SIST EN ISO 10993-2:2006

SLOVENSKI STANDARD
SIST EN ISO 10993-2:2006
01-september-2006
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SIST EN ISO 10993-2:2000
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,62
Biological evaluation of medical devices - Part 2: Animal welfare requirements (ISO
10993-2:2006)
Biologische Beurteilung von Medizinprodukten - Teil 2: Tierschutzbestimmungen (ISO
10993-2:2006)
Évaluation biologique des dispositifs médicaux - Partie 2: Exigences relatives a la
protection des animaux (ISO 10993-2:2006)
Ta slovenski standard je istoveten z: EN ISO 10993-2:2006
ICS:
11.100.20 %LRORãNRRYUHGQRWHQMH Biological evaluation of
PHGLFLQVNLKSULSRPRþNRY medical devices
SIST EN ISO 10993-2:2006 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.

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SIST EN ISO 10993-2:2006

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SIST EN ISO 10993-2:2006


EUROPEAN STANDARD
EN ISO 10993-2

NORME EUROPÉENNE

EUROPÄISCHE NORM
July 2006
ICS 11.100.20 Supersedes EN ISO 10993-2:1998
English Version
Biological evaluation of medical devices - Part 2: Animal welfare
requirements (ISO 10993-2:2006)
Évaluation biologique des dispositifs médicaux - Partie 2: Biologische Beurteilung von Medizinprodukten - Teil 2:
Exigences relatives à la protection des animaux (ISO Tierschutzbestimmungen (ISO 10993-2:2006)
10993-2:2006)
This European Standard was approved by CEN on 14 July 2006.

CEN members are bound to comply with the CEN/CENELEC Internal Regulations which stipulate the conditions for giving this European
Standard the status of a national standard without any alteration. Up-to-date lists and bibliographical references concerning such national
standards may be obtained on application to the Central Secretariat or to any CEN member.

This European Standard exists in three official versions (English, French, German). A version in any other language made by translation
under the responsibility of a CEN member into its own language and notified to the Central Secretariat has the same status as the official
versions.

CEN members are the national standards bodies of Austria, Belgium, Cyprus, Czech Republic, Denmark, Estonia, Finland, France,
Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania,
Slovakia, Slovenia, Spain, Sweden, Switzerland and United Kingdom.






EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION

EUROPÄISCHES KOMITEE FÜR NORMUNG

Management Centre: rue de Stassart, 36  B-1050 Brussels
© 2006 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 10993-2:2006: E
worldwide for CEN national Members.

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SIST EN ISO 10993-2:2006

EN ISO 10993-2:2006 (E)





Foreword


This document (EN ISO 10993-2:2006) has been prepared by Technical Committee ISO/TC 194
"Biological evaluation of medical devices" in collaboration with Technical Committee CEN/TC
206 "Biocompatibility of medical and dental materials and devices", the secretariat of which is
held by NEN.

This European Standard shall be given the status of a national standard, either by publication of
an identical text or by endorsement, at the latest by January 2007, and conflicting national
standards shall be withdrawn at the latest by January 2007.

This document supersedes EN ISO 10993-2:1998.

According to the CEN/CENELEC Internal Regulations, the national standards organizations of
the following countries are bound to implement this European Standard: Austria, Belgium,
Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary,
Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland,
Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland and United Kingdom.


Endorsement notice

The text of ISO 10993-2:2006 has been approved by CEN as EN ISO 10993-2:2006 without any
modifications.

2

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SIST EN ISO 10993-2:2006

INTERNATIONAL ISO
STANDARD 10993-2
Second edition
2006-07-15


Biological evaluation of medical
devices —
Part 2:
Animal welfare requirements
Évaluation biologique des dispositifs médicaux —
Partie 2: Exigences relatives à la protection des animaux





Reference number
ISO 10993-2:2006(E)
©
ISO 2006

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SIST EN ISO 10993-2:2006
ISO 10993-2:2006(E)
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ii © ISO 2006 – All rights reserved

