EN ISO 10993-16:1997

Biological evaluation of medical devices - Part 16: Toxicokinetic study design for degradation products and leachables (ISO 10993-16:1997)

This part of ISO 10993 gives principles on how toxicokinetic studies relevant to medical devices should be designed and performed. Annex A describes the considerations for inclusion of toxicokinetic studies in the biological evaluation of medical devices.

Biologische Beurteilung von Medizinprodukten - Teil 16: Entwurf und Auslegung toxikokinetischer Untersuchungen hinsichtlich Abbauprodukten und Extrakten (ISO 10993-16:1997)

Dieser Teil der ISO 10993 beschreibt Prinzipien dafür, wie toxikokinetische Untersuchungen, die bei Medizinprodukten von Bedeutung sind, entworfen und durchgeführt werden sollten. Anhang A beschreibt die Umstände zur Durchführung toxikokinetischer Untersuchungen zur biologischen Beurteilung von Medizinprodukten.

Evaluation biologique des dispositifs médicaux - Partie 16: Conception des études toxicocinétiques des produits de dégration et des substances relargables (ISO 10993-16:1997)

NEW!IEC 60601-2-16:2018 est disponible sous forme de IEC 60601-2-16:2018 RLV qui contient la Norme internationale et sa version Redline, illustrant les modifications du contenu technique depuis l'édition précédente.

L'IEC 60601-2-16:2018 s'applique à la sécurité de base et aux performances essentielles des appareils d'hémodialyse, d'hémodiafiltration et d'hémofiltration. L'IEC 60601-2-16:2018 ne prend pas en compte le système de contrôle du liquide de dialyse de l'appareil d'hémodialyse utilisant la régénération du liquide de dialyse et les systèmes de transmission centralisés. Toutefois, elle prend en compte les exigences de sécurité spécifiques de l'appareil d'hémodialyse concernant la sécurité électrique et la sécurité du patient. L'IEC 60601-2-16:2018 spécifie les exigences minimales de sécurité relatives aux appareils d'hémodialyse. Ces appareils sont destinés à être utilisés soit par le personnel médical, soit par le patient, soit par d'autres personnes formées, sous le contrôle d'un personnel ayant une bonne compétence médicale. La présente Norme internationale s'applique à tout appareil electromédical destiné à fournir un traitement d'hémodialyse, d'hémodiafiltration et d'hémofiltration à un patient souffrant d'insuffisance rénale. Cette cinquième édition annule et remplace la quatrième édition de l'IEC 60601-2-16 parue en 2012. Cette édition constitue une révision technique. Cette édition inclut les modifications techniques majeures suivantes par rapport à l'édition précédente:
a) actualisation des références à l'IEC 60601-1:2005 et l'IEC 60601-1:2005/AMD1:2012, des références et des exigences à l'IEC 60601-1-2:2014, des références à l'IEC 60601-1-6:2010 et l'IEC 60601-1-6:2010/AMD1:2013, des références et des exigences à l'IEC 60601-1-8:2006 et l'IEC 60601-1-8:2006/AMD1:2012, des références à l'IEC 60601-1-9:2007 et l'IEC 60601-1-9:2007/AMD1:2013, des références à l'IEC 60601-1-10:2007 et l'IEC 60601-1-10:2007/AMD1:2013 ainsi que des références à l'IEC 60601-1-11:2015;
b) élargissement du domaine d'application;
c) améliorations d'ordre rédactionnel;
d) ajout d'exigences concernant les dispositifs de transmission d'anticoagulant;
e) quelques autres modifications techniques limitées.

