3
GMO Regulations 303 facilities, and harmonisation is required in the guide- lines for these. The regulations at first appear identical but they differ in a few words. The COSHH Regulations (1995) do clarify many of the issues of harmonisation. Some designers criticise the regulations because there is insufficient detail. Others prefer the status quo, believ- ing that they state what should be done, but not how to do it. This approach is likely to permit innovation and ensure that safety features can range according to the severity of the hazard. The advantages of an equipment supplier being able to categorise a device as ‘Level 2 containment’ are obvious. However, he has no control on how it is installed, maintained or operated. The preferred approach by many is that the device is qualified at the factory or the workplace to demonstrate that it can be contained. The design of a plant which is easy to clean and sani- tise, and is able to operate without contamination can be achieved in many ways. I know of vaccine manufac- turing facilities which have only ball valves, have threaded pipe, single mechanical seals on fermenters and no automation, and which have rarely had a con- tamination nor have given rise to a release of virus. They do have excellent staff and good environmental monitoring programmes, and all liquid transfers are contained. If more detail of containment is needed, how shall we decide what is acceptable? The temptation is to recommended sterile pipework systems used in the manufacture of dosage forms which are derived from the dairy industry, where pipes were demounted for cleaning. Such systems are IDF or Triclover systems. These were designed for cleanability, nor for contain- ment, where all welded systems are preferred. The ideal situation is that we may turn to a performance stan- dard, such as CEN/TC233/WG4 N97 ‘Performance Cri- teria for Biotechnology Equipment’ and ensure that the system does conform to the standard in terms of leak- tightness, cleanability and sterilisability. The risk assess- ment will dictate the requirements and the definition of validated test methods is the key step in evaluating a satisfactory design. Risk assessment The onus is on the user to carry out a risk assessment. Sometimes the designer participates. More usually for reasons of confidentiality or because of a better under- standing, the user carries out the assessment alone. Per- sonally, I request a copy of the assessment, and copies of the ACGM notification from the user. This has always been readily given. Many users prefer to make contact directly with the HSE and do not wish to involve the contractor. The best approach is for joint meetings where the contractor is able to support the user with technical details. The HSE Inspectorate, and the Advisory Committees have a very high reputation for giving advice. They are pleased to be involved at the design stage. All enquiries are taken seriously and followed up. Although commu- nication with the HSE is bested controlled and docu- mented, I personally feel that some companies are over-anxious about the full exchange of views between their own experts and their counterparts in the HSE. Recommendations The use of case studies to illustrate the features required for the containment of micro-organisms is to be encour- aged. Several papers have attempted to do this. There should be no real issue of confidentiality where safety is concerned, and visits to sites where explanations can be given of the safety features should be encouraged. The SCI and IChemE subject groups would be ideal for organising such events. The publication of industrial case studies and exam- ples of the validation of containment are still infrequent. Although there are pressures on the time of industrial- ists, the advantages are significant because over-design can be minimised, and common methods of analysis can be improved and reviewed. Even a common approach to the estimate of leakage rates would be an advantage. Research into containment and biosafety must con- tinue, and be fully funded. The requirement for numbers describing leak-tightness, for example, are being estab- lished and the assessment of risk has forned a part of the EU funded research. The collaboration between uni- versities and equipment manufacturers is encouraging. The unversities are then able to integrate their research and teaching and provide graduates who are familiar with the issues involved and able to resolve problems from a sound scientific base. What Makes Good Regulation? L. E. Ferris, M. Noble, E. Keshavarz-Moore and M. K. Turner Advanced Centre for Biochemical Enginering, University College London, London WClE 7JE, UK The framework for regulation In the UK, the current approach to the regulations of technology is embodied in the Health and Safety at Work Act, 1974 (HASAW). Its subsequent revision, and the many other official documents which have appeared since, have not changed its basic philosophy which was a radical departure from what went before. The earlier legislation was based on a retrospective analysis of accidents and it defined regulations to

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G M O Regulations 303

facilities, and harmonisation is required in the guide- lines for these. The regulations at first appear identical but they differ in a few words. The COSHH Regulations (1995) do clarify many of the issues of harmonisation.

