SIST EN ISO 10993-12:2012
(Main)Biological evaluation of medical devices - Part 12: Sample preparation and reference materials (ISO 10993-12:2012)
Biological evaluation of medical devices - Part 12: Sample preparation and reference materials (ISO 10993-12:2012)
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 device testing in biological systems in accordance with one or more parts of ISO 10993. Specifically, this part of ISO 10993 addresses the following: - test sample selection; - selection of representative portions from a device; - test sample preparation; - experimental controls; - selection of, and requirements, for reference materials; - preparation of extracts. This part of ISO 10993 is not applicable to live cells, but can be relevant to the material or device components of combination products containing live cells.
Biologische Beurteilung von Medizinprodukten - Teil 12: Probenvorbereitung und Referenzmaterialien (ISO 10993-12:2012)
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-Reihe zu befolgen sind.
Dieser Teil der ISO 10993 bezieht sich insbesondere auf die:
- Auswahl der Prüfmuster,
- Auswahl repräsentativer Teile eines Medizinproduktes,
- Probenvorbereitung,
- Kontrollen der Prüfmethoden,
- Auswahl und Anforderungen an die Referenzmaterialien und
- Herstellung der Extrakte.
Dieser Teil der ISO 10993 ist nicht anwendbar auf Materialien oder Produkte, die lebende Zellen enthalten.
Évaluation biologique des dispositifs médicaux - Partie 12: Préparation des échantillons et matériaux de référence (ISO 10993-12:2012)
Biološko ovrednotenje medicinskih pripomočkov - 12. del: Priprava vzorcev in referenčni materiali (ISO 10993-12:2012)
Ta del standarda ISO 10993 določa zahteve in smernice za postopke, ki jih je treba upoštevati pri pripravi vzorcev in izbiranju referenčnih materialov za preskušanje medicinskih pripomočkov v bioloških sistemih v skladu z enim ali več deli standarda ISO 10993. Ta del standarda ISO 10993 obravnava zlasti naslednje: – izbiranje preskusnega vzorca; – izbiranje reprezentativnih delov pripomočka, – pripravo preskusnega vzorca; – kontrole preskusa; –izbiranje referenčnih materialov in zahteve zanje; – pripravo izvlečkov. Ta del standarda ISO 10993 se ne uporablja za žive celice, vendar je lahko ustrezen za materiale ali sestavne dele kombiniranih izdelkov, ki vsebujejo žive celice.
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Related Packages
Standards Content (Sample)
SLOVENSKI STANDARD
SIST EN ISO 10993-12:2012
01-oktober-2012
1DGRPHãþD
SIST EN ISO 10993-12:2009
%LRORãNRRYUHGQRWHQMHPHGLFLQVNLKSULSRPRþNRYGHO 3ULSUDYDY]RUFHYLQ
UHIHUHQþQLPDWHULDOL ,62
Biological evaluation of medical devices - Part 12: Sample preparation and reference
materials (ISO 10993-12:2012)
Biologische Beurteilung von Medizinprodukten - Teil 12: Probenvorbereitung und
Referenzmaterialien (ISO 10993-12:2012)
Évaluation biologique des dispositifs médicaux - Partie 12: Préparation des échantillons
et matériaux de référence (ISO 10993-12:2012)
Ta slovenski standard je istoveten z: EN ISO 10993-12:2012
ICS:
11.100.20 %LRORãNRRYUHGQRWHQMH Biological evaluation of
PHGLFLQVNLKSULSRPRþNRY medical devices
SIST EN ISO 10993-12:2012 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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SIST EN ISO 10993-12:2012
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SIST EN ISO 10993-12:2012
EUROPEAN STANDARD
EN ISO 10993-12
NORME EUROPÉENNE
EUROPÄISCHE NORM
July 2012
ICS 11.100.20 Supersedes EN ISO 10993-12:2009
English Version
Biological evaluation of medical devices - Part 12: Sample
preparation and reference materials (ISO 10993-12:2012)
Évaluation 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 10993-12:2012) 12:2012)
This European Standard was approved by CEN on 30 June 2012.
