PHARMACEUTICALENGINEERING GUIDE

PharmaceuticalEngineering

for Newand RenovatedFacilities

First Edition/ June 2004

BiopharmaceuticalManufacturing

facilities

TABLE OF CONTENTS

1 INTRODUCTION

1.1 BACKGROUND 111.2 SCOPE OFTHIS GUIDE 111.3 KEY CONCEPTS OFTHIS GUIDE 121.4 USING THIS GUIDE 18

2 INTERPRETATION OF THE REGULATORY BASIS FOR FACILITY REQUIREMENTS

2.1 INTRODUCTION 212.2 SCOPE 222.3 DEFINITIONS 222.4 REGULATORY CONSIDERATIONS 232.5 GENERAL CONCEPTS 25

3 MANUFACTURING OPERATIONS AND ACTIVITIES

3.1 INTRODUCTION 333.2 OPEN VERSUS CLOSED SYSTEMS 343.3 "BIOBURDEN-CONTROLLED PROCESSING" 353.4 PYROGEN-CONTROLLED PROCESSING : 383.5 SEGREGATION AND FLOW 383.6 CONSIDERATIONS FOR MULTI-PRODUCT OPERATIONS 403.7 VIRAL CLEARANCE 423.8 STAGE OF PRODUCT DEVELOPMENT 443.9 OPERATIONAL UPSET 453.10 OPERABILITY AND MAINTAINABILITY 453.11 CLEANING AND HOUSEKEEPING CONSIDERATIONS 48

4 PROCESS AND EQUIPMENT

4.1 INTRODUCTION 514.2 TYPICAL BIOPHARMACEUTICAL PROCESSES 524.3 CRITICAL PROCESS VARIABLES 524.4 GENERAL CONSIDERATIONS FOR EQUIPMENT DESIGN 534.5 SPECIFIC EQUIPMENT DESIGN CONSIDERATIONS 614.6 SUMMARY 67

5 PROCESS SUPPORT AND UTILITIES

5.1 INTRODUCTION 695.2 REGULATORY ISSUES 705.3 SYSTEM IMPACT DESCRIPTIONS 715.4 SYSTEM LAYOUT AND ROUTING 735.5 SPECIFIC SERVICE CONSIDERATIONS 73

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6 FACILITY

6.1 INTRODUCTION 836.2 PROCESS CONSIDERATIONS 836.3 OPERATIONAL CONSIDERATIONS 866.4 FACILITY LAYOUT CONSIDERATIONS 886.5 OPERATIONAL SUPPORT 936.6 AREA ENVIRONMENT 966.7 ARCHITECTURE AND FINISHES 1056.8 DISCRETIONARY CONSIDERATIONS 105

7 PROCESS CONTROLS AND AUTOMATION

7.1 INTRODUCTION 1077.2 BIOPHARMACEUTICAL AUTOMATION ISSUES 1087.3 LEVEL OF AUTOMATION 1107.4 BIOPHARMACEUTICAL UNIT OPERATIONS 1137.5 CONTROL SYSTEMS MAINTENANCE 1167.6 VALIDATION OF BIOPHARMACEUTICAL AUTOMATION SYSTEMS 1177.7 OTHER SYSTEMS 118

8 COMMISSIONING AND QUALIFICATION

8.1 INTRODUCTION 1198.2 IMPACT ASSESSMENT 1198.3 QUALIFICATION 124

9 APPENDIX - EUROPEAN ASPECTS

9.1 INTRODUCTION (GENERAL) 1259.2 WATER QUALITY 1279.3 BIOCONTAMINANT AND ENVIRONMENTAL PROTECTION 1289.4 ENVIRONMENTAL IMPACT ISSUES 1319.5 CHROMATOGRAPHY SKID SHARING 1329.6 QUALIFICATION AND VALIDATION 132

10 APPENDIX - NIH LEVELS

10.1 BIOSAFETY LEVELS IN LABORATORIES 133

10.2 NIH GOOD LARGE SCALE PRACTICES (GLSP) 135

11 PRODUCT PROTECTION CONTROL STRATEGY 137

12 PROCESSTECHNOLOGY

12.1 "PROCESS FLOW DIAGRAMS" 13912.2 SINGLE-USE TECHNOLOGY " [_ " 1 4 2

TABLE OF CONTENTS

13 ADDITIONAL FACILITY INFORMATION

13.1 TYPICAL UNIT OPERATIONS IN A BIOPHARMACEUTICAL FACILITY 14713.2 FACILITY LAYOUT CONCEPT DIAGRAMS 14813.3 CLOSED PROCESSES 15613.4 LAYOUT FOR MULTI-LEVEL PROCESSING 15713.5 GOWNING FACILITIES 15913.6 ADDITIONAL HVAC INFORMATION 159

14 GLOSSARY, ABBREVIATIONS, AND ACRONYMS

14.1 GLOSSARY 16714.2 ABBREVIATIONS AND ACRONYMS 186

15 BIBLIOGRAPHY 189