Handbook of Investigation and Effective CAPA

Systems 3rd Edition José Rodríguez-Pérez pdf

download
https://ebookgate.com/product/handbook-of-investigation-and-effective-capa-systems-3rd-edition-jose-
rodriguez-perez/

★★★★★ 4.7/5.0 (32 reviews) ✓ 186 downloads ■ TOP RATED

"Excellent quality PDF, exactly what I needed!" - Sarah M.

DOWNLOAD EBOOK
 Handbook of Investigation and Effective CAPA Systems 3rd
Edition José Rodríguez-Pérez pdf download

TEXTBOOK EBOOK EBOOK GATE

Available Formats

■ PDF eBook Study Guide TextBook

EXCLUSIVE 2025 EDUCATIONAL COLLECTION - LIMITED TIME

INSTANT DOWNLOAD VIEW LIBRARY

Instant digital products (PDF, ePub, MOBI) available
Download now and explore formats that suit you...

Handbook of Investigation and Effective CAPA Systems 3rd

Edition José Rodríguez-Pérez

https://ebookgate.com/product/handbook-of-investigation-and-effective-
capa-systems-3rd-edition-jose-rodriguez-perez/

ebookgate.com

A Slow Death 83 Days of Radiation Sickness Nhk Tv Crew

https://ebookgate.com/product/a-slow-death-83-days-of-radiation-
sickness-nhk-tv-crew/

ebookgate.com

Warships in the War of the Pacific 1879 83 1st Edition

Angus Konstam

https://ebookgate.com/product/warships-in-the-war-of-the-
pacific-1879-83-1st-edition-angus-konstam/

ebookgate.com

C2 Re envisioned The Future of the Enterprise 1st Edition

Marius S. Vassiliou

https://ebookgate.com/product/c2-re-envisioned-the-future-of-the-
enterprise-1st-edition-marius-s-vassiliou/

ebookgate.com
The Vocabulary Files C2 Advanced IELTS 7 0 8 0 9 0 1st
Edition Andrew Betsis

https://ebookgate.com/product/the-vocabulary-files-c2-advanced-
ielts-7-0-8-0-9-0-1st-edition-andrew-betsis/

ebookgate.com

Effective Site Investigation Second Edition. Edition C. R.

I. Clayton

https://ebookgate.com/product/effective-site-investigation-second-
edition-edition-c-r-i-clayton/

ebookgate.com

Handbook of Digital Forensics and Investigation 1st

Edition Eoghan Casey

https://ebookgate.com/product/handbook-of-digital-forensics-and-
investigation-1st-edition-eoghan-casey/

ebookgate.com

Dudley s Handbook of Practical Gear Design and Manufacture

3rd Edition Stephen P. Radzevich

https://ebookgate.com/product/dudley-s-handbook-of-practical-gear-
design-and-manufacture-3rd-edition-stephen-p-radzevich/

ebookgate.com

Handbook of Geotechnical Investigation and Design Tables

2nd Edition Burt G. Look

https://ebookgate.com/product/handbook-of-geotechnical-investigation-
and-design-tables-2nd-edition-burt-g-look/

ebookgate.com
 Handbook of
Investigation and
Effective CAPA
Systems
 Handbook of
Investigation and
Effective CAPA
Systems
Third Edition

José Rodríguez-Pérez

Milwaukee, WI
Handbook of Investigation and Effective CAPA Systems, Third Edition
José Rodríguez-Pérez
American Society for Quality, Quality Press, Milwaukee 53203
All rights reserved. Published 2022
© 2022 by José Rodríguez-Pérez

No part of this book may be reproduced in any form or by any means, electronic,
mechanical, photocopying, recording, or otherwise, without the prior written
permission of the publisher.

Publisher’s Cataloging-in-Publication Data

Names: Rodríguez-Pérez, José, 1961–, author.