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, Former Yugoslav Republic of Macedonia, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania,
Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey and United
Kingdom.
EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION
EUROPÄISCHES KOMITEE FÜR NORMUNG
Management Centre: Avenue Marnix 17, B-1000 Brussels
© 2012 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 10993-12:2012: E
worldwide for CEN national Members.
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SIST EN ISO 10993-12:2012
EN ISO 10993-12:2012 (E)
Contents Page
Foreword .3
Annex ZA (informative) Relationship between this European Standard and the Essential
Requirements of EU Directive 93/42/EEC on medical devices .4
Annex ZB (informative) Relationship between this European Standard and the Essential
Requirements of EU Directive 90/385/EEC on active implantable medical devices .5
2
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SIST EN ISO 10993-12:2012
EN ISO 10993-12:2012 (E)
Foreword
This document (EN ISO 10993-12:2012) has been prepared by Technical Committee ISO/TC 194 "Biological
evaluation of medical devices" in collaboration with Technical Committee CEN/TC 206 “Biological evaluation
of medical devices” the secretariat of which is held by NEN.
This European Standard shall be given the status of a national standard, either by publication of an identical
text or by endorsement, at the latest by January 2013, and conflicting national standards shall be withdrawn at
the latest by January 2013.
Attention is drawn to the possibility that some of the elements of this document may be the subject of patent
rights. CEN [and/or CENELEC] shall not be held responsible for identifying any or all such patent rights.
This document supersedes EN ISO 10993-12:2009.
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 Directives.
For relationship with EU Directives, see informative Annex ZA and ZB, which are an integral parts 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, Bulgaria, Croatia, Cyprus, Czech
Republic, Denmark, Estonia, Finland, Former Yugoslav Republic of Macedonia, France, Germany, Greece,
Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal,
Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland and the United Kingdom.
Endorsement notice
The text of ISO 10993-12:2012 has been approved by CEN as a EN ISO 10993-12:2012 without any
modification.
3
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SIST EN ISO 10993-12:2012
EN ISO 10993-12:2012 (E)
Annex ZA
(informative)
Relationship between this European Standard and the Essential
Requirements of EU Directive 93/42/EEC on medical devices
This European Standard has been prepared under a mandate given to CEN by the European Commission
and the European Free Trade Association to provide a means of conforming to Essential Requirements of the
New Approach Directive 93/42/EEC on medical devices.
Once this standard is cited in the Official Journal of the European Union under that Directive and has been
implemented as a national standard in at least one Member State, compliance with the 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 Essential Requirements of that Directive and associated EFTA regulations.
Table ZA.1 — Correspondence between this European Standard
and Directive 93/42/EEC on medical devices
Clauses of this Essential Requirements (ERs) Qualifying remarks/Notes
European Standard of Directive 93/42/EEC
This standard provides a means of preparing
samples to assess conformity with this part of
this ER in conjunction with other relevant parts
4, 5, 6, 7, 8, 9, 10, 11 7.2 first sentence only
of EN ISO 10993 for the design and
manufacture of medical devices. Packaging is
not covered.
This standard provides a means of preparing
samples of medical devices to assess
4, 5, 6, 7, 8, 9, 10 , 11 7.5 first paragraph only conformity with this part of this ER in
conjunction with other relevant parts of EN ISO
10993.
WARNING — Other requirements and other EU Directives may be applicable to the product(s) falling
within the scope of this standard.
4
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SIST EN ISO 10993-12:2012
EN ISO 10993-12:2012 (E)
Annex ZB
(informative)
Relationship between this European Standard
and the Essential Requirements of EU Directive 90/385/EEC
on active implantable medical devices
This European Standard has been prepared under a mandate given to CEN by the European Commission
and the European Free Trade Association to provide a means of conforming to Essential Requirements of the
New Approach Directive 90/385/EEC on active implantable medical devices.
