C6LS] 977179 Advisory Committee on Dangerous Pathogens The large-scale contained use of biological agents HSE BOOKS Saran Pane Omen (eh aluet et (eiiel isi ef (ey ¢:i s) “ee 16 «'e, elie! oi ee) \el ‘ele ee SMe AT 8) 1070) (et (eu ey (ee) fer 6) 6" (9) 0a (ee 16; 16)( 6! wl 6! s Advisory Committee on Dangerous Pathogens The large-scale contained use of biological agents HSE BOOKS St ei 9) the 109) ecole es 6! aftay toute! aji s! "er ‘e)\(e) ep ols). @) wi n)).ofl eo) es: 'e)) «) ©) i) e' “= e) 6.0) 4) ‘we! ye) “el @) 6)[ 0 ¢) 6) @ 0) ©) © -@ @) & 6 i606 © “i El iw. SP len le, eles ere’ <oF 6b Jey, ‘ep ee let el) leh eo piy e) ey 10. (0) She) ermetyion oN te oiler joi semen ‘ou veiL ey (oj te) of esveries Lemiemiomes) eice) le eauue. secu lele mate, © Crown copyright 1998 Applications for reproduction should be made to: Copyright Unit, Her Majesty’s Stationery Office, St Clements House, 2-16 Colegate, Norwich NR3 1BQ First published 1998 All rights reserved. No part of this publication may be reproduced, stored ina retrieval system, or transmitted in any form or by any means (electronic, mechanical, photocopying, recording or otherwise) without the prior written permission of the copyright owner. ISBN 0 7176 1544 8 This guidance was prepared for the Health and Safety Executive by Eur Ing John F Thorley, B.Sc., C.Eng., M.l.Chem.E., in consultation with the Advisory Committee on Dangerous Pathogens which was appointed by the Health and Safety Commission as part of its formal advisory structure and by Health Ministers. The guidance represents what is considered to be good practice by the members of the Committee. It has been agreed by the Commission and Health Ministers. Following the guidance is not compulsory and you are free to take other action but if you do follow it you will normally be doing enough to comply with the law. Health and safety inspectors seek to secure compliance with the law and may refer to this and other relevant guidance as illustrating good practice. LIBRARY General Collections Front cover photograph shows a fermenter operating at Containment Level 3. Source: Centre for Applied Microbiology and Research (CAMR) LL eaaeapneneaaaaa 719207 Page ii visory Committee on Dangerous Pathogens Preface v Introduction 17 Health and safety legislation 1 Purpose of guidance 2 Management systems 5 Health and safety management 5 Quality management 6 Training 6 Safe working procedures 6 Permit-to-work procedures 7 Plant and process modification procedures 7 Emergency procedures 8 Emergency planning 9 Spillage procedure 12 Primary containment - fermentation systems for use with biological agents 13 General layout design parameters 15 Fermenter system containment 15 Pipework 15 Couplings 16 Static seals 17 Valves 20 Pressure relief systems 22 Agitator seals 22 Inlet air treatment 25 Exhaust air treatment 25 Fermenter operating pressure 30 Seed systems and inoculation 30 Sampling systems 32 Measurement probes 35 Addition systems 36 Downstream processing 36 Secondary containment - process rooms and buildings (contained areas) 38 Separation of organisms from the environment 38 Restricted access 39 Biohazard signs 39 Internal room operating pressure 39 Ventilation and room air filtration 47 Entrance, exit and changing areas 42 Fumigation 43 SEipetie (el eisl pists elinivelis (a liclis im! 6s 4.60.8 \6 oe (6. 61.6 61) 618 6) sis ie) 9! $i) 16) @! 6,6: 0 ‘ee ©.j e) 6) 656. 6: © 16: <6 10 © 0 <6, ‘0 Page iii Advisory Committee on Dangerous Pathogens Ze le es eo i eet ey ow) ho. 6! el Tot 036) 0)n e: (6 tele! jeer fel teiiie, seme) Wate isirie Ae) (6) (eoc felli e, cel, 0116) “0 leea diss) pee) (ey feues se) ie Me? ea 70146) Personnel washing arrangements 44 Spillage containment 44 Materials used in building construction 45 Personal protection 46 Lockers 46 Overalls, gowns andhats 46 Frequency of change 46 Personal protective equipment (PPE) 46 Smoking, eating, drinking, cosmetics and medicines 47 Respiratory protective equipment 47 Appendices 1 Classification of biological agents 49 2 General characteristics and standards for the large-scale use of micro-organisms 50 3 Engineering standards in biotechnology industries 55 References 56 ee ee St Me a ae JS ee a te TO I Pe eC eC PROCES nye OO Seth Cl Oo meee SS a Go Oe i SG