Biosafety in Industrial Biotechnology

Biosafety in Industrial Biotechnology Edited by ... 2.4.4 Duties of manufacturers and suppliers 20 ... 10.6.4 Ablation and back-migration of vacuum pu...

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Biosafety in Industrial Biotechnology Edited by P. HAMBLETON, J. MELLING Centre for Applied Microbiology and Research Porton Down Wiltshire UK and T.T. SALUSBURY Science and Technology Section British Embassy Japan

BLACKIE ACADEMIC & PROFESSIONAL An Imprint of Chapman & Hall

London • Glasgow - Weinheim • New York • Tokyo • Melbourne • Madras

Contents 1

The development of European legislation on genetically modified organisms A . J . TAYLOR 1.1 Introduction 1.2 The development of the EC directives 1.3 The EC Directives on genetic modification 1.3.1 Directive 90/219/EEC - Contained use of genetically-modified micro-organisms 1.3.2 Directive 90/220/EEC - Deliberate release of genetically-modified organisms 1.4 The situation in the twelve Member States (as of February 1993) 1.4.1 United Kingdom 1.4.2 Federal Republic of Germany 1.4.3 Netherlands 1.4.4 France 1.4.5 Denmark 1.4.6 Belgium 1.4.7 Remaining EC Member States 1.5 Situation in the EFTA nations (as of February 1993) 1.6 Europe vs. the USA Disclaimer References

2 Occupational and environmental safety: the UK legislative framework A . N . COTTAM 2.1 Introduction 2.2 International influences 2.2.1 The UK approach 2.3 Occupational health and safety legislation 2.4 The Health and Safety at Work Act 2.4.1 Duties of employers 2.4.2 Duties of employees 2.4.3 Duty not to misuse 2.4.4 Duties of manufacturers and suppliers 2.4.5 Management systems 2.5 The Environmental Protection Act 2.6 Specific regulations 2.6.1 Control of Substances Hazardous to Health Regulations 1988(COSHH) 2.6.2 Genetically Modified Organisms (Contained Use) Regulations 1992 and Genetically Modified Organisms (Contained Use) Regulations 1993 2.6.3 Pressure Systems and Transportable Gas Containers Regulations 1989 2.6.4 Electricity at Work Regulations 1989

1 1 1 2 3 5 8 8 8 9 10 10 11 11 11 12 13 13

14 14 14 15 16 18 18 19 19 20 20 21 21 21 22 23 24

CONTENTS 2.7 Advisory committees 2.7.1 Guidelines 2.7.2 Local involvement 2.8 Inspection and enforcement 2.8.1 Aims of inspection 2.8.2 Powers of inspectors 2.8.3 Enforcement 2.9 The way forward References

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Regulation of biotechnology in the United States, Canada, and Latin America D . T . KINGSBURY

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3.1 Introduction 3.2 The United States 3.2.1 Federal regulatory structure 3.2.2 Food and Drug Administration 3.2.3 Environmental Protection Agency 3.2.4 Department of Agriculture 3.2.5 Coda 3.2.6 State regulatory bodies 3.3 Canada 3.3.1 Veterinary biologies 3.3.2 Genertically modified plants and micro-organisms 3.4 Latin America and the Caribbean

32 32 33 36 43 49 51 51 52 53 54 54

The legal and regulatory framework for biotechnology in Japan T. SALUSBURY

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4.1 An overview of the Japanese biotechnology industry 4.2 Government attitudes to biotechnology 4.3 The government bodies involved in biotechnology 4.3.1 Laboratory-scale experiments 4.3.2 Monbusho and STA Guidelines 4.4 Industrial-scale applications of r-DNA technology 4.4.1 Industrial uses of r-DNA technology 4.4.2 Guidance for the use of r-DNA technology in the pharmaceutical sector 4.5 Agricultural applications of r-DNA technology 4.6 Foods and food additives 4.7 Deliberate release of genetically-modified micro-organisms Acknowledgements References

Biotechnology and industrial microbiology regulations in Russia and the former Soviet republics A. RIMMINGTON 5.1 Introduction 5.2 Regulations governing work with micro-organisms containing recombinantDNA

