SIST EN ISO 10993-16:2018
(Main)Biological evaluation of medical devices - Part 16: Toxicokinetic study design for degradation products and leachables (ISO 10993-16:2017)
Biological evaluation of medical devices - Part 16: Toxicokinetic study design for degradation products and leachables (ISO 10993-16:2017)
This document provides principles on designing and performing toxicokinetic studies relevant to
medical devices. 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 herauslösbaren Substanzen (ISO 10993-16:2017)
Dieser Teil von ISO 10993 beschreibt Prinzipien dafür, wie toxikokinetische Untersuchungen, die bei Medizinprodukten von Bedeutung sind, entworfen und durchgeführt werden sollten. Anhang A beschreibt die Überlegungen zur Durchführung toxikokinetischer Untersuchungen zur biologischen Beurteilung von Medizinprodukten.
Évaluation biologique des dispositifs médicaux - Partie 16: Conception des études toxicocinétiques des produits de dégradation et des substances relargables (ISO 10993-16:2017)
ISO 10993-16:2017 énonce les principes de conception et de mise en ?uvre des études toxicocinétiques relatives aux dispositifs médicaux. L'Annexe A décrit les considérations relatives à l'inclusion d'études toxicocinétiques dans l'évaluation biologique des dispositifs médicaux.
Biološko ovrednotenje medicinskih pripomočkov - 16. del: Načrt toksikokinetičnih raziskav razgradnih produktov in izlužnin (ISO 10993-16:2017)
Ta dokument določa načela za načrtovanje in izvajanje toksikokinetičnih študij, ki se nanašajo na medicinske pripomočke. Dodatek A podaja razloge za vključitev toksikokinetičnih študij pri biološkem vrednotenju medicinskih pripomočkov.
General Information
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Related Packages
Standards Content (Sample)
SLOVENSKI STANDARD
SIST EN ISO 10993-16:2018
01-februar-2018
1DGRPHãþD
SIST EN ISO 10993-16:2010
%LRORãNRRYUHGQRWHQMHPHGLFLQVNLKSULSRPRþNRYGHO 1DþUWWRNVLNRNLQHWLþQLK
UD]LVNDYUD]JUDGQLKSURGXNWRYLQL]OXåQLQ ,62
Biological evaluation of medical devices - Part 16: Toxicokinetic study design for
degradation products and leachables (ISO 10993-16:2017)
Biologische Beurteilung von Medizinprodukten - Teil 16: Entwurf und Auslegung
toxikokinetischer Untersuchungen hinsichtlich Abbauprodukten und herauslösbaren
Substanzen (ISO 10993-16:2017)
Évaluation biologique des dispositifs médicaux - Partie 16: Conception des études
toxicocinétiques des produits de dégradation et des substances relargables (ISO 10993-
16:2017)
Ta slovenski standard je istoveten z: EN ISO 10993-16:2017
ICS:
11.100.20 %LRORãNRRYUHGQRWHQMH Biological evaluation of
PHGLFLQVNLKSULSRPRþNRY medical devices
SIST EN ISO 10993-16:2018 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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SIST EN ISO 10993-16:2018
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SIST EN ISO 10993-16:2018
EN ISO 10993-16
EUROPEAN STANDARD
NORME EUROPÉENNE
December 2017
EUROPÄISCHE NORM
ICS 11.100.20 Supersedes EN ISO 10993-16:2010
English Version
Biological evaluation of medical devices - Part 16:
Toxicokinetic study design for degradation products and
leachables (ISO 10993-16:2017)
Évaluation biologique des dispositifs médicaux - Partie Biologische Beurteilung von Medizinprodukten - Teil
16: Conception des études toxicocinétiques des 16: Entwurf und Auslegung toxikokinetischer
produits de dégradation et des substances relargables Untersuchungen hinsichtlich Abbauprodukten und
(ISO 10993-16:2017) herauslösbaren Substanzen (ISO 10993-16:2017)
This European Standard was approved by CEN on 9 August 2017.
CEN members are bound to comply with the CEN/CENELEC Internal Regulations which stipulate the conditions for giving this
European Standard the status of a national standard without any alteration. Up-to-date lists and bibliographical references
concerning such national standards may be obtained on application to the CEN-CENELEC Management Centre or to any CEN
member.
This European Standard exists in three official versions (English, French, German). A version in any other language made by
translation under the responsibility of a CEN member into its own language and notified to the CEN-CENELEC Management
Centre has the same status as the official versions.
CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia,
Finland, Former Yugoslav Republic of Macedonia, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania,
Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland,
Turkey and United Kingdom.
EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION
EUROPÄISCHES KOMITEE FÜR NORMUNG
CEN-CENELEC Management Centre: Rue de la Science 23, B-1040 Brussels
© 2017 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 10993-16:2017 E
worldwide for CEN national Members.
