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EUROPEAN STANDARD EN ISO 10993-
NORME EUROPÉENNE 18:2020/A1

EUROPÄISCHE NORM
July 2023
ICS 11.100.20
English Version
Biological evaluation of medical devices - Part 18:

Chemical characterization of medical device materials
within a risk management process - Amendment 1:
Determination of the uncertainty factor (ISO 10993-
18:2020/Amd 1:2022)
Évaluation biologique des dispositifs médicaux - Partie Biologische Beurteilung von Medizinprodukten - Teil
18: Caractérisation chimique des matériaux des 18: Chemische Charakterisierung von Werkstoffen für
dispositifs médicaux au sein d'un processus de gestion Medizinprodukte im Rahmen eines
du risque - Amendement 1: Détermination du Risikomanagementsystems - Änderung 1: Bestimmung
coefficient d'incertitude (ISO 10993-18:2020/Amd des Unsicherheitsfaktors (ISO 10993-18:2020/Amd
1:2022) 1:2022)
This amendment A1 modifies the European Standard EN ISO 10993-18:2020; it was approved by CEN on 30 April 2022.
CEN members are bound to comply with the CEN/CENELEC Internal Regulations which stipulate the conditions for inclusion of
this amendment into the relevant 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 amendment 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, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway,
Poland, Portugal, Republic of North Macedonia, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Türkiye 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
© 2023 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 10993-18:2020/A1:2023 E
worldwide for CEN national Members.
Este documento ha sido adquirido por: UNIVERSIDAD INTERNACIONAL DE LA RIOJA a través de la suscripción AENORmás. Para uso en red interna se requiere de
autorización previa de AENOR.
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EN ISO 10993-18:2020/A1:2023 (E)
Contents Page
European foreword....................................................................................................................................................... 3
Annex ZA (informative) Relationship between this European Standard the General Safety
and Performance Requirements of Regulation (EU) 2017/745 aimed to be covered ........... 4
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EN ISO 10993-18:2020/A1:2023 (E)
European foreword
This document (EN ISO 10993-18:2020/A1:2023) has been prepared by Technical Committee ISO/TC
194 "Biological and clinical evaluation of medical devices" in collaboration with Technical Committee
CEN/TC 206 “Biological and clinical evaluation of medical devices” the secretariat of which is held by
DIN.
This Amendment to the European Standard EN ISO 10993-18:2020 shall be given the status of a
national standard, either by publication of an identical text or by endorsement, at the latest by January
2024, and conflicting national standards shall be withdrawn at the latest by January 2024.
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 has been prepared under a Standardization Request given to CEN by the European
Commission and the European Free Trade Association, and supports essential requirements of EU
Directive(s) / Regulation(s).
For the relationship with EU Directive(s) / Regulation(s), see informative Annex ZA, which is an integral
part of this document.
Any feedback and questions on this document should be directed to the users’ national standards
body/national committee. A complete listing of these bodies can be found on the CEN website.
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, France, Germany, Greece, Hungary, Iceland,
Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Republic of
North Macedonia, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Türkiye and the
United Kingdom.
Endorsement notice
The text of ISO 10993-18:2020/Amd 1:2022 has been approved by CEN as EN ISO 10993-
18:2020/A1:2023 without any modification.
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EN ISO 10993-18:2020/A1:2023 (E)
Annex ZA
(informative)
Relationship between this European Standard the General Safety and