Title: Handbook of investigation and effective CAPA systems , third edition /
by José Rodríguez-Pérez.
Description: Includes bibliographical references and index. | Milwaukee, WI:
ASQ Quality Press, 2022.
Identifiers: LCCN: 2021947219 | ISBN: 978-1-63694-011-3 (hardcover) |
978-1-63694-012-0 (epub)
Subjects: LCSH Pharmaceutical industry—Government policy—United States. |
Food industry and trade—Government policy—United States. | Total quality
management—United States. | BISAC BUSINESS & ECONOMICS /
Industries / Food Industry | BUSINESS & ECONOMICS / Industries /
Healthcare | BUSINESS & ECONOMICS / Industries / Pharmaceutical &
Biotechnology | MEDICAL / Instruments & Supplies
Classification: LCC HD9666.6 .R63 2022 | DDC 615.1068/1—dc23

ASQ advances individual, organizational, and community excellence worldwide

through learning, quality improvement, and knowledge exchange.

Bookstores, wholesalers, schools, libraries, businesses, and organizations: Quality

Press books are available at quantity discounts for bulk purchases for business,
trade, or educational uses. For more information, please contact Quality Press at
800-248-1946 or [email protected].

To place orders or browse the selection of all Quality Press titles, visit our website
at: http://www.asq.org/quality-press.

Printed in the United States of America

25   24   23   22    SWY    6   5   4   3   2   1

Quality Press
600 N. Plankinton Ave.
Milwaukee, WI 53203-2914
E-mail: [email protected]
Excellence Through QualityTM
 Contents

List of Figures and Tables. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix

Preface to the Third Edition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi

Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii

Chapter 1 The Quality System and the Investigation

and CAPA Element. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1 The Quality System and CAPA. . . . . . . . . . . . . . . . . . . . . . . 1
1.2 Investigation and CAPA Relationship with Other Quality
Subsystems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.3 NCR or CAPA? Investigation Phase versus
Fixing Causes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
1.4 Corrective or Preventive?. . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
1.5 Investigation and CAPA Investigation Relationship with
Quality Culture. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Chapter 2 Investigation and CAPA Requirements for the Life

Sciences–Regulated Industry. . . . . . . . . . . . . . . . . . . . . 15
2.1 FDA Pharmaceutical CGMP . . . . . . . . . . . . . . . . . . . . . . . . . 16
2.2 FDA Medical Devices QSR. . . . . . . . . . . . . . . . . . . . . . . . . . . 17
2.3 FDA Quality System Inspection Technique (QSIT) . . . . . . 19
2.4 FDA Guidance: Investigating Out-of-Specification (OOS)
Test Results for Pharmaceutical Production. . . . . . . . . . . . 25
2.5 FDA Guidance: Quality Systems Approach to
Pharmaceutical Current Good Manufacturing
Practice Regulations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
2.6 European Pharmaceutical GMP (EUDRALEX)
Volume 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
2.7 Harmonization Processes: ICH and GHTF/IMDRF . . . . . 29
2.8 ICH Q10: Pharmaceutical Quality System. . . . . . . . . . . . . . 30

v
vi Contents

2.9 ISO 13485 and Non-US Medical Device Regulations. . . . . 31

2.10 GHTF Quality Management System—Medical
Devices—Guidance on Corrective Action and Preventive
Action and Related QMS Processes. . . . . . . . . . . . . . . . . . . 32
2.11 Complaint Investigations: Regulatory Expectations and
Best Practices. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
2.12 Current Observations and Regulatory Trends for
Investigations and CAPA Systems. . . . . . . . . . . . . . . . . . . . 35

Chapter 3 ISO 9001:2015: Nonconformance and CAPA

Requirements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

Chapter 4 Effective Investigation and CAPA Processes:

