ENVIRONMENTALMONITORING

A Comprehensive Handbook

JEANNE MOLDENHAUEREditor

Volume Eight

PDABethesda, MD, USA

DHI Publishing, LLCRiver Grove, IL, USA

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ISBN: 978-1-942911-13-5Copyright © 2017 J. MoldenhauerAll rights reserved.

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CONTENTS

Introduction xi

REGULATORY/COMPENDIAL UPDATES

1 APPLICATION OF ISO 14644 PARTS 1AND 2FOR CLEANROOM CONTAMINATION CONTROL 3Tim SandleIntroduction 3Cleanrooms and Contamination Control 4Brief History of Cleanroom Standards 6ISO 14644 7ISO 14644 and Cleanroom Classification 10

Particle sizes to be measured 11Number of locations to be measured within the cleanroom 12Location of particle counters within the cleanroom 13Volume of air to be sampled 13Assessing results 14Particle counter probe locations 14Test certification 14

Particle Counters 15On-going Compliance with ISO 14644-1 15

Particle count cleanroom test 16Air pressure differentials 16

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Airflow 16Installed filter leakage 17Containment leakage 18Recovery 18Airflow visualization 18Risk assessment 18

Conclusion 19References 20About the Author 27

2 MICROBIAL MONITORING IN CLEANROOMS: USE OFCONTAMINATION RECOVERY RATES (USP <1116>),REALTIME MONITORING,ANDTHE STATE OFCONTAMINATION CONTROL 23Claudio Denoya and Gilberto DalmasoKey Objectives of the Chapter 23Introduction 23Pharmaceutical Industry and the Need for Aseptic Processing 24Aseptic Processing and Environmental Monitoring 25Microbiological Control and Monitoring of Aseptic Processing Environments 26

Title 26Scope 26Aseptically filled product 27Room classes 27Risk assessment 28Air changes 29The case for CRR 29Case study 1: garment contamination rates 30Case study 2: critical area — freeze drying 33Case study 3: routine active air — Grade B 35Conclusions on CRR 36

Microbial Monitoring: Instrumentation and Real Time Monitoring 36Real Time Microbial Monitoring Using Laser-Induced Fluorescence 37Surface Sampling 40FinalWords 40References 41About the Authors 42

3 ENVIRONMENTAL MONITORING FORSTERILE COMPOUNDING 45Fran McAteerIntroduction 45History 46

Drug Quality and Security Act 47

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USP <797> Lexicon 48Definitions 48

USP <797> CSP Microbiological Contamination Risk Levels 50Low-risk level CSPs 50Medium-risk level CSPs 50High-risk level CSPs 51Intermediate use CSPs 51

Physical Facilities and Equipment 51Environmental monitoring 52Nonviable airborne particle testing program 54Viable airborne particle testing program 54Surface disinfection sampling and assessment 55Gloved fingertip testing 56

Conclusion 57References 58About the Author 58

4 THE CHANGING EXPECTATIONS FOR MICROBIOLOGICALTESTING OF PHARMACEUTICAL PRODUCTS 61Jeanne MoldenhauerAbstract 61Quality Attributes 61

Route of administration 61Patient population 62Dosage form/product formulation 62

Sources of Microorganisms in Pharmaceutical Manufacturing 62Raw materials 62Manufacturing process 63Manufacturing environment 63Control mechanisms 63Aqueous and multi-dose products 64Burkholderia cepacia complex (BCC) 64

Regulatory Updates —The Compliance Perspective 65Applicable standards 65Quality control strategy 65Environmental monitoring 66

Conclusion 66References 66About the Author 69Appendix 69

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TESTING METHODS

5 PARTICLE COUNTINGAND ENVIRONMENTAL MONITORING 75Mark HallworthIntroduction 75Particle Counting Cleanroom Standards — ISO 14644 76

