Pharmaceutical Microbiological Quality Assurance and Control Practical Guide for Non-Sterile Manufacturing

Relying on practical examples from the authors’ experience, this book provides a thorough and modern approach to controlling and monitoring microbial contaminations during the manufacturing of non-sterile pharmaceuticals.

• Offers a comprehensive guidance for non-sterile pharmaceuticals microbiological QA/QC
• Presents the latest developments in both regulatory expectations and technical advancements
• Provides guidance on statistical tools for risk assessment and trending of microbiological data
• Describes strategy and practical examples from the authors’ experience in globalized pharmaceutical companies and expert networks

David Roesti, PhD, works at Novartis Pharma AG in Stein, Switzerland, and is responsible for defining the microbial control strategy at the site and is a global subject matter expert in microbiology for the Novartis group. He is also is an elected member of the General Chapters Microbiology Expert Committee of the Unites States Pharmacopoeia 2015–2020 revision cycle.

Marcel Goverde, PhD, runs MGP Consulting GmbH for consulting, training and project management in GMP-relevant areas with a focus on microbiology, hygiene and deviation management. He is the Swiss expert in the EDQM group for Modern Microbiological Methods since 2003, which was then integrated into Group 1 (Microbiological Methods and Statistical Analysis) in 2015.

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 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

4.5 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 Stärk

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

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