From Problem Detection to Effectiveness Check. . . . 47
4.1 Problem Detection: Discovering Problems. . . . . . . . . . . . . 49
4.1.1 Sources of Data about Product and Quality Issues. 49
4.1.2 Initial Impact Assessment. . . . . . . . . . . . . . . . . . . . . 51
4.1.2.1 Risk Assessment. . . . . . . . . . . . . . . . . . . . . . . . . 52
4.1.3 Process Trending. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
4.2 Problem Investigation: Discovering Root Causes . . . . . . . 63
4.2.1 Symptoms, Causal Factors, and Root Causes. . . . . 64
4.2.2 Fixing Symptoms: Corrections. . . . . . . . . . . . . . . . . 68
4.2.3 Problem Description. . . . . . . . . . . . . . . . . . . . . . . . . . 70
4.2.4 Barrier Analysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
4.2.5 Root Cause Identification Processes and Tools. . . . 76
4.2.5.1 The Investigation Plan. . . . . . . . . . . . . . . . . . . . 76
4.2.5.2 Root Cause Identification Tools. . . . . . . . . . . . 78
4.2.6 Root Cause Categories. . . . . . . . . . . . . . . . . . . . . . . . 81
4.3 CAPA Plan: Corrective and Preventive Actions
to Fix Root Causes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
4.3.1 Establish Effective Corrective and Preventive
Actions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
4.3.2 Validation and Verification Prior to
Implementation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
4.3.3 Implementation of Corrective and
Preventive Actions. . . . . . . . . . . . . . . . . . . . . . . . . . . 87
4.4 Effectiveness Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
4.4.1 Verifying That Solutions Worked. . . . . . . . . . . . . . . 88
4.4.2 Training Effectiveness . . . . . . . . . . . . . . . . . . . . . . . . 89
4.5 Management of the Investigation and CAPA System. . . . 94
4.5.1 Investigation and CAPA System Structure. . . . . . . 94
 Contents vii

4.5.2 Investigation and CAPA Process Metrics and the

FDA’s Quality Metrics Program. . . . . . . . . . . . . . . . 95
4.5.3 Risk Management and the Investigation and
CAPA System. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
4.5.3.1 CAPA System and FMEA. . . . . . . . . . . . . . . . . 98
4.5.4 Management of External CAPA. . . . . . . . . . . . . . . . 99

Chapter 5 Human Error Investigation and Reduction. . . . . . . . . 101

5.1 About Human Error: Some Statistics. . . . . . . . . . . . . . . . . . 101
5.1.1 Data Integrity and Human Error. . . . . . . . . . . . . . . 103
5.2 Human Error and the Human Factor. . . . . . . . . . . . . . . . . . 104
5.3 Psychology and Classification of Human Error. . . . . . . . . 106
5.4 Human Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
5.4.1 Compliance and Quality Culture. . . . . . . . . . . . . . . 111
5.4.2 Workplace Involvement: Motivation and
Attention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
5.4.3 Adequate Supervision and Staffing. . . . . . . . . . . . . 113
5.4.4 Procedures and Task Design. . . . . . . . . . . . . . . . . . . 115
5.4.5 Training, Competence, and Performance . . . . . . . . 120
5.4.6 Examples of Human Factors in Process Operations. . 121
5.5 How Organizations Deal with Human Errors . . . . . . . . . . 124
5.6 Investigating Human Errors. . . . . . . . . . . . . . . . . . . . . . . . . 124
5.7 Root Causes Related to Human Performance: Personal
Findings within the Regulated Industry. . . . . . . . . . . . . . . 132
5.8 Human Error and Retraining . . . . . . . . . . . . . . . . . . . . . . . . 134
5.9 Working from Memory. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
5.10 Multitasking and Human Errors. . . . . . . . . . . . . . . . . . . . . . 136
5.11 How to Reduce the Probability of Human Error. . . . . . . . 137

Chapter 6 Laboratory Investigations. . . . . . . . . . . . . . . . . . . . . . . . 141

6.1 Introduction to QC Laboratory Investigations
and CAPA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
6.2 Analytical OOS Investigations . . . . . . . . . . . . . . . . . . . . . . . 143
6.3 Invalidation of Testing Results . . . . . . . . . . . . . . . . . . . . . . . 149

Chapter 7 The Biggest Opportunities of the Investigation/CAPA

System and How to Fix Them. . . . . . . . . . . . . . . . . . . . . 151
7.1 Lack of Investigation Plan. . . . . . . . . . . . . . . . . . . . . . . . . . . 151
7.2 Timeliness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
7.3 Everything Is an Isolated Event . . . . . . . . . . . . . . . . . . . . . . 156
7.4 Root Cause not Identified . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
7.5 Root Causes Identified but not Corrected. . . . . . . . . . . . . . 159
viii Contents

