SIST EN ISO 10993-4:2009
(Main)Biological evaluation of medical devices - Part 4: Selection of tests for interactions with blood (ISO 10993-4:2002, including Amd 1:2006)
Biological evaluation of medical devices - Part 4: Selection of tests for interactions with blood (ISO 10993-4:2002, including Amd 1:2006)
This part of ISO 10993 provides general requirements for evaluating the interactions of medical devices with blood. It describes a) a classification of medical and dental devices that are intended for use in contact with blood, based on the intended use and duration of contact as defined in ISO 10993-1, b) the fundamental principles governing the evaluation of the interaction of devices with blood, c) the rationale for structured selection of tests according to specific categories, together with the principles and scientific basis of these tests. Detailed requirements for testing cannot be specified because of limitations in the knowledge and precision of tests for interactions of devices with blood. This part of ISO 10993 describes biological evaluation in general terms and may not necessarily provide sufficient guidance for test methods for a specific device.
Biologische Beurteilung von Medizinprodukten - Teil 4: Auswahl von Prüfungen zur Wechselwirkung mit Blut (ISO 10993-4:2002, einschließlich Änderung 1:2006)
Dieser Teil von ISO 10993 legt allgemeine Anforderungen zur Beurteilung der Wechselwirkungen von
Medizinprodukten mit Blut fest.
Dieser Teil enthält:
a) eine Klassifizierung von für den Kontakt mit Blut vorgesehenen medizinischen und zahnmedizinischen
Produkten, die nach der Festlegung in ISO 10993-1 auf der bestimmungsgemäßen Verwendung und
Dauer des Kontakts beruht;
b) die Grundprinzipien, die für die Beurteilung der Wechselwirkungen von Medizinprodukten mit Blut maßgebend
sind;
c) die Begründung für die strukturierte Auswahl von Prüfungen nach bestimmten Kategorien, zusammen mit
den Prinzipien und der wissenschaftlichen Grundlage dieser Prüfungen.
Einzelheiten von Prüfanforderungen können wegen des eingeschränkten Wissensstandes und der
mangelnden Präzision von Prüfungen auf Wechselwirkungen von Medizinprodukten mit Blut nicht festgelegt
werden. Außerdem beschreibt dieser Teil von ISO 10993 die biologische Beurteilung im allgemeinen Sinne
und braucht nicht unbedingt eine ausreichende Anleitung für Prüfverfahren für ein bestimmtes Medizinprodukt
zu sein. Die Auswahl und das Design des Prüfverfahrens sollten das Produktdesign, die Werkstoffe, den
klinische Nutzen, die Verwendungsumgebung und die Risikoabschätzung in Betracht ziehen. Diese
spezifische Ebene kann nur durch vertikale Normen abgedeckt werden.
Évaluation biologique des dispositifs médicaux - Partie 4 : Choix des essais concernant les interactions avec le sang (ISO 10993-4:2002, Amd 1:2006 inclus)
L'ISO 10993-4:2002 fournit des exigences générales pour évaluer les interactions des dispositifs médicaux avec le sang.
Elle décrit
une classification des dispositifs médicaux et dentaires destinés à être en contact avec le sang lors de leur utilisation; cette classification est fondée sur l'utilisation prévue et sur la durée du contact telle qu'elle est définie dans l'ISO 10993-1;
les principes fondamentaux qui gouvernent l'évaluation de l'interaction des dispositifs avec le sang;
la justification du choix des essais retenus conformément aux catégories spécifiques, ainsi que les principes et les bases scientifiques de ces essais.
Les exigences détaillées pour les essais ne peuvent pas être spécifiées en raison de limites de connaissance et de précision des essais relatifs aux interactions des dispositifs avec le sang. L'ISO 10993-4:2002 décrit l'évaluation biologique en termes généraux et il se peut qu'elle ne fournisse pas nécessairement une aide suffisante concernant les méthodes d'essai relatives à un dispositif spécifique.
