SIST EN ISO 11979-5:2020
(Main)Ophthalmic implants - Intraocular lenses - Part 5: Biocompatibility (ISO 11979-5:2020)
Ophthalmic implants - Intraocular lenses - Part 5: Biocompatibility (ISO 11979-5:2020)
This document specifies particular requirements for the biocompatibility evaluation of materials for
intraocular lenses (IOLs) including the processing conditions to produce them. These requirements
include evaluation of physicochemical properties that are relevant to biocompatibility. It also gives
guidance on conducting an ocular implantation test.
Ophthalmische Implantate - Intraokularlinsen - Teil 5: Biokompatibilität (ISO 11979-5:2020)
Dieses Dokument legt die besonderen Anforderungen an die Bewertung der Biokompatibilität von Materialien für Intraokularlinsen (IOLs) sowie der bei deren Herstellung angewendeten Verfahren bzw. Bedingungen fest. Diese Anforderungen beinhalten die Bewertung der physikalisch-chemischen Eigen-schaften, die für die Biokompatibilität von Belang sind. Zudem gibt es eine Anleitung zur Durchführung einer Untersuchung zur intraokularen Implantation.
Implants ophtalmiques - Lentilles intraoculaires - Partie 5: Biocompatibilité (ISO 11979-5:2020)
Le présent document spécifie des exigences particulières relatives à l'évaluation de la biocompatibilité des matériaux des lentilles intraoculaires (LIO), y compris les conditions de traitement liées à leur fabrication. Ces exigences comprennent l'évaluation des propriétés physicochimiques relatives à la biocompatibilité. Le présent document donne également des recommandations relatives à la réalisation d'un essai d'implantation oculaire.
Očesni vsadki (implantati) - Intraokularne leče - 5. del: Biokompatibilnost (ISO 11979-5:2020)
General Information
Relations
Standards Content (Sample)
SLOVENSKI STANDARD
SIST EN ISO 11979-5:2020
01-december-2020
Nadomešča:
SIST EN ISO 11979-5:2006
Očesni vsadki (implantati) - Intraokularne leče - 5. del: Biokompatibilnost (ISO
11979-5:2020)
Ophthalmic implants - Intraocular lenses - Part 5: Biocompatibility (ISO 11979-5:2020)
Ophthalmische Implantate - Intraokularlinsen - Teil 5: Biokompatibilität (ISO 11979-
5:2020)
Implants ophtalmiques - Lentilles intraoculaires - Partie 5: Biocompatibilité (ISO 11979-
5:2020)
Ta slovenski standard je istoveten z: EN ISO 11979-5:2020
ICS:
11.040.70 Oftalmološka oprema Ophthalmic equipment
SIST EN ISO 11979-5:2020 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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SIST EN ISO 11979-5:2020
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SIST EN ISO 11979-5:2020
EN ISO 11979-5
EUROPEAN STANDARD
NORME EUROPÉENNE
October 2020
EUROPÄISCHE NORM
ICS 11.040.70 Supersedes EN ISO 11979-5:2006
English Version
Ophthalmic implants - Intraocular lenses - Part 5:
Biocompatibility (ISO 11979-5:2020)
Implants ophtalmiques - Lentilles intraoculaires - Ophthalmische Implantate - Intraokularlinsen - Teil 5:
Partie 5: Biocompatibilité (ISO 11979-5:2020) Biokompatibilität (ISO 11979-5:2020)
This European Standard was approved by CEN on 22 September 2020.
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, 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, 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
© 2020 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 11979-5:2020 E
worldwide for CEN national Members.
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SIST EN ISO 11979-5:2020
EN ISO 11979-5:2020 (E)
Contents Page
European foreword . 3
2
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SIST EN ISO 11979-5:2020
EN ISO 11979-5:2020 (E)
European foreword
This document (EN ISO 11979-5:2020) has been prepared by Technical Committee ISO/TC 172 "Optics
and photonics" in collaboration with Technical Committee CEN/TC 170 “Ophthalmic optics” 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 April 2021, and conflicting national standards shall be
withdrawn at the latest by April 2021.
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 11979-5:2006.
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, Turkey and the
United Kingdom.
Endorsement notice
The text of ISO 11979-5:2020 has been approved by CEN as EN ISO 11979-5:2020 without any
modification.