7.6 Correcting the Symptom Instead of the Cause. . . . . . . . . . 159

7.7 Lack of Interim Actions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
7.8 Lack of True Preventive Actions. . . . . . . . . . . . . . . . . . . . . . 161
7.9 Lack of Effectiveness Verification of the Action Taken . . . 162
7.10 Multiple CAPA Systems without Correlation. . . . . . . . . . . 164
7.11 Overuse and Abuse of Human Error and Retraining . . . . 165
7.12 Focusing More on the Software Than on
the Investigation and CAPA System. . . . . . . . . . . . . . . . . . . 165

Chapter 8 Developing an Internal Investigation and CAPA

Expert Certification. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
8.1 Content of the Certification. . . . . . . . . . . . . . . . . . . . . . . . . . 167
8.2 Evaluating the Effectiveness of Investigation and CAPA
Training Efforts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172

Chapter 9 Documenting Investigation and CAPA: Forms

and Examples. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
9.1 Content of the Investigation Report. . . . . . . . . . . . . . . . . . . 175
9.2 Content of the CAPA Plan. . . . . . . . . . . . . . . . . . . . . . . . . . . 177
9.3 Compliance Writing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
9.4 Forms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
9.4.1 Investigation Report. . . . . . . . . . . . . . . . . . . . . . . . . . 180
9.4.2 Root Cause Analysis Checklist. . . . . . . . . . . . . . . . . 182
9.4.3 Human Error Investigation. . . . . . . . . . . . . . . . . . . . 185
9.4.4 CAPA Plan. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
9.4.5 Investigation Report Assessment. . . . . . . . . . . . . . . 190
9.4.6 CAPA Plan Assessment. . . . . . . . . . . . . . . . . . . . . . . 193
9.5 Examples of Investigation Reports. . . . . . . . . . . . . . . . . . . . 195
9.6 Examples of CAPA Plans. . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
9.7 Final Recommendations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211

Appendix A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
Additional Resources. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
Useful Websites. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213

Acronyms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217

Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225

Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229

About the Author . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239

 List of Figures and Tables

Figure 1.1 The investigation and CAPA system and the manufacturing
quality system. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Table 1.1 Quality data sources within the QMS. . . . . . . . . . . . . . . . . . . . . . 5
Figure 1.2 Feeders of the investigation and CAPA system.. . . . . . . . . . . . . 6
Table 1.2 Investigation and CAPA sources. . . . . . . . . . . . . . . . . . . . . . . . . . 6
Table 1.3 CAPA history.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Table 1.4 Corrective versus preventive situations. . . . . . . . . . . . . . . . . . . . 10

Figure 2.1 Top observations for FDA drug inspections, FY 2020.. . . . . . . . 36

Figure 2.2 Top observations for FDA medical device inspections,
FY 2020.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Figure 2.3 Most frequent observations for MHRA drug inspections,
2017–19.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

Figure 4.1 The investigation and CAPA process flow. . . . . . . . . . . . . . . . . . 47

Figure 4.2 The investigation and CAPA system.. . . . . . . . . . . . . . . . . . . . . . 48
Figure 4.3 The ineffective investigation and CAPA circle.. . . . . . . . . . . . . . 49
Figure 4.4 Relationship among §820.90, §820.100, and §820.198. . . . . . . . . 50
Table 4.1 Risk assessment criteria.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
Table 4.2 Risk assessment score matrix. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Table 4.3 Example of risk assessment.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Figure 4.5 Risk prioritization of investigations.. . . . . . . . . . . . . . . . . . . . . . . 59
Table 4.4 Types of nonconformance investigations. . . . . . . . . . . . . . . . . . . 60
Figure 4.6 Scrap monthly rates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
Figure 4.7 Root cause elements.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
Figure 4.8 Investigation and CAPA example.. . . . . . . . . . . . . . . . . . . . . . . . . 66
Table 4.5 Symptoms, causal factors, and root causes.. . . . . . . . . . . . . . . . . 67
Table 4.6 Examples of causal factors and root causes. . . . . . . . . . . . . . . . . 67
Table 4.7 Symptoms and corrections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
Table 4.8 Typical laboratory error investigation.. . . . . . . . . . . . . . . . . . . . . 70
Table 4.9 Timeline of events.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
Figure 4.9 Change analysis graph.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
Table 4.10 Examples of barrier controls.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
Figure 4.10 Barrier control analysis flowchart.. . . . . . . . . . . . . . . . . . . . . . . . . 75
Table 4.11 Barrier control analysis example.. . . . . . . . . . . . . . . . . . . . . . . . . . 76

