|
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
Code Number:BY96002
Size of Files:
Text: 24.7K
No associated graphics files
SUMMARY
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
The conditions for acceptance of a draft standard at the
Formal Vote stage are:
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.
WORKING GROUP 2 Large scale process and production
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
WORKING GROUP 3 Characterisation of GMOs
- 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.
Standards required to implement quality control
procedures
- 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
WORKING GROUP 4
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
DIFFICULTIES
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
Published by Bioline Publications and Science and
Technology Letters.
Copyright held by the author
Editorial Office: biosafe@biostrat.demon.co.uk
|