Ophthalmic implants -- Ocular endotamponades

This document applies to ocular endotamponades (OE), a group of non-solid surgically invasive medical devices introduced into the vitreous cavity of the eye to flatten and position a detached retina onto the retinal pigment epithelium (RPE), or to tamponade the retina. With regard to the safety and efficacy of OE, this document specifies requirements for their intended performance, design attributes, pre-clinical and clinical evaluation, sterilization, product packaging, product labelling and the information supplied by the manufacturer.

Implants ophtalmiques -- Produits de tamponnement endoculaires

Le présent document s'applique aux produits de tamponnement endoculaires, un groupe de dispositifs médicaux invasifs non solides de type chirurgical introduits dans la cavité vitréenne de l'œil pour mettre ŕ plat et repositionner une rétine décollée sur l'épithélium pigmentaire rétinien (EPR), ou pour tamponner la rétine. Tout en tenant compte de la sécurité et de l'efficacité des produits de tamponnement endoculaires, le présent document définit les exigences relatives ŕ leurs performances attendues, ŕ leurs données de conception, ŕ une évaluation préclinique et clinique, ŕ la stérilisation, au conditionnement du produit, ŕ son étiquetage et aux informations fournies par le fabricant.

General Information

Status
Published
Publication Date
25-Jun-2020
Current Stage
6000 - International Standard under publication
Start Date
26-Jun-2020
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INTERNATIONAL ISO
STANDARD 16672
Third edition
2020-06
Ophthalmic implants — Ocular
endotamponades
Implants ophtalmiques — Produits de tamponnement endoculaires
Reference number
ISO 16672:2020(E)
ISO 2020
---------------------- Page: 1 ----------------------
ISO 16672:2020(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
---------------------- Page: 2 ----------------------
ISO 16672:2020(E)
Contents Page

Foreword ........................................................................................................................................................................................................................................iv

1 Scope ................................................................................................................................................................................................................................. 1

2 Normative references ...................................................................................................................................................................................... 1

3 Terms and definitions ..................................................................................................................................................................................... 1

4 Intended performance ................................................................................................................................................................................... 3

5 Design attributes .................................................................................................................................................................................................. 3

5.1 General ........................................................................................................................................................................................................... 3

5.2 Chemical description and contaminants .......................................................................................................................... 3

5.3 Density ........................................................................................................................................................................................................... 4

5.4 Gaseous expansion .............................................................................................................................................................................. 4

5.5 Interfacial tension ................................................................................................................................................................................ 4

5.6 Kinematic viscosity ............................................................................................................................................................................. 4

5.7 Dynamic viscosity ................................................................................................................................................................................. 4

5.8 Molecular mass distribution ....................................................................................................................................................... 4

5.9 Particulates................................................................................................................................................................................................. 5

5.10 Refractive index ...................................................................................................................................................................................... 5

5.11 Spectral transmittance ..................................................................................................................................................................... 5

5.12 Surface tension ........................................................................................................................................................................................ 5

5.13 Vapour pressure ..................................................................................................................................................................................... 5

6 Design evaluation ................................................................................................................................................................................................ 5

6.1 General ........................................................................................................................................................................................................... 5

6.2 Evaluation of biological safety ................................................................................................................................................... 6

6.2.1 General...................................................................................................................................................................................... 6

6.2.2 Bacterial endotoxins test .......................................................................................................................................... 6

6.2.3 Intraocular implantation test ................................................................................................................................ 6

6.2.4 Ethylene oxide .................................................................................................................................................................... 6

6.3 Clinical investigation .......................................................................................................................................................................... 7

7 Sterilization ............................................................................................................................................................................................................... 7

8 Product stability ................................................................................................................................................................................................... 7

9 Integrity and performance of the delivery system ............................................................................................................ 7

10 Packaging ..................................................................................................................................................................................................................... 8

10.1 Protection from damage during storage and transport....................................................................................... 8

10.2 Maintenance of sterility in transit .......................................................................................................................................... 8

11 Information supplied by the manufacturer ............................................................................................................................. 8

Annex A (normative) Intraocular implantation test .........................................................................................................................10

Annex B (informative) Clinical investigation ............................................................................................................................................11

Annex C (informative) Method for quantifying incompletely fluorinated contaminants in

perfluorocarbon liquids ............................................................................................................................................................................14

Bibliography .............................................................................................................................................................................................................................16

© ISO 2020 – All rights reserved iii
---------------------- Page: 3 ----------------------
ISO 16672:2020(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.

This third edition cancels and replaces the second edition (ISO 16672:2015), which has been technically

revised.
The main changes compared to the previous edition are as follows:

a) the following terms and their definitions have been included: "secondary packaging", surgical

invasive medical product" and "minimum utilization pressure";

b) the subclause on chemical description and contaminants has been substantially revised;

c) the bacterial endotoxin limit has been revised from 0,5 to 0,2 Endotoxin Units per ml;

d) the total level of EO in the product has been revised: it shall not exceed 1,25 µg/dose for EO and

5,0 µg/dose for ethylene chlorohydrin (ECH);

e) minimum utilization pressure has been included in the list of information supplied by the

manufacturer;

f) B.2.2 giving the clinical variables in a clinical investigation has been revised;

g) Annex C "Method for quantifying incompletely fluorinated contaminants in perfluorocarbon

liquids" has been added.

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.
iv © ISO 2020 – All rights reserved
---------------------- Page: 4 ----------------------
INTERNATIONAL STANDARD ISO 16672:2020(E)
Ophthalmic implants — Ocular endotamponades
1 Scope

This document applies to ocular endotamponades (OE), a group of non-solid surgically invasive medical

devices introduced into the vitreous cavity of the eye to flatten and position a detached retina onto the

retinal pigment epithelium (RPE), or to tamponade the retina.

With regard to the safety and efficacy of OE, this document specifies requirements for their intended

performance, design attributes, pre-clinical and clinical evaluation, sterilization, product packaging,

product labelling and the information supplied by the manufacturer.
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 10993-6, Biological evaluation of medical devices — Part 6: Tests for local effects after implantation

ISO 11607-1, Packaging for terminally sterilized medical devices — Part 1: Requirements for materials,

sterile barrier systems and packaging systems

ISO 13408-1, Aseptic processing of health care products — Part 1: General requirements

ISO 14155, Clinical investigation of medical devices for human subjects — Good clinical practice

ISO 14630, Non-active surgical implants — General requirements
ISO 14971, Medical devices — Application of risk management to medical devices

ISO 15223-1, Medical devices — Symbols to be used with medical device labels, labelling and information to

be supplied — Part 1: General requirements
EN 1041+A1, Information supplied by the manufacturer with medical devices

OECD Guidelines for the Testing of Chemicals, Section 1: Physical-Chemical properties, Test No. 104:

Vapour Pressure
3 Terms and definitions
For the purposes of this document, the following terms and definitions 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/
© ISO 2020 – All rights reserved 1
---------------------- Page: 5 ----------------------
ISO 16672:2020(E)
3.1
delivery system

sealed container in which the product is supplied including any additional component provided to

introduce the product into the eye
3.2
dynamic viscosity
quotient of shear stress and shear velocity
Note 1 to entry: The dynamic viscosity is expressed in pascal seconds (Pa⋅s).
3.3
interfacial tension
tension against liquids
Note 1 to entry: The interfacial tension is expressed in newton per metre (N/m).
3.4
kinematic viscosity
quotient of dynamic viscosity (3.2) and gravity

Note 1 to entry: The kinematic viscosity is expressed in square metres per second (m /s).