Biološko ovrednotenje medicinskih pripomočkov - 4. del: Izbira preskusov za ugotavljanje interakcij s krvjo (ISO 10993-4:2002, vključno z Amd 1:2006)
General Information
Relations
Standards Content (Sample)
SLOVENSKI STANDARD
SIST EN ISO 10993-4:2009
01-september-2009
1DGRPHãþD
SIST EN ISO 10993-4:2003
SIST EN ISO 10993-4:2003/A1:2006
%LRORãNRRYUHGQRWHQMHPHGLFLQVNLKSULSRPRþNRYGHO ,]ELUDSUHVNXVRY]D
XJRWDYOMDQMHLQWHUDNFLMVNUYMR ,62 YNOMXþQR]$PG
Biological evaluation of medical devices - Part 4: Selection of tests for interactions with
blood (ISO 10993-4:2002, including Amd 1:2006)
Biologische Beurteilung von Medizinprodukten - Teil 4: Auswahl von Prüfungen zur
Wechselwirkung mit Blut (ISO 10993-4:2002, einschließlich Änderung 1:2006)
Évaluation biologique des dispositifs médicaux - Partie 4 : Choix des essais concernant
les interactions avec le sang (ISO 10993-4:2002, Amd 1:2006 inclus)
Ta slovenski standard je istoveten z: EN ISO 10993-4:2009
ICS:
11.100.20 %LRORãNRRYUHGQRWHQMH Biological evaluation of
PHGLFLQVNLKSULSRPRþNRY medical devices
SIST EN ISO 10993-4:2009 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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SIST EN ISO 10993-4:2009
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SIST EN ISO 10993-4:2009
EUROPEAN STANDARD
EN ISO 10993-4
NORME EUROPÉENNE
EUROPÄISCHE NORM
May 2009
ICS 11.100.20 Supersedes EN ISO 10993-4:2002
English Version
Biological evaluation of medical devices - Part 4: Selection of
tests for interactions with blood (ISO 10993-4:2002, including
Amd 1:2006)
Évaluation biologique des dispositifs médicaux - Partie 4: Biologische Beurteilung von Medizinprodukten - Teil 4:
Choix des essais pour les interactions avec le sang (ISO Auswahl von Prüfungen zur Wechselwirkung mit Blut (ISO
10993-4:2002, Amd 1:2006 inclus) 10993-4:2002, einschließlich Änderung 1:2006)
This European Standard was approved by CEN on 28 April 2009.
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 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 Management Centre has the same status as the
official versions.
CEN members are the national standards bodies of Austria, Belgium, Bulgaria, 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.
EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION
EUROPÄISCHES KOMITEE FÜR NORMUNG
Management Centre: Avenue Marnix 17, B-1000 Brussels
© 2009 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 10993-4:2009: E
worldwide for CEN national Members.
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SIST EN ISO 10993-4:2009
EN ISO 10993-4:2009 (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 10993-4:2009
EN ISO 10993-4:2009 (E)
Foreword
The text of ISO 10993-4:2002, including Amd 1:2006 has been prepared by Technical Committee
ISO/TC 194 “Biological evaluation of medical devices” of the International Organization for Standardization
(ISO) and has been taken over as EN ISO 10993-4:2009 by 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 November 2009, and conflicting national standards shall be withdrawn
at the latest by March 2010.
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 10993-4:2002.
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 EC Directive.
For relationship with EC Directive, see informative Annex ZA, 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, Bulgaria, 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 the United Kingdom.
Endorsement notice
The text of ISO 10993-4:2002, including Amd 1:2006 has been approved by CEN as a EN ISO 10993-4:2009
without any modification.
3
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SIST EN ISO 10993-4:2009
EN ISO 10993-4:2009 (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 Communities 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 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 — Correspondence between this European Standard and Directive 93/42/EEC on medical
devices
Clause(s)/sub-clause(s) of this Essential Requirements (ERs) of Qualifying remarks/Notes
EN Directive 93/42/EEC
6
Annex I:
7.1, 7.2, 7.5
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 10993-4:2009
EN ISO 10993-4:2009 (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 Communities 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 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 — Correspondence between this European Standard and Directive 90/385/EEC on active
implantable medical devices
Clause(s)/sub-clause(s) of this Essential Requirements (ERs) of Qualifying remarks/Notes
EN Directive 90/385/EEC
6
Annex I :
9
6 I.9 of Annex I of 90/385/EEC
6.1.10 18 of 86/609/EEC
A.1 I.9 of Annex I of 90/385/EEC
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 10993-4:2009
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SIST EN ISO 10993-4:2009
INTERNATIONAL ISO
STANDARD 10993-4
Second edition
2002-10-15
Biological evaluation of medical devices —
Part 4:
Selection of tests for interactions with
blood
Évaluation biologique des dispositifs médicaux —
Partie 4: Choix des essais concernant les interactions avec le sang
Reference number
ISO 10993-4:2002(E)
©
ISO 2002
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SIST EN ISO 10993-4:2009
ISO 10993-4:2002(E)
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ii © ISO 2002 – All rights reserved
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SIST EN ISO 10993-4:2009
ISO 10993-4:2002(E)
Contents Page
Foreword . iv
Introduction. vi
1 Scope. 1
2 Normative references. 1
3 Terms and definitions. 1
4 Abbreviated terms. 2
5 Types of device in contact with blood (as categorized in ISO 10993-1). 3
5.1 Non-contact devices. 3
5.2 External communicating devices. 3
5.3 Implant devices. 4
6 Characterization of blood interactions . 5
6.1 General requirements. 5
6.2 Categories of tests and blood interactions . 8
6.3 Types of test . 11
Annex A (informative) Preclinical evaluation of cardiovascular devices and prostheses. 13
Annex B (informative) Laboratory tests — Principles, scientific basis and interpretation. 17
Annex C (informative) Evaluation of haemolytic properties of medical devices and their components . 23
Bibliography. 30
© ISO 2002 – All rights reserved iii
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SIST EN ISO 10993-4:2009
ISO 10993-4:2002(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 3.
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 part of ISO 10993 may be the subject of
patent rights. ISO shall not be held responsible for identifying any or all such patent rights.
ISO 10993-4 was prepared by Technical Committee ISO/TC 194, Biological evaluation of medical devices.
