GROWTH – DEDICATED CALL – 1/00
TOPIC III.23
Biological Evaluation Of Medical Devices
1. CONFORMITY WITH THE WORK PROGRAMME
This topic falls under the Competitive and Sustainable Growth Programme, generic
activity Measurement and Testing. Specifically, it is related to Objective GROW-20006.3 support to the development of certified reference materials for which expressions of
interest have been called.
The project clearly meets two of the work programme’s three socio-economic
objectives, i.e. mainly pre-normative research and technical support to standardisation,
but also improvement of quality.
The project clearly meets two of the work programme’s three objectives (6.2 and 6.3)
through support to the development and validation of reference materials and generic
measurement and testing methods which assist a) in the production of data defining
performance, reliability, quality and safety requirements of medical devices, and b) with
the provision of improved analytical services supporting mandated European standards
and medical device Directives.
2. KEYWORDS
Reference materials; standardised test methods; validation; biomaterials; medical
devices; physico-chemical characterisation; mechancial characterisation; biological
characterisation.
3. SUMMARY OF OBJECTIVES AND JUSTIFICATION
Part 12 ‘Sample preparation and reference materials’ of the EN ISO series of standards
30993/10993 ‘Biological evaluation of medical devices’ specifies requirements and
gives guidance on the use of reference materials for testing biological evaluation. There
is a clear need for a supporting range of well-characterised reference materials, with
known surface and bulk compositions, whose responses to appropriate biological
environments are quantified and validated.
The potential exploitation of medical device (bio)materials is restricted by problems
associated with achieving reliable, consistent and quantifiable assessments of biological
response. New and/or existing test methods need to be developed and/or standardised.
Interested parties will then be able to demonstrate conformity with one or more parts of
the EN ISO series. There are also further implications with respect to the new Approach
medical device Directives 90/385/EEC and 93/42/EEC.
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4. BACKGROUND
In the late seventies, the United States reviewed progress in developing medical device
materials and determined significant gaps in the understanding of blood-material
interactions. Expert panels, established to define reliable approaches to this issue,
emphasised the need for the production of reference materials for use as negative
controls. By the mid-eighties, two materials had been fully characterised physicochemically. However, no associated biological evaluation was carried out.
In Europe, CEN/TC 206 (Biological testing of medical and dental materials and
devices) shadows most of the ISO work programme, and a limited number of potential
reference materials have been identified for both in vitro and in vivo evaluation. Recent
activities outside the CEN arena also offer the possibility of a very limited number of
additional materials. However, the majority of these potential materials tend only to
show a very severe, or no/minimal, biological reaction when tested.
Few Member State institutions have yet truly recognised the importance of the role of
both reference materials and standardised test methods as the means by which to further
understand and develop effective and reliable materials and biological testing
techniques.
5. ECONOMIC AND SOCIAL BENEFITS
The end of 1992 saw the completion of the Single Market within the European
Community (now Union) and with it the removal of all remaining trade barriers
currently restricting free movement of goods. European standards are used increasingly
and so there is a need to encourage accreditation of test laboratories and adoption by
industry of certified quality systems. Reciprocal recognition of test data can only be
achieved by increased co-operation between laboratories.
Whilst the worldwide market for medical device (bio)materials has continued to rise
from its estimated $12 billion in 1992 to an estimated $20-25 billion in 1998, the full
potential of some biomaterials has been limited by the inability to achieve reliable,
consistent and quantifiable evaluations repeatable both within, and between,
laboratories. This problem has been specifically highlighted by both the biomaterials
industry and Member States laboratories, and has already begun to manifest itself in the
‘failure’ of specific medical devices with corresponding large social and economic
consequences.
The presence of reference materials for biological evaluation will impact heavily on
every other biological standard where the use of reference materials is to become
essential.
Rectification of the measurement problems related to this area will also help remove the
direct economic significance associated with the means whereby problematic materials
can pass successfully through existing procedures of approval. This will result in an
increased cohesion of activity within the European Union and will address the
imbalance with the United States.
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6. SCIENTIFIC AND TECHNOLOGICAL OBJECTIVES
A. To develop/supply well-characterised reference materials, of known surface and bulk
compositions, whose responses to appropriate biological environments are quantified
and validated.
The reference materials should correlate with the shapes, forms and final treatments of
related implants, bearing in mind the test method(s) in which they may have to be used.
The reference materials should, wherever possible, cover the various major medical
device (bio)material applications: it is envisaged that both ‘stable’ and ‘degradable’
materials will be supplied.
Note: it should be noted that degradable materials represent a real challenge due to the
continuous interaction between material and biological environment (and vice-versa),
no steady state for evaluation of implant reactions being present.
Candidate reference materials should be made available for interlaboratory trials with
the validation data generated being supplied as data reports and/or certificates (ISO
Guide 31) to a suitable office for future storage, distribution and sale of the reference
materials, and provision of any associated support to standards.
The reference materials and their producers should meet the requirements of the
relevant ISO Guides 34 and 35.