3.5
ocular endotamponade

non-solid surgically invasive medical device (3.11) introduced into the vitreous cavity of the eye to flatten

and position a detached retina onto the retinal pigment epithelium (RPE), or to tamponade the retina

3.6
primary container
container providing mechanical and microbiological protection of the content
3.7
sterile barrier

minimum package that prevents ingress of microorganisms and allows aseptic presentation of the

product at the point of use
3.8
storage container

part of the packaging intended to protect the device during transport and storage, containing the sterile

barrier (3.7)
3.9
secondary packaging

container external to and providing protection and support for the primary container (3.6)

3.10
surface tension
tension against air
Note 1 to entry: Surface tension is expressed in newton per metre (N/m).
3.11
surgically invasive medical device

invasive device which penetrates inside the body through the surface with the aid or in the context of a

surgical operation
2 © ISO 2020 – All rights reserved
---------------------- Page: 6 ----------------------
ISO 16672:2020(E)
3.12
vapour pressure

pressure exerted by the vapour of a liquid OE when in equilibrium with the liquid OE

Note 1 to entry: Vapour pressure is expressed in pascal (Pa) at (35 ± 2) °C.
3.13
minimum utilization pressure

limiting value of the pressure below which the gas or gases mixture shall no longer be withdrawn from

the container for its intended use
4 Intended performance

The general requirements for the intended performance of non-active surgical implants specified in

ISO 14630 shall apply.

This document describes surgically invasive medical devices that are compatible with the internal

ocular environment and, through a primary mechanical action, are used to reposition and/or tamponade

a detached retina. They are used either intra-operatively and removed at the end of surgery, as in the

case of perfluorocarbon liquids, or are designed to remain in the vitreous cavity until removal at a later

date as in the case of silicone oils, or they are completely absorbed as in the case of gaseous OE.

The manufacturer shall describe and document the functional characteristics of the OE in terms of its

chemical composition and physical properties, the intended surgical applications, the conditions of

use and the maximum duration of contact with, and effects upon ocular tissues, with particular regard

to safety.

All available published standards and published scientific and clinical literature, validated test results,

clinical investigations, and pre-clinical and clinical evaluations shall be considered in determining the

intended device.
5 Design attributes
5.1 General

The general requirements for non-active surgical implants specified in ISO 14630 shall apply.

All testing requirements specified below shall be performed with finished and sterilized product, ready

for release. Any analytical methods utilized shall be validated.

NOTE Tests described herein are intended to apply when qualifying materials and not necessarily as a

routine quality assurance/control programme.
5.2 Chemical description and contaminants

The manufacturer shall provide a description of each of the components in the finished product, and

their respective quality specifications and concentrations.

If the component material is derived from biological sources, the organism from which it is obtained

shall be stated along with its source.

Whenever possible, for all polymers, the backbone, any side groups and end-groups shall be identified.

The identification of potentially hazardous chemical or biological contaminants shall be determined

by a risk analysis. For raw materials of biological origin, these impurities can include proteins, nucleic

acids, or other biological materials.

Contaminants of the finished product derived from the source materials or from the manufacturing

process, such as by-products, residual monomers, cross-linking agents, catalysts, products derived from

© ISO 2020 – All rights reserved 3
---------------------- Page: 7 ----------------------
ISO 16672:2020(E)

auto-oxidation processes or from containers transport and packaging that are potentially hazardous

either systemically or to the tissues of the eye, shall be identified and quantified, whenever possible,

and their concentration in the finished product reported. Limits for identified contaminants shall be

set, justified and documented. Testing of the biological effects of these contaminants during evaluation

of biological safety may be required if the risk analysis determines it necessary. Chemical changes

during transport and storage shall be considered. Any contaminant being identified to cause, directly

or by being the source for other contaminants, considerable harm to the patient, the user or any third

party shall be reduced to a level that the health risk associated with the contaminant is considered

acceptable.

The following list, although not exhaustive, provides some information on likely contaminants of

common endotamponade materials: Materials of biological origin may contain proteins, nucleic acids,

or other biological materials as contaminants. Perfluorocarbon liquids may contain oxygen containing

compounds and incompletely fluorinated contaminants, including HF. Specifically incompletely

fluorinated contaminants, including HF, are likely to occur and they bear a high risk for the patient

already at the ppm level. Therefore, the concentration of incompletely fluorinated contaminants,

including HF, shall be as low as possible. Different methods can be used for which the specific limits

need to be specified based on the risk analysis. In Annex C a method is described for which a level of

10 ppm has been published, to assure material safety in regard of the aforementioned impurities.

Silicone oils may contain catalysts, heavy metals, residual monomers and short chain oligomers and

polymers as a result from their synthesis.

For any liquid OE, control over synthesis of the tamponade material according to applicable standards

and monographs and analytically controlled purification procedures according to applicable standards

or monographs are minimum requirements.
5.3 Density

The density of liquid forms of OE shall be specified in kilograms per cubic metre (kg/m ).

5.4 Gaseous expansion

For gaseous forms of OE the intraocular gaseous expansion at (35 ± 2) °C and its dependence on

atmospheric pressure shall be expressed.
5.5 Interfacial tension

Where applicable, the interfacial tension against water shall be determined and expressed in newton

per metre (N/m) at (35 ± 2) °C.
5.6 Kinematic viscosity

Where applicable, the kinematic viscosity at (35 ± 2) °C shall be determined and expressed in

millimetres squared per second (mm /s).
5.7 Dynamic viscosity

For viscous or viscoelastic OE, the dynamic viscosity shall be determined at (35 ± 2) °C in the frequency

−1 −1
range between 0,01 s and 100 s and expressed in millipascal second (mPa⋅s).
5.8 Molecular mass distribution

If the OE is a polymer, the average molecular mass, the range of molecular mass distribution and the

polydispersity shall be reported.
4 © ISO 2020 – All rights reserved
---------------------- Page: 8 ----------------------
ISO 16672:2020(E)

The manufacturer shall conduct and report such additional tests as necessary to provide an adequate

description of the molecular mass distribution of the components in the finished product. Whenever

possible, standard methods shall be named and used.
5.9 Particulates

A risk assessment shall evaluate the potential for the formation of and contamination by particulates

in the product throughout the life of the product including manufacture, transport and storage under

specified conditions, and during use. The potential for associated hazards shall be described.

The manufacturer shall characterize and set limits for the types, range of sizes and levels of particles

present in the finished product. Limits according to USP <789> are deemed acceptable. Alternatively,

the manufacturer shall investigate the level of particles in the clinical study. For each type of particle

present, a limit which has been validated in a clinical study shall be set and an adequate justification for

the limit shall be documented.
5.10 Refractive index

Where applicable, the refractive index between OE and air shall be measured with a refractometer at

(35 ± 2) °C and (546 ± 10) nm or (589 ± 10) nm wavelength.
5.11 Spectral transmittance

The spectral transmittance of the OE shall be measured by transmission spectrophotometry over the

range 300 nm to 1 100 nm. Results shall be presented graphically, plotting percentage transmission

against wavelength.
5.12 Surface tension

Where applicable, the surface tension shall be determined and expressed in newton per metre (N/m) at

(35 ± 2) °C.
5.13 Vapour pressure

If the vapour pressure exceeds 100 Pa, the vapour pressure shall be determined and expressed in pascal

(Pa) at (35 ± 2) °C (OECD Test No. 104: Vapour Pressure).
6 Design evaluation
6.1 General

The OE shall be evaluated for safety by performing a risk assessment in accordance with ISO 14971. The

results of the risk assessment shall determine the tests required to evaluate the safety of the OE.

The risk assessment shall take into consideration the following:
a) the type of product and the location and duration of intraocular contact;

b) potential interactions of the OE with other materials and energy sources, e.g. laser likely to be used

in ophthalmic surgery;

c) for intraocular gases, any impurity profile changes as the gas is withdrawn from the tank.