Performance Requirements of Regulation (EU) 2017/745 aimed to be
covered
This European standard has been prepared under a Commission’s standardization request M/575 to
provide one voluntary means of conforming to the General Safety and Performance Requirements of
Regulation (EU) 2017/745 of 5 April 2017 concerning medical devices [OJ L 117] and to system or
process requirements including those relating to quality management systems, risk management, post-
market surveillance systems, clinical investigations, clinical evaluation or post-market clinical follow-
up.
Once this standard is cited in the Official Journal of the European Union under that Regulation,
compliance with the normative clauses of this standard given in Table ZA.1 and application of the
edition of the normatively referenced standards as given in Table ZA.2 confers, within the limits of the
scope of this standard, a presumption of conformity with the corresponding General Safety and
Performance Requirements of that Regulation, and associated EFTA Regulations.
Where a definition in this standard differs from a definition of the same term set out in Regulation (EU)
2017/745, the differences shall be indicated in the Annex Z. For the purpose of using this standard in
support of the requirements set out in Regulation (EU) 2017/745, the definitions set out in this
Regulation prevail.
Where the European standard is an adoption of an International Standard, the scope of this document
can differ from the scope of the European Regulation that it supports. As the scope of the applicable
regulatory requirements differ from nation to nation and region to region the standard can only
support European regulatory requirements to the extent of the scope of the European Regulation for
medical devices ((EU) 2017/745).
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 Regulation (EU) 2017/745. This means that risks have to be
‘reduced as far as possible’, ‘reduced to the lowest possible level’, ‘reduced as far as possible and appropriate’,
‘removed or reduced as far as possible’, ‘eliminated or reduced as far as possible’, ’removed or minimized as far as
possible’, or ‘minimized’, according to the wording of the corresponding General Safety and Performance
Requirement.
NOTE 2 The manufacturer’s policy for determining acceptable risk must be in compliance with General Safety
and Performance Requirements 1, 2, 3, 4, 5, 8, 9, 10, 11, 14, 16, 17, 18, 19, 20, 21 and 22 of the Regulation.
NOTE 3 When a General Safety and Performance Requirement does not appear in Table ZA.1, it means that it is
not addressed by this European Standard.
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EN ISO 10993-18:2020/A1:2023 (E)
Table ZA.1 — Correspondence between this European Standard and Annex I of

Regulation (EU) 2017/745 [OJ L 117] and to system or process requirements including those relating
to quality management systems, risk management, post-market surveillance systems, clinical
investigations, clinical evaluation or post-market clinical follow-up
General Safety and

Performance Clause(s) / sub-
Requirements of clause(s) Remarks / Notes
Regulation (EU) of this EN
2017/745
10.1 a), b) and h) 5 and 6 This standard provides requirements and
recommendations for the chemical
characterization of medical devices as part of a
risk management process, including a qualitative
characterization of the chemicals and materials
used, a quantitative characterization of the
amounts of chemicals and materials used and an
evaluation of chemical release (leachable and
extractable profile) in both the design and
manufacturing processes. This chemical
characterization can be used to define or confirm
chemical specifications [10.1 h)] and evaluate the
risk of toxicity [10.1 a) and b)] and
biocompatibility [10.1 b)]. Flammability [10.1 a)]
is not covered.
For 10.1 b), ADME (absorption, distribution,

metabolism, and excretion) is not covered. .
For 10.1 h), physical specifications are not

covered.
10.2 5 and 6 This standard provides requirements and
recommendations for the chemical
risk management process, including an evaluation
of the release of contaminants and residues
(composition, leachable and extractable profile)
in both the design and manufacturing processes.
Packaging is not covered. Aspects of
contaminants and residues during transport and
storage are not covered.
10.4.1 (First paragraph, 5 and 6 This standard provides requirements and
first sentence) recommendations for the chemical
risk management process, including an evaluation
of chemical substances that may be released from
the medical device (composition, leachable and
extractable profile) in both the design and
manufacturing processes.
Particles and wear debris are not covered.
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EN ISO 10993-18:2020/A1:2023 (E)
Table ZA.2 — Applicable Standards to confer presumption of conformity as described in this

Annex ZA
Column 1 Column 2 Column 3 Column 4

Reference in International Title Corresponding European
Clause 2 Standard Edition Standard Edition
ISO 10993-1 ISO 10993-1:2018 Biological evaluation of medical EN ISO 10993-1:2020
devices — Part 1: Evaluation and
testing within a risk management
process
ISO 10993-17 ISO 10993-17:2002 Biological evaluation of medical EN ISO 10993-17:2009
devices — Part 17: Establishment of
allowable limits for leachable
substances
ISO 14971 ISO 14971:2019 Medical devices — Application of EN ISO 14971:2019
risk management to medical EN ISO 14971:2019 +
devices A11:2021
The documents listed in the Column 1 of table ZA.2, in whole or in part, are normatively referenced in
this document, i.e. are indispensable for its application. The achievement of the presumption of
conformity is subject to the application of the edition of Standards as listed in Column 4 or, if no
European Standard Edition exists, the International Standard Edition given in Column 2 of table ZA.2.
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 product(s) falling within the scope of
this standard.
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INTERNATIONAL ISO
STANDARD 10993-18
Second edition
2020-01
AMENDMENT 1
2022-05
Biological evaluation of medical

