions 155Applicability and conformance 156Procedure for entities using the ANSI/ASSE Z9.14 Standard 158Overview 159Roles and responsibilities 162Risk assessment 164

Guidelines for Implementing Testing andPerformance-Verification 166Verification 166Documentation overview 167Visual inspection 170Testing methodologies 171

References 189About the Authors 195

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6 MICROBIOLOGY LABORATORY SPEARHEADINGMICROBIAL CONTAMINATION CONTROL 197Mary J. GriffinIntroduction 197Microbial Contamination Control PlanChecklist 198

Internal (laboratory elements) 198External (cross functional elements) 199

Checklist Element Descriptions (Internal) 199Best laboratory practices 199Educated/experienced microbiologists 200Environmental and water monitoring 202Raw material/API testing 203Bioburden (limits) — specifications 203Endoxotin (limits) — specifications 204Microbial identification program 205Stock culture collection (reference strains and

facility isolates) 209Know the enemy (bacteria, yeast, mold, mycoplasma

and virus) 210Tracking and trending of microorganisms 211Tools for risk analysis 212Scientific studies (protocols and reports) 213Rapid methods 214Contract laboratory/resources 214

Checklist Element Descriptions (External/Cross Functional) 215Partnership (collaboration) 215Communication 217Aseptic training 217Investigation team 218Shutdown and startup support (activities) 218

Conclusion 219References 220About the Author 224

7 UNDERSTANDING, PREVENTING,ANDREMEDIATING MOLD IN CLEANROOMS 225Ziva AbrahamIntroduction 225Nature of Fungi 227Classification 227

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Zygomycetes 228Ascomycetes 229Basidiomycetes 230Deuteromycetes 230

Medically Important Fungi 233Prevention of Mold 233Cleaning and Disinfection 236Fogging 239Conclusion 240References 241About the Author 242

8 CONTAMINATION CONTROLCONSIDERATIONS FOR MICROAEROPHILLICSIN CONTROLLEDASEPTIC MANUFACTURINGAREAS 243Veronica Marshall and Daniel EsheteMicroaerophillics/Anaerobes in Controlled Aseptic

Manufacturing Environments 243Assessing the Anticipated Microbial Profile in Controlled

Aseptic Manufacturing Environments 244Propionibacterium acnes 245Peptostreptococcus 246Actinomyces and related species 247Clostridium species 248Enterococcus faecium 249

Determination ofWhere Microorganisms can Occurand be Harbored 249

Considerations for Effective Monitoring and Controlof Microaerophillics/Anaerobes 250

Response Limit Excursions and Product Contamination Events 252References 256About the Authors 258

9 THE PROBLEM OF BURKHOLDERIA CEPACIA 261Jeanne MoldenhauerBackground on Burkholderia Cepacia 261FDA’s Recommendation for Removing B. Cepacia from

Pharmaceutical Environments 265

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Opposing Positions to B. cepacia Treated as anObjectionable Organism 270

Conclusion 272References 272Letter to the Editor 273About the Author 284

10 CLEANING VALIDATION: PROCESS LIFECYCLE APPROACH 285Paul Lopolito and Elizabeth RiveraIntroduction 285Stage 1: Cleaning Process Design 290

Selection of cleaning agents and suppliers 291Defining critical parameters and cleaning methods 292Design of laboratory and pilot testing 293Utility design considerations 294Process equipment design review 295Product and equipment grouping 298Analytical detection method 299Recovery studies 301Residual limits and acceptance criteria 301Documentation of the process design stage 304

Stage 2: Process Qualification 305Cleaning validation master plan 306Supplier qualification 308Utility readiness 309Equipment readiness 309Analytical method readiness 311Selection of sampling sites 315Cleaning validation protocols 316Standard Operating Procedures 319Personnel training 320Validation execution 321Interim documentation and final package 322

Stage 3: Continued Process Verification 323Monitoring and process capability 323Process Analytical Technologies 325Change control procedures 326Deviations and Out of Specification (OOS) results 327Procedure review and retraining 328Corrective and Preventive Action (CAPA) procedures 328

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Preventive Maintenance (PM) procedures 329Quality management review 331Revalidation versus new validation 331

Conclusions 332References 334About the Authors 339

11 RISK MANAGEMENT OF MICROBIALCONTAMINATION CONTROL IN ASEPTICPROCESSING AND INTERVENTIONSRISK ASSESSMENT MODEL (IREM):THE USE OF CRITICAL THINKING TOMAKE INFORMED DECISIONS 341Hal Baseman and Mike LongIntroduction: Risk Management and Risk Assessment 342Regulatory Expectations 343

Is aseptic processing risky? 347The Assurance of Quality 348The Design of Process Control Strategies 352The Contamination Control of Aseptic Processes 355A Risk-Based Approach to Process Validation:

Risk Assessment of the Aseptic Process 358The Appreciation of Risk Management 361

Ten points to consider for more effective riskassessments and approaches to decision making 364

The Avoidance of Risk Assessment Bias 372Performance of Aseptic Process Risk Assessments 373Addressing Residual Risk and the Unintended Consequences

of Actions 373The Risk Assessment of Aseptic Process Interventions 375Intervention Risk Evaluation Model (IREM) 377

Background 378Considerations in the design of the IREM model 379Key word design approach 380Duration 380Complexity 382Proximity 383

Overall Intervention Risk Determination 384IREM Case Studies 386

Case study 1: removal of fallen vials 386Case study 2: fill system assembly 390

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Evaluation of Overall Aseptic Process 397Conclusion 398References 400About the Authors 404

12 UNDERSTANDING CLEANROOMCLASSIFICATIONS 407Jeanne MoldenhauerFederal Standard 209e 411Lesser Known Air Cleanliness Standards 414ISO 14644-1 Classification System 415FDA’s Aseptic Processing Guidance 417The European Union’s GMPs —Annex 1 418ICH Q7A 421Aseptic Processes 423The Problem 423References 425About the Author 427

13 DISINFECTION QUALIFICATIONTESTINGCONSIDERATIONS FORASEPTICANDCLEANROOM MANUFACTURINGENVIRONMENTS 429Dave Rottjakob and Scott SteinagelIntroduction 429What is Disinfection Qualification? 430Why are Disinfection Qualification Studies Important? 430

Some FDAWarning Letter excerpts 432Why Does the FDA Require Disinfection Qualification Studies? 433When Should Disinfection Qualification Studies be Conducted? 434How Should Disinfection Qualification Studies be Performed? 435

Suspension-based testing vs. coupon-based testing 435Scope of qualification testing 436

Overview of Study Design 438Conclusion 439References 439About the Authors 440

Appendix 443

Index 447

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