57 57 58 58 58 61 61 62 63 64 65 66 66

67 67 68

CONTENTS

5.2.1 History 5.2.2 The current guidelines 5.2.3 Regulatory authorities 5.3 Regulations governing labour safety in biotechnology research institutes and the microbiological industry 5.3.1 Labour safety standards 5.3.2 Rules governing the release of micro-organisms into the workplace 5.3.3 Regulations governing the release of micro-organisms into the environment 5.4 Adherence to regulations governing the containment and safe use of micro-organisms 5.4.1 The environment 5.4.2 Waste water 5.4.3 Industrial personnel 5.5 Conclusions References

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Physical aspects of the uncontrolled release of material in biotechnology operations K . P . NORRIS 6.1 6.2 6.3 6.4 6.5 6.6

Introduction The generation of aerosols Persistence of aerosols in a closed space Persistence of aerosols in the atmosphere Retention, clearance and absorption in the respiratory tract The biological behaviour of airborne particles 6.6.1 The stability of the organism 6.6.2 Particle size 6.6.3 Relative humidity and temperature 6.6.4 Oxygen 6.6.5 Sunlight 6.6.6 Protecting agents 6.7 Airborne allergens 6.8 Conclusions References

7

XI

68 70 74 77 77 78 79 80 81 83 84 86 87

90 90 92 95 98 99 100 100 101 101 102 102 103 103 104 105

Health hazards in biotechnology A . M . BENNETT

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7.1 Introduction 7.2 Health hazards 7.2.1 Laboratory-associated infection 7.2.2 Allergic reactions 7.2.3 Endotoxin reactions 7.2.4 Toxic reactions to products or by-products 7.2.5 Hazards posed by genetic modification 7.2.6 Hazards posed by animal cell culture 7.2.7 Hazards posed by plant cell culture 7.3 Hazards of bioprocessing equipment 7.3.1 Fermentation 7.3.2 Centrifugation 7.3.3 Cell disruption 7.3.4 Filtration 7.3.5 Product handling 7.3.6 Risk assessment 7.3.7 Prevention

109 110 111 112 116 118 119 120 121 122 122 122 122 123 123 123 124

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CONTENTS Acknowledgements References

8

Containment of unit processes P. HAMBLETON and J. MELLING 8.1 8.2 8.3 8.4

Introduction Unit processes in biotechnology Categories of containment Safety cabinets 8.4.1 Classification 8.4.2 Air filtration 8.4.3 Class I cabinets 8.4.4 Class II cabinets 8.4.5 Class III cabinets 8.4.6 Laminar flow work stations 8.4.7 Application of Class III cabinets to process containment 8.4.8 Fermentation 8.4.9 Other processes 8.4.10 Flexiblefilmisolators 8.5 Design engineering for secondary containment 8.5.1 Fermentation 8.5.2 Other processes 8.6 The cost of containment 8.7 Conclusions References

9 Containment in downstream processing J.S. DEANS and I.W. STEWART 9.1 Introduction 9.2 Regulations and guidelines 9.3 Cell separation 9.3.1 Filtration 9.3.2 Centrifugation 9.4 Cell disruption 9.4.1 Physical methods 9.4.2 Non-physical techniques 9.5 Fluid handling 9.6 Discussion and conclusions 9.7 Recommendations References

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129 129 130 131 132 132 134 135 136 136 137 137 137 139 143 144 144 145 146 146 147

149 149 151 152 152 154 166 166 172 173 174 175 176

10 Freeze-drying of biohazardous products G.D.J. ADAMS

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10.1 Introduction 10.2 Principles of the freeze-drying process 10.2.1 Product preparation 10.2.2 Prefreezing 10.2.3 Primary drying 10.2.4 Secondary drying 10.2.5 Stoppering and removal 10.2.6 Storage and reconstitution 10.2.7 Technical features of the freeze-drier