oad Page iv Advisory Committee on Dangerous Pathogens This publication is intended to provide advice and information on good practice in the large-scale use of micro-organisms. It is intended as a supplement to guidance on the requirements of the Control of Substances Hazardous to Health Regulations 1994 (COSHH), which can be found in the Advisory Committee on Dangerous Pathogen’s publication Categorisation of biological agents according to hazard and categories of containment.' The main focus of this publication is to provide advice on safe standards of operation for the large-scale use of biological agents in Hazard Groups 2, 3 and 4. It is not principally aimed at those who wish to use Hazard Group 1 agents. By definition these are still potentially hazardous, for example they may be allergenic and/or toxic and therefore, where appropriate, reference will be made to such uses. It also does not seek to provide advice on the use of low-risk organisms which fall outside the definition of a biological agent, although for the sake of completeness, references to such agents are made in the text and appendices. Because of the great diversity of the industries which use biotechnology and their accepted modes of ‘good practice’, a publication such as this cannot cover in detail all the accepted processing standards. Appropriate standards are being gathered together for each sector in the form of good manufacturing practice (GMP) guidelines.* Some of these will be quoted but it must be remembered that they are primarily concerned with the maintenance of product quality rather than health and safety. Appendix 1 of this guidance sets out definitions of the classification of biological agents into four hazard groups. Appendices 2 and 3 are included with the guidance for information only. The tables were originally developed for the European Commission as part of a major survey of all the important industry sectors which use biotechnology.? Many of the industry sectors do not use organisms which are biological agents within the meaning of the COSHH Regulations. The practices shown for each sector will therefore be appropriate for the organisms used and will not necessarily apply to the use of biological agents. Appendix 2 gives a summary of the industry characteristics on a sector basis and shows a consensus view on subjects such as building construction, fermentation systems, personnel protection and restrictions. Appendix 3 summarises engineering standards on an industry sector basis. It covers valve, pipework and building standards and shows industry norms. * In the context of this guidance, the term GMP means good manufacturing practice, not good microbiological practice. Cac hr ch ce anGh Nick cist alven a’ stitial af aie) cals)is 7 s-a)-0 s*elkel wie: 8 0) elve sel ee, so) | 018 6 8!i s)X el sel ee) 6 8) 6! 8 @) 9 8) © Page v Advisory Committee on Dangerous Pathogens j u a w d o j e r e q p u e y o r e e s e y S W O D | | a / \ O X e | D :201nN0S A modern computer-controlled conta ine d fermenter Page vi Advisory Committee on Dangerous Pathogens 1 Modern biotechnology as we know it, like most other current technologies, has developed during the nineteenth and twentieth centuries. It is based in a wide range of traditional industries, many of which have existed in one form or another for thousands of years. These traditional processes enabled products liable to quick spoilage, which were often seasonal, to be converted into stable and storable products for use in the leaner months. 2 Non-pathogenic micro-organisms are widely used in a number of major industry sectors, foods, drinks, waste treatment and the large-scale production of antibiotics. They involve micro-organisms with long histories of safe use. 3 The use of micro-organisms with some known capacity to cause ill health, either by infection, allergic response or toxicity, has also developed in recent years, for example: e the production of citric acid using Aspergillus species (for example Aspergillus niger) which have a known potential to cause allergic response and, more rarely, infection; © the large-scale manufacture of industrial enzymes for enzymatic washing powders which can cause sensitisation and allergic responses. 