SIST EN ISO 10993-12:2000
(Main)Biological evaluation of medical devices - Part 12: Sample preparation and reference materials (ISO 10993-12:1996)
Biological evaluation of medical devices - Part 12: Sample preparation and reference materials (ISO 10993-12:1996)
This part of ISO 10993 specifies requirements and gives guidance on procedures to be followed in the preparation of samples of medical devices for testing in biological systems in accordance with one or more other parts of ISO 10993. These include: a) test material selection; b) selection of representative portions from a device; c) test sample preparation; d) the selection of reference materials to demonstrate the suitability of the test system and/or to enable relative comparison of the biological activity of the test sample; and, e) preparation of extracts.
Biologische Beurteilung von Medizinprodukten - Teil 12: Probenvorbereitung und Referenzmaterialien (ISO 10993-12:1996)
Der vorliegende Teil der ISO 10993 legt Anforderungen fest und gibt Anleitungen für Verfahren, die bei der Vorbereitung von Proben von Medizinprodukten für die Prüfung in biologischen Systemen nach einem oder mehreren Teilen der ISO 10993 zu befolgen sind.
Evaluation biologique des dispositifs médicaux - Partie 12: Préparation des échantillons et matériaux de référence (ISO 10993-12:1996)
Biološko ovrednotenje medicinskih pripomočkov - 12. del: Priprava vzorcev in referenčni materiali (ISO 10993-12:1996)
General Information
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Standards Content (Sample)
SLOVENSKI STANDARD
SIST EN ISO 10993-12:2000
01-januar-2000
%LRORãNRRYUHGQRWHQMHPHGLFLQVNLKSULSRPRþNRYGHO 3ULSUDYDY]RUFHYLQ
UHIHUHQþQLPDWHULDOL ,62
Biological evaluation of medical devices - Part 12: Sample preparation and reference
materials (ISO 10993-12:1996)
Biologische Beurteilung von Medizinprodukten - Teil 12: Probenvorbereitung und
Referenzmaterialien (ISO 10993-12:1996)
Evaluation biologique des dispositifs médicaux - Partie 12: Préparation des échantillons
et matériaux de référence (ISO 10993-12:1996)
Ta slovenski standard je istoveten z: EN ISO 10993-12:1996
ICS:
11.100.20 %LRORãNRRYUHGQRWHQMH Biological evaluation of
PHGLFLQVNLKSULSRPRþNRY medical devices
SIST EN ISO 10993-12:2000 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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SIST EN ISO 10993-12:2000
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SIST EN ISO 10993-12:2000
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SIST EN ISO 10993-12:2000
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SIST EN ISO 10993-12:2000
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SIST EN ISO 10993-12:2000
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SIST EN ISO 10993-12:2000
INTERNATIONAL
IS0
STANDARD
1099342
First edition
1996-09-15
Biological evaluation of medical devices -
Part 12:
Sample preparation and reference materials
ivalua tion biologique des dispositifs mgdicaux -
Partie 72: P&par-a tion des khan tillons et mat&iaux de r6f&-ence
Reference number
IS0 10993-12:1996(E)
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SIST EN ISO 10993-12:2000
IS0 10993=12:1996(E)
Contents
Page
Scope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1
2 Normative references . . 1
3 Definitions . . . 1
4 Experimental controls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
5 Test material selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
6 Test sample and reference material preparation . 3
7 Preparation of extracts of test materials . 3
Test report
8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Annexes
6
A Experimental controls .
8
B Guidance for test material preparation .
9
C Guidance for extraction of samples .
D Bibliography . . 11
0 IS0 1996
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 photocopyrng and
microfilm, without permission in writing from the publisher.
International Organization for Standardization
Case Postale 56 l CH-1211 Geneve 20 l Switzerland
Printed in Switzerland
II
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SIST EN ISO 10993-12:2000
0 IS0
IS0 1099342:1996(E)
Foreword
IS0 (the International Organization for Standardization) is a worldwide
federation of national standards bodies (IS0 member bodies). The work
of preparing International Standards is normally carried out through IS0
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. IS0
collaborates closely with the International Electrotechnical Commission
(IEC) on all matters of electrotechnical standardization.
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.
International Standard IS0 10993-I 2 was prepared by Technical Commit-
tee lSO/TC 194, Biological evaluation of medical devices.
IS0 10993 consists of the following parts, under the general title Biologica/
evaluation of medical devices:
- Part 1: Evaluation and testing
- Part 2: Animal welfare requirements
- Part 3: Tests for geno toxicity, carcinogenicity and reproductive
toxicity
- Part 4: Selection of tests for interactions with blood
- Part 5: Tests for cytotoxicity: in vitro methods
- Part 6: Tests for local effects after implantation
- Part 7: Ethylene oxide sterilization residuals
- Part 9: Degradation of materials related to biological testing
[Technical Report]
- Part ? 0: Tests for irritation and sensitization
- Part ? I: Tests for systemic toxicity
- Part 72: Sample preparation and reference materials
- Part 13: /den tifica tion and quantification of degradation products
from polymers
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SIST EN ISO 10993-12:2000
0 IS0
IS0 1099342:1996(E)
- Part 74: /den tification and quantification of degradation products
from ceramics
- Part 15: /den tification and quantification of degradation products
from coated and uncoated metals and alloys
- Part 16: Toxicokinetic study design for degradation products and
leachables
- Part 77: Glutaraldehyde and formaldehyde residues in industrially
sterilized medical devices
Future parts will deal with other relevant aspects of biological testing.
