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 Conducting Compliant
Investigations

Jeanne Moldenhauer
Editor

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ISBN: 978-1-942911-28-9
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Front matter.indd 2 3/16/2020 11:03:32 AM

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 CONTENTS

ABOUT  
THE  
EDITOR xi

1 INTRODUCTION 1
Jeanne Moldenhauer
Background1
Book Overview 7
Literature Cited 8

2 WHY INVESTIGATIONS AND

CORRECTIVE  ACTIONS  MATTER 9
James L.Vesper
A Different Industry 10
What Other Industries Have Done 11
High Reliability Organizations 15
What can we learn from others and apply to what
we do? 17
Conclusion18
References18
About the Author 20

3 BACKGROUND ON DEVIATIONS AND

INVESTIGATIONS 23
Jeanne Moldenhauer
What is a Deviation or Failure? 23
Planned Deviations versus Unplanned Deviations 27
Regulatory Basis for Deviations and Investigations 29
Why do an Investigation? 31
What is a Timely Investigation? 31

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 Tracking and Trending of Investigations 32
What is an Established Specification? 33
Literature Cited 34

4 PLANNING THE INVESTIGATION 35

Jeanne Moldenhauer
Introduction35
Expectations for a Compliant Investigation 36
Prerequisites for the Investigation 38
Planning the Investigation 40
Executing the Investigation 42
Documenting the Investigation 42
Conclusion42
Literature Cited 43

5 GETTING TO THE HEART OF THE

MATTER:  APPROACHING ROOT CAUSE
ANALYSIS 45
Tim Sandle
Introduction45
Root Causes Analysis 47
The Process 54
Examples of Root Cause Analysis Tools 54
Data Gathering 54
Successful Root Cause Analysis 88
Failures with Root Cause Analysis 88
Reporting Root Cause Analysis 92
Criticism of Root Cause Analysis 102
Conclusion103
References104
About the Author 107

6 PREPARING FOR AND CONDUCTING

SUCCESSFUL INVESTIGATIONS 109
INTRODUCTION109
Scott VW Sutton
Difficulties in Phase I Microbiological Investigations 111

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 Common Mistakes in Conducting the Phase I
Microbiology Investigation 115
Preparing for a Successful Investigation 119
Conducting a Successful Laboratory Investigation 123
Closing the Laboratory Investigation 130
Corrective Action Plan 131
Investigating Specific Test Failures 132
Water systems testing 137
References137

7 QUALITY CONTROL CHEMISTRY LABORA-

TORY INVESTIGATIONS 139
Paula J. Shadle
What is different about lab investigations in the
chem lab? 140
Compendial Methods in QC Chemistry – A Case Study142
QC Chem Lab investigations – Typical FDA (Food and
Drug Administration) Inspection Findings 144
Method by Method 151
Summary: Best Practices for QC Chemistry Lab
Investigations 174
Conclusion177
References177
About the Author 181
Acknowledgments182

8 PRODUCTION AND UTILITY SYSTEM

DEVIATION INVESTIGATIONS 183
Jeanne Moldenhauer
Abstract183
Examples of Deviations in the Production System 184
Examples of Deviations in the Utility System 184
Conducting a Strong Investigation 185
Assessing Other Affected Products 198
Establishing Corrective and Preventative Actions 198
Conclusion199
Literature Cited 200

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9 DOCUMENTATION ERROR INVESTIGATIONS
AND DATA INTEGRITY:  DATA INTEGRITY
ISSUES 201
Jeanne Moldenhauer
Abstract201
Background on Documentation 202
The Data Lifecycle 202
Why Record Keeping is Important 203
Typical Items to Record 204
What is Data Integrity? 205
What is ALCOA+? 205
The Importance of Ethics 207
The Importance of a Quality Culture 208
The Need for a Data Management System 209
Regulatory Expectations 217
Conducting an Investigation for Documentation
and/or Data Integrity 219
Considerations for Conducting Investigations for
Documentation Errors and/or Data Integrity 221
Conclusion223
Literature Cited 223

10 INVESTIGATING STERILITY TEST FAILURES 227

Tim Sandle
Introduction227
Sterility Testing 229
Investigation Procedure 232
Immediate Actions 232
Conducting Investigations 234
Laboratory Investigation 234
Manufacturing Investigation 238
Sterility Test and Process Area Link 243
Re-testing244
Concluding Sterility Test Failure Investigations 244
Follow-up Actions 245
Sterility Test Failure Investigation Case Study 246
Investigation Areas 249
Summary264
References265
About the Author 268

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11 INVESTIGATING MEDIA FILL FAILURES 269
Jeanne Moldenhauer
Introduction269
Regulatory Background for Media Fills (Process
Simulation Tests) 270
Acceptance Criteria for Media Fills 312
Investigating Media Fill Failures 320
Corrective and Preventative Actions 324
Conclusion324
Literature Cited 325

12 LEVERING RISK ASSESSMENTS IN

ENVIRONMENTAL MONITORING
INVESTIGATIONS 329
Karen Ginsbury
Introduction329
Risk Management and the Quality System 331
Environmental Monitoring – Proactive Quality
Management 336
Data Trending 340
Microbiological Data Deviations and Environmental
Monitoring Excursions 340
Knowledge Management and Lessons Learned 360
References363
About the Author 363

13 MICROBIOLOGICAL OOS AND OOT

INVESTIGATIONS IN NON-STERILE
PHARMACEUTICAL MANUFACTURING – A
CONTRACT LAB PERSPECTIVE 365
Rick Jakober
Introduction365
Types of OOS and OOT  367
OOS, OOT, and Objectionable Microorganisms 369
Investigations371
Case Study 374
References381
About the Author 382

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14 COMPLAINT INVESTIGATIONS 385
Jeanne Moldenhauer
Introduction385
Regulatory Basis for Complaints and Complaint
Investigations 386
Developing a Systematic or 4-Step Approach for
Complaint Handling and Investigations 396
A Procedure for Handling Complaints 400
Conclusion410
Literature Cited 410

15 INVESTIGATING STABILITY FAILURES

413
Jeanne Moldenhauer
Background413
Typical Stability Testing  414
Stability Failures 421
Batteries438
Other Failures 439
Conclusion439
Literature Cited 439

16 ANALYZING PRODUCT IMPACT IN

INVESTIGATION REVIEW 443
Jeanne Moldenhauer
Abstract443
Background443
Classification of Deviations 445
It Is All About the Risk 446
Understanding the Product Risks 447
Understanding the History of the Deviation 448
Understanding How the Product is Used 448
Understanding the Impact of the Deviation Upon the
Patient449
Understanding the Types of Patients that Use this
Product 449
Other Investigation Concerns 450
Quality Determines the Final Batch Disposition 451
Conclusion451

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17 HOW TO WRITE A GOOD INVESTIGATION
REPORT 453
Jeanne Moldenhauer
Introduction453
Background454
The Ten Commandments of Investigations 454
The Investigation Report 455
Conclusion468
Literature Cited 468

18 TRACKING AND TRENDING INVESTIGATIONS   471

J. Edgar Guerzon
Introduction471
What’s causing all this pain? 472
Root Cause Identification 475
Historical Analysis 476
Purpose477
Conclusion479
About the Author 479

APPENDIX: AUTOMATED SYSTEMS FOR TRACK-

ING AND TRENDING INVESTIGATIONS 481
Jeanne Moldenhauer
Abstract481
Commercial Automated Systems 481
Precautions482
Literature Cited 484

INDEX 485

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