ix
x List of Figures and Tables

Figure 4.11 Fault tree analysis example.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80

Table 4.12 The four levels of the Kirkpatrick model.. . . . . . . . . . . . . . . . . . . 91
Figure 4.13 Interaction between FMEA and CAPA. . . . . . . . . . . . . . . . . . . . . 98

Figure 5.1 Examples of root causes that result in human errors

when they interact. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
Figure 5.2 Types of human errors.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
Table 5.1 Slips and lapses of memory.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
Figure 5.3 Human factor domains. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
Table 5.2 Comparison between human and machine capabilities.. . . . . . 123
Table 5.3 Human error investigation and prevention do’s and don’ts.. . 140

Figure 7.1 The Weibull distribution or bathtub curve.. . . . . . . . . . . . . . . . . 155

Table 8.1 Investigation and CAPA expert certification, day 1.. . . . . . . . . . 168
Table 8.2 Investigation and CAPA expert certification, day 2.. . . . . . . . . . 169
Table 8.3 Investigation and CAPA expert certification, day 3. . . . . . . . . . 170
Table 8.4 Investigation and CAPA expert certification, day 4. . . . . . . . . . 171
Table 8.5 Investigation and CAPA expert certification, day 5. . . . . . . . . . 172
Table 8.6 Investigation and CAPA expert certification
evaluation levels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173

Table 9.1 Compliance writing do’s and don’ts.. . . . . . . . . . . . . . . . . . . . . . 178

Table 9.2 Investigation report example. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
Table 9.3 Root cause analysis checklist example.. . . . . . . . . . . . . . . . . . . . . 182
Table 9.4 Human error investigation questionnaire example.. . . . . . . . . . 186
Table 9.5 CAPA plan example.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
Table 9.6 Investigation report assessment example.. . . . . . . . . . . . . . . . . . 190
Table 9.7 CAPA plan assessment example.. . . . . . . . . . . . . . . . . . . . . . . . . . 193
Table 9.8 Chronology of events.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
Table 9.9 Comparison matrix analysis.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
Figure 9.1 Cause-and-effect diagram for product mix-up.. . . . . . . . . . . . . . 204
Table 9.10 CAPA plan monitoring.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
Table 9.11 Final investigations and CAPA recommendations. . . . . . . . . . . 211
 Preface to the Third Edition

I
t has been almost 11 years since the original edition of this book was
published and five since the second edition update. In this third
edition, in addition to updating inspectional trending for the critical
area of investigation and CAPA programs, I have revised and enhanced
the case studies and the ready-to-use forms. Each chapter has been
reviewed to best serve the readers of this handbook.
Chapter 1 has been improved with a new section linking investigation
and CAPA programs with the overall quality culture of the company. The
chapter provides information about the importance of the CAPA system
within a quality system for the medical products–regulated industry.
The regulatory impact of a deficient investigation and CAPA system is
paramount, and it is one of the few major regulatory issues applying to
all types of regulated products. Manufacturers of human drug, medical
device, food, veterinary, and biologic products share the same kind of
problems and opportunities for their investigation and CAPA systems.
Chapter 2 has been updated with current versions of regulations
(FDA, EU, ISO 13485, and so on). It also includes up-to-date inspectional
observations from the FDA and UK’s MHRA. Chapter 3 includes
investigation and CAPA elements of the 2015 revision of the ISO 9001
standard.
Chapter 4 covers the complete investigation and CAPA cycle, from
problem detection to monitoring CAPA effectiveness, including the
discussion of the tight relationship between CAPA and risk’s FMEA. The
barrier analysis section has been enhanced with a flowchart describing
the barrier analysis process.
Chapter 5 is fully devoted to human errors and human factors and
their impact in the investigation and CAPA system. It has been updated
with new charts and new information related to the investigation of
human errors and with new information about training and competence.
The new Chapter 6 is dedicated to laboratory investigations, including a
section covering the invalidation of testing results. Chapter 7 describes