Some designers criticise the regulations because there is insufficient detail. Others prefer the status quo, believ- ing that they state what should be done, but not how to do it. This approach is likely to permit innovation and ensure that safety features can range according to the severity of the hazard.

The advantages of an equipment supplier being able to categorise a device as ‘Level 2 containment’ are obvious. However, he has no control on how it is installed, maintained or operated. The preferred approach by many is that the device is qualified at the factory or the workplace to demonstrate that it can be contained.

The design of a plant which is easy to clean and sani- tise, and is able to operate without contamination can be achieved in many ways. I know of vaccine manufac- turing facilities which have only ball valves, have threaded pipe, single mechanical seals on fermenters and no automation, and which have rarely had a con- tamination nor have given rise to a release of virus. They do have excellent staff and good environmental monitoring programmes, and all liquid transfers are contained. If more detail of containment is needed, how shall we decide what is acceptable? The temptation is to recommended sterile pipework systems used in the manufacture of dosage forms which are derived from the dairy industry, where pipes were demounted for cleaning. Such systems are IDF or Triclover systems. These were designed for cleanability, nor for contain- ment, where all welded systems are preferred. The ideal situation is that we may turn to a performance stan- dard, such as CEN/TC233/WG4 N97 ‘Performance Cri- teria for Biotechnology Equipment’ and ensure that the system does conform to the standard in terms of leak- tightness, cleanability and sterilisability. The risk assess- ment will dictate the requirements and the definition of validated test methods is the key step in evaluating a satisfactory design.

Risk assessment

The onus is on the user to carry out a risk assessment. Sometimes the designer participates. More usually for reasons of confidentiality or because of a better under- standing, the user carries out the assessment alone. Per- sonally, I request a copy of the assessment, and copies of the ACGM notification from the user. This has always been readily given.

Many users prefer to make contact directly with the HSE and do not wish to involve the contractor. The best approach is for joint meetings where the contractor is able to support the user with technical details.

The HSE Inspectorate, and the Advisory Committees have a very high reputation for giving advice. They are pleased to be involved at the design stage. All enquiries are taken seriously and followed up. Although commu- nication with the HSE is bested controlled and docu- mented, I personally feel that some companies are over-anxious about the full exchange of views between their own experts and their counterparts in the HSE.

Recommendations

The use of case studies to illustrate the features required for the containment of micro-organisms is to be encour- aged. Several papers have attempted to do this. There should be no real issue of confidentiality where safety is concerned, and visits to sites where explanations can be given of the safety features should be encouraged. The SCI and IChemE subject groups would be ideal for organising such events.

The publication of industrial case studies and exam- ples of the validation of containment are still infrequent. Although there are pressures on the time of industrial- ists, the advantages are significant because over-design can be minimised, and common methods of analysis can be improved and reviewed. Even a common approach to the estimate of leakage rates would be an advantage.

Research into containment and biosafety must con- tinue, and be fully funded. The requirement for numbers describing leak-tightness, for example, are being estab- lished and the assessment of risk has forned a part of the EU funded research. The collaboration between uni- versities and equipment manufacturers is encouraging. The unversities are then able to integrate their research and teaching and provide graduates who are familiar with the issues involved and able to resolve problems from a sound scientific base.

What Makes Good Regulation?

L. E. Ferris, M. Noble, E. Keshavarz-Moore and M. K. Turner

Advanced Centre for Biochemical Enginering, University College London, London WClE 7JE, UK

The framework for regulation

In the UK, the current approach to the regulations of technology is embodied in the Health and Safety at Work Act, 1974 (HASAW). Its subsequent revision, and the many other official documents which have appeared since, have not changed its basic philosophy which was a radical departure from what went before.

The earlier legislation was based on a retrospective analysis of accidents and it defined regulations to

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304 Extended Summaries-Biotechnology Group

prevent their happening again. The Robens Report,’ which preceded the 1974 Act, argued that, although the earlier process had served the community well, tech- nology had begun to advance so fast that a change was needed. It had become essential to assess the adverse effects of a new technology before its introduction and to require the user ‘... to carry out any necessary research with a view to the elimination or minimisation of any risks to health and safety ...’. Legislation and regulation which had once been retrospective now became prospective.

