1、AUTOMATION APPLICATIONS IN BIO-PHARMACEUTICALSBuckbee.book Page i Thursday, January 3, 2008 11:17 AMSeries page or blankBuckbee.book Page ii Thursday, January 3, 2008 11:17 AMAUTOMATION APPLICATIONS IN BIO-PHARMACEUTICALSBYGEORGE BUCKBEE, P.E.cm.Includes bibliographical references and index.ISBN 978
2、-1-934394-25-0 (softbound)1. Pharmaceutical biotechnology-Automation. I. Alford, Joseph, Ph.D. II. Title. DNLM: 1. Biopharmaceutics-methods. 2. Technology, Pharmaceutical.3. Drug Industry. QV 778 B922a 2008RS380.B83 2008615.190285dc222007049480Buckbee.book Page iv Thursday, January 3, 2008 11:17 AMv
3、CONTENTSPreface xiAcknowledgments xiiAbout the Authors xiiiList of Figures xivList of Tables xvii1 Introduction11.1 Overview 11.2 Factors Affecting Automation inBio-pharmaceuticals 1Biological Processes 2Government Regulations 3Good Engineering Practices 4Validation and Qualification Requirements 5S
4、anitary Design, CIP and SIP 6Containment 7Quality 7Procedures 8Personnel 8Vendor Management 91.3 How this Book Is Organized 10Chapter 2Hardware and Software 10Chapter 3Applications 10Chapter 4People, Projects, and Profitability 10Chapter 5Computer System Validation 11Chapter 6Batch Control 12Chapter
5、 7Advanced Automation Techniques 12Appendices 12What is NOT Covered in this Book 122 Hardware and Software152.1 General Hardware Design Considerations 15Sanitary Design Considerations 15Materials 16Surface Finish 16Drainability 18Maintainability 18Buckbee.book Page v Thursday, January 3, 2008 11:17
6、AMvi Contents2.2 Valves 18Diaphragm Valves 18Actuators and Feedback Devices 20Multi-port Valve Clusters 21Ball Valves 22Regulating Valves 222.3 Transfer Panels 252.4 Bioprocess Measurement: Instrumentation 26General Considerations for Instrumentation 26Calibration 27Temperature 28Level and Weight 29
7、Flow 30pH Measurement 30Dissolved Oxygen 33Process Analytical Technology 342.5 Computer Equipment 352.6 Controllers, Chart Recorders, Other 36Single-Loop Controller 36System Architecture Design 36DCS 47HMIs 482.7 Process Information Management 49Data Storage Considerations 49Chart Recorders 50Electr
8、onic Data Historians 50Alarm Logging and Alarm Management 52Performance Supervision 52Statistical Process Control 53Reporting 54Maintenance Systems 552.8 Software Design 56Good Automation Manufacturing Practices (GAMP) 56Modular Designs 56Modular Software 58Skid Integration 58Historization and Repor
9、ting 65Batch Control Software 663 Applications 733.1 Automation Applications in Bio-pharmaceuticals 73Process Description and Challenges 73Typical Instrumentation Requirements 73Buckbee.book Page vi Thursday, January 3, 2008 11:17 AMContents viiControl Strategies 73How Much Automation Do You Need? 7
10、53.2 Utility Applications 763.3 Clean-In-Place: CIP 76Process Description and Challenges 76Typical CIP Instrumentation Requirements 77Control Strategies for CIP 803.4 Steam-In-Place: SIP 82SIP Process Description and Challenges 82Typical Instrumentation Requirements 82Control Strategies for SIP 843.
11、5 Water-for-Injection: WFI 87Process Description and Challenges 87Typical Instrumentation Requirements 873.6 Clean Steam 91Process Description and Challenges 91Typical Instrumentation Requirements 91Control Strategies 913.7 Clean Compressed Air 92Process Description and Challenges 92Typical Instrume
12、ntation Requirements 93Control Strategies 933.8 Formulation 94Process Description and Challenges 94Typical Instrumentation Requirements 95Control Strategies 953.9 HVAC 97Process Description and Challenges 97Communications 98Typical Instrumentation Requirements 98Control Strategies 983.10 Bioreactors
13、 99Process Description and Challenges 99Typical Instrumentation Requirements 100Control Strategies 1023.11 Bioprocess Filtration 108Process Description and Challenges 108Typical Instrumentation Requirements 108Control Strategies 1083.12 Precipitation 112Process Description and Challenges 112Buckbee.