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SIST EN ISO 10993-16:2018
EN ISO 10993-16:2017 (E)
Contents Page
European foreword . 3
Annex ZA (informative) Relationship between this European Standard and the essential
requirements of Directive 93/42/EEC [OJ L 169] aimed to be covered . 5
Annex ZB (informative) Relationship between this European Standard and the essential
requirements of Directive 90/385/EEC [OJ L 189] aimed to be covered . 7
2
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SIST EN ISO 10993-16:2018
EN ISO 10993-16:2017 (E)
European foreword
The text of ISO 10993-16:2017 has been prepared by Technical Committee ISO/TC 194 "Biological and
clinical evaluation of medical devices" of the International Organization for Standardization (ISO) and
has been taken over as EN ISO 110993-16:2017 by Technical Committee CEN/TC 206 “Biological and
clinical evaluation of medical devices” the secretariat of which is held by DIN.
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 June 2018, and conflicting national standards shall be
withdrawn at the latest by June 2018.
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. CEN shall not be held responsible for identifying any or all such patent rights.
This document supersedes EN ISO 10993-16:2010.
This document has been prepared under a mandate given to CEN by the European Commission and the
European Free Trade Association, and supports essential requirements of EU Directive(s).
For relationship with EU Directive(s), see informative Annex ZA and Annex ZB, which is an integral part
of this document.
The following referenced documents are indispensable for the application of this document. For
undated references, the latest edition of the referenced document (including any amendments) applies.
For dated references, only the edition cited applies. However, for any use of this standard ‘within the
meaning of Annex ZA’, the user should always check that any referenced document has not been
superseded and that its relevant contents can still be considered the generally acknowledged state-of-
art.
When an IEC or ISO standard is referred to in the ISO standard text, this shall be understood as a
normative reference to the corresponding EN standard, if available, and otherwise to the dated version
of the ISO or IEC standard, as listed below.
NOTE The way in which these referenced documents are cited in normative requirements determines the
extent (in whole or in part) to which they apply.
Table — Correlations between undated normative references and dated EN and ISO standards
Normative references Equivalent dated standard
as listed in Clause 2 of
EN ISO or IEC
the ISO standard
ISO 10993-1 EN ISO 10993-1:2009 ISO 10993-1:2009
NOTE This part of EN ISO 10993 refers to ISO 10993-1 which itself refers to ISO 14971. In Europe, it should
be assumed that the reference to ISO 14971 is to EN ISO 14971:2012.
3
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SIST EN ISO 10993-16:2018
EN ISO 10993-16:2017 (E)
According to the CEN-CENELEC Internal Regulations, the national standards organizations of the
following countries are bound to implement this European Standard: Austria, Belgium, Bulgaria,
Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, Former Yugoslav Republic of Macedonia,
France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta,
Netherlands, Norway, Poland, Portugal, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland,
Turkey and the United Kingdom.
Endorsement notice
The text of ISO 10993-16:2017 has been approved by CEN as EN ISO 10993-16:2017 without any
modification.
4
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SIST EN ISO 10993-16:2018
EN ISO 10993-16:2017 (E)
Annex ZA
(informative)
Relationship between this European Standard and the essential
requirements of Directive 93/42/EEC [OJ L 169] aimed to be covered
This European Standard has been prepared under a Commission’s joint standardization request
M/BC/CEN/89/9 concerning harmonized standards relating to horizontal aspects in the field of medical
devices to provide one voluntary means of conforming to essential requirements of Council Directive
93/42/EEC of 14 June 1993 concerning medical devices [OJ L 169].
Once this standard is cited in the Official Journal of the European Union under that Directive,
compliance with the normative clauses of this standard given in Table ZA.1 confers, within the limits of
the scope of this standard, a presumption of conformity with the corresponding essential requirements
of that Directive and associated EFTA regulations.
NOTE 1 Where a reference from a clause of this standard to the risk management process is made, the risk
management process needs to be in compliance with Directive 93/42/EEC as amended by 2007/47/EC. This
means that risks have to be reduced ‘as far as possible’, ‘to a minimum’, ‘to the lowest possible level’, ‘minimized’
or ‘removed’, according to the wording of the corresponding essential requirement.
NOTE 2 The manufacturer’s policy for determining acceptable risk must be in compliance with Essential
Requirements 1, 2, 5, 6, 7, 8, 9, 11 and 12 of the Directive.
NOTE 3 This Annex ZA is based on normative references according to the table of references in the European
foreword, replacing the references in the core text.
NOTE 4 When an Essential Requirement does not appear in Table ZA.1, it means that it is not addressed by this
European Standard.
Table ZA.1 — Correspondence between this European Standard and Annex I of Directive
93/42/EEC [OJ L 169]
Essential Requirements of Clause(s)/subclause(s) Remarks/Notes
Directive 93/42/EEC of this EN
ER 7.1 is only partly covered by EN ISO
10993-16, since the standard does not
provide requirements on design and
manufacture, and the compatibility
between the materials used and
biological tissues, cells and body fluids.
However, this standard provides a
means to evaluate the absorption,
7.1 (First and second indent) 4, 5, and Annex A
distribution, metabolism and excretion,
with time, of degradation products and
leachables from materials which are
used in the device and circumstances in
which such studies shall be considered.