This second edition cancels and replaces the first edition (ISO 10993-4:1992), 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 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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SIST EN ISO 10993-4:2009
ISO 10993-4:2002(E)
— 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
Future parts will deal with other relevant aspects of biological testing.
Annexes A, B and C of this part of ISO 10993 are for information only.
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SIST EN ISO 10993-4:2009
ISO 10993-4:2002(E)
Introduction
The selection and design of test methods for the interactions of medical devices with blood should take into
consideration device design, materials, clinical utility, usage environment and risk benefit. This level of specificity
can only be covered in vertical standards.
The initial source for developing this part of ISO 10993 was the publication, Guidelines for blood/material
[29]
interactions, Report of the National Heart, Lung, and Blood Institute ; chapters 9 and 10. This publication has
[32]
since been revised .
vi © ISO 2002 – All rights reserved
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SIST EN ISO 10993-4:2009
INTERNATIONAL STANDARD ISO 10993-4:2002(E)
Biological evaluation of medical devices —
Part 4:
Selection of tests for interactions with blood
1 Scope
This part of ISO 10993 provides general requirements for evaluating the interactions of medical devices with blood.
It describes
a) a classification of medical and dental devices that are intended for use in contact with blood, based on the
intended use and duration of contact as defined in ISO 10993-1,
b) the fundamental principles governing the evaluation of the interaction of devices with blood,
c) the rationale for structured selection of tests according to specific categories, together with the principles and
scientific basis of these tests.
Detailed requirements for testing cannot be specified because of limitations in the knowledge and precision of tests
for interactions of devices with blood. This part of ISO 10993 describes biological evaluation in general terms and
may not necessarily provide sufficient guidance for test methods for a specific device.
2 Normative references
The following normative documents contain provisions which, through reference in this text, constitute provisions of
this part of ISO 10993. For dated references, subsequent amendments to, or revisions of, any of these publications
do not apply. However, parties to agreements based on this part of ISO 10993 are encouraged to investigate the
possibility of applying the most recent editions of the normative documents indicated below. For undated
references, the latest edition of the normative document referred to applies. Members of ISO and IEC maintain
registers of currently valid International Standards.
ISO 10993-1:1997, Biological evaluation of medical devices — Part 1: Evaluation and testing
ISO 10993-2:1992, Biological evaluation of medical devices — Part 2: Animal welfare requirements
3 Terms and definitions
For the purposes of this part of ISO 10993, the terms and definitions given in ISO 10993-1 and the following apply.
3.1
blood/device interaction
any interaction between blood or any component of blood and a device resulting in effects on the blood, or on any
organ or tissue, or on the device
NOTE Such effects may or may not have clinically significant or undesirable consequences. Annex A contains further
information on these interactions.
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SIST EN ISO 10993-4:2009
ISO 10993-4:2002(E)
3.2
ex vivo
term applied to a test system that shunts blood directly from a human subject or test animal into a test chamber
located outside the body
NOTE If using an animal model, the blood may be shunted directly back into the animal (recirculating) or collected into test
tubes for evaluation (single pass).
3.3
thrombosis
in vivo phenomenon resulting in the partial or complete occlusion of a vessel or device by a thrombus
NOTE 1 Characterization of thrombosis includes ex vivo and in vivo methods, in either animals or the clinical setting.
NOTE 2 A thrombus is composed of a mixture of red cells, aggregated platelets, fibrin and other cellular elements.
3.4
coagulation
phenomenon that results from activation of the clotting factor cascade
NOTE Factors of the coagulation cascade and fibrinolytic systems can be measured following exposure to devices either in
vitro or in vivo.
3.5
platelet
anuclear, cellular body that is present in the circulation which adheres to surfaces and aggregates to form a
hemostatic plug to minimize bleeding
NOTE Platelet testing includes quantification of platelet numbers as well as analysis of their structure and function. The
testing can include analysis of platelet factors, or components on the platelet surface which are released from platelets or
adherent to the device surface.
3.6
haematology
study of blood, including quantification of cellular and plasma components of the blood
3.7
complement system
part of the innate immune system, consisting of several plasma proteins, including enzymes and cellular receptors
NOTE Effector molecules produced from complement components are involved in inflammation, phagocytosis and cell
lysis.
4 Abbreviated terms
Bb product of alternative pathway complement activation
β-TG beta-thromboglobulin
C4d product of classical pathway complement activation
C3a, C5a (active) complement split products from C3 and C5
CD62L L-selectin
CH-50 50% total haemolytic complement
CT computerized tomography
D-Dimer specific fibrin degradation products (F XIII cross-linked fibrin)
ECMO extracorporeal membrane oxygenator
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SIST EN ISO 10993-4:2009
ISO 10993-4:2002(E)
ELISA enzyme/linked immunosorbent assay
EM electron microscopy
FDP fibrin/fibrinogen degradation products
FPA fibrinopeptide A
F prothrombin activation fragment 1 + 2
1+2
iC3b product of central C complement activation
IVC inferior vena cava
MRI magnetic resonance imaging
PAC-1 monoclonal antibody which recognizes the activated form of platelet surface glycoprotein IIb/IIIa
PET positron emission tomography
PF-4 platelet factor 4
PRP platelet-rich plasma
PT prothrombin time
PTT partial thromboplastin time
P-selectin receptor exposed during either platelet or endothelial cell release reaction
RIA radioimmunoassay
S-12 monoclonal antibody, which recognizes the alpha-granule membrane component P-selectin exposed
during the platelet release reaction
SC5b-9 product of terminal pathway complement activation
TAT thrombin-antithrombin complex
TCC terminal complement complex
TT thrombin time
VWF von Willebrand factor
5 Types of device in contact with blood (as categorized in ISO 10993-1)
5.1 Non-contact devices
An in vitro diagnostic device is an example of a non-contact device.