14、book Page vii Thursday, January 3, 2008 11:17 AMviii ContentsTypical Instrumentation Requirements 113Control Strategies 1133.13 Centrifugation 116Process Description and Challenges 116Typical Instrumentation Requirements 116Control Strategies 1183.14 Waste Containment and Processing Systems 119Proce
15、ss Description and Challenges 119Typical Instrumentation Requirements 120Control Strategies 1203.15 Controlled Temperature Environments 122Process Description and Challenges 122Typical Instrumentation Requirements 1224 People, Projects, and Profitability1254.1 People 126Engineering 127Process Defini
16、tion Personnel 138Validation Personnel 142Quality 147Information Systems/Information Technology 150Operations 155Maintenance 1574.2 Projects 161Getting Organized 161Schedule 162Budget 163Managing Automation Resources 165Reducing the Cost of Automation Projects 1654.3 Profitability 168Value Engineeri
17、ngChoices to Reduce Cost 170Project Cost versus Life Cycle Cost 171Reducing Batch Cycle Time 172Improving Product Quality 176Reducing Operating Costs 179Ensuring Optimal Performance 1815 Computer System Validation 1835.1 Introduction 183Overview 183Validation Master Plan 185Computer Systems 186Buckb
18、ee.book Page viii Thursday, January 3, 2008 11:17 AMContents ix5.2 Historical Perspective 188The FDA and PMA 188Validation Life Cycle Diagram 1895.3 Computer Validation General Considerations 190Validation Master Plan 190Standard Operating Procedures 190Electronic Records and Electronic Signatures 1
19、935.4 Designing and Building Quality into the System 195Functional (User and System) Requirements 195Design 196Source Code Review 199Vendor Audits 200Testing 202User Acceptance 2055.5 Operating the System 205SOPs 205Training 205Monitoring the System 2065.6 Ensuring the System Stays in a State of Val
20、idation 207General 207Maintenance 207Contingency Planning 208Security 209Periodic Review 210Change Control 212Automated Audit Trails 2176 Batch Processing.2216.1 Introduction: “To Batch or Not to Batch” 2216.2 Upstream “Inter-Unit” Operations 2256.3 Upstream “Intra-Unit” Operations 2296.4 Downstream
21、 “Inter-Unit” Operations 2336.5 Downstream “Intra-Unit” Operations 2376.6 ISA-88.01 Batch Standard 2416.7 Use and Value of Batch Sequencing/Management Software 2466.8 Use and Value of Batch Historians 2506.9 Discrete Event Modeling 254Buckbee.book Page ix Thursday, January 3, 2008 11:17 AMx Contents
22、7 Advanced Techniques2597.1 Bioprocess Measurement 259PAT (Process Analytical Technology) 259Process Mass Spectrometry 260On-line HPLC 262Other Examples of PAT Sensors 262Online Estimators (i.e., Virtual Sensors) 2637.2 Dynamic Modeling 268Fermentation Models 2687.3 Advanced Control Techniques 273Ne
23、ural Networks 273Fuzzy Logic 279Model Predictive Control 281Adaptive Control 285Process Performance Supervision and Control System Asset Management 288Glossary 293Index 297ch00b_TOC.fm Page x Thursday, January 3, 2008 1:59 PMxiPREFACEThe bio-pharmaceutical industry demands exacting detail in design,
24、 devel-opment, operation, quality, and just about every other aspect of the busi-ness. As such, there is a degree of specialty in most every field of endeavorin this industry. This book was developed to try to accelerate the learningprocess for the application of automation in bio-pharmaceuticals. T
25、heauthors hope is that the content of this book will help scientists and engi-neers continue to contribute to the manufacture of high-quality medicinesvia improving process control and on-line availability of informationwhile reducing costs, cycle time, and process variability. Some readers may come
26、 into this industry with previous automationexperience. Others may be in the bio-pharmaceutical industry, but havelimited automation knowledge. In either case, the authors strived to bringthe reader to a more thorough understanding of the topics. This book is supplemented by a wealth of reference ma
27、terials in the indus-try. Each chapter contains a list of recommended reference materials.Buckbee.book Page xi Thursday, January 3, 2008 11:17 AMxiiACKNOWLEDGMENTSThe authors would like to acknowledge the individuals and organizationswho helped to make this book possible. Susan Colwell and the staff
28、 at ISAprovided excellent, concise, and professional guidance. Greg McMillanhelped conceive of the book, and provided detailed and thoughtfulreview. Gregs colleague at Emerson Process, Terry Blevins, also providedexcellent review of materials. John Gerry at ExperTune lent us his decadesof experience
29、 in control loop performance metrics. The authors alsothank Eli Lillys Dr. Jeff Baker for his input regarding process validation,Ben Paterson regarding content on downstream bioprocess unit opera-tions, and Dave Dzirbik for content regarding the automation of down-stream bioprocess unit operations.
