SIST EN ISO 10993-12:2005

Biological evaluation of medical devices - Part 12: Sample preparation and reference materials (ISO 10993-12:2002)

UAP instead of VA/ISO (CC/020416)

Biologische Beurteilung von Medizinprodukten - Teil 12: Probenvorbereitung und Referenzmaterialien (ISO 10993-12:2002)

Der vorliegende Teil der ISO 10993 legt Anforderungen fest und gibt Anleitungen zu Verfahren, die bei der Probenvorbereitung und bei der Auswahl von Referenzmaterialien für die biologische Prüfung von Medizinprodukten nach einem oder mehreren Teilen der ISO 10993 zu befolgen sind.
Dieser Teil der ISO 10993 bezieht sich insbesondere auf die:
-   Auswahl der Prüfmaterialien;
-   Auswahl repräsentativer Teile eines Medizinproduktes;
-   Probenvorbereitung;
-   Kontrollen der Prüfmethoden;
-   Auswahl und Anforderungen an die Referenzmaterialien und;
-   Herstellung der Extrakte.
Die Anwendbarkeit dieses Teils der ISO 10993 auf resorbierbare Materialien, Materialien, die in situ polymerisieren, auf Materialien aus dem Bereich des Tissue-Engineerings und auf Materialien mit Bestandteilen tierischen Ursprungs sollte sorgfältig überprüft werden.

Evaluation biologique des dispositifs médicaux - Partie 12: Préparation des échantillons et matériaux de référence (ISO 10993-12:2002)

Biološko ovrednotenje medicinskih pripomočkov - 12. del: Priprava vzorcev in referenčni materiali (ISO 10993-12:2002)

General Information

• Status: Withdrawn
• Publication Date: 28-Feb-2005
• Withdrawal Date: 03-Feb-2008
• ICS: 11.100.20 - Biological evaluation of medical devices
• Technical Committee: VAZ - Healthcare
• Current Stage: 9900 - Withdrawal (Adopted Project)
• Start Date: 28-Jan-2008
• Due Date: 20-Feb-2008
• Completion Date: 04-Feb-2008
• Directive: 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
• Directive: 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 10993-12:2004 - Biological evaluation of medical devices - Part 12: Sample preparation and reference materials (ISO 10993-12:2002)

Relations

• Replaces: SIST EN ISO 10993-12:2000 - Biological evaluation of medical devices - Part 12: Sample preparation and reference materials (ISO 10993-12:1996)
• Effective Date: 01-Sep-2005
• Replaced By: SIST EN ISO 10993-12:2008 - Biological evaluation of medical devices - Part 12: Sample preparation and reference materials (ISO 10993-12:2007)
• Effective Date: 01-Apr-2008

Standards Content (Sample)

SLOVENSKI STANDARD
SIST EN ISO 10993-12:2005
01-marec-2005
1DGRPHãþD
SIST EN ISO 10993-12:2000
%LRORãNRRYUHGQRWHQMHPHGLFLQVNLKSULSRPRþNRYGHO3ULSUDYDY]RUFHYLQ
UHIHUHQþQLPDWHULDOL,62
Biological evaluation of medical devices - Part 12: Sample preparation and reference
materials (ISO 10993-12:2002)
Biologische Beurteilung von Medizinprodukten - Teil 12: Probenvorbereitung und
Referenzmaterialien (ISO 10993-12:2002)
Evaluation biologique des dispositifs médicaux - Partie 12: Préparation des échantillons
et matériaux de référence (ISO 10993-12:2002)
Ta slovenski standard je istoveten z: EN ISO 10993-12:2004
ICS:
11.100.20 %LRORãNRRYUHGQRWHQMH Biological evaluation of
PHGLFLQVNLKSULSRPRþNRY medical devices
SIST EN ISO 10993-12:2005 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.

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EUROPEAN STANDARD
EN ISO 10993-12

NORME EUROPÉENNE

EUROPÄISCHE NORM
November 2004
ICS 11.100 Supersedes EN ISO 10993-12:1996
English version
Biological evaluation of medical devices - Part 12: Sample
preparation and reference materials (ISO 10993-12:2002)
Evaluation biologique des dispositifs médicaux - Partie 12: Biologische Beurteilung von Medizinprodukten - Teil 12:
Préparation des échantillons et matériaux de référence Probenvorbereitung und Referenzmaterialien (ISO 10993-
(ISO 10993-12:2002) 12:2002)
This European Standard was approved by CEN on 27 October 2004.

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, 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
© 2004 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 10993-12:2004: E
worldwide for CEN national Members.