NOTE Impurity profile changes can occur as the concentration of the chemical species changes due to

the differences in vapour pressure as the tank is depleted.

The OE shall be evaluated to demonstrate that the intended performance is achieved. The requirements

for evaluation of non-active implants specified in ISO 14630 shall apply.
© ISO 2020 – All rights reserved 5
---------------------- Page: 9 ----------------------
ISO 16672:2020(E)
6.2 Evaluation of biological safety
6.2.1 General

If the OE is of hydrophobic nature, special consideration shall be taken when performing biocompatibility

testing.

The relevant biocompatibility endpoints specified in ISO 10993-1 and identified by the risk analysis

shall be taken into account when selecting the tests to evaluate the biological safety of an OE.

NOTE 1 Based upon the typical clinical applications in the posterior segment, OE are categorized as “Implant

devices, tissue/bone”. The tests for this and other categories of devices identified in Table A.1 of ISO 10993-1:2018

are for guidance only; they do not represent maximum or minimum test requirements.

NOTE 2 To evaluate the biological safety of perfluorocarbon liquids (PFCL), their hydrophobic and volatile

nature will have to be taken in consideration. Several methods to evaluate the cytotoxicity of these particular OE

including direct contact and extractive methods are described in References [8], [9] and ISO 10993-5.

6.2.2 Bacterial endotoxins test

Where applicable, the OE shall be evaluated for the presence of bacterial endotoxins using the Limulus

Amoebocyte Lysate (LAL) test, in accordance with applicable pharmacopoeias or an equivalent

[1][2][3]

validated test procedure . Any product that exceeds a bacterial endotoxin limit of 0,2 Endotoxin

Units (EU) per ml fails the test.
6.2.3 Intraocular implantation test

Tests for intraocular irritation, inflammation, intraocular pressure (IOP) and other local effects of the

OE shall be conducted in a suitable animal model, in accordance with animal welfare requirements

specified in ISO 10993-2.

Due to vascularisation differences between the human retina and the rabbit retina an alternate suitable

animal should be considered, especially for non-aqueous substances.

The particular requirements of the intraocular implantation test are specified in Annex A.

The study design shall mirror the intended clinical use as closely as possible.

The study design should assess the intra-operative and postoperative intraocular irritation,

inflammation, and local effects of the ophthalmic surgery with comparative use of the OE under

evaluation and a control OE which is a well-documented OE of the same type as the OE under

investigation, marketed widely for at least five years for the same use.

The volume of OE used should simulate the intended use, accounting for ocular volume differences

between the human and animal models.

The post-surgical irritation, inflammation, and local effects shall be monitored and graded at intervals

appropriate to the duration of the intended use. All adverse events shall be documented.

The OE shall show intraocular irritation, inflammation and local effects results comparable to or less

than a control OE of the same intended use. If the OE induces intraocular irritation, inflammation and

local effects in excess of the control OE, these should be justified by risk benefit analysis.

6.2.4 Ethylene oxide

If ethylene oxide (EO) is used during the manufacturing of ingredients or in justified sterilization of the

packaging, the total level of EO in the product shall not exceed 1,25 µg/dose for EO and 5,0 µg/dose for

ethylene chlorohydrin (ECH).
6 © ISO 2020 – All rights reserved
---------------------- Page: 10 ----------------------
ISO 16672:2020(E)
6.3 Clinical investigation

A preclinical evaluation and risk assessment shall be performed to determine if a clinical investigation

is needed. If a clinical investigation is needed, Annex B shall be considered. In addition, the general

requirements concerning the clinical investigations of medical devices for human subjects specified in

ISO 14155 shall apply.
7 Sterilization

Wherever possible, the product shall be terminally sterilized in its final container. The requirements

for sterilization of non-active surgical implants specified in ISO 14630 shall apply and an appropriate

standard for the method of sterilization shall be applied.

Ethylene oxide shall not be used unless there is documented justification for its use.

In accordance with the relevant standards one of the following sterilization methods can be used:

— ISO 17665-1: for products, or components thereof, sterilized by moist heat;
— ISO 20857: for products, or components thereof, sterilized by dry heat;
— ISO 11137-1: for products, or components thereof, sterilized by radiation;
— ISO 11135: for products, or components thereof, sterilized by ethylene oxide.
If a
...

DRAFT INTERNATIONAL STANDARD
ISO/DIS 16672
ISO/TC 172/SC 7 Secretariat: DIN
Voting begins on: Voting terminates on:
2018-07-30 2018-10-22
Ophthalmic implants — Ocular endotamponades
Implants ophtalmiques — Produits de tamponnement endoculaires
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 16672:2018(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 2018
---------------------- Page: 1 ----------------------
ISO/DIS 16672:2018(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2018

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 2018 – All rights reserved
---------------------- Page: 2 ----------------------
ISO/DIS 16672:2018(E)
Contents Page

Foreword ........................................................................................................................................................................................................................................iv

1 Scope ................................................................................................................................................................................................................................. 1

2 Normative references ...................................................................................................................................................................................... 1

3 Terms and definitions ..................................................................................................................................................................................... 2

4 Intended performance ................................................................................................................................................................................... 3

5 Design attributes .................................................................................................................................................................................................. 3

5.1 General ........................................................................................................................................................................................................... 3

5.2 Chemical description and contaminants .......................................................................................................................... 3

5.3 Density ........................................................................................................................................................................................................... 4

5.4 Gaseous expansion .............................................................................................................................................................................. 4

5.5 Interfacial tension ................................................................................................................................................................................ 4

5.6 Kinematic viscosity ............................................................................................................................................................................. 4

5.7 Dynamic viscosity ................................................................................................................................................................................. 4

5.8 Molecular mass distribution ....................................................................................................................................................... 5

5.9 Particulates................................................................................................................................................................................................. 5

5.10 Refractive index ...................................................................................................................................................................................... 5

5.11 Spectral transmittance ..................................................................................................................................................................... 5

5.12 Surface tension ........................................................................................................................................................................................ 5

5.13 Vapour pressure ..................................................................................................................................................................................... 5

6 Design evaluation ................................................................................................................................................................................................ 5

6.1 General ........................................................................................................................................................................................................... 5

6.2 Evaluation of biological safety ................................................................................................................................................... 6

6.2.1 General...................................................................................................................................................................................... 6

6.2.2 Bacterial endotoxins test .......................................................................................................................................... 6

6.2.3 Intraocular implantation test ................................................................................................................................ 6

6.2.4 Ethylene oxide .................................................................................................................................................................... 6

6.2.5 Perfluorocarbon liquids (PFCL) cytotoxicity testing ........................................................................ 7

6.3 Clinical investigation .......................................................................................................................................................................... 7

7 Sterilization ............................................................................................................................................................................................................... 7

8 Product stability ................................................................................................................................................................................................... 7

9 Integrity and performance of the delivery system ............................................................................................................ 8

10 Packaging ..................................................................................................................................................................................................................... 8

10.1 Protection from damage during storage and transport....................................................................................... 8

10.2 Maintenance of sterility in transit .......................................................................................................................................... 8

11 Information supplied by the manufacturer ............................................................................................................................. 8

Annex A (normative) Intraocular implantation test .........................................................................................................................10

Annex B (informative) Clinical investigation ............................................................................................................................................11

Annex C (informative) Method for quantifying incompletely fluorinated contaminants in

perfluorocarbon liquids ............................................................................................................................................................................14

Annex ZA (informative) Relationship between this European Standard and the Essential

Requirements of EU Directive 93/42/EEC [OJ L 169] aimed to be covered ..........................................16

Bibliography .............................................................................................................................................................................................................................18

