ISO 4802-2:2023

INTERNATIONAL ISO
STANDARD 4802-2
Fourth edition
2023-12
Glassware — Hydrolytic resistance
of the interior surfaces of glass
containers —
Part 2:
Determination by flame spectrometry
and classification
Verrerie — Résistance hydrolytique des surfaces internes des
récipients en verre —
Partie 2: Détermination par spectrométrie de flamme et classification
Reference number
© ISO 2023
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Published in Switzerland
ii
Contents Page
Foreword .iv
Introduction .v
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 1
4 Principle . 4
5 Reagents . 4
6 Apparatus . 6
7 Sample preparation .7
7.1 Sample size . 7
7.2 Determination of the filling volume . 7
7.2.1 Flat-bottomed containers ≤20 mm outer flange diameter (except ampoules,
syringes and cartridges) . 7
7.2.2 Flat-bottomed containers >20 mm outer flange diameter. 7
7.2.3 Round-bottomed containers . 8
7.2.4 Lipped containers . 8
7.2.5 Ampoules. 8
7.2.6 Syringes and cartridges . 8
8 Procedure .9
8.1 General . 9
8.2 Cleaning of samples . 9
8.3 Filling and heating . 9
8.4 Analysis of the extraction solutions . 10
8.4.1 Containers of hydrolytic resistance container classes HC 1, HC 2 and
F F
HC B or those known to be made from borosilicate glass . 10
F
8.4.2 Containers of hydrolytic resistance container classes HC 3 and HC D, or
F F
those known to be made from soda-lime-silica glass. 10
8.5 Test to determine whether the containers have been surface-treated. 11
9 Expression of results .12
9.1 Determination . 12
9.2 Classification .12
9.3 Distinction between containers of hydrolytic resistance container class HC 1 and
F
hydrolytic resistance container class HC 2 . 13
F
9.4 Designation . 13
10 Test report .13
11 Reproducibility .13
Bibliography .15
iii
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
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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 document should be noted. This document was drafted in accordance with the
editorial rules of the ISO/IEC Directives, Part 2 (see www.iso.org/directives).
ISO draws attention to the possibility that the implementation of this document may involve the use
of (a) patent(s). ISO takes no position concerning the evidence, validity or applicability of any claimed
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www.iso.org/iso/foreword.html.
This document was prepared by Technical Committee ISO/TC 76, Transfusion, infusion and injection, and
blood processing equipment for medical and pharmaceutical use.
This fourth edition cancels and replaces the third edition (ISO 4802-2:2016), which has been technically
revised.
The main changes are as follows:
— the explanation of the hydrolytic classes HC 1, HC 2, HC 3, HC B, HC D for different glass types;
F F F F F
— clarification of needed properties of purified water and test water;
— harmonization of the samples cleaning and the autoclavation process with Ph.Eur.;
— including containers up to 0,5 ml filling volume.
A list of all parts in the ISO 4802 series can be found on the ISO website.
Any feedback or questions on this document should be directed to the user’s national standards body. A
complete listing of these bodies can be found at www.iso.org/members.html.
iv
Introduction
This document is largely based on a test method approved by the International Commission on Glass
(ICG), Technical Committee 2, Chemical Durability and Analysis, for measuring the hydrolytic resistance
of the interior surfaces of glass containers.
This document contains a classification which is related to but not equivalent to the classification set up
in ISO 4802-1 for the titration method.
The hydrolytic resistance of the inner glass surface is evaluated by determination of the released
alkali reacting ions. According to their hydrolytic resistance, glass containers are classified in defined
categories.
HC 1 glass containers are suitable for most preparations whether or not for parenteral administration.
F
HC 2 glass containers are suitable for most acidic and neutral, aqueous preparations whether or not for
F
parenteral administration.
HC 3 glass containers are in general suitable for non-aqueous preparations for parenteral
F
administration, for powders for parenteral administration (except for freeze-dried preparations) and
for preparations not for parenteral administration.
HC B glass containers are in general suitable for drinking ampoules (Container Class HGB 2 according
F
to ISO 719).
HC D glass containers are in general suitable for lower demands on hydrolytic resistance (Container
F
Class HGB 4 and HGB 5 according to ISO 719).
v
INTERNATIONAL STANDARD ISO 4802-2:2023(E)
Glassware — Hydrolytic resistance of the interior surfaces
of glass containers —
Part 2:
Determination by flame spectrometry and classification
1 Scope
This document specifies:
a) a method for determining the hydrolytic resistance of the interior surfaces of glass containers
when subjected to attack by water at (121 ± 1) °C for (60 ± 1) min. The resistance is measured by
determining the amount of sodium and other alkali metal or alkaline earth oxides in the extraction
solution using flame atomic emission or absorption spectrometry (flame spectrometry);
b) a classification of glass containers according to the hydrolytic resistance of the interior surfaces
determined by the methods specified in this document.