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EN ISO 10993-12:2004 (E)

Foreword


The text of the International Standard from Technical Committee ISO/TC 194 "Biological
evaluation of medical devices” of the International Organization for Standardization (ISO) has
been taken over as a European Standard by 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 May 2005, and conflicting national standards
shall be withdrawn at the latest by May 2005.

This document supersedes EN ISO 10993-12:1996.

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 relationship with EU Directive(s), see informative Annex ZB, which is an integral part of this
document.

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,
Slovakia, Slovenia, Spain, Sweden, Switzerland and United Kingdom.

Endorsement notice

The text of ISO 10993-12:2002 has been approved by CEN as a European Standard, EN ISO
10993-12:2004, without any modifications.

NOTE Normative references to International Standards are listed in annex ZA (normative).

2

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EN ISO 10993-12:2004 (E)
Annex ZA
(normative)

Normative references to international publications with their
relevant European publications


This European Standard incorporates by dated or undated reference, provisions from other
publications. These normative references are cited at the appropriate places in the text and the
publications are listed hereafter. For dated references, subsequent amendments to or revisions of
any of these publications apply to this European Standard only when incorporated in it by
amendment or revision. For undated references the latest edition of the publication referred to
applies (including amendments).

NOTE Where an International Publication has been modified by common modifications, indicated by (mod.),
the relevant EN/HD applies.



Publication Year Title EN Year


ISO 14971 2000 Medical devices – Application of risk EN ISO 14971 2000
management to medical devices


3

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EN ISO 10993-12:2004 (E)
Annex ZB
(Informative)

Clauses of this International Standard addressing essential
requirements or other provisions of EU Directives
This European standard 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 93/42/EEC of 14 June 1993 concerning medical devices.

WARNING : Other requirements and other EU Directives may be applicable to the product(s)
falling within the scope of this standard.

The following clauses of this standard are likely to support requirements of UE Directive
93/42/EEC of 14 June 1993 concerning medical devices

Compliance with the clauses of this standard provides one means of conforming with the specific
essential requirements of the Directive concerned and associated EFTA regulations.

Table ZB.1 — Correspondence between this European Standard and EU Directives
Clauses/subclauses of this Essential requirements Qualifying remarks/Notes
International Standard (ERs) of Directive 93/42/EEC

4, 5, 6, 7, 8, 9, 10, 11 7.1, 7.2, 7.3, 7.5 EN ISO 10993-12 'Biological
evaluation of medical devices –
Part 12: Sample preparation
and reference materials' should
be used in conjunction with th
tests indicated in EN ISO
10993-1 'Biological evaluation
of medical devices – Part 1:
Evaluation and testing'.





4

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INTERNATIONAL ISO
STANDARD 10993-12
Second edition
2002-12-15
Corrected version
2003-06-01

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 10993-12:2002(E)
©
ISO 2002

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ISO 10993-12:2002(E)
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Published in Switzerland

ii © ISO 2002 — All rights reserved

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ISO 10993-12:2002(E)
Contents Page
Foreword. iv
Introduction . vi
1 Scope. 1
2 Normative references . 1
3 Terms and definitions. 1
4 Experimental controls . 3
5 Reference materials . 3
5.1 General. 3
5.2 Certification of RMs for biological safety testing .4
6 Use of RMs as experimental controls . 4
7 Test material selection . 4
8 Test sample and RM preparation . 4
9 Selection of representative portions from a device . 5
10 Preparation of extracts of samples . 5
10.1 General. 5
10.2 Containers for extraction . 5
10.3 Extraction conditions and methods. 6
10.4 Extraction conditions for hazard identification and risk estimation in exaggerated-use
condition . 8
11 Records. 8
Annex A (informative) Experimental controls. 9
Annex B (informative) General principles and practices of test material preparation and sample
selection. 11
Annex C (informative) Principles of test material extraction . 13
Bibliography . 15

© ISO 2002 — All rights reserved iii

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ISO 10993-12:2002(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 10993-12 was prepared by Technical Committee ISO/TC 194, Biological evaluation of medical devices.
This second edition cancels and replaces the first edition (ISO 10993-12:1996), 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 8: Selection and qualification of reference materials for biological tests
 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
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ISO 10993-12:2002(E)
 Part 15: Identification and quantification of degradation products from metals and alloys
 Part 16: Toxicokinetic study design for degradation products and leachables
 Part 17: Establishment of allowable limits for leachable substances
Future parts will deal with other relevant aspects of biological testing.
This corrected version of ISO 10993-12:2002 incorporates a correction in 10.3.4, in which a note clarifies use
of other media in some countries.
© ISO 2002 — All rights reserved v