3
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SIST EN ISO 11979-5:2020
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SIST EN ISO 11979-5:2020
INTERNATIONAL ISO
STANDARD 11979-5
Third edition
2020-09
Ophthalmic implants — Intraocular
lenses —
Part 5:
Biocompatibility
Implants ophtalmiques — Lentilles intraoculaires —
Partie 5: Biocompatibilité
Reference number
ISO 11979-5:2020(E)
©
ISO 2020
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SIST EN ISO 11979-5:2020
ISO 11979-5:2020(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2020
All rights reserved. Unless otherwise specified, or required in the context of its implementation, 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
CP 401 • Ch. de Blandonnet 8
CH-1214 Vernier, Geneva
Phone: +41 22 749 01 11
Email: copyright@iso.org
Website: www.iso.org
Published in Switzerland
ii © ISO 2020 – All rights reserved
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SIST EN ISO 11979-5:2020
ISO 11979-5:2020(E)
Contents Page
Foreword .iv
Introduction .vi
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 2
4 General requirements applying to biocompatibility evaluation of intraocular lenses .2
5 Physicochemical tests. 3
5.1 General . 3
5.2 Physical/Chemical description . 4
5.3 Exhaustive extraction test . 4
5.4 Test for leachables . 4
5.5 Test for hydrolytic stability . 4
5.6 Photostability test . 5
5.7 Nd-YAG laser exposure test . 6
5.8 Evaluation of insoluble inorganics . 6
6 Biological tests . 7
6.1 General . 7
6.2 Test for cytotoxicity. 7
6.3 Tests for sensitization . 7
6.4 Tests for genotoxicity . 7
6.5 Test for local effects . 8
6.6 Ocular implantation test . 8
Annex A (normative) Exhaustive extraction test . 9
Annex B (normative) Test for leachables .13
Annex C (normative) Hydrolytic stability .15
Annex D (normative) Photostability test .18
Annex E (normative) Nd-YAG laser exposure test .20
Annex F (normative) Supplemental conditions of test for local effects after implantation .22
Annex G (normative) Ocular implantation test .23
Bibliography .27
© ISO 2020 – All rights reserved iii
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SIST EN ISO 11979-5:2020
ISO 11979-5:2020(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 172, Optics and photonics, Subcommittee
SC 7, Ophthalmic optics and instruments, in collaboration with the European Committee for
Standardization (CEN) Technical Committee CEN/TC 170, Ophthalmic optics, in accordance with the
Agreement on technical cooperation between ISO and CEN (Vienna Agreement).
This third edition cancels and replaces the second edition (ISO 11979-5:2006), which has been
technically revised.
The main changes compared to the previous edition are as follows:
— correction and addition of references throughout the document;
— added more specific guidance on risk-based approach throughout the document;
— added requirement to use state of the art analytical methods;
— update of apparatus lists where applicable;
— clarification of test material in Tables 1 and 2, reference to ISO/TR 22979 when the IOL is a
modification of a parent IOL and requirement for a biological evaluation plan added to Clause 4;
— combination and re-writing of physicochemical test methods and their objectives in Table 3 of 5.1;
— added requirement for physical/chemical description and contaminants in 5.2;
— revised order of tests in 6.1 for alignment with ISO 10993 and added subclauses for every test;
— clarification of ratio for material and extraction medium in biological tests in 6.1;
— principle and procedure of exhaustive extraction is explained in more detail (Annex A);
— in hydrolytic stability, products are their own control for spectral transmittance and dioptric power
(Annex C);
iv © ISO 2020 – All rights reserved
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SIST EN ISO 11979-5:2020
ISO 11979-5:2020(E)
— removed the allowance of representative test material for photostability testing, added the
requirement to measure lens power and image quality (Annex D);
— Annex F change from informative to normative;
— duration of subcutaneously or intramuscularly implantation increased from 4 weeks to 3 months
(Annex F);
— duration of ocular implantation test in rabbits reduced from 6 months to 3 months (Annex G).
A list of all parts in the ISO 11979 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 2020 – All rights reserved v
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SIST EN ISO 11979-5:2020
ISO 11979-5:2020(E)
Introduction
This document follows the general principles given in ISO 10993-1. ISO 10993-1 describes the principles
governing the biological evaluation of medical devices, the definitions of categories based on the nature
and duration of contact with the body, and selection of appropriate tests. Other parts of ISO 10993
present biological test methods, tests for ethylene oxide residues, tests for degradation and principles
for sample preparation.
vi © ISO 2020 – All rights reserved
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SIST EN ISO 11979-5:2020
INTERNATIONAL STANDARD ISO 11979-5:2020(E)
Ophthalmic implants — Intraocular lenses —
Part 5:
Biocompatibility
1 Scope
This document specifies particular requirements for the biocompatibility evaluation of materials for
intraocular lenses (IOLs) including the processing conditions to produce them. These requirements
include evaluation of physicochemical properties that are relevant to biocompatibility. It also gives
guidance on conducting an ocular implantation test.
