SIST EN ISO 8871-1:2005
(Main)Elastomeric parts for parenterals and for devices for pharmaceutical use - Part 1: Extractables in aqueous autoclavates (ISO 8871-1:2003)
Elastomeric parts for parenterals and for devices for pharmaceutical use - Part 1: Extractables in aqueous autoclavates (ISO 8871-1:2003)
ISO 8871-1:2003 defines procedures for classifying elastomeric parts for primary packs and medical devices used in direct contact with preparations for parenteral use, including both aqueous preparations and dry preparations which have to be dissolved before use.
It specifies a series of comparative test methods for chemical evaluation by the determination of extractables in aqueous autoclavates and describes the various fields of application for elastomeric parts. Dimensions and functional characteristics are specified in the relevant International Standards. Required properties as specified in this part of ISO 8871 are regarded as minimum requirements.
Elastomeric parts for empty syringes for single use are excluded from the scope of this part of ISO 8871 as they are not in contact with the injected preparation for a significant length of time.
Compatibility studies with the intended preparation have to be performed before the approval for final use can be given; however, this part of ISO 8871 does not specify procedures for carrying out compatibility studies.
Elastomere Teile für Parenteralia und für Geräte zur pharmazeutischen Verwendung - Teil 1: Extrahierbare Substanzen in wässrigen Autoklavaten (ISO 8871-1:2003)
1.1 Dieser Teil von ISO 8871 legt Verfahren zur Einteilung von Elastomerteilen für Primärverpackungen und Medizinprodukte fest, die in direktem Kontakt mit wässrigen Zubereitungen zur parenteralen Anwendung (einschließlich Trockenpräparaten, die vor Gebrauch aufgelöst werden müssen) stehen, fest.
Sie legt eine Reihe vergleichender Prüfverfahren zur chemischen Bewertung (siehe Abschnitt 4) fest und beschreibt die vielfältigen Anwendungsgebiete für Elastomerteile. Maße und funktionelle Eigenschaften sind in den entsprechenden Internationalen Normen festgelegt. Die in diesem Teil von ISO 8871 festgelegten geforderten Eigenschaften sind als Mindestanforderungen zu verstehen.
1.2 Dieser Teil von ISO 8871 gilt für die in Abschnitt 3 aufgeführten Kategorien von Elastomerteilen; spezifische Anforderungen sind jedoch in den entsprechenden Internationalen Normen festgelegt, die die in Abschnitt 3 aufgeführten Gegenstände oder Geräte behandeln.
Elastomerteile für leere Einmalspritzen sind vom Anwendungsbereich dieses Teils von ISO 8871 ausgeschlossen, da sie nur kurzzeitig mit dem Injektionspräparat in Kontakt sind.
1.3 Bevor die endgültige Zulassung zur Anwendung gegeben werden kann, sind Verträglichkeitsuntersuchungen mit dem vorgesehenen Präparat durchzuführen; dieser Teil von ISO 8871 legt jedoch keine Verfahren zur Durchführung von Verträglichkeitsuntersuchungen fest.
Eléments en élastomere pour administration parentérale et dispositifs a usage pharmaceutique - Partie 1: Substances extractibles par autoclavage en milieu aqueux (ISO 8871-1:2003)
L'ISO 8871-1:2003 définit des modes opératoires permettant de classer les éléments en élastomère constituant les emballages primaires et les dispositifs médicaux qui entrent directement en contact avec les préparations à usage parentéral, y compris les préparations aqueuses et les préparations sèches qui doivent être dissoutes avant utilisation.
Elle spécifie une série de méthodes d'essai comparatives pour l'évaluation chimique par la détermination des substances extractibles par autoclavage en milieu aqueux et décrit les divers champs d'application des éléments en élastomère. Les dimensions et les caractéristiques fonctionnelles sont spécifiées dans les Normes internationales appropriées. Les propriétés requises spécifiées dans l'ISO 8871-1:2003 sont considérées comme des exigences minimales.
Les éléments en élastomère pour seringues vides non réutilisables sont exclus du domaine d'application de l'ISO 8871-1:2003, car ils n'entrent pas en contact avec la préparation injectée pendant une période de temps significative.
Des études de compatibilité avec les préparations prévues doivent être entreprises avant de pouvoir approuver ces éléments pour leur emploi final; toutefois, l'ISO 8871-1:2003 ne spécifie pas les procédures à suivre pour effectuer des études de compatibilité.