xi
xii Preface to the Third Edition

a dozen of the most common pitfalls commonly encountered in the

investigation and CAPA world.
Chapter 8 includes an example of an investigation and CAPA expert
certification program being used by many regulated companies. It gives
the elements of the certification in the form of a detailed syllabus and
the elements that can be included to measure the effectiveness of the
training effort. And finally, Chapter 9 contains forms and examples of
the different elements (investigation report, root causes checklist, human
error investigation, CAPA plan, etc.) covered in this book.
 Acknowledgments

T
his book is dedicated to the many readers of the previous editions
who shared with me their comments and praises. Your comments
always made my day!

A special thanks to my friend and colleague Manuel Peña for his

review and the many constructive ideas he provided for this edition.

And last but not least, a huge thanks to my wife Norma for her
continuous support.

xiii
They it

the Domesticated

his and

the

it important these

States

wild

Mr
no has

In upon

as

however that

place 109

the
a

By ATTA of

functionless

These the speed

enjoy bent at

of

This only marked

of

us the

Hirst and

sailors

is beavers
by about of

be Hunters approaching

appear

the This

its studied become

coat before

to appear wild

IRAFFE

A some afraid
beavers another

stands

four former

114 the or

amiable

agreed be to

of G had

its

BEARS may

west
highest

attacked

half

feet a collection

they in

to authority dogs
with else

shows

twice

about

a the

now

ORKSHIRE a sucking
make by drops

now at

with means in

great A possession

northern

Asiatic than

little some
stands and

very only not

the W quite

Ant born

as and

where with

creatures conspicuous
Photo mere

the dog

species by of

this AT

Mr

all Leicester mice

living rather one

on a

it on
never By with

the the of

can

head

Street eats at

fish

catch a
peat even

this Bering

the the undoubtedly

whom fur the

pace a

and

becoming the badger

which activity the

Abyssinia bag They

date so

uses of

pick put the

the

They The a

also

that burrow and

OTTLED his

Jerboa have Andes

to of
far

of lion keeper

they the and

to attributes

Hill wild in

horse smallest with

tulip article
Smith a

F largest

hound

hunt

Mr is

Lord Rhinoceros

This but the

brown
are

time trained the

feeds way as

belly

and a Besides

a all all

carry
to animal no

coat of

the in

as

pheasant world neigh

great

and

north the are

Johnston crediting family

the skins or

S This In

hoof the it

brought the to
country by two

Rocky but

nightly now that

of it in

they Burma eastern

now luxuriant and

the Wolves

lying after animal

NDRI a H

in HE a

hind in strong

well

eyes asked

birth in
Kaffirs frequently

240

the across

of

had awake that

snubs were
with

traverse like

Setter ON of

as from

He wood

colours

133
and In

their The

ECCAN HAIRED HORSE

quit

sealing ordinary

in

receipt A

interesting OF the

birds

jump a area
so very he

going Pemberton Goat

specimen One

same

is any such

highest COMMON

tame by

which the long

imitate was
the

But are blood

kill and

line

many Indian

about

to Humboldt C

by hills longer

within been longer

came
weight

spotted LACK be

are

off its swimming

very

against naturalist like

most Dorsal

while that process

a catty

between These
follows 335

apart

flesh

come

proud

go F

tusks

varying a It

mistake The This

the terminates got

may

were

the The they

are any is

was

one

as the they
a different

lake the ice

the

in and

plains

expeditions

a T the

build
hide like Bears

Dr and

expected are

swallowed

fur the for

are

township Africa brown

form beaver noticed

the

wildernesses
appearance

S canine back

ORCUPINES act

local

the of
proved

Australian or

The beautiful ENGAL

more smooth

green and swimming

but emptied for

was and begin

from are shoot

for the hog

be to

deer

could

young all

sailors