The test method specified in this document might not be applicable to containers whose surfaces have
been treated for functional modifications, e.g. silicone (e.g. containers that are ready for direct filling).
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 385, Laboratory glassware — Burettes
ISO 719, Glass — Hydrolytic resistance of glass grains at 98 °C — Method of test and classification
ISO 720, Glass — Hydrolytic resistance of glass grains at 121 °C — Method of test and classification
ISO 1042, Laboratory glassware — One-mark volumetric flasks
ISO 3819, Laboratory glassware — Beakers
ISO 9187-1, Injection equipment for medical use — Part 1: Ampoules for injectables
3 Terms and definitions
For the purposes of this document, the following terms and definitions apply.
ISO and IEC maintain terminology databases for use in standardization at the following addresses:
— ISO Online browsing platform: available at https:// www .iso .org/ obp
— IEC Electropedia: available at https:// www .electropedia .org/
3.1
ampoule
small, normally flat-bottomed container having stems in many different forms
Note 1 to entry: Ampoules are usually thin-walled and have a capacity normally up to 30 ml. They are intended to
be closed, after filling, by flame sealing.
3.2
bottle
flat-bottomed container, made from moulded glass
Note 1 to entry: Bottles are normally thick-walled and have a capacity usually of more than 5 ml. They may be
of circular or other geometric cross-section. Bottles are sealed with a closure made from a material other than
glass, and not by flame-sealing.
3.3
brimful capacity
volume of water required to fill a container, placed on a flat, horizontal surface
3.4
container
article made from glass to be used as primary packaging material intended to come into direct contact
with a pharmaceutical preparation
EXAMPLE Bottles, vials, syringes, ampoules and cartridges. See also Figure 1.
Note 1 to entry: These containers are made from borosilicate or soda-lime-silica glass.
3.5
filling volume
defined volume of water to fill the test specimen
Note 1 to entry: For the determination of the filling volume, see 7.2. The filling volume is a test specific quantity
that is used to compare container sets from different sources or lots. It has no relation to the nominal product
volume.
3.6
borosilicate glass
silicate glass having a very high hydrolytic resistance due to its composition containing significant
amounts of boric oxide
Note 1 to entry: Borosilicate glass contains a mass fraction of boric oxide between 5 % and 13 %. This glass type
may also contain aluminium oxide and/or alkaline earth oxides.
Note 2 to entry: Neutral glass is a borosilicate glass having a very high hydrolytic resistance and a high thermal
shock resistance. When tested according to ISO 720, it meets the requirements of class HGA 1. Containers
properly made from this glass conform with hydrolytic resistance container class HC 1 of this document.
F
3.7
soda-lime-silica glass
silicate glass containing a mass fraction up to approximately 15 % of alkali metal oxides, mainly sodium
oxide, and a mass fraction up to about 15 % of alkaline earth oxides, mainly calcium oxide
Note 1 to entry: Containers made from this glass will have a moderate hydrolytic resistance due to the chemical
composition of the glass, and conform with hydrolytic resistance container class HC 3.
F
a) Example of a glass cylinder for a pen-injec- b) Example of an injection vial made of glass
tor/cartridge (see ISO 13926-1) tubing (see ISO 8362-1)
c) Example of a syringe glass barrel d) Example of a stem cut ampoule with con-
(see ISO 11040-4) striction (see ISO 9187-1)
Figure 1 — Examples of containers
3.8
surface treatment
treatment of the internal surface of glass containers with reagents in order to achieve a de-alkalized
surface and to produce a significantly lower release of alkali metal ions (and alkali earth metal ions)
Note 1 to entry: Surface treatment is used, for example, in order to change a soda-lime-silica glass container of
hydrolytic resistance class HC 3 to a container of hydrolytic resistance class HC 2 container. Treated containers
F F
are rinsed before use.
3.9
vial
small, flat-bottomed container, made from tubing or from moulded glass
Note 1 to entry: Vials are normally thick-walled and have a capacity up to 100 ml. They are normally sealed with
a closure made from a material other than glass, and not by flame-sealing.
4 Principle
This test method is a surface test applied to glass containers as produced and/or as delivered.
The containers to be tested are filled with specified water to a specified capacity. They are loosely
capped and then heated under specified conditions. The degree of the hydrolytic attack is measured
by flame spectrometric analysis of the extraction solutions. The measurement data shall be classified
in accordance with the limits defined in appropriate container specific limit values in accordance with
Table 2.
Dependent on different glass types, specific limit values are defined in the following:
The hydrolytic resistance is evaluated by determination of the released alkali reacting ions. According
to their hydrolytic resistance, glass containers are classified as follows:
— HC 1 glass containers: neutral glass, borosilicate glass with a high hydrolytic resistance due to the
F
chemical composition of the glass itself;
[12] [15]
NOTE 1 In the Ph.Eur. 3.2.1 and the USP <660> the hydrolytic resistance classification are designated
Type I.
