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
1.4 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
2.4 Risk Assessment Tools 29
2.5 Organizational Risk Management Maturity 35
2.6 Hierarchy of Risks 35
2.7 Effect of Product Attributes 46
2.8 Emerging Manufacturing Technologies 48
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
3.3 Critical Aspects of Microbiological Methods 68
3.4 Practical Examples for Qualification of Laboratory Personnel 72
Acknowledgments 76
Bibliography 76
4 Introduction to Culture Media in Pharmaceutical Microbiology for Non-sterile Products 79
Marion Louis, Laurent Leblanc, and Felix 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
4.5 Innovation in Regard to Culture Media 91
4.6 Quality Controls 92
4.7 Culture Media Troubleshooting 98
4.8 Conclusion 103
Bibliography 103
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
5.2 Testing Frequency 112
5.3 Procedure if Microbial Growth Occurs in Routine Testing 117
5.4 Sampling 117
5.5 Nutrient Medium Controls 120
5.6 Test Method Overview 125
5.7 Verification of the Suitability of the Method 127
5.8 Microbiological Examination of Non-sterile Products 142
5.9 Elements to Consider for Raw Data Sheets 148
Acknowledgments 149
Bibliography 149
6 Microbial Requirements and Testing of Primary Packaging 153
Marcel Goverde
6.1 Introduction 154
6.2 Guidelines and Literature 161
6.3 Acceptance Criteria and Testing Frequency 164
6.4 Test Methods 170
6.5 Suitability Test 174
6.6 OOS Procedure 177
6.7 Examples of OOS or OOE Cases 178
6.8 Conclusion 184
Bibliography 185
7 Utilities Design and Testing 189
Tim Sandle
7.1 Introduction 190
7.2 Defining, Developing, and Maintaining Utilities 191
7.3 Review of Critical Utilities 198
7.4 Conclusion 226
Bibliography 227
8 Microbiological Environmental Monitoring 231
Alexandra Stark
8.1 Introduction 232
8.2 Microbiological Control Strategy 233
8.3 Cleanliness Zoning Concept for Non-sterile Products 233
8.4 Microbiological Environmental Monitoring Strategy 234
8.5 Microbiological Environmental Monitoring Methods 235
8.6 Method Validations and Suitability Tests for Microbiological Environmental Monitoring 238
8.7 Initial Validation of Cleanrooms and Production Equipment 244
8.8 Definition of a Microbiological Environmental Routine Monitoring Program 246
8.9 Microbiological Environmental Monitoring: Examples for Users 253
8.10 Conclusion 261
Bibliography 262
9 Identification of Microorganisms 265
Christine E. Farrance
9.1 Introduction 266
9.2 History and Challenges of Bacterial Taxonomy and Classification 268
9.3 History and Challenges of Fungal Taxonomy and Classification 276
9.4 Current Identification Technologies 279
9.5 Strengths and Weaknesses with Each Categorical Method 306
9.6 Case Studies from a Contract Testing Lab 309
9.7 Conclusion 313
Bibliography 314
10 Calculating Alert Levels and Trending of Microbiological Data 329
David Roesti
10.1 Introduction 330
10.2 Goal of the Chapter 332
10.3 Alert Levels Based on Historical Data 332
10.4 Trending 355
10.5 Conclusion 367
Acknowledgments 367
Bibliography 367
11 Exclusion of Objectionable Microorganisms from Non-sterile Pharmaceutical Drug Products 371
Tony Cundell
11.1 Introduction 372
11.2 What is an Objectionable Microorganism? 374
11.3 Screening for Objectionable Microorganisms 383
11.4 Risk-Based Microbial Testing of Non-sterile Drug Products 388
11.5 Sources of Objectionable Microorganisms 389
11.6 Risk Assessment to Determine if a Microorganism is Objectionable in a Non-sterile Drug Product 392
11.7 Case Histories 395
11.8 Conclusions 398
Bibliography 399
12 Data Integrity and Microbiological Excursion Handling 401
David Roesti and Marcel Goverde
12.1 Data Integrity 401
12.2 General Concept for Microbiological Excursion 410
12.3 Considerations for Excursions 420
Bibliography 427
13 Rapid Microbiological Methods 429
Michael J. Miller
13.1 Introduction 429
13.2 The Current State of Microbiology Testing 431
13.3 Rapid Microbiological Methods 432
13.4 Applications for Non-sterile Pharmaceutical Drug Products 433
13.5 Technology Review 435
13.6 Validating Rapid Microbiological Methods 447
13.7 Developing a Business Case for Rapid Methods 454
13.8 Summary 455
Bibliography 456
14 Validation of a Rapid Microbiological Method for the Microbiological Examination of Non-sterile and Nonfilterable Drug Products, APIs, and Excipients 459
Oliver Gordon and David Roesti
14.1 Introduction 460
14.2 Method Validation 462
14.3 Suitability Test (Product-Specific Method Validation) 479
14.4 Discussion 483
14.5 Conclusion 486
Acknowledgments 486
Bibliography 487
15 An Ex-Regulator's View of the Microbiology QA/QC Functions in the US Pharmaceutical Industries 489
David Hussong
15.1 Foods, Drugs, and Quality 489
15.2 Why Microbes Confound a Census 492
15.3 Microbiological QA Decisions 494
15.4 Who Has Responsibility for Quality? 495
15.5 Product and Process Planning 496
15.6 Quality and Documentation in Drug Manufacturing 499
15.7 Summary 500
Bibliography 501
16 Practical Guide for Microbiological QA/QC of Non-sterile Pharmaceuticals Manufacturing for EU 505
Ina Bach
16.1 Introduction 505
16.2 General Requirements 506
16.3 Audit Assessment Tools of a Microbiological Laboratory 508
16.4 Regulatory Audits in the Microbiology Department 514
16.5 Conclusions 516
Bibliography 517
17 Which Microbiological Tests Can Better Be Performed In-house and What Can Be Easily Outsourced 519
Thomas Meindl and Ingo Grimm
17.1 Introduction 519
17.2 Advantages and Disadvantages of Outsourcing 522
17.3 Business Case and Hidden Costs 524
17.4 Hidden Costs 528
17.5 Quality Agreement Between the Contract Laboratory and the Requesting Company 529
17.6 Auditing Contract Laboratories 532
17.7 A Case History 532
17.8 Conclusions 535
Bibliography 536
Index 539
