Guidelines for Process Safety in Bioprocess Manufacturing Facilities

List of Tables xi

List of Figures xiii

Items on the Web Accompanying This Book xv

Acknowledgements xvii

Preface xix

1 INTRODUCTION 1

1.1 Bioprocess Engineering Information Transfer and Management Practices 3

1.2 The Need for Bioprocess Safety Management Systems 7

1.2.2 Bioprocessing Incidents and Releases 8

1.3 Our Target Audience 14

1.4 How to use this Guideline 15

2 AN OVERVIEW OF THE BIOPROCESSING INDUSTRY 17

2.1 Bioprocessing’s History 17

2.1.1 Bioprocessing’s Historical Advancement 18

2.1.1.1 Microbiological Advancements 18

2.1.1.2 Food Science and Food Process Technology Advancements 19

2.1.1.3 Genetic Advancements 19

2.1.1.4 Future Bioprocessing Developments 20

2.2 Industrial Applications 20

2.2.1 Processes 21

2.2.2 Products 21

2.3 The Bioprocess Lifecycle 22

2.3.1 Discovery 23

2.3.2 Development Phase: Laboratory and Pilot Plant 23

2.3.3 Scale-up Phase 24

2.3.4 Upstream Operations and Downstream Operations 26

2.3.4.1 Inoculation / Seed and Production Biosafety Containment and Production Risk 27

2.3.4.2 Fermentation / Cell Culture 31

2.3.4.3 Scale of Manufacturing 36

2.3.5 General Biosafety Recommendations for Large Scale Work 38

2.3.5.1 Facility Design 39

2.3.5.2 Equipment Design 39

2.3.5.3 Cleaning, Inactivation, and Sterilization 41

2.3.5.4 Maintenance 42

2.3.5.5 Air and Gas Emissions 42

2.3.5.6 Waste Handling 42

2.3.5.7 Accidental Release 43

2.3.6 Product Safety Information 43

2.3.6.1 Product Handling 44

2.3.6.2 Material Disposal 44

2.3.63 Disposable Process Technology 44

2.3.7 Outsourced Manufacturing Concerns 45

3 BIOPROCESSING SAFETY MANAGEMENT PRACTICES 47

3.1 Sample Approach 48

3.1.2 Develop and Document a System to Manage Bioprocess Safety Hazards 50

3.1.3 Appoint a Biological Safety Officer 50

3.1.4 Collect Bioprocess Hazard Information 51

3.1.5 Identify Bioprocess Safety Hazards 51

3.1.5.1 Point of Decision 51

3.1.6 Assess Bioprocess Safety Risks and Assign Bioprocess Safety Hazard Level 52

3.1.7 Identify Bioprocess Controls and Risk Management Options 52

3.1.8 Document Bioprocess Safety Hazard Risks and Management Decisions 53

3.1.9 Communicate and Train on Bioprocess Safety Hazards 53

3.1.10 Investigate & Learn from Bioprocess Incidents 53

3.1.11 Review, Audit, Manage Change, and Improve Hazard Management Practices and Program 54

3.2 Existing Management Systems 54

3.2.1 Product Stewardship for Byproducts 61

3.3 Establishing a Bioprocess Safety Management System 62

3.3.1 Select a Management System Model Based Upon Your Needs 63

3.3.2 Identifying the Elements that Apply to Your Operations 64

3.3.3 Establish a Review and Approval Cycle for the Documents 65

3.3.4 Rolling Out the Management System to the Users 66

3.4 Biosafety Training for the Workforce 67

3.5 Investigating Incidents 69

3.5.1 A Generic Procedure for Initial Biohazard Incident Response 71

3.6 Managing Change 75

3.7 Reviewing and Auditing for Continuous Improvement 76

3.8 Applying Behavior-Based Safety to Bioprocesses 76

4.IDENTIFYING BIOPROCESS HAZARDS 79

