INTERNATIONAL ISO

STANDARD 15798

Fourth edition
2022-01

Ophthalmic implants - Ophthalmic

viscosurgical devices
Implants ophtalmiques - Dispositifs ophtalmiques viscoe/astiques

Reference number
ISO 15798:2022(E)

© ISO 2022
ISO 15798:2022(E)

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© ISO 2022
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 ISO 15798:2022(E)

Contents Page

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

1 Scope ................................................................................................................................................................................................................................. 1
2 Normative references ............................. ................................. ................................ ................................................................................. 1
3 Terms and definitions .................................................................................................................................................................................... 2
4 Intended performance............................................................................................... .
5 Design attributes ................................................................................................................................................................................................. 4
5.1 General ........................................................................................................................................................................................................... 4
5.2 Characterization ,of t he components................................................................................................................................... 4
5.3 Characterization of the finished product....................................................................................................................... 4
G) 5.3.1 General ........................................................................................................................................................................................ 4
C:
(I) 5.3.2 Absolute complex viscosity ....................................................................................................................................... 5
!a.
C 5.3.3 Chemical and biological contaminants ........................................................................................................... 5
"'~ 5.3.4 Concentration .................................. ............................ ................ S
5.3.5 Elasticity............................ .................. ............. S
5.3.6 Molecular mass d istribution .................... ............... S
5.3.7 Osmolality ............................................ .................. ............... S
5.3.8 Particulates ............................................................................................................................................................................ 6
5.3.9 pH ................................................................................................................................................................................ 6
5.3.10 Refractive index ................................................................................................................................................................. 6
5.3.11 Shear visc,o sity ..................................................................................................................................................................... 6
5.3.12 Spectral transmit tance ................................................................................................................................................. 6
5.4 Usability ........................................................................................................................................................................................................ 7
6 Design evaluation ....................... ............................... .................. ................................ .............7
6.1 Gene ral ..................................................... .................................................................................................................................................... 7
6.2 Evaluation of biological safety.......................................................................................................... ................................ 7
6.2.1 General ........................................................................................................................................................................................ 7
6.2.2 Bacterial endotoxins test ............................................................................................................................................ 8
6.2.3 Clearance of residual OVD from the anterior chamber.. .................................................................. 8
6.2.4 Degradation and toxicokinetics ............................................................................................................................ 8
6.2.5 Evaluation of inflammation and int raocular pressure .................................................................... 8
6.3 Clinical evaluation ............................................................................................................................................................................... 8
6.3.1 General ........................................................................................................................................................................................ 8
6.3.2 Clinical investigation design .................................................................................................................................... 9
6.3.3 Corneal endothelial cell density ........................................................................................................................... 9
6.3.4 Postoperative inflammation .................................................................................................................................... 9
6.3.5 Post-operative intraocular pressure change.......................................................................................... 10
6.3.6 Adverse events .................................................................................................................................................................. 10
7 Sterilization ............................................................................................................................................................................................................ 10
8 Product stability ............................................................................................................................................................................................... 11
9 Integrity and performance of the delivery system ...................................................................................................... 11
10 Packaging.................................................................................................................................................................................................................. 11
10.1 Protection from damage during storage and transport................................................................................. 11
10.2 Maintenance of sterility in transit ..................................................................................................................................... 11
11 Information to be supplied by the manufacturer ....................................................................................................... 11
Annex A (normative) Intraocular implantation test ....................................................................................................................... 13
Annex B (informative) Patient numbers for clinical investigation of intraocular pressure ................ 16
Annex C(informative) Analyses of OVD clinical data ..................................................................................................................... 17
Bibliography............................................................ ................................................................................................................................................... .......... 19

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ISO 15798:2022(E)

Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards
bodies (ISO member bodies). The work of preparing International Standards is normally carried out
through ISO technical committees. Each member body interested in a subject for which a technical
committee has been established has the right to be represented on that committee. International
organizations, governmental and non-governmental, in liaison with ISO, also take part in the work.
ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of
electrotechnical standardization.
The procedures used to develop this document and those intended for its further maintenance are
described in the ISO/IEC Directives, Part 1. In particular, the different approval criteria needed for the
different types of ISO documents should be noted. This document was drafted in accordance w ith the
editorial rules of the ISO/IEC Directives, Part 2 (see www.iso.org/directiyes).
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 jso 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 !SO'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 techn ical cooperation between ISO and CEN (Vienna Agreement).
This fourth edition cancels and replaces the third edition (ISO 15798:2013 and its Amendment,
ISO 15798:2013/Amd.l:2017), which has been technically revised.
The main changes compared to the previous edition are as follows:
a) Inclusion of applicable sections from ISO 14630 throughout the document, but removal of any
reference to that standard. It was further clarified that ophthalmic viscosurgical devices (OVD) are
no implant by their intended use but are likely to share some of the risks related to non-active
implants. Therefore, the following clauses and subclauses have been revised: Clauses 4 and .5., U
.6.2.1. Clause 7 A new subclause 5....4: has been added.
b) minor clarifications in Clause 3 (.3...3, M ) and addit ion of term surgical invasive medical device;
c) clarification in Clause 4 that a recommended removal procedure shall enable removal of the OVD as
completely as possible;
d) revised wording in 5...2 to align with defined terminology from Clause 3;
e) revised note in 5..,12: narrowed recommended measuring range;
f) revised note in 53.R: more accu rate description of the risk;
g) clarification that control OVO for the intraocular implantation test and the clinical investigation
shall be the same in both studies; therefore, the following subclauses have been revised: U .6..2....5.,
.6....3....2., and Annex A;
h) revised wording in n.U of this document to include ISO 15798:2013/Amd.1:2017 and guidance on
standard LAL-test;

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 ISO 15798:2022(E)

i) revised wording in 6 .2.3 to address the potential risk of interaction of the OVD with fluorescence or
radioisotope labelling;
j) revised 6.3 to clarify requirement of a clinical evaluation, clarification of the clinical investigation
protocol, revision of the clinical investigation design, and additional standardization for evaluation
and reporting of result from the clinical investigation;
k) inclusion of reference to ISO 10993-7 for acceptable levels of ethylene oxide and ethylene
chlorohydrin in Clause 7;
1) packaging integrity has been specifically included into the scope of product stability Clause 8; in
addition, reference to ISO 14971 has been included into this clause;

m) "Do not use if sterile barrier is breached" has been aligned with the recommended wording from
ISO 15223-1 "Do not use if package is damaged"; in addition, molecular mass distribution has been
removed from the list of information to be supplied by the manufacturer in Table 1;
n) major revision of Annex A;

o) correction of a typo in the formula for calculating the minimum number of evaluable patients per
treatment group in Annex B.
p) Addition of new informative Annex C on analyses of OVD clinical data.
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.

