1、CAPA for the FDA-Regulated IndustryAlso available from ASQ Quality Press:The FDA and Worldwide Quality System Requirements Guidebook for Medical Devices, Second Edition Amiram Daniel and Ed KimmelmanDevelopment of FDA-Regulated Medical Products: Prescription Drugs, Biologics and Medical Devices Elai
2、ne WhitmoreSafe and Sound Software: Creating an Efficient and Effective Quality System for Software Medical Device Organizations Thomas H. FarisRoot Cause Analysis: Simplified Tools and Techniques, Second Edition Bjrn Andersen and Tom FagerhaugMastering and Managing the FDA Maze: Medical Device Over
3、view Gordon HarnackRoot Cause Analysis: The Core of Problem Solving and Corrective Action Duke OkesGet It Right: A Guide to Strategic Quality Systems Ken ImlerThe Internal Auditing Pocket Guide: Preparing, Performing, Reporting and Follow-up, Second EditionJ.P. RussellMeasurement Matters: How Effect
4、ive Assessment Drives Business and Safety Performance Brooks Carder and Patrick RaganLean Kaizen: A Simplified Approach to Process Improvements George Alukal and Anthony ManosThe Certified Manager of Quality/Organizational Excellence Handbook: Third Edition Russell T. Westcott, editorEnabling Excell
5、ence: The Seven Elements Essential to Achieving Competitive Advantage Timothy A. PineTo request a complimentary catalog of ASQ Quality Press publications, call 800-248-1946, or visit our Web site at http:/www.asq.org/quality-press.CAPA for the FDA-Regulated IndustryJos Rodrguez-Prez ASQ Quality Pres
6、s Milwaukee, WisconsinAmerican Society for Quality, Quality Press, Milwaukee, WI 53203 2011 by ASQ All rights reserved. Published 2010. Printed in the United States of America.16 15 14 13 12 11 10 5 4 3 2 1Library of Congress Cataloging-in-Publication DataRodrguez Prez, Jos, 1961- CAPA for the FDA-r
7、egulated industry / Jos Rodrguez Prez. p. cm. Includes bibliographical references and index. ISBN 978-0-87389-797-6 (hardcover : alk. paper) 1. Pharmaceutical industry Government policy United States. 2. Food industry and trade Government policy United States. 3. Total quality management United Stat
8、es. I. Title. HD9666.6.R63 2010 615.10681dc222010031139No 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: William A. Tony Acquisitions Editor: Matt T. Mein
9、holz Project Editor: Paul OMara Production Administrator: Randall BensonASQ Mission: The American Society for Quality advances individual, organizational, and community excellence worldwide through learning, quality improvement, and knowledge exchange.Attention Bookstores, Wholesalers, Schools, and
10、Corporations: ASQ Quality Press books, video, audio, and software are available at quantity discounts with bulk purchases for business, educational, or instructional use. For information, please contact ASQ Quality Press at 800-248-1946, or write to ASQ Quality Press, P.O. Box 3005, Milwaukee, WI 53
11、201-3005.To place orders or to request ASQ membership information, call 800-248-1946. Visit our Web site at www.asq.org/quality-press.Printed on acid-free paperDedicationThis book is dedicated to my wife Norma and my son Jos Andrs. Their continuous support and love made this book possible.(This page
12、 intentionally left blank)viiList of Figures and Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ixPreface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiiiChapter 1 The Quality System and CAPA . . . . .