In practice the user community as a whole, rather than as individuals separately, has defined the risks of the new technologies and has designed the necessary controls. For much new biotechnology a consensus emerged from committees such as the Advisory Com- mittee on Genetic Modification (ACGM). The result for the use of recombinant micro-organisms must be judged successful in regard to ‘. . . the elimination or mini- misation of any risks to health and safety . . .’. Less suc- cessful is the technical justification for the control proposed. This is true of both the official documenta- tion, as is evident from the current debate over the content of European Directives, and of the proposed engineering standards which might underpin these Directives (see for example Ref. 2). Less successful also is the outcome for the acceptance of the technology by the public at large, despite the social benefits gained.

Who defines risk?

Good regulation must succeed in all three aspects, not simply in the first. This is a difficult problem because the ‘... risks to health and safety ...’ are not similarly defined in all three. It is only necessary to ask what ‘risk’ is, and who defines it, to find the problem. At one extreme it is simply the probability of an accident, at the other it is a concept which balances the social impact of the hazards and benefits which accompany a technology. There may be good technical methods for estimating the former but there are simply too many groups which have a legitimate stake in discussing the latter, and in defining what is, in their terms, an accept- able r i ~ k ~ , ~ for anything other than a compromise to emerge.

It is wrong to assume that the assessment of the risks which arise from the introduction of a new technology could ever be the sole province of the technologists themselves. Their role in setting good regulation must be to present the technical issues as clearly as possible, to indicate their limits, and then to take part in the social debate which follows. The role may be privileged in its leadership of some of the debate, but it must accept that it has limits. A regulatory framework which has no basis in science is likely to be unworkable but one which is only science-based may not be acceptable

to the community at large. Nor, as technologists should we be surprised if the community reorders the priorities of the technical issues themselves, particularly if the technical base for the regulation is not clearly exposed.

Definition of risk

One barrier which hampers the technical input to the social debate is the imprecise and varied meanings of the words used to conduct the argument, and particu- larly the meaning of the word ‘risk‘ itself. Some new definitions are necessary.

The ‘hazards’ inherent in processes with micro- organisms take a variety of forms : electrical, mechani- cal, and chemical as well as microbiological. If they are under proper control they will have no ‘adverse effect’ as envisaged in the HASAW. However, there is a ‘risk’ of their breaching that control when an ‘adverse effect’ will appear. It will cause loss or injury, for example to personnel, to the environment or to the product. The word ‘risk’ in this context is sometimes defined as the probability linking the ‘hazard’ to the ‘adverse effect’, while at others its meaning combines the ‘probability’ of the linkage with the ‘effect’. For example we talk of the ‘risk’ of the event occurring, and of the ‘risk’ from the ‘adverse effect’ itself. In contrast the word ‘hazard’ seems less debased by common usage.

In describing this relationship between ‘hazard’, ‘risk’ and ‘adverse effect’ some new terms would free the tech- nical input to regulation from any associated impreci- sion. We could define the ‘adverse effect’ of a ‘hazard‘ as its ‘detriment’. The link between the two would be created by events which release or activate the ‘hazard’ to a greater or lesser extent and with a particular fre- quency or ‘probability’. The actual nature and scale of the ‘detriment’ would be determined by the events themselves.

The words ‘hazard‘, ‘probability’ and ‘detriment’ so defined would allow the technical analysis which the HASAW requires to take place unaffected by any dis- cussion of ‘risk’, which more properly belongs to the social debate.

Accidental and incidental release

At the Advanced Centre we are attempting, as an example of such an analysis, to estimate the size of the components in this relationship as they apply to the contained use of micro-organisms. We presume that the microbial hazard in a process will cause a detriment in proportion to the scale and probability of any microbial release. The release may be an incidental feature of the process, that is to say a consequence of its normal oper- ation. This is likely to occur in processes which use safe micro-organisms for example in the manufacture of foods, beverages and some antibiotics. The release is

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G M O Regulations 305

often almost continuous, so that the probability of release is close to 100%. However, the level of release is compatible with good hygiene and safe microbial prac- tice, and the detriment is negligible.

