SIST EN ISO 11979-5:2006
(Main)Ophthalmic implants - Intraocular lenses - Part 5: Biocompatibility (ISO 11979-5:2006)
Ophthalmic implants - Intraocular lenses - Part 5: Biocompatibility (ISO 11979-5:2006)
This part of ISO 11979 specifies particular requirements for the biocompatibility evaluation of materials for intraocular lenses (IOLs) including the processing conditions to produce them. These requirements include evaluation of physicochemical properties that are relevant to biocompatibility. It also gives guidance on conducting an ocular implantation test.
Ophthalmische Implantate - Intraokularlinsen - Teil 5: Biokompatibilität (ISO 11979-5:2006)
Dieser Teil von ISO 11979 legt die besonderen Anforderungen an die Bewertung der Biokompatibilität von Materialien für Intraokularlinsen (IOLs) sowie der bei deren Herstellung angewendeten Verfahren bzw. Bedingungen fest. Diese Anforderungen beinhalten die Bewertung der physikalisch-chemischen Eigenschaften, die für die Biokompatibilität von Belang sind. Zudem gibt er eine Anleitung zur Durchführung einer Untersuchung zur intraokularen Implantation.
Implants ophtalmiques - Lentilles intraoculaires - Partie 5: Biocompatibilité (ISO 11979-5:2006)
L'ISO 11979-5:2006 spécifie les exigences particulières de l'évaluation de la biocompatibilité des matériaux utilisés pour la fabrication des lentilles intraoculaires (LIO), y compris les conditions de traitement de leur fabrication. Ces exigences comprennent l'évaluation des propriétés physicochimiques relatives à la biocompatibilité. L'ISO 11979-5:2006 donne également des directives relatives à la mise en oeuvre d'un essai d'implantation oculaire.
Očesni vsadki (implantati) - Intraokularne leče - 5. del: Biokompatibilnost (ISO 11979-5:2006)
General Information
Relations
Standards Content (Sample)
SLOVENSKI STANDARD
SIST EN ISO 11979-5:2006
01-september-2006
1DGRPHãþD
SIST EN 13503-5:2002
2þHVQLYVDGNL LPSODQWDWL ,QWUDRNXODUQHOHþHGHO %LRNRPSDWLELOQRVW ,62
Ophthalmic implants - Intraocular lenses - Part 5: Biocompatibility (ISO 11979-5:2006)
Ophthalmische Implantate - Intraokularlinsen - Teil 5: Biokompatibilität (ISO 11979-
5:2006)
Implants ophtalmiques - Lentilles intraoculaires - Partie 5: Biocompatibilité (ISO 11979-
5:2006)
Ta slovenski standard je istoveten z: EN ISO 11979-5:2006
ICS:
11.040.70 Oftalmološka oprema Ophthalmic equipment
SIST EN ISO 11979-5:2006 en,fr,de
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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SIST EN ISO 11979-5:2006
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SIST EN ISO 11979-5:2006
EUROPEAN STANDARD
EN ISO 11979-5
NORME EUROPÉENNE
EUROPÄISCHE NORM
June 2006
ICS 11.040.70 Supersedes EN 13503-5:2001
English Version
Ophthalmic implants - Intraocular lenses - Part 5:
Biocompatibility (ISO 11979-5:2006)
Implants ophtalmiques - Lentilles intraoculaires - Partie 5: Ophthalmische Implantate - Intraokularlinsen - Teil 5:
Biocompatibilité (ISO 11979-5:2006) Biokompatibilität (ISO 11979-5:2006)
This European Standard was approved by CEN on 13 April 2006.
CEN members are bound to comply with the CEN/CENELEC Internal Regulations which stipulate the conditions for giving this European
Standard the status of a national standard without any alteration. Up-to-date lists and bibliographical references concerning such national
standards may be obtained on application to the Central Secretariat or to any CEN member.
This European Standard exists in three official versions (English, French, German). A version in any other language made by translation
under the responsibility of a CEN member into its own language and notified to the Central Secretariat has the same status as the official
versions.