Other forms of toxicity and
flammability are not dealt with in this
standard.
5
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SIST EN ISO 10993-16:2018
EN ISO 10993-16:2017 (E)
ER 7.2 is not covered by EN ISO 10993-
16, since the standard does not provide
requirements on design and
manufacture and does not oblige to
minimize risk.
However, this standard provides a
means to evaluate the absorption,
7.2 4, 5, and Annex A
distribution, metabolism and excretion,
with time, of residuals in exposed
persons and circumstances in which
such studies shall be considered. This
evaluation can be a preliminary step
for risk minimization. Other forms of
toxicity are not dealt with in this
standard.
ER 7.5 is not covered by EN ISO 10993-
16, since the standard does not provide
requirements on design and
manufacture and does not oblige to
minimize risk.
However, this standard provides a
means to evaluate the absorption,
7.5 (First paragraph) 4, 5, and Annex A
distribution, metabolism and excretion,
with time, of substances leaking from
the device and circumstances in which
such studies shall be considered. This
evaluation can be a preliminary step
for risk minimization. Other forms of
toxicity are not dealt with in this
standard.
General Note: Presumption of conformity depends on also complying with all relevant
clauses/subclauses of ISO 10993-1.
WARNING 1 — Presumption of conformity stays valid only as long as a reference to this European
Standard is maintained in the list published in the Official Journal of the European Union. Users of this
standard should consult frequently the latest list published in the Official Journal of the European
Union.
WARNING 2 — Other Union legislation may be applicable to the products falling within the scope of
this standard.
6
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SIST EN ISO 10993-16:2018
EN ISO 10993-16:2017 (E)
Annex ZB
(informative)
Relationship between this European Standard and the essential
requirements of Directive 90/385/EEC [OJ L 189] aimed to be covered
This European Standard has been prepared under a Commission’s joint standardization request
M/BC/CEN/89/9 concerning harmonized standards relating to horizontal aspects in the field of medical
devices to provide one voluntary means of conforming to essential requirements of 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 [OJ L 189].
Once this standard is cited in the Official Journal of the European Union under that Directive,
compliance with the normative clauses of this standard given in Table ZB.1 confers, within the limits of
the scope of this standard, a presumption of conformity with the corresponding essential requirements
of that Directive and associated EFTA regulations.
NOTE 1 Where a reference from a clause of this standard to the risk management process is made, the risk
management process needs to be in compliance with Directive 90/385/EEC as amended by 2007/47/EC. This
means that risks have to be reduced ‘as far as possible’, ‘to a minimum’, ‘to the lowest possible level’, ‘minimized’
or ‘removed’, according to the wording of the corresponding essential requirement.
NOTE 2 The manufacturer’s policy for determining acceptable risk must be in compliance with Essential
Requirements 1, 4, 5, 8, 9 and 10 of the Directive.
NOTE 3 This Annex ZB is based on normative references according to the table of references in the European
foreword, replacing the references in the core text.
NOTE 4 When an Essential Requirement does not appear in Table ZB.1, it means that it is not addressed by this
European Standard.
Table ZB.1 — Correspondence between this European Standard and Annex I of Directive
90/385/EEC [OJ L 189]
Essential Requirements of Clause(s)/subclause(s) Remarks/Notes
Directive 90/385/EEC of this EN
The first and second indents of this
relevant Essential Requirement are
only partly covered by EN ISO 10993-
16, since the standard does not
provide requirements on design and
manufacture.
However, this standard provides a
means to evaluate the absorption,
9 (only first and second indent) 4, 5, and Annex A
distribution, metabolism and
excretion, with time, of degradation
products and leachables from
materials which are used in the device
and circumstances in which such
studies shall be considered.
Other forms of toxicity are not
covered.
7
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SIST EN ISO 10993-16:2018
EN ISO 10993-16:2017 (E)
General Note: Presumption of conformity depends on also complying with all relevant
clauses/subclauses of ISO 10993-1.
WARNING 1 — Presumption of conformity stays valid only as long as a reference to this European
Standard is maintained in the list published in the Official Journal of the European Union. Users of this
standard should consult frequently the latest list published in the Official Journal of the European
Union.
WARNING 2 — Other Union legislation may be applicable to the products falling within the scope of
this standard.
8
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SIST EN ISO 10993-16:2018
INTERNATIONAL ISO
STANDARD 10993-16
Third edition
2017-05
Biological evaluation of medical
devices —
Part 16:
Toxicokinetic study design for
degradation products and leachables
Évaluation biologique des dispositifs médicaux —
Partie 16: Conception des études toxicocinétiques des produits de
dégradation et des substances relargables
Reference number
ISO 10993-16:2017(E)
©
ISO 2017
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SIST EN ISO 10993-16:2018
ISO 10993-16:2017(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2017, Published in Switzerland
All rights reserved. Unless otherwise specified, no part of this publication may be reproduced or utilized otherwise in any form
or by any means, electronic or mechanical, including photocopying, or posting on the internet or an intranet, without prior
written permission. Permission can be requested from either ISO at the address below or ISO’s member body in the country of
the requester.