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
ISO 10993-2, Biological evaluation of medical devices — Part 2: Animal welfare requirements
ISO 10993-3, Biological evaluation of medical devices — Part 3: Tests for genotoxicity, carcinogenicity and
reproductive toxicity
ISO 10993-5, Biological evaluation of medical devices — Part 5: Tests for in vitro cytotoxicity
ISO 10993-6, Biological evaluation of medical devices — Part 6: Tests for local effects after implantation
ISO 10993-10, Biological evaluation of medical devices — Part 10: Tests for irritation and skin sensitization
ISO 10993-12, Biological evaluation of medical devices — Part 12: Sample preparation and reference
materials
ISO 10993-17, Biological evaluation of medical devices — Part 17: Establishment of allowable limits for
leachable substances
ISO 11979-1, Ophthalmic implants — Intraocular lenses — Part 1: Vocabulary
ISO 11979-2, Ophthalmic implants — Intraocular lenses — Part 2: Optical properties and test methods
ISO 11979-3, Ophthalmic implants — Intraocular lenses — Part 3: Mechanical properties and test methods
ISO 14971, Medical devices — Application of risk management to medical devices
ISO 18369-4, Ophthalmic optics — Contact lenses — Part 4: Physicochemical properties of contact lens
materials
ISO/TS 21726, Biological evaluation of medical devices — Application of the threshold of toxicological
concern (TTC) for assessing biocompatibility of medical device constituents
ISO/TR 22979, Ophthalmic implants — Intraocular lenses — Guidance on assessment of the need for clinical
investigation of intraocular lens design modifications
© ISO 2020 – All rights reserved 1
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SIST EN ISO 11979-5:2020
ISO 11979-5:2020(E)
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 11979-1 apply.
ISO and IEC maintain terminological databases for use in standardization at the following addresses:
— ISO Online browsing platform: available at https:// www .iso .org/ obp
— IEC Electropedia: available at http:// www .electropedia .org/
4 General requirements applying to biocompatibility evaluation of
intraocular lenses
The evaluation of the biocompatibility of the test material shall start with an initial assessment of risk
in accordance with ISO 14971. Refer to Table 1, Table 2 and ISO 11979-1 for definition of test material
and allowance of representative samples. At a minimum, independent from the initial risk assessment
outcome, the tests described in Clause 5 shall be performed to characterize the physicochemical
properties of the intraocular lens. The evaluation of the material for biological safety shall then be
undertaken per biological evaluation plan, in accordance with the principles and requirements of
ISO 10993-1 and ISO 10993-2, taking into consideration the results from the physicochemical tests.
Furthermore, the risk assessment shall include an assessment of the potential for material changes
such as calcification. This risk assessment should consider the history of clinical use of the material,
and animal models to test the long-term stability of the material.
Carry out the biocompatibility testing in accordance with ISO 10993-1, ISO 10993-2, ISO 10993-3,
ISO 10993-5, ISO 10993-6, ISO 10993-10, ISO 10993-12, ISO 10993-17 and ISO/TS 21726 and as noted in
this document.
The pre-existing information on the material and all the information obtained in the evaluation process
shall be integrated in an overall risk benefit assessment in accordance with ISO 14971. ISO 10993-1
describes the content of such evaluation.
Refer to ISO/TR 22979 when the IOL is a modification of a parent IOL.
Table 1 — Allowance of representative samples for physicochemical tests
Test material
Test
Sterile finished Representative
a
IOL sample
Exhaustive extraction X X
Leachables X X
Hydrolytic stability X X
Photostability against UV/Vis irradiation X
Stability against Nd-YAG laser exposure X
Insoluble inorganics X
a
Sample, manufactured and processed, including intended sterilization, using a procedure
equivalent to that used for the intraocular lens, that has the same central thickness as the final
product (typically 20,0 D IOL).
2 © ISO 2020 – All rights reserved
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SIST EN ISO 11979-5:2020
ISO 11979-5:2020(E)
Table 2 — Allowance of representative samples for biological tests
Test material
Test
Sterile finished Representative
a
IOL sample
Cytotoxicity X X
Sensitization X X
Genotoxicity X X
Local effects after implantation X X
b
Ocular implantation test X
a
Sample, manufactured and processed, including intended sterilization, using a procedure
equivalent to that used for the intraocular lens, that has the same central thickness as the final
product (typically 20,0 D IOL).
b
To allow for dimensional differences between human and animal eyes, the IOL could require
scaling to fit the anatomical placement site of the animal.
5 Physicochemical tests
5.1 General
The physicochemical tests listed in Table 3 shall be performed to characterize the physicochemical
properties of the IOL and to facilitate an analysis of any risk introduced by chemical compounds which
may result from processing, treatment in use, or (simulated) ageing of the test material. The results of
the tests in Table 3 should be used as input for the risk assessment in accordance with ISO 14971.
The outcomes of the physicochemical tests should be subjected to systemic toxicologically evaluation
according to ISO 10993-17 and ISO/TS 21726.
