1、Statistical Process Control for the FDA-Regulated IndustryAlso available from ASQ Quality Press:Quality Risk Management in the FDA-Regulated IndustryJos Rodrguez-PrezThe FDA and Worldwide Quality System Requirements Guidebook for Medical Devices, Second EditionAmiram Daniel and Ed KimmelmanCAPA for
2、the FDA-Regulated IndustryJos Rodrguez-PrezDevelopment of FDA-Regulated Medical Products: A Translational Approach, Second EditionElaine WhitmoreMedical Device Design and RegulationCarl T. DeMarcoThe Quality Toolbox, Second EditionNancy R. TagueThe Certified Six Sigma Green Belt HandbookRoderick A.
3、Munro, Matthew J. Maio, Mohamed B. Nawaz, Govindarajan Ramu, and Daniel J. ZrymiakThe Certified Manager of Quality/Organizational Excellence Handbook, Third EditionRussell T. Westcott, editorThe Certified Six Sigma Black Belt Handbook, Second EditionT. M. Kubiak and Donald W. BenbowThe ASQ Auditing
4、Handbook, Fourth EditionJ.P. Russell, editorThe Internal Auditing Pocket Guide: Preparing, Performing, Reporting, and Follow-Up, Second EditionJ.P. RussellRoot Cause Analysis: Simplified Tools and Techniques, Second EditionBjrn Andersen and Tom FagerhaugTo request a complimentary catalog of ASQ Qual
5、ity Press publications, call 800-248-1946, or visit our website at www.asq.org/quality-press.ASQ Quality PressMilwaukee, WisconsinStatistical Process Control for the FDA-Regulated IndustryManuel E. Pea-RodrguezAmerican Society for Quality, Quality Press, Milwaukee 53203 2013 by ASQAll rights reserve
6、d. Published 2013Printed in the United States of America19 18 17 16 15 14 13 5 4 3 2 1Library of Congress Cataloging-in-Publication DataPena-Rodriguez, Manuel E.Statistical process control for the FDA-regulated industry / Manuel E. Pena-Rodriguez.pages cmIncludes bibliographical references and index
7、.ISBN 978-0-87389-852-2 (hardcover : alk. paper)1. Process controlStatistical methods. 2. Manufacturing processesUnited States Quality control. I. Title.TS156.8.P45 2013658.50727dc23 2013003376ISBN: 978-0-87389-852-2No part of this book may be reproduced in any form or by any means, electronic, mech
8、anical, photocopying, recording, or otherwise, without the prior written permission of the publisher.Publisher: William A. TonyAcquisitions Editor: Matt T. MeinholzProject Editor: Paul Daniel OMaraProduction Administrator: Randall BensonASQ Mission: The American Society for Quality advances individu
9、al, organizational, and community excellence worldwide through learning, quality improvement, and knowledge exchange.Attention Bookstores, Wholesalers, Schools, and Corporations: ASQ Quality Press books, video, audio, and software are available at quantity discounts with bulk purchases for business,
10、 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 53201-3005.To place orders or to request ASQ membership information, call 800-248-1946. Visit our website at http:/www.asq.org/quality-pr
11、ess.Printed on acid-free paperTo my daughter Stacey Marie and to my mom Sonia Rodrguez. Thanks for always being my inspiration in everything I do.And to my best friend Jos (Pepe) Rodrguez-Prez. Thanks for believing in me and helping me to make this dream come true.viiTable of ContentsList of Figures
12、 and Tables . xiPreface xviiChapter 1 Regulatory Importance of Statistical Process Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.1 Overview 11.2 Process Control within the Code of Federal Regulations. 21.2.1 Current Good Manufacturing Practices
13、(21 CFR 211) 21.2.2 Quality System Regulation (21 CFR 820) . 31.3 Process Control within the FDA Guidances. 51.3.1 Quality System Approach to Pharmaceutical cGMP Regulations . 51.3.2 Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production . 61.3.3 Process Validation: Gene
14、ral Principles and Practices . 61.4 Process Control within International Guidances and Standards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71.4.1 ICH Q10 . 71.4.2 ISO 13485:2003 Standard 81.5 Summary 9Chapter 2 SPC and the Life Sciences Regulated Industry . . .