Updated ISO 14644-1 76Updated ISO 14644-2 79

Certification and Monitoring for GMP Compliance 80EU GMP Annex 1 81

FDA Guidance on Sterile Manufacture 82Data Reporting, Interpretation, and Action Management 83

Data reporting 84Setting alert and action limits 85

Summary 87References 87About the Author 88

RISK METHODSANDTOOLS

6 CONTAMINATION CONTROL USINGA RISK-BASED,AUTOMATED CLEANINGVALIDATION SOFTWARE SYSTEM 91Susan Cleary and Parsa FamiliIntroduction 91Contamination Risks 92Contamination Control 94Operators and the Cleaning Crew 95Equipment Design 95Residues 95

Bacteria 96Fungi —Yeasts 96Fungi — Mold 97

Environmental Monitoring 97Sampling 97

Analytical methods 98Cleaning Validation Data Management 99Automating Cleaning Validation 9921 CFR Part 11 — Compliancy and Data Integrity 101Change and Risk Control Integration 103Multi-Departmental Visibility 103Risk BasedWorst Case 104Calculating and Establishing Limits and Specifications 104

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Validation Events and Monitoring Events 106Results Entry 106Reporting Requirements 107Trending — Statistical Tools 107Paper vs Automated System 108Conclusion 110References 111About the Authors 113

ROUTINE MONITORING —AND NON-ROUTINE

7 A PRACTICALAPPROACHTO INVESTIGATINGENVIRONMENTAL EXCURSIONS 117RobertWestneyIntroduction 117Fundamentals of an Investigation Plan 118Step-by-Step Investigation Points 118

Alert level 119Action level 119

Root Cause Analysis 122Corrective/Preventive Action and Assessing Effectiveness 123Assessing Facility and Product Impact 123Summary 124References 125About the Author 126

8 ENVIRONMENTAL MONITORING:TABOOS,INVESTIGATIONS,AND IMPACTANALYSIS 127Olivier ChancelIntroduction 127Taboos onViable Particle Monitoring 128Taboos for Non-viable Particle Monitoring 132What About Rapid Microbiology Methods? 135Suggestions for Investigating an Environmental Monitoring Excursion 137

Detection of the excursion 138Investigation 139Investigation report 143

Conclusions 150References 151About the Author 152

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9 ENVIRONMENTAL MONITORINGAND ITS IMPACTONASSURANCE OF STERILITY 153Randy HuttIntroduction 153Non-viable Monitoring Performance 154Viable Monitoring Performance 154Alert and Action Levels 157

Setting of Alert and Action Levels 157Contamination Recovery Rate (CRR) per USP <116> 158

Investigation Section 158Data from QCmicrobiology 158Data from production filling operations 158Data specifically needed for a PM excursion 159Risk Assessment (RA) 159

Who Should Oversee Functions Related to Sterility Assurancefor EM and PM? 161Sterility assurance functions 161

Failure Mode and Effects Analysis (FMEA) 162Master Plan for Microbial Control 163Conclusion 163References 164About the Author 165

10 CHANGINGTHE PARADIGM OF CLEANINGANDDISINFECTION OF CLEANROOMS 167Jeanne Moldenhauer and Brian G. HubkaAbstract 167Background 167Typical Cleaning and Disinfection Agents 168

Alcohols 168Aldehydes 168Halogens 169Peroxygen compounds 170Phenolics 170Quaternary Ammonium Compounds (Quats) 171

Alternative Cleaning and Disinfectant Products 171Ozonated water 171Hydrogen activated water 172

Moving to Prevention Technologies 173Conclusion 173References 173About the Authors 174

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11 AGING FACILITIES AND MODERNIZINGASEPTICPROCESSES 175Michael HodgkinsonIntroduction 175Background and Context 175Aging Facility and Process Risks 177

Facility and equipment risks 177Process risks 179Personnel risks 179

Barriers to Modernization 180Identifying Opportunities to Modernize 181

Process performance indicators 181Quality system data 182Voice of the user 182Engineering assessments of facilities 183

