Sterile Pharmaceutical Products : Process Engineering Applications

428 Pages·2017·20.73 MB·English

by  Avis

sterile Pharmaceutical
Products
Process
Engineering
Applications
Drug Manufacturing
Technology Series
Edited by
Kenneth E. Avis
e
Interpharm /CRC
Boca Raton London New York Washington, D.C.
Transferred to Digital Printing 2010
Library of Congress Cataloging-in-Publication Data
Sterile pharmaceutical projects : process engineering applications /
Kenneth E. Avis, editor,
p. cm.
Includes bibliographical references and index.
ISBN 0-935184-81-3
1. Sterilization. 2. Pharmaceutical technology. 3. Clean rooms.
I. Avis, Kenneth E., 1918-
RS199.S73S75 1995
614.477—dc20 95-24999
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© 1995 by CRC Press EEC
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No claim to original U.S. Government works
International Standard Book Number 0-935184-81-3
Eibrary of Congress Card Number 95-24999
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but points out that some imperfections in the original may be apparent.
CONTENTS
Foreword XÌ
1. Introduction
Kenneth E. Avis
Chapter Contents 2
2. Engineering Control of the Aseptic
Filling Environment 7
Howard R. Leary
Objective and Introduction 7
Creating and Maintaining Aseptic
Environments for Pharmaceutical Filling 9
The Enclosure 10
Particulate Control 11
Ingress to and Egress front the Controlled
Environment 11
Machine Design Issues in Aseptic Packaging 13
Asepsis: A Hostile Environment for Filling Equipment 13
Designing to Protect the Machinery 16
Designing to Enhance Bioburden Control 23
Designing for Particulate Control 32
Conclusion 34
References 35
ui
IV Contents
3. Air Handling Systems for
Cleanroom Control 37
Brian D. Moore
Genercil Design Guidelines 37
Cost Effectiveness 38
Characteristics of Pharmaceutical Clean Rooms 39
Air Quality Standards and Guidelines 40
Cleanroom Attributes 43
Operational Cleanroom Classifications 46
Air Distribution to the Clean Room 46
Terminal HEPA Filters 46
Cleanroom Return Air 49
Air Distribution to Product Exposure Areas 54
General Cleanroom HVAC System Concepts 58
System Configuration 59
Equipment Sizing and Selection 65
Aseptic Area Pressurization 66
Mechanical Space Location 66
Air Handling Units 71
Air Handling Unit Construction 71
Air Handling Unit Design 72
Ductwork Design and Construction 74
Ductwork Design 74
Ductwork Construction 75
HVAC System Controls 77
Temperature and Humidity Control 77
Pressure Control 78
Details 83
System Testing, Commissioning, and Validation 83
Testing 84
Commissioning 84
Validation 85
The Future 86
References 87
Contents
4. High Speedy Automated Filling
of Sterile Liquids and Powders 89
F. William Rahe
Scope 89
Speed, Automated Filling 8P
Aseptic Processing 90
Containers 90
Small Volume Liquids and Powders 90
Trends 90
General Machine Features 91
Common Design Issues 92
Dose Control 92
Cleanliness 94
Sterilizdble Parts 94
Materials of Construction 95
Validation 95
Machine Capacity Sizing 97
Liquid Filling 99
Metering 99
Container Handling 111
Powder Filling 113
Why Powder Filling? 113
Pneumatic Cylinder and Piston Wheel 113
Totally Enclosed Pneumatic Pump 119
Volumetric Compression 123
Auger Filling 126
Future Developments 131
Recommended Readings 132
5. Engineering Considerations for
CIP/SIP Systems 135
Dale A. Seiberling
Alfred]. Ratz
Historical Review, Evolution, and
Applicable Criteria 135
VI Contents
CIP Pharmaceutical Processes 136
CIP and SIP Technology Defined 136
"types of Equipment That Are CIP Candidates 136
Criteria for the Design of CIP Equipment 137
The CIP Procedure 139
Additional Components and Criteria for
Incorporating SIP 140
Design Overview of a CIP Process 141
CIP Systems Defined 144
CIP System Components 144
CIP Recirculating Units 144
Engineering Considerations 144
Single-Use Versus Reuse Operation 148
Desirable Criteria for Pharmaceutical and
Biotech CIP Systems 152
Location of CIP Recirculating Units and
Chemical Feed Equipment 156
CIP Program Control Systems 158
CIP Program Data Acquisition 162