Once this standard is cited in the Official Journal of the European Union under that Directive and has been
implemented as a national standard in at least one Member State, compliance with the clauses of this
standard given in Table ZB.1 confers, within the limits of the scope of this standard, a presumption of
conformity with the corresponding Essential Requirements of that Directive and associated EFTA regulations.
Table ZB.1 — Correspondence between this European Standard
and Directive 90/385/EEC on active implantable medical devices
Clauses of this Essential Requirements (ERs) Qualifying remarks/Notes
European Standard of Directive 90/385/EEC
This standard provides a means of preparing
samples of medical devices to assess
4, 5, 6, 7, 8, 9, 10, 11 9 (first and second indents only) conformity with these parts of this ER in
conjunction with other relevant parts of EN ISO
10993.
WARNING — Other requirements and other EU Directives may be applicable to the product(s) falling
within the scope of this standard.
5
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SIST EN ISO 10993-12:2012
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SIST EN ISO 10993-12:2012
INTERNATIONAL ISO
STANDARD 10993-12
Fourth edition
2012-07-01
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 10993-12:2012(E)
©
ISO 2012
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SIST EN ISO 10993-12:2012
ISO 10993-12:2012(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2012
All rights reserved. Unless otherwise specified, no part of this publication may be reproduced or utilized in any form or by any means,
electronic or mechanical, including photocopying and microfilm, without permission in writing from either ISO at the address below or ISO’s
member body in the country of the requester.
ISO copyright office
Case postale 56 • CH-1211 Geneva 20
Tel. + 41 22 749 01 11
Fax + 41 22 749 09 47
E-mail copyright@iso.org
Web www.iso.org
Published in Switzerland
ii © ISO 2012 – All rights reserved
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SIST EN ISO 10993-12:2012
ISO 10993-12:2012(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 device . 5
10 Preparation of extracts of samples . 6
10.1 General . 6
10.2 Containers for extraction . 6
10.3 Extraction conditions and methods . 6
10.4 Extraction conditions for hazard identification and risk estimation in the exaggerated-use
condition (points to consider in relation to Annex D) . 9
11 Records . 9
Annex A (informative) Experimental controls .10
Annex B (informative) General principles on, and practices of, test sample preparation and
sample selection .12
Annex C (informative) Principles of test sample extraction.14
Annex D (informative) Exhaustive extraction of polymeric materials for biological evaluation .17
Bibliography .19
© ISO 2012 – All rights reserved iii
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SIST EN ISO 10993-12:2012
ISO 10993-12:2012(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 fourth edition cancels and replaces the third edition (ISO 10993-12:2007), 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 within a risk management process
— Part 2: Animal welfare requirements
— Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity
— Part 4: Selection of tests for interactions with blood
— Part 5: Tests for in vitro cytotoxicity
— Part 6: Tests for local effects after implantation
— Part 7: Ethylene oxide sterilization residuals
— Part 9: Framework for identification and quantification of potential degradation products
— Part 10: Tests for irritation and skin sensitization
— Part 11: Tests for systemic toxicity
— Part 12: Sample preparation and reference materials
— Part 13: Identification and quantification of degradation products from polymeric medical devices
— Part 14: Identification and quantification of degradation products from ceramics
— Part 15: Identification and quantification of degradation products from metals and alloys
— Part 16: Toxicokinetic study design for degradation products and leachables
— Part 17: Establishment of allowable limits for leachable substances
— Part 18: Chemical characterization of materials
— Part 19: Physico-chemical, morphological and topographical characterization of materials [Technical
Specification]
— Part 20: Principles and methods for immunotoxicology testing of medical devices [Technical Specification]
iv © ISO 2012 – All rights reserved
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SIST EN ISO 10993-12:2012
ISO 10993-12:2012(E)
Introduction
This part of ISO 10993 specifies methods of sample preparation and provides requirements and guidance for
the selection of reference materials for the biological evaluation of medical devices.