ISO copyright office
Ch. de Blandonnet 8 • CP 401
CH-1214 Vernier, Geneva, Switzerland
Tel. +41 22 749 01 11
Fax +41 22 749 09 47
copyright@iso.org
www.iso.org
ii © ISO 2017 – All rights reserved
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SIST EN ISO 10993-16:2018
ISO 10993-16:2017(E)
Contents Page
Foreword .iv
Introduction .v
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 1
4 Principles for design of toxicokinetic studies . 3
5 Guidance on test methods . 3
5.1 General considerations . 3
5.2 Guidance on specific types of test . 5
5.2.1 General. 5
5.2.2 Absorption . 5
5.2.3 Distribution . 5
5.2.4 Metabolism and excretion . 6
Annex A (normative) Circumstances in which toxicokinetic studies shall be considered .7
Bibliography . 9
© ISO 2017 – All rights reserved iii
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SIST EN ISO 10993-16:2018
ISO 10993-16:2017(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.
The procedures used to develop this document and those intended for its further maintenance are
described in the ISO/IEC Directives, Part 1. In particular the different approval criteria needed for the
different types of ISO documents should be noted. This document was drafted in accordance with the
editorial rules of the ISO/IEC Directives, Part 2 (see www .iso .org/ directives).
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of
any patent rights identified during the development of the document will be in the Introduction and/or
on the ISO list of patent declarations received (see www .iso .org/ patents).
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
For an explanation on the voluntary nature of standards, the meaning of ISO specific terms and
expressions related to conformity assessment, as well as information about ISO’s adherence to the
World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT) see the following
URL: w w w . i s o .org/ iso/ foreword .html.
This document was prepared by Technical Committee ISO/TC 194, Biological and clinical evaluation of
medical devices.
This third edition cancels and replaces the second edition (ISO 10993-16:2010), which has been
technically revised with the following changes:
a) definition in 3.1 has been modified for clarification;
b) Clause 4 has been modified for clarification;
c) Clause 5 has been modified for clarification;
d) information regarding toxicokinetic studies on nano-objects have been added;
e) A.4 has been modified for clarification.
A list of all the parts in the ISO 10993 series can be found on the ISO website.
iv © ISO 2017 – All rights reserved
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SIST EN ISO 10993-16:2018
ISO 10993-16:2017(E)
Introduction
Toxicokinetics describe the absorption, distribution, metabolism and excretion, with time, of foreign
compounds in the body. 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 intended and unintended leachables and
degradation products. Toxicokinetic studies can 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.
Toxicokinetic studies can also be applicable to medical devices containing active ingredients, in which
case, pharmaceutical legislation are to be considered. The need for and extent of toxicokinetic studies
should be carefully considered based on the nature and duration of contact of the device with the body
(see A.2). Existing toxicological literature and toxicokinetic data can be sufficient for this consideration.
The potential hazard posed by a medical device can be attributed to the interactions of its components
or their metabolites with the biological system. Medical devices can release leachables (e.g. residual
catalysts, processing aids, residual monomers, fillers, antioxidants, plasticizers, etc.) 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 Bibliography). The methodologies and techniques utilized in such
studies form the basis of the guidance in this document. Annex A provides a rationale for the use of this
document.
© ISO 2017 – All rights reserved v
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SIST EN ISO 10993-16:2018
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SIST EN ISO 10993-16:2018
INTERNATIONAL STANDARD ISO 10993-16:2017(E)
Biological evaluation of medical devices —
Part 16:
Toxicokinetic study design for degradation products and
leachables
1 Scope
This document provides principles on designing and performing toxicokinetic studies relevant to
medical devices. Annex A describes the considerations for inclusion of toxicokinetic studies in the
biological evaluation of medical devices.
2 Normative references
The following documents are referred to in the text in such a way that some or all of their content
constitutes requirements of this document. For dated references, only the edition cited applies. For
undated references, the latest edition of the referenced document (including any amendments) applies.
ISO 10993-1, Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk
management process
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 10993-1 and the following apply.
ISO and IEC maintain terminological databases for use in standardization at the following addresses:
— IEC Electropedia: available at http:// www .electropedia .org/
— ISO Online browsing platform: available at http:// www .iso .org/ obp
3.1
absorption
process of uptake of substance into or across tissue, blood and/or lymph system
3.2
bioavailability
extent of systemic absorption (3.1) of specified substance
3.3
biodegradation
degradation due to the biological environment
Note 1 to entry: Biodegradation might be modelled by in vitro tests.
