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Biological evaluation of medical devices - Part 12: Sample preparation and reference materials (ISO 10993-12:2021)

This document specifies requirements and gives guidance on the procedures in the preparation of
samples and the selection of reference materials for medical device testing primarily in biological test
systems primarily in accordance with one or more parts of the ISO 10993 series.
Specifically, this document addresses the following:
— test sample selection;
— selection of representative portions from a medical device;
— test sample preparation;
— experimental controls;
— selection of, and requirements for, reference materials;
— preparation of extracts.
This document is not applicable to live cells but can be relevant to the material or medical device
components of combination products containing live cells.
Extractions for chemical characterization are covered in ISO 10993-18. Clause 7, 8, 9, 10 [with the
exception of 10.3.5 and 10.3.11 b)], and 11 can apply to extractions for chemical characterization.
Information given in C.1 to C.4 can also be relevant.

Biologische Beurteilung von Medizinprodukten - Teil 12: Probenvorbereitung und Referenzmaterialien (ISO 10993-12:2021)

Das vorliegende Dokument legt Anforderungen fest und gibt Anleitungen zu Verfahren für die Herstellung der Prüfmuster und bei der Auswahl von Referenzmaterialien für die Prüfung von Medizinprodukten vor allem in biologischen Prüfsystemen vor allem nach einem oder mehreren Teilen der Normenreihe ISO 10993.
Das vorliegende Dokument behandelt insbesondere die folgenden Aspekte:
—   Auswahl der Prüfmuster;
—   Auswahl repräsentativer Teile eines Medizinproduktes;
—   Herstellung der Prüfmuster;
—   Kontrollen der Prüfmethoden;
—   Auswahl der und Anforderungen an die Referenzmaterialien;
—   Herstellung der Extrakte.
Das vorliegende Dokument ist nicht anwendbar auf lebende Zellen, kann aber für Materialien und Produktkomponenten von Kombinationsprodukten, die lebende Zellen enthalten, zutreffend sein.
Extraktionen für die chemische Charakterisierung werden in ISO 10993 18 behandelt. Abschnitt 7, Abschnitt 8, Abschnitt 9, Abschnitt 10 [ausgenommen 10.3.5 und 10.3.11 b)] und Abschnitt 11 können für Extraktionen zur chemischen Charakterisierung anwendbar sein. In C.1 bis C.4 enthaltene Informationen können ebenfalls relevant sein.

Évaluation biologique des dispositifs médicaux - Partie 12: Préparation des échantillons et matériaux de référence (ISO 10993-12:2021)

Le présent document spécifie les exigences et fournit des recommandations sur les modes opératoires relatifs à la préparation des échantillons et le choix des matériaux de référence dans le cadre d'essais relatifs aux dispositifs médicaux, dans la mesure où ils sont mis en œuvre principalement dans des systèmes d'essai biologique, essentiellement en conformité avec une ou à plusieurs parties de la série ISO 10993.
Le présent document traite plus spécifiquement des points suivants:
—          le choix des échantillons;
—          le choix des parties représentatives d'un dispositif médical;
—          la préparation des échantillons;
—          les témoins expérimentaux;
—          le choix des matériaux de référence et les exigences qui s'y rapportent;
—          la préparation des extraits.
Le présent document n'est pas applicable aux cellules vivantes, mais il peut s'appliquer aux matériaux ou aux composants de dispositifs médicaux de produits combinés contenant des cellules vivantes.
Les extractions relatives à la caractérisation chimique sont couvertes par l'ISO 10993-18. Les articles 7, 8, 9, 10 [hormis pour 10.3.5 et 10.3.11 b)], et 11 sont applicables aux extractions relatives à la caractérisation chimique. Les informations fournies de C.1 à C.4 peuvent également être pertinentes.

Biološko ovrednotenje medicinskih pripomočkov - 12. del: Priprava vzorcev in referenčni materiali (ISO 10993-12:2021)

General Information

Status

Published

Public Enquiry End Date

19-Jul-2019

Publication Date

22-Jul-2021

ICS

11.100.20 - Biological evaluation of medical devices

Technical Committee

VAZ - Healthcare

Current Stage

6060 - National Implementation/Publication (Adopted Project)

Start Date

23-Jun-2021

Due Date

28-Aug-2021

Completion Date

23-Jul-2021

Directive

2007/47/EC - Directive 2007/47/EC of the European Parliament and of the council of 5 September 2007 amending Council Directive 90/385/EEC on the approximation of the laws of the Member States relating to active implantable medical devices, Council Directive 93/42/EEC concerning medical devices and Directive 98/8/EC concerning the placing of biocidal products on the market