Table 3 — Physicochemical tests and their objectives
Test Objectives
a) Exhaustive extraction To identify and quantify the total amount of extractable material that is
present in the IOL, possible residues from synthesis and additives or
impurities from manufacturing and packaging and to be used for
performing the risk assessment.
b) Leachables To identify and quantify the substances that are released from IOL
under simulated physiological conditions and to be used for determining
the risk during the clinical use.
c) Hydrolytic stability To identify and quantify possible degradation products due to
hydrolysis to determine the stability of an IOL in an aqueous
environment and to assess the risk for potentially harmful effects
due to hydrolytic degradation products.
d) Photostability against To characterize the effect of UV/Vis irradiation on the optical,
ultraviolet/visible (UV/Vis) mechanical and chemical properties of the IOL and to assess the
irradiation risk for potentially harmful effects of degradation products due to
irradiation.
e) Stability against Nd-YAG To identify the effect of Nd-YAG laser treatment on the chemical
laser exposure properties of the IOL and to assess the risk for potentially harmful
effects of degradation products due to Nd-YAG laser exposure.
f) Insoluble inorganics To quantify the levels of insoluble inorganics which may result from
manufacturing processing and packaging and to assess the risk from
insoluble inorganics.
© ISO 2020 – All rights reserved 3
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SIST EN ISO 11979-5:2020
ISO 11979-5:2020(E)
5.2 Physical/Chemical description
The manufacturer shall provide a description of each of the components in the formulation to facilitate
the interpretation of physical and chemical test results.
For description of each component the manufacturer shall provide, if available:
a) Name — Provide the chemical name and Chemical Abstracts Service (CAS) registry number;
b) Structure formula — Provide the chemical structure and molecular formula;
c) If the component material is derived from biological sources, the organism from which it is obtained
shall be stated along with its source.
For the finished polymer the manufacturer shall provide, if available:
d) Structure formula — Provide the chemical structure and molecular formula.
5.3 Exhaustive extraction test
The test material shall be tested for extractables under exhaustive extraction conditions in accordance
with the method specified in Annex A. Alternative methods can be used, provided that they have been
validated and are reflective of the current state of the art.
The following shall be observed:
a) The reasons for selecting each solvent shall be justified and documented.
b) The test material shall be weighed before and after extraction and any change in mass shall be
calculated.
c) The extraction media shall be qualitatively and quantitatively analysed at the end of extraction
for possible extractable components of the material, such as process contaminants, residual
monomers, additives, and other extractable components.
The results shall be evaluated to assess the risk for potentially harmful effects due to extractable
components.
5.4 Test for leachables
The test material shall be tested for leachables under simulated physiological conditions in accordance
with the method specified in Annex B. Alternative analytical methods can be used that are reflective of
the current state of the art in common use.
The following shall be observed:
a) The reasons for selecting each solvent shall be justified and documented.
b) The extraction media shall be qualitatively and quantitatively analysed at the end of extraction for
possible leachables of the material, such as process contaminants, residual monomers, additives,
and other leachables.
The results shall be evaluated to assess the risk for potentially harmful effects due to leachable
components.
5.5 Test for hydrolytic stability
Hydrolytic stability testing shall be conducted in accordance with the method specified in Annex C.
4 © ISO 2020 – All rights reserved
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SIST EN ISO 11979-5:2020
ISO 11979-5:2020(E)
The following shall be observed:
a) The study shall be designed to evaluate the stability of the material in an aqueous environment at
35 °C ± 2 °C for a period of at least five years or at an elevated temperature for a simulated exposure
time of at least five years.
NOTE Five years is considered sufficiently long to show changes when the product is not hydrolytically
stable and is considered appropriate since only limited test acceleration is possible.
b) The simulated exposure time is to be determined by multiplying the actual study time with the
following acceleration factor F:
(Ta-To)/10
F = 2,0
where
T is the accelerated temperature;
a
T is the temperature of the inside of the eye (35 °C).
o
c) The exposure medium shall be qualitatively and quantitatively analysed for any chemical entities
at the end of the exposure period.
d) The test material shall be examined by light microscopy at ×10 or higher and by scanning electron
microscopy (SEM) at ×500 or higher before and after testing. The test material shall be compared
with the untreated material and there shall be no significant difference in surface appearance
(e.g. bubbles, dendrites, breaks and fissures).
e) Optical transmittance spectra of the test material in the ultraviolet and visible spectral regions
(UV/Vis) shall be recorded before and after testing. By comparison of the spectra, assurance shall
be obtained that there are no significant changes in spectral transmittance.
f) The dioptric power shall be determined before and after testing if finished IOLs are used in the
testing. The refractive index shall be determined instead if a facsimile material is used. There
shall be no average absolute change in dioptric power greater than 0,25 D for a 20 D lens or a
corresponding change in refractive index comparing before testing and after exposure to the
simulated time of at least 5 years.
The results shall be evaluated to assess the risk for potentially harmful effects due to instability of the
material in an aqueous environment.
5.6 Photostability test
Photostability testing shall be conducted in accordance with Annex D.
The following shall be observed:
a) There shall be no changes in appearance of the irradiated test material when compared with non-
irradi
...