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 part of ISO 10993 is based on existing national and international specifications, regulations and standards
wherever possible. It is periodically reviewed and revised.
© ISO 2012 – All rights reserved v
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SIST EN ISO 10993-12:2012
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SIST EN ISO 10993-12:2012
INTERNATIONAL STANDARD ISO 10993-12:2012(E)
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 device testing in biological systems
in accordance with one or more parts of ISO 10993. Specifically, this part of ISO 10993 addresses the following:
— test sample selection;
— selection of representative portions from a device;
— test sample preparation;
— experimental controls;
— selection of, and requirements, for reference materials;
— preparation of extracts.
This part of ISO 10993 is not applicable to live cells, but can be relevant to the material or device components
of combination products containing live cells.
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 (all parts), Biological evaluation of medical devices
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 leachable or extractable materials of the device or material, using
conditions that shorten the time for leaching of the substances into the extraction vehicle but do not result in a
chemical change of the substances being extracted
EXAMPLE Elevated temperature, agitation, changing of the extraction vehicle.
3.2
blank
extraction vehicle not containing the test material, which is retained in a vessel identical to that holding the test
sample and subjected to conditions identical to the ones the test sample is subjected to during its extraction
NOTE The purpose of the blank is to evaluate possible confounding effects due to the extraction vessel, extraction
vehicle and extraction process.
© ISO 2012 – All rights reserved 1
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SIST EN ISO 10993-12:2012
ISO 10993-12:2012(E)
3.3
CRM
certified reference material
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 30:1992, definition 2.2]
3.4
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 It is important to ensure that the exaggerated extraction does not result in a chemical change of the material.
3.5
exhaustive extraction
extraction conducted until the amount of extractable material in a subsequent extraction is less than 10 % by
gravimetric analysis of that detected in the initial extraction
NOTE 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.
3.6
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
3.7
extract
liquid that results from extraction of the test sample or control
3.8
extractables
substances that can be released from a medical device or material using extraction solvents and/or extraction
conditions that are expected to be at least as aggressive as the conditions of clinical use
3.9
homogeneous
property of a material and its relationship to a biological endpoint, meaning that it is of uniform structure or
composition, thereby consistently rendering, or not, a specific biological response
NOTE A 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 extracted.
3.10
leachables
substances that can be released from a medical device or material during clinical use
3.11
negative control
any 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 In practice, negative controls are reference materials but can include blanks and extraction vehicles/solvents.
3.12
positive control
any 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
2 © ISO 2012 – All rights reserved
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SIST EN ISO 10993-12:2012
ISO 10993-12:2012(E)
3.13
RM
reference material
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
NOTE 1 Adapted from ISO Guide 30:1992, definition 2.1.
NOTE 2 For the purpose of this part of ISO 10993, an RM 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.
3.14
simulated-use extraction
extraction conducted to demonstrate compliance with the requirements of this part of ISO 10993 by evaluating
leachable material levels available to the patient or user from devices during the routine use of a device, using
an extraction method that simulates product use
NOTE The burden of validation on the analytical laboratory is to demonstrate that the simulated-use extraction is
carried out under conditions that provide the greatest challenge to the intended use. Product-use simulation is carried
out assuming the 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.
3.15
stability
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
NOTE Adapted from ISO Guide 30:1992, definition 2.7.
3.16
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 or chemical testing or evaluation
4 General requirements
4.1 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
residues, e.g. trace elements and cleaning and disinfection agents, of manufacturing processes.
4.2 ISO 10993 describes many different biological assay systems. Therefore, the individual parts shall be
consulted to ascertain whether these are appropriate for specific test systems.
4.3 Experimental controls shall be used in biological evaluations carried out in order 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, depending on what is appropriate to the test.
NOTE The same type of control can 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 might be affected by animal welfare regulations.
© ISO 2012 – All rights reserved 3
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SIST EN ISO 10993-12:2012
ISO 10993-12:2012(E)
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 RM.
NOTE 1 See also ISO Guide 35.
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.
