BioSafety Journal Pontificia Universidad Católica de Valparaíso ISSN: 1366 0233 Vol. 2, Num. 1, 1996

BioSafety, Volume 2, Paper 2 (BY96002) May 22nd 1996 
Online Journal, URL - http://bioline.bdt.org.br/by

European Standardisation in Biotechnology

Ray P. Clark

Thermal Biology Research Unit, Kings College London, Campden Hill Road, London, W8 7AH.

Convenor, Working Group 1 of CEN Technical Committee 233: Chairman British Standards Institution Committee CII 58 - Biotechnology

ray@medi.demon.co.uk

Received May 11th 1996 Accepted May 20th 1996

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This paper describes work in progress to develop European standards in biotechnology. It describes the scope of the programme, giving the titles of the 54 standards being developed by four working groups of a Technical Committee of the European Standards Organisation, CEN, and considers the technical, legal and political difficulties which have been experienced. The standards being developed cover aspects of biotechnology that have direct relevance to biosafety of people and the environment.

INTRODUCTION.

Techniques pioneered in the 1970s enabled the transfer of hereditary material (genes) between organisms to be carried out in a more controlled way than in the past. This made it possible to move genes across species barriers, creating genetically modified organisms (GMOs) that could not have arisen through natural reproduction or selective breeding. These techniques offered great promise, but scientists and regulators were concerned that the recombinant DNA technology involved could be wrongly applied with unforeseen and potentially dangerous consequences.

These concerns prompted regulatory action around the world, and in the European Community, (EC), now the European Union (EU), ultimately led to two key Directives regulating the ways in which genetic modification can be used,(EEC 1990a, EEC 1990b). A third Directive (EEC, 1990c, amended EEC, 1993) embraced GMOs as well as unmodified microorganisms in the context of the safety of workers.

Even while these Directives were being formulated, there was a strong scientific view that many of the hypothetical hazards had been greatly overstated. Nevertheless, in December 1992 the European Commission asked CEN (the European Committee for Standardisation) to produce a series of 54 standards in the field of biotechnology. To achieve this, CEN has set up a Technical Committee (TC 233) to produce the standards. The programme as a whole is designed to generate standards to underpin the implementation of Directives 90/219/EEC (on the contained use of genetically modified organisms), 90/220/EEC (on the deliberate release into the environment of genetically modified organisms) and 90/679/EEC and its amendment EEC, 1993 (on the protection of workers from risks related to exposure to biological agents at work).

The standards are intended to be state of the art documents in specifically identified areas so that industrialists and regulatory authorities will be able to know with certainty:

a) what is required and how it is to be achieved
b) what is recommended.

Not only will this facilitate the implementation of the Directives but it will support the development of the European Biotechnology Industry and enhance its competitiveness as well as provide a safety framework for workers, consumers and the environment.

Many of these standards will be published during the next 2 years and this paper examines some of the issues involved in their production.

ADMINISTRATIVE ARRANGEMENTS

The mechanism for the production of a European Standard under CEN rules is undoubtedly complex (CEN/CENELEC, 1994); the essential organisational structure and stages may be summarised as follows.

Standards drafting is the responsibility of a TECHNICAL COMMITTEE (TC). CEN TC 233, with some 40 members nominated by the 18 European National Standards Organisations, is responsible for producing the 54 standards, identified at the drafting stage as Work Items.

The TC sets up WORKING GROUPS (WG) each with a CONVENOR. Each WORKING GROUP may include up to 3 experts from each National Standards Body. CEN TC 233 has 4 WORKING GROUPS

Each Work Item has a PROJECT LEADER appointed by the relevant WORKING GROUP.

PROJECT LEADERS are ex officio members of the WORKING GROUP.

PROJECT LEADERS are responsible for preparing the first draft of a standard (first working document) either alone or with the help of a PROJECT GROUP.

A PROJECT GROUP comprises no more than 6 experts (including the leader)

Stages in the production of a standard.

When a first working document has been agreed by the WORKING GROUP, it must be considered by the TECHNICAL COMMITTEE, who either approve it or return it to the WORKING GROUP for modification. All documents up to this stage are produced in one language, which in the case of TC 233 is English; subsequently, documents are made available in French and German.