30、We owe a debt of gratitude to thosewho have gone before us in developing the literature on topics related tobio-pharmaceuticals and automation. We also owe many thanks to thecontributions of our colleagues who, during our careers, provided techni-cal input, insights, support, and challenging questio
31、ns. The authors would like to recognize the special role of the Pharmaceuti-cal/Biotech industries for providing an environment where employees cancome to work and develop and manufacture medicines that make a differ-ence in the quality of life of their customers. Additionally, the authorswould like
32、 to thank the management of their employers (Expertune andLilly) for providing the opportunity and encouragement to evaluate newautomation technologies, develop applications, and share automationknowledge with others. Finally, we extend a very special thank you to our families and dedicatethis book
33、to them. What started as a small project grew quickly into a sec-ond job. Our families have done without us for hours on end as weworked to finalize the materials in this book. To Mary Ellen Buckbee, yourwisdom and understanding are boundless. Alyssa, Brendan, and CameronBuckbee, thanks for being so
34、 patient with this process. To Marti Alford,your support and encouragement throughout your husbands career hasbeen invaluable and greatly appreciated. Buckbee.book Page xii Thursday, January 3, 2008 11:17 AMxiiiABOUT THE AUTHORSGeorge Buckbee, P.E. is a process control industry veteran. George holds
35、 aB.S. in Chemical Engineering from Washington University in St. Louis,and an M.S. in Chemical Engineering from the University of California atSanta Barbara. George has 17 years of direct industry experience, atProcter computer and network under-standing; and the abilities to read, write, and review
36、 engineering draw-ings. Internal competencies include understanding of the particularprocess being controlled, as well as training in company-specific or site-specific procedures. Both internal and external competencies must beaddressed and documented.Chapter 4, “People, Projects, and Profitability,
37、” addresses key issues in theselection and qualification of personnel for automation work.Vendor ManagementIt is very typical for an automation project to employ many different ven-dors to handle design, construction, commissioning, qualification, andmaintenance of the automation system.To ensure th
38、e quality of the automation system design, companies mustemploy qualified vendors. A proper vendor evaluation program, coupledwith direct oversight of all contracted deliverables and services, is vital toa high-quality outcome.The first step in ensuring a quality result with any vendor is to have ac
39、learly-defined scope. Scope definition is addressed in the “ManagingAutomation Projects” section in Chapter 4.Industry groups are a valuable resource for establishing docu-mentation of external competencies. For example, the ISA “Cer-tified Automation Professional” program and the “Certified Control
40、 System Technician” program provide a solid measure of assur-ance and documentation that personnel are qualified. ISPE also offers courses in the application of GAMP. 1.7, 1.8Buckbee.book Page 9 Thursday, January 3, 2008 10:49 AM10 Chapter 1Introduction1.3 How this Book Is OrganizedChapter 2Hardware
41、 and SoftwareChapter 2 focuses on design criteria for hardware and software in the bio-pharmaceutical industry. The focus is on the most commonly used sys-tems in bio-pharmaceuticals.The first part of the chapter focuses on hardware, including valves, instru-mentation, and transfer panels. We discus
42、s the key design and implemen-tation considerations for each of these devices.The second half of this chapter discusses software design considerations,including Good Automated Manufacturing Practices (GAMP), ModularDesign, Skid Integration, and System Security.Chapter 3ApplicationsChapter 3 provides
43、 a great deal of information on the design of automa-tion systems for the most common processes. For each process, wedescribe:Process Description and ChallengesInstrumentationControl StrategiesThe engineer must develop a solid understanding of the process beingcontrolled to effectively design the au
44、tomation system. The goal of thischapter is to provide a basis for understanding some of the most commonprocesses in bio-pharmaceuticals.Chapter 4People, Projects, and ProfitabilityChapter 4 provides guidance on some of the “soft” issues affecting auto-mation system implementation. It is crucial for
45、 the engineer to under-stand that an excellent design, if poorly implemented, will result infailure. To ensure success, we must consider the critical “soft” issues. Thechapter is divided into three sections: People, Projects, and Profitability.Buckbee.book Page 10 Thursday, January 3, 2008 10:49 AMH
46、ow this Book Is Organized 11In the “People” section we discuss the impact of process automation:Roles and ResponsibilitiesTrainingQualificationsIn the “Projects” section we discuss the most important procedural issuesfor automation, including:Scope Definition and Scope ControlChange ControlVendor Se
47、lection and Commercial IssuesIn the “Profitability” section we discuss some of the financial consider-ations of automation system design. This includes discussion of the fol-lowing topics:Project ManagementVendor ManagementBalancing Quality, Cost, and ScheduleValue Engineering for AutomationAutomati
48、on may be a relatively new technology in some plants. The goalof Chapter 4 is to identify key adaptations that may be required for theorganization to implement and support automation.Chapter 5Computer System ValidationProcesses used in the manufacture of pharmaceuticals for human con-sumption must b
49、e validated. The scope of validation includes not onlythe chemical processing unit operations themselves but also supportingaspects of manufacturing operations such as assay validation, cleaningvalidation, utility validation (e.g., use of purified water), and computervalidation. Chapter 5 summarizes validation requirements for computersystems.Buckbee.book Page 11 Thursday, January 3, 2008 10:49 AM12 Chapter 1IntroductionChapter 6Batch ControlMany bioprocesses are batch in nature, rather than continuous processes.Automation of batch systems brings some special challeng
