prEN ISO 10993-2

Biological evaluation of medical devices - Part 2: Animal welfare requirements (ISO/DIS 10993-2:2020)

Biologische Beurteilung von Medizinprodukten - Teil 2: Tierschutzbestimmungen (ISO/DIS 10993-2:2020)

Dieses Dokument legt die Mindestanforderungen fest, die zu erfüllen sind, um sicherzustellen und nachzuweisen, dass die richtigen Vorkehrungen getroffen wurden, um Schmerzen und Leiden, die sich nachteilig auf die Validität der Daten auswirken können, auf ein Mindestmaß herabzusetzen. Dieses Dokument richtet sich an den Personenkreis, der Versuche in Auftrag gibt, sie plant und durchführt oder die Daten auswertet, um die Bioverträglichkeit von Materialien, die für die Verwendung in Medizinprodukten vorgesehen sind, oder von Medizinprodukten selbst, zu beurteilen.
In diesem Dokument werden Empfehlungen gegeben und eine Anleitung angeboten, deren Ziel eine weitere Verminderung der Gesamtzahl der verwendeten Tiere, eine Verbesserung der Prüfverfahren zur Verringerung oder Ausschaltung von Schmerz oder Leiden bei Tieren, und der Ersatz von Tierversuchen durch andere wissenschaftlich valide Mittel ist, bei denen Tierversuche nicht erforderlich sind, ist.
Dieses Dokument gilt für Versuche an lebenden Wirbeltieren, außer dem Menschen, zur Feststellung der Bioverträglichkeit von Materialien oder Medizinprodukten.
Diese Dokument gilt nicht für Versuche an Wirbellosen und anderen niedrigeren Formen des Lebens, auch nicht (außer für die Vorkehrungen hinsichtlich Tierart, Bezugsquellen, Gesundheitszustand, Pflege und Unterbringung) für Versuche an isolierten Geweben und Organen, die aus auf humane Weise getöteten Wirbeltieren entnommen wurden.

Évaluation biologique des dispositifs médicaux - Partie 2: Exigences relatives à la protection des animaux (ISO/DIS 10993-2:2020)

Biološko ovrednotenje medicinskih pripomočkov - 2. del: Zahteve za varstvo živali (ISO/DIS 10993-2:2020)

General Information

• Status: Not Published
• ICS: 11.100.20 - Biological evaluation of medical devices
• Technical Committee: CEN/TC 206 - Biocompatibility of medical and dental materials and devices
• Current Stage: 4599 - Dispatch of FV draft to CMC - Finalization for Vote
• Due Date: 09-Aug-2021
• Ref Project: oSIST prEN ISO 10993-2:2020 - Biological evaluation of medical devices - Part 2: Animal welfare requirements (ISO/DIS 10993-2:2020)

RELATIONS

• Revised: EN ISO 10993-2:2006 - Biological evaluation of medical devices - Part 2: Animal welfare requirements (ISO 10993-2:2006)
• Effective Date: 03-Jul-2019

Standards Content (sample)

SLOVENSKI STANDARD
oSIST prEN ISO 10993-2:2020
01-april-2020

Biološko ovrednotenje medicinskih pripomočkov - 2. del: Zahteve za varstvo živali

(ISO/DIS 10993-2:2020)

Biological evaluation of medical devices - Part 2: Animal welfare requirements (ISO/DIS

10993-2:2020)
Biologische Beurteilung von Medizinprodukten - Teil 2: Tierschutzbestimmungen
(ISO/DIS 10993-2:2020)

Évaluation biologique des dispositifs médicaux - Partie 2: Exigences relatives à la

protection des animaux (ISO/DIS 10993-2:2020)
Ta slovenski standard je istoveten z: prEN ISO 10993-2
ICS:
11.100.20 Biološko ovrednotenje Biological evaluation of
medicinskih pripomočkov medical devices
oSIST prEN ISO 10993-2:2020 en

2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.