NOTE 2 It is desirable for users to obtain a commitment from suppliers of RMs or CRMs stating that these materials
will be available to the user for at least five 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 ensure 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 specified test conditions, 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.
NOTE See also ISO Guide 34.
5.2.2 Suppliers of RMs shall certify the materials. The supplier determines the extent of chemical and physical
characterization that is performed. The individual laboratories that use the RM shall identify the biological
characterization necessary to qualify a RM for a specific test or procedure. Commercially available materials
may be used as RM, provided they are certified and qualified.
5.2.3 Certification of a 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, i.e. 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.
NOTE The use of an RM will facilitate the comparability of the response between laboratories and help assess
reproducibility of the 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 e
...
SLOVENSKI STANDARD
oSIST prEN ISO 10993-12:2010
01-julij-2010
%LRORãNRRYUHGQRWHQMHPHGLFLQVNLKSULSRPRþNRYGHO 3ULSUDYDY]RUFHYLQ
UHIHUHQþQLPDWHULDOL ,62',6
Biological evaluation of medical devices - Part 12: Sample preparation and reference
materials (ISO/DIS 10993-12:2010)
Biologische Beurteilung von Medizinprodukten - Teil 12: Probenvorbereitung und
Referenzmaterialien (ISO/DIS 10993-12:2010)
Évaluation biologique des dispositifs médicaux - Partie 12: Préparation des échantillons
et matériaux de référence (ISO/DIS 10993-12:2010)
Ta slovenski standard je istoveten z: prEN ISO 10993-12
ICS:
11.100.20 %LRORãNRRYUHGQRWHQMH Biological evaluation of
PHGLFLQVNLKSULSRPRþNRY medical devices
oSIST prEN ISO 10993-12:2010 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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oSIST prEN ISO 10993-12:2010
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oSIST prEN ISO 10993-12:2010
EUROPEAN STANDARD
DRAFT
prEN ISO 10993-12
NORME EUROPÉENNE
EUROPÄISCHE NORM
May 2010
ICS 11.100.20 Will supersede EN ISO 10993-12:2009
English Version
Biological evaluation of medical devices - Part 12: Sample
preparation and reference materials (ISO/DIS 10993-12:2010)
Évaluation biologique des dispositifs médicaux - Partie 12: Biologische Beurteilung von Medizinprodukten - Teil 12:
Préparation des échantillons et matériaux de référence Probenvorbereitung und Referenzmaterialien (ISO/DIS
(ISO/DIS 10993-12:2010) 10993-12:2010)
This draft European Standard is submitted to CEN members for parallel enquiry. It has been drawn up by the Technical Committee
CEN/TC 206.
If this draft becomes a European Standard, 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.
This draft European Standard was established by CEN 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 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, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland and United Kingdom.
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.
Warning : This document is not a European Standard. It is distributed for review and comments. It is subject to change without notice and
shall not be referred to as a European Standard.
EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION
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© 2010 CEN All rights of exploitation in any form and by any means reserved Ref. No. prEN ISO 10993-12:2010: E
worldwide for CEN national Members.
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oSIST prEN ISO 10993-12:2010
prEN ISO 10993-12:2010 (E)
Contents Page
Foreword .3
2
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oSIST prEN ISO 10993-12:2010
prEN ISO 10993-12:2010 (E)
Foreword
This document (prEN ISO 10993-12:2010) has been prepared by Technical Committee ISO/TC 194
"Biological evaluation of medical devices" in collaboration with Technical Committee CEN/TC 206 “Biological
evaluation of medical devices” the secretariat of which is held by NEN.
This document is currently submitted to the parallel Enquiry.
This document will supersede EN ISO 10993-12:2009.
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).
Endorsement notice
The text of ISO/DIS 10993-12:2010 has been approved by CEN as a prEN ISO 10993-12:2010 without any
modification.