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SIST EN ISO 10993-2:2006
ISO 10993-2:2006(E)
Contents Page
Foreword. iv
Introduction . vi
1 Scope . 1
2 Normative references . 1
3 Terms and definitions. 1
4 Requirements . 3
4.1 General. 3
4.2 Justification for animal tests . 4
4.3 Competence of personnel. 4
4.4 Planning and performance of animal tests .4
4.5 Test strategy — Sequence of in vitro and in vivo tests. 5
4.6 Animal care and accommodation . 5
4.7 Humane endpoints. 6
4.8 Study documentation . 7
4.9 Validity of test results and mutual acceptance of data. 7
Annex A (informative) Rationale for the development of this part of ISO 10993. 8
Annex B (informative) Further suggestions for replacing, reducing and refining animal tests . 12
Bibliography . 13

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SIST EN ISO 10993-2:2006
ISO 10993-2:2006(E)
Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards bodies
(ISO member bodies). The work of preparing International Standards is normally carried out through ISO
technical committees. Each member body interested in a subject for which a technical committee has been
established has the right to be represented on that committee. International organizations, governmental and
non-governmental, in liaison with ISO, also take part in the work. ISO collaborates closely with the
International Electrotechnical Commission (IEC) on all matters of electrotechnical standardization.
International Standards are drafted in accordance with the rules given in the ISO/IEC Directives, Part 2.
The main task of technical committees is to prepare International Standards. Draft International Standards
adopted by the technical committees are circulated to the member bodies for voting. Publication as an
International Standard requires approval by at least 75 % of the member bodies casting a vote.
Attention is drawn to the possibility that some of the elements of this document may be the subject of patent
rights. ISO shall not be held responsible for identifying any or all such patent rights.
ISO 10993-2 was prepared by Technical Committee ISO/TC 194, Biological evaluation of medical devices.
This second edition cancels and replaces the first edition (ISO 10993-2:1992), which has been technically
revised.
ISO 10993 consists of the following parts, under the general title Biological evaluation of medical devices:
⎯ Part 1: Evaluation and testing
⎯ Part 2: Animal welfare requirements
⎯ Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity
⎯ Part 4: Selection of tests for interactions with blood
⎯ Part 5: Tests for in vitro cytotoxicity
⎯ Part 6: Tests for local effects after implantation
⎯ Part 7: Ethylene oxide sterilization residuals
⎯ Part 9: Framework for identification and quantification of potential degradation products
⎯ Part 10: Tests for irritation and delayed-type hypersensitivity
⎯ Part 11: Tests for systemic toxicity
⎯ Part 12: Sample preparation and reference materials
⎯ Part 13: Identification and quantification of degradation products from polymeric medical devices
⎯ Part 14: Identification and quantification of degradation products from ceramics
⎯ Part 15: Identification and quantification of degradation products from metals and alloys
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SIST EN ISO 10993-2:2006
ISO 10993-2:2006(E)
⎯ Part 16: Toxicokinetic study design for degradation products and leachables
⎯ Part 17: Establishment of allowable limits for leachable substances
⎯ Part 18: Chemical characterization of materials
⎯ Part 19: Physico-chemical, morphological and topographical characterization of materials
⎯ Part 20: Principles and methods for immunotoxicology testing of medical devices
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SIST EN ISO 10993-2:2006
ISO 10993-2:2006(E)
Introduction
The goal of the ISO 10993 series of International Standards is the protection of humans in the context of the
use of medical devices.
This part of ISO 10993 supports the goal of the ISO 10993 series by promoting good science through paying
proper regard to maximizing the use of scientifically sound non-animal tests and by ensuring that those animal
tests performed to evaluate the biological properties of materials used in medical devices are conducted
humanely according to recognized ethical and scientific principles.
The application of such humane experimental techniques, including high standards of animal care and
accommodation, both help to ensure the scientific validity of safety testing and enhance the welfare of the
animals used.