Annexes A, B, C and D of this part of IS0 10993 are for information only.
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SIST EN ISO 10993-12:2000
0 IS0 IS0 10993=12:1996(E)
Introduction
This part of IS0 10993 gives guidance on methods of sample preparation
and on the use of reference materials for use in biological evaluation. Be-
cause of the many different biological assay systems described in
IS0 10993, the individual standards should be consulted to ascertain the
appropriateness of these recommendations for a specific test system.
Sample preparation methods should consider both the biological evalu-
ation methods and the materials being evaluated. Each biological test re-
stricts selection of solid samples and extraction solvents or conditions by
its own methodology.
This part of IS0 10993 is based on existing national and international
specifications, regulations and standards wherever possible. It is open to
regular review whenever new research work is presented to improve the
state of scientific knowledge.
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SIST EN ISO 10993-12:2000
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SIST EN ISO 10993-12:2000
INTERNATIONAL STANDARD 0 ISO
IS0 10993=12:1996(E)
Biological evaluation of medical devices -
Part 12:
Sample preparation and reference materials
IS0 9000-2: 1993, Quality management and quality
1 Scope
assurance standards - Part 2: Generic guidelines for
the application of IS0 9001, IS0 9002 and IS0 9003.
This part of IS0 10993 specifies requirements and
gives guidance on procedures to be followed in the
I SO 9000-3: 1991, Quality management and quality
preparation of samples of medical devices for testing
assurance standards
- Part 3: Guidelines for the
in biological systems in accordance with one or more
application of IS0 9001 to the development, supply
other parts of IS0 10993. These include:
and maintenance of software.
a) test material selection;
IS0 9000-4: 1993, Quality management and quality
assurance standards - Part 4: Guide to dependability
b) selection of representative portions from a device;
programme management.
c) test sample preparation;
IS0 Guide 25:1990, General requirements for com-
d) the selection of reference materials to demon- pe tence of calibration and testing labora tories.
strate the suitability of the test system and/or to
IS0 Guide 30:1992, Terms and definitions used in
enable relative comparison of the biological activ-
connection with reference materials.
ity of the test sample; and,
e) preparation of extracts.
3 Definitions
For the purposes of this part of IS0 10993, the defi-
2 Normative references
nitions given in IS0 Guide 30 and the following defi-
nitions apply.
The following standards contain provisions which,
through reference in this text, constitute provisions
3.1 blank liquid: Liquid treated in the same manner
of this part of IS0 10993. At the time of publication,
as that for preparing extract liquid but without test
the editions indicated were valid. All standards are
material, and used for comparison with extract liquid.
subject to revision, and parties to agreements based
on this part of IS0 10993 are encouraged to investi-
3.2 extract liquid: Liquid resulting from the ex-
gate the possibility of applying the most recent edi-
traction of the test material.
tions of the standards indicated below. Members of
IEC and IS0 maintain registers of currently valid
International Standards. 3.3 negative control: Material or substance which,
when tested by the procedure described, demon-
IS0 9000-I : 1994, Quality management and quality
strates the suitability of the procedure to yield a re-
assurance standards
- Part 7: Guidelines for selec- producible,
appropriate negative, nonreactive or
tion and use. background response in the test system.
1
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SIST EN ISO 10993-12:2000
0 IS0
IS0 10993=12:1996(E)
4.2.1 Reference materials and certified reference
3.4 positive control: Material or substance which,
materials should be in the same material class as the
when tested by the procedure described, demon-
strates the suitability of the procedure to yield a re- test sample, e.g. polymer, ceramic, metal, colloid, etc.
producible, appropriate positive or reactive response
in the test system.
4.2.2 Reference materials are established by indi-
vidual laboratories. The extent of chemical, physical
3.5 reference material: Material or substance one
and biological characterization is determined by the
or more of whose property values are sufficiently ho-
individual laboratory. Commercially available articles
mogeneous and well established to be used for the
may be used as reference materials (see note 2, in
calibration of an apparatus, the assessment of a
. .
4 1)
measurement method, or for assigning values to ma-
terials. [ISO Guide 301
4.2.3 Certified reference materials are selected for
their high purity, critical characteristics, suitability for
When tested by the procedure described, the
NOTE 1
the intended purpose and general availability. The
reference material demonstrates the suitability of the pro-
critical chemical, physical and biological characteristics
cedure to yield a reproducible, predictable response. The
shall be determined by collaborative testing in three
response may be negative or positive.
or more laboratories, and made available to the in-
vestigator by the distributor.