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oSIST prEN ISO 10993-2:2020
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oSIST prEN ISO 10993-2:2020
DRAFT INTERNATIONAL STANDARD
ISO/DIS 10993-2
ISO/TC 194 Secretariat: DIN
Voting begins on: Voting terminates on:
2020-02-13 2020-05-07
Biological evaluation of medical devices —
Part 2:
Animal welfare requirements
Évaluation biologique des dispositifs médicaux —
Partie 2: Exigences relatives à la protection des animaux
ICS: 11.100.20
THIS DOCUMENT IS A DRAFT CIRCULATED
This document is circulated as received from the committee secretariat.
FOR COMMENT AND APPROVAL. IT IS
THEREFORE SUBJECT TO CHANGE AND MAY
NOT BE REFERRED TO AS AN INTERNATIONAL
STANDARD UNTIL PUBLISHED AS SUCH.
IN ADDITION TO THEIR EVALUATION AS
ISO/CEN PARALLEL PROCESSING
BEING ACCEPTABLE FOR INDUSTRIAL,
TECHNOLOGICAL, COMMERCIAL AND
USER PURPOSES, DRAFT INTERNATIONAL
STANDARDS MAY ON OCCASION HAVE TO
BE CONSIDERED IN THE LIGHT OF THEIR
POTENTIAL TO BECOME STANDARDS TO
WHICH REFERENCE MAY BE MADE IN
Reference number
NATIONAL REGULATIONS.
ISO/DIS 10993-2:2020(E)
RECIPIENTS OF THIS DRAFT ARE INVITED
TO SUBMIT, WITH THEIR COMMENTS,
NOTIFICATION OF ANY RELEVANT PATENT
RIGHTS OF WHICH THEY ARE AWARE AND TO
PROVIDE SUPPORTING DOCUMENTATION. ISO 2020
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oSIST prEN ISO 10993-2:2020
ISO/DIS 10993-2:2020(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2020

All rights reserved. Unless otherwise specified, or required in the context of its implementation, no part of this publication may

be reproduced or utilized otherwise in any form or by any means, electronic or mechanical, including photocopying, or posting

on the internet or an intranet, without prior written permission. Permission can be requested from either ISO at the address

below or ISO’s member body in the country of the requester.
ISO copyright office
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Website: www.iso.org
Published in Switzerland
ii © ISO 2020 – All rights reserved
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oSIST prEN ISO 10993-2:2020
ISO/DIS 10993-2:2020(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

4.2.1 General...................................................................................................................................................................................... 4

4.2.2 Oversight framework of animal use and welfare ................................................................................. 5

4.3 Competence of personnel .............................................................................................................................................................. 5

4.4 Planning and performance of animal tests ..................................................................................................................... 5

4.4.1 General...................................................................................................................................................................................... 5

4.4.2 Re-use ........................................................................................................................................................................................ 5

4.5 Test strategy — Sequence of in vitro and in vivo tests ....................................................................................... 6

4.6 Animal care and accommodation ........................................................................................................................................... 6

4.6.1 General...................................................................................................................................................................................... 6

4.6.2 Restraint .................................................................................................................................................................................. 7

4.6.3 Surgical procedures ........................................................................................................................................... ............ 7

4.7 Humane endpoints .............................................................................................................................................................................. 7

4.7.1 General...................................................................................................................................................................................... 7

4.7.2 Euthanasia ............................................................................................................................................................................. 7

4.8 Study documentation ........................................................................................................................................................................ 8

4.9 Validity of test results and mutual acceptance of data ......................................................................................... 8

Annex A (informative) Rationale for the development of this document ...................................................................... 9

Annex B (informative) Further suggestions for replacing, reducing and refining animal tests ..........15

Bibliography .............................................................................................................................................................................................................................16

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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.