Biološko ovrednotenje medicinskih pripomočkov - 16. del: Načrt toksikokinetičnih raziskav razgradnih produktov in izlužnin (ISO 10993-16:1997)

General Information

• Status: Withdrawn
• Publication Date: 31-Aug-1997
• Withdrawal Date: 28-Apr-2009
• ICS: 11.020 - Medical sciences and health care facilities in general
• Technical Committee: CEN/TC 206 - Biocompatibility of medical and dental materials and devices
• Drafting Committee: CEN/TC 206 - Biocompatibility of medical and dental materials and devices
• Current Stage: 9960 - Withdrawal effective - Withdrawal
• Start Date: 29-Apr-2009
• Completion Date: 29-Apr-2009
• Directive: 90/385/EEC - Council Directive 90/385/EEC of 20 June 1990 on the approximation of the laws of the Member States relating to active implantable medical devices
• Directive: 93/42/EEC - Council Directive 93/42/EEC of 14 June 1993 concerning medical devices
• Mandate: M/023 - Standardization mandate to CEN/CENELEC concerning the development of European standards relating to medical devices
• Mandate: M/095 - In vitro diagnostic (prog.)
• Ref Project: SIST EN ISO 10993-16:2000 - Biological evaluation of medical devices - Part 16: Toxicokinetic study design for degradation products and leachables (ISO 10993-16:1997)

Relations

• Replaced By: EN ISO 10993-16:2009 - Biological evaluation of medical devices - Part 16: Toxicokinetic study design for degradation products and leachables (ISO 10993-16:1997)
• Effective Date: 06-May-2009

Standards Content (Sample)

SLOVENSKI STANDARD
SIST EN ISO 10993-16:2000
01-januar-2000
%LRORãNRRYUHGQRWHQMHPHGLFLQVNLKSULSRPRþNRYGHO1DþUWWRNVLNRNLQHWLþQLK
UD]LVNDYUD]JUDGQLKSURGXNWRYLQL]OXåQLQ,62
Biological evaluation of medical devices - Part 16: Toxicokinetic study design for
degradation products and leachables (ISO 10993-16:1997)
Biologische Beurteilung von Medizinprodukten - Teil 16: Entwurf und Auslegung
toxikokinetischer Untersuchungen hinsichtlich Abbauprodukten und Extrakten (ISO
10993-16:1997)
Evaluation biologique des dispositifs médicaux - Partie 16: Conception des études
toxicocinétiques des produits de dégration et des substances relargables (ISO 10993-
16:1997)
Ta slovenski standard je istoveten z: EN ISO 10993-16:1997
ICS:
11.100.20 %LRORãNRRYUHGQRWHQMH Biological evaluation of
PHGLFLQVNLKSULSRPRþNRY medical devices
SIST EN ISO 10993-16:2000 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.

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IS0
INTERNATIONAL
109934 6
STANDARD
First edition
1997-09-01
Biological evaluation of medical devices -
Part 16:
Toxicokinetic study design for degradation
products and leachables
halua tion biologique des dispositifs medicaux -
Partie 16: Conception des etudes toxicocinktiques des produits de
dhgradation et des substances relargables
Reference number
IS0 1099346:1997(E)

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ISOlO993=16:1997(E)
Contents
1
.,.,.,.*.~~~~~~~~~~~~**~~B~~~*9~*~~~~~~9~~~~~~~~~~~D~~~.
1 Scope
. . . . . . .‘.‘.‘. 1
2 Normative reference
1
3 Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .~.
. . . . . . . . . . . . . . . . . . .~.~. 2
4 Principles for design of toxicokinetic studies
3
5 Guidance on test methods .,,.,,.,.~,.,.,.~.*
3
5.1 General considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .*.
4
5.2 Guidance on specific types of test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .~.
Annexes
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
A Circumstances in which toxicokinetic studies shall be considered
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .~~~~D~8~~~~~~~~~~~BB~~*~~89=~~~9.~. 8
B Bibliography
0 IS0 1997
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 the publisher.
International Organization for Standardization
Case postale 56 l CH-1211 Geneve 20 l Switzerland
Internet central @ iso.ch
x.400
c=ch; a=40Onet; p=iso; o=isocs; s=central
Printed in Switzerland
ii