2017/745 - Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC

90/385/EEC - Council Directive 90/385/EEC of 20 June 1990 on the approximation of the laws of the Member States relating to active implantable medical devices

93/42/EEC - Council Directive 93/42/EEC of 14 June 1993 concerning medical devices

Mandate

M/BC/CEN/89/9 - Joint Standardization request to CEN/CENELEC concerning harmonized standards relating to horizontal aspects in the field of medical devices

Ref Project

EN ISO 10993-12:2021 - Biological evaluation of medical devices - Part 12: Sample preparation and reference materials (ISO 10993-12:2021)

Relations

Replaces

SIST EN ISO 10993-12:2012 - Biological evaluation of medical devices - Part 12: Sample preparation and reference materials (ISO 10993-12:2012)

Effective Date

01-Sep-2021

Replaces

SIST EN ISO 10993-12:2012 - Biological evaluation of medical devices - Part 12: Sample preparation and reference materials (ISO 10993-12:2012)

Effective Date

08-Jun-2022

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Standards Content (Sample)

SLOVENSKI STANDARD
SIST EN ISO 10993-12:2021
01-september-2021
Nadomešča:
SIST EN ISO 10993-12:2012
Biološko ovrednotenje medicinskih pripomočkov - 12. del: Priprava vzorcev in
referenčni materiali (ISO 10993-12:2021)

Biological evaluation of medical devices - Part 12: Sample preparation and reference

materials (ISO 10993-12:2021)
Biologische Beurteilung von Medizinprodukten - Teil 12: Probenvorbereitung und
Referenzmaterialien (ISO 10993-12:2021)

Évaluation biologique des dispositifs médicaux - Partie 12: Préparation des échantillons

et matériaux de référence (ISO 10993-12:2021)
Ta slovenski standard je istoveten z: EN ISO 10993-12:2021
ICS:
11.100.20 Biološko ovrednotenje Biological evaluation of
medicinskih pripomočkov medical devices
SIST EN ISO 10993-12:2021 en

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

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SIST EN ISO 10993-12:2021
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SIST EN ISO 10993-12:2021
EN ISO 10993-12
EUROPEAN STANDARD
NORME EUROPÉENNE
June 2021
EUROPÄISCHE NORM
ICS 11.100.20 Supersedes EN ISO 10993-12:2012
English Version
Biological evaluation of medical devices - Part 12: Sample
preparation and reference materials (ISO 10993-12:2021)

Évaluation biologique des dispositifs médicaux - Partie Biologische Beurteilung von Medizinprodukten - Teil

12: Préparation des échantillons et matériaux de 12: Probenvorbereitung und Referenzmaterialien (ISO

référence (ISO 10993-12:2021) 10993-12:2021)
This European Standard was approved by CEN on 15 September 2020.

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 CEN-CENELEC Management Centre 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 CEN-CENELEC Management

Centre has the same status as the official versions.

CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia,

Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway,

Poland, Portugal, Republic of North Macedonia, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey and

United Kingdom.
EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION
EUROPÄISCHES KOMITEE FÜR NORMUNG
CEN-CENELEC Management Centre: Rue de la Science 23, B-1040 Brussels

worldwide for CEN national Members.
---------------------- Page: 3 ----------------------
SIST EN ISO 10993-12:2021
EN ISO 10993-12:2021 (E)
Contents Page

European foreword ....................................................................................................................................................... 3

Annex ZA (informative) Relationship between this European standard and the General

Safety and Performance Requirements of Regulation (EU) 2017/745 aimed to be

covered................................................................................................................................................................ 5

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SIST EN ISO 10993-12:2021
EN ISO 10993-12:2021 (E)
European foreword

This document (EN ISO 10993-12:2021) has been prepared by Technical Committee ISO/TC 194

"Biological and clinical evaluation of medical devices" in collaboration with Technical Committee

CEN/TC 206 “Biological and clinical evaluation of medical devices” the secretariat of which is held by

DIN.

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 December 2021, and conflicting national standards

shall be withdrawn at the latest by December 2021.

Attention is drawn to the possibility that some of the elements of this document may be the subject of

patent rights. CEN shall not be held responsible for identifying any or all such patent rights.

This document supersedes EN ISO 10993-12:2012.