© ISO 2018 – All rights reserved iii
---------------------- Page: 3 ----------------------
ISO/DIS 16672:2018(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 16672:2015), which has been technically

revised.
The main changes compared to the previous edition are as follows:

a) the following terms and their definitions have been included: "secondary packaging", surgical

invasive medical product" and "minimum utilization pressure";

b) the subclause on chemical description and contaminants has been substantially revised;

c) the bacterial endotoxin limit has been revised from 0,5 to 0,2 Endotoxin Units per ml;

d) the total level of EO in the product has been revised: it shall not exceed 1,25 µg/dose for EO and

5,0 µg/dose for ethylene chlorohydrin (ECH);

e) a new subclause on "Perfluorocarbon liquids (PFCL) cytotoxicity testing" has been added;

f) minimum utilization pressure has been included in the list of information supplied by the

manufacturer;

g) subclause B.2.2 giving the clinical variables in a clinical investigation has been revised;

h) Annex C "Method for quantifying incompletely fluorinated contaminants in perfluorocarbon

liquids" has been added.
iv © ISO 2018 – All rights reserved
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DRAFT INTERNATIONAL STANDARD ISO/DIS 16672:2018(E)
Ophthalmic implants — Ocular endotamponades
1 Scope

This document applies to ocular endotamponades (OE), a group of non-solid surgically invasive medical

devices introduced into the vitreous cavity of the eye to flatten and position a detached retina onto the

retinal pigment epithelium (RPE), or to tamponade the retina.

With regard to the safety and efficacy of OE, this document specifies requirements for their intended

performance, design attributes, pre-clinical and clinical evaluation, sterilization, product packaging,

product labelling and the information supplied by the manufacturer.
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 10993-6, Biological evaluation of medical devices — Part 6: Tests for local effects after implantation

ISO 11135, Sterilization of health-care products — Ethylene oxide — Requirements for the development,

validation and routine control of a sterilization process for medical devices

ISO 11137-1+Amd.1, Sterilization of health care products — Radiation — Part 1: Requirements for

development, validation and routine control of a sterilization process for medical devices

ISO 11607-1+Amd.1, Packaging for terminally sterilized medical devices — Part 1: Requirements for

materials, sterile barrier systems and packaging systems

ISO 13408-1+Amd.1, Aseptic processing of health care products — Part 1: General requirements

ISO 14155, Clinical investigation of medical devices for human subjects — Good clinical practice

ISO 14630, Non-active surgical implants — General requirements
ISO 14971, Medical devices — Application of risk management to medical devices

ISO 15223-1, Medical devices — Symbols to be used with medical device labels, labelling and information to

be supplied — Part 1: General requirements

ISO 17665-1, Sterilization of health care products — Moist heat — Part 1: Requirements for the development,

validation and routine control of a sterilization process for medical devices

ISO 20857, Sterilization of health care products — Dry heat — Requirements for the development,

validation and routine control of a sterilization process for medical devices
EN 1041+A1, Information supplied by the manufacturer with medical devices

OECD Guidelines for the Testing of Chemicals. Section 1: Physical-Chemical properties, Test No. 104:

Vapour Pressure
© ISO 2018 – All rights reserved 1
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ISO/DIS 16672:2018(E)
3 Terms and definitions
For the purposes of this document, the following terms and definitions 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 https: //www .iso .org/obp
3.1
delivery system

sealed container in which the product is supplied including any additional component provided to

introduce the product into the eye
3.2
dynamic viscosity
quotient of shear stress and shear velocity
Note 1 to entry: The dynamic viscosity is expressed in pascal seconds (Pa⋅s).
3.3
interfacial tension
tension against liquids
Note 1 to entry: The interfacial tension is expressed in newton per metre (N/m).
3.4
kinematic viscosity
quotient of dynamic viscosity and gravity

Note 1 to entry: The kinematic viscosity is expressed in square metres per second (m /s).

3.5
ocular endotamponade

non-solid surgically invasive medical devices introduced into the vitreous cavity of the eye to flatten

and position a detached retina onto the RPE, or to tamponade the retina
3.6
primary container
container providing mechanical and microbiological protection of the content
3.7
sterile barrier system

minimum package that prevents ingress of microorganisms and allows aseptic presentation of the

product at the point of use
3.8
storage container

part of the packaging intended to protect the device during transport and storage, containing the

sterile barrier
3.9
secondary packaging

container external to and providing protection and support for the primary container

3.10
surface tension
tension against air
Note 1 to entry: Surface tension is expressed in newton per metre (N/m).
2 © ISO 2018 – All rights reserved
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ISO/DIS 16672:2018(E)
3.11
surgically invasive medical device

invasive device which penetrates inside the body through the surface the with the aid or in the context

of a surgical operation
3.12
vapour pressure

pressure exerted by the vapour of a liquid OE when in equilibrium with the liquid OE

Note 1 to entry: Vapour pressure is expressed in Pascal (Pa) at (35 ± 2) °C.
3.13
minimum utilization pressure

limiting value of the pressure below which the gas or gases mixture shall no longer be withdrawn from

the container for its intended use
4 Intended performance

The general requirements for the intended performance of non-active surgical implants specified in

ISO 14630 shall apply.

This document describes surgically invasive medical devices that are compatible with the internal

ocular environment and, through a primary mechanical action, are used to reposition and/or tamponade

a detached retina. They are used either intra-operatively and removed at the end of surgery, as in the

case of perfluorocarbon liquids, or are designed to remain in the vitreous cavity until removal at a later

date as in the case of silicone oils, or they are completely absorbed as in the case of gaseous OE.

The manufacturer shall describe and document the functional characteristics of the OE in terms of its

chemical composition and physical properties, the intended surgical applications, the conditions of

use and the maximum duration of contact with, and effects upon ocular tissues, with particular regard

to safety.

All available published standards and published scientific and clinical literature, validated test results,

clinical investigations, and pre-clinical and clinical evaluations shall be considered in determining the

intended device.
5 Design attributes
5.1 General

The general requirements for non-active surgical implants specified in ISO 14630 shall apply.

All testing requirements specified below shall be performed with finished and sterilized product, ready

for release. Any analytical methods utilized shall be validated.

NOTE Tests described herein are intended to apply when qualifying materials and not necessarily as a

routine quality assurance/control programme.
5.2 Chemical description and contaminants

The manufacturer shall provide a description of each of the components in the finished product, and

their respective quality specifications and concentrations.

If the component material is derived from biological sources, the organism from which it is obtained

shall be stated along with its source.

Whenever possible, for all polymers, the backbone, any side groups and end-groups shall be identified.

© ISO 2018 – All rights reserved 3
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ISO/DIS 16672:2018(E)

The identification of potentially hazardous chemical or biological contaminants shall be determined

by a risk analysis. For raw materials of biological origin, these impurities may include proteins, nucleic

acids, or other biological materials.

The identification of potentially hazardous chemical or biological contaminants shall be determined

by a risk analysis. Contaminants of the finished product derived from the source materials or from

the manufacturing process, such as by-products, residual monomers, cross-linking agents and

antioxidants, that are potentially hazardous either systemically or to the tissues of the eye, shall be

identified and quantified, whenever possible, and their concentration in the finished product reported.

Limits for identified contaminants shall be set and documented. Testing of the biological effects of these

contaminants during evaluation of biological safety may be required if the risk analysis determines it

necessary. Chemical changes during transport and storage shall be considered. Any contaminant being

identified to cause, directly or by being the source for other contaminants, considerable harm to the

patient, the user or any third party must be reduced to a level that the health risk associated with the

contaminant is considered acceptable.

The following list, although not exhaustive, provides some information on likely contaminants of

common endotamponade materials: Materials of biological origin may contain proteins, nucleic acids,

or other biological materials as contaminants. Perfluorocarbon liquids may contain oxygen containing

compounds and incompletely fluorinated contaminants, including HF. Specifically incompletely

fluorinated contaminants, including HF, are likely to occur and they bear a high risk for the patient

already at the ppm level. Therefore, the concentration of incompletely fluorinated contaminants,

including HF, shall not exceed 10 ppm. A suitable method is described in Annex C.