devices —
Part 18:
Chemical characterization of medical
device materials within a risk
management process
AMENDMENT 1: Determination of the
uncertainty factor
Évaluation biologique des dispositifs médicaux —
Partie 18: Caractérisation chimique des matériaux des dispositifs
médicaux au sein d'un processus de gestion du risque
AMENDEMENT 1: Détermination du coefficient d'incertitude
Reference number
ISO 10993-18:2020/Amd.1:2022(E)
© ISO 2022
18/02/2024
ISO 10993-18:2020/Amd.1:2022(E)
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© ISO 2022
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Email: copyright@iso.org
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Published in Switzerland
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18/02/2024
ISO 10993-18:2020/Amd.1:2022(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 of 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
www.iso.org/iso/foreword.html.
This document was prepared by Technical Committee ISO/TC 194, Biological and clinical evaluation of
medical devices, in collaboration with the European Committee for Standardization (CEN) Technical
Committee CEN/TC 206, Biocompatibility of medical and dental materials and devices, in accordance
with the Agreement on technical cooperation between ISO and CEN (Vienna Agreement).
A list of all parts in the ISO 10993 series can be found on the ISO website.
Any feedback or questions on this document should be directed to the user’s national standards body. A
complete listing of these bodies can be found at www.iso.org/members.html.
© ISO 2022 – All rights reserved iii

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ISO 10993-18:2020/Amd.1:2022(E)
Biological evaluation of medical devices —

Part 18:
Chemical characterization of medical device materials
within a risk management process
AMENDMENT 1: Determination of the uncertainty factor
5.6, paragraph below Figure 3

In the last sentence of the paragraph below Figure 3, replace "Table 3" by "Table 4".
6.2, Table 3
In the column “Qualitative” for the example method “Gravimetric”, insert “—”.
6.3, Table 4
In the columns “Qualitative” and “Quantitative” for the example methods “HPLC, with UV, CAD, ELSD
and/or MS*” insert “X” in both columns.
Clause D.1, last paragraph

Replace the "where" list for Formula (D.1) with:
ΦA is the mole fraction of solvent A;
PA is the polarity of solvent A;
ΦB is the mole fraction of solvent B;
PB is the polarity of solvent B.
Table D.2, footnote a

Replace the text of footnote a with the following:
a Abbreviations include:
ABS poly(acrylonitrile-butadiene-styrene);
ACN acetonitrile;
EA ethyl acetate;
DCM dichloromethane;
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ISO 10993-18:2020/Amd.1:2022(E)
DMF dimethylformamide;
HFIP hexafluoroisopropanol;
PET poly(ethylene terephthalate);
TCB trichlorobenzene;
THF tetrahydrofuran;
MeOH methanol;
EtOH ethanol;
iPrOH isopropyl alcohol.
Table D.2
In the column “Anti-solvents” for “Polymer” Polystyrene and Styrenics (ABS), replace “can” by “ACN”.
Clause E.3
Replace Clause E.3 with the following:
Quantification in extractables profiling is accomplished by various means which differ with respect to
the accuracy of the estimated and reported concentration, where the accuracy can vary significantly
depending on the quantification means employed. For example, quantification can involve the use
of a surrogate standard to normalize the responses obtained for all relevant analytes. In such an
approach, one estimates the concentration of each analyte based on the simplifying assumption that
all analytes respond similarly, among themselves and with respect to the surrogate standard (i.e. all
substances have the same response factor). Depending on the validity of this simplifying assumption,
the concentration estimates thus obtained can have widely differing uncertainties and degrees of
accuracy. If the simplifying assumption is true and response factors are constant, then the resulting
concentration estimates for all analytes is highly accurate. If the simplifying assumption is false and
the response factors vary widely, then the resulting concentration estimates for the analytes will have
widely varying accuracies and the accuracy of the concentration estimate for each analyte will vary
in proportion to the difference between the analyte’s response factor and the surrogate standard’s
response factor.
Other quantitation means can produce highly accurate concentration estimates. For example, if
quantification is achieved via the use of calibration curves generated via the analysis of authentic
standards employed in qualified analytical methods, the concentration estimates obtained for the
qualified analytes will be highly accurate. As noted above, if response factors are constant, then
quantitation with a surrogate standard will also be highly accurate.
Other quantification strategies can produce concentration estimates whose accuracy is somewhere
between these two extremes; greater accuracy than use of a surrogate standard’s response factor but
lesser accuracy than use of a calibration curve generated with an authentic reference standard. For
example, relative response factors can be obtained for extractables, where the relative response factor
is the ratio of the response of the extractable versus that of a surrogate standard at equal concentrations
of extractable and surrogate standard. Use of relative response factors in quantification accounts and
adjusts for differences in response factors, extractable versus surrogate standard.
Recognizing that response factors for extractables and surrogate standards can vary, the AET is
adjusted to account for more poorly responding analytes. Such an adjustment increases the likelihood
that even a poorly responding analyte can be recognized as being above the AET when it is present
in a sample at levels greater than or equal to the AET. The adjustment is accomplished by adding an
2 © ISO 2022 – All rights reserved