4 The first successful vaccines, based on the use of pathogenic organisms, were made more than 100 years ago. Methods had to be devised for this work to be carried out safely. What we refer to as containment methodology has developed from this. 5 Developments in molecular biology have led to a number of new techniques, including genetic modification. This has allowed micro-organisms to be tailored to perform specific functions, rather than relying on traditional methods of mutation and strain selection. Health and safety 6 European Council Directive 90/679/EEC, now implemented in Schedule 9 legislation of the COSHH Regulations 1994, is concerned with the protection of workers from risks related to exposure to biological agents at work. As such it encompasses micro-organisms which are naturally occurring, or result from a conventional strain selection programme or are genetically modified. The Directive also includes the use of relevant cell cultures and human endoparasites. 7 It should be noted that the Directive and the national legislation arising from it, do not differentiate between traditional and genetically modified organisms. Both are concerned only with the risks to workers which might arise due to infection or disease caused by exposure to biological agents including allergenic and toxic effects. All these factors must be taken into account when designing safe, large-scale plant, buildings and systems of work suitable for use with such agents. CR ae re ene Mro s ree Aol icpr omic lcethe/_ ele MOLi sic e) clKotie gobo leh e uel,s ilieucst eich sil c/b s" 97.2) eite ieigtl eels) 8%. 8.7% 88 Oe PS Page 1 Advisory Committee on Dangerous Pathogens a (8) else! cet yell fei 0) 8) ceurer .@, ofu e: le)c ep efi e) se) (6)\ 8\ren el Veloso) Wenlen te oiM'cl Refinish (ely sji io) (ei +e) 10! 0; 10; .'@ (6/ <e7 #10) 46.160 67 erR e lene neuen sy 18 8 The use of any biological agent which is also a genetically modified organism requires compliance with: e COSHH 1994; e Genetically Modified Organisms (GMO) (Contained Use) Regulations 1992; e Genetically Modified Organisms (GMO) (Contained Use) (Amendment) Regulations 1996. 9 Management of Health and Safety at Work Regulations 1992 (MHSW) and other relevant legislation also apply to any work with biological agents. Purpose of guidance 10 This guidance provides an amplification of Parts II and III in Schedule 9 of COSHH and the associated guidance from the Advisory Committee on Dangerous Pathogens (ACDP). It also draws on guidance produced on the advice of the Advisory Committee on Genetic Modification (ACGM). 5. It is divided into four main sections: ® management systems; e primary containment - fermentation systems for use with biological agents; e secondary containment - process rooms and buildings (contained areas); e personal protection. 12 For the purposes of this publication the model used will relate to the pharmaceutical and allied industries’ concept of sterile fermentation which, although it employs mainly low-risk organisms, does use higher containment level organisms in Hazard Groups 2, 3 and 4 for a very small proportion of its products. Containment at higher levels is also used by the enzyme industry which largely follows similar practice. 13 ‘It is emphasised that the pharmaceutical industry concept is not the only way of carrying out large-scale fermentation at higher containment levels. Up to now, however, no other major industry sector applications have been developed and it is therefore not possible to give pragmatic and proven guidance using different concepts. This will not necessarily continue in the future and the guidance may be revised as necessary to incorporate new techniques and new applications. 14. +The guidance is based primarily on Containment Level 2, where traditionally words such as ‘minimise’ and ‘optional’ have been used. Because this is the area of greatest uncertainty, the guidance will attempt to provide practical advice by expansion of the concepts behind the use of these terms in the legislation. As each section is discussed, the additional requirements for Containment Levels 3 and 4 will be introduced as necessary. Ce So a Sa TOC TO YO OC TU TO ST a Sr Ye a ee Ce CC CCC th Cec) ce CleGert ce Oo che od Ct ee Goeth io om Page 2 Advisory Committee on Dangerous Pathogens