Risk Assessments 183Education and training 185

Analyzing Opportunities and Action Planning 185Organizing opportunities 185Prioritizing actions 185Building a business case and plan 187

Modernization Options 188Facility and equipment modernization 188Aseptic process modernization 190Training and education modernization 191

Conclusion 192References 192About the Author 193

NEWTECHNOLOGIESAND SYSTEMS

12 PROSAND CONS OF USING MALDI-TOF MSFOR MICROBIOLOGICAL IDENTIFICATION 197Elvira Engelmann and Frank KuglerMALDI-TOF MS Methodology 198

Sample preparation 198Measurement 198Data evaluation 200Reference database 202

Pros and Cons of Using MALDI-TOF MS for Microbial Identification 202Fast identification 202Simple handling 203

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Cost-effectiveness 204Identification from liquid cultures 205Accurate and reliable identification 205Precision and consistency 206Robustness 206

MALDI-TOF Method in GMP Environment 207Limitations of the MALDI-TOF Method 207Creation of an In-house Database 209Continuous Fine-tuning Necessary 209Conclusions 209References 211About the Authors 214

13 ENVIRONMENTAL MONITORING METHODS FORPRODUCTION ISOLATORS 215Claire Fritz Briglia, Anne Connors, and Tim CserIntroduction 215Active Air Samplers 216Biological and Physical Efficiency 216Particle Counting 217Settling Plates 218Portable vs FixedViable Air Samplers 219

Fixed air sampler 222Simplifying EM in Isolators 224Glove/Sleeve Testing 225Swabs 227Risk Assessment 229Summary 229References 230About the Authors 231

Appendix 233

Index 243

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INTRODUCTION

This is volume 8 of the Environmental Monitoring Handbook series. Each volume of this seriesdiscusses different aspects of environmental monitoring. The Appendix describes the varioustopics and authors that can be found in volumes 1 through 7 of this series.

There are a variety of topics covered in this book. In some cases, it may be a topicintroduced in other volumes, but this chapter is a new take on an old subject. Other topics arebrand new to the series.

Dr. Tim Sandle discusses the changes in ISO 14644-1 and 2. Like all of Dr. Sandle’s work,you won’t want to miss this definitive piece! In other regulatory topics, Dr. Claudio Denoyaand Dr. Gilberto Dalmasso provide a detailed discussion on the Suggested Use ofContamination Rates as shown in USP <1116> for Aseptic Processes. Both of these authorshave a long history working in production facilities, so this is a really practical chapter. FranMcAteer wrote a great chapter on compounding pharmacies and implementation of USP<797>. This is a hot topic in the industry. Ending this section Jeanne Moldenhauer provides anupdate on changing regulatory requirements — presenting information presented by Dr. LynneEnsor and Mr. Thomas Arista at recent PDA meetings.

Dr. Olivier Chancel has a great chapter on environmental monitoring excursions, with lotsof interesting case studies. Dr. Randy Hutt and Dr. Robert Westney also provide theirperspective on environmental excursions. Jeanne Moldenhauer and Brian Hubka have a chapteron changing the paradigm for disinfectants and cleaning. Another great chapter is by MichaelHodgkinson, which deals with handling aging facilities.

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Elvira Engelmann and Frank Kugler work in a company that is a major source ofmicrobial identifications in Europe. They have extensively evaluated the Maldi-TOF fororganism identification. Their chapter describes the pros and cons of using thisinstrumentation. Claire Briglia, Anne Connors, and Tim Cser describe environmentalmonitoring methods to utilize for production isolators. Parsa Famili and Susan Cleary describea new automated tool used in the cleaning validation program to determine when validation isdue, and whether new product formulations fit into your validation matrix.

There is a wealth of useful information that you can use in establishing, maintaining andupdating your environmental monitoring program!

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