CEN members are the national standards bodies of Austria, Belgium, Cyprus, Czech Republic, Denmark, Estonia, Finland, France,
Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania,
Slovakia, Slovenia, Spain, Sweden, Switzerland and United Kingdom.
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EUROPÄISCHES KOMITEE FÜR NORMUNG
Management Centre: rue de Stassart, 36 B-1050 Brussels
© 2006 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 11979-5:2006: E
worldwide for CEN national Members.
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SIST EN ISO 11979-5:2006
EN ISO 11979-5:2006 (E)
Foreword
This document (EN ISO 11979-5:2006) has been prepared by Technical Committee ISO/TC 172
"Optics and optical instruments" in collaboration with Technical Committee CEN/TC 170
"Ophthalmic optics", the secretariat of which is held by DIN.
This European Standard shall be given the status of a national standard, either by publication of
an identical text or by endorsement, at the latest by December 2006, and conflicting national
standards shall be withdrawn at the latest by December 2006.
This document supersedes EN 13503-5:2001.
According to the CEN/CENELEC Internal Regulations, the national standards organizations of
the following countries are bound to implement this European Standard: Austria, Belgium,
Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary,
Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland,
Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland and United Kingdom.
Endorsement notice
The text of ISO 11979-5:2006 has been approved by CEN as EN ISO 11979-5:2006 without any
modifications.
2
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SIST EN ISO 11979-5:2006
INTERNATIONAL ISO
STANDARD 11979-5
Second edition
2006-06-01
Ophthalmic implants — Intraocular
lenses —
Part 5:
Biocompatibility
Implants ophtalmiques — Lentilles intraoculaires —
Partie 5: Biocompatibilité
Reference number
ISO 11979-5:2006(E)
©
ISO 2006
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SIST EN ISO 11979-5:2006
ISO 11979-5:2006(E)
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ii © ISO 2006 – All rights reserved
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SIST EN ISO 11979-5:2006
ISO 11979-5:2006(E)
Contents Page
Foreword. iv
Introduction . v
1 Scope . 1
2 Normative references . 1
3 Terms and definitions. 1
4 General requirements applying to biocompatibility evaluation of intraocular lenses. 2
5 Physicochemical tests . 2
6 Biological tests . 5
Annex A (normative) Exhaustive extraction test . 7
Annex B (normative) Test for leachables . 10
Annex C (normative) Hydrolytic stability. 12
Annex D (normative) Photostability test. 15
Annex E (normative) Nd-YAG laser exposure test . 17
Annex F (informative) Supplemental conditions of test for local effects after implantation. 19
Annex G (normative) Ocular implantation test . 20
Bibliography . 24
© ISO 2006 – All rights reserved iii
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SIST EN ISO 11979-5:2006
ISO 11979-5:2006(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.
International Standards are drafted in accordance with the rules given in the ISO/IEC Directives, Part 2.
The main task of technical committees is to prepare International Standards. Draft International Standards
adopted by the technical committees are circulated to the member bodies for voting. Publication as an
International Standard requires approval by at least 75 % of the member bodies casting a vote.
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.
ISO 11979-5 was prepared by Technical Committee ISO/TC 172, Optics and photonics, Subcommittee SC 7,
Ophthalmic optics and instruments.
This second edition cancels and replaces the first edition (ISO 11979-5:1999), which has been technically
revised.
ISO 11979 consists of the following parts, under the general title Ophthalmic implants — Intraocular lenses:
⎯ Part 1: Vocabulary
⎯ Part 2: Optical properties and test methods
⎯ Part 3: Mechanical properties and test methods
⎯ Part 4: Labelling and information
⎯ Part 5: Biocompatibility
⎯ Part 6: Shelf-life and transport stability
⎯ Part 7: Clinical investigations
⎯ Part 8: Fundamental requirements
⎯ Part 9: Multifocal intraocular lenses
⎯ Part 10: Phakic intraocular lenses
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SIST EN ISO 11979-5:2006
ISO 11979-5:2006(E)
Introduction
This part of ISO 11979 follows the general principles given in ISO 10993-1. ISO 10993-1 describes the
principles governing the biological evaluation of medical devices, the definitions of categories based on the
nature and duration of contact with the body, and selection of appropriate tests. Other parts of ISO 10993
present biological test methods, tests for ethylene oxide residues, tests for degradation and principles for
sample preparation.