5.2 External communicating devices
These are devices that contact the circulating blood and serve as a conduit into the vascular system. Examples
include but are not limited to those in ISO 10993-1.
a) External communicating devices that serve as an indirect blood path include but are not limited to
cannulae,
extension sets,
blood collection devices,
devices for the storage and administration of blood and blood products (e.g. tubing, needles and bags),
cell savers.
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SIST EN ISO 10993-4:2009
ISO 10993-4:2002(E)
b) External communicating devices in contact with circulating blood include but are not limited to
atherectomy devices,
blood monitors,
catheters,
guidewires,
intravascular endoscopes,
intravascular ultrasound,
intravascular laser systems,
retrograde coronary perfusion catheters,
cardiopulmonary bypass circuitry,
extracorporeal membrane oxygenators,
haemodialysis/haemofiltration equipment,
donor and therapeutic apheresis equipment,
devices for absorption of specific substances from blood,
interventional cardiology and vascular devices,
percutaneous circulatory support systems.
5.3 Implant devices
Implant devices are placed largely or entirely within the vascular system. Examples include but are not limited to
annuloplasty rings,
mechanical or tissue heart valves,
prosthetic or tissue vascular grafts,
circulatory support devices (ventricular-assist devices, artificial hearts, intra-aortic balloon pumps),
inferior vena cava filters,
embolization devices,
endovascular grafts,
implantable defibrillators and cardioverters,
stents,
arteriovenous shunts,
blood monitors,
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SIST EN ISO 10993-4:2009
ISO 10993-4:2002(E)
internal drug delivery catheters,
pacemaker leads,
intravascular membrane oxygenators (artificial lungs),
leukocyte-removal filters.
6 Characterization of blood interactions
6.1 General requirements
6.1.1 Figure 1 illustrates a decision tree that can be used to determine whether testing for interaction with blood
is necessary.
Blood interactions can be classified into five categories based on the primary process or system being measured.
Tables 1 and 2 list examples of devices which contact circulating blood and the categories of testing appropriate to
the device.
NOTE Since this is a horizontal International Standard, good rationales can be developed to justify the choice of category
based on the device being characterized. Thrombosis testing is frequently the preferred method for device characterization. In
many cases, rationales can be used to substitute some combination of coagulation, platelets, haematology and complement
system testing for thrombosis testing.
For medical devices where a specific International Standard (vertical standard) exists, the biological evaluation
requirements and test methods set forth in that vertical standard shall take precedence over the general
requirements suggested in this part of ISO 10993.
6.1.2 Where possible, tests shall use an appropriate model or system which simulates the geometry and
conditions of contact of the device with blood during clinical applications, including duration of contact, temperature,
sterile condition and flow conditions. For devices of defined geometry, the ratio of test parameter (concentration per
2
unit volume) to exposed surface area (cm ) shall be evaluated.
Only blood-contacting parts should be tested. The selected test methods and parameters should be in accordance
with the current state of the art.
6.1.3 Controls shall be used unless their omission can be justified. Where possible, testing should include a
[7]
relevant device already in clinical use or a well-characterized reference material .
Reference materials used should include negative and positive controls. All materials and devices tested shall meet
all quality control and quality assurance specifications of the manufacturer and test laboratory. All materials and
devices tested shall be identified as to source, manufacturer, grade and type.
6.1.4 Testing of materials which are candidates for components of a device may be conducted for screening
purposes. However, such preliminary tests do not serve as a substitute for the requirement that the complete
device or device component be tested under conditions which simulate or exaggerate clinical application.
6.1.5 Tests which do not simulate the conditions of a device during use may not predict accurately the nature of
the blood/device interactions which can occur during clinical applications. For example, some short-term in vitro or
[25], [26]
ex vivo tests are poor predictors of long-term in vivo blood/device interactions .
6.1.6 It follows from the above that devices whose intended use is ex vivo (external communication) should be
tested ex vivo and devices whose intended use is in vivo (implants) should be tested in vivo in an animal model
simulating as closely as possible conditions of clinical use.