3.6 certified reference material: Reference ma-
terial, accompanied by a certificate, one or more of
whose property values are certified by a procedure
5 Test material selection
which establishes its traceability to an accurate real-
ization of the unit in which the property values are
expressed, and for which each certified value is ac- 5.1 It is preferable to test medical devices in their
companied by an uncertainty at a stated level of con- final product form and condition; this should be the
fidence. [ISO Guide 301 first choice whenever practical. The second choice is
to test representative portions of the device (see
3.7 test material: Material, device, device portion
5.2). When neither of these is possible or practical,
or component thereof that is sampled for biological representative specimens of the formulated material
or chemical testing. that have been preconditioned by the same process-
ing as the final product should be tested.
3.8 test sample: Extract or portion of the test ma-
terial that is subjected to biological or chemical test-
5.2 If a device cannot be tested as a whole and
ing.
contains several materials, each individual material
which can come into contact with body tissues in the
final product shall be represented proportionally in the
4 Experimental controls
test sample, except as described in 5.3.
4.1 Experimental controls shall be used in biological
5.2.1 The test sample of devices with surface
evaluations to validate a test procedure. Depending
coatings shall include both coating material and
on the biological test being used, negative and posi-
substrate.
tive controls and blanks shall be used as appropriate.
The same control may be applicable to different tests
5.2.2 The test sample shall include a representative
to allow cross-reference to established materials and
portion of the joint and/or seal if adhesives, radio-
test methods. Additional guidance on the selection of
frequency (RF) seals, or solvent seals are used.
experimental controls is given in annex A.
5.2.3 Composite materials shall be tested as fin-
NOTE 2 A comparable clinically accepted device may
ished materials
satisfy this requirement.
s which cure in situ, e.g. cements,
5.2.4 Materia
4.2 Reference materials used as experimental con-
adhesives and monomers, shall be tested after the
trols shall meet the established quality assurance
specified mini num cure which may occur during
procedures of the manufacturer and test laboratory
clinical use.
consistent with IS0 Guide 25 and IS0 9000-1,
IS0 9000-2, IS0 9000-3 and IS0 9000-4. Reference
5.3 There may be exceptions to the proportionality
materials shall be identified as to source, manufac-
of materials in the test sample.
turer, type, grade and lot number, as appropriate.
2
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SIST EN ISO 10993-12:2000
0 IS0 IS0 1099342:1996(E)
5.3.1 Selected tests (e.g. implantation) may require fect of allowed multiple sterilization of the final
product.
that individual materials be evaluated.
5.3.2 The test sample may be chosen to maximize
6.3 When test samples and reference materials
the exposure of the test system to any material of a
need to be cut into pieces, the influence of previously
device tha t is known to have a potential for a biologi-
unexposed surfaces, e.g. lumens or cut surfaces,
cal respon se.
shall be considered. Techniques used for cutting
medical devices into representative portions for test-
5.3.3 For specific tests, the influence of the geo-
ing should be as clean as practical to prevent con-
metric shape of the test sample may be stronger than
tamination.
the influence of the type of material. The geometric
shape should prevail above the proportional compo-
7 Preparation of extracts of test
sition regarding the different materials in the selection
materials
of a representative portion of the device as test
sample to be used in these tests.
7.1 General
5.3.4 When different materials are present in a sin-
gle device, the potential for synergies or interactions If extracts of the device are required for a test proto-
shall be considered in the choice of the test sample. col, the extraction liquid and conditions of extraction
used shall be appropriate to the nature and use of the
final product. Additional guidance on the extraction of
5.4 The same test material selection procedures
samples is given in annex C. Special requirements for
apply when an extract of that material is required.
preparing extracts of samples are sometimes
necessary for special biological tests described in
6 Test sample and reference material
other parts of IS0 10993. In these cases, such re-
preparation
quirements described in the corresponding parts of
IS0 10993 shall take precedence over those in this
part.
61 . Test samples and reference materials shall be
handled so as to prevent contamination. Residues
from the processes of manufacturing, fabrication,
7.2 Containers for extraction
cleaning, sterilization, etc., shall be considered to be
integral to the device, device portion or component.
The extraction shall be performed in clean, chemically
Additional guidance on the preparation of test sam-
inert closed containers with minimum headspace
ples and reference materials is given in annex B.
consistant with safety. Extractions shall be performed
under conditions which prevent contamination of the
6.1.1 Test samples from sterilized devices and ref- sample.
erence materials shall be handled aseptically if appro-
priate to the test procedure.
7.3 Extraction conditions
6.1.2 Test samples from devices which are normally
Extraction is a complex process influenced by time,
supplied nonsterile but are sterilized before use shall
temperature, surface-area-to-volume ratio, extraction
be sterilized by the method recommended by the
medium and the phase equilibriuml) of the material.
manufacturer and handled aseptically if appropriate to
The effects of higher temperatures or other con-
the test procedure.
ditions on extraction kinetics and the identity of the
extractant shall be considered carefully if acceler-
ated or exaggerated extraction is used. Based on
6.2 If sterilized test samples are prepared for the
current practices, standard conditions that have been
test procedure, the effect of the sterilization and any
used to provide a measure of the hazard potential of
resterilization process on the test sample and refer-
ence materials shall be considered, including the ef- the device or material are d
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