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ISO 10993-12:2002(E)
Introduction
This part of ISO 10993 specifies methods of sample preparation and the selection of reference materials in the
biological evaluation of medical devices. Because ISO 10993 describes many different biological assay systems,
the individual parts should be consulted to ascertain if these recommendations are appropriate for specific test
systems.
Sample preparation methods should 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 part of ISO 10993 is based on existing national and international specifications, regulations and standards
wherever possible. It is periodically reviewed and revised.

vi © ISO 2002 — All rights reserved

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INTERNATIONAL STANDARD ISO 10993-12:2002(E)

Biological evaluation of medical devices —
Part 12:
Sample preparation and reference materials
1 Scope
This part of ISO 10993 specifies requirements and gives guidance on the procedures to be followed in the
preparation of samples and the selection of reference materials for medical devices testing in biological
systems in accordance with one or more parts of the ISO 10993 series.
Specifically, this part of ISO 10993 addresses:
 test material selection;
 selection of representative portions from a device;
 test sample preparation;
 experimental controls;
 selection of and requirements for reference materials; and
 preparation of extracts.
The applicability of this part of ISO 10993 to absorbable materials, materials that polymerize in situ,
tissue-engineered medical products and materials of biological origin should be carefully evaluated.
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 10993-1:1997, Biological evaluation of medical devices — Part 1: Evaluation and testing
ISO 14971, Medical devices — Application of risk management to medical devices
3 Terms and definitions
For the purposes of this document, the following terms and definitions apply.
3.1
accelerated extraction
extraction that provides a measure of the hazard potential of the device or material using conditions that
shorten the time for leaching of the substances into the medium
NOTE 1 Examples of accelerated extraction conditions are elevated temperature, agitation, changing medium, etc.
NOTE 2 Accelerated extraction will not result in a chemical change in the substances being extracted.
© ISO 2002 — All rights reserved 1

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ISO 10993-12:2002(E)
3.2
blank
extraction medium not containing the test material, retained in a vessel identical to that which holds the test
material and subjected to identical conditions to which the test material is subjected during its extraction
NOTE The purpose of the blank is to evaluate possible confounding effects due to the extraction vessel, vehicle and
extraction process.
3.3
certified reference material
CRM
reference material, accompanied by a certificate, one or more of whose property values are certified by a
procedure which establishes its traceability to an accurate realization of the unit in which the property values
are expressed, and for which each certified value is accompanied by an uncertainty at a stated level of
confidence
[ISO Guide 30]
NOTE Standard Reference Material (SRM) is a trademark of the National Institute of Standards and Technology,
Gaithersburg, MD, USA.
3.4
exaggerated extraction
any extraction that is intended to result in a greater amount of a chemical constituent being released as
compared to the amount generated under simulated-use conditions
NOTE Exaggerated extraction is not intended to result in a chemical change of the material or the substances being
extracted (see 10.3).
3.5
experimental control
substance with well characterized responses, which is used in a specific test system to assist in evaluating
whether the test system has responded in a reproducible and appropriate manner
3.6
extract
liquid that results from extraction of test material or control
3.7
homogeneous
property of a material and its relationship to a biological endpoint such that it is of uniform structure or
composition to consistently render or not a specific biological response
NOTE The reference material is said to be homogeneous if the biological response to 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
removed.
3.8
negative control
any well characterized material, 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 In practice, negative controls include blanks, vehicles/solvents and reference materials.
3.9
positive control
any well characterized material, 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
2 © ISO 2002 — All rights reserved

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ISO 10993-12:2002(E)
3.10
reference material
RM
material with one or more property values that are sufficiently reproducible and well established to enable use
of the material or substance for the calibration of an apparatus, the assessment of a measurement method, or
for the assignment of values to materials
[ISO Guide 30]
NOTE For the purposes of this part of ISO 10993, a reference material is any well characterized material or
substance, which when tested by the procedure described, demonstrates the suitability of the procedure to yield a
reproducible, predictable response. The response may be negative or positive.
3.11
simulated-use extraction
extraction of a test material or sample with an appropriate medium and under conditions that simulate product
use, for the purpose of evaluating its potential hazard to the patient or user during its routine clinical use
3.12
stability of property values
ability of a material, when stored under specified conditions, to maintain a specific stated biological response,
within specified limits, for a specific period of time
[ISO Guide 30]
3.13
test material
material, device, device portion, or component thereof subject to biological testing
3.14
test sample
test material or extract subject to biological testing
4 Experimental controls
Experimental controls shall be used in biological evaluations to validate a test procedure and/or to compare
the results between materials. Depending on the biological test, negative controls, blanks and/or positive
controls shall be used as is appropriate to the test.
NOTE The same type of control may be applicable to different tests and may 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 may be affected by animal welfare regulations.
5 Reference materials
5.1 General
Reference materials (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.
Certified Reference Materials (CRMs) are selected for their high purity, critical characteristics, suitability for
the intended purpose and general availability. The critical chemical, physical and biological characteristics
shall be determined by collaborative testing in three or more laboratories, and made available to the
investigator by the distributor.
© ISO 2002 — All rights reserved 3