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IS0 10993=16:1997(E)
0 IS0
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 was prepared by Technical Committee ISOmC 194, Ho/ogica/ evaluation of
medical devices.
IS0 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 cytotoxicity: in vitro methods
- Part 6: Tests for local effects after implantation
- Part 7: Ethylene oxide sterilization residuals
II degradation products rechnica
- Part 9: Framework for the identification and quantification of potentia ,I Report]
- 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 polymers
- 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
Future parts will deal with other relevant aspects of biological testing.
Annex A forms an integral part of this part of IS0 10993. Annex 6 is for information only.
. . .
III

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IS0 10993=16:1997(E) 0 IS0
Introduction
This part of IS0 10993 provides guidance and requirements on the design and performance of toxicokinetic
studies.
Toxicokinetics describes the absorption, distribution, metabolism and excretion of foreign compounds in
the body with time. Essential to the evaluation of the safety of a medical device is consideration of the
stability of the material(s) in vivo and the disposition of leachables and degradation products. Toxicokinetic
studies may be of value in assessing the safety of materials used in the development of a medical device or
in elucidating the mechanism of observed adverse reactions. The need for and extent of such studies
should be carefully considered based on the nature and duration of contact of the device with the body.
The potential hazard posed by a medical device may be attributed to the interactions of its components or
their metabolites with the biological system. Medical devices may release leachables (e.g. residual catalysts,
processing aids, residual monomers, fillers, antioxidants, plasticizers) and/or degradation products which
migrate from the material and have the potential to cause adverse effects in the body.
A considerable body of published literature exists on the use of toxicokinetic methods to study the fate of
chemicals in the body (see annex B). The methodologies and techniques utilized in such studies form the
basis of the guidance in this standard. A rationale for the use of this part of IS0 10993 is given in annex A.

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IS0 109934 6: 1997(E)
INTERNATIONAL STANDARD o IS0
Biological evaluation of medical devices -
Part 16:
Toxicokinetic study design for degradation products and leachables
1 Scope
This part of IS0 10993 gives principles on how toxicokinetic studies relevant to medical devices should be
designed and performed. Annex A describes the considerations for inclusion of toxicokinetic studies in the
biological evaluation of medical devices.
2 Normative reference
The following standard contains provisions which, through reference in this text, constitute provisions of
this part of IS0 10993. At the time of publication, the edition indicated was valid. All standards are subject to
revision, and parties to agreements based on this part of IS0 10993 are encouraged to investigate the
possibility of applying the most recent edition of the standard indicated below. Members of IEC and IS0
maintain register of currently valid International Standards.
IS0 10993-I : 1992, Biological evaluation of medical devices - Part I: Guidance on selection of tests.
3 Definitions
For the purposes of this part of IS0 10993, the definitions given in IS0 10993-I and the following definitions
apply.
3.1 degradation product: Product of a material which is generated by the chemical breakdown or decompo-
sition of the material.
Extractable component, such as an additive, monomeric or oligomeric constituent of
3.2 leachable:
polymeric material.
3.3 test substance: Degradation product or leachable used for toxicokinetic study.
3.4 absorption: Process by which a substance enters the blood and/or lymph system.
Process by which an absorbed substance and/or its metabolites circulate and partition
3.5 distribution:
within the body.
3.6 metabolism: Process by which an absorbed substance is structurally changed within the body by
chemical and/or enzymatic reactions.
NOTE - The products of the initial reaction may subsequently be modified by either enzymatic or non-enzymatic
reactions prior to excretion.
3.7 excretion: Process by which an absorbed substance and/or its metabolites are removed from the body.