CIP Data Logger Capability 162
Summary Reports 164
Spray Device Selection and Application 164
Design of the Pharmaceutical Tank for
Effective Spray Cleaning 166
An Example of a CIP Dry Drug Process 169
CIP Supply/Retum System Criteria 172
CIP Supply/Retum Piping Concepts 174
CIP Supply/Retum Engineering 176
Return Flow Motivation 179
Return Pump Selection 181
Eductor Return Systems 181
Uniform Flow Rates 182
Automation of the Pharmaceutical or
Biotech Process 182
CIP Air-Operated Values 182
Automated Process Piping Design 186
Air-Operated Valve Pulsing and Sequencing 188
U-Bend Transfer Panels 190
Integrated Process/CIP Piping with U-Bend
Transfer Panels in a Hypothetical Process 196
Integrated Process/CIP Piping in a Biotech Process 199
Integrated Process/CIP Piping with Transfer
Panels in the Pharmaceutical Process 200
Contents vii
Typical Cleaning Programs and Water Requirements 202
Steam-in-Place 204
The Application of Single-Use Eductor-Assisted
CIP Systems to Automate COP Operations 208
Installation of CIP Systems in the Qean Room 209
Evaluation of Results 215
Advantages and Disadvantages of CIP 216
Summary 217
References 218
Suggested Additional Reading 219
6. Engineering Aspects of
WEI Systems Design 221
Henry Kuhltnan
Drew Coleman
Definition of Water for Injection 222
Uses of Water for Injection 222
Historical Backgroimd and General
Engineering Practices 223
Pretreatment Requirements 224
Why Water Pretreatment Is Required 224
The Standard System Design Components 224
Contemporary Feedwater Systems Design
Components 226
Design Considerations 228
Production Equipment 228
Equipment Sizing and Selection 229
Storage and Distribution System Design Components 238
Piping Design 242
Construction Standards and Procedures 243
Acceptance Criteria 243
Welding Procedures 244
Slope Verification 244
Validation Requirements 244
WFI System Description 244
Validation Master Plan 246
vm Contents
Outside Validation Resources 248
Document Handling and Storage 250
The Start-Up and Validation Sequence-An Example 250
Start-Up Concerns and Case Histories 259
System Preventive Maintenance 259
Conclusion 266
References 267
7. Engineering Considerations in
Sterile Powder Processes 269
Alpaslan Yaman
Sterilization of the Bulk Drug Substance 270
Packaging of the Bulk Drug Substance 273
Container Considerations 273
Characterization of the Bulk Drug Process 274
Powder Density 275
Angle of Repose 276
Particle Size Distribution 277
Crystal History 280
Aseptic Transfer of Raw Material to the
Filling Room 281
Factors Affecting Filling Rate 281
Single Versus Double Stroke Filling 281
Multiple Powder Fill 286
Aseptic Milling and Blending 287
Double Shot Filling 292
Environmental Concerns and Their Effects
on Finished Product Characteristics 295
Humidity 296
Electrostatic Discharge 296
Oxygen Control 297
Dust Containment 298
Particulate Matter 298
Acknowledgements 302
References 304
Contents ix
8. Engineering Considerations in
Sterile Filtration Processes 305
Holly Haughney
Introduction to Membréuie Filters Used in
Sterile Filtration Processes 305
Filtration Mechanisms 305
Membrane Filter Ratings for Particulate
Removal Filters 306
Sterilizing Grade Membrane Filter Rating
and Integrity Tests 307
Membrane Filter Construction 308
Filter Assemblies Used in Processes 311
Sterile Liquid Filtration Design and
Operational Considerations 312
Design Considerations for a Filtration Process 312
Operational Considerations for a Filtration Process 329
Integrity Testing Design and Operation
Considerations 338
Sterile Gas Filtration Process Design and
Operational Considerations 348
Considerations for Sterile Filtration of Fermenter Air 348
Considerations for Sterile Tank Vent Filters 349
Summary 353
References 353
9. The Development of Integrated^
Automated Filling and Packaging
Equipment Using Hybrid Robotics 357
Hans W. Trechsel
Understanding Integrated, Automated
Manufactiuing: The Integration Process 359
The Challenges of Designing a Processing System 360
Processing Requirements 360
Machine Design 361
Robotic Design 362