3
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oSIST prEN ISO 10993-12:2010
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oSIST prEN ISO 10993-12:2010
DRAFT INTERNATIONAL STANDARD ISO/DIS 10993-12
ISO/TC 194 Secretariat: DIN
Voting begins on: Voting terminates on:
2010-05-06 2010-10-06
INTERNATIONAL ORGANIZATION FOR STANDARDIZATION • МЕЖДУНАРОДНАЯ ОРГАНИЗАЦИЯ ПО СТАНДАРТИЗАЦИИ • ORGANISATION INTERNATIONALE DE NORMALISATION
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
[Revision of third edition (ISO 10993-12:2007)]
ICS 11.100.20
ISO/CEN PARALLEL PROCESSING
This draft has been developed within the International Organization for Standardization (ISO), and
processed under the ISO-lead mode of collaboration as defined in the Vienna Agreement.
This draft is hereby submitted to the ISO member bodies and to the CEN member bodies for a parallel
five-month enquiry.
Should this draft be accepted, a final draft, established on the basis of comments received, will be
submitted to a parallel two-month approval vote in ISO and formal vote in CEN.
To expedite distribution, this document is circulated as received from the committee secretariat.
ISO Central Secretariat work of editing and text composition will be undertaken at publication
stage.
Pour accélérer la distribution, le présent document est distribué tel qu'il est parvenu du
secrétariat du comité. Le travail de rédaction et de composition de texte sera effectué au
Secrétariat central de l'ISO au stade de publication.
THIS DOCUMENT IS A DRAFT CIRCULATED 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 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 NATIONAL REGULATIONS.
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.
©
International Organization for Standardization, 2010
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Contents Page
Foreword .iv
Introduction.vi
1 Scope.1
2 Normative references.1
3 Terms and definitions .1
4 General requirements.3
5 Reference materials.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 device.5
10 Preparation of extracts of samples .6
10.1 General.6
10.2 Containers for extraction.6
10.3 Extraction conditions and methods .6
10.4 Extraction conditions for hazard identification and risk estimation in the exaggerated-use
condition (points to consider in relation to Annex D) .9
11 Records.9
Annex A (informative) Experimental controls .10
Annex B (informative) General principles on and practices of test sample preparation and sample
selection .12
Annex C (informative) Principles of test sample extraction .14
Annex D (informative) Exhaustive extraction of polymeric materials for biological evaluation .16
D.1 General.16
D.2 Selection of appropriate solvent for extracting LMWCs from polymeric devices.16
D.3 Other Points-to-Consider for designing extraction condition.17
D.4 Usages of residue obtained by exhaustive extraction in biological evaluation .17
Annex ZA (informative) Relationship between this European Standard and the Essential
Requirements of EU Directive 93/42/EEC on Medical Devices.18
Annex ZB (informative) Relationship between this European Standard and the Essential
Requirements of EU Directive 90/385/EEC on Active Implantable Medical Devices.19
Bibliography.20
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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.
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
and by Technical Committee CEN/TC 206, Biological evaluation of medical devices in collaboration.
This fourth edition cancels and replaces the third edition (EN ISO 10993-12:2007), 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 within a risk management system
⎯ Part 2: Animal welfare requirements
⎯ Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity
⎯ Part 4: Selection of tests for interactions with blood
⎯ Part 5: Tests for in vitro cytotoxicity
⎯ Part 6: Tests for local effects after implantation
⎯ Part 7: Ethylene oxide sterilization residuals
⎯ Part 9: Framework for identification and quantification of potential degradation products
⎯ Part 10: Tests for irritation and sensitization
⎯ Part 11: Tests for systemic toxicity
⎯ Part 12: Sample preparation and reference materials
⎯ Part 13: Identification and quantification of degradation products from polymeric medical devices
⎯ Part 14: Identification and quantification of degradation products from ceramics
⎯ Part 15: Identification and quantification of degradation products from metals and alloys
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⎯ Part 16: Toxicokinetic study design for degradation products and leachables
⎯ Part 17: Establishment of allowable limits for leachable substances using health-based risk assessment
⎯ Part 18: Chemical characterization of materials
⎯ Part 19: Physico-chemical, morphological and topographical characterization of materials [Technical
Specification]
⎯ Part 20: Principles and methods for immunotoxicology testing of medical devices [Technical Specification]
Future parts will deal with other relevant aspects of biological testing.