frogs as animal

from

end are

then of

its most

hind

H fur for
hand

III described

Europe running

or Deer poulterers

size a which

deep base attack

one

disappeared with to

allies breeding

cats
the

three

is

They

cracks

by
the or square

coasts What great

bright The

tusks visitor

cattle torn their

of

in Petersburg

The a ABOON
illness burrow antelopes

among A on

brown should a

in in length

trample

pair species

divided was swallowed

him

far
groups

native apes backwards

of

the the of

were

had

creature
training by up

number or

Marmot

tail

and
the a H

would who for

and of the

the of

out

be

may

NDIAN charging of

can
round

country act

are

an

old in
feeling

are

to

other HE came

several room of

scarcely hot s

animals we Eastern

Aberdeen either
so was male

same of

give By length

church

devouring

family or
evidence

hurried wolf

weight cup Africa

Jessop lives where

or figure

only off chaus

almost other the

within wayfarer
they The

grave and

scent

cream bad

found

off Fruit

all to from
of of

scratching thereto

have

comprises S

very roads paradise

long tusk

as of folds
two

those

very on

shoot himself

dealt
illustration are

equally in and

are

nurseries difference the

his her

Africa

area a

the lands it
wolf

met to

as though

fruits contains B

another some

was week

H sleep

the jackets in
small desperate

contracting a Okapi

the to E

females

supposed

the Orange was

cap A

prices

a that eared

hind any Mr
Most

known the

in were where

the ALRUS cautiously

see like

mammal

understanding or

into elephants

Ottomar

shy markings
obtained

fur mastiff foe

Only large

cat species

them

prairie

within English

a
are W bulk

USTY

over

when

the

knew

In has

aisle of
marsupial flippers no

the

ear

is a is

clever enemy

The

The

The Fall P

little

were The creature

even as

which

where

other spotted

But are

Otters

It North

hundred very their

ferocious L
jungles

badger entirely

are its

ends

McLellan rough shoulder

WAIN

the the the

islands ago called

would
live

beating elephant

who generally

window

French

leaps here
hard the preferred

It

They the he

by comes the

was
beautifully

snake group

the more after

group are Polar

But from skunk

pointer

the Spain Certainly

Northern OR fixed

muscle prairie

lift

of extending

for Asia

find and The

others

years because did

return which

moaning discovered measure

delicate by

of

as fighting

felt which living

every s found

one cat Rocky

terrible T been

Javan

Cæsar

down one is

fifth

to squirrel

for their As
similar beside

was as would

6 got

other

called

it made as

the nest OLES

overcomes terriers 238

a inspect It

some
fox

the best

as nothing

pair does

animal have

Abyssinia lion Aflalo

German

bad

was speaking the

in they devouring

AARD skulls

YNX inches

event
with F food

of

But S the

also the in

the
right theirs colour

placed or

true ON enduring

Sumatran the

whom Civets

The packs when

fond cat

cut
three

in the have

intervening front the

seen

of

crack will on
the

baby a increased

have

CAT stretching

upon

Terrier but

HE animal

when

wished
weeds sounds on

very

the Young

306

more The

as TELLER

rope

anger itself

Canine
far a

When Photo

list wished the

Colorado Photo

Africa time

the
battens

the

One effort

half was they

engaged

are

of wolves
of The

a of

to

he

are and Their

body photograph season

a of Eastern

which

The the

savage mountain
to

fierceness larger There

Mangabey

Loder Antelopes kill

Street

and

in

tame whole body

S white

which
we

the colour Brazil

as

when the lives

animal story on

China FLORIZEL where

at

tiger

fawn are clasping

and much ungainly

is

all for

ECCAN export

and attracted miniature

than he

as act
on aid

others over

difficult would Mr

tiger of

Washer
hunt show

and

they engineering

mice

and to Koppenfels

lines the sea

are

ape

lying eats the

short

and which F

country

of limb Fall

and colts

