Table Of ContentPharmaceutical Microbiological Quality
Assurance and Control
Pharmaceutical Microbiological Quality
Assurance and Control
Practical Guide for Non‐Sterile Manufacturing
Edited by
David Roesti
Novartis Pharma Stein AG, Switzerland
Marcel Goverde
MGP Consulting GmbH, Switzerland
This edition first published 2020
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10 9 8 7 6 5 4 3 2 1
v
Contents
Editors xix
List of Contributors xxi
Preface xxvii
Foreword xxxiii
Acknowledgments xxxv
1 Microbiological Control Strategy 1
David Roesti and Marcel Goverde
1.1 Introduction 1
1.2 Overview of a Microbial Control Strategy Program 2
1.3 Main Factors to Be Controlled 4
1.3.1 Controlled Facilities 4
1.3.2 Controlled Procedures 10
1.3.3 Controlled Product Ingredients 10
1.3.4 Controlled Utilities 12
1.3.5 Controlled Equipment 13
1.3.6 Controlled Formulation 15
1.4 Conclusion 18
Bibliography 18
2 Microbial Contamination Risk Assessment in Non‐sterile
Drug Product Manufacturing and Risk Mitigation 23
Tony Cundell
2.1 Introduction 24
2.2 Regulatory, Compendia, and Industry Guidance 24
2.3 Putting into Perspective the Microbiological Risk Associated
with Non‐sterile Products 25
2.3.1 75 000 Deaths Annually Caused by Infectious Diseases! 26
2.3.2 Susceptibility of Different Patient Populations 28
2.3.3 Frequency of Drug Product Recall 29
vi Contents
2.4 Risk Assessment Tools 29
2.4.1 Impact Matrix 30
2.4.2 Failure Mode and Effects Analysis (FMEA) 31
2.4.3 Hazard Analysis and Critical Control Points (HACCP) 31
2.4.3.1 Application of HACPP to Tablet Manufacturing 32
2.5 Organizational Risk Management Maturity 35
2.6 Hierarchy of Risks 35
2.6.1 Hierarchy of Risk by Pharmaceutical Ingredient 35
2.6.2 Hierarchy of Risk by Dosage Form and Processing Steps 42
2.6.2.1 Processing Steps 42
2.6.2.2 Risk Associated with Different Processing Steps 43
2.6.3 Hierarchy of Risk by Utility System 45
2.7 Effect of Product Attributes 46
2.7.1 What Are the Critical Quality Attributes for
a Pharmaceutical Drug? 46
2.7.2 Role of Formulation in Bioburden Control 46
2.7.3 Hurdle Technology Concept 46
2.7.4 Concept of Hostility Level 48
2.8 Emerging Manufacturing Technologies 48
2.8.1 Jet Milling Micronization 48
2.8.2 Hot Melt Extrusion 50
2.8.3 Continuous Tablet Manufacturing 51
2.9 A Case History 52
2.10 Conclusions 53
Bibliography 53
3 Qualification of Microbiological Laboratory Personnel
and Equipment 57
Robert Schwarz
3.1 Introduction 57
3.2 Reasons, Requirements, and Strategies for Qualification 58
3.2.1 Qualification and Re‐Qualification of Laboratory Personnel 58
3.2.2 Equipment Qualification: Which Equipment Needs to Be
Qualified in a Microbiological Laboratory? 60
3.2.2.1 Equipment Classification According to ISPE 61
3.2.2.2 Equipment Classification According to USP 64
3.2.3 Equipment Qualification: How to Qualify
Laboratory Equipment 65
3.3 Critical Aspects of Microbiological Methods 68
3.3.1 Antibiotic Susceptibility Testing (AST) 69
3.4 Practical Examples for Qualification of Laboratory
Personnel 72
3.4.1 Titrations 72
Contents vii
3.4.2 Verification of Spore Count on Biological Indicators 73
3.4.3 Recovery Rate of Microbiological Swab Sampling 73