SLOVENSKI STANDARD
oSIST prEN ISO 11979-5:2019
01-september-2019
Očesni vsadki (implantati) - Intraokularne leče - 5. del: Biokompatibilnost (ISO/DIS
11979-5:2019)
Ophthalmic implants - Intraocular lenses - Part 5: Biocompatibility (ISO/DIS 11979-
5:2019)
Ophthalmische Implantate - Intraokularlinsen - Teil 5: Biokompatibilität (ISO/DIS 11979-
5:2019)
Implants ophtalmiques - Lentilles intraoculaires - Partie 5: Biocompatibilité (ISO/DIS
11979-5:2019)
Ta slovenski standard je istoveten z: prEN ISO 11979-5
ICS:
11.040.70 Oftalmološka oprema Ophthalmic equipment
oSIST prEN ISO 11979-5:2019 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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oSIST prEN ISO 11979-5:2019
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oSIST prEN ISO 11979-5:2019
DRAFT INTERNATIONAL STANDARD
ISO/DIS 11979-5
ISO/TC 172/SC 7 Secretariat: DIN
Voting begins on: Voting terminates on:
2019-05-31 2019-08-23
Ophthalmic implants — Intraocular lenses —
Part 5:
Biocompatibility
Implants ophtalmiques — Lentilles intraoculaires —
Partie 5: Biocompatibilité
ICS: 11.040.70
THIS DOCUMENT IS A DRAFT CIRCULATED
This document is circulated as received from the committee secretariat.
FOR COMMENT AND APPROVAL. IT IS
THEREFORE SUBJECT TO CHANGE AND MAY
NOT BE REFERRED TO AS AN INTERNATIONAL
STANDARD UNTIL PUBLISHED AS SUCH.
IN ADDITION TO THEIR EVALUATION AS
ISO/CEN PARALLEL PROCESSING
BEING ACCEPTABLE FOR INDUSTRIAL,
TECHNOLOGICAL, COMMERCIAL AND
USER PURPOSES, DRAFT INTERNATIONAL
STANDARDS MAY ON OCCASION HAVE TO
BE CONSIDERED IN THE LIGHT OF THEIR
POTENTIAL TO BECOME STANDARDS TO
WHICH REFERENCE MAY BE MADE IN
Reference number
NATIONAL REGULATIONS.
ISO/DIS 11979-5:2019(E)
RECIPIENTS OF THIS DRAFT ARE INVITED
TO SUBMIT, WITH THEIR COMMENTS,
NOTIFICATION OF ANY RELEVANT PATENT
RIGHTS OF WHICH THEY ARE AWARE AND TO
©
PROVIDE SUPPORTING DOCUMENTATION. ISO 2019
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oSIST prEN ISO 11979-5:2019
ISO/DIS 11979-5:2019(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2019
All rights reserved. Unless otherwise specified, or required in the context of its implementation, 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
CP 401 • Ch. de Blandonnet 8
CH-1214 Vernier, Geneva
Phone: +41 22 749 01 11
Fax: +41 22 749 09 47
Email: copyright@iso.org
Website: www.iso.org
Published in Switzerland
ii © ISO 2019 – All rights reserved
---------------------- Page: 4 ----------------------
oSIST prEN ISO 11979-5:2019
ISO/DIS 11979-5:2019(E)
Contents Page
Foreword .iv
Introduction .vi
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 2
4 General requirements applying to biocompatibility evaluation of intraocular lenses .2
5 Physicochemical tests. 3
5.1 General . 3
5.2 Physical/Chemical description . 3
5.3 Exhaustive extraction test . 4
5.4 Test for leachables . 4
5.5 Test for hydrolytic stability . 5
5.6 Photostability test . 5
5.7 Nd-YAG laser exposure test . 6
5.8 Evaluation of insoluble inorganics . 7
6 Biological tests . 7
6.1 General . 7
6.2 Tests for genotoxicity . 7
6.3 Tests for sensitization . 8
6.4 Ocular implantation test . 8
Annex A (normative) Exhaustive extraction test . 9
Annex B (normative) Test for leachables .13
Annex C (normative) Hydrolytic stability .15
Annex D (normative) Photostability test .18
Annex E (normative) Nd-YAG laser exposure test .20
Annex F (normative) Supplemental conditions of test for local effects after implantation .22
Annex G (normative) Ocular implantation test .23
Bibliography .27
© ISO 2019 – All rights reserved iii
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oSIST prEN ISO 11979-5:2019
ISO/DIS 11979-5:2019(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: www .iso .org/iso/foreword .html.
This document was prepared by Technical Committee ISO/TC 172, Optics and photonics, Subcommittee
SC 7, Ophthalmic optics and instruments.
This third edition cancels and replaces the second edition (ISO 11979-5:2006), which has been
technically revised.