On approval by the Technical Committee, the document is translated and copies sent to each National Standards Body for CEN ENQUIRY. At this stage, the drafts are available to anyone in the member countries of CEN who wishes to comment.

After CEN ENQUIRY modifications can be made to the draft, if necessary, by the WORKING GROUP in an effort to satisfy the requirements of all National Standards Bodies, prior to a FORMAL VOTE on acceptance of the document (or not) as a European Standard.

In a FORMAL VOTE countries are allocated weightings as follows:

Member Country      Weighting 

Austria                 4 
Belgium                 5 
Denmark                 3 
Finland                 3  
France                 10  
Germany                10  
Greece                  5 
Iceland                 1 
Ireland                 3 
Italy                  10  
Luxembourg              2 
Norway                  3 
Portugal                5 
Spain                   8 
Sweden                  4  
Switzerland             5 
The Netherlands         5  
United Kingdom         10

1 A minimum of 71% of the total weighted votes cast in favour; 2 The Number of members voting affirmatively to be more than that of members voting negatively (simple majority, abstentions excluded).

If approved at the Formal Vote stage the Standard is adopted as a European Norm.

WORKING GROUPS

In order to carry out the biotechnology work programme, CEN TC 233 set up 4 Working Groups as follows:
- WG1 in charge of preparing 10 standards concerning the handling of microorganisms in laboratory research, development and analysis

- WG2 charged with preparing 7 standards concerning large scale production operations

- WG3 in charge of preparing 13 standards concerning the release into the environment of genetically modified microorganisms and also the implementation of quality control procedures.

- WG4 in charge of preparing 24 standards concerning performance criteria for equipment used in biotechnology, especially as regards the problems of cleanability, sterilizability and leak tightness.

The specific work items for each Working Group are listed below:

WORKING GROUP 1 Laboratories for research, development and analysis

     - Categorisation of microbiological laboratories          
     - Definition of the equipment needed for microbiological  
       laboratories according to the degree  of hazard         
     - Methods for the handling, inactivation and testing of   
       waste                                                   
     - Code of good laboratory practice                        
     - Guidelines for the containment of plants in experiments 
     - Guidelines for the containment of animals in            
       experiments

Microorganisms 

     - Examination of the various existing lists of animal     
       pathogens and production of a report                    
     - Examination of the various lists of plant pathogens     
       and production of a report. (BSI 1996b)                 
     - Further examination of organisms in support of the work 
       carried out under directive 90/679/EEC. (BSI 1996a)     
     - Examination of hosts and vectors which have been used   
       to construct group 1 organisms for  use in various      
       industrial applications and production of a report.

Plant design, process design and operating procedures for large scale fermentation and extraction processes

     - Plant building, according to the degree of hazard       
     - Equipment implementation according to the degree of     
       hazard                                                  
     - Procedures for strain conservation                      
     - Control procedures for raw materials and energy         
       supplies                                                
     - Personnel: code of good practice, procedures and        
       training control                                        
     - Procedures for fermentation and extraction operations   
     - Methods for the handling, inactivation and testing of   
       waste

     - Analysis of the genetic modification                
     - Analysis of stability of genomic modification       
     - Analysis of the functional expression of the        
       genomic modification

Sampling                                                
     - Sampling strategies for deliberate release of    
       genetically modified microorganisms              
     - Sampling strategies for deliberate release of    
       genetically modified viruses                     
     - sampling strategies for deliberate release of    
          genetically modified plants

Monitoring      
     - Strategies for monitoring genetically modified          
       microorganisms                                          
     - Strategies for monitoring genetically modified viruses  
     - Strategies for monitoring genetically modified plants.

           
     - Guidance on assessment of the purity, biological        
       activity and stability of microorganisms  based         
       products.                                               
     - Guidance for quality control diagnostic kits used in    
       agriculture, plants and animal pest  controls and       
       environmental contamination