Acknowledgments 76
Bibliography 76
4 Introduction to Culture Media in Pharmaceutical Microbiology
for Non‐sterile Products 79
Marion Louis, Laurent Leblanc, and Félix A. Montero Julian
4.1 Introduction 80
4.2 Culture Media Challenges and Development 83
4.3 Importance of Culture Media for Patient Safety 83
4.4 Culture Media Are all Different 83
4.4.1 Importance of Raw Materials 84
4.4.1.1 Origins 84
4.4.1.2 Selection 85
4.4.1.3 Variability and Controls 85
4.4.2 Manufacturing Process 87
4.4.3 Development of Culture Media 87
4.4.4 Stability Studies 88
4.4.4.1 Thermal Shocks 89
4.5 Innovation in Regard to Culture Media 91
4.5.1 Objectionable Organisms Recall 91
4.5.2 Increase Media Flexibility and Ease of Use 92
4.6 Quality Controls 92
4.6.1 Quality Release Test Performed by the Culture Media Manufacturer
(External Provider or In‐house Media Manufacturer) 92
4.6.2 Quality Control Test Performed on Ready‐to‐Use Culture Media
Purchased from External Manufacturers 95
4.6.3 Importance of the Quality Control Strains 96
4.6.4 Outsourcing Strategy and How to Perform an Audit at a Growth
Media Partner 97
4.6.4.1 Quality System 98
4.6.4.2 Facilities and Equipment 98
4.7 Culture Media Troubleshooting 98
4.7.1 Temperature Storage Issues 99
4.7.1.1 Storage Conditions Below 2 °C 99
4.7.1.2 Exceptional Excursions of Temperature During Shelf Life 99
4.7.2 Water Condensation and Excessive Moisture 100
4.7.3 Fertility Issues 100
4.7.4 Crystals in Xylose Lysine Deoxycholate (XLD) Culture
Medium 102
4.8 Conclusion 103
Bibliography 103
viii Contents
5 Microbiological Examination of Non‐sterile Final Dosage Forms
and Raw Material Including Acceptance Criteria and Testing
Frequency 105
David Roesti
5.1 Microbiological Acceptance Criteria 106
5.1.1 Final Dosage Forms 106
5.1.2 Raw Materials 110
5.1.3 Internal Out of Expectation (OOE) Limits 111
5.2 Testing Frequency 112
5.2.1 Final Dosage Forms 112
5.2.1.1 Which Frequency to Set by Skip‐lot Testing? 113
5.2.2 Drug Substances and Excipients 116
5.3 Procedure if Microbial Growth Occurs in Routine Testing 117
5.4 Sampling 117
5.5 Nutrient Medium Controls 120
5.5.1 pH Value 121
5.5.2 Absence of Microbial Contamination 121
5.5.3 Growth Promotion Tests 121
5.6 Test Method Overview 125
5.7 Verification of the Suitability of the Method 127
5.7.1 Sample Preparation 127
5.7.2 Method Suitability for Microbial Enumeration Tests 129
5.7.2.1 Membrane Filtration 129
5.7.2.2 Plate Count Methods 131
5.7.2.3 Most Probable Number Method 134
5.7.3 Suitability of the Test Method for Absence of Specified
Microorganisms 139
5.7.4 Examples of Procedures in Case the Method Suitability Fails 140
5.8 Microbiological Examination of Non‐sterile Products 142
5.8.1 Microbial Enumeration Tests: Membrane Filtration
and Plate Count Methods 142
5.8.1.1 Membrane Filtration 142
5.8.1.2 Pour Plate Method 142
5.8.1.3 Surface Spread Method 143
5.8.1.4 Incubation 143
5.8.1.5 Counting 143
5.8.2 Microbial Enumeration Tests: MPN Method 145
5.8.2.1 Enumeration by Means of Serial Dilutions (MPN Method) 145
5.8.3 Test for Specified Microorganisms Procedure 145
5.8.4 Method Transfer 148
5.9 Elements to Consider for Raw Data Sheets 148
Acknowledgments 149
Bibliography 149