— HC 2 glass containers: usually of soda-lime-silica glass with a high hydrolytic resistance resulting
F
from suitable treatment of the inner surface;
[12] [15]
NOTE 2 In the Ph.Eur. 3.2.1 and the USP <660> the hydrolytic resistance classification are designated
Type II.
— HC 3 glass containers: usually of soda-lime-silica glass with only moderate hydrolytic resistance;
F
[12] [15]
NOTE 3 In the Ph.Eur. 3.2.1 and the USP <660> the hydrolytic resistance classification are designated
Type III.
— HC B glass containers: usually made of borosilicate or soda-lime-silica glass composition with
F
higher hydrolytic resistance (container class: HGB 2 according to ISO 719);
— HC D glass containers: usually made of soda-lime-silica glass with low hydrolytic resistance
F
(container class: HGB 4 or HGB 5 according to ISO 719).
The index “F” indicates that the measures for the classification is based on Flame Spectrometry.
5 Reagents
During the test, unless otherwise stated, use only reagents of recognised analytical grade.
5.1 Test water, to be prepared as follows:
Prepare the test water from purified water (5.5) by multiple distillations. Remove the carbon dioxide
by boiling for at least 15 min before use in a boiling flask (6.3) of fused silica or borosilicate glass and
cool.
NOTE 1 Any other suitable method can be used, e.g. preparation of carbon dioxide-free water according to
[12] [15]
Ph.Eur. 3.2.1 , USP 660 .
When tested immediately before use, water prepared as described above shall produce an orange-
red (not violet-red or yellow) colour corresponding to the neutral point of methyl red indicator of
pH 5,5 ± 0,1 when 0,05 ml of methyl red indicator solution (5.5) is added to 50 ml of the water to be
examined.
This water may also be used as the reference solution (see 8.4).
The conductivity of the water shall not exceed 1 µS/cm, determined at 25 °C by an in-line conductivity
meter.
Where the use of test water is specified in the following analytical procedures the requirements for
bacterial endotoxins and microbial contamination are not relevant.
[12]
NOTE 2 This description is based on the Ph.Eur. 3.2.1 . In the Ph.Eur., water prepared as described above is
designated water R1.
[2]
NOTE 3 Water of Grade 2 according to ISO 3696 is suitable for this test.
5.2 Hydrochloric acid, solution, c(HCl) ≈ 2 mol/l.
5.3 Hydrochloric acid, solution, c(HCl) ≈ 6 mol/l (≈ 1 + 1).
5.4 Hydrofluoric acid, c(HF) ≈ 22 mol/l (i.e. ≈400 g HF/l solution).
CAUTION — Hydrofluoric acid is very toxic and highly corrosive. Consider using a material safety
data sheet.
5.5 Purified water, prepared by distillation, by ion exchange, by reverse osmosis or by any other
suitable method from water having drinking water quality.
Where the use of purified water is specified in the following analytical procedures, the requirements
for bacterial endotoxins and microbial contamination are not relevant.
NOTE 1 National or regional regulation on water intended for human consumption can apply.
NOTE 2 Water that corresponds to Grade 3 according to ISO 3696 is suitable.
[12]
NOTE 3 In the Ph.Eur. 3.2.1 , water as described above is designated water R.
5.6 Spectrochemical buffer solution (caesium chloride solution, CsCl).
Dissolve 80 g of caesium chloride in approximately 300 ml of test water (5.1), add 10 ml of hydrochloric
acid (5.3) and transfer to a 1 000 ml volumetric flask (6.3). Dilute to the mark with the test water (5.1)
and mix.
5.7 Stock solutions.
5.7.1 Dry sodium chloride, potassium chloride and calcium carbonate at (110 ± 5) °C for 2 h. Prepare
aqueous stock solutions, using the test water (5.1), directly from the chlorides and from the calcium
carbonate, after dissolving in the minimum amount of hydrochloric acid so that all solutions have
concentrations of 1 mg/ml, calculated as sodium oxide, potassium oxide and calcium oxide.
5.7.2 Commercially available standard solutions may also be used.
5.8 Standard solutions.
5.8.1 Prepare standard solutions by diluting the stock solutions (5.7) with the test water (5.1) to
obtain concentrations suitable for establishing the reference solutions in an appropriate manner, e.g.
with concentrations of 20 µg/ml of sodium oxide, potassium oxide and calcium oxide respectively.
5.8.2 Commercially available standard solutions may also be used.
5.9 Reference solutions.
The reference solutions for establishing the calibration graph (set of calibration solutions) shall be
prepared by diluting suitable concentrated standard solutions (5.8) with the
...