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SIST EN ISO 10993-4:2009
ISO 10993-4:2002(E)
Figure 1 — Decision tree to determine whether testing for interaction with blood is necessary
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SIST EN ISO 10993-4:2009
ISO 10993-4:2002(E)
Table 1 — Devices or device components which contact circulating blood
and the categories of appropriate testing — External communicating devices
Device examples Test category
Complement
Thrombosis Coagulation Platelets Haematology
system
a
Atherectomy devices x
a
Blood monitors x x
a
Blood storage and administration equipment, x x x
blood collection devices, extension sets
Extracorporeal membrane oxygenator systems,
haemodialysis/haemofiltration equipment, x x x x x
percutaneous circulatory support devices
Catheters, guidewires, intravascular endoscopes,
a
intravascular ultrasound, laser systems, x x x
retrograde coronary perfusion catheters,
a
Cell savers x x x
Devices for absorption of specific substances from x x x x
blood
Donor and therapeutic apheresis equipment x x x x
a
Haemolysis testing only.
Table 2 — Devices or device components which contact circulating blood
and the categories of appropriate
...
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.Biologische Beurteilung von Medizinprodukten - Teil 4: Auswahl von Prüfungen zur Wechselwirkung mit Blut (ISO 10993-4:2002, einschließlich Änderung 1:2006)Évaluation biologique des dispositifs médicaux - Partie 4 : Choix des essais concernant les interactions avec le sang (ISO 10993-4:2002, Amd 1:2006 inclus)Biological evaluation of medical devices - Part 4: Selection of tests for interactions with blood (ISO 10993-4:2002, including Amd 1:2006)11.100.20Biological evaluation of medical devicesICS:Ta slovenski standard je istoveten z:prEN ISO 10993-4kSIST prEN ISO 10993-4:2009en01-marec-2009kSIST prEN ISO 10993-4:2009SLOVENSKI
STANDARD
kSIST prEN ISO 10993-4:2009
EUROPEAN STANDARDNORME EUROPÉENNEEUROPÄISCHE NORMFINAL DRAFTprEN ISO 10993-4November 2008ICS 11.100.20Will supersede EN ISO 10993-4:2002
English VersionBiological evaluation of medical devices - Part 4: Selection oftests for interactions with blood (ISO 10993-4:2002, includingAmd 1:2006)Évaluation biologique des dispositifs médicaux - Partie 4:Choix des essais pour les interactions avec le sang (ISO10993-4:2002, Amd 1:2006 inclus)Biologische Beurteilung von Medizinprodukten - Teil 4:Auswahl von Prüfungen zur Wechselwirkung mit Blut (ISO10993-4:2002, einschließlich Änderung 1:2006)This draft European Standard is submitted to CEN members for unique acceptance procedure. It has been drawn up by the TechnicalCommittee CEN/TC 206.If this draft becomes a European Standard, CEN members are bound to comply with the CEN/CENELEC Internal Regulations whichstipulate 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 languagemade by translation under the responsibility of a CEN member into its own language and notified to the CEN Management Centre has thesame status as the official versions.CEN members are the national standards bodies of Austria, Belgium, Bulgaria, 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.Warning : This document is not a European Standard. It is distributed for review and comments. It is subject to change without notice andshall not be referred to as a European Standard.EUROPEAN COMMITTEE FOR STANDARDIZATIONCOMITÉ EUROPÉEN DE NORMALISATIONEUROPÄISCHES KOMITEE FÜR NORMUNGManagement Centre: rue de Stassart, 36
B-1050 Brussels© 2008 CENAll rights of exploitation in any form and by any means reservedworldwide for CEN national Members.Ref. No. prEN ISO 10993-4:2008: EkSIST prEN ISO 10993-4:2009
prEN ISO 10993-4:2008 (E) 2 Contents Page Foreword .3Annex ZA (informative)
Relationship between this
European
Standard and the Essential Requirements
of EU Directive 93/42/EEC on Medical Devices .4Annex ZB (informative)
Relationship between this
European
Standard and the Essential Requirements
of EU Directive 90/385/EEC on Active Implantable Medical Devices .5 kSIST prEN ISO 10993-4:2009
prEN ISO 10993-4:2008 (E) 3 Foreword The text of ISO 10993-4:2002, including Amd 1:2006 has been prepared by Technical Committee ISO/TC 194 “Biological evaluation of medical devices” of the International Organization for Standardization (ISO) and has been taken over as prEN ISO 10993-4:2008 by 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 Unique Acceptance Procedure. This document will supersede EN ISO 10993-4:2002. 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 EC Directives. For relationship with EC Directives, see informative Annex ZA et ZB which are integral part of this document. Endorsement notice The text of ISO 10993-4:2002, including Amd 1:2006 has been approved by CEN as a prEN ISO 10993-4:2008 without any modification. kSIST prEN ISO 10993-4:2009
prEN ISO 10993-4:2008 (E) 4 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 Communities 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 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 — Correspondence between this European Standard and Directive 93/42/EEC on medical devices Clause(s)/sub-clause(s) of this EN Essential Requirements (ERs) of Directive 93/42/EEC Qualifying remarks/Notes 6
Annex I: 7.1, 7.2, 7.5
WARNING — Other requirements and other EU Directives may be applicable to the product(s) falling within the scope of this standard.