4.1 Key Considerations for Assessing Risk to Manage Bioprocess Safety 79

4.1.1 Testing for Bioactivity 79

4.1.2 Non-biological Hazards 80

4.2 Bioprocess Risk Assessment 80

4.2.1 Three Types of Assessment 80

4.2.2 Agent Considerations 80

4.2.3 Process Considerations 81

4.2.4 Environmental Considerations 82

4.2.5 Microorganisms 83

4.3 Recombinant Organisms 85

4.4 Cell Culture 86

5 BIOPROCESS DESIGN CONSIDERATIONS AND UNIT OPERATIONS 89

5.1 Physical Plant Design 89

5.1.1 Architectural Aspects 90

5.1.1.1 Finishes and Materials 90

5.1.1.2 Layout Strategies 91

5.1.1.3 People and Material Flow 94

5.1.1.4 Non-bio logical Hazards 94

5.1.1.5 Seismic and Building Loads 96

5.1.1.6 Hardened Construction 97

5.1.1.7 Equipment Mezzanines and Subfloors 97

5.1.1.8 Heating, Ventilation, and Air Conditioning Aspects 98

(a) Supply and Exhaust Systems 98

(b) Special Exhaust Stream Mitigation 100

(c) HVAC Issues from a Biosafety Perspective 101

(d) Microenvironments 103

(e) Cascading Pressure Differentials 105

(f) Containment versus Clean Room Environments 107

5.1.1.9 Waste and Waste Treatment 109

5.1.1.10 Process Support Systems: High Purity Water 112

5.1.1.11 Process Support Systems: Hand Washing Sinks and Personnel showers 112

5.1.2 Plant Siting Issues 113

5.1.2.1 Zoning & Permitting 113

5.1.2.2 Regional Environmental Agencies and Environmental Impact Reports 113

5.1.2.3 Building and Site Security 114

5.2 Bioprocess Unit Operations 116

5.2.1 General Equipment Design Considerations 117

5.2.2 Closed-System Design 118

5.2.2.2 Impact on Operations 123

5.2.3 Upstream Equipment and Facility Design 124

5.2.3.1 Additional Upstream Design Considerations 124

5.2.3.2 Equipment and Facility Integration 127

5.2.3.3 Production Segregation and Flows 127

5.2.3.4 Segregation from a Biosafety Perspective 129

5.2.3.5 Cleaning the Equipment 130

5.2.4.1 Harvest and Recovery 134

5.2.4.2 Centrifugation 134

5.2.4.3 Filtration 135

5.2.4.4 Chromatography 137

5.2.5 Facility Support Issues 139

5.2.6 Biosafety for Personnel: SOP, Protocols, and PPE 140

6 THE EFFECTS OF EMERGING TECHNOLOGY ON BIOPROCESSING RISK MANAGEMENT 143

6.1 Researching and Staying Informed 143

6.1.1 Biopharmaceutical 144

6.1 .1 .1 Drug Discovery and Development 144

6.1.1.2 Gene-based Pharmaceuticals 144

6.1.1.3 Drug Delivery Research 146

6.1.2 Renewable-resources 147

6.1.3 Environmental 148

6.1.3.1 Bioprocessing and Waste Management 148

6.2 Communicating the Impacts of New Technology 149

6.2.1 Industry (Communication at Your Site) 150

APPENDIX A - REFERENCES & SELECTED REGULATIONS 153

APPENDIX B - LARGE SCALE BIOSAFETY GUIDELINES 161

APPENDIX C - A GENERIC LABORATORY/LARGE SCALE BIOSAFETY CHECKLIST 177

APPENDIX D - BIOLOGICAL ASSESSMENT QUESTIONNAIRE & BIOPROCESS SAFETY CHECKLIST 179

APPENDIX E - BIOPROCESS FACILITY AUDIT CHECKLIST 189

APPENDIX F - DIRECTIVE 2000/54/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL 199

APPENDIX G - COMPARISON OF GOOD LARGE SCALE PRACTICE (GLSP) AND BIOSAFETY LEVEL (BL) - LARGE SCALE (LS) PRACTICE 203

GLOSSARY 209

ACRONYMS AND ABBREVIATIONS 217

INDEX 221