15、. 112.1 Overview 112.2 Recent Observations About Misuse of Statistical Process Control . 112.3 SPC and CAPA. 152.4 Summary . 16viii Table of ContentsChapter 3 Process Variation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193.1 Overview 193.2 The Causes of Variation 213.3 Summary 22Chapte
16、r 4 Basic Principles of Statistics . . . . . . . . . . . . . . . . . . . 234.1 Overview 234.2 Types of Data 244.3 Sampling 244.4 Describing the Sample . 294.5 The Normal Distribution . 304.6 Summary 32Chapter 5 Graphical Tools . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355.1 Overvie
17、w 355.2 Histogram . 355.3 Box Plot. 365.4 Dot Plot . 385.5 Pareto Diagram. 405.6 Scatter Plot 425.7 Run Chart . 445.8 Normality Test . 515.9 The Importance of Assessing Normality . 535.10 Summary. 53Chapter 6 Measurement Systems Analysis . . . . . . . . . . . . . . . . 556.1 Overview 556.2 Metrics .
18、 566.3 Performing a Gage R instead, it is intended to provide a how-to guide about the application of the diverse array of statistical tools available to analyze and improve the processes in an organization regulated by FDA. This book is aimed at engineers, scientists, analysts, technicians, manager
19、s, supervisors, and all other professionals responsible to measure and improve the quality of their processes. Although the examples and case studies pre-sented throughout the book are based on situations found in an organization regulated by FDA, the book can also be used to understand the applicat
20、ion of those tools in any type of industry.Prefacexviii PrefaceThe book comprises 12 chapters and four appendixes. In Chapter 1, the regulatory importance of SPC is presented. Some of the FDA regu-lations and guidances are analyzed in terms of the agencys expectations about the use of statistical pr
21、ocess control tools. Also, some of the inter-national standards applicable to the life sciences industry are analyzed for SPC requirements. Chapter 2 presents various instances in which FDA has issued observations about the misuse of SPC tools. Also, the concepts of SPC and corrective action and pre
22、ventive action (CAPA) are integrated in this chapter.Then, Chapter 3 presents the concept of process variation. The common causes and special causes of variation are explained in detail. Chapter 4 presents some basic statistical concepts, such as types of data, sampling, descriptive statistics, the
23、normal distribution, and so on. Next, Chapter 5 presents some of the most useful graphical tools with which to start analyzing processes. Tools such as the histogram, dot plot, box plot, Pareto diagram, and others, as applied to several FDA-regulated industries, are presented in the chapter.In Chapt
24、er 6, one of the most important but less frequently used tools is presented: the measurement systems analysis. In this chapter, the impor-tance of addressing measurement system variability prior to implementing any other improvement initiative is thoroughly explored. Chapter 7 presents the concept o
25、f process capability. Here, we study the different indices used to measure capability: Cp, Cpk, Pp, and Ppk. Then, in Chapter 8, an intro-duction to hypothesis testing is presented. Several tools used to compare means, medians, and variances are introduced for normal and nonnormal data. Many example
26、s are provided detailing the use of these tools in an FDA-regulated organization.Chapter 9 explains how to use regression analysis to understand the relationship between input variables and output variables. Then, Chapter 10 provides a brief introduction to design of experiments and its applica-tion
27、 in an FDA-regulated environment. The concepts of full factorial and fractional factorial experiments are introduced in this chapter. In Chapter 11, control charts are introduced as a tool to facilitate process control. The control charts for variable data and attribute data are presented, along wit
28、h some applications. Finally, Chapter 12 presents a summary of the appropri-ate tools necessary to reach a state of statistical process control.In order to visualize the difference between attribute and variable data, Appendix A shows some different tools for analyzing attribute or variable data, in
29、cluding control charts, probability distributions, sampling plans, and measurement instruments for each type of data. Appendix B presents many graphical and statistical tools to be used for different situations, and a ref-erence to the section in the book in which the tool can be found. Appendix Pre
30、face xixC shows an example of the basic statistics to apply for an annual product review or management review. Finally, Appendix D shows some of the most commonly used hypothesis tests in an easy-to-understand tabular format.By means of this book, I expect that the reader will obtain a better unders
31、tanding of some of the statistical tools available to control their pro-cesses. Also, I expect the reader to be encouraged to study, with a greater level of detail, each of the statistical tools presented throughout the book. The content of this book is the result of almost 20 years of experience in
32、 the application of statistics in various industries, and the combination of my engineering and law educational backgrounds, specifically through provid-ing consulting services to dozens of FDA-regulated organizations.11Regulatory Importance of Statistical Process Control1.1 OveRvIewThe Food and Dru