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ISO 10993-18:2020/Amd.1:2022(E)
uncertainty factor (UF) to the calculation of the AET to account for response factor variation. Use of a
UF is the same principle as calculation of a final AET from an estimated AET (e.g. see Reference [45]).
In essence, use of the UF adjusts the AET down to a lower value, ensuring that poorly responding
compounds are properly flagged as being at or above the AET and therefore being reportable.
In cases where the response factor variation is known to be acceptably low, a UF value of 1 can be
justified. Examples of these cases are methods with comparable response factors between expected
extractables and applied surrogate standards, qualified methods for targeted extractables and use
of a poorly responding compound as a surrogate standard. Otherwise, the value of the uncertainty
factor is based on an assessment of the analytical methodology to which the AET is applied. For
example, a UF value of 2 has been proposed[39],[45] as being appropriate, in certain situations, to the
screening of extracts for organic extractables via GC-FID or GC-MS, as analytical FID or MS response
factors for extractables are somewhat consistent, extractable to extractable. Alternatively, the UF for
other analytical methods used for extractables screening, such as HPLC-MS, can be higher, given the
frequently wide variation in response factors among extractables by this methodology. At the current
time, there is no available general guidance which recommends a specific value for the UF for these
methods; however, the user should justify the UF values selected.
One approach to establishing and justifying a particular UF is statistical analysis of a database of
response factors specific to the analytical method being considered and the population of extractables
for which that method is applicable. In this approach, the value of the UF is linked to the relative
standard deviation of the response factors according to Formula (E.2):
1
UF = (E.2)
(1 − RSD )
where RSD is the relative standard deviation of the response factors from the reference database.
Formula (E.2) presumes a more or less normal distribution of response factors, which is not exhibited
for all chromatographic detection methods. The database of response factors used to calculate a UF
according to this formula should be described and reviewed to establish whether the resulting UF is
sufficiently conservative to properly account for low response factor analytes. In certain circumstances,
alternate means of establishing the UF can be considered and justified if adopted.
Formula (E.2) is equivalent to formulae proposed by PQRI and Jordi (see References [41] and [46]).
When the variation in responses factors is large relative to the mean response factor (e.g. standard
deviation = 0,9 X mean), the variation in response factors is so large that although a UF can be calculated,
its scientific validity becomes questionable. For example, although a UF > 10 can be calculated, the
reality of a UF as large as 10 (or larger) is that the quantification method being used is inherently
inaccurate and thus can be inappropriate for the purpose of producing the data that is the foundation
of a toxicological risk assessment. Additionally, the use of a large value for UF can produce an adjusted
AET that is so small that it cannot be achieved by the specified analytical method; that is, the method’s
limit of detection (LoD) is greater than the AET. In these cases, while it is possible to establish an
adjusted AET, it is inappropriate to do so. The AET concept should not be applied in these cases and
consideration should be given to further improvement of the method before it is used for the purpose of
quantification of the supporting toxicological risk assessment.
In cases where the standard deviation is greater than or equal to the mean (i.e. RSD ≥ 1), a UF cannot be
calculated via Formula (E.2), as the result is either infinity or a negative number. Clearly an analytical
method with this much variation in response factors is not optimal for the purpose of reporting data
that is the foundation of a toxicological risk assessment. Optimization of the method to reduce response
factor variation should be considered.
In cases where the variation in response factors among extractables cannot be established or where the
variation is established to be large, the value of UF can be so large (e.g. UF values of 10 or greater) that
the adjusted AET is so low that the AET concept has little practical value (e.g. the analytical method’s
LoD or LoQ are greater than the AET). In such cases, it is necessary that all the compounds associated
with all observed analytical responses obtained by the screening analyses be identified and quantified,
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ISO 10993-18:2020/Amd.1:2022(E)
as all the observed analytical responses can be greater than the AET. Optimization of the method to
reduce response factor variation should be considered in such cases.
It is noted that screening for extractables is typically accomplished via the use of orthogonal and
complementary analytical methods, for example, GC-MS and LC-MS. The use of multiple analytical
methods can reduce response factor variation and can be considered in the determination of the
necessary UF that is then applied to all the complementary methods. See References [56] and [57].
In any event and in all circumstances, the use of the uncertainty factor, the value of the uncertainty
factor that is used and the means by which the uncertainty factor is established should always be
justified.
Clause E.4, Example C.2, paragraph after fourth indent