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I NTERNATIONAL STANDARD I SO 15798:2022(E)

Ophthalmic implants - Ophthalmic viscosurgical devices

1 Scope
This document is applicable to ophthalmic viscosurgical devices (OVDs), a class of surgical invasive
medical devices with viscous and/or viscoelastic properties, intended for use during surgery in
the anterior s egment of the human eye. OVOs are designed to create and maintain space, to protect
intraocular tissues and to manipulate tissues during surgery.
This document specifies requi rements with regard to safety for the intended performance, design
attributes, preclinical and clinical evaluation, sterilization, product packaging, product labelling and
information supplied by the manufacturer of these devices.

2 Normative references
The following documents are referred to in the text in such a way that some or all of their content
constitutes requirements of this document. For dated references, only the edition cited applies. For
undated references, the latest edition of the referenced document (including any amendments) applies.
ISO 10993-1, Biological evaluat.ion of medical devices - Part 1: Evaluation and testing within a risk
management process
ISO 10993-6, Biological evaluation of medical devices - Part 6: Tests for local effects after implantation
ISO 10993-7, Biological evaluation of medical devices - Part 7: Ethylene oxide sterilization residuals
ISO 10993-9, Biological evaluation of medical devices - Part 9: Framework for identification and
quantification of potential degradation products
ISO 10993-16, Biological evaluation of medical devices - Part 16: Toxicokinetic study design for
degradation products and leachables
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, Sterilization of health care products - Radiation - Part 1: Requirements for development,
validation and routine control of a sterilizat ion process for medical devices
ISO 11137-2, Sterilization of heal.th care products - Radiation - Part 2: Establishing the sterilization dose
ISO 11137-3, Sterilization ofhealth care products - Radiation - Part 3: Guidance on dosimetric aspects of
development, validation and routine control
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 14971, Medical devices - Application of risk management to medical devices
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 22442-1, Medical devices utilizing animal tissues and their derivatives - Part 1: Application of risk
management

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ISO 15798:2022(E)

ISO 22442-2, Medical devices utilizing animal tissues and their derivatives - Part 2: Controls on sourcing,
collection and handling
ISO 22442-3, Medical devices utilizing animal tissues and their derivatives - Part 3: Validation of the
elimination and/or inactivation of viruses and transmissible spongiform encephalopathy (TSE) agents
EN 1041, Information supplied by the manufacturer of medical devices

3 Terms and definitions

For the purposes of t his document, t he following terms and definitions apply.
ISO and !EC maintain terminological databases for use in standardization at the following add resses:
ISO Online browsing platform: available at https:j/www.iso.org/obp
IEC Electropedia: available at http://www.electropedia.org/
3.1
absolute complex viscosity
111·1=[(11')2+(77#)2 ]°'5
absolute value of complex viscosity (3.2)
Note 1 to entry: Absolute complex viscosity is expressed in pascal seconds (Pa·s).

3.2
complex viscosity
'I*= ri'- i. r,"
viscosity consisting of a viscous r,' and an elastic ry" component where i is an imaginary number defined
by i = (-l )O,S

3.3
delivery system
primary container in which the product is supplied and any additional components provided to
introduce the product into the eye
3.4
elasticity
C '= a0/r 0 -cos8
tendency of a body to return to its original shape after having been deformed
Note 1 to entry: Elasticity is quantitatively defined as stress (the force generated w ithin the body) divided by
strain (the change in dimens ions of the body) multip lied by cosine of the phase lag between stress and strain.

Note 2 to entry: Elasticity is expressed in pascal (Pa).

3.5
lost to follow-up subject
subject for which the final post-operative case report form is overdue and who cannot be contacted
despite extensive written and telephone follow-ups to determine t he final clinical outcome
Note 1 to entry: This catego ry does not include subjects who have died.

3 .6
ophthalmic viscosurgical device
OVD
generic term t hat includes a va riety of materials wit h viscous and/or viscoelastic properties, which are
designed to create a nd maintai n space, to protect int raocu lar tissues and to man ipula te tissues during
surgery in the ante rior segment of the human eye

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 ISO 15798:2022(E)

3.7
primary container
vial or syringe that contains the OVD

Note 1 to entry: This container fo rms part of the delivery system.

3.8
rheologically active component
compound or mixture of compo u nds in the finished OVD giving the product viscous and/or viscoelastic
properties

3.9
shear viscosity
tendency of a fluid to resist flow when subjected to stress

Note 1 to entry: Quantitatively, shear viscosity is the quotient of shear stress divided by shear rate in steady
shear flow.

Note 2 to entry: Shear viscosity is expressed in pascal seconds (Pa·s), traditionally in millipascal seconds (mPa·s).

Note 3 to entry: Shear rate is the velocity gradient in a flow ing fluid, expressed in s-1 (per second).

Note 4 to entry: The shear viscosity divided by the solution density gives the kinematic viscosity, which is a
measure of the viscosity of a fluid influenced by inertia (e.g. gravity).

3.10
sterile barrier
sealed packaging, containing the product and delivery system (U ), which mainta ins sterility during
transport and storage

3.11
storage container
that part of the packaging intended to protect the device during transport and storage, containing the
sterile barrier

3.12
surgical invasive medical device
invasive device which penetrates inside the body through the surface of the body with the aid or in the
context of a surgical operation

3.13
viscoelasticity
characteristics of a fluid having both viscous and elastic properties
Note 1 to entry: The viscous modulus, G", is frequently called the loss modulus and the elastic modulus, G', is
frequently called the storage modulus, both moduli are expressed in Pascal (Pa). The moduli can be combined to
show the elasticity of the OVD (see .5...3....5.).