Silicone oils may contain catalysts, heavy metals, residual monomers and short chain oligomers and

polymers as a result from their synthesis.

For any liquid OE, control over synthesis of the tamponade medium according to applicable standards

and monographs and analytically controlled purification procedures according to applicable standards

or monographs are minimum requirements.
5.3 Density

The density of liquid forms of OE shall be specified in kilograms per cubic metre (kg/m ).

5.4 Gaseous expansion

For gaseous forms of OE the intraocular gaseous expansion at (35 ± 2) °C and its dependence on

atmospheric pressure shall be expressed.
5.5 Interfacial tension

Where applicable, the interfacial tension against water shall be determined and expressed in newton

per metre (N/m) at (35 ± 2) °C.
5.6 Kinematic viscosity

Where applicable, the kinematic viscosity at (35 ± 2) °C shall be determined and expressed in

millimetres squared per second (mm /s).
5.7 Dynamic viscosity

For viscous or viscoelastic OE, the dynamic viscosity shall be determined at (35 ± 2) °C in the range

between 0,01 and 100 s and expressed in mPa⋅s.
4 © ISO 2018 – All rights reserved
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ISO/DIS 16672:2018(E)
5.8 Molecular mass distribution

If the OE is a polymer, the average molecular mass, the range of molecular mass distribution and the

polydispersity shall be reported.

The manufacturer shall conduct and report such additional tests as necessary to provide an adequate

description of the molecular mass distribution of the components in the finished product. Whenever

possible, standard methods shall be named and used.
5.9 Particulates

A risk assessment shall evaluate the potential for the formation of and contamination by particulates

in the product throughout the life of the product including manufacture, transport and storage under

specified conditions, and during use. The potential for associated hazards shall be described.

The manufacturer shall characterize and set limits for the types, range of sizes and levels of particles

present in the finished product. Limits according to USP < 789> are deemed acceptable. Alternatively,

the manufacturer shall investigate the level of particles in the clinical study. For each type of particle

present, a limit which has been validated in a clinical study shall be set and an adequate justification for

the limit shall be documented.
5.10 Refractive index

Where applicable, the refractive index between OE and air shall be measured with a refractometer at

(35 ± 2) °C and (546 ± 10) nm, or (589±10) nm wavelength.
5.11 Spectral transmittance

The spectral transmittance of the OE shall be measured by transmission spectrophotometry over the

range 300 nm to 1 100 nm. Results shall be presented graphically, plotting percentage transmission

against wavelength.
5.12 Surface tension

Where applicable, the surface tension shall be determined and expressed in newton per metre (N/m) at

(35 ± 2) °C.
5.13 Vapour pressure

If the vapour pressure exceeds 100 Pa, the vapour pressure shall be determined and expressed in Pascal

(Pa) at (35 ± 2) °C (OECD Test No. 104: Vapour Pressure).
6 Design evaluation
6.1 General

The OE shall be evaluated for safety by performing a risk assessment in accordance with ISO 14971. The

results of the risk assessment shall determine the tests required to evaluate the safety of the OE.

The risk assessment shall take into consideration the following:
a) the type of product and the location and duration of intraocular contact;

b) potential interactions of the OE with other materials and energy sources, e.g. laser likely to be used

in ophthalmic surgery;

c) for intraocular gases, any impurity profile changes as the gas is withdrawn from the tank.

© ISO 2018 – All rights reserved 5
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ISO/DIS 16672:2018(E)

NOTE Impurity profile changes can occur as the concentration of the chemical species changes due to the

differences in vapour pressure as the tank is depleted.

The OE shall be evaluated to demonstrate that the intended performance is achieved. The requirements

for evaluation of non-active implants specified in ISO 14630 shall apply.
6.2 Evaluation of biological safety
6.2.1 General

The relevant biocompatibility endpoints specified in ISO 10993-1 and identified by the risk analysis

shall be taken into account when selecting the tests to evaluate the biological safety of an OE.

NOTE Based upon the typical clinical applications in the posterior segment, OE are categorized as “Implant

devices, tissue/bone/dentin”. The tests for this and other categories of devices identified in Table A.1 of

ISO 10993-1:2009 are for guidance only; they do not represent maximum or minimum test requirements.

6.2.2 Bacterial endotoxins test

Where applicable, the OE shall be evaluated for the presence of bacterial endotoxins using the Limulus

Amoebocyte Lysate (LAL) test, in accordance with applicable pharmacopoeias or an equivalent

validated test procedure. [1, 2, 3] Any product that exceeds a bacterial endotoxin limit of 0,2 Endotoxin

Units (EU) per ml fails the test.
6.2.3 Intraocular implantation test

Tests for intraocular irritation, inflammation, intraocular pressure (IOP) and other local effects of the

OE shall be conducted in a suitable animal model, in accordance with animal welfare requirements

specified in ISO 10993-2 or following any local legislation.

Due to vascularisation differences between the human retina and the rabbit retina an alternate suitable

animal should be considered, especially for non-aqueous substances.

The particular requirements of the intraocular implantation test are specified in Annex A.

The study design shall mirror the intended clinical use as closely as possible.

The study design should assess the intra-operative and postoperative intraocular irritation,

inflammation, and local effects of the ophthalmic surgery with comparative use of the OE under

evaluation and a control OE which is a well-documented OE of the same type as the OE under

investigation, marketed widely for at least five years for the same use.

The volume of OE used should simulate the intended use, accounting for ocular volume differences

between the human and animal models.

The post-surgical irritation, inflammation, and local effects shall be monitored and graded at intervals

appropriate to the duration of the intended use. All adverse events shall be documented.

The OE shall show intraocular irritation, inflammation and local effects results comparable to or less

than a control OE of the same intended use. If the OE induces intraocular irritation, inflammation and

local effects in excess of the control OE, these should be justified by risk benefit analysis.

6.2.4 Ethylene oxide

If ethylene oxide (EO) is used during the manufacturing of ingredients or in justified sterilization of the

packaging, the total level of EO in the product shall not exceed 1,25 µg/dose for EO and 5,0 µg/dose for

ethylene chlorohydrin (ECH).
6 © ISO 2018
...

NORME ISO
INTERNATIONALE 16672
Troisième édition
2020-06
Implants ophtalmiques — Produits de
tamponnement endoculaires
Ophthalmic implants — Ocular endotamponades
Numéro de référence
ISO 16672:2020(F)
ISO 2020
---------------------- Page: 1 ----------------------
ISO 16672:2020(F)
DOCUMENT PROTÉGÉ PAR COPYRIGHT
© ISO 2020

Tous droits réservés. Sauf prescription différente ou nécessité dans le contexte de sa mise en œuvre, aucune partie de cette

publication ne peut être reproduite ni utilisée sous quelque forme que ce soit et par aucun procédé, électronique ou mécanique,

y compris la photocopie, ou la diffusion sur l’internet ou sur un intranet, sans autorisation écrite préalable. Une autorisation peut

être demandée à l’ISO à l’adresse ci-après ou au comité membre de l’ISO dans le pays du demandeur.