Equipment

                                            
     - Standard testing procedure for cleanability    
     - Standard testing procedure for sterilization   
     - Standard testing procedure for leak tightness  
     - Performance criteria for gas/liquid filters    
     - Performance criteria for autoclaves            
     - Performance criteria for couplings             
     - Performance criteria for sampling methods      
     - Performance criteria for tubes                 
     - Performance criteria for valves                
     - Performance criteria for pumps                 
     - Performance criteria for shaft seals           
     - Performance criteria for level transmitters    
     - Performance criteria for probes                
     - Performance criteria for pressure protection   
       devices                                        
     - Performance criteria for glass pressure        
       vessels                                        
     - Performance criteria for safety cabinets       
     - Performance criteria for bioreactors           
     - Performance criteria for kill tanks            
     - Performance criteria for chromatography        
       columns                                        
     - Performance criteria for centrifuges           
     - Performance criteria for cell disrupters       
     - Performance criteria for sampling devices      
     - Performance criteria for HEPA filters and      
       off-gas systems                                
     - Performance criteria for micro/ultra           
       filtration

Lack of existing literature

At the start of this Standards initiative it was assumed that the scope of the documents would comprehensively cover a wide range of biotechnology activity not only in the area of safety but more generally where good practice in relation to product quality was concerned.

It was also considered by many involved that there pre-existed in the world literature good documents (standards, guidelines codes of practice, peer reviewed papers etc.) that would form the basis for most of these work items and that it would be a relatively easy matter to take the appropriate documents and modify them to be European Standards.

In the event this was not possible either because the documents did not exist or the expertise in the fast changing technical world of biotechnology, only existed within companies who were not willing to publish or allow such information into the public domain.

These problems gave rise to inevitable delay and a decision was eventually made to limit the standards to cover those aspects of biotechnology that have direct relevance to safety of personnel or the environment. This more realistic scope has enabled progress to be made.

National differences.

In some countries, notably Germany, safety standards are an intrinsic part of law and regulation and therefore they must not conflict with legal requirements. In other countries standards are applied voluntarily and have no legal basis although they may be used by regulators in support of legislation. The situation becomes more complex when considering that the biotechnology standards are in support of two Directives (i.e. 90/219/EEC and 90/679/EEC) which are based on Article 118A of the EU Treaty, which means that the member countries may have legislation with more strict demands than a Directive. However, national legislation always overrules a standard. It is the responsibility of the user of the standards to establish appropriate safety and health practices and determine the applicability of regulatory limitations prior to their use.

One result of these national differences is that some countries have seen potential conflict between the requirements in standards and their national legal framework. In consequence there has been pressure to remove from the standards documents any requirements which might be unpopular or difficult to implement. This can easily result in empty standards which have no real value in terms of safety to personnel or the environment and which ultimately bring the standards making bodies into disrepute. However, the standards organisations which make up CEN have a tradition of producing high quality standards within a strict protocol of drafting rules. As well as giving rise to clear unambiguous standards this approach fulfils the duty of care which is the responsibility of all standards makers and which may well be lacking in empty standards.

The CEN rules for drafting standards appear at first sight to be similar to rules in other standards bodies but differences in detail emerge which often result from differences in language. Thus although the rules of CEN and BSI are apparently similar, difficulties have arisen because some English words do not readily translate into French or German. The result of this, for example, can be the mixing of requirements and recommendations, which can lead to ambiguity putting the duty of care at risk. For example, the BSI clearly lays down that where a standard has a clear requirement the word shall is used and where there is a recommendation the word should is used. Furthermore, in any clause no mixture of shall and should is allowed and in guidance documents the word shall is not present.

This type of drafting rule has become widely accepted and established in English speaking nations and is a central principle for standards makers who are conscious of difficulties of interpretation that may occur in a legal context. Such a rigorous application of language removes much potential ambiguity in cases where safety standards are used by regulatory authorities as a basis for their legal requirements. However, in some EU countries there is less precision in the application and use of such words and it has recently been suggested that guidance documents may be drafted using the word shall.

Validation of safety requirements

The problems due to the general lack of availability of documents suitable as a basis for these standards have been compounded by a dearth of accepted test methods for validating the safety requirements in the standards. Whilst it may be fairly simple to require that, for example, equipment can be cleaned and/or sterilised, typical standards terminology is that specified tests must be available to verify the cleanability and sterilizability of the equipment: generally, these tests do not exist at present in the area covered by the CEN biotechnology standards. To some extent this problem has been overcome by writing the documents as a guide for establishing testing procedures.