3.14
zero shear viscosity
plateau viscosity at vanishing shear rate in a log-log plot of viscosity versus shear rate

Note 1 to entry: Zero shear viscos'ity is expressed in pascal seconds (Pa·s), t raditionally in millipascal seconds
(mPa·s), or as a logarithm of the zero shear viscosity.

4 Intended performance
OVDs are surgically invasive medical devices. They shall be compatible with the internal ocular
environment. Intended performance is primarily provided for by their viscous and/or viscoelastic
properties, which are designed to create and maintain space, to protect intraocular tissues and to
manipulate tissues during surgery in the anterior segment of the human eye. OVDs are used intra-

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 ISO 15798:2022(E)

operatively and intended to be removed at the end of surgery. The manufacturer shall describe any
performance characteristic to be provided for by the OVO. In addition, the manufacturer shall
particularly describe the intended way of application, the performance in protecting the corneal
endothelium, the intended time that the OVD resides in the anterior chamber of the eye, and the method
for removal. This method shall enable removal of the OVD as completely as possible.
In addition, the manufacturer shall describe and document the funct ional characteristics of the OVD in
terms of its:
a) chemical composition;
b) rheological properties.

5 Design attributes
G)
C:
; 5.1 General
C
"'~ The following subclauses are listing specific design attributes to be met for the intended performance.
o Tests described therein are intended to apply when qualifying materials but not necessarily apply as a
g routine quality assurance/control programme.
~ A risk assessment shall be performed in accordance with ISO 14971. OVD design attributes shall be
~
N documented. Where any of the design attributes is not considered to be relevant, the reason shall be
documented and justified.

5.2 Characterization of the components

The manufacturer s hall provide a description of the rheologically active component(s).
The manufacturer shall provide a description of each compound belonging to the rheologically active
component(s).
The raw materials used in the manufacture of the product shall be listed qualitatively, along with their
quality specifications. These shall comply wit h recognized compend ia! standards wherever possible.
If the rheologically active component or one of its compounds is derived from animal sources, the
requirements of ISO 22442-1, ISO 22442-2, and ISO 22442-3 shall apply.
If the rheologically active component is a synthetic polymer, the repeating subunits that comprise it
shall be chemically identified and the li.nkages between them described. Any cross linking shall also be
described.
The purity of water used s hall be water for injection.

5.3 Characterization of the finished product

5.3.1 General
All testing requirements described in 5.3.2 to 5.3.12 shall be performed with the finished, sterilized
product. The rheological and optical properties of OVDs are physical characteristics that determine
their performance in ophthalmic surgery. It is therefore imperative that the physical properties of OVDs
identified below are fully and accurately described. The rheological properties shall be measured under
the conditions expected and relevant at the time of use and be reported.

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 ISO 15798:2022(E)

5.3.2 Absolute complex viscosity

The logarith m of the absolute complex viscosity versus t he logarith m of the oscillation frequency
shall be graphed to simu ltaneously de monstrate the resistance to flow and deformation of the OVD
formulation. At ve ry low frequencies the absolute complex viscosity approaches t he ze ro shear viscosity.
NOTE Complex viscosity are usua lly determined at frequenc ies between (0,01 to 100) Hz (s- 1). For products
of very high viscosity (>2 x 103 Pa·s), frequencies below 0,01 Hz will be required to show the zero shear viscosity.

5.3.3 Chemical and biological contaminants

All chemical or biological contaminants shall be identified, and their potential ocular hazard shall be
determined by risk analysis. For raw materials of biological origin, these contaminants can include
proteins, nucleic acids, viruses and other transmissible agents (unclassified pathogenic entities, prions
and similar entities, or other biological materials). Contaminants derived from the sou rce materials
or from the manufactu ring process (including sterilization), e.g. cross-linking agents and antioxidants,
shall be identified whenever possible, and their concentrations in the finished product shall be reported.
Assessment of contaminants shall consider degradation characteristics of active component, including
interactions w ith laser light, ultrasou nd energy, or other high energy sources likely to be used along
w ith the OVD du ri ng sur gery, and leachables/extractables from the p ri ma r y container.
Contaminants shall be determined using standard analytical met hods, when available, and all met hods
shall be described. Limits for identified contaminants shall be set and included. Testing for the biological
effects of these contaminants d u ring evaluation of biological safety is required, if t he risk analysis
deems it necessary.
Droplets of silicone lubricant, derived from the syringe, are frequent contaminants, often misinterpreted
as air bubbles or particulates. Contamination of the p roduct from th is source should be considered in
t he risk assessment.

5.3.4 Concentration
The concentration of each rheologically active component material shall be reported as weight of
material per unit volume of solut ion. Since the testing met hodology can affect the actual concentration
reported, the standard physical or chemical techniques utilized shall be described.

5.3.5 Elasticity
The elasticity of the OVD shall be demonstrated at the same frequencies used to determine the complex
viscosity. It shall be demonstrated up to at least 100 Hz. Measurements shall be made at 25 °C ± 2 °C.
The test equipment and other conditions of measu rement shall be documented. Both the log viscous, G",
and log elastic, G', moduli shall be plotted against the log frequency. Data can also be presented as a plot
of percent elasticity against log frequency, for example as 100 x [G'/(G'+G")] versus log frequency.

5.3.6 Molecular mass distribution

If the r heologically ac tive component of t he OVD is a polymer, the mass average relative molecular mass
and the mass distribution shall be reported.
It is recognized that many OVDs contain high molecular mass polymers that are polydisperse and
that the molecular mass distribution may be complex. In these circumstances the manufacturer shall
conduct and report such additional tests as are necessary to provide an adequate description of the
molecular mass distribution of the components. Standard methods shall be used wherever possible.

5.3. 7 Osmolality
The ma nufacture r shall determi ne and document the osmolality ra nge of t he OVD. Osmolalit y of t he
fi nished product shall not be less tha n 200 mmol/kg or greater than 400 m mol/kg. Osmolality shall be
determ ined using either a vapour p ressu re or a cryoscopic osmometer u nder sta nda r d conditions.

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ISO 15798:2022(E)

5.3.8 Particulates
A risk assessment shall evaluate the potential for contamination by, or formation of, particulates in the
product during manufacture, the conditions expected during transport and storage and during u se of
the product. In particular, the potential for aggregation, polymerization and adhesion of particles to
ocular tissues s hall be taken into account.
NOTE OVDs containing synthetic polymers have shown in the past a significantly higher risk of formation
of microgels, which are difficult to identify and quantify and which resulted in significant intraocular pressure
(IOP) spikes.