kSIST prEN ISO 10993-4:2009
prEN ISO 10993-4:2008 (E) 5 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 Communities 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 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 — Correspondence between this European Standard and Directive 90/385/EEC on active implantable medical devices Clause(s)/sub-clause(s) of this EN Essential Requirements (ERs) of Directive 90/385/EEC Qualifying remarks/Notes 6 Annex I : 9
6 7.1 of Annex I and Annex II of 93/42/EEC I.9 of Annex I of 90/385/EEC
6.1.10 18 of 86/609/EEC
A.1 7.1 of Annex I and Annex II of 93/42/EEC I.9 of Annex I of 90/385/EEC
WARNING — Other requirements and other EU Directives may be applicable to the product(s) falling within the scope of this standard. kSIST prEN ISO 10993-4:2009
kSIST prEN ISO 10993-4:2009
Reference numberISO 10993-4:2002(E)© ISO 2002
INTERNATIONAL STANDARD ISO10993-4Second edition2002-10-15Biological evaluation of medical devices —Part 4: Selection of tests for interactions with blood Évaluation biologique des dispositifs médicaux — Partie 4: Choix des essais concernant les interactions avec le sang
kSIST prEN ISO 10993-4:2009
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kSIST prEN ISO 10993-4:2009
ISO 10993-4:2002(E) © ISO 2002 – All rights reserved iii Contents Page Foreword.iv Introduction.vi 1 Scope.1 2 Normative references.1 3 Terms and definitions.1 4 Abbreviated terms.2 5 Types of device in contact with blood (as categorized in ISO 10993-1).3 5.1 Non-contact devices.3 5.2 External communicating devices.3 5.3 Implant devices.4 6 Characterization of blood interactions.5 6.1 General requirements.5 6.2 Categories of tests and blood interactions.8 6.3 Types of test.11 Annex A (informative)
Preclinical evaluation of cardiovascular devices and prostheses.13 Annex B (informative)
Laboratory tests — Principles, scientific basis and interpretation.17 Annex C (informative)
Evaluation of haemolytic properties of medical devices and their components.23 Bibliography.30
kSIST prEN ISO 10993-4:2009
ISO 10993-4:2002(E) iv © ISO 2002 – All rights reserved 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 3. 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 part of ISO 10993 may be the subject of patent rights. ISO shall not be held responsible for identifying any or all such patent rights. ISO 10993-4 was prepared by Technical Committee ISO/TC 194, Biological evaluation of medical devices. This second edition cancels and replaces the first edition (ISO 10993-4:1992), 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 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 kSIST prEN ISO 10993-4:2009
ISO 10993-4:2002(E) © ISO 2002 – All rights reserved v — 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 Future parts will deal with other relevant aspects of biological testing. Annexes A, B and C of this part of ISO 10993 are for information only. kSIST prEN ISO 10993-4:2009
ISO 10993-4:2002(E) vi © ISO 2002 – All rights reserved Introduction The selection and design of test methods for the interactions of medical devices with blood should take into consideration device design, materials, clinical utility, usage environment and risk benefit. This level of specificity can only be covered in vertical standards. The initial source for developing this part of ISO 10993 was the publication, Guidelines for blood/material interactions, Report of the National Heart, Lung, and Blood Institute [29]; chapters 9 and 10. This publication has since been revised [32]. kSIST prEN ISO 10993-4:2009
INTERNATIONAL STANDARD ISO 10993-4:2002(E) © ISO 2002 – All rights reserved 1 Biological evaluation of medical devices —
Part 4: Selection of tests for interactions with blood 1 Scope This part of ISO 10993 provides general requirements for evaluating the interactions of medical devices with blood. It describes a) a classification of medical and dental devices that are intended for use in contact with blood, based on the intended use and duration of contact as defined in ISO 10993-1, b) the fundamental principles governing the evaluation of the interaction of devices with blood, c) the rationale for structured selection of tests according to specific categories, together with the principles and scientific basis of these tests. Detailed requirements for testing cannot be specified because of limitations in the knowledge and precision of tests for interactions of devices with blood. This part of ISO 10993 describes biological evaluation in general terms and may not necessarily provide sufficient guidance for test methods for a specific device. 2 Normative references The following normative documents contain provisions which, through reference in this text, constitute provisions of this part of ISO 10993. For dated references, subsequent amendments to, or revisions of, any of these publications do not apply. However, parties to agreements based on this part of ISO 10993 are encouraged to investigate the possibility of applying the most recent editions of the normative documents indicated below. For undated references, the latest edition of the normative document referred to applies. Members of ISO and IEC maintain registers of currently valid International Standards. ISO 10993-1:1997, Biological evaluation of medical devices — Part 1: Evaluation and testing ISO 10993-2:1992, Biological evaluation of medical devices — Part 2: Animal welfare requirements 3 Terms and definitions For the purposes of this part of ISO 10993, the terms and definitions given in ISO 10993-1 and the following apply. 3.1 blood/device interaction any interaction between blood or any component of blood and a device resulting in effects on the blood, or on any organ or tissue, or on the device NOTE Such effects may or may not have clinically significant or undesirable consequences. Annex A contains further information on these interactions. kSIST prEN ISO 10993-4:2009