3.4
bioresorption
process by which a biomaterial is degraded in the physiological environment and the product(s)
eliminated and/or absorbed
© ISO 2017 – All rights reserved 1
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SIST EN ISO 10993-16:2018
ISO 10993-16:2017(E)
3.5
clearance
rate of removal of a specified substance from the body or parts of the body by metabolism (3.14) and/or
excretion (3.9)
3.6
c
max
maximum concentration of a specified substance in plasma
Note 1 to entry: When the maximum concentration in fluid or tissue is being referred to, it should have an
appropriate identifier, e.g. c , liver, and be expressed in mass per unit volume or mass.
max
3.7
degradation product
product of a material which is derived from the chemical breakdown of the original material
3.8
distribution
process by which an absorbed substance and/or its metabolites circulate and partition within the body
3.9
excretion
process by which an absorbed substance and/or its metabolites are removed from the body
3.10
extract
liquid that results from extraction of the test substance (3.15) or control
3.11
half-life
t
1/2
time for the concentration of a specified substance to decrease to 50 % of its initial value in the same
body fluid or tissue
3.12
leachable
chemical that can migrate from a device or component under storage conditions or conditions of use
Note 1 to entry: A leachable (e.g. additives, monomeric or oligomeric constituent of polymeric material) can be
extracted under laboratory conditions that simulate normal conditions of exposure.
3.13
mean residence time
statistical moment related to half-life (3.11) which provides a quantitative estimate of the persistence of
a specified substance in the body
3.14
metabolism
process by which an absorbed substance is structurally changed within the body by enzymatic and/or
non-enzymatic reactions
Note 1 to entry: The products of the initial reaction can subsequently be modified by either enzymatic or non-
enzymatic reactions prior to excretion (3.9).
3.15
test substance
degradation product (3.7) or leachable (3.12) used for toxicokinetic study
3.16
t
max
time at which c (3.6) is observed
max
2 © ISO 2017 – All rights reserved
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SIST EN ISO 10993-16:2018
ISO 10993-16:2017(E)
3.17
volume of distribution
V
d
parameter for a single-compartment model describing the apparent volume which would contain the
amount of test substance (3.15) in the body if it were uniformly distributed
4 Principles for design of toxicokinetic studies
4.1 Toxicokinetic studies should be designed on a case-by-case basis, see Annex A.
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 in 4.3 to 4.7 and in
Clause 5.
4.3 The results of extraction studies (see ISO 10993-12 and ISO 10993-18) 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 flow rate in the physiological milieu.
4.4 It is recommended to undertake toxicokinetic studies with a characterized leachable or degradation
product that has the potential of being toxic. However, the performance of toxicokinetic studies on
mixtures is possible under certain conditions. An extract liquid (see ISO 10993-12), or a ground or
powdered form of the material or device, may be used in exceptional circumstances and shall be justified
in the study design.
4.5 Analytical methods shall be able to detect and characterize degradation products, leachables and
metabolites in biological fluids and tissues.
For analytical methods, other parts of ISO 10993 shall
...
SLOVENSKI STANDARD
oSIST prEN ISO 10993-16:2016
01-april-2016
%LRORãNRRYUHGQRWHQMHPHGLFLQVNLKSULSRPRþNRYGHO 1DþUWWRNVLNRNLQHWLþQLK
UD]LVNDYUD]JUDGQLKSURGXNWRYLQL]OXåQLQ ,62',6
Biological evaluation of medical devices - Part 16: Toxicokinetic study design for
degradation products and leachables (ISO/DIS 10993-16:2016)
Biologische Beurteilung von Medizinprodukten - Teil 16: Entwurf und Auslegung
toxikokinetischer Untersuchungen hinsichtlich Abbauprodukten und herauslösbaren
Bestandteilen (ISO/DIS 10993-16:2016)
Évaluation biologique des dispositifs médicaux - Partie 16: Conception des études
toxicocinétiques des produits de dégradation et des substances relargables (ISO/DIS
10993-16:2016)
Ta slovenski standard je istoveten z: prEN ISO 10993-16
ICS:
11.100.20 %LRORãNRRYUHGQRWHQMH Biological evaluation of
PHGLFLQVNLKSULSRPRþNRY medical devices
oSIST prEN ISO 10993-16:2016 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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oSIST prEN ISO 10993-16:2016
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oSIST prEN ISO 10993-16:2016
DRAFT INTERNATIONAL STANDARD
ISO/DIS 10993-16
ISO/TC 194 Secretariat: DIN
Voting begins on: Voting terminates on:
2016-02-18 2016-05-18
Biological evaluation of medical devices —
Part 16:
Toxicokinetic study design for degradation products and
leachables
Évaluation biologique des dispositifs médicaux —
Partie 16: Conception des études toxicocinétiques des produits de dégradation et des substances relargables
ICS: 11.100.20
ISO/CEN PARALLEL PROCESSING
This draft has been developed within the International Organization for
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Contents Page
Foreword .iv
Introduction .vi
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 1
4 Principles for design of toxicokinetic studies . 3
5 Guidance on test methods . 4
5.1 General considerations . 4
5.2 Guidance on specific types of test . 5
5.2.1 General. 5
5.2.2 Absorption . 5
5.2.3 Distribution . 5
5.2.4 Metabolism and excretion . 6
Annex A (normative) Circumstances in which toxicokinetic studies shall be considered .7
Annex ZA (informative) Relationship between this European Standard and the essential
requirements of Directive 93/42/EEC [OJ L 169] aimed to be covered .8
Annex ZB (informative) Relationship between this European Standard and the essential
requirements of Directive 90/385/EEC [OJ L 189] aimed to be covered .9
Bibliography .10
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Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards
bodies (ISO member bodies). The work of preparing International Standards is normally carried out
through ISO technical committees. Each member body interested in a subject for which a technical
committee has been established has the right to be represented on that committee. International
organizations, governmental and non-governmental, in liaison with ISO, also take part in the work.
ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of
electrotechnical standardization.
The procedures used to develop this document and those intended for its further maintenance are
described in the ISO/IEC Directives, Part 1. In particular the different approval criteria needed for the
different types of ISO documents should be noted. This document was drafted in accordance with the
editorial rules of the ISO/IEC Directives, Part 2 (see www.iso.org/directives).
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of
any patent rights identified during the development of the document will be in the Introduction and/or
on the ISO list of patent declarations received (see www.iso.org/patents).
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
For an explanation on the meaning of ISO specific terms and expressions related to conformity
assessment, as well as information about ISO’s adherence to the WTO principles in the Technical
Barriers to Trade (TBT) see the following URL: Foreword - Supplementary information
The committee responsible for this document is ISO/TC 194 “Biological and clinical evaluation of
medical devices”
This third edition cancels and replaces the second edition (ISO 10993-16:2010), of which it constitutes a
major revision with the following technical changes:
ISO 10993 consists of the following parts under the general title Biological evaluation of medical devices:
— Part 1: Evaluation and testing within a risk management system
— Part 2: Animal welfare requirements
— Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity
— Part 4: Selection of tests for interactions with blood
— Part 5: Tests for in vitro cytotoxicity
— Part 6: Tests for local effects after implantation
— Part 7: Ethylene oxide sterilization residuals
— Part 9: Framework for identification and quantification of potential degradation products
— Part 10: Tests for irritation and delayed-type hypersensitivity
— Part 11: Tests for systemic toxicity
— Part 12: Sample preparation and reference materials
— Part 13: Identification and quantification of degradation products from polymeric medical devices
— Part 14: Identification and quantification of degradation products from ceramics
— Part 15: Identification and quantification of degradation products from metals and alloys
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— Part 16: Toxicokinetic study design for degradation products and leachables
— Part 17: Method for the establishment of allowable limits for leachable substances
— Part 18: Chemical characterization of materials
— Part 19: Physico-chemical, morphological and topographical characterization of materials [Technical
specification]
— Part 20: Principles and methods for immunotoxicology testing of medical devices [Technical
specification]
— Part 33: Guidance on tests to evaluate genotoxicity -- Supplement to ISO 10993-3 [Technical Report]
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Introduction
Toxicokinetics describe the absorption, distribution, metabolism and excretion, with time, of foreign
compounds in the body. 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 intended and unintended leachables and
degradation products. Toxicokinetic studies can 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.
Toxicokinetic studies can also be applicable to medical devices containing active ingredients. 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 (see Annex A). Existing toxicological literature and toxicokinetic
data can be sufficient for this consideration.
The potential hazard posed by a medical device can be attributed to the interactions of its components
or their metabolites with the biological system. Medical devices can 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 Bibliography). The methodologies and techniques utilized in such studies
form the basis of the guidance in this part of ISO 10993. Annex A provides a rationale for the use of this
part of ISO 10993.
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Biological evaluation of medical devices —
Part 16:
Toxicokinetic study design for degradation products and
leachables
1 Scope
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.
2 Normative references
The following referenced documents are indispensable for the application of this document. For dated
references, only the edition cited applies. For undated references, the latest edition of the referenced
document (including any amendments) applies.
ISO 10993-1:2009, Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk
management process
ISO 10993-1:2010, Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk
management process; Technical Corrigendum 1
ISO 10993-2:2006, Biological evaluation of medical devices — Part 2: Animal welfare requirements
ISO 10993-12:2012, Biological evaluation of medical devices — Part 12: Sample preparation and
reference materials
ISO 10993-17:2002, Biological evaluation of medical devices — Part 17: Establishment of allowable limits
for leachable substances
ISO 10993-18:2005, Biological evaluation of medical devices — Part 18: Chemical characterization of
materials
1)
ISO/TR 10993-22:2016, Biological evaluation of medical devices — Part 22: Guidance on nanomaterials
ISO 14971:2007, Medical devices — Application of risk management to medical devices
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 10993-1 and the following apply.
3.1
absorption
process by which a substance enters the blood and/or lymph system
3.2
bioavailability
extent of systemic absorption of specified substance
1) Under preparation
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3.3
biodegradation
degradation due to the biological environment
Note 1 to entry: Biodegradation might be modelled by in vitro tests.