The procedures used to develop this document and those intended for its further maintenance are

described in the ISO/IEC Directives, Part 1. In particular, the different approval criteria needed for the

different types of ISO documents should be noted. This document was drafted in accordance with the

editorial rules of the ISO/IEC Directives, Part 2 (see www .iso .org/ directives).

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. Details of

any patent rights identified during the development of the document will be in the Introduction and/or

on the ISO list of patent declarations received (see www .iso .org/ patents).

Any trade name used in this document is information given for the convenience of users and does not

constitute an endorsement.

For an explanation of the voluntary nature of standards, the meaning of ISO specific terms and

expressions related to conformity assessment, as well as information about ISO's adherence to the

World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT), see www .iso .org/

iso/ foreword .html.

This document was prepared by Technical Committee ISO/TC 194, Biological and clinical evaluation of

medical devices.

This third edition cancels and replaces the second edition (ISO 10993-2:2006), which has been

technically revised.
The main changes compared to the previous edition are as follows:
Addition of veterinary care:

— clarification on laboratory animal veterinarian and their responsibilities and authority;

— requirements for trained veterinary care staff;
— addition of ILAR Guide, IACLAM and AAALAC International

— addition of aseptic methods, monitoring, pharmaceutical grade of chemical usage for surgery;

— usage of other analgesics than NSAIDs;
— other alternatives such as TTC are mentioned.
A list of all parts in the ISO 10993 series can be found on the ISO website.

Any feedback or questions on this document should be directed to the user’s national standards body. A

complete listing of these bodies can be found at www .iso .org/ members .html.
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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 document 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, and mimimizing pain and distress to ensure the scientific validity of safety testing and

enhance the welfare of the animals used.
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oSIST prEN ISO 10993-2:2020
DRAFT INTERNATIONAL STANDARD ISO/DIS 10993-2:2020(E)
Biological evaluation of medical devices —
Part 2:
Animal welfare requirements
1 Scope

This document specifies the minimum requirements to be satisfied to ensure and demonstrate that

proper provision has been made to minimize pain and distress, which can negatively affect the validity

of the data. This document is for those who commission, design and perform testing or evaluate the data

to assess the biocompatibility of materials intended for use in medical devices, or that of the medical

devices themselves.

This document makes recommendations and offers guidance intended to facilitate 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.

This document applies to tests performed on living vertebrate animals, other than man, to establish the

biocompatibility of materials or medical devices.

This document 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 documents are referred to in the text in such a way that some or all of their content

constitutes requirements 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 10993-1:2018, Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk

management process
3 Terms and definitions

For the purposes of this document, the terms and definitions given in ISO 10993-1:2018 and the

following apply.

ISO and IEC maintain terminological databases for use in standardization at the following addresses:

— IEC Electropedia: available at http:// www .electropedia .org/
— ISO Online browsing platform: available at http:// www .iso .org/ obp
3.1
acclimatization

some period following transportation of animal to restore homeostasis and physiological measures

return to normal
Note 1 to entry: 7 days may be appropriate for most cases.
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3.2
alternative method

any test method that replaces an animal test, reduces the numbers of animals used, or refines the

procedures applied
3.3
animal

any live non-human vertebrate, including immature forms during gestation where the ability to sense

pain is known
3.4
animal test
experimental use of animals for medical and scientific purposes

Note 1 to entry: 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 to entry: 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.

3.5
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 document
3.6
euthanasia

humane killing of an animal by a method causing a minimum of physical and mental suffering

3.7
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
— it is realized that the scientific endpoints cannot be met, or

— the animal welfare problems being encountered are greater than can be justified by the importance,

potential benefits, objectives and nature of the study
3.8
laboratory animal veterinarian (qualified)

person qualified and responsible for the health and wellbeing of all laboratory animals at the institution

through certification in their specialty by training, experience, research, and publication, and a

demonstrable knowledge and skill

Note 1 to entry: There is an International Association of Colleges of Laboratory Animal Medicine (IACLAM) that

is an association of associations, specifically the member Colleges of laboratory animal medicine. Each college

has members that, in addition to their demonstrated proficiency in laboratory animal medicine, also possess

subspecialization in a variety of areas that have direct bearing on the care, use and welfare of laboratory animals.