33、g Administration (FDA) is the administrative agency in the United States responsible for protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biologi-cal products, medical devices, our nations food supply, cosmetics, prod-ucts that emit radiation
34、, and tobacco products. FDA is also responsible for advancing the public health by helping to speed innovations that make med-icines and foods more effective, safer, and more affordable, and helping the public get the accurate, science-based information they need to use medi-cines and foods to impro
35、ve their health.1The Federal Food, Drug, and Cosmetic Act (FD consequently, not following a guidance could have regulatory consequences.1.2 PROCeSS COntROl wIthIn the COde Of fedeRal RegulatIOnSSeveral sections within Title 21 of the Code of Federal Regulations mention the concept of process control
36、s. I will focus the discussion on two specific sections of Title 21: the section related to finished pharmaceutical products4and the section related to medical devices.5It is important to understand that regulations are not intended to provide a specific way to achieve pro-cess controls. Regulations
37、 provide the minimum requirements. For instance, the regulation for finished pharmaceutical products states that:The regulations in this part contain the minimum current good manufacturing practice for preparation of drug products for administration to humans or animals.6The regulation for medical d
38、evices establishes that:. . . This part establishes basic requirements applicable to manu-facturers of finished medical devices.7Both regulations explicitly state that requirements established therein are the minimum that the manufacturer must accomplish; they are not intended to be a “one-size-fits
39、-all” type of requirement. Let us start with the process controls within the regulation for finished pharmaceutical products.1.2.1 Current good Manufacturing Practices (21 CfR 211)Published in 1978, the current Good Manufacturing Practices (cGMP) provide a framework to control finished pharmaceutica
40、l processes. Con-trol over the processes is important so that the product meets standards of safety, efficacy, purity, and stability. Section 211.22 establishes the respon-sibilities of the quality control unit (QCU). This section states that:There shall be a quality control unit that shall have the
41、 responsibil-ity and authority to approve or reject all components, drug prod-uct containers, closures, in-process materials, packaging material, Regulatory Importance of Statistical Process Control 3labeling, and drug products, and the authority to review produc-tion records to assure that no error
42、s have occurred or, if errors have occurred, that they have been fully investigated. The quality control unit shall be responsible for approving or rejecting drug products manufactured, processed, packed, or held under contract by another company.8In order to comply with this section of the regulati
43、on, the manufacturer shall establish written procedures, which shall be followed. It should be noted that the QCU is responsible to establish all process controls, monitor those process controls, and take actions whenever those process controls are not followed. In other words, the QCU becomes the “
44、arms and eyes” of FDA within the manufacturer. One of the best examples of this applica-tion is found in section 211.100, “Written procedures; deviations,” which states that:There shall be written procedures for production and process con-trol designed to assure that the drug products have the ident
45、ity, strength, quality, and purity they purport or are represented to pos-sess. Such procedures shall include all requirements in this sub-part. These written procedures, including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved
46、 by the quality control unit.9As noted, two key elements in establishing process controls in a pharma-ceutical manufacturing environment, as established by the regulations, are the appointment of a quality control unit and the development of written procedures.1.2.2 Quality System Regulation (21 CfR
47、 820)Published in 1996, the current Quality System Regulation (QSR) provides a framework to control medical device processes. Although the regulation related to pharmaceutical products (21 CFR 211) does not have a specific section dedicated solely to statistical process control, the regulation relat
48、ed to medical devices addresses SPC explicitly. Section 820.250, “Statistical techniques,” establishes that:(a) Where appropriate, each manufacturer shall establish and maintain procedures for identifying valid statistical techniques required for establishing, controlling, and verifying the accept-a
49、bility of process capability and product characteristics.4 Chapter One(b) Sampling plans, when used, shall be written and based on a valid statistical rationale. Each manufacturer shall estab-lish and maintain procedures to ensure that sampling methods are adequate for their intended use and to ensure that when changes occur the sampling plans are reviewed. These activities shall be documented.10Furthermore, section 820.100, “Corrective and preventive action,” states that: (a) Each manufacturer shall establish and maintain proce-dures for implementing corrective and p