The manufacturer shall identify the potential hazards associated with each type of particle identified
by the risk assessment.
The manufacturer shall characterize the types, range of sizes and levels of particulates present using a
validated method.

A limit for the overall number of particles (e.g. ~10 µm and ~25 rim) present, and a limit for each type of
particle identified by the risk analysis as a potential ocular hazard at the levels allowed by the overall
particle specification, shall be set and an adequate justification for the limits shall be documented.

5.3.9 pH

The pH of the finished product shall be measured w ith a calibrated pH meter at 25 °C ± 2 °C. The pH of
the product shall be between 6,8 and 7,6.
The pH meter should be fitted with an electrode suitable for high viscosity solutions. The pH of the
product should be close to that of the aqueous humour (pH 7,38) in order to prevent damage to the
corneal endothelial cells. In vitro studies have shown that the pH range tolerated by the endothelium
narrows as exposure time increases.

5.3.10 Refractive index

The refractive index between air and the OVD shall be measured with a refractometer at 25 °C ± 2 °C
stating at which wavelength it was determined.

5.3.11 Shear viscosity

The shear viscosity of the product as provided to the end-user shall be measured over the range of
shear rates that are likely to be encountered during routine use of the device. Measurements shall be
made at 25 °C ± 2 °C. The test results, equipment and conditions of measurement shall be documented.
NOTE The suggested shear rate range is from 0,001 s- 1 at one extreme, approximate to zero shear, when
the viscoelastic fluid is stationary, for example within the anterior chamber, to a shear rate of approximately
1 000 s· I at the other extreme, approximate to the conditions when the viscoelastic fluid is being injected into
the eye through a cannula. It is recognized that, for products of low viscosity, it is problematic to measure the
shear viscosity at very low shear rates. In such circumstances the viscosity can be measured at shear rates from
1 000 s·1 to the lowest shear rate at which the viscosity can be practically determined. For products of very high
viscosity (>2 x 103 Pa·s), shear rates below 0,001 s· l might be required to determine the zero shear viscosity.

The viscosity-shear rate relationship sh all be graphically presented on a standard plot of log v iscosity
versus log shear rate. The zero shear viscosity is determined as the steady shear plateau viscosity at
vanishing shear rate. For highly viscous formulations, measurement with a controlled stress rheometer
is preferred.

5.3.12 Spectral transmittance

The spectral transmittance shall be recorded over the range 300 nm to 1 100 nm. Results shall b e
presented graphically, plotting percent transmission against wavelength.

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 ISO 15798:2022(E)

5.4 Usability
The design of the OVD shall be suitable for its intended use.
The viscoelastic properties of the OVD shall support the surgical procedure. Possible effects of the
viscoelastic properties on the ocular environment shall be assessed in the risk assessment. The OVD
shall have the ability to be removed after surgery and a recommended technique for removal shall be
provided by the manufacturer i.n the instruction for use. The risk assessment shall consider potential
changes in the physicochemical properties of the OVD when subjected to the shear forces associated
with the various steps in the surgical procedurel6117 1.
The delivery system shall be suitable for injection of the OVD into the anterior part of the eye. Potential
impact of the manufacturing processes (including sterilization) on the performance of the delivery
system shall be assessed in the risk assessment.
If no complete delivery system is supplied, the design development shall include assessment of
additional relevant devices, such as recommended type of cannula.

Design development shall include assessment of potential effects on the OVD and its function due to
interactions w ith other materials and substances likely to be used along with the OVD during surgery.
Interactions with high energy sources likely to be used along with the OVD during surgery, such as laser
light or ultrasound energy, at the conditions likely to be used during surgery, shall not compromise
functionality of the OVD.

6 Design evaluation

6.1 General
OVDs shall be evaluated to demonstrate that the intended performance (see Clause 4) is achieved. The
extent to which the intended performance has been achieved shall be determined and documented.
Safety and intended performance shall be demonstrated by pre-clinical evaluation, clinical evaluation
and post market surveillance, including appropriate risk management at all stages of the life cycle of the
product in accordance with ISO 14971.
Design evaluation shall include use of a control OVD for the intraocular implantation test and the clinical
investigation. The control OVD shall be the same in both studies. The control shall be an OVD with
physical properties relevant for the surgical procedure and shall be approved for the same indication
as the study OVD. If available, the control OVD shall have been widely used for at least five years. The
control OVD shall not have been associated with significant material-related adverse events. A rationale
for the choice of the control OVD sha ll be given.

6.2 Evaluation of biological safety

6.2.1 General
The procedure for evaluation of biological s afety of an OVD shall commence with an assessment of
risk, carried out and documented in accordance with ISO 14971. The results of the risk analysis shall
determ ine the tests required to evaluate the biological safety of the OVD.
For OVDs containing material of animal origin, the risk analysis and management requirements
outlined in ISO 22442-1, ISO 22442-2, and ISO 22442-3 shall apply.
For all OVDs the requirements for evaluation of biological safety specified in ISO 10993-1 shall apply,
together with the following part icular requirements.
In addition to the biocompatibility tests identified in ISO 10993-1 and by the risk analysis, all of the
following tests shall be considered in the selection of tests to evaluate the biological safety of an OVD.

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ISO 15798:2022(E)

Currently a significant risk associated with OVDs is related to residual material that remains in the eye
after surgery. The severity for this risk shall be evaluated.
NOTE 1 Based upon the typical clinical applications in the anterior segment of the eye, OVDs are categorized
as "Implant devices, tissue/bone". The tests for this and other categories of device identified in ISO 10993-1:2018,
Table 1, are for guidance only; they do not represent maximum or minimum test requirements.

NOTE 2 It can be possib le to combine biocompatibility tests, thereby reducing the number of anima ls required
for testing. 1\.vo tests can be conducted simultaneously in a single anima l provided that the test animal is not
subjected to undue pain or distress.