3.9
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
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3.10
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

3.11
purpose-bred animal

animal bred with the intention that it be used in animal tests or for other experimental or scientific

purposes
3.12
reduction

methods which minimize the number of animals used in an animal test to meet a defined scientific

objective
3.13
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
3.14
replacement

scientifically valid, reasonably and practically available test method that either completely or partially

replaces the use of living vertebrate animals with test methods that do not have the potential to cause

pain or distress to animals
3.15
Specific Pathogen Free (SPF) animal
animal that are free of defined pathogens
3.16
test animal

animal used in vivo tests, or used to provide tissue for ex vivo or in vitro tests

3.17
validation

formal process by which the reliability and relevance of a test method is established for a particular

purpose
3.18
veterinary care

promoting an animal’s health and welfare before, during and after animal procedures and providing

advice and guidance based on best practice.
4 Requirements
4.1 General

This document sets forth essential requirements when animal tests are being considered, planned or

performed for the biological evaluation of materials and 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 document 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.
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This document 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 document sets out essential requirements that safeguard animal welfare by minimizing the pain

and distress caused when animal tests are considered or undertaken by:

— 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;

— 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;

— 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;

— 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.

— Implementing appropriate veterinary care program overseen by a qualified laboratory animal

veterinarian. The laboratory animal veterinarian shall have authority and responsibility for making

judgements concerning animal welfare. Veterinary advice and care shall be available at all times.

— close monitoring of animals housed in pairs or groups for signs of aggression and/or bullying; if

such signs are observed, animals should be immediately separated, and adequate veterinary care

provided, if needed.

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

document.

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.

4.2 Justification for animal tests
4.2.1 General

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:

a) 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;

b) no suitable scientifically validated test method not involving the use of living animals is reasonably

and practically available;

c) 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;

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.

To avoid unnecessary duplication, before animal tests are undertaken to evaluate the biocompatibility

of devices or medical device materials used in medical devices are undertaken, a review of available,

relevant information on the properties of the test articles shall be undertaken and documented. This

shall include taking reasonable steps to enable data sharing.
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4.2.2 Oversight framework of animal use and welfare

An oversight framework of proper and ethical animal use shall be established to include the following:

— critical thought, judgment and analysis shall be used when deciding to conduct an animal study;

— scientists conducting the animal studies shall primarily be responsible for the ethical use and care

of the animals.

The ethical review committee (or equivalent institutional committee) shall ensure the ethical conduct

of animal usage. The composition of the ethical review committee shall be in accordance with national

regulations. To provide diverse opinions on animal welfare, individuals with different backgrounds

should be selected, such as scientists experienced in animal testing, qualified laboratory animal

veterinarians, persons with non-scientific background and public members to represent general

community. See A.8.1

All committee members should have appropriate training and education in ethical care and use of

animals for scientific purposes. The activities of this committee are referred to in A.8.

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 medicine, 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 document 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

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.
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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, animal tests shall not be performed before appropriate,

scientifically valid, and reasonably and practically available 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 device

or device material, including processing and geometry of the final device, for a sound, relevant risk

assessment to be undertaken in accordance with ISO 10993-1.
The rationale for the testing strategy shall be documented.
4.6 Animal care and accommodation
4.6.1 General

Purpose-bred SPF animals should be used whenever possible and specific justification is required for

the use of non-purpose bred or non-SPF animals.

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, national or regional regulations, 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.

Adequate acclimatization period should be considered after the animal transportation. Generally, 7

days may be appropriate for most cases.

Any component of the husbandry system that does not make best provision for the welfare of the test

animals, and that might compromise the scientific validity of the test or inappropriately influence the

nature or int
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