ISO copyright office
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Web: www.iso.org
Publié en Suisse
ii © ISO 2020 – Tous droits réservés
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ISO 16672:2020(F)
Sommaire Page

Avant-propos ..............................................................................................................................................................................................................................iv

1 Domaine d'application ................................................................................................................................................................................... 1

2 Références normatives ................................................................................................................................................................................... 1

3 Termes et définitions ....................................................................................................................................................................................... 1

4 Performances prévues .................................................................................................................................................................................... 3

5 Attributs de conception ................................................................................................................................................................................. 3

5.1 Généralités .................................................................................................................................................................................................. 3

5.2 Description chimique et contaminants .............................................................................................................................. 3

5.3 Masse volumique................................................................................................................................................................................... 4

5.4 Expansion gazeuse ............................................................................................................................................................................... 4

5.5 Tension d'interface .............................................................................................................................................................................. 4

5.6 Viscosité cinématique ....................................................................................................................................................................... 5

5.7 Viscosité dynamique .......................................................................................................................................................................... 5

5.8 Distribution de la masse moléculaire .................................................................................................................................. 5

5.9 Particules ..................................................................................................................................................................................................... 5

5.10 Indice de réfraction ............................................................................................................................................................................. 5

5.11 Transmission spectrale .................................................................................................................................................................... 5

5.12 Tension superficielle .......................................................................................................................................................................... 5

5.13 Pression de vapeur .............................................................................................................................................................................. 5

6 Évaluation de la conception ...................................................................................................................................................................... 6

6.1 Généralités .................................................................................................................................................................................................. 6

6.2 Évaluation de la sécurité biologique .................................................................................................................................... 6

6.2.1 Généralités ............................................................................................................................................................................ 6

6.2.2 Essai des endotoxines bactériennes ............................................................................................................... 6

6.2.3 Essai d'implantation intraoculaire ................................................................................................................... 6

6.2.4 Oxyde d'éthylène.............................................................................................................................................................. 7

6.3 Investigation clinique ........................................................................................................................................................................ 7

7 Stérilisation................................................................................................................................................................................................................ 7

8 Stabilité du produit ............................................................................................................................................................................................ 8

9 Intégrité et performance du système d'injection ............................................................................................................... 8

10 Emballage..................................................................................................................................................................................................................... 8

10.1 Protection contre les dommages au cours du stockage et du transport ............................................... 8

10.2 Maintien de la stérilité lors du transit ................................................................................................................................ 8

11 Informations fournies par le fabricant ......................................................................................................................................... 9

Annexe A (normative) Essai d'implantation intraoculaire ........................................................................................................11

Annexe B (informative) Investigation clinique .......................................................................................................................................12

Annexe C (informative) Méthode de quantification des contaminants incomplètement

fluorés dans les perfluorocarbones liquides .......................................................................................................................16

Bibliographie ...........................................................................................................................................................................................................................18

© ISO 2020 – Tous droits réservés iii
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ISO 16672:2020(F)
Avant-propos

L'ISO (Organisation internationale de normalisation) est une fédération mondiale d'organismes

nationaux de normalisation (comités membres de l'ISO). L'élaboration des Normes internationales est

en général confiée aux comités techniques de l'ISO. Chaque comité membre intéressé par une étude

a le droit de faire partie du comité technique créé à cet effet. Les organisations internationales,

gouvernementales et non gouvernementales, en liaison avec l'ISO participent également aux travaux.

L'ISO collabore étroitement avec la Commission électrotechnique internationale (IEC) en ce qui

concerne la normalisation électrotechnique.

Les procédures utilisées pour élaborer le présent document et celles destinées à sa mise à jour sont

décrites dans les Directives ISO/IEC, Partie 1. Il convient en particulier de prendre note des différents

critères d'approbation requis pour les différents types de documents ISO. Le présent document a été

rédigé conformément aux règles de rédaction données dans les Directives ISO/IEC, Partie 2 (voir www

.iso .org/ directives).

L'attention est attirée sur le fait que certains des éléments du présent document peuvent faire l'objet de

droits de propriété intellectuelle ou de droits analogues. L'ISO ne saurait être tenue pour responsable

de ne pas avoir identifié de tels droits de propriété et averti de leur existence. Les détails concernant

les références aux droits de propriété intellectuelle ou autres droits analogues identifiés lors de

l'élaboration du document sont indiqués dans l'Introduction et/ou dans la liste des déclarations de

brevets reçues par l'ISO (voir www .iso .org/ brevets).

Les appellations commerciales éventuellement mentionnées dans le présent document sont données

pour information, par souci de commodité, à l'intention des utilisateurs et ne sauraient constituer un

engagement.

Pour une explication de la nature volontaire des normes, la signification des termes et expressions

spécifiques de l'ISO liés à l'évaluation de la conformité, ou pour toute information au sujet de l'adhésion

de l'ISO aux principes de l'Organisation mondiale du commerce (OMC) concernant les obstacles

techniques au commerce (OTC), voir le lien suivant: www .iso .org/ iso/ fr/ avant -propos.

Le présent document a été élaboré par le comité technique ISO/TC 172, Optique et photonique, sous-

comité SC 7, Optique et instruments ophtalmiques.

Cette troisième édition annule et remplace la deuxième édition (ISO 16672:2015), qui a fait l'objet d'une

révision technique.

Les principales modifications par rapport à l'édition précédente sont les suivantes:

a) inclusion des termes suivants et de leurs définitions: «emballage secondaire», «dispositif médical

invasif de type chirurgical» et «pression d'utilisation minimale»;

b) révision substantielle du paragraphe sur la description chimique et les contaminants;

c) révision de la concentration limite d'endotoxines bactériennes de 0,5 à 0,2 unité d'endotoxine par ml;

d) révision du niveau total d'OE dans le produit: il ne doit pas dépasser 1,25 µg/dose pour l'OE

et 5,0 µg/dose pour la chlorhydrine d'éthylène (CHE);

e) inclusion d'une pression d'utilisation minimale dans la liste d'informations fournie par le fabricant;

f) révision du paragraphe B.2.2 indiquant les variables cliniques dans une investigation clinique;

g) ajout de l'Annexe C «Méthode de quantification des contaminants incomplètement fluorés dans des

perfluorocarbones liquides».

Il convient que l'utilisateur adresse tout retour d'information ou toute question concernant le présent

document à l'organisme national de normalisation de son pays. Une liste exhaustive desdits organismes

se trouve à l'adresse www .iso .org/ members .html.
iv © ISO 2020 – Tous droits réservés
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NORME INTERNATIONALE ISO 16672:2020(F)
Implants ophtalmiques — Produits de tamponnement
endoculaires
1 Domaine d'application

Le présent document s'applique aux produits de tamponnement endoculaires, un groupe de dispositifs

médicaux invasifs non solides de type chirurgical introduits dans la cavité vitréenne de l'œil pour

mettre à plat et repositionner une rétine décollée sur l'épithélium pigmentaire rétinien (EPR), ou pour

tamponner la rétine.

Tout en tenant compte de la sécurité et de l'efficacité des produits de tamponnement endoculaires, le

présent document définit les exigences relatives à leurs performances attendues, à leurs données de

conception, à une évaluation préclinique et clinique, à la stérilisation, au conditionnement du produit, à

son étiquetage et aux informations fournies par le fabricant.
2 Références normatives

Les documents suivants sont cités dans le texte de sorte qu'ils constituent, pour tout ou partie de leur

contenu, des exigences du présent document. Pour les références datées, seule l'édition citée s'applique.

Pour les références non datées, la dernière édition du document de référence s'applique (y compris les

éventuels amendements).