This document has been prepared under a mandate given to CEN by the European Commission and the

European Free Trade Association, and supports essential requirements of EU Directive(s).

For the relationship with EU Directive(s) see informative Annex ZA, which is integral part of this

document.

The following referenced documents are indispensable for the application of this document. For

undated references, the latest edition of the referenced document (including any amendments) applies.

For dated references, only the edition cited applies. However, for any use of this standard ‘within the

meaning of Annex ZA, the user should always check that any referenced document has not been

superseded and that its relevant contents can still be considered the generally acknowledged state-of-

art.

When an IEC or ISO standard is referred to in the ISO standard text, this shall be understood as a

normative reference to the corresponding EN standard, if available, and otherwise to the dated version

of the ISO or IEC standard, as listed below.

NOTE The way in which these referenced documents are cited in normative requirements determines the

extent (in whole or in part) to which they apply.

Table — Correlations between undated normative references and dated EN and ISO standards

Equivalent dated standard
References as listed in the ISO
standard
EN ISO or IEC
ISO 10993-1 EN ISO 10993-1:2020 ISO 10993-1:2018
ISO 10993-5 EN ISO 10993-5:2009 ISO 10993-5:2009
ISO 10993- 17 EN ISO 10993-17: 2009 ISO 10993-17:2002
ISO 10993-18 EN ISO 10993-18:2020 ISO 10993-18:2020
Under preparation at European level.
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SIST EN ISO 10993-12:2021
EN ISO 10993-12:2021 (E)

According to the CEN-CENELEC Internal Regulations, the national standards organizations of the

following countries are bound to implement this European Standard: Austria, Belgium, Bulgaria,

Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland,

Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Republic of

North Macedonia, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey and the

United Kingdom.
Endorsement notice

The text of ISO 10993-12:2021 has been approved by CEN as EN ISO 10993-12:2021 without any

modification.
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SIST EN ISO 10993-12:2021
EN ISO 10993-12:2021 (E)
Annex ZA
(informative)
Relationship between this European standard and the General Safety and
Performance Requirements of Regulation (EU) 2017/745 aimed to be
covered

This European standard has been prepared under a Commission’s standardisation request to provide

one voluntary means of conforming to the General Safety and Performance Requirements of Regulation

(EU) 2017/745 of 5 April 2017 concerning medical devices [OJ L 117].

Once this standard is cited in the Official Journal of the European Union under that Regulation,

compliance with the normative clauses of this standard given in Table ZA.1 confers, within the limits of

the scope of this standard, a presumption of conformity with the corresponding General Safety and

Performance Requirements of that Regulation, and associated EFTA regulations.

NOTE 1 Where a reference from a clause of this standard to the risk management process is made, the risk

management process needs to be in compliance with Regulation (EU) 2017/745. This means that risks have to be

‘reduced as far as possible’, ‘reduced to the lowest possible level’, ‘reduced as far as possible and appropriate’,

‘removed or reduced as far as possible’, ‘eliminated or reduced as far as possible’, ’removed or minimized as far as

possible’, or ‘minimized’, according to the wording of the corresponding General Safety and Performance

Requirement.

NOTE 2 The manufacturer’s policy for determining acceptable risk must be in compliance with General Safety

and Performance Requirements 1, 2, 3, 4, 5, 8, 9, 10, 11, 14, 16, 17, 18, 19, 20, 21 and 22 of the Regulation.

NOTE 3 This Annex ZA is based on normative references according to the table of references in the European

Foreword, replacing the references in the core text.

NOTE 4 When a General Safety and Performance Requirement does not appear in Table ZA.1, it means that it is

not addressed by this European Standard.
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SIST EN ISO 10993-12:2021
EN ISO 10993-12:2021 (E)
Table ZA.1 — Correspondence between this European Standard and
Annex I of Regulation (EU) 2017/745 [OJ L 117]
General Safety and
Performance Requirements Clause(s)/sub-clause(s) of
Remarks/Notes
of Regulation this EN
(EU) 2017/745
10.2 is only partly covered by this
standard, since the standard does not
provide requirements on design and
manufacture and does not oblige to
minimize risk.
However, this standard provides a
means of preparing samples to assess
conformity with this part of this general
10.2 (first sentence only) 4, 5, 6, 7, 8, 9, 10 and 11
health and safety requirment in
conjunction with other relevant parts of
ISO 10993 for the design and
manufacture of medical devices.
Packaging is not covered.
Risks from residues to person involved
in the transport or storage of medical
devices are not covered.
10.4.1 is only partly covered by this
standard, since the standard does not
provide requirements on design and
manufacture and does not oblige to
minimize risk.
However, this standard provides a

10.4.1 (First paragraph only) 4, 5, 6, 7, 8, 9, 10 and 11 means of preparing samples of medical

devices to assess conformity with this
part of this general health and safety
requirment in conjunction with other
relevant parts of ISO 10993.
Other forms of toxicity are not dealt
with in this standard.