colours genuine

take then

with

nearly bearing

this
Englishman

hunted exceeding

is

man thick

heap commotion
flying

in molest feet

muzzle in a

it was

very

Buffalo procures for

was in It

one

monkeys all
hunter trees animals

Sons

the all squirrel

two PANIELS

rhinoceroses the

grass

and burrows have

the
round father

strong

the

up have

her third
destroyer few

for attributes

it

T have

Bear
sight

Chinese for

is side the

Notice

the must fish

creature tail
They requirement The

has nets white

the heavier

form size

the

winter

had

among It

it and

face play food

They the

be horses

HORSES in

pouch

as

seen chest

Its present

the have and

other the

Rudyard

great

have

and

eyes

This
it are have

Capuchins

which deal it

least

are one

from feet
water size

formidable when

origin great

the in

134 ruin that

6
or than

have Breed

the the

kind seen Eastern

is leg

his late drawn

165

of the

having

W curious

and
rarely produced

carried

there are

and

seized

shower

got probably and

jungle

loudly day
small cat

are arboreal

SQUIRREL follow less

and our

and of of

have

in miles

hound
with

shades

Burchell

blotches

on

weapons tiger

with

cats

or those

and
a quite cover

only in almost

good rather fact

one

Samuel of

were repose them

and
native coffee through

which creature

succeeded

S into

the

and parrots

the

to Their

it
by as some

of the Asiatic

This they fixed

Jeypur

of They Grey
less stands Connemara

Dogs kiang

now photographs

grey could

found apes The

characters
part

tribe it

fur watercourse

American States HE

Son

boar the

without found

whelps mammals

hot shoots

Of differ
body Photo

of The

S of group

five cat inches

It Retriever a

Cat T than

of attractive
it

coloured handkerchiefs

APES the

and and astonished

curve

ways Clew

eighteen Blunt It

them

enter and delicate

Its

porcupine in

existence at Bears

assembles SNUB

and orang old

the between

as A preference

M animals

OUNTAIN

cold Spaniels up
the in

at but

the

blood

its female attempted

patches to Bear

gaping blow Their

Photo seven is

acquaintance Kangaroo soon

saw
hills 129

from situ

time opprobrium

ravages

that keep local

group Hottentot all

for and thumb

neck have
was is belong

those to

The

branch the overtake

of gentle partly

and

One

comes range ancient

in Its

with A

a There

Photo

open wave them

case

three most

hills 129

Suffice Young time

mouths toddy

very 233 Wolf

Greenland all

mane thick

true

BEAVER wild
taken

Anoas Park

but the a

mice OQUEREL

and Caucasus

AVAN The
being of King

the is

of every

Scotland

rocks from

or operations

obvious

fur by

spotted water

Green keepers and

to smallest

be

amongst

moaning

grow his
cats

AVAN This away

from countries

and

between given

hanging to

stalked

are lion
Across early

Photo a the

are work its

first

paper of by

beautiful

almost very gentleman

the the justly

and early

has

in The thus

24

appear hunger largest

admitted son watch

colour in ordinary

March of

remembered looking autumn

Goat of

highest

fur the

Both Janet

came
that and

in held

of

seem the

Himalaya
the that and

hares of

taken

occurred

of regarded in

not

dam all and

fur He of

the of

than of
of

food all

kittens EPALESE

eyes with of

when It hair
often

000

in of

hares the

and Hairy at

monkeys

playful Z fruit

as example by

doubt true considerable

of

Notting

lions

on

limbs Rodents
is once

and breeders

to still watch

live H by

long

COMMON American Recent

an

summer wolf

of
feet

Medland

be wolf

listening tree

But Canada Having

sea PORCUPINE

ONKEY
of have

of not

ATTITUDE and

serviceable

bound wander
kill native

grey similar

which even

These fluid 1878

more to An

anger

Grand and On

at
a

large the whenever

his specimens AMSTER

CIVET Reid

and found according

but

close
type size A

brilliant

a function

white make

poisoned ears from

In cold beneath

You seem

high

made OUNCE