ISO 10993-1, Évaluation biologique des dispositifs médicaux — Partie 1: Évaluation et essais au sein d'un

processus de gestion du risque

ISO 10993-2, Évaluation biologique des dispositifs médicaux — Partie 2: Exigences relatives à la protection

des animaux

ISO 10993-6, Évaluation biologique des dispositifs médicaux — Partie 6: Essais concernant les effets locaux

après implantation

ISO 11607-1, Emballages des dispositifs médicaux stérilisés au stade terminal — Partie 1: Exigences

relatives aux matériaux, aux systèmes de barrière stérile et aux systèmes d'emballage

ISO 13408-1, Traitement aseptique des produits de santé — Partie 1: Exigences générales

ISO 14155, Investigation clinique des dispositifs médicaux pour sujets humains — Bonnes pratiques cliniques

ISO 14630, Implants chirurgicaux non actifs — Exigences générales

ISO 14971, Dispositifs médicaux — Application de la gestion des risques aux dispositifs médicaux

ISO 15223-1, Dispositifs médicaux — Symboles à utiliser avec les étiquettes, l'étiquetage et les informations

à fournir relatifs aux dispositifs médicaux — Partie 1: Exigences générales
EN 1041+A1, Informations fournies par le fabricant de dispositifs médicaux

Lignes directrices de l'OCDE pour les essais de produits chimiques, Section 1: Propriétés physico-

chimiques, Essai n° 104: Pression de vapeur
3 Termes et définitions

Pour les besoins du présent document, les termes et définitions suivants s'appliquent.

© ISO 2020 – Tous droits réservés 1
---------------------- Page: 5 ----------------------
ISO 16672:2020(F)

L'ISO et l'IEC tiennent à jour des bases de données terminologiques destinées à être utilisées en

normalisation, consultables aux adresses suivantes:

— ISO Online Browsing Platform (OBP): disponible à l'adresse https:// www .iso .org/ obp

— IEC Electropedia: disponible à l'adresse http:// www .electropedia .org/
3.1
système d'injection

récipient hermétique dans lequel le produit est fourni, accompagné de tous les éléments complémentaires

nécessaires à l'introduction du produit dans l'œil
3.2
viscosité dynamique
rapport de la contrainte de cisaillement sur la vitesse de cisaillement

Note 1 à l'article: La viscosité dynamique est exprimée en pascal secondes (Pa⋅s).

3.3
tension d'interface
tension par rapport aux liquides

Note 1 à l'article: La tension d'interface est exprimée en newtons par mètre (N/m).

3.4
viscosité cinématique
rapport de la viscosité dynamique (3.2) et de la gravité

Note 1 à l'article: La viscosité cinématique est exprimée en mètres carrés par seconde (m /s).

3.5
produit de tamponnement endoculaire

dispositif médical invasif de type chirurgical (3.11) non solide introduit dans la cavité vitréenne de l'œil

pour mettre à plat et repositionner une rétine décollée sur l'épithélium pigmentaire rétinien (EPR), ou

pour tamponner la rétine
3.6
conteneur primaire
conteneur assurant la protection mécanique et microbiologique du contenu
3.7
barrière stérile

emballage minimal empêchant la pénétration des micro-organismes et permettant une présentation

aseptique du produit à son point d'utilisation
3.8
conteneur de stockage

partie de l'emballage destinée à protéger le dispositif pendant le transport et le stockage et contenant

la barrière stérile (3.7)
3.9
emballage secondaire
conteneur externe de protection contenant le conteneur primaire (3.6)
3.10
tension superficielle
tension par rapport à l'air

Note 1 à l'article: La tension superficielle est exprimée en newtons par mètre (N/m).

2 © ISO 2020 – Tous droits réservés
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ISO 16672:2020(F)
3.11
dispositif médical invasif de type chirurgical

dispositif invasif pénétrant à l'intérieur du corps par la surface à l'aide, ou dans le contexte, d'une

opération chirurgicale
3.12
pression de vapeur

pression exercée par la vapeur d'un produit de tamponnement endoculaire liquide lorsqu'elle est en

équilibre avec le produit de tamponnement endoculaire liquide

Note 1 à l'article: La pression de vapeur est exprimée en pascal (Pa) à (35 ± 2) °C.

3.13
pression d'utilisation minimale

valeur limite de la pression en-dessous de laquelle le gaz ou le mélange de gaz ne doit plus être prélevé

du conteneur pour son utilisation prévue
4 Performances prévues

Les exigences générales pour les performances prévues des implants chirurgicaux non actifs abordées

dans l'ISO 14630 doivent s'appliquer.

Le présent document décrit des dispositifs médicaux invasifs de type chirurgical qui sont compatibles

avec l'environnement oculaire et, par une action principalement mécanique, sont utilisés pour

repositionner et/ou tamponner une rétine décollée. Soit ils sont utilisés de manière peropératoire et

sont retirés à la fin de l'intervention, comme dans le cas des perfluorocarbones liquides, soit ils sont

conçus pour rester dans la cavité vitréenne jusqu'à ce qu'ils soient retirés ultérieurement comme dans

le cas des huiles de silicone, soit ils sont complètement absorbés comme dans le cas des produits de

tamponnement endoculaires gazeux.

Le fabricant doit décrire et consigner par écrit les caractéristiques fonctionnelles du produit

de tamponnement endoculaire, en termes de composition chimique et de propriétés physiques,

d'applications chirurgicales prévues, de conditions d'utilisation, et de durée maximale de contact avec

les tissus oculaires, ainsi que ses effets sur lesdits tissus, en tenant particulièrement compte de la

sécurité.

Les performances prévues doivent être déterminées en prenant en considération les normes publiées,

la littérature scientifique et clinique publiée, les résultats d'essais validés, les investigations cliniques et

les évaluations précliniques et cliniques.
5 Attributs de conception
5.1 Généralités

Les exigences générales définies dans l'ISO 14630 pour les implants chirurgicaux non actifs doivent

s'appliquer.

Toutes les exigences d'essai mentionnées ci-dessous doivent s'appliquer à des produits finis stérilisés et

prêts à être commercialisés. Toutes les méthodes analytiques utilisées doivent être validées.

NOTE Les essais décrits dans le présent document s'appliquent lors de la qualification de matériaux et pas

nécessairement comme programme d'assurance/de contrôle qualité de routine.
5.2 Description chimique et contaminants

Le fabricant doit fournir une description de chaque composant présent dans le produit fini, ainsi que

ses spécifications de qualité et ses concentrations respectives.
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ISO 16672:2020(F)

Si le matériau du composant est d'origine biologique, l'organisme à partir duquel il est obtenu doit être

cité, ainsi que son origine.

Dans la mesure du possible, pour tous les polymères, le squelette, les groupements latéraux et les

groupements terminaux doivent être identifiés.

Les contaminants chimiques ou biologiques potentiellement dangereux doivent être déterminés par

une analyse des risques. Pour les matières premières d'origine biologique, ces contaminants peuvent

comprendre notamment des protéines, des acides nucléiques ou d'autres matières biologiques.

Les contaminants du produit fini dérivés des matières premières ou du processus de fabrication,

tels que les sous-produits, les monomères résiduels, les agents de réticulation, les catalyseurs, les

produits dérivés des processus d'auto-oxydation ou du transport et de l'emballage des récipients, qui

sont potentiellement dangereux pour les tissus de l'œil, ou par voie systémique, doivent être identifiés

et quantifiés, dans la mesure du possible, et leurs concentrations dans le produit fini indiquées. Les

valeurs limites pour les contaminants identifiés doivent être définies, justifiées et documentées. Des

essais pour déterminer les effets biologiques de ces contaminants lors de l'évaluation de la sécurité

biologique peuvent s'avérer nécessaires si c'est ce que révèle l'analyse des risques. Les modifications

chimiques pendant le transport et le stockage doivent être prises en compte. Tout contaminant identifié

comme causant, directement ou en étant à l'origine d'autres contaminants, un grand danger pour le

patient, l'utilisateur ou un tiers doit être réduit à un niveau tel que le risque pour la santé associé au

contaminant est considéré acceptable.