Another problem area is in, for example, measuring the leakage of organisms from pumps, valves etc. Whilst it may ultimately be possible to specify and validate the performance of individual components under type test conditions the effect on people and the environment when hundreds/thousands of such components may be put together in a pilot or production process is extremely difficult to measure and validate, especially on a routine basis. Whilst there are a number of ways of sampling for airborne micro-organisms, many of the techniques rely on sampling particles (of skin for instance) or droplets that are larger than the individual organisms. The sampling efficiency dramatically reduces for single small organisms and this has important implications for safety assessments.

Perhaps the most comprehensive standard for equipment (and a model for CEN) in the TC 233 work programme is that for biological safety cabinets. The CEN document is based on the successful UK BS 5726 (BSI 1992) where clear requirements for workers safety are defined and specific test methods (type, commissioning and maintenance tests) are clearly described.

CEN TC 233 has identified a number of these basic problems concerned with the validation of requirements and has called for research projects to be funded which will ultimately provide techniques to support the safety requirements of the standards. It is vital that immediate research is carried out to enable validation methods to be established and become accepted. The European Commission issued a call for such projects in 1995 but financial support has not been forthcoming in the current round of supported research projects. CEN TC 233 is pressing for this urgent research to be initiated as soon as possible.

With the development of techniques such as computational fluid dynamics it may, in the future, be possible to consider validation procedures for complex installations using computer modelling methods to assess environmental and safety issues. However, such systems would only have credibility if comprehensive physical measurements were able to provide real data from which to build such modelling systems. These are substantial research issues that need to be addressed.

THE WAY FORWARD.

To some extent the experience of TC 233 has been one of learning to cope with technical, legal and political difficulties. This initiative with 54 standards was considered by some to be too ambitious and difficult and this has occasioned some re-organisation of the work programme and time schedules, in consultation with the European Commission.

On a positive note, the Commission maintains its confidence in the work and has invited the TC members to take a pro-active role in advising as to the safety content of Directives. There is also the view within the Commission that regulations can become outdated (especially in the fast changing field of biotechnology) and that standards can fill the gap. Although it would be possible to have harmonised standards, where the requirements in the standards, the Directives and legislation are identical, such standards would be inflexible and difficult to define and change. It is considered better to have standards with the minimum requirements for regulation (and safety) which can always be added to at national level and can be revised upwards as regulations themselves become outdated.

The concept of deregulation should rather be replaced by one of adequate regulation which, especially in the sensitive area of biotechnology, would be likely to gain general acceptance from the public and consumer. Furthermore, the Commission feels that standards having the minimum requirements for regulation should include greater rather than lesser detail in their specifications. It recognises that greater detail gives greater safety which overrides the penalty that such standards are more easily obsolete and will require revision more frequently.

The difficulties with these standards might encourage attempts to seek alternative ways of reducing risks to people and the environment. It may be valuable to assess the European approach to standardisation in comparison to other concepts (as in the USA for example) where, in addition to specifications for design and performance embodied in standards, there is a broader judgement of safety based on whether or not the use of the equipment and systems of work represents an insurable risk. In seeking alternatives to the European approach care should be taken, as some equipment based on ideas of insurable risk has not been of the same overall quality in safety terms as similar equipment subject to more detailed standards.

CONCLUSION

In conclusion, although the biotechnology standards coming from CEN TC 233 in the next two years will not be perfect and there may not be universal agreement as to their content, they should be sufficient to form an initial base for a systematic approach to safety in biotechnology: a base which will need to keep pace with the ever increasing knowledge and experience in this field.

REFERENCES

BSI, 1992. British Standard BS 5726, 1992. British Standards Institution, 389 Chiswick High Road, London W4 4AL, UK

BSI, 1996a English language version of CEN CR 12250, 1995 British Standards Institution, 389 Chiswick High Road, London W4 4AL, UK

BSI, 1996a. English language version of CEN CR 12292, 1996, British Standards Institution, 389 Chiswick High Road, London W4 4AL, UK

CEN/CENELEC, 1994. Internal Regulation Part 2: Common Rules for standards work

European Commission 1990a. Directive 90/219/EEC, Official Journal, L117, 8 May 1990, 1-14.

European Commission, 1990b. Directive 90/220/EEC, Official Journal, L117, 8 May 1990, 15-27.

European Commission, 1990. Directive 90/679/EEC, Official Journal, L374, 31 December 1990, 1-12.

European Commission, 1993. Directive 93/88/EEC, Official Journal, L 268, 29 October 1993, 71-81

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