WARNING 1 — Presumption of conformity stays valid only as long as a reference to this European

standard is maintained in the list published in the Official Journal of the European Union. Users of this

standard should consult frequently the latest list published in the Official Journal of the European

Union.

WARNING 2 — Other Union legislation may be applicable to the product(s) falling within the scope of

this standard.
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SIST EN ISO 10993-12:2021
INTERNATIONAL ISO
STANDARD 10993-12
Fifth edition
2021-01
Biological evaluation of medical
devices —
Part 12:
Sample preparation and reference
materials
Évaluation biologique des dispositifs médicaux —
Partie 12: Préparation des échantillons et matériaux de référence
Reference number
ISO 10993-12:2021(E)
ISO 2021
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SIST EN ISO 10993-12:2021
ISO 10993-12:2021(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2021

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
CP 401 • Ch. de Blandonnet 8
CH-1214 Vernier, Geneva
Phone: +41 22 749 01 11
Email: copyright@iso.org
Website: www.iso.org
Published in Switzerland
ii © ISO 2021 – All rights reserved
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SIST EN ISO 10993-12:2021
ISO 10993-12:2021(E)
Contents Page

Foreword ........................................................................................................................................................................................................................................iv

Introduction ..................................................................................................................................................................................................................................v

1 Scope ................................................................................................................................................................................................................................. 1

2 Normative references ...................................................................................................................................................................................... 1

3 Terms and definitions ..................................................................................................................................................................................... 1

4 General requirements ..................................................................................................................................................................................... 3

5 Reference materials (RMs) ........................................................................................................................................................................ 4

5.1 General ........................................................................................................................................................................................................... 4

5.2 Certification of RMs for biological safety testing ....................................................................................................... 4

6 Use of RMs as experimental controls .............................................................................................................................................. 4

7 Test sample selection ....................................................................................................................................................................................... 5

8 Test sample and RM preparation ........................................................................................................................................................ 5

9 Selection of representative portions from a medical device .................................................................................. 6

10 Preparation of extracts of samples .................................................................................................................................................... 6

10.1 General ........................................................................................................................................................................................................... 6

10.2 Containers for extraction ............................................................................................................................................................... 6

10.3 Extraction conditions and methods ...................................................................................................................................... 7

10.4 Extraction conditions for materials that polymerize in situ .......................................................................10

11 Records ........................................................................................................................................................................................................................10

Annex A (informative) Experimental controls ........................................................................................................................................11

Annex B (informative) General principles on, and practices of, test sample preparation and

sample selection ................................................................................................................................................................................................13

Annex C (informative) Principles of test sample extraction .....................................................................................................15

Annex D (informative) Exhaustive extraction of polymeric materials for biological evaluation .......18

Bibliography .............................................................................................................................................................................................................................20

© ISO 2021 – All rights reserved iii
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SIST EN ISO 10993-12:2021
ISO 10993-12:2021(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.

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/

is o/ f or ewor d . ht m l .

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

medical devices, in collaboration with the European Committee for Standardization (CEN) Technical

Committee CEN/TC 206, Biological and clinical evaluation of medical devices, in accordance with the

Agreement on technical cooperation between ISO and CEN (Vienna Agreement).

This fifth edition cancels and replaces the fourth edition (ISO 10993-12:2012), which has been

technically revised.
The main changes compared to the previous edition are as follows:
— change of scope to cover extractions only for biological evaluation tests;
— harmonization of definitions with ISO 10993-18;

— revision of 10.3.1 extraction condition table and Annex D regarding exhaustive extraction.

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.
iv © ISO 2021 – All rights reserved
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SIST EN ISO 10993-12:2021
ISO 10993-12:2021(E)
Introduction

It is important that sample preparation methods be appropriate for both the biological evaluation

methods and the materials being evaluated. Each biological test method requires the selection of

materials, extraction solvents and conditions.