6.2.2 Bacterial endotoxins test

The OVD shall be evaluated for the presence of bacterial endotoxins using the limulus amoebocyte
lysate (LAL) test, in accordance with applicable Pharmacopoeia (see Bibliography). Any product that
exceeds a bacterial endotoxin limit of0,2 endotoxin units (EU) per millilitre fails the test.
The standard LAL test is not designed to determine endotoxin levels in liquids w ith viscosities typical
of DVDs. The accuracy and repeatability of the method shall be validated using DVDs produced with
defined levels of endotoxins. Additional guidance is provided in References [8] to (11].

6.2.3 Clearance of residual OVD from the anterior chamber

Where no adequate literature exists, the rate at which residual product is cleared from the anterior
chamber through the trabecular meshwork shall be determined using an appropriate test method,
such as fluorescence or radioisotope labelling, and then reported. The test method shall not impact the
physicochemical characteristics of the device.

6.2.4 Degradation and toxicokinetics

Where no adequate literature exists c,o ncerning the fate of the OVD, the manufacturer shall provide
evidence of the route of elimination, biotransformation and catabolic products of the components. With
regard to degradation and toxicokinetics, the requirements of ISO 10993-9 and ISO 10993-16 shall
apply.

6.2.5 Evaluation of inflammation and intraocular pressure

A test for inflammatory and intraocular pressure responses shall be performed to compare the test
OVD with a control OVD in accordance with the procedure outlined in Annex A.

The general requirements for implantation tests outlined in ISO 10993-6 shall apply. The particular
requirements for the intraocular implantation test are outlined in Annex A.
If the test OVD causes a significantly hig her or more prolonged inflammation or intraoc ular pressure
(IOP) increase than the OVD used as control, a risk/benefit eva luation s hall be performed.
The results of the test shall be used to determine the likely magnitude and duration of the post-surgical
inflammatory reaction and pressure rise. This will influence the design of the clinical investigation and
may necessitate additional post-surgical time points for the measurement of IOP in addition to those
listed in 6.3.5.
In accordance with ISO 10993-2, animal testing should be reduced to the justifiable minimum.

6.3 Clinical evaluation

6.3.1 General
A clinical evaluation shall be performed for the OVD. If the risk assessment indicates a need for, or
if regional or national regulations req uire a clinical investigation, the following applies. The general

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 ISO 15798:2022(E)

requirements concerning clinical investigations of medical devices for human subjects specified in
ISO 14155 shall apply, together with the following particular requirements and the recommended
removal procedure.

6.3.2 Clinical investigation design

A randomized controlled clinical investigation shall be performed. The objective of the study shall be
to document the safety and performance of the new OVD when compared to a well documented control
OVD. The su rgical procedure shall be described in detail in the clin ical investigation plan (CIP) including
the type of any implant used. To validate the recommended method of removal of the new OVD, the
potential method(s) s hall be specified in the CIP. The recommended method of removal for the control
OVD consistent with its approved instructions for use shall also be specified in the CIP. Each step of the
method shall be fully described in the CIP for each arm. The method of removal shall be recorded on the
Case Report Forms (CRF). A rationale for the choice of control OVD shall be given in the CIP.
If a double blinded study comparing the new OVD and the control cannot be achieved, an independent
observer, who is unaware of which device has been used in each case, shall perform the postoperative
measurements.
A risk analysis shall determ ine the primary hypothesis, and standard biostatistical formu la s hall
be used to calcu late the required number of subjects per treatment group. The primary safety and
performance hypotheses to be tested shall be included in the CIP. A method to determine the number
of subjects is provided in Annex B. If the manufacturer wishes to make claims, e.g. regarding the intra-
operative performance of the device, specific endpoints to support those claims shall be included in the
CIP together with the appropriate power calculation.
A subject may only submit one eye in the investigation.
No investigator shall contribute less than 20 subjects or more than 25 % of the total number of subjects
in the investigation.
Investigations conducted at a single site may result in additional regulations in some countries.
Efforts shall be made to keep the number of patients lost to follow-up below 10 % of the number
enrolled.
The following variables shall be eva luated during the clin ical investigation:
a) intraocular pressure;
b) corneal endothelial cell density;
c) intraocular inflammation.
The ClP shall include a description of the analyses to be performed. Some suggested analyses are
presented in Annex C.

6.3.3 Corneal endothelial cell density

The condition of the corneal endothelium shall be assessed by measuring central corneal endothelial
cell density using specular microscopy pre-operatively and 3 months ±2 weeks postoperatively on all
s ubjects in the investigation.

6.3.4 Postoperative inflammation

Postoperative inflammation shall be evaluated by slit-lamp biomicroscopy and graded clinically at each
visit using a standard grading system, such as The Standardization of Uveitis Nomenclature (SUN)
Working group112J.

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ISO 15798:2022(E)

6.3.5 Post-operative intraocular pressure change

The intraocular pressu re shall be measured using a Gold mann type appla nation tonometer pre-
operatively and at least at the follow ing ti mes postoperatively:
a) 8 h ± 2 h;
b) 24 h ± 4 h;
c) 7 d ± 2 d;
d) 30 d ± 7 d;
e) 90d±14d.
At least fo r the first examination, the time after surgery of t he !OP measurement shall be docu mented.
If a literat ure review, animal testing, or clinical experience indicates t hat the peak !OP occurs at a time
outside the 6 h to 10 h postoperative range, t he manufacturer shall mod ify t he clinical investigational
design to measure the !OP at times closer to the predicted appearance of the peak, for both the test and
the cont ro l group.
When IOP in an individual subject is elevated at 24 h after surgery, additional IOP measurements shall
be performed until the !OP no rmalizes. The mag nitude of the IOP e levation and the frequency of the
add itional IOP measure ments shall be described in t he CIP.
The criteria and protocol for use of !OP lowering drugs or interventions shall be specified in t he CIP.
The administration, at any time, of !OP-reducing drugs, or other interventions, shall be documented
(includi ng date and time) and t he data from those subjects shall be presented separately. Steroid use
shall a lso be documented at each visit, including generic name, st rength, route of ad minist ration, dose,
frequency of administration, and date and time of last administration prior to !OP measurement. It is
suggested that known steroidresponders be excluded from enrollment.
If any subject in the investigation has a n IOP ~ 30 mm Hg at one week or later, early term ination of the
inves tigation shall be consideredl13J. This a nalysis shall be performed during the s tudy fo r all subjects
and at t he end of the st udy for each treat ment group. At the completion of t he study, analysis of the
IOP measurements at the required time points shall include calculations of t he means as well as the
frequencies ofIOP values~ 30 mmHg.