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SIST EN ISO 10993-2:2006
INTERNATIONAL STANDARD ISO 10993-2:2006(E)

Biological evaluation of medical devices —
Part 2:
Animal welfare requirements
1 Scope
This part of ISO 10993 is aimed at those who commission, design and perform tests or evaluate data from
animal tests undertaken to assess the biocompatibility of materials intended for use in medical devices, or that
of the medical devices themselves. It specifies the minimum requirements to be satisfied to ensure and
demonstrate that proper provision has been made for the welfare of animals used in animal tests to assess
the biocompatibility of materials used in medical devices.
It also makes recommendations and offers guidance intended to facilitate future further reductions in the
overall number of animals used, refinement of test methods to reduce or eliminate pain or distress in animals,
and the replacement of animal tests by other scientifically valid means not requiring animal tests.
It applies to tests performed on living vertebrate animals, other than man, to establish the biocompatibility of
materials or medical devices.
It does not apply to tests performed on invertebrate animals and other lower forms; nor (other than with
respect to provisions relating to species, source, health status, and care and accommodation) does it apply to
testing performed on isolated tissues and organs taken from vertebrate animals that have been euthanized.
2 Normative references
The following referenced documents are indispensable for the application of this document. For dated
references, only the edition cited applies. For undated references, the latest edition of the referenced
document (including any amendments) applies.
ISO 10993-1:2003, Biological evaluation of medical devices — Part 1: Evaluation and testing
3 Terms and definitions
For the purposes of this document, the definitions given in ISO 10993-1 and the following apply.
3.1
alternative method
any test method that replaces an animal test, reduces the numbers of animals used, or refines the procedures
applied
3.2
animal
any live non-human vertebrate, excluding immature forms during the first half of gestation of incubation
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SIST EN ISO 10993-2:2006
ISO 10993-2:2006(E)
3.3
animal test
any use of an animal for scientific purposes
NOTE 1 The definition of an animal test excludes acts of recognized veterinary practice applied for the benefit of an
animal or the group of animals of which it is part; recognized husbandry practices to manage or conserve the animal or the
group of which it is part; marking by methods which cause no more than momentary pain or distress; and euthanasia.
NOTE 2 The prevention of pain, suffering, distress or lasting harm by the effective use of anaesthesia or analgesia or
other methods of rendering the animal insentient to pain (e.g. decerebration) does not place animal tests outside the
scope of this definition. The administration of anaesthetics, analgesics or other methods of rendering the animal insentient
to pain are considered to constitute an integral part of the animal test.
3.4
competent authority
body designated or recognized by a national government to take responsibility for overseeing, supervising or
regulating animal tests, or the breeding and supply of purpose-bred animals for use on such tests, within the
scope of this part of ISO 10993
3.5
euthanasia
humane killing of an animal by a method causing a minimum of physical and mental suffering
3.6
humane endpoints
pre-determined, specific criteria and measures to be implemented to minimize or terminate pain, suffering or
distress caused by animal tests as soon as the scientific objectives have been met, or when it is realized they
cannot be met, or when the animal welfare problems being encountered are greater than can be justified by
the importance, potential benefits, objectives and nature of the study
3.7
procedural training
prior training and acclimatizing of animals to the interventions to be performed during an animal test, with a
view to minimizing stress to the animal when animal tests are conducted
3.8
protocol
documentation prepared in advance of animal tests being undertaken setting out the justification, rationale
and test method (including scientific and humane endpoints) for the animal tests
3.9
purpose-bred animal
any animal bred with the intention that it be used in animal tests or for other experimental or scientific
purposes
3.10
reduction
reducing to the essential minimum the number of animals used in an animal test to meet a defined scientific
objective
3.11
refinement
sum total of measures taken to safeguard the welfare of the test animals by minimizing any resulting pain,
suffering, distress or lasting harm to the animals that are used
3.12
replacement
any scientifically valid and reasonably and practically available test method that either completely or partially
replaces the use of living vertebrate animals with test methods that have not the potential to cause pain or
distress to animals
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SIST EN ISO 10993-2:2006
ISO 10993-2:2006(E)
3.13
test animal
any animal used in in vivo animal tests, or used to provide tissue for ex vivo or in vitro tests
3.14
validation
formal process by which the reliability and relevance of a test method is established for a particular purpose
4 Requirements
4.1 General
This part of ISO 10993 sets forth essential requirements when animal tests are being considered, planned or