13、. . . . . . . . . . . . . . 11.1 The Quality System and CAPA . 11.2 CAPA Relationship W ith Other Quality Subsystems 41.3 Corrective or Preventive? 6Chapter 2 CAPA and the Life Sciences Regulated Industry . . . . 92.1 FDA Pharmaceutical CGMP . 102.2 FDA Medical Devices QSR . 112.3 FDA Quality System
14、 Inspection Technique (QSIT), 1999 . 132.4 FDA Guidance: Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production, 2006 . 192.5 FDA Guidance: Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations, 2006 . 212.6 European Pharmaceutical GM
15、P (EudraLex Volume 4), 2003 232.7 Harmonization Processes: ICH and GHTF . 242.8 ICH Q10: Pharmaceutical Quality System, 2008. . . . . . . . . 252.9 ISO 13485:2003 and Non-U.S. Medical Devices Regulations 252.10 GHTF Quality Management SystemMedical DevicesGuidance on Corrective Action and Preventive
16、 Action and Related QMS Processes, 2009 272.11 Current FDA Regulatory Trends for the CAPA System . 28Contentsviii ContentsChapter 3 Effective CAPA Process: From Problem Detection to Effectiveness Check . . . . . . . . . . . . . . . . . . 31 3.1 Problem Detection: Discovering Problems . 333.1.1 Sourc
17、e of Data About Product and Quality Issues . 33 3.1.2 Risk Assessment 353.1.3 Initial Impact Assessment 423.1.4 Process Trending . 433.2 Problem Investigation: Discovering Root Causes . 463.2.1 Symptoms, Causal Factors, and Root Causes . 473.2.2 Problem Description 503.2.3 Barrier Analysis 553.2.4 R
18、oot Cause Identification Processes and Tools 563.2.5 Root Cause Categories 603.2.6 Investigating Human Errors . 623.3 CAPA Plan: Corrective and Preventive Actions to Fix Root Causes 763.3.1 Establish Effective Corrective and Preventive Actions 76 3.3.2 Validation and Verification Prior to Implementa
19、tion 773.3.3 Implementation of Corrective and Preventive Actions 783.4 Effectiveness Evaluation 793.4.1 Verifying That Solutions Worked . 793.4.2 Training Effectiveness . 803.5 Management of the CAPA System 843.5.1 CAPA System Structure . 853.5.2 CAPA Process Metrics . 853.5.3 Risk Management and th
20、e CAPA System 863.5.4 Management of External CAPA . 87Chapter 4 Documenting CAPA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 894.1 Content of the Investigation Report/CAPA Plan Report 894.2 Compliance Writing 91 Contents ixChapter 5 The Ten Biggest Opportunities of the CAPA System and
21、How to Fix Them . . . . . . . . . . . . . . . 93 5.1 Timeliness (Lack of) 935.2 Everything is an Isolated Event (Lack of Adequate Trending) 96 5.3 Root Cause Not Identified . 985.4 Correcting the Symptoms Instead of the Cause . 995.5 Lack of Interim Corrective Actions 1005.6 Root Causes Identified b
22、ut Not Corrected . 1005.7 Lack of True Preventive Actions 1015.8 Lack of Effectiveness Verification of the Action Taken . 1025.9 Multiple CAPA Systems W ithout Correlation 1035.10 Abuse of Human Error and Retraining 103Chapter 6 Developing an Internal CAPA Expert Certification . . 105 6.1 Content of
23、 the Certification 1056.2 Evaluating the Effectiveness of Internal CAPA Training Efforts 1096.3 CAPA Certification Exam Example . 110Chapter 7 CAPA Forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1137.1 Event Description and Investigation 1147.2 CAPA Plan 1167.3 Investi
24、gation Report and CAPA Assessment Form 1187.4 Human Error Investigation Form . 122Chapter 8 CAPA Final Recommendations . . . . . . . . . . . . . . . . . . . 125Appendix A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127Additional Resources 127Useful W
25、eb Sites 127Acronyms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131Bibliography . . . . . . . . . . . . . . . . . . . . . . . . .
26、 . . . . . . . . . . . . . . . . . . . . . . . 137Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141(This page intentionally left blank)xiFigure 1.1 The CAPA system and the manufacturing quality system 5 Figure 1.2 Feeders of the CAP
27、A system . 5Table 1.1 Corrective or preventive? 7Figure 2.1 Top ten FDA observations during drug manufacturer inspections for fiscal year 2009 28Table 2.1 Comparison of top ten observations during drug manufacturer inspections 29Figure 2.2 Top ten FDA observations during medical devices manufacturer
28、 inspections for fiscal year 2009 . 29Table 2.2 Comparison of top ten observations during medical devices manufacturer inspections . 30Figure 3.1 The CAPA process flow . 31Figure 3.2 The CAPA system 32Figure 3.3 The ineffective CAPA circle 33Table 3.1 Risk assessment criteria . 36Table 3.2 Risk asse
29、ssment score matrix 39Table 3.3 Example of risk assessment 40Figure 3.4 Risk prioritization of investigations . 41Table 3.4 Type of nonconformance investigations . 41Figure 3.5 Scrap monthly rates 46Figure 3.6 Root cause elements 47Figure 3.7 CAPA example . 49Table 3.5 Symptoms, causal factors, and
30、root causes . 50Table 3.6 Examples of causal factors and root causes 51Figure 3.8 Timeline of event . 53Figure 3.9 Change analysis graph 53Table 3.7 Barrier controls 55Table 3.8 Barrier control analysis example 55List of Figures and Tablesxii List of Figures and TablesFigure 3.10 Fault tree analysis
31、 example 58Figure 3.11 Types of human errors 64Table 3.9 Slips and lapses of memory 65Table 3.10 Human error investigation and prevention Dos and Donts . 75Table 3.11 The four levels of the Kirkpatrick model . 82Table 4.1 Compliance writing Dos and Donts 92Table 6.1 Content of the CAPA expert certif