ISO 10993-4:2002(E) 2 © ISO 2002 – All rights reserved 3.2 ex vivo term applied to a test system that shunts blood directly from a human subject or test animal into a test chamber located outside the body NOTE If using an animal model, the blood may be shunted directly back into the animal (recirculating) or collected into test tubes for evaluation (single pass). 3.3 thrombosis in vivo phenomenon resulting in the partial or complete occlusion of a vessel or device by a thrombus NOTE 1 Characterization of thrombosis includes ex vivo and in vivo methods, in either animals or the clinical setting. NOTE 2 A thrombus is composed of a mixture of red cells, aggregated platelets, fibrin and other cellular elements. 3.4 coagulation phenomenon that results from activation of the clotting factor cascade NOTE Factors of the coagulation cascade and fibrinolytic systems can be measured following exposure to devices either in vitro or in vivo. 3.5 platelet anuclear, cellular body that is present in the circulation which adheres to surfaces and aggregates to form a hemostatic plug to minimize bleeding NOTE Platelet testing includes quantification of platelet numbers as well as analysis of their structure and function. The testing can include analysis of platelet factors, or components on the platelet surface which are released from platelets or adherent to the device surface. 3.6 haematology study of blood, including quantification of cellular and plasma components of the blood 3.7 complement system part of the innate immune system, consisting of several plasma proteins, including enzymes and cellular receptors NOTE Effector molecules produced from complement components are involved in inflammation, phagocytosis and cell lysis. 4 Abbreviated terms Bb product of alternative pathway complement activation β-TG beta-thromboglobulin C4d product of classical pathway complement activation C3a, C5a (active) complement split products from C3 and C5 CD62L L-selectin CH-50 50% total haemolytic complement CT computerized tomography D-Dimer specific fibrin degradation products (F XIII cross-linked fibrin) ECMO extracorporeal membrane oxygenator kSIST prEN ISO 10993-4:2009
ISO 10993-4:2002(E) © ISO 2002 – All rights reserved 3 ELISA enzyme/linked immunosorbent assay EM electron microscopy FDP fibrin/fibrinogen degradation products FPA fibrinopeptide A F1+2 prothrombin activation fragment 1 + 2 iC3b product of central C complement activation IVC inferior vena cava MRI magnetic resonance imaging PAC-1 monoclonal antibody which recognizes the activated form of platelet surface glycoprotein IIb/IIIa PET positron emission tomography PF-4 platelet factor 4 PRP platelet-rich plasma PT prothrombin time PTT partial thromboplastin time P-selectin receptor exposed during either platelet or endothelial cell release reaction RIA radioimmunoassay S-12 monoclonal antibody, which recognizes the alpha-granule membrane component P-selectin exposed during the platelet release reaction SC5b-9 product of terminal pathway complement activation TAT thrombin-antithrombin complex TCC terminal complement complex TT thrombin time VWF von Willebrand factor 5 Types of device in contact with blood (as categorized in ISO 10993-1) 5.1 Non-contact devices An in vitro diagnostic device is an example of a non-contact device. 5.2 External communicating devices These are devices that contact the circulating blood and serve as a conduit into the vascular system. Examples include but are not limited to those in ISO 10993-1. a) External communicating devices that serve as an indirect blood path include but are not limited to cannulae, extension sets, blood collection devices, devices for the storage and administration of blood and blood products (e.g. tubing, needles and bags), cell savers. kSIST prEN ISO 10993-4:2009
ISO 10993-4:2002(E) 4 © ISO 2002 – All rights reserved b) External communicating devices in contact with circulating blood include but are not limited to atherectomy devices, blood monitors, catheters, guidewires, intravascular endoscopes, intravascular ultrasound, intravascular laser systems, retrograde coronary perfusion catheters, cardiopulmonary bypass circuitry, extracorporeal membrane oxygenators, haemodialysis/haemofiltration equipment, donor and therapeutic apheresis equipment, devices for absorption of specific substances from blood, interventional cardiology and vascular devices, percutaneous circulatory support systems. 5.3 Implant devices Implant devices are placed largely or entirely within the vascular system. Examples include but are not limited to annuloplasty rings, mechanical or tissue heart valves, prosthetic or tissue vascular grafts, circulatory support devices (ventricular-assist devices, artificial hearts, intra-aortic balloon pumps), inferior vena cava filters, embolization devices, endovascular grafts, implantable defibrillators and cardioverters, stents, arteriovenous shunts, blood monitors, kSIST prEN ISO 10993-4:2009
ISO 10993-4:2002(E) © ISO 2002 – All rights reserved 5 internal drug delivery catheters, pacemaker leads, intravascular membrane oxygenators (artificial lungs), leukocyte-removal filters. 6 Characterization of blood interactions 6.1 General requirements 6.1.1 Figure 1 illustrates a decision tree that can be used to determine whether testing for interaction with blood is necessary. Blood interactions can be classified into five categories based on the primary process or system being measured. Tables 1 and 2 list examples of devices which contact circulating blood and the categories of testing appropriate to the device. NOTE Since this is a horizontal International Standard, good rationales can be developed to justify the choice of category based on the device being characterized. Thrombosis testing is frequently the preferred method for device characterization. In many cases, rationales can be used to substitute some combination of coagulation, platelets, haematology and complement system testing for thrombosis testing. For medical devices where a specific International Standard (vertical standard) exists, the biological evaluation requirements and test methods set forth in that vertical standard shall take precedence over the general requirements suggested in this part of ISO 10993. 