This document is based on existing national and international standards and regulations, wherever

possible.
© ISO 2021 – All rights reserved v
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SIST EN ISO 10993-12:2021
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SIST EN ISO 10993-12:2021
INTERNATIONAL STANDARD ISO 10993-12:2021(E)
Biological evaluation of medical devices —
Part 12:
Sample preparation and reference materials
1 Scope

This document specifies requirements and gives guidance on the procedures in the preparation of

samples and the selection of reference materials for medical device testing primarily in biological test

systems primarily in accordance with one or more parts of the ISO 10993 series.
Specifically, this document addresses the following:
— test sample selection;
— selection of representative portions from a medical device;
— test sample preparation;
— experimental controls;
— selection of, and requirements for, reference materials;
— preparation of extracts.

This document is not applicable to live cells but can be relevant to the material or medical device

components of combination products containing live cells.

Extractions for chemical characterization are covered in ISO 10993-18. Clause 7, 8, 9, 10 [with the

exception of 10.3.5 and 10.3.11 b)], and 11 can apply to extractions for chemical characterization.

Information given in C.1 to C.4 can also be relevant.
2 Normative references
There are no normative references in this document.
3 Terms and definitions
For the purposes of this document, the following terms and definitions apply.

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

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

extraction vehicle not containing the test material, which is exposed to identical vessels and conditions

as the test sample during extraction

Note 1 to entry: The purpose of the blank is to evaluate possible confounding effects due to the extraction vessel,

extraction vehicle and extraction process.
© ISO 2021 – All rights reserved 1
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SIST EN ISO 10993-12:2021
ISO 10993-12:2021(E)
3.2
CRM
certified reference material

reference material (RM) characterized by a metrologically valid procedure for one or more specified

properties, accompanied by an RM certificate that provides the value of the specified property, its

associated uncertainty, and a statement of metrological traceability

Note 1 to entry: The concept of value includes a nominal property or a qualitative attribute such as identity or

sequence. Uncertainties for such attributes may be expressed as probabilities or levels of confidence.

Note 2 to entry: Metrologically valid procedures for the production and certification of RMs are given in, among

others, ISO 17034 and ISO Guide 35.
Note 3 to entry: ISO Guide 31 gives guidance on the contents of RM certificates.
Note 4 to entry: ISO/IEC Guide 99:2007 has an analogous definition (5.14).
[SOURCE: ISO Guide 30:2015, 2.1.2]
3.3
exaggerated extraction

extraction that is intended to result in a greater amount of a chemical constituent being released as

compared to the amount generated under the simulated conditions of use

Note 1 to entry: It is important to ensure that the exaggerated extraction does not result in a chemical change of

the material.
3.4
exhaustive extraction

extraction conducted until the amount of extractable material in a subsequent extraction is less than

10 % by gravimetric analysis (or that achieved by other means) of that detected in the initial extraction

Note 1 to entry: As it is not possible to demonstrate the exhaustive nature of residual recovery, the definition of

exhaustive extraction adopted is as above. See also Annex C.
3.5
experimental control

substance with well-characterized responses, which is used in a specific test system to assist in

evaluating if the test system has responded in a reproducible and appropriate manner

3.6
extract
liquid that results from extraction of the test sample or control
3.7
extractable substance

substance that can be released from a medical device or material using either extraction solvents

or extraction conditions, or both, that are expected to be at least as aggressive as the conditions of

clinical use
3.8
homogeneity

consistency of a material's chemical and physical compositions, and uniformity in response to a

biological endpoint

Note 1 to entry: A reference material is said to be homogeneous if the biological response in a specific test is

found to lie within the specified uncertainty limits of the test, irrespective of the batch or lot of material from

which the test sample is extracted.
3.9
leachable substance

substance that can be released from a medical device or material during clinical use

2 © ISO 2021 – All rights reserved
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SIST EN ISO 10993-12:2021
ISO 10993-12:2021(E)
3.10
negative control

well-characterized material and/or substance, which, when tested by a specific procedure, demonstrates

the suitability of the procedure to yield a reproducible, appropriately negative, non-reactive or minimal

response in the test system

Note 1 to entry: In practice, negative controls are reference materials but can include blanks and extraction

vehicles/solvents.
3.11
positive control

well-characterized material and/or substance, which, when evaluated by a specific test method,

demonstrates the suitability of the test system to yield a reproducible, appropriately positive or reactive

response in the test system
3.12
reference material

material, sufficiently homogeneous and stable with respect to one or more specified properties, which

has been established to be fit for its intended use in a measurement process
Note 1 to entry: RM is a generic term.