performed for the biological evaluation of materials used in medical devices.
It has been developed to protect the welfare of animals used in the biological evaluation of materials used in
medical devices without compromising, indeed to help to ensure, the scientific validity of the test results and
the risk assessments that shall subsequently be performed.
This part of ISO 10993 focuses on the need to demonstrate that animal welfare is properly considered when
expert judgement has to be exercised in relation to the biological evaluation of medical device materials, and
that the principles of humane experimental technique are demonstrably applied to the design and conduct of
animal tests.
This part of ISO 10993 requires that the need to perform animal tests is justified, and any pain, suffering,
distress or lasting harm that is caused during essential animal tests is minimized.
This part of ISO 10993 sets out essential requirements that safeguard animal welfare by minimizing the pain
and distress caused when animal tests are considered or undertaken by:
a) establishing a framework that reflects the relevant ethical and, in many jurisdictions, the legal
considerations relating to the use of animals for experimental or other scientific purposes;
b) minimizing the number of animal tests by the appropriate use of literature searches, data-sharing,
validated replacement alternatives, and appropriate testing strategies and study designs;
c) minimizing any pain, suffering, distress and lasting harm caused to animals used in tests to evaluate the
biocompatibility of materials used in medical devices by requiring appropriate use of relevant reduction
and refinement alternatives;
d) promoting consistent, high standards of accommodation and care to safeguard both the welfare of the
animals used and the scientific validity and the reproducibility of the data generated.
To these ends the design and conduct of animal tests to evaluate the biocompatibility of materials used in
medical devices shall be formed by, and incorporate, relevant strategies for the replacement, reduction and
refinement of animal tests.
Commissioning animal tests without seeking and obtaining this information, exercising these judgements and
implementing these measures does not comply with the essential requirements of this part of ISO 10993.
NOTE These principles, and the essential requirements of this part of ISO 10993, can also be relevant to animal
tests conducted on medical device materials and medical devices, in other contexts.
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SIST EN ISO 10993-2:2006
ISO 10993-2:2006(E)
4.2 Justification for animal tests
When required to make proper provision to ensure human safety, animal testing to enable the proper
biological characterization of materials used in medical devices is acceptable.
For the purposes of the ISO 10993 series, animal tests shall only be deemed to be justified when:
⎯ the resulting data are not otherwise available, but are essential to properly characterize the test material
in the context in which it is to be used;
⎯ when no suitable scientifically validated test method not involving the use of living animals is reasonably
and practically available;
⎯ when relevant reduction and refinement strategies have been identified and implemented including, if
appropriate, obtaining test data from manufacturers and suppliers, and literature searches for toxicity and
biocompatibility data.
To avoid unnecessary duplication, before animal tests to evaluate the biocompatibility of materials used in
medical devices are undertaken, a review of available, relevant information on the properties of the test
material shall be undertaken and documented. This shall include taking reasonable steps to enable data
sharing.
Animal tests are deemed to be justified only when:
a) they have been shown to be relevant and reliable for the purposes for which they are undertaken;
b) the resulting data are essential to properly characterize and evaluate the test material in the context in
which it is to be used in medical devices;
c) no scientifically valid test method not requiring the use of living animals is reasonably and practically
available;
d) other relevant and appropriate strategies to minimize the pain, suffering, distress and lasting harm caused
to the animals that are used have been identified and implemented.
4.3 Competence of personnel
Animal tests shall be designed, conducted and interpreted by persons competent to discharge the
responsibilities assigned to them.
Animal tests shall be designed and conducted with the involvement of personnel with expertise in veterinary
science, laboratory animal science, and animal husbandry and care.
Details of how staff are equipped by experience, qualification and training (including continued professional
development) to satisfy these requirements shall be documented.
NOTE Although this part of ISO 10993 does not provide an objective specification, it is considered important that those
involved in the conduct of animal tests demonstrate a caring and respectful attitude to the animals used, i.e., that they
have an appropriate “culture of care”.
4.4 Planning and performance of animal tests
4.4.1 General
The selection and design of animal tests shall be appropriate to meet the specific scientific objectives of the
study whilst minimizing the pain, suffering, distress or lasting harm that might be produced to the test animals.