6.1.2 Where possible, tests shall use an appropriate model or system which simulates the geometry and conditions of contact of the device with blood during clinical applications, including duration of contact, temperature, sterile condition and flow conditions. For devices of defined geometry, the ratio of test parameter (concentration per unit volume) to exposed surface area (cm2) shall be evaluated. Only blood-contacting parts should be tested. The selected test methods and parameters should be in accordance with the current state of the art. 6.1.3 Controls shall be used unless their omission can be justified. Where possible, testing should include a relevant device already in clinical use or a well-characterized reference material [7]. Reference materials used should include negative and positive controls. All materials and devices tested shall meet all quality control and quality assurance specifications of the manufacturer and test laboratory. All materials and devices tested shall be identified as to source, manufacturer, grade and type. 6.1.4 Testing of materials which are candidates for components of a device may be conducted for screening purposes. However, such preliminary tests do not serve as a substitute for the requirement that the complete device or device component be tested under conditions which simulate or exaggerate clinical application. 6.1.5 Tests which do not simulate the conditions of a device during use may not predict accurately the nature of the blood/device interactions which can occur during clinical applications. For example, some short-term in vitro or ex vivo tests are poor predictors of long-term in vivo blood/device interactions [25], [26]. 6.1.6 It follows from the above that devices whose intended use is ex vivo (external communication) should be tested ex vivo and devices whose intended use is in vivo (implants) should be tested in vivo in an animal model simulating as closely as possible conditions of clinical use. kSIST prEN ISO 10993-4:2009
ISO 10993-4:2002(E) 6 © ISO 2002 – All rights reserved
Figure 1 — Decision tree to determine whether testing for interaction with blood is necessary
kSIST prEN ISO 10993-4:2009
ISO 10993-4:2002(E) © ISO 2002 – All rights reserved 7 Table 1 — Devices or device components which contact circulating blood and the categories of appropriate testing — External communicating devices Device examples Test category
Thrombosis Coagulation Platelets Haematology Complement system Atherectomy devices
xa
Blood monitors x
xa
Blood storage and administration equipment, blood collection devices, extension sets
x x xa
Extracorporeal membrane oxygenator systems, haemodialysis/haemofiltration equipment, percutaneous circulatory support devices
x
x
x
x
x Catheters, guidewires, intravascular endoscopes, intravascular ultrasound, laser systems, retrograde coronary perfusion catheters,
x
x
xa
Cell savers
x x xa
Devices for absorption of specific substances from blood
x x x x Donor and therapeutic apheresis equipment
x x x x a Haemolysis testing only.
Table 2 — Devices or device components which contact circulating blood and the categories of appropriate testing — Implant devices Test category Device examples Thrombosis CoagulationPlatelets Haematology Complement system Annuloplasty rings, mechanical heart valves x
xa
Intra-aortic balloon pumps x x x x x Total artificial hearts, ventricular-assist devices x
x
Embolization devices
xa
Endovascular grafts x
xa
Implantable defibrillators and cardioverters x
xa
Pacemaker leads x
xa
Leukocyte removal filter
x x xa
Prosthetic (synthetic) vascular grafts and patches, including arteriovenous shunts x
xa
Stents x
xa
Tissue heart valves x
xa
Tissue vascular grafts and patches, including arteriovenous shunts x
xa
Vena cava filters x
xa
a Haemolysis testing only. kSIST prEN ISO 10993-4:2009
ISO 10993-4:2002(E) 8 © ISO 2002 – All rights reserved 6.1.7 In vitro tests are regarded as useful in screening external communicating devices or implants, but may not be accurate predictors of blood/device interactions occurring upon prolonged or repeated exposure or permanent contact (see 6.3.1). Devices intended for non-contact use only do not require evaluation of blood/device interactions. Devices which come into very brief contact with circulating blood (e.g. lancets, hypodermic needles, capillary tubes) generally do not require blood/device interaction testing. 6.1.8 The recommendations in 6.1.6 and 6.1.7, together with clause 5, Figure 1 and Table 2, serve as a guide for the selection of tests listed in 6.2.1. 6.1.9 Disposable laboratory equipment used for the collection of blood and performance of in vitro tests on blood shall be evaluated to ascertain that there is no significant interference with the test being performed. 6.1.10 If tests are selected in the manner described and testing is conducted under conditions which simulate clinical applications, the results of such testing have the greatest probability of predicting clinical performance of devices. However, species differences and other factors may limit the predictability of any test. 6.1.11 Because of species differences in blood reactivity, human blood should be used where possible. When animal models are necessary, for example for evaluation of devices used for prolonged or repeated exposure or permanent contact, species differences in blood reactivity shall be considered. Blood values and reactivity in humans and non-human primates are very similar [26]. The use of animals such as the rabbit, pig, calf, sheep, or dog may also yield satisfactory results. Because species differences may be sign
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