Note 2 to entry: Properties can be quantitative or qualitative, e.g. identity of substances or species.

Note 3 to entry: Uses may include the calibration of a measurement system, assessment of a measurement

procedure, assigning values to other materials, and quality control.

Note 4 to entry: ISO/IEC Guide 99:2007 has an analogous definition (5.13), but restricts the term “measurement”

to apply to quantitative values. However, Note 3 of ISO/IEC Guide 99:2007, 5.13 (VIM), specifically includes

qualitative properties, called “nominal properties”.

Note 5 to entry: The laboratory is to demonstrate that the simulated-use extraction is carried out under

conditions that provide an appropriate representation of intended use. Product-use simulation is carried out

assuming the medical device is assigned to the most stringent category possible for the duration of exposure and

takes into consideration both the tissue(s) exposed and the temperature of exposure.

[SOURCE: ISO Guide 30:2015, 2.1.1 — Note 5 to entry has been added.]
3.13
stability

characteristic of a material, when stored under specified conditions, to maintain a specified property

value within specified limits for a specified period of time
[5]
Note 1 to entry: See also the IUPAC Compendium of Analytical Nomenclature .
3.14
test sample

medical device, component or material (or a representative sample thereof, manufactured and

processed by equivalent methods), or an extract or portion thereof that is subjected to biological

evaluation testing
4 General requirements

When identifying hazards and estimating risk in relation to medical devices, hazards that arise from

changes in the manufacturing process, or insufficient control of the manufacturing process, shall be

considered in the design and preparation of test samples, as described in ISO 14971. Particular attention

shall be given to material additives, unintentional base material impurities and manufacturing process

residues, e.g. trace elements and cleaning and disinfection agents.
© ISO 2021 – All rights reserved 3
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SIST EN ISO 10993-12:2021
ISO 10993-12:2021(E)

The ISO 10993 series describes many different biological assay systems. Therefore, the individual parts

shall be consulted to ascertain whether these are appropriate for specific test systems.

Experimental controls shall be used in biological evaluations carried out in order to either validate a

test procedure or compare the results between materials, or both. Depending on the specifications of a

particular test, either negative controls, blanks or positive controls, or all three, shall be used.

NOTE The same type of control can be applicable to different tests and can allow cross-reference to other

established materials and test methods. Additional guidance on the selection of experimental controls is given in

Annex A. Use of positive controls for in vivo testing might be affected by animal welfare regulations.

5 Reference materials (RMs)
5.1 General

RMs are established by individual laboratories. The extent of chemical, physical and biological

characterization is determined by the individual laboratory. Commercially available articles may be

used as RMs.
NOTE See also ISO Guide 35.

CRMs are selected for their high purity, critical characteristics, suitability for the intended purpose and

general availability. The critical chemi
...

SLOVENSKI STANDARD
oSIST prEN ISO 10993-12:2019
01-julij-2019
Biološko ovrednotenje medicinskih pripomočkov - 12. del: Priprava vzorcev in
referenčni materiali (ISO/DIS 10993-12:2019)

Biological evaluation of medical devices - Part 12: Sample preparation and reference

materials (ISO/DIS 10993-12:2019)
Biologische Beurteilung von Medizinprodukten - Teil 12: Probenvorbereitung und
Referenzmaterialien (ISO/DIS 10993-12:2019)

Évaluation biologique des dispositifs médicaux - Partie 12: Préparation des échantillons

et matériaux de référence (ISO/DIS 10993-12:2019)
Ta slovenski standard je istoveten z: prEN ISO 10993-12
ICS:
11.100.20 Biološko ovrednotenje Biological evaluation of
medicinskih pripomočkov medical devices
oSIST prEN ISO 10993-12:2019 en

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

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oSIST prEN ISO 10993-12:2019
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oSIST prEN ISO 10993-12:2019
DRAFT INTERNATIONAL STANDARD
ISO/DIS 10993-12
ISO/TC 194 Secretariat: DIN
Voting begins on: Voting terminates on:
2019-05-08 2019-07-31
Biological evaluation of medical devices —
Part 12:
Sample preparation and reference materials
Évaluation biologique des dispositifs médicaux —
Partie 12: Préparation des échantillons et matériaux de référence
ICS: 11.100.20
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oSIST prEN ISO 10993-12:2019
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oSIST prEN ISO 10993-12:2019
ISO/DIS 10993-12:2019(E)
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