6.3.6 Adverse events

Clinical investigators shall file reports of serious intra-operative and post-operative adverse events
with the sponsor immediately after learning of their occurrence. These and a ll other adverse events
shall be documented in the case reports. Manufacturers shall take into account adverse events reports
when reviewing their risk analysis.

7 Sterilization
Wherever possible, the product shall be terminally sterilized.
For an OVD, or components thereof, steri lized using moist heat, the require ments of ISO 17665 -1 shall
apply.
For an OVD, or components thereof, sterilized by rad iation, the requirements of! SO 11137-1, ISO 11137-2
and ISO 11137-3 shall apply.
NOTE 1 It is recognized that many OVDs co nta in high molecular mass polymers that are labile and that the
rheological properties of the product can be adversely influenced by ste rilizat ion with moist heat or radiation.
When a product cannot be terminally sterilized by moist heat or radiation, asep tic processing is an accepted
alternative.

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 ISO 15798:2022(E)

For OVDs that are aseptically processed, the requirements specified in ISO 13408-1 shall apply.
For components of an OVD sterilized using ethylene oxide, the requirements of ISO 11135 shall apply.
The potential for EO derived reaction in products in the OVD shall be taken into account in the risk
analysis. Acceptable levels of residues from EO and ECH shall be established using ISO 10993-7,
subclause "Special situations", considering injection of OVD, typically 0,5 ml. Applicable methods for
determination of ethylene oxide•and ethylene chlorohydrin are provided in ISO 10993-7.
NOTE 2 The OVD itself, being an aqueous solution, cannot be sterilized by EO, but EO can diffuse into the OVD
if the packaging containing it is sterilized with EO. If so, EO will immediately react with water to form derivatives
(e.g. ethylene glycol, ethylene chlorohydrin).

8 Product stability
The manufacturer shall define and state the shelf life of the OVD and its delivery system. Real time
or validated accelerated (at temperatures not to exceed 45 °C) shelf-life testing shall be performed to
demonstrate that the essential characteristics for safe and effective performance of the finished product
and delivery system remain within product specifications over the labelled shelf life under expected
conditions of transport and storage. The parameters that shall be followed during shelf-life studies are
the rheological profile, pH, packaging integrity, and sterility, plus any other factors identified by risk
analysis following ISO 14971 as crucial for the use of the product.

9 Integrity and performance of the delivery system

An OVD is typically supplied in a sealed container, and is often accompanied by a cannula for injection
of the product into the eye. These two components comprise the delivery system. Appropriate testing
shall demonstrate that mechanical failure of the delivery system will not result from intended use.
Chemical and physical compatibility of the OVD and the delivery system and biocompatibility of the
components of the delivery system shall be evaluated.

10 Packaging

10.1 Protection from damage during storage and transport

The packaging requirements for medical devices outlined in ISO 11607-1 shall apply.

10.2 Maintenance of sterility in transit

OVDs shall be packaged in s uch a way that they remain sterile within the limits specified for conditions
of transport, storage and handling. The sterile packaging requirements outlined in ISO 11607-1 shall
apply.

11 Information to be supplied by the manufacturer

The general requirements for information provided by the manufacturer of medical devices specified
in EN 1041 shall apply, together with the following particular requirements for viscosurgical devices.
Symbols may be used instead of text, where appropriate. When symbols are used, ISO 15223-1,
ISO 15223-2 or EN 980, depending on region, apply.
If the product is vulnerable to damage by exposure to environmental elements, there shall be clear
warning signs on the shipping container.
The batch number and expiration date may also be provided on a self-adhesive label for use in records.
Instructions for use shall be included within the storage container, provided in such a way that it can be
read without damaging the sterile barrier.

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ISO 15798:2022(E)

The minimum information required on the storage container, instructions for use, sterile barrier and
primary container is listed in Table l.

Table 1 - Information to be s upplied by the manufacturer

Storage Instructions Sterile Primary
Point of information
container for use barrier container
Name of the manufacturer and, if applicable, the
X X x• X
authorized representative
Address of the manufacturer or authorized
X X
representative
Trade name of the product X X xa X
Description of the delivery system and instructions
for its proper use X

Brief description of the chemical composition of

X X
the product and the vo lume supplied
Description of the relevant design attributes that may
affect the safety and performance of the p.-oduct,
X
including, but not limited to, all of the following: con-
centration; pH; osmolality
Graphical presentation of the rheological profile,
plotting the log viscosity (Pa·s) versus log shear rate X
(s-1) over the range defined in .s.:i.11
Conditions for storage X X
Indications for use X
Contra-indications for use X
Instructions for use, including recommendations for
X
removal of the product
Warnings and precautions X
Statement "For single use" X X x•
Statement "Sterile" and the method(s) of sterilization xa
X X
of the product and primary container
Statement "Do not use if package is damaged" xa
Expiration date X xa X
Batch number preceded by the word "LOT" X x• X
Date of issue or the latest revision of the instructions
X
for use
a This information or part of it can be alternatively given on the primary container and need not be provided on the
sterile barrier if that is transparent and the required information is given on and can be read directly from the primary
container without breaking the seal. Irrespective of choice, exp iration date and the batch number shall in all cases be given
on the primary container.

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 ISO 15798:2022(E)

Annex A
(normative)

Intraocular implantation test

A.1 General
A transient increase in intraocular pressure (IOP) and an inflammatory reaction can follow anterior
segment surgery in which DVDs are utilized. It is an accepted consequence of their use, and should not
significantly impair ocular function or the repair of ocular tissues. A significant or prolonged increase
in the IOP can cause pain or discomfort and result in permanent damage to the eye. This test monitors
the rise in the intraocular pressure and any inflammatory reaction, following replacement of aqueous
humour by an equal volume of OVD in the anterior chamber of a suitable test animal. The OVD remains
in the eye; thus, the test does not mimic clinical use, where the surgeon removes as much of the OVD
as possible prior to closure of the incision. Thus, the duration and magnitude of the change in IOP
during preclinical testing can be greater than that encountered during clinical use. This test is only for
comparison of the OVD with a control material approved for the same use.

A.2 Test material

The sterile finished OVD under investigation is used as test material.