On the other hand there are processes which operate at higher levels of containment (BL3), and from which the incidental release is undetectable. In effect the engin- eering of the process ensures that the probability of release is close to zero, so preventing any possible detri- ment.

However, in all of these processes, release following an accident must be taken seriously. This accidental loss of containment is independent of the incidental release, and the total loss will progressively accumulate over time in a stepwise fashion. In contrast the total inciden- tal loss will accumulate at a more or less steady rate. Any effort to contain a process ought to keep the two modes of release in balance so that losses from one do not overwhelm the actions taken to prevent losses from the other.

A balanced view of regulation

Recently we have examined the losses of micro- organisms from large-scale process equipment operating in a contained environment at level BL2. Under these conditions the primary engineering is not completely closed, and some release might be expected. The first results suggest that even at this minimal level of con- tainment the incidental loss of micro-organisms is small, and that too little effort is being devoted to the control of accidental release. We are presently engaged in research to make quantitative estimates of both so that a balance could be struck between the two.

It is quite practical to drive the level of incidental release well below the levels demonstrated in our study. Most studies of well-maintained equipment at higher levels of containment fail to detect any release at all. In contrast the accidental releases do occur. One estimate attributes a major outbreak of anthrax in the human population to the accidental release of no more than one gram of Bacillus anthracis spores.6 The accidental loss of one gram of cellular material from a process stream must be considered a likely hazard; it represents only a few millilitres of some concentrated process fluids. Although such accidents are more likely to arise from inadequate training and maintenance than from bad process design, it is notable that regulation places more emphasis on improving the latter rather than the former.

It is crucial to keep a proper balance in this debate. Nothing yet attempted in the large-scale manufacture with recombinant micro-organisms comes close to posing hazards commensurate with those of B. anthra- cis, or of any other natural pathogen. Not only is it generally accepted at a technical level that few of the

processes require containment simply because the organism is recombinant, but it is also evident that recombinant organisms actually provide safer methods of obtaining products which were once only available from pathogenic sources.

The difficulties over their regulation arise because the recombinant organisms are new, and created by human intervention. It therefore becomes possible to argue, quite independently of any hazard they might pose, for their complete containment within the processes for which they were designed. Simply because they did not exist in the environment they should not be dispersed to it. Sound technical advise has blunted this argument, and may in time help to counter it completely. It is, however, important to recognise that it is a legitimate part of a social debate for which a different risk-benefit analysis is required. It actually lies outside a purely technical approach to good regulation.

Acknowledgements

We acknowledge the support of the Leverhulme Trust and of the BBSRC in this research.

References

1. Robens, A,, Safety and Health at Work. Report of the Com- mittee. Cmnd 5034, HMSO, London, 1972.

2. Titchener-Hooker, N. J., Sinclair, P. A., Hoare, M., Vranch, S. P., Cottam, A. & Turner, M. K., The specifications of static seals for contained operations: an engineering appraisal. Biopharm., 6(8) (1993) 32-7.

3. Turner, G. & Wynne, B., Risk communication: a literature review and some implications for biotechnology. In Bio- technology in Public: a Review of Recent Research, ed. J. Durant. Science Museum, London, 1992, pp. 109-41.

4. Royal Society, Risk Analysis, Perception and Management. Report of a Royal Society Study Group. Royal Society, London, 1992.

5. Ferris, L. E., Keshavarz-Moore, E., Noble, M. & Turner, M. K., Microbial population balancing as a quantitative aid for evluating release from a high-pressure homogeniser. Trans. 1.Chem.E. (in press).

6. Meselson, M., Guillemin, J., Hugh-Jones, M., Langmuir, A. Popova, I., Shelokov, A. & Yampolskaya, O., The Sverd- lovsk anthrax outbreak of 1979. Science, 266 (1994) 1202- 08.

Impact of EC Regulations on a UK Biotechnology Company

Duncan Casson

Genzyme Biochemicals, 50 Gibson Drive, Kings Hill, West Malling, Kent ME19 6HG, UK

Most biotechnology companies are relatively small organisations which often have a disparate range of interests relative to their size. Genzyme’s interests for