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SIST EN ISO 11979-5:2006
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SIST EN ISO 11979-5:2006
INTERNATIONAL STANDARD ISO 11979-5:2006(E)
Ophthalmic implants — Intraocular lenses —
Part 5:
Biocompatibility
1 Scope
This part of ISO 11979 specifies particular requirements for the biocompatibility evaluation of materials for
intraocular lenses (IOLs) including the processing conditions to produce them. These requirements include
evaluation of physicochemical properties that are relevant to biocompatibility. It also gives guidance on
conducting an ocular implantation test.
2 Normative references
The following referenced documents are indispensable for the application of this document. For dated
references, only the edition cited applies. For undated references, the latest edition of the referenced
document (including any amendments) applies.
ISO 10993-1, Biological evaluation of medical devices — Part 1: Evaluation and testing
ISO 10993-2, Biological evaluation of medical devices ― Part 2: Animal welfare requirements
ISO 10993-3, Biological evaluation of medical devices ― Part 3: Tests for genotoxicity, carcinogenicity and
reproductive toxicity
ISO 10993-6, Biological evaluation of medical devices — Part 6: Tests for local effects after implantation
ISO 10993-10, Biological evaluation of medical devices ― Part 10: Tests for irritation and delayed-type
hypersensitivity
ISO 10993-12, Biological evaluation of medical devices ― Part 12: Sample preparation and reference
materials
ISO 11979-1, Ophthalmic implants — Intraocular lenses — Part 1: Vocabulary
ISO 11979-2, Ophthalmic implants — Intraocular lenses — Part 2: Optical properties and test methods
ISO 11979-3, Ophthalmic implants — Intraocular lenses — Part 3: Mechanical properties and test methods
ISO 14971, Medical devices — Application of risk management to medical devices
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 11979-1 apply.
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SIST EN ISO 11979-5:2006
ISO 11979-5:2006(E)
4 General requirements applying to biocompatibility evaluation of intraocular
lenses
The evaluation of the biocompatibility of the test material shall start with an initial assessment of risk in
accordance with ISO 14971. The physicochemical tests described in Clause 5 shall first be considered. The
evaluation of the material for biological safety shall then be undertaken in accordance with the principles and
requirements of ISO 10993-1 and ISO 10993-2, taking into consideration the results from the physicochemical
tests.
Furthermore, the risk assessment shall include an assessment of the potential for material changes such as
calcification. This risk assessment should consider the history of clinical use of the material, and animal
models to test the long-term stability of the material.
Carry out the biocompatibility testing in accordance with ISO 10993-1, ISO 10993-3, ISO 10993-5,
ISO 10993-6 and ISO 10993-10 and as noted in this part of ISO 11979.
The pre-existing information on the material and all the information obtained in the evaluation process shall be
integrated in an overall risk benefit assessment in accordance with ISO 14971.
5 Physicochemical tests
5.1 General
5.1.1 The following physicochemical tests shall be considered:
a) exhaustive extraction;
b) leachables;
c) hydrolytic stability;
d) photostability against ultraviolet/visible (UV/Vis) irradiation;
e) stability against Nd-YAG laser exposure;
f) insoluble inorganics.
5.1.2 The objectives of this group of tests are:
a) to quantify possible residues from synthesis and additives or impurities from manufacturing and
packaging;
b) to quantify possible degradation products due to hydrolysis;
c) to quantify leachable chemical components; and
d) to facilitate an analysis of any risks introduced by toxic products which may result from processing,
treatment in use, or ageing of the test material.
5.1.3 The results of the tests given in 5.1.1 and 5.1.2 shall be recorded and included in the assessment for
risk in accordance with ISO 14971. If any of the above tests was not performed, a rationale justifying this
decision shall be documented.