B. To develop and/or standardise appropriate test methods which fully characterise the
physico-chemical, mechanical and biological evaluation of the selected reference
materials.
Note: this assumes that one generic method for each form of envisaged characterisation
will be suitable for each type of reference material selected; it is likely that more will be
required for full characterisation purposes.
The physicochemical test methods should, wherever possible, be readily available in
many laboratories, unless good justification is provided.
The induced biological response(s) should neither be too severe nor too low.
The test methods should be applicable to the appropriate biological environments of the
selected medical device (bio)material end-use applications and be drawn, at least in the
first instance, from the existing tests specified in the relevant parts of the EN ISO series
of standards, unless good justification is provided.
Test method results obtained for the reference materials should, wherever possible, be
correlated with the observed material surface and bulk characteristics or other
properties.
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C. To disseminate the information.
A suitable dissemination and technology transfer plan for the supplied reference
materials and standard operating protocols should be provided. This shall at least
include delivery of the project deliverables to the relevant CEN/ISO working groups
through relevant national Committee members.
7. TIME SCALE
The work is to be completed within 42 months of commencement of the project to allow
for both the development and the lengthy validation process by interlaboratory
comparisons. This would suggest mid-late 2004 as the project delivery date (allowing
for the tender and contractual stages of the process). However, due to the envisaged
separate components of the project, reflecting the differences in likely timescales for
existing and new materials to be made available, it would be advantageous to submit the
individual (certified) reference materials and test methods to CEN/TC 206 as they
become available.
8. IMPORTANT ADDITIONAL INFORMATION
Result format: The project deliverables shall be presented as (certified) reference
materials in line with ISO Guides 31, 33-35 and as test methods in CEN format. They
shall be ready for use by manufacturers, enforcement organisations and others to test for
conformance to EN ISO 30993/10993 series, particularly Part 12. The methods shall
include validation data produced during development.
Restrictions: A minimum of three leading European organisations shall directly
take part in the development of the (certified) reference materials and test
methods. A minimum of five laboratories giving acceptable results shall take part
in the validation exercises.
Cost
The estimated cost of the work to the Measurements and Testing sub-programme is
500,000 Euros.
References
EN ISO 30993/10993 series of standards, particularly Part 8 ‘Guidance on the selection
and qualification of reference materials for biological tests’ and Part 12 ‘Sample
preparation and reference materials’ (or preferably current draft revision of Part 12
which incorporates Part 8).
European Market for Biomaterials: Perspective and Opportunities, Willems & Van der
Wildenberg, 1992.
ISO Guide 31 Contents of certificates of reference materials.
ISO Guide 33 Uses of certified reference materials.
ISO Guide 34 General requirements for the competence of reference material producers.
ISO Guide 35 Certification of reference materials – General and statistical principles.
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Addendum to the supporting document for all topics related to
the development of Certified Reference Materials (CRMs)
Introduction
Research in support of the development of CRMs is an objective of the Growth
Programme. The modality for this research is a shared cost action on RTD (cf work
programme Competitive and Sustainable Growth). The guidelines for the submission of
the proposal are laid down in the Guides for Proposers.
In addition to the requirements for research on a specific topic that are laid down in the
supporting document*, there are general requirements for the development of CRMs.
These requirements are described below and are in addition to the general requirements
for shared cost actions, as described in the guides for proposers and the model contract.
The requirements have been divided in 2 major parts:
I) Description of the work
This part concentrates on the technical requirements of the research as well as
the reporting requirements in view of the future certification.
II) Implementation of the objectives of the research
The research on CRMs consists of the development of the ability to produce and
certify reference materials that are fit for purpose. The planned exploitation of
the results has to aim at the production and certification of the reference
material(s) in accordance with prevailing international quality standards.
*
The dedicated call system enables the Commission to identify priority topics that have
been forwarded under the call for the expressions of interest. The supporting document
that has been used to evaluate the topic now serves as a reference document to the
proposers for the preparation of the proposal.
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I) Description of the work
Research on CRMs consists of the development of the ability to produce and certify
reference materials. The actual production of the CRM is not part of the research but is
part of the exploitation of the result(s).
In the first phase of the research project the certification strategy should be elaborated
(development of the materials and methods for characterisation), in the second phase of
the research project the ability to produce and certify should be demonstrated and
finally the specifications for the final CRM should be set.
The development of a CRM normally consists of 4 major parts:
1) development of the know-how required to produce (and package) the future CRM
2) development of the methods needed for future certification of the material
3) demonstration of the feasibility of the CRM production (production of a small batch
+ mimicking its certification)
4) reporting of detailed and realistic specifications for the future CRM
1. Development of the know-how required to produce (and package) the future
CRM
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specify the sort of material that is most likely to meet both the targets laid down in
the supporting document and be suitably homogeneous, stable, safe to handle, and
acceptable in cost
identify the options available for selecting / preparing such a material
take into account special storage and / or transport requirements existing for certain
types of materials
develop of methods for production / selection and preparation, homogenisation,
stabilisation, protection and packaging of material as required, to enable the
production of a CRM which will be fit for purpose
if a material needs to be altered substantially (e.g. freeze drying), or when it is
artificially spiked with the substance of interest, it is necessary to check if the material
behaves in the same manner as the routine samples when applying the relevant
methods of measurement.