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SIST EN ISO 10993-2:2006
ISO 10993-2:2006(E)
As stated in 4.2, animal testing shall only be undertaken when the information required is essential to
characterize the test material, is not otherwise available and when no suitable scientifically validated test
method not involving the use of living animals is reasonably and practically available.
Following consideration of relevant and reasonably available potential replacement, reduction and refinement
strategies, and before animal tests are undertaken, principal investigators and/or sponsors shall attest and
document that no other replacement, reduction or refinement strategies are required to minimize the animal
welfare costs of the studies.
NOTE In some instances pilot studies can be required to optimize study design before definitive studies can be
designed and performed.
Where the provisions of the ISO 10993 series of International Standards require or permit that an informed
choice be made from a range of species, stages of development or animal numbers for an animal test, the
decisions taken shall both safeguard the scientific validity of the test and minimize any pain, suffering, distress
or lasting harm to the animals used. The rationale for the decisions taken shall be documented.
4.4.2 Re-use
The need to avoid undue cumulative welfare costs to the individual animals used shall be balanced against
the need to minimize the number of animals used.
In general, an animal should not be used for more than one test.
Animals that have experienced pain and distress in the course of an animal test, or whose previous use might
influence the outcome of further tests, shall not be re-used.
Re-use shall be consistent with the scientific objective and shall not impose unreasonable cumulative welfare
costs on the individual animal.
Any re-use shall be documented, giving summary details of the earlier use and confirming that the
requirements set out in this subclause were considered and met.
4.5 Test strategy — Sequence of in vitro and in vivo tests
Testing strategies shall, as appropriate, adopt a tiered or hierarchical approach to minimize both the amount
of animal testing required and any pain or distress that might be caused when animal tests are justified and
undertaken. Specifically, unnecessary animal tests shall not be performed before appropriate, scientifically
valid, and reasonably and practically available preliminary in vitro tests have been carried out, and the results
evaluated.
Animal tests shall not be performed if the available data (e.g. from literature and/or database searches, results
from previous screening tests, validated in vitro tests, previous animal tests or any other available relevant
evidence) provide sufficient information on the biocompatibility of the test material for a sound, relevant risk
assessment to be undertaken.
The rationale for the testing strategy shall be documented.
4.6 Animal care and accommodation
4.6.1 General
Purpose-bred animals shall be used whenever possible and specific justification is required for the use of non-
purpose bred animals.
When purpose-bred animals are not used, the justification and details of the provenance of the animals that
are used shall be documented.
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SIST EN ISO 10993-2:2006
ISO 10993-2:2006(E)
High standards of care and accommodation enhance the welfare of the animals used and promote the
scientific validity of animal testing. Animal care and accommodation shall demonstrably, as a minimum,
conform to relevant, published national or international animal care, accommodation and husbandry
guidelines.
The relevant guidelines or requirements shall be referenced, and evidence of compliance (or details of non-
compliance accompanied by an assessment of its likely impact on the welfare of the animals used and the
validity of the data obtained) shall be explained, justified and documented.
Any component of the husbandry system that does not make best provision for the welfare of the test animals,
might compromise the scientific validity of the test or inappropriately influence the nature or interpretation of
the test result, shall be documented.
Social species shall be housed as stable, compatible pairs or groups unless single-housing is required for
veterinary, husbandry, animal welfare or scientific reasons.
When it is not possible to pair- or group-house social species, the veterinary, husbandry, animal welfare or
scientific justification for the need for single housing and its duration shall be documented. The impact of the
decision made on the scientific outcome should also be evaluated and documented.
Custom and practice shall not, of themselves, be deemed to be acceptable justifications.
4.6.2 Restraint
When animal tests require that animals be restrained, the degree, duration and nature of the restraint shall be
the minimum consistent with achieving the scientific objective, and shall be documented.
4.6.3 Surgical procedures
All surgical procedures shall be performed on anaesthetized animals, incorporating surgical principles and
practices to minimize the incidence of intra-operative sepsis. The incidence of surgical sepsis shall be
documented.
Proper provision shall be made for the pre-, peri- and post-operative care of the animals, including the
responsible and effective use of analgesics in accordance with good contemporary clinical veterinary practice.
The regi
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