The main changes compared to the previous edition are as follows:
— Correction and addition of references throughout the document
— Added more specific guidance on risk-based approach throughout the document
— Clarification of requirements throughout the document
— Added requirement to use state of the art analytical methods
— Update of apparatus lists where applicable
— Clarification of test material and parent IOLs, added the requirement for a biological evaluation plan
(Section 4)
— Combination and re-write of physicochemical test methods and objectives (Section 5.1)
— Added requirement for physical/chemical description and contaminants (Section 5.2)
— Adjustment of ratio for material and extraction medium in genotoxicity testing (Section 6.2)
— In hydrolytic stability, products are their own control for spectral transmittance and dioptric power
(Annex C)
— Removed the allowance of representative test material for photostability testing, added the
requirement to measure lens power and resolution (Annex D)
— Clarification of Nd-YAG post exposure test (Annex E.6)
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— Annex F change from informative to normative
— Duration of subcutaneously or intramuscularly implantation increased from 4 weeks to 3 months
(Annex F)
— Duration of ocular implantation test in rabbits reduced from 6 to 3 months (Annex G).
A list of all parts in the ISO 11979- series can be found on the ISO website.
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oSIST prEN ISO 11979-5:2019
ISO/DIS 11979-5:2019(E)
Introduction
This part of ISO 11979 follows the general principles given in ISO 10993-1. ISO 10993-1 describes the
principles governing the biological evaluation of medical devices, the definitions of categories based
on the nature and duration of contact with the body, and selection of appropriate tests. Other parts of
ISO 10993 present biological test methods, tests for ethylene oxide residues, tests for degradation and
principles for sample preparation.
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oSIST prEN ISO 11979-5:2019
DRAFT INTERNATIONAL STANDARD ISO/DIS 11979-5:2019(E)
Ophthalmic implants — Intraocular lenses —
Part 5:
Biocompatibility
1 Scope
This part of ISO 11979 specifies particular requirements for the biocompatibility evaluation of materials
for intraocular lenses (IOLs) including the processing conditions to produce them. These requirements
include evaluation of physicochemical properties that are relevant to biocompatibility. It also gives
guidance on conducting an ocular implantation test.
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
ISO 10993-2, Biological evaluation of medical devices — Part 2: Animal welfare requirements
ISO 10993-3, Biological evaluation of medical devices — Part 3: Tests for genotoxicity, carcinogenicity and
reproductive toxicity
ISO 10993-5, Biological evaluation of medical devices — Part 5: Tests for in vitro cytotoxicity
ISO 10993-6, Biological evaluation of medical devices — Part 6: Tests for local effects after implantation
ISO 10993-10, Biological evaluation of medical devices — Part 10: Tests for irritation and skin sensitization
ISO 10993-12, Biological evaluation of medical devices — Part 12: Sample preparation and reference
materials
ISO 10993-17, Biological evaluation of medical devices — Part 17: Establishment of allowable limits for
leachable substances
ISO 11979-1, Ophthalmic implants — Intraocular lenses — Part 1: Vocabulary
ISO 11979-2, Ophthalmic implants — Intraocular lenses — Part 2: Optical properties and test methods
ISO 11979-3, Ophthalmic implants — Intraocular lenses — Part 3: Mechanical properties and test methods
ISO 14971, Medical devices — Application of risk management to medical devices
ISO 18369-4:2006, Ophthalmic optics — Contact lenses — Part 4: Physicochemical properties of contact
lens materials
ISO/TS 21726, Biological evaluation of medical devices — Application of the threshold of toxicological
concern (TTC) for assessing biocompatibility of medical device constituents
ISO/TR 22979, Ophthalmic implants — Intraocular lenses — Guidance on assessment of the need for clinical
investigation of intraocular lens design modifications
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oSIST prEN ISO 11979-5:2019
ISO/DIS 11979-5:2019(E)
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 11979-1 apply.
ISO and IEC maintain terminological databases for use in standardization at the following addresses:
— ISO Online browsing platform: available at http: //www .iso .org/obp
— IEC Electropedia: available at http: //www .electropedia .org/
4 General requirements applying to biocompatibility evaluation of
intraocular lenses
The evaluation of the biocompatibility of the test material (refer to 11979-1 and Table 1 for definition
of test material and allowance of representative samples) shall start with an initial assessment of risk
in accordance with ISO 14971. The tests described in Clause 5 shall first be performed to characterize
the physicochemical properties of the intraocular lens. The evaluation of the material for biological
safety shall then be undertaken in accordance with the principles and requirements of ISO 10993-1
and ISO 10993-2, taking into consideration the results from the physicochemical tests. Following the
risk assessment, establish a biological evaluation plan in accordance with ISO 10993-1 addressing the
residual risk and execute the biocompatibility testing.
Furthermore, the risk assessment shall include an assessment of the potential for material changes
such as calcification. This risk assessment should consider the history of clinical use of the material,
and animal models to test the long-term stability of the material.
Carry out the biocompatibility testing in accordance with ISO 10993-1, ISO 10993-3, ISO 10993-5,
ISO 10993-6, ISO 10993-10, ISO 10993-17 and ISO/TS 21726 and as noted in this part of ISO 11979.
The pre-existing information on the material and all the information obtained in the evaluation process
shall be integrated in an overall risk benefit assessment in accordance with ISO 14971.
Refer to TR 22979 when the IOL is a modification of a parent IOL.