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ISO 10993-12:2002(E)
NOTE It is desirable for users to obtain a commitment from suppliers of RMs or CRMs that these materials will be
available to the user for at least 5 years. A second, but less desirable, option is for the source of the RM or CRM to publish
an “open formulation” for the material, i.e. publication of the source materials and details of the processing needed to
insure uniform batches of the RM.
5.2 Certification of RMs for biological safety testing
5.2.1 Qualification of an RM is a procedure that establishes the numerical or qualitative value of the
biological response of the material under test conditions specified, ensuring reproducibility of the response
within and/or between laboratories. The range of biological responses associated with the material shall be
established through laboratory tests.
5.2.2 Suppliers of RMs certify the materials. The supplier determines the extent of chemical and physical
characterization that is performed. The individual laboratories that use the RMs identify the biological
characterization necessary to qualify an RM for a specific test or procedure. Commercially available materials
may be used as RMs providing they are certified and qualified.
5.2.3 Certification of an RM is a procedure that establishes the numerical or qualitative value of the
biological response of the material under the specified test conditions. This process serves to validate the
testing of the material for that particular response and results in the issuance of a certificate. The biological
response of the material shall be established through interlaboratory tests.
6 Use of RMs as experimental controls
6.1 RMs or CRMs shall be used in biological tests as control materials to demonstrate the suitability of a
procedure to yield a reproducible response, such as either positive and/or negative. Any material used in this
way shall be characterized with each biological test procedure for which the use of the material is desired. A
material characterized and then certified for one reference test method or response, e.g. delayed-type
hypersensitivity, shall not be used as an RM for another, e.g. cytotoxicity, without additional validation.
Use of an RM facilitates the comparability of the response between laboratories and assists in assessing
reproducibility of test performance within individual laboratories. For comparison of the biological response, it is
desirable to use RMs having a range of responses, e.g. minimum, intermediate or severe.
6.2 RMs used as experimental controls shall meet the established quality assurance procedures of the
manufacturer and test laboratory. They shall be identified as to source, manufacturer, grad, and type. RMs are
processed in accordance with Clause 8.
6.3 When RMs are used as experimental controls, they shall be in the same material class as the test
sample, i.e. polymer, ceramic, metal, colloid, etc. However, pure chemicals may be used as experimental
controls for mechanistically based test procedures, e.g. genotoxicity and immune delayed-type
hypersensitivity assays.
7 Test material selection
7.1 Testing shall be performed on the final product, or representative samples from the final products, or
materials processed in the same manner as the final product (see ISO 10993-1).
7.2 The same test material selection procedure applies when an extract is required.
8 Test sample and RM preparation
8.1 Test samples and RMs shall be handled with care to prevent contamination. Any residues from the
manufacturing processes shall be considered to be integral to the device, device portion or component.
NOTE For additional guidance on preparation, see Annex B.
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ISO 10993-12:2002(E)
8.1.1 Test samples from sterilized devices and RMs shall be handled aseptically if appropriate to the test
procedure.
8.1.2 Test samples from a device which is normally supplied non-sterile, but which requires sterilization
prior to use, shall be sterilized by the method recommended by the manufacturer and handled aseptically if
appropriate to the test procedure.
8.1.3 If test samples are cleaned prior to sterilization, the influence of the cleaning process and cleaning
agent shall be considered in the selection and handling of the test sample.
8.2 If sterile test samples are required for the test procedure, the effect of the sterilization or resterilization
process on the test sample and RMs shall be considered.
8.3 When test samples and RMs need to be cut into pieces as described in 10.3.2.2, the influence of
previously unexposed surfaces, e.g. lumens or cut surfaces, shall be considered. Tools used for cutting
medical devices into representative portions for testing shall be clean to prevent contamination.
9 Selection of representative portions from a device
9.1 If a device cannot be tested as a whole, each individual material in the final product shall be
represented proportionally in the test sample.
9.1.1 The test sample of devices with surface coatings shall include both coating material and the substrate.
9.1.2 The test sample shall include a representative portion of the joint and/or seal if adhesives, radio
frequency (RF) seals, or solvent seals are used in the manufacture of a portion of the device which contacts
patients.
9.2 Composite materials shall be tested as finished materials.
9.3 When different materials are present in a single device, the potential for synergies and interactions shall
be considered in the choice of test sample.
9.4 The test sample shall
...