3.4
bioresorption
process by which a biomaterial is degraded in the physiological environment and the product(s)
eliminated and/or absorbed
3.5
clearance
rate of removal of a specified substance from the body or parts of the body by metabolism and/or excretion
3.6
c
max
maximum concentration of a specified substance in plasma expressed in mass per unit volume
Note 1 to entry: When the maximum concentration in fluid or tissue is being referred to, it should have an
appropriate identifier, e.g. c , liver, and be expressed in mass per unit volume or mass.
max
3.7
degradation product
product of a material which is derived from the chemical breakdown of the original material
3.8
distribution
process by which an absorbed substance and/or its metabolites circulate and partition within the body
3.9
excretion
process by which an absorbed substance and/or its metabolites are removed from the body
3.10
extract
liquid that results from extraction of the test substance or control
3.11
half-life
t
1/2
time for the concentration of a specified substance to decrease to 50 % of its initial value in the same
body fluid or tissue
3.12
leachable
chemical that can migrate from a device or component under storage conditions or conditions of use
Note 1 to entry: A leachable (e.g. additives, monomeric or oligomeric constituent of polymeric material) can be
extracted under laboratory conditions that simulate normal conditions of exposure.
3.13
mean residence time
statistical moment related to half-life which provides a quantitative estimate of the persistence of a
specified substance in the body
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3.14
metabolism
process by which an absorbed substance is structurally changed within the body by enzymatic and/or
non-enzymatic reactions
Note 1 to entry: The products of the initial reaction can subsequently be modified by either enzymatic or non-
enzymatic reactions prior to excretion.
3.15
test substance
degradation product or leachable used for toxicokinetic study
3.16
t
max
time at which c is observed
max
3.17
volume of distribution
V
d
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
4 Principles for design of toxicokinetic studies
4.1 Toxicokinetic studies should be designed on a case-by-case basis, see Annex A.
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 in 4.3 to 4.7
and in Clause 5.
4.3 The results of extraction studies (see ISO 10993-12 and ISO 10993-18) 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 flow rate in the physiological milieu.
4.4 It is recommended to undertake toxicokinetic studies with a characterized leachable or
degradation product that has the potential of being toxic. However, the performance of toxicokinetic
studies on mixtures is possible under certain conditions. An extract liquid (see lSO 10993-12), or a
ground or powdered form of the material or device, may be used in exceptional circumstances and shall
be justified in the study design.
4.5 Analytical methods shall be able to detect and characterize degradation products, leachables
and metabolites in biological fluids and tissues. For analytical methods, other parts of ISO 10993 shall
be used as relevant. The methods shall be fully described in the study report (see 5.1.10). Quantitative
analytical methods shall be specific, sensitive and reproducible (see ISO 10993-18).
Validation/qualification of the method shall be performed.
4.6 The study design shall state the physiological fluid, tissue or excreta in which analyte levels will
be determined.
NOTE Blood is convenient to sample and thus is often the fluid of choice for kinetic parameter and absorption
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. Analyte recovery from the
matrix shall be documented.
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4.7 There should be sufficient data points with adequate time intervals to allow determination of
kinetic parameters. ln 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; consider utilizing the same
species used for the systemic tox studies. The animal welfare conditions should be as recommended in
guidelines for the care and use of animals (see ISO 10993-2).
5.1.2 A non-radiolabelled test substance may be utilized provided suitable validated assay procedures
for the test substance in the relevant samples exist and the metabolism of the test substance is well
characterized.
5.1.3 If necessary, the test substance should be radiolabelled in a metabolically stable position,
preferably with Text 14C or Text 3H, and of suitable radiochemical purity (> 97 %). When using Text 3H,
the possibility of tritium exchange should be considered. The specific activity and radiochemical purity
of the test substance shall be known.
5.1.4 The test substance should be administered by an appropriate route. This route should be
relevant to the use of the medical device. The test substance should be prepared in a suitable vehicle
taking into account the physicochemical properties of the test substance (leachable or degradation
product) using appropriate route and dose of administration. The stability of the test substance in the
vehicle shall be known and reported.
NOTE The study design might require the inclusion of other route(s) for comparison of percent absorption.
5.1.5 In dose balance studies, animals should be housed only in metabolism cages.
5.1.6 Urine and faeces should be collected in low temperature vessels (or in vessels containing
preservative that does not interfere with the analysis) to prevent post-elimination microbial or
spontaneous modification. Blood for whole-blood or plasma analysis should be collected in the presence
of a suitable anticoagulant.
5.1.7 Controls should, wherever possible, be collected prior to dosing. In some studies collection
of controls (e.g. tissues) is not possible from the test animals and these should be obtained from a
control group.
5.1.8 Collection times should be appropriate to the type of study being performed, and may be carried
out, as necessary, over periods of minutes, hours, days, weeks or even months. For studies involving
excreta, this is usually 24 h periods over at least 96 h. Where blood sampling is required, blood is
collected according to a specified schedule ranging from minutes to hours over a period up to 72 h.
5.1.9 Toxicokinetic studies should be performed in accordance with good laboratory practice.
5.1.10 The study report shall include the following information, where relevant:
a) strain and source of animals, age, sex, environmental conditions, diet;
b) test substance and sample, purity, stability, formulation, amount administered;
c) test conditions, including route of administration;
d) assay methods, extraction, detection, validation/qualification;
e) overall recovery of material;
f) tabulation of individual results at each time point;
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g) quality standard or good laboratory practice compliance statement;
h) presentation and discussion of results;
i) interpretation of results.