Table 1A — Allowance of representative samples for physicochemical tests
Test Test material
Sterile finished IOL Representative
a
Sample
Exhaustive extraction X X
Leachables X X
Hydrolytic stability X X
Photostability against UV/Vis irradiation X
Stability against Nd-YAG laser exposure X
Insoluble inorganics X
a
Sample, manufactured and processed using a procedure equivalent to that used for the
intraocular lens, that has the same central thickness as the final product (typically 20.0 D IOL).
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Table 1B — Allowance of representative samples for biological tests
Test Test material
Sterile finished Representative
a
IOL Sample
Cytotoxicity X X
Genotoxicity X X
Local effects after implantation X X
Sensitization X X
b
Ocular implantation test X
a
Sample, manufactured and processed using a procedure equivalent to that used for the
intraocular lens, that has the same central thickness as the final product (typically 20.0 D IOL).
b
To allow for dimensional differences between human and animal eyes, the IOL could require
custom design to fit the anatomical placement site of the animal.
5 Physicochemical tests
5.1 General
The physicochemical tests listed in Table 2 shall be performed to characterize the physicochemical
properties of the IOL and to facilitate an analysis of any risk introduced by chemical compounds which
may result from processing, treatment in use, or (simulated) ageing of the test material. A risk-based
approach should be used; the results of the tests in Table 2 should be used as input for a risk assessment
and further testing when deemed necessary, in accordance with ISO 14971. The risk assessment should
evaluate the potential local and systemic effects.
5.2 Physical/Chemical description
To facilitate the explaining of physical and chemical test results, the manufacturer shall provide a
description of each of the components in the formulation. For description of each component the
manufacturer shall provide, if available:
a) Name — Provide the chemical name and Chemical Abstracts Service (CAS) registry number;
b) Structure Formula — Provide the chemical structure and molecular formula;
c) If the component material is derived from biological sources, the organism from which it is obtained
shall be stated along with its source.
For the finished polymer the manufacturer shall provide, if available:
a) Structure Formula — Provide the chemical structure and molecular formula.
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Table 2 — Physicochemical tests and their objectives
Test Objectives
a) Exhaustive extraction To identify and quantify the total amount of extractable material that is
present in the IOL, possible residues from synthesis and additives or im-
purities from manufacturing and packaging and to be used for perform-
ing the risk assessment.
b) Leachables To identify and quantify the substances that are released from IOL
under simulated conditions and to be used for determining the risk
during the clinical use.
c) Hydrolytic stability To identify and quantify possible degradation products due to hydrol-
ysis to determine the stability of an IOL material in an aqueous envi-
ronment and to assess the risk for potentially harmful effects due to
hydrolytic degradation products.
d) Photostability against To characterize the effect of UV/Vis irradiation on the optical, mechan-
ultraviolet/visible (UV/Vis) ical and chemical properties of the IOL and to assess the risk for poten-
irradiation tially harmful effects of degradation products due to irradiation.
e) Stability against Nd-YAG laser To identify the effect of Nd-YAG laser treatment on the chemical prop-
exposure erties of the IOL and to assess the risk for potentially harmful effects of
degradation products due to Nd-YAG laser exposure.
f) Insoluble inorganics To quantify the levels of insoluble inorganics which may result from
manufacturing processing and packaging and to assess the risk from
insoluble inorganics.
5.3 Exhaustive extraction test
The test material shall be tested for extractables under exhaustive extraction conditions in accordance
with the method described in Annex A. Alternate methods can be used, provided that they have been
validated and are reflective of the current state of the art.
The following shall be observed:
a) The reasons for selecting each solvent shall be justified and documented.
b) The test material shall be weighed before and after extraction and any change in mass shall be
calculated.
c) The extraction media shall be qualitatively and quantitatively analysed at the end of extraction
for possible extractable components of the material, such as process contaminants, residual
monomers, additives, and other extractable components.
The results shall be evaluated to assess the risk for potentially harmful effects due to extractable
components.
All extractables shall be evaluated toxicologically according to ISO 10993-17 and ISO/TS 21726.
5.4 Test for leachables
The test material shall be tested for leachables under simulated physiological conditions in accordance
with the method described in Annex B. Alternative analytical methods can be used that are reflective of
the current state of the art in common use.
The following shall be observed:
a) The reasons for selecting each solvent shall be justified and documented.
b) The extraction media shall be qualitatively and quantitatively analysed at the end of extraction
for possible extractable components of the material, such as process contaminants, residual
monomers, additives, and other extractable components.
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The results shall be evaluated to assess the risk for potentially harmful effects due to leachable
components.
All leachables shall be evaluated toxicologically according to ISO 10993-17 and ISO/TS 21726.
5.5 Test for hydrolytic stability
Hydrolytic stability testing shall be conducted in accordance with the method described in Annex C.
The following shall be observed:
a) The study shall be designed to evaluate the stability of the material in an aqueous environment at
35 °C ± 2 °C for a period of at least five years or at an elevated temperature for a simulated exposure
time of at least five years.
