ISO 4802-1:2023

INTERNATIONAL ISO
STANDARD 4802-1
Fourth edition
2023-12
Glassware — Hydrolytic resistance
of the interior surfaces of glass
containers —
Part 1:
Determination by titration method
and classification
Verrerie — Résistance hydrolytique des surfaces internes des
récipients en verre —
Partie 1: Détermination par analyse titrimétrique 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 . 5
7 Sample preparation .6
7.1 Sample size . 6
7.2 Determination of the filling volume . 6
7.2.1 Flat-bottomed containers ≤20 mm outer flange diameter (except ampoules,
syringes and cartridges) . 6
7.2.2 Flat-bottomed containers >20 mm outer flange diameter. 7
7.2.3 Round-bottomed containers . 7
7.2.4 Lipped containers . 7
7.2.5 Ampoules. 7
7.2.6 Syringes and cartridges . 7
8 Procedure .8
8.1 General . 8
8.2 Cleaning of samples . 8
8.3 Filling and heating . 8
8.4 Analysis of the extraction solutions . 9
8.5 Test to determine whether the containers have been surface-treated. 10
9 Expression of results .10
9.1 Determination . 10
9.2 Classification . 10
9.3 Distinction between containers of hydrolytic resistance container class HC 1 and
T
hydrolytic resistance container class HC 2 . 10
T
9.4 Designation . 11
10 Test report .11
11 Reproducibility .12
Bibliography .13
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
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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 4802-1:2016), which has been technically
revised.
The main changes are as follows:
— adding a complete description of the categories HC 1, HC 2, HC 3, HC B, HC D;
T T T T T
— aligning the autoclaving to the 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.
The European Pharmacopoeia Commission has adopted the principle of the determination by titration
and has set up a classification for glass containers for injectable preparations, which is included in this
document. In addition, this document contains a classification of containers other than for injectable
preparations.
According to international interlaboratory tests, this document specifies the test conditions in more
detail than the European Pharmacopoeia in order to increase the reproducibility of the test results. In
particular, the autoclaving cycle is described in detail.
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.
T
HC 2 glass containers are suitable for most acidic and neutral, aqueous preparations whether or not for
T
parenteral administration.
HC 3 glass containers are in general suitable for non-aqueous preparations for parenteral
T
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
T
to ISO 719).
HC D glass containers are in general suitable for lower demands on hydrolytic resistance (Container
T
Class HGB 4 and HGB 5 according to ISO 719).
v
INTERNATIONAL STANDARD ISO 4802-1:2023(E)
Glassware — Hydrolytic resistance of the interior surfaces
of glass containers —
Part 1:
Determination by titration method 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 titration
of a known aliquot portion of the extraction solution produced with hydrochloric acid solution, in
which case the resistance is inversely proportional to the volume of acid required;
b) a classification of glass containers according to the hydrolytic resistance of the interior surfaces
determined by the methods specified in this document.
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 648, Laboratory glassware — Single-volume pipettes
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 1773, Laboratory glassware — Narrow-necked boiling 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 usually between 5 % and 13 %. This
glass type can 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 in accordance with 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.
T
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 have a moderate hydrolytic resistance due to the chemical
composition of the glass, and conform with hydrolytic resistance container class HC 3.
T
a) Example of a glass cylinder for a pen–injector b) Example of an injection vial made of glass
/ 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
T T
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
titration of the extraction solutions. The measurement data shall be classified according to 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
T
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
T
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;
T
[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
T
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
T
(container class: HGB 4 or HGB 5 according to ISO 719).
The index “T” indicates that the measures for the classification are based on titration.
5 Reagents
During the test, unless otherwise stated, use only reagents of recognized analytical grade.
5.1 Test water, to be prepared as follows:
Prepare the test water from purified water (5.6) 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 and 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 acco
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