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IS0 10993=16:1997(E) 0 IS0
3.8 bioavailability: Extent of systemic absorption of intact substance.
3.9 clearance: Rate of removal of a substance from the body by metabolism and/or excretion.
3.10 half-life (t1/2): Time for the concentration of a particular molecular species to decrease to 50% of its
initial value in the same body fluid or tissue.
related to half-life which provides a quantitative estimate of
3.11 mean residence time: Statistical moment
the persistence of a substance in the body.
Maximum concentration of a substance in plasma expressed in mass per unit volume.
3.12 Cmax:
or tissue is being refe rred to, it should have an appropriate
NOTE - When the maximum concentration in fluid
identifier and be expressed in mass per unit volume or mass.
emg- cmax, liver
3.13 tmax: Time at which Cmax is observed.
3.14 AUCo+ Area under the plasma concentration versus time curve, from time zero to time tfollowing a
single dose of a substance.
NOTE - t is normally extrapolated to infinity.
3.15 AUMCO-~ : Area under the first moment plasma concentration versus time curve, from time zero to
time tfollowing a single dose of a substance.
NOTE -
t is normally extrapolated to infinity.
3.16 volume of distribution (vd): Parameter for a single-compartment model describing the apparent
volume which would contain the amount of test substance in the body if it were uniformly distributed.
3.17 extract liquid: Liquid which is the result of the extraction process on the test material.
3.18 biodegradation: Alteration of a medical device or biomaterial involving loss of integrity and/or
performance when exposed to a physiological or simulated environment.
a biomaterial is degraded in the physiological environment and the
3.19 bioresorption: Process by which
product(s) eliminated and/or absorbed.
4 Principles for design of toxicokinetic studies
4.1 Toxicokinetic studies should be designed on a case-by-case basis.
4.2 A study protocol shall be written prior to commencement of the study. The study design, including
methods, shall be defined in this protocol. Details of areas to be defined are given below and in clause 5.
4.3 The results of leaching studies should be considered in order to determine the methods to be used for
toxicokinetic studies. Information on the chemical and physicochemical properties, surface morphology of
the material and biochemical properties of any leachable should also be considered.
NOTE - The extent and rate of release of leachables depend on the concentration at the surface, migration to the
surface within the material, solubility and flowrate in the physiological milieu.
4.4 It is recommended to undertake toxicokinetic studies with a characterized leachable or degradation
product which has the potential of being toxic. However, the performance of toxicokinetic studies on
mixtures is possible under certain conditions. An extract liquid (see IS0 10993-12), or a ground or powdered

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IS0 109934 6: 1997(E)
0 IS0
excepti onal circumstances and shall be justified in the study
form of the material or device, may be used in
design.
4.5 Analytical methods shall be able to detect and characterize degradation products, leachables and
metabolites in biological fluids and tissues. They shall be fully described in the study report (see 5.1.11).
Quantitative analytical methods shall be specific, sensitive and reproducible, and produce data which show
linearity over the range of expected analyte concentrations. Validation of the assay method shall be
presented in the report.
4.6The study design shall state the physiological fluid, tissue or excreta in which analyte levels will be
determined.
Blood is convenient to sample and thus is often the fluid of choice for kinetic parameter and absorption
NOTE -
studies. It is necessary to specify whether analysis is on whole blood, serum or plasma and to provide validation of this
choice. Binding to circulating proteins or red cells can be determined in vitro.
4.7 The study report should contain information on analyte binding in the sample (e.g. amount and affinity)
and demonstrate that this does not lead to underestimation of analyte concentration.
4.8There should be sufficient data points with adequate spacing to allow determination of kinetic
parameters. In theory this should cover several terminal half-lives; in practice the constraints of the
analytical method may necessitate a compromise.
5 Guidance on test methods
5.1 General considerations
5.1.1 The study should be performed in an appropriate sex and species. Healthy young adult animals should
be acclimatized to laboratory conditions for at least 7 days. They should be transferred to individual
metabolism cages, when used, for an acclimatization period of at least 24 h. The environmental conditions
should be as recommended in guidelines for the care and use of animals (see IS0 10993-2). During the
study conventional animal diets and drinking water should be freely available unless otherwise specified in
the protocol. Animals should be randomly selected into groups for each time period studied; group sizes of
at least three for small animals and at least two for larger species should be used. At the appropriate
specified times, animals should be humanely killed.
5.1.2 A non-r
...