A.3 Control material

Choose a control OVD that has been widely used for at least five years and has not been associated
with significant material related adverse events. The same control OVD shall be used in the animal and
clinical study. Provide a rationale for the choice of the control OVD. The control OVD is in the same form
as supplied to the market.

A.4 Test procedure

Use a minimum of six animals for the test. If rabbits are used, they should preferably be of the New
Zealand white strain and weigh approximately 2,5 kg.
Evaluate the eyes pre-operatively using applanation tonometry, slit-lamp biomicroscopy and
pachymetry and record the results. The order in which the assessments are performed is recorded and
justified. Use of local medication (anaesthetic, mydriatic agent) may interfere with subsequent ocular
assessments. Therefore, provide a justification for the medications used during ophthalmic evaluations
and ensure that they do not interfere with the assessments. Reject animals with abnormalities in any
eye.
Appoint a person with experience in surgery on the ocular anterior segment to perform the
implantations.

Exchange approximately 25 % of the liquid volume in the anterior chamber with the test OVD, in one
eye of the test animal. The contra lateral eye is treated in the same way with the control OVD. The eyes
of each animal are treated one after the other, preferably in a randomized order, before continuing with
the next animal. Record intra-operative complications, if any.
A bilateral implantation is preferred, but unilateral implantation is permitted, if local regulations so
require. In this case a minimum of 12 animals should b e used.

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ISO 15798:2022(E)

Implantation should be achieved with the minimum possible trauma to the eye to avoid physical damage
to ocular tissue, which can mask the intraocular changes resulting from exposure to the test or control
material.

A.5 Test evaluation

A.5.1 Intraocular pressure evaluation
Measure the intraocular pressure by applanation tonometry at the following times, post-operatively:
a) 2 h ± 0,5 h;
b) 4 h ± 1 h;
c) 6 h ± 1 h;
d) 8 h ± 1 h;
e) 12 h ± 1 h;
f) 24 h ± 2 h;
g) 7 d ± 1 d;
h) 30 d ± 7 d;
i) 90 d ± 14 d.
The rate of change of the intraocular pressure and duration can vary considerably with the nature of
the OVD and in particular its viscosity. Once a pattern has been established, the times at which the
intraocular pressure is measured can be altered to more accurately follow its change. Additional
evaluation times may be necessary if the !OP remains elevated for more than 24 h post-injection. !OP
can vary during the day. Therefore, the time when the !OP is measured shall be carefully considered
and documented. In addition, use of anaesthetic agents shall be carefully considered since sedation
may lower !OP. Furthermore, the location on the cornea where !OP is measured and the number of
measurements taken/eye will be determined. Document all test results and compare the !OP changes
from baseline (prior to implantation) between the investigational and control eyes.
The administration, at any time, of !OP-reducing drugs, or other interventions, shall be documented and
the data from those eyes/animals shall be presented separately.

A.5.2 Inflammatory response evaluation

The inflammatory response is monitored and graded according to a standardized ocular scoring
system for slit-lamp biomicroscopic examination and pachymetry, such as the standardization of
uveitis nomenclature (SUN) working group (for flare and anterior chamber cells)[121and the McDonald-
Shadduck scale (for corneal, iris observations)[141, at the following times post-operatively:
a) 6 h ± 1 h;
b) 24 h ± 2 h;
c) 48 h ± 2 h;
d) 72 h ± 2 h;
e) 7 d ± 1 d;
f) 30 d ± 7 d;
g) 90 d ± 14 d.

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 ISO 15798:2022(E)

Additional evaluation times may be necessary if an inflammatory response is noted.

The slit-lamp observations should include at least the following:
corneal clarity;
cells;
fibrin;
flare;
iritis;
lens clarity.
Document all test results.

A.6 Test report

The test report shall include, as a minimum, the following:
a) a reference to this document, i.e. ISO 15798:2022;
b) all information necessary for identification of the samples tested;
c) the results of the test, including the results of the individual determinations and their means,
where applicable;
d) any deviations from the procedure specified;
e) any unusual features (anomalies) observed during the test;
f) dates for all surgery, tests and subsequent analyses.

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ISO 15798:2022(E)

AnnexB
(informative)

Patient numbers for clinical investigation of intra ocular pressure

The sample size calculation for the study is based on an increase in intraocular pressure (IOP) as the
primary endpoint. A transient increase in the !OP is the main safety concern with currently used OVOs.
The clinical investigation is designed to compare the test product with the control in terms of the
incidence of IOP observations ~30 mm Hg.
The null hypothesis, H0, is that the test incidence, n t, of !OP observations ~30 mm Hg minus the control
incidence, nc, of !OP observations ~ 30 mmHg is greater than or equal to the minimally detectable
difference, 8, between the two incidences.
The alternative hypothesis, H1, is that the test incidence, nt, of !OP observations~ 30 mm Hg minus the
control incidence, nc, ofIOP observations ~30 mmHg is less than the minimally detectable difference, o,
between the two incidences.
Thus:
H0 : nt -
nc~8
H1: nt- nc< o
The minimum number, N, of evaluable patients necessary for each treatment group is determined by
Formula (B.1) below:

(z1_.8 +z1-a )2 x[nt x(1-n t) + n c x(1-n c )]

N=-'-----'-------'------------- (B.1)
82
Assuming a control incidence, nc, and a test incidence, nt, of 0,10, a minimally detectable difference, o, of
0,10, a power (1- /3) of 0,80, and an a of 0,05, the minimum number of evaluable patients per treatment
group is given by Formula (B.2):

(0,842+ 1,645) 2 x(O, lx(O, 9)+0,lx(O, 9)]

N=-------------,,,112 (B.2)
0,10 2
It should be noted that the control incidence can vary substantially from the incidence of 0,10 used
in this example. In cases where the incidence, nc, of IOL observations greater than 30 mmHg for the
control OVD chosen is believed to be substantially different from 0,10, it will be necessary to recalculate
the sample size for the investigation.