La liste suivante, bien qu'elle ne soit pas exhaustive, fournit des informations sur les contaminants

potentiels des matériaux du produit de tamponnement endoculaire courants: les matériaux d'origine

biologique peuvent contenir des contaminants tels que: des protéines, des acides nucléiques ou d'autres

matériaux biologiques. Les perfluorocarbones liquides peuvent comprendre des composés contenant

de l'oxygène et des contaminants incomplètement fluorés, notamment le HF. Les contaminants

incomplètement fluorés, notamment le HF, risquent particulièrement d'être présents et constituent

un risque élevé pour le patient, ne serait-ce qu'au niveau ppm. Par conséquent, la concentration en

contaminants incomplètement fluorés, notamment le HF, doit être aussi faible que possible. Différentes

méthodes peuvent être utilisées pour lesquelles des limites spécifiques doivent être spécifiées sur la

base de l'analyse des risques. L'Annexe C décrit une méthode pour laquelle un niveau de 10 ppm a été

publié, afin d'assurer la sécurité du matériau en ce qui concerne les impuretés susmentionnées.

Les huiles de silicone peuvent contenir des catalyseurs, des métaux lourds, des monomères résiduels et

des oligomères et polymères à chaîne courte produits par leur synthèse.

Pour un produit de tamponnement endoculaire liquide, les exigences minimales sont un contrôle de la

synthèse du produit de tamponnement conformément aux normes et monographies applicables ainsi

qu'une purification analytiquement contrôlée conformément aux normes et monographies applicables.

5.3 Masse volumique

La masse volumique des formes liquides du produit de tamponnement endoculaire, en kilogrammes par

mètre cube (kg/m ), doit être spécifiée.
5.4 Expansion gazeuse

Pour les formes gazeuses du produit de tamponnement endoculaire, l'expansion gazeuse intraoculaire

à (35 ± 2) °C, ainsi que sa dépendance vis-à-vis de la pression atmosphérique doivent être spécifiées.

5.5 Tension d'interface

Le cas échéant, la tension d'interface en fonction de l'eau doit être déterminée et exprimée en newtons

par mètre (N/m) à (35 ± 2) °C.
4 © ISO 2020 – Tous droits réservés
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ISO 16672:2020(F)
5.6 Viscosité cinématique

Le cas échéant, la viscosité cinématique à (35 ± 2) °C doit être déterminée et exprimée en millimètres

carrés par seconde (mm /s).
5.7 Viscosité dynamique

Pour les produits de tamponnement endoculaires visqueux ou viscoélastiques, la viscosité dynamique

−1 −1

doit être déterminée à (35 ± 2) °C sur une plage de fréquences allant de 0,01 s à 100 s et exprimée en

millipascal-seconde (mPa⋅s).
5.8 Distribution de la masse moléculaire

Si le produit de tamponnement endoculaire est un polymère, la masse moléculaire moyenne, la plage de

distribution de la masse moléculaire et la polydispersité doivent être enregistrées.

Le fabricant doit effectuer et enregistrer autant d'essais supplémentaires que nécessaire afin de fournir

une description appropriée de la distribution de la masse moléculaire des composants présents dans le

produit fini. Lorsque c'est possible, des méthodes normalisées doivent être désignées et utilisées.

5.9 Particules

Une évaluation des risques doit évaluer le potentiel de formation de particules et de contamination

particulaire dans le produit tout au long de sa vie, y compris au cours de sa fabrication, son transport

et son stockage dans des conditions spécifiées, et au cours de son utilisation. Les dangers potentiels

associés doivent être décrits.

Le fabricant doit caractériser et établir des limites pour les types, gammes de tailles et niveaux de

particules présentes dans le produit fini. Des limites conformes à l'USP <789> sont jugées acceptables.

En variante, le fabricant doit étudier le niveau de particules au cours de l'étude clinique. Pour chaque

type de particule présente, une limite, validée au cours d'une étude clinique, doit être établie et une

justification adaptée à cette limite doit être consignée par écrit.
5.10 Indice de réfraction

Le cas échéant, l'indice de réfraction entre le produit de tamponnement endoculaire et l'air doit

être mesuré à l'aide d'un réfractomètre à (35 ± 2) °C et à une longueur d'onde de (546 ± 10) nm

ou (589 ± 10) nm.
5.11 Transmission spectrale

La transmission spectrale du produit de tamponnement endoculaire doit être mesurée par

spectrophotométrie de transmission sur une plage allant de 300 nm à 1 100 nm. Les résultats doivent

être présentés sous la forme d'un diagramme, en pourcentage de la transmission par rapport à la

longueur d'onde.
5.12 Tension superficielle

Le cas échéant, la tension superficielle doit être déterminée et exprimée en newtons par mètre (N/m),

à (35 ± 2) °C.
5.13 Pression de vapeur

Si la pression de vapeur dépasse 100 Pa, elle doit être déterminée et exprimée en pascal (Pa), à (35 ± 2) °C

(essai OCDE n° 104: Pression de vapeur).
© ISO 2020 – Tous droits réservés 5
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ISO 16672:2020(F)
6 Évaluation de la conception
6.1 Généralités

La sécurité du produit de tamponnement endoculaire doit être évaluée en effectuant une évaluation des

risques conformément à l'ISO 14971. Les résultats de l'évaluation des risques doivent déterminer les

essais requis pour évaluer la sécurité du produit de tamponnement endoculaire.
L'évaluation des risques doit prendre en considération les points suivants:

a) le type de produit ainsi que l'emplacement et la durée du contact intraoculaire;

b) les interactions potentielles entre le produit de tamponnement endoculaire et les autres matériaux

et sources d'énergie, par exemple le laser, susceptibles d'être utilisés en chirurgie ophtalmique;

c) pour les gaz intraoculaires, tout changement du profil d'impureté lorsque le gaz est prélevé du

réservoir.

NOTE Les variations du profil d'impureté peuvent se produire au moment où la concentration des

espèces chimiques change à cause des différences de pression de vapeur à mesure que le réservoir est vidé.

Le produit de tamponnement endoculaire doit être évalué afin de démontrer que les performances

prévues sont atteintes. Les exigences relatives à l'évaluation des implants non actifs définies

dans l'ISO 14630 doivent s'appliquer.
6.2 Évaluation de la sécurité biologique
6.2.1 Généralités

Si le produit de tamponnement endoculaire est de nature hydrophobe, les essais de biocompatibilité

doivent faire l'objet d'une attention particulière.

Les résultats de biocompatibilité appropriés spécifiés dans l'ISO 10993-1 et identifiés par l'analyse

des risques doivent être pris en compte lors de la sélection des essais destinés à évaluer la sécurité

biologique d'un produit de tamponnement endoculaire.

NOTE 1 D'après les applications cliniques courantes dans le segment postérieur de l'œil, les produits de

tamponnement endoculaires sont classés comme «dispositifs d'implantation, tissu/os». Les essais pour ce type

de dispositif et d'autres types de dispositifs, identifiés dans le Tableau A.1 de l'ISO 10993-1:2018, sont seulement

des recommandations; ils ne constituent pas les exigences d'essai maximales ou minimales.

NOTE 2 La nature hydrophobe et volatile des perfluorocarbones liquides (PFCL) devra être prise en

considération pour l'évaluation de leur sécurité biologique. Différentes méthodes permettant d'évaluer la

[8] [9]

cytotoxicité de ces produits de tamponnement endoculaires particuliers sont décrites dans les Références , et

dans l'ISO 10993-5, y compris par contact direct et au moyen de méthodes par extraction.

6.2.2 Essai des endotoxines bactériennes

Le cas échéant, la présence d'endotoxines bactériennes dans le produit de tamponnement endoculaire

doit être évaluée à l'aide d'un essai au lysat d'amébocytes de Limulus (LAL), conformément aux

[1][2][3]

pharmacopées applicables ou à un mode opératoire d'essai équivalent et validé . Tout produit

dont l
...

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