32、ication 106Table 6.2 CAPA expert certification evaluation levels 110Table 7.1 Human error investigation form. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123xiiiMedical devices, biopharmaceutical, and traditional drug manu-facturing companies devote an important part of their resou
33、rces to dealing with incidents, investigations, and corrective and preventive actions. The corrective and preventive action system is known as the CAPA system. The CAPA system is second to none in terms of frequency and criticality of its deviations, and most of the regulatory actions taken by the F
34、DA and foreign regulators are linked to inadequate CAPA systems. This guidance book provides useful and up-to-date information about this critical topic to thousands of engineers, scientists, and manufacturing and quality personnel across the life sciences industries. Understanding the CAPA system i
35、s a fundamental prerequisite to improving it. Investigating and discovering the root cause of any event is just the starting point of the CAPA journey. After that, we must develop and implement adequate and effective corrective and/or preventive actions. A formal process must be established to evalu
36、ate how well implemented actions prevent the recurrence of those causes. Although preventive actions are half of the CAPA system, many companies do not have any true preventive actions. Understanding and improving the corrective and preventive actions system as a whole is the focal point of this boo
37、k, the first of its kind dealing exclusively with this critical system within this highly regulated industry. These pages evolved from hundreds of training sessions I have conducted as a consultant to dozens of regulated companies. By reviewing CAPA systems of nearly one hundred manufacturing plants
38、 (pharma-ceuticals, medical devices, biological products, and food manufacturing), I developed firsthand awareness of the real issues of the CAPA system. These are addressed in this book in the form of a decalogue, a set of ten basic rules. Thus, the objective of this book is to help these industrie
39、s improve their CAPA systems and succeed in their mission of producing safe and effective products. Prefacexiv PrefaceChapter 1 establishes the relationship between the CAPA system (identification, investigation, and fixing of problems) and the quality system environment. It also includes the most i
40、mportant definitions and concept of the CAPA world. I strongly recommend you begin by reading and understanding those critical concepts. Many people involved in developing and implementing corrective and preventive actions have trouble providing correct definitions of those concepts.Chapter 2 descri
41、bes the current requirements and regulations by type of products and by country (U.S., European Community) and by international harmonized documents. It also includes a review of ISO 13485:2003 requirements as they apply to medical device manu-facturers as well as a review of the recent internationa
42、l guidance on CAPA for medical devices published September 2009. This chapter finishes with an overview of the current FDA regulatory trends related to the CAPA system.Chapter 3 describes sequentially the entire CAPA process. It starts with problem detection, continues with root cause investigation,
43、 genera-tion, and implementation of corrective and preventive actions, and ends with the evaluation of their effectiveness and the management of the CAPA system. Topics such as trending, evaluation of training effective-ness, and risk management concepts and their relation to CAPA are discussed in t
44、his chapter. Special emphasis is dedicated to the inves-tigation of so-called “human error.”Chapter 4 contains useful hints to properly document the elements of the CAPA process.Chapter 5 describes a decalogue containing the ten most common opportunities found in the CAPA system and how to fix them.
45、 Real examples are analyzed and best practices are discussed for each.Chapter 6 presents the basic elements to be included as part of an internal CAPA expert certification, which is one of the recommended ways to reinforce your CAPA system.Chapter 7 includes several forms that can be used as templat
46、es during failure investigations, development of corrective and preventive actions, and evaluations of effectiveness. These forms include dozens of questions that provide guidance and are a great help during the process of investigation and generation of effective actions to avoid the recurrence of
47、unwanted situations. Also included is a form to be used when investigating human errors.Finally, Chapter 8 presents a list of key recommendations to improve your CAPA system.11.1 THE QUALITY SYSTEM AND CAPAA quality system is a set of formalized business practices that define manage ment responsibil
48、ities for organizational structure, processes, proce dures, and resources needed to fulfill product or service requirements, customer satisfaction, and continuous improvement. A quality manage ment system (QMS) is a set of interrelated elements (processes) used to direct and control an organization
49、with regard to quality. In other words, a quality system dictates how quality policies are implemented and quality objectives are achieved.Continuous improvement is the result of ongoing activities to evaluate and enhance products, processes, and the entire quality system to increase effectiveness. The organization must continuously improve the effectiveness and efficacy of its QMS through the use of its quality policy, quality objectives, audit results, analysis of data, corrective and preventive actions, and the management review processes.Analyzing