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Introduction
This part of ISO 10993 specifies methods of sample preparation and the selection of reference materials in
the biological evaluation of medical devices.
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.
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oSIST prEN ISO 10993-12:2010
DRAFT INTERNATIONAL STANDARD ISO/DIS 10993-12
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 device testing in biological
systems in accordance with one or more parts of the ISO 10993 series. Specifically this part of ISO 10993
addresses:
⎯ test sample selection;
⎯ selection of representative portions from a device;
⎯ test sample preparation;
⎯ experimental controls;
⎯ selection of and requirements for reference materials;
⎯ preparation of extracts.
This part of ISO 10993 is not applicable to materials or devices containing live cells.
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 10993-1:2009, 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
blank
extraction vehicle not containing the test material, retained in a vessel identical to that which holds the test
sample and subjected to identical conditions to which the test sample is subjected during its extraction
NOTE The purpose of the blank is to evaluate possible confounding effects due to the extraction vessel, extraction
vehicle and extraction process.
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3.2
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, definition 2.2]
3.3
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
3.4
extract
liquid that results from extraction of the test sample or control
3.5
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 A 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.
3.6
negative control
any 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 In practice, negative controls are reference materials but may include blanks and extraction vehicles/solvents.
3.7
positive control
any 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
3.8
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, definition 2.1]
NOTE For the purpose 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.
3.9
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
NOTE Adapted from ISO Guide 30, definition 2.7.
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3.10
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 or chemical testing or
evaluation
3.11
simulated-use extraction
extraction to demonstrate compliance with the requirements of this part of ISO 10993, by evaluating leachable
material levels available to the patient or user from devices during the routine use of a device using an
extraction method that simulates product use
NOTE The burden of validation on the analytical laboratory is to demonstrate that the simulated-use extraction is
carried out under conditions that provide the greatest challenge to the intended use. Product-use simulation is carried out
assuming the device is assigned to the most stringent category probable for duration of exposure and takes into
consideration both tissue(s) exposed and temperature of exposure.
3.12
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 the simulated conditions of use
NOTE Exaggerated extraction might result in a chemical change of the material or the substances being extracted.
3.13
accelerated extraction
extraction that provides a measure of the leachable materials of the device or material using conditions that
shorten the time for leaching of the substances into the extraction vehicle but do not result in a chemical
change of the substances being extracted
NOTE Examples of accelerated extraction conditions are as follows: elevated temperature, agitation, changing of the
extraction vehicle, etc.
3.14
exhaustive extraction
extraction until the amount of leachable material in a subsequent extraction is less than 10 % by gravimetric
analysis of that detected in the initial extraction
NOTE 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.
4 General requirements
4.1 As described in ISO 14971, in the identification of hazard and risk estimation for 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 samples for test and preparation of extracts of
those devices. Particular attention shall be given to residues, e.g., trace elements and cleaning and
disinfection agents, of those manufacturing processes.
4.2 Because ISO 10993 describes many different biological assay systems, the individual standards shall
be consulted to ascertain if these recommendations are appropriate for specific test systems.
4.3 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 can 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.
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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 reference materials.
NOTE 1 See also ISO Guide 35.
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.
NOTE 2 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 five 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 ensure 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 specified test conditions, 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.
NOTE See also ISO Guide 34.
5.2.2 Suppliers of RMs shall certify the materials. The supplier determines the extent of chemical and
physical characterization that is performed. The individual laboratories that use the RMs shall identify the
biological characterization necessary to qualify an RM for a specific test or procedure. Commercially available
materials may be used as RMs provided 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.
NOTE Use of an RM will facilitate the comparability of the response between laboratories and assist 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, grade and type. RMs
are processed as described in Clause 8.
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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 sample select
...
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