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SIST EN ISO 11979-5:2006
ISO 11979-5:2006(E)
5.2 Exhaustive extraction test
The test material shall be tested for extractables under exhaustive extraction conditions in accordance with
the method described in Annex A, which describes several extraction conditions, including the extraction
media, temperature and duration. Alternate methods can be used provided that they have been validated.
The following shall be observed.
a) The reasons for selecting each solvent shall be justified and documented.
b) The extraction media shall be qualitatively and quantitatively analysed at the end of extraction for possible
extractable components of the material, such as process contaminants, residual monomers, additives,
and other extractable components. The detection limit for the extractables shall be established based on
a risk assessment of the total exposure to the patient and it shall be expressed as µg/g of material.
c) The test material shall be weighed before and after extraction and any change in mass shall be calculated.
The results shall be evaluated to assess the risk for potentially harmful effects due to extractable components
and they shall be recorded.
5.3 Test for leachables
The test material shall be tested for leachables under simulated physiological conditions in accordance with
the method described in Annex B, which specifies several extraction conditions including the extraction media,
temperature and duration.
The following shall be observed.
a) The reasons for selecting each solvent shall be justified and documented.
b) The extraction media shall be qualitatively and quantitatively analysed at the end of extraction for possible
extractable components of the material, such as process contaminants, residual monomers, additives,
and other extractable components. The detection limit for the extractables shall be established based on
a risk assessment of the total exposure to the patient and it shall be expressed as µg/g of material.
The results shall be evaluated to assess the risk for potentially harmful effects from extractable components
and they shall be recorded.
5.4 Test for hydrolytic stability
Hydrolytic stability testing shall be conducted in accordance with the method described in Annex C. The
following shall be observed.
a) The study shall be designed to evaluate the stability of the material in an aqueous environment at
35 °C ± 2 °C for a period of at least five years or at an elevated temperature for a simulated exposure
time of at least five years.
b) The simulated exposure time is to be determined by multiplying the actual study time with the following
factor F:
(T−T )/10
a o
F = 2,0
where
T is the accelerated temperature;
a
T is the temperature of the inside of the eye (35 °C).
o
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SIST EN ISO 11979-5:2006
ISO 11979-5:2006(E)
c) The exposure medium shall be qualitatively and quantitatively analysed for any chemical entities at the
end of the exposure period.
d) The test material shall be examined by light microscopy at 10× or higher and by scanning electron
microscopy (SEM) at 500× or higher before and after testing. The test material shall be compared with the
untreated material and there shall be no significant difference in surface appearance (e.g. bubbles,
dendrites, breaks and fissures).
e) Optical transmittance spectra of the test material in the ultraviolet and visible spectral regions (UV/Vis)
shall be recorded before and after testing. By comparison of the spectra, assurance shall be obtained that
there are no significant changes in spectral transmittance. The dioptric power shall be determined before
and after testing if finished IOLs are used in the testing. The refractive index shall be determined instead
if a facsimile material is used. There shall be no significant change in dioptre power (± 0,25 D for a 20 D
lens) or refractive index before and after testing.
The results shall be evaluated to assess the risk for potentially harmful effects due to instability of the material
in an aqueous environment and they shall be recorded.
5.5 Photostability test
Photostability testing shall be conducted in accordance with Annex D.
Furthermore, when performing the testing for anterior chamber IOLs, it shall be shown that no significant
change in mechanical properties of the irradiated test material has occurred when compared with non-
irradiated test material.
No significant change shall be detected between the UV/Vis spectra of the test material exposed to UV
radiation and controls receiving no radiation.
NOTE 1 The loops of implanted anterior chamber IOLs are exposed to radiation, hence the rationale for requiring
mechanical testing after irradiation.