5.2 Guidance on specific types of test
5.2.1 General
5.2.1.1 The study should be designed to provide the necessary information for risk assessment, and
therefore it is usually not necessary to examine all aspects.
5.2.1.2 Absorption, distribution, metabolism and excretion studies are a range of studies capable of
being performed either individually, examining one of these aspects, or collectively, examining several
aspects in one study.
5.2.1.3 Depending on the design of the study, a number of kinetic parameters may be determined
including absorption rate, area under the plasma concentration versus time curve, area under the first
moment plasma concentration versus time curve, volume of distribution, c , t , half-life, mean
max max
residence time, elimination rate and clearance.
5.2.1.4 Kinetic parameters can only be determined for a particular molecular species and hence
the assay needs to be specific and sensitive to this molecular species. True kinetic parameters of a
relevant compound can only be determined following intravenous administration. It may therefore be
necessary to include a limited intravenous administration study in the design of the kinetic parameter
studies. This allows the fraction of the dose absorbed to be calculated and this serves as a correction in
estimating parameters in other studies.
5.2.1.5 The appropriate kinetic model should be used in determining the kinetic parameters. A number
of computer programs exist for estimating kinetic parameters. The software should be validated prior
to use and this validation should be documented. The assumptions entered into the program and the
choices in modelling should be documented.
5.2.2 Absorption
Absorption depends on the route of administration, the physicochemical form of the test substance and
the vehicle. lt can be estimated from blood, serum, excreta and tissue concentrations. Bioavailability
studies may be considered. The choice of the appropriate type of study depends on the other information
required, availability of radiolabelled material and assay method. The absorption rate constant can be
estimated reliably only if sufficient samples are taken in the absorption phase.
NOTE In vitro methods exist which can give important information on gastrointestinal and dermal
absorption of chemicals.
5.2.3 Distribution
5.2.3.1 Distribution studies generally require radiolabelled compounds.
Studies may be
— quantitative, determining levels in dissected tissues;
— qualitative, using whole-body autoradiography (WBA);
— semiquantitative, using graded WBA reference doses.
5.2.3.2 In general, sampling times in distribution studies may be based on kinetic data and will depend
on test sample elimination. Multiple sampling times may be used. Sampling is normally more frequent
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in the early phase of absorption and elimination; however. samples need to be obtained over as much of
the elimination phase as possible. The major determinant is often assay sensitivity.
5.2.4 Metabolism and excretion
5.2.4.1 Metabolism cages should permit a separate collection of urine and faeces throughout the study.
For studies of up to 14 d, the urine and faeces should be individually collected over 24 hour intervals
until the end of the experiment. In some study designs, animals may be sacrificed at intermediate times.
Samples may be collected prior to 24 h when it is probable that the test substance or its metabolites
will be rapidly excreted. For studies of longer duration, sampling over the initial period should occur
as for the short-term studies. Thereafter samples should be obtained for a continuous 24 h period per
assessment period.
NOTE 1 The use of metabolism cages for prolonged periods might be detrimental to animal welfare. Therefore
at the longer times, representative discontinuous samples can be collected and these results extrapolated to
continuous sampling.
NOTE 2 The use of metabolic cages designed for the collection of CO and volatile metabolites should be
2
considered.
5.2.4.2 The carcasses and/or target organs of the individual animals should be retained for analysis,
and blood collected for analysis of plasma and whole-blood concentrations. After collection of the
samples from the metabolism cages at the sacrifice time, the cages and their traps should be washed
with an appropriate solvent. The resulting washes can be pooled and a representative fraction retained
for analysis.
5.2.4.3 The recovery or calculated recovery of a test substance should ideally be (100 ± 10) % when
a radiolabelled compound is used (see NOTE). The amount of test substance in each fraction should
be analysed by suitably validated procedures for either a radiolabelled or non-radiolabelled compound
in the appropriate milieu. Where a radiolabelled compound is used, both parent compound and
metabolites are assessed unless a specific assay is used.
NOTE The recovery range specified might not be achievable in all cases, and reasons for any deviation
should be stated and discussed in the report.
5.2.4.4 Levels of radioactivity in the biological milieu should be determined, for example by liquid
scintillation counting; however it must be stressed that this represents a mixed concentration of
compound and metabolites, and no kinetic parameters can be derived from it. Where isolation of
metabolites is considered necessary, this may involve a number of extractions and chromatographic
procedures (e.g. high-pressure liquid chromatography, thin layer chromatography, gas-liquid
chromatography), and the resulting material should be characterized by chemical methods and a variety
of physical chemistry techniques (e.g. mass spectrometry, nuclear magnetic resonance spectroscopy).
5.2.4.5 The use of tissues, cells, homogenates and isolated enzymes for the study of metabolism in
vitro is well documented. These methods identify potential metabolism which may not occur in vivo
unless the compound is available at the appropriate site. The extents and rates of
...
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