Ensure the availability of a suitable reconstitution procedure if a material will need
reconstitution
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2. Development of the methods needed for future certification of the material
Certification can be performed according to different criteria. The research will
define which certification route, following internationally recognised quality
requirements and standards, will be followed.
Certification on the basis of pure substances
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If the CRM is a pure substance the preparation methods should be such that the
presence of impurities are reduced to a minimum. Additionally the substance should
be tested for impurities by carefully selected methods at least in two laboratories.
Certification on the basis of preparation data
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When dealing with a synthetic CRM and a quantity which is directly related to (or
depends in a well-established way on) composition, examine if preparation under
metrological conditions and certification on that basis (e.g. using gravimetric data) is
possible
 Identify nevertheless a method of measurement that can be used as an independent
check for large errors
Certification on the basis of measurements - method-dependent quantities
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If the quantity to be certified is defined on the basis of a specific (standard) sample
treatment or method of measurement, certification will be based on statistical
processing of results produced by a sufficient number of laboratories (e.g. 12 - 15),
which follow strictly the standard protocol but include all variability which is
allowed by the protocol (do not use common sources of calibrants, reagents, ...
unless these will be available to the future CRM users and prescribed in the
protocol). Such protocol may have to be developed
 Work may be necessary to achieve an acceptable level of reproducibility
Certification on the basis of measurements - method-independent quantities
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As error-free, matrix-independent, calibration-independent methods are exceptional,
the basis for certification will usually be an agreement between different methods and
different laboratories, applied under conditions of independence which rule out the
risk of a common systematic error. Methods with a high potential for matrixindependence and/or calibration-independence (e.g. IDMS for determining
polyisotopic elements) should be included if available
 it may be necessary to perform a substantial collaborative method improvement (to
achieve the required level of agreement between methods and between laboratories),
or even research (method development) to achieve the required ability to measure.
Guidance for collaborative method improvement is given in the BCR Guidelines*
*
Guidelines for the production and certification of BCR reference materials, available from the
Commission on request (E. Michel, tel: 32/2-295.11.33, fax: 32/2-295.80.72, email:
ellen.michel@cec.eu.int )
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3. Demonstration of the feasibility of the CRM production
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prepare a small batch of material, similar to that intended to be prepared as a CRM,
using the method intended to be used to prepare the actual reference material
 Check the fitness for purpose:
 form, shape or texture of the material; if applicable, contamination (air, moisture,
vapours, dust and dirt, micro-organisms etc.)
 homogeneity
 stability (the analyte / measurand as well as the matrix)
 safety of packaging when exposed to shocks, extreme temperatures and other possible
causes of damage during storage and transport
 ease of opening and use
 lyophilisation and reconstitution procedures
Guidance for homogeneity and stability testing is given in the BCR Guidelines.
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Use the test batch to mimic the certification of a future CRM in a measurement
campaign, designed as a certification exercise (see BCR Guidelines)
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If the results show that a CRM prepared and certified as in the test round is not good
enough, then the development work (1. or 2. above) must be recommended
4. Reporting of detailed and realistic specifications for the future CRM
The reporting requirements are set in the guidelines for reporting. In addition to the
Final Technical Report the coordinator should prepare an overview of all the results,
as foreseen in the Technical Implementation Plan. In this report the outcome of the
research that sets the boundaries for the future CRM production should be given
preferably in the form of a technical data sheet. It should contain the following
information:
 form / type of samples (with preference for individually packed portions for single
use)
 lyophilisation and reconstitution procedures
 specify bottling, labelling, packing, storage and transport requirements
 identify any legal restrictions on the transport of such material and need for safety
labelling, collect data for material safety data sheets
 magnitude of the quantity of interest (acceptable range)
 acceptable uncertainty on the certified value for an individual sample (this includes
at least: acceptable uncertainty on the mean value for the entire batch, and
acceptable level of inhomogeneity of the batch)
 method requirements (if the CRM is method dependent)
 acceptable magnitude of other quantities
 an estimate of the quantity of CRM that should be produced as well as an estimate
of the production costs.
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II) Implementation of the objectives of the research
As for all shared cost contracts the contractors are obliged to exploit the knowledge
arising from the project. In the case of research on CRMs the contractors are, among
others, obliged to assure that the CRM is produced and certified within a reasonable
time limit (article 10 of Annex II General Conditions of model contract).
The "Technological Implementation Plan" (TIP), which has to be prepared in any
RTD project of the 5th Framework Programme, shall explain the actions planned to
assure that results of the project will be exploited. In case of CRMs this TIP has to
outline the strategy for the CRM production, certification and marketing within a
reasonable time frame, at a reasonable cost and according to internationally
recognised quality requirements. A draft TIP has to be available at the project midterm. Options, ranging from production by the consortium to production by a third
party or the Commission, will be explored in consultation with the Commission
Services.