NOTE 2 The following parameters have been found to be relevant to in situ exposure of an IOL to UV radiation:
a) in vivo UV-A radiation intensity in the range 300 nm to 400 nm at the position of the IOL at diffuse light conditions (I ):
1
2
0,3 mW/cm ;
2 2
The internationally accepted estimation for full intensity of sunlight is an average of 1 kW/m = 100 mW/cm in sunny
areas close to the Tropic of Cancer. The portion of near ultraviolet wavelengths in the 300 nm to 400 nm range is
2
approximately 6,5 % of the total intensity, i.e. about 6,5 mW/cm . Intraocular lenses are exposed to sunlight which
reaches behind the cornea and the aqueous humour. Within the spectrum of sunlight, that part of the near ultraviolet
radiation which is not absorbed by the cornea and the aqueous humour and which can potentially damage IOLs by
photochemical degradation, amounts to approximately 40 % to 50 % of the total UV-A radiation. Assuming that the
2
cornea and the aqueous humour absorb 50 % of the UV-A, the IOL is exposed to an irradiation of 3,25 mW/cm in
the 300 nm to 400 nm range at full intensity of sunlight. The diffuse, reflected light intensity is estimated to be one-
2
tenth of the above value. The irradiation of an intraocular lens in vivo is therefore approximately 0,3 mW/cm .
b) daily exposure time to sunlight (t): 3 h;
c) in vivo exposure time (T ): 20 years;
1
d) intensity factor (n): 1 (i.e. maximum intensity under consideration of sunny regions).
The in vitro test period (T , in days) can be calculated using the following equation (see Reference [1]), with (I ) being
2 2
the in vitro intensity of the radiation source in the 300 nm to 400 nm range,
−1
n
⎡⎤
⎛⎞
I ⎛⎞24
2
⎢⎥
TT=×365 ×
⎜⎟
21 ⎜⎟
⎜⎟
⎢⎥
It
⎝⎠
1
⎝⎠
⎣⎦
2
EXAMPLE If I = 10 mW/cm , T = 27,4 d.
2 2
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SIST EN ISO 11979-5:2006
ISO 11979-5:2006(E)
The results shall be evaluated to assess the risk of potential harmful effects due to degradation products
identified in the photostability test and they shall be recorded.
5.6 Nd-YAG laser exposure test
The effect of Nd-YAG laser exposure shall be evaluated in accordance with Annex E.
There shall be no cytotoxic substances released due to Nd-YAG laser exposure.
5.7 Evaluation of insoluble inorganics
The IOL material shall be assessed for the presence of residual insoluble inorganics on and in the lens arising
from manufacturing materials and process aids. Where possible residues have been identified, the lens shall
be evaluated for such residuals. The test methods used for this evaluation shall be identified, validated and
justified. Consideration shall be given to methods with a detection limit of 0,2 µg/lens or 10 µg/g, and in which
the solvents will dissolve the material.
The results shall be evaluated to assess the risk of potentially harmful effects due to the presence of residual
insoluble inorganics on and in the lens and they shall be recorded.
6 Biological tests
6.1 General
An evaluation of biological safety shall be undertaken in accordance with the principles and requirements of
ISO 10993-1 taking into consideration the results of the physicochemical tests. The following biological
endpoints shall be considered:
⎯ the effects on cell growth and cell damage;
⎯ genotoxicity;
⎯ local effects after implantation;
⎯ sensitization potential.
Where testing is deemed necessary, the appropriate parts of ISO 10993 shall apply. Supplements to these
parts are described in 6.2 and 6.3. Sample preparation shall be performed in accordance with ISO 10993-12
taking into consideration the supplemental requirements. In addition, an ocular implantation test shall also be
considered in accordance with 6.4.
If the risk assessment has identified the potential for material change when exposed to an in vivo environment,
a test shall be performed to assess the reciprocal tolerance of the test material and local tissue. An example
of such a test is the test for local effects after implantation as described in ISO 10993-6 supplemented as
indicated in informative Annex F.
NOTE As the mass of an intraocular lens is typically only about 20 mg, in general no systemic or chronic toxicity
testing is required.
6.2 Tests for genotoxicity
Testing for genotoxicity shall be performed in accordance with ISO 10993-3 supplemented with the following:
⎯ Two separate extractions of the material shall be performed, one with physiological saline, and the other
with a lipophilic or dipolar solvent. The lipophilic or dipolar solvent shall not dissolve or degrade the
material.
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SIST EN ISO 11979-5:2006
ISO 11979-5:2006(E)
⎯ Extraction shall be performed with agitation at 37 °C ± 2 °C for 72 h ± 2 h at a ratio of 1 g of material per
10 ml of extracting medium.