178 178 178 179 179 179 180 180 180

CONTENTS 10.3 Risk assessment 10.3.1 Potential hazards 10.3.2 Processing biohazardous materials 10.3.3 Liquid and particulate aerosols 10.4 Hazards associated with product dispensing and handling finished materials 10.4.1 Dispensing pumps 10.4.2 Dispensing needles 10.4.3 Filling reservoirs 10.4.4 Tray dispensing 10.4.5 Ampoules 10.4.6 Vials 10.4.7 Container breakage 10.4.8 Spillages 10.4.9 Stoppering 10.4.10 Product removal 10.4.11 Container sealing 10.4.12 Product storage 10.4.13 Container leakage during storage 10.4.14 Leak testing of sealed vials and ampoules 10.4.15 Reconstitution 10.5 Formulation 10.5.1 General concepts 10.5.2 Prefreezing 10.5.3 Freeze-drying 10.5.4 Freeze-dryingexcipients 10.5.5 Container breakage and miscellaneous consequences of product freezing 10.5.6 Storage 10.5.7 Comparison of protection during aerosolation or freeze-drying 10.6 Ablation 10.6.1 Loss of contents 10.6.2 Influence of product formulation on ablation 10.6.3 Ablation and spillage 10.6.4 Ablation and back-migration of vacuum pump oil 10.7 Practical aspects of the design and operation of freeze-driers and associated equipment 10.7.1 Freeze-drier design 10.7.2 Freeze-drier fabrication 10.7.3 Chamber/condenser geometry 10.7.4 Protective devices 10.7.5 Electrostatic precipitation and ultraviolet irradiators 10.7.6 Incineration 10.7.7 Filtration 10.7.8 Selection and position of filters 10.7.9 Decontamination of the interior of the freeze-drier 10.7.10 Biocides and sanitising agents 10.7.11 Sterilisation by gaseous biocides 10.7.12 Dry heat 10.7.13 Atmospheric pressure steam (live steam) 10.7.14 Pressurised steam 10.7.15 Integrated approach to safe freeze-drying of biohazardous materials 10.7.16 Factors affecting operational safety 10.7.17 Dispensing product 10.8 Conclusions Acknowledgement References

Xlii 181 181 181 182 183 183 183 184 184 184 185 185 185 186 186 186 186 187 187 188 188 188 189 189 189 190 190 191 191 191 191 192 192 192 193 194 194 195 195 195 196 196 199 199 200 204 204 204 206 206 207 207 209 209

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CONTENTS

11 Interpretation of regulatory requirements to large scale biosafety - the role of the Industrial Biosafety Project G. LEAVER 11.1 11.2 11.3 11.4

Introduction Regulatory issues Risk assessment Human health and safety 11.4.1 Estimation of GMO hazard 11.4.2 Elaboration of containment principles 11.4.3 Equipment containment design principles 11.4.4 Measuring and monitoring containment 11.4.5 Maintenance and training 11.5 Environmental safety 11.6 Conclusions Acknowledgements References

12 Managing the effluent from bio-industrial processes J.R. COURT 12.1 12.2 12.3 12.4 12.5 12.6 12.7

213 213 213 214 215 215 217 218 228 232 232 235 236 236

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Introduction Regulatory background Assessment of risk and appropriate action Categories of waste Liquid effluent Choice of treatment method Containment considerations 12.7.1 Multiplicity of containment devices 12.7.2 'Dead legs'and crevice avoidance 12.7.3 Leak testing 12.7.4 Standard operating procedure (SOPs) and process records 12.7.5 Planned preventative maintenance (PPM) schedule 12.7.6 Commissioning and validation 12.8 Practical treatment methods 12.8.1 Filtration 12.8.2 Disinfection using chemical agents 12.8.3 Heat treatment using steam 12.9 Testing effluent for sterility 12.10 Design and qualification of a heat treatment effluent plant 12.10.1 Design considerations 12.10.2 Qualification of effluent treatment plant 12.11 The approach to effluent at CAMR References

240 241 241 242 242 244 244 245 246 246 247 248 248 248 248 249 250 251 252 252 256 257 266

13 Sampling methods for testing and monitoring biosafety of biotechnology equipment and activities J . E . BENBOUGH

268

13.1 13.2 13.3 13.4

Introduction Samplingmicrobial aerosols Sampling methods Air sampling devices 13.4.1 Inertial collectors 13.4.2 Air centrifuges

268 269 270 272 273 280

CONTENTS 13.4.3 Filtration 13.5 Sample assessment 13.5.1 Background 13.5.2 Detection methods 13.6 Practical applications of sampling techniques References

Index

XV 284 286 286 286 288 291

293