NOTE Five years is considered sufficiently long to show changes when the product is not hydrolytically
stable and is considered appropriate since only limited test acceleration is possible.
b) The simulated exposure time is to be determined by multiplying the actual study time with the
following factor F:
(Ta-To)/10
F = 2,0
where
T is the accelerated temperature;
a
T is the temperature of the inside of the eye (35 °C).
o
c) The exposure medium shall be qualitatively and quantitatively analysed for any chemical entities
at the end of the exposure period.
d) The test material shall be examined by light microscopy at 10´ or higher and by scanning electron
microscopy (SEM) at 500´ or higher before and after testing. The test material shall be compared
with the untreated material and there shall be no significant difference in surface appearance (e.g.
bubbles, dendrites, breaks and fissures).
e) Optical transmittance spectra of the test material in the ultraviolet and visible spectral regions
(UV/Vis) shall be recorded before and after testing. By comparison of the spectra, assurance shall
be obtained that there are no significant changes in spectral transmittance.
f) The dioptric power shall be determined before and after testing if finished IOLs are used in the
testing. The refractive index shall be determined instead if a facsimile material is used. There
shall be no average absolute change in diopter power greater than 0,25 D for a 20 D lens or a
corresponding change in refractive index comparing before testing and after exposure to the
simulated time of at least 5 years.
The results shall be evaluated to assess the risk for potentially harmful effects due to instability of the
material in an aqueous environment.
All degradation products shall be evaluated toxicologically according to ISO 10993-17 and ISO/
TS 21726.
5.6 Photostability test
Photostability testing shall be conducted in accordance with Annex D.
The following shall be observed:
a) There shall be no changes in appearance of the irradiated test material when compared with non-
irradiated test material, such as bulk and surface defects induced by photo irradiation.
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b) No significant change shall be detected between the UV/Vis spectra, power and resolution of the
test material exposed to UV radiation and controls receiving no radiation.
c) The exposure medium shall be qualitatively and quantitatively analysed for any chemical entities
after irradiation and compared to non-irradiated controls.
d) Furthermore, when performing the testing for anterior chamber IOLs, it shall be shown that no
significant change in mechanical properties of the irradiated test material has occurred when
compared with non-irradiated test material.
The results shall be evaluated to assess the risk for potentially harmful effects due to instability of the
material from exposure to UV/Vis irradiation.
All chemical substances detected after irradiation shall be evaluated toxicologically according to
ISO 10993-17 and ISO/TS 21726.
NOTE 1 The loops of implanted anterior chamber IOLs are exposed to radiation, hence the rationale for
requiring mechanical testing after irradiation.
NOTE 2 The following parameters have been found to be relevant to in situ exposure of an IOL to UV radiation:
a) in vivo UV-A radiation intensity in the range 300 nm to 400 nm at the position of the IOL at diffuse light
2
conditions (I ): 0,3 mW/cm ;
1
2 2
The internationally accepted estimation for full intensity of sunlight is an average of 1 kW/m = 100 mW/cm in
sunny areas close to the Tropic of Cancer. The portion of near ultraviolet wavelengths in the 300 nm to 400 nm
2
range is approximately 6,5 % of the total intensity, i.e. about 6,5 mW/cm . Intraocular lenses are exposed to
sunlight which reaches behind the cornea and the aqueous humour. Within the spectrum of sunlight, that part
of the near ultraviolet radiation which is not absorbed by the cornea and the aqueous humour and which can
potentially damage IOLs by photochemical degradation, amounts to approximately 40 % to 50 % of the total
UV-A radiation. Assuming that the cornea and the aqueous humour absorb 50 % of the UV-A, the IOL is exposed to
2
an irradiation of 3,25 mW/cm in the 300 nm to 400 nm range at full intensity of sunlight. The diffuse, reflected
light intensity is estimated to be one-tenth of the above value. The irradiation of an intraocular lens in vivo is
2
therefore approximately 0,3 mW/cm .
b) daily exposure time to sunlight (t): 3 h.
c) in vivo exposure time (T ): 20 years.
1
d) intensity factor (n): 1 (i.e. maximum intensity under consideration of sunny regions).
The in vitro test period (T , in days) can be calculated using the following equation (see Reference [1]), with (I )
2 2
being the in vitro intensity of the radiation source in the 300 nm to 400 nm range:
−1
n
I 24
2
TT=×365 ×
21
It
1
2
EXAMPLE If I = 10 mW/cm , T = 27,4 d.
2 2
5.7 Nd-YAG laser exposure test
The effect of Nd-YAG laser exposure shall be evaluated in accordance with Annex E.
The exposure medium shall be qualitatively and quantitatively analysed for any chemical entities after
laser exposure.
NOTE Nd-YAG laser treatment can lead to a higher concentration of released chemicals during the laser
treatment, which can have a local effect.
The results shall be evaluated to assess the risk for potentially harmful effects, due to instability of the
material from exposure to Nd-YAG laser.
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