6.3 Tests for sensitization
Testing for sensitization shall be performed in accordance with ISO 10993-10 supplemented with the following.
⎯ Either the maximization sensitization test or the local lymph node assay (LLNA) can be used for testing.
⎯ The test material shall be extracted with two different extractants, one of which is physiological saline,
and the second a lipophilic or dipolar solvent. The lipophilic or dipolar solvent should not dissolve or
degrade the test material. The solvent itself should also not be a known irritant, adjuvant or sensitizer.
6.4 Ocular implantation test
An intraocular implantation test shall be performed when the manufacturer has no documented evidence on
the safety of the material in the intraocular environment. Testing shall be conducted in accordance with the
general principles in ISO 10993-6, supplemented as described in Annex G. When this test is deemed not
necessary, the risk assessment shall provide reasonable assurance that the risks arising from the new use of
the material are deemed acceptable based on information from previous clinical use and other relevant
literature.
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SIST EN ISO 11979-5:2006
ISO 11979-5:2006(E)
Annex A
(normative)
Exhaustive extraction test
A.1 Purpose
The purpose of this test is to detect and quantify extractable additives and other leachables from intraocular
lens material under exhaustive extraction conditions.
A.2 General considerations
Select analytical methods that are justified in terms of being well established and of sufficient sensitivity to
detect significant concentrations.
A.3 Principle
The method of extraction described in this annex employs the normal Soxhlet apparatus. This annex also
describes the particular precautions necessary when handling intraocular lenses; it also gives guidance on the
range of solvents that may be employed. In selecting the solvent, give consideration to the ability of the
solvent to swell the material to enable extraction without destroying the polymeric structure or dissolving the
material and the solubility of the potential residual monomers in the solvent to obtain complete extraction. Use
water or a suitable organic solvent for the extraction. Extraction of some materials such as hydrophilic IOLs
can require both aqueous and organic solvent extraction to insure extraction of both hydrophilic (salts) and
hydrophobic components (monomers, UV absorbers, etc).
The material extracted from the intraocular lenses should be examined by appropriate chromatographic,
spectrophotometric and wet analysis methods to identify residual monomers, cross-linking agents, catalysts
etc. employed in the manufacturing process.
The following method can be utilized when the solvent swells the material enough to ensure complete
extraction.
A.4 Test samples
Sterile finished IOLs weighing no less than 200 mg.
A.5 Reagents
A.5.1 Water, distilled or deionized.
A.5.2 Organic solvent, of analytical grade or purer.
A.5.3 Boiling stones or anti-bumping granules.
A.5.4 Active desiccant.
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SIST EN ISO 11979-5:2006
ISO 11979-5:2006(E)
A.6 Apparatus
The following list is advisory. Other suitable means can be used.
A.6.1 Soxhlet extraction apparatus, including condenser, round-bottom flask and heating mantle with
glass components of standard borosilicate laboratory glassware.
A.6.2 Extraction thimble, made from perforated stainless steel, sintered glass, paper or equivalent, fitted
with a glass wool plug or other suitable closure.
A.6.3 Drying apparatus, vacuum oven, or other suitable drying apparatus.
A.6.4 Analytical balance, precise to 0,1 mg or better.
A.6.5 High-pressure liquid chromatography (HPLC).
A.6.6 Gas chromatography (GC).
A.6.7 Gas chromatography/mass spectroscopy (GC/MS).
A.6.8 Rotary evaporator.
A.7 Test procedure
CAUTION — When using a volatile or flammable solvent the equipment should be placed in a
fume-hood.
Dry the intraocular lenses to constant mass preferably under vacuum at 60 °C ± 5 °C. Allow the intraocular
lenses to cool to room temperature under vacuum before weighing. If they are hygroscopic, transfer the
intraocular lenses from the oven to a desiccator and allow to cool over active desiccant.
Weigh the dry intraocular lenses to the nearest 0,1 mg.
Put the intraocular lenses into the extraction thimble. Place the boiling stones in the flask if necessary, and
partly fill the flask (to
...
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