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 ISO 15798:2022(E)

Annexe
(informative)

Analyses of OVD clinical data

C.1 General
The pri ma ry clinical data utilized to eva luate the safety and performance of the new OVO is corneal
e ndothelial cell density, postoperative intraocular inflammation, a nd intraocular pressure. The data
from subjects that have received t he new OVO a re to be compared to subjects that received the control
OVO. Some suggested analyses comparing the clinical performa nce of t he new OVO to t he control OVO
are described below. The number of eyes included in each analysis should be reported

C.2 Corneal endothelial cell density

Corneal endothel ial cell density (ECO) measu rements are take n pre-operatively and at t he final
examination at 3 months. The following analyses are to be considered.
a) ECO mean, standard deviation, median, minimum, maximum at pre-operative and th ree-mont h
examinations, along with incidence of ECO ~ 1 000 and ~ 500 cells/mm 2 at both time points.
b) With in-eye change in ECO and withi n-eye percent change in ECO at th ree-month examination from
pre-operative levels in terms of mean, standard deviatio n, media n, minimum, maximum.
c) Percent of eyes that show losses from preoperative levels of: ~o %, ~10 %, ~20 %, ... 100 %, for
every 10 % interval.

C.3 Postoperative intraocular inflammation

Postoperative intraocular inflammation is assessed at each postoperative examination. The times
associated with these examinations are described in .6..3.!i. The following analyses are to be considered.

a) The number (and percentage) of eyes with each grade of Anterior Chamber cells (AC cell) at each
examination out of the tota l number with the assessment of AC cell at that examination for each
treatment group. Stratification is suggested by subjects who are on steroids at the time of the
examination and subjects who a re not because steroids may suppress int raocular infla mmation.
b) The total num ber (and percentage) of eyes at each postoperative examination with an increase in
grade of AC cell from the prior examination by treatment group because this can indicate that t he
OVO is causing t he inflammation.
c) The number of eyes at each examination with an increase in AC cell grade from the prior examination
during steroid taper and the total number of subjects at each examination for whom steroid taper
is underway. Cessation of steroids, if tapered too quickly, can result in rebound inflammation
confounding the analysis of inflammatio n resulti ng from the OVO.
d) After analyses of !OP, the number of eyes in each group at each examination with an increase in AC
cell grade from the prior examination associated with a significant increase in !OP (see .GA).

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 ISO 15798:2022(E)

C.4 Intraocular pressure (IOP)

lntraocular pressure is assessed at each postoperative examination. The times associated with these
examinations are described in 6.3.5. The following IOP analyses are to be considered.
a) Mean, sta ndard dev iation, media n, minimum, maximum at each pre- and post-operative
exam ination timepoint (in 2 h intervals for t he 1st postoperative exami nation window).
b) Mean, standard deviation, median, minimum, maximum at each post-operative examination
timepoint of change in IOP from baseline (in 2 h intervals for the ist postoperative examination
window).
c) Define the following 5 cohorts in each treatment group:
all subjects,
G)
C:
(I)
those subjects for whom an !OP-lowering drug or intervention may have confounded the result,
!a.
C those subjects for whom such an !OP-lowering confounding effect was not possible,
"'~
t hose subjects for whom a steroid may have confounded the result (taking steroid med ication),
and
for those subjects for whom such a steroid-confounding effect was not possible.
With the following suggested analysis:
a) Distribution of percentage of eyes at each postoperative examination timepoint (in 2 h intervals
for theist postoperative examination window) with change in !OP from baseline of ±4 mmHg (e.g.,
increase >4 but <10 mmHg, and then in intervals of 10 mmHg) for both increases and decreases in
IOP.
b) Cumulative incidence of JOP "spike".:: 30 mmHg (1st JOP spike of an eye) th rough each postoperative
examination timepoint (in 2 h intervals for the 1st postoperative examination window).
c) Cumulative incidence of an increase in IOP 2: 10 mmHg above baseline through each postoperative
examination timepoint (in 2 h intervals for t he 1st postoperative examination window).

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 ISO 15798:2022(E)

Bibliography

[1] ISO 8601, Data elements and interchange formats · Information interchange · Representation of
dates and times
[2] ISO 10993-2, Biological evaluation of medical devices - Part 2: Animal welfare requirements
[3] ISO 15223·1, Medical devices - Symbols to be used with information to be supplied by the
manufacturer - Part 1: General requirements
[4] ISO 15223·2, Medical devices - Symbols to be used with medical device labels, labelling, and
information to be supplied - Part 2: Symbol development, selection and validation
[5] EN 980, Symbols for use in the labelling of medical devices
[6] AUFFARTH G.U., HOLZER M.P., VISSESOOK N., APPLE D.J., VOLCKER H.E. Removal times and
techniques of a viscoadaptive ophthalmic viscosurgical device. J Cataract Refract Surg 2004
April; 3 0: pp. 879 - 883.
[7] ARSHINOFF S.A., WONG E. Understanding, retaining, and removing dispersive and
pseudodispersive ophthalmic viscosurgical devices. J Cataract Refract Surg 2003 December; 29:
pp. 2318 - 2323.
[8] European Pharmacopoeia, Appendix XIV C. Test for Bacterial Endotoxins
[9] Japanese Pharmacopoeia, XIV 6. Bacterial Endotoxins Test
[10] Unites States Pharmacopoeia, <85> Bacterial Endotoxins Test
[11] ENDOTOXIN TESTING RECOMMENDATIONS FOR SINGLE·USE INTRAOCULAR OPHTHALMIC DEVICES
https://www.fda.gov/media/88615/download
[12] JABS D.A., NUSSENBLATT R.B., ROSENBAUM J.T., Standardization of Uveitis Nomenclature (SUN)
Working Group, Standardization of uveitis nomenclature for reporting clinical data. Results of
the First International Workshop. Am. J. Ophthalmol. 2005 Sep, 140 (3) pp. 509- 516
[13] HERRINGTON R.J., BALL S.F., UPDEGRAFF S.A. Delayed sustained increase in intraocular
pressure secondary to the use of polyacrylamide gel (Orcolon) in the anterior chamber.
Ophthalmic Surg. 1993 Oct; 24(10) pp. 658-662.
[14] McDONALD T.0., SHADDUCK J.A., Eye irritation. In: Marzulli F.N., Maibach H.I., eds. Advances
in Modern Toxicology, Volume IV: Dermatotoxicology and Pharmacology. Washington, D.C.:
Hemisphere Publishing Corp; 1977; p. 139-191.

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ISO 15798:2022(E)

JCS 11.040.70
Price based on 19 pages

© ISO 2022 - All rights reserved