Replace the paragraph with the following:
Note that 20 μg/d for 31 d means an exposure of 620 μg, 10 μg/d for 365 d which means an exposure of
3 650 μg, and 1,5 μg/d for 3 650 d which in turn means an exposure of 5 475 μg. Each of these theoretical
extreme approaches are therefore less conservative.
Bibliography
Add the following references:
[56] Jenke D., Christiaens P., Beusen J.M., Verlinde P., Baeten J., A practical derivation of the uncer-
tainty factor applied to adjust the extractables/leachables analytical evaluation threshold (AET)
for response factor variation. PDA J Pharm Sci Technol. 2021 [Online ahead of print] Available from
https://journal.pda.org/content/early/2021/11/15/pdajpst.2021.012692
[57] Jordi M.A., Rowland K., Liu W., Cao X., Zong J., Ren Y., Liang Z., Zhou X., Louis M., Lerner
K., Reducing relative response factor variation using a multidetector system forextractables
and leachables (E&L) analysis to mitigate the need for uncertainty factors. J. Pharm. Biomed.
Anal. 2020; 186:1-14 Available from https://w ww. sciencedirect.com/science/a rticle/pii/
S073170 8520304283?via%3Dihub
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EUROPEAN STANDARD EN ISO 10993-

NORME EUROPÉENNE 18:2020/A1

Biological evaluation of medical devices - Part 18:

EUROPEAN COMMITTEE FOR STANDARDIZATION

CEN-CENELEC Management Centre: Rue de la Science 23, B-1040 Brussels

Relationship between this European Standard the General Safety and

Table ZA.1 — Correspondence between this European Standard and Annex I of

General Safety and

For 10.1 b), ADME (absorption, distribution,

For 10.1 h), physical specifications are not

Table ZA.2 — Applicable Standards to confer presumption of conformity as described in this

Column 1 Column 2 Column 3 Column 4

Biological evaluation of medical

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© ISO 2022 – All rights reserved ﻿ iii

Biological evaluation of medical devices —

5.6, paragraph below Figure 3

Clause D.1, last paragraph

ΦA is the mole fraction of solvent A;

PA is the polarity of solvent A;

ΦB is the mole fraction of solvent B;

PB is the polarity of solvent B.

Table D.2, footnote a

© ISO 2022 – All rights reserved ﻿ 1

PET poly(ethylene terephthalate);

iPrOH isopropyl alcohol.

2 ﻿ © ISO 2022 – All rights reserved

© ISO 2022 – All rights reserved ﻿ 3

Clause E.4, Example C.2, paragraph after fourth indent

4 ﻿ © ISO 2022 – All rights reserved

© ISO 2022 – All rights reserved ﻿

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