Deli iz elastomera za parenteralne farmacevtske oblike - 1. del: Izločki v vodnih avtoklavih (ISO 8871-1:2003)
General Information
Relations
Standards Content (Sample)
SLOVENSKI STANDARD
SIST EN ISO 8871-1:2005
01-marec-2005
'HOLL]HODVWRPHUD]DSDUHQWHUDOQHIDUPDFHYWVNHREOLNHGHO ,]ORþNLYYRGQLK
DYWRNODYLK ,62
Elastomeric parts for parenterals and for devices for pharmaceutical use - Part 1:
Extractables in aqueous autoclavates (ISO 8871-1:2003)
Elastomere Teile für Parenteralia und für Geräte zur pharmazeutischen Verwendung -
Teil 1: Extrahierbare Substanzen in wässrigen Autoklavaten (ISO 8871-1:2003)
Eléments en élastomere pour administration parentérale et dispositifs a usage
pharmaceutique - Partie 1: Substances extractibles par autoclavage en milieu aqueux
(ISO 8871-1:2003)
Ta slovenski standard je istoveten z: EN ISO 8871-1:2004
ICS:
11.040.20 Transfuzijska, infuzijska in Transfusion, infusion and
injekcijska oprema injection equipment
SIST EN ISO 8871-1:2005 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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SIST EN ISO 8871-1:2005
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SIST EN ISO 8871-1:2005
EUROPEAN STANDARD
EN ISO 8871-1
NORME EUROPÉENNE
EUROPÄISCHE NORM
September 2004
ICS 11.040.20 Supersedes EN ISO 8871:1997
English version
Elastomeric parts for parenterals and for devices for
pharmaceutical use - Part 1: Extractables in aqueous
autoclavates (ISO 8871-1:2003)
Eléments en élastomère pour administration parentérale et
dispositifs à usage pharmaceutique - Partie 1: Substances
extractibles par autoclavage en milieu aqueux (ISO 8871-
1:2003)
This European Standard was approved by CEN on 15 July 2004.
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, Slovakia,
Slovenia, Spain, Sweden, Switzerland and United Kingdom.
EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION
EUROPÄISCHES KOMITEE FÜR NORMUNG
Management Centre: rue de Stassart, 36 B-1050 Brussels
© 2004 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 8871-1:2004: E
worldwide for CEN national Members.
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SIST EN ISO 8871-1:2005
EN ISO 8871-1:2004 (E)
Foreword
The text of ISO 8871-1:2003 has been prepared by Technical Committee ISO/TC 76
"Transfusion, infusion and injection equipment for medical and pharmaceutical use" of the
International Organization for Standardization (ISO) and has been taken over as EN ISO 8871-
1:2004 by CMC.
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 March 2005, and conflicting national
standards shall be withdrawn at the latest by March 2005.
This document supersedes EN ISO 8871:1997.
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, Slovakia, Slovenia, Spain, Sweden, Switzerland and United Kingdom.
Endorsement notice
The text of ISO 8871-1:2004 has been approved by CEN as EN ISO 8871-1:2004 without any
modifications.
NOTE Normative references to International Standards are listed in annex ZA (normative).
2
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SIST EN ISO 8871-1:2005
EN ISO 8871-1:2004 (E)
Annex ZA
(normative)
Normative references to international publications
with their relevant European publications
This European Standard incorporates by dated or undated reference, provisions from other
publications. These normative references are cited at the appropriate places in the text and the
publications are listed hereafter. For dated references, subsequent amendments to or revisions of
any of these publications apply to this European Standard only when incorporated in it by
amendment or revision. For undated references the latest edition of the publication referred to
applies (including amendments).
NOTE Where an International Publication has been modified by common modifications, indicated
by (mod.), the relevant EN/HD applies.
Publication Year Title EN Year
ISO 8362-2 1988 Injection containers for injectables EN 28362-2 1993
and accessories - Part 2: Closures
for injection vials
3
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SIST EN ISO 8871-1:2005
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SIST EN ISO 8871-1:2005
INTERNATIONAL ISO
STANDARD 8871-1
First edition
2003-10-01
Elastomeric parts for parenterals and for
devices for pharmaceutical use —
Part 1:
Extractables in aqueous autoclavates
Éléments en élastomère pour administration parentérale et dispositifs à
usage pharmaceutique —
Partie 1: Substances extractibles par autoclavage en milieu aqueux
Reference number
ISO 8871-1:2003(E)
©
ISO 2003
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SIST EN ISO 8871-1:2005
ISO 8871-1:2003(E)
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Published in Switzerland
ii © ISO 2003 — All rights reserved
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SIST EN ISO 8871-1:2005
ISO 8871-1:2003(E)
Contents Page
Foreword. iv
Introduction . v
1 Scope. 1
2 Normative references . 1
3 Classification. 2
4 Requirements . 2
5 Sampling . 2
6 Apparatus and reagents. 3
7 Preparation of test solutions . 4
Annex A (normative) Appearance of solution . 5
Annex B (normative) Acidity or alkalinity . 9
Annex C (normative) Absorbance . 10
Annex D (normative) Reducing substances. 11
Annex E (normative) Extractable heavy metals . 12
Annex F (normative) Extractable zinc . 14
Annex G (normative) Extractable ammonia. 15
Annex H (normative) Residue on evaporation . 16
Annex I (normative) Volatile sulfides .17
Annex J (informative) Conductivity . 18
Bibliography . 19
© ISO 2003 — All rights reserved iii
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SIST EN ISO 8871-1:2005
ISO 8871-1:2003(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 8871-1 was prepared by Technical Committee ISO/TC 76, Transfusion, infusion and injection equipment
for medical and pharmaceutical use.
Together with the other parts (see below), this part of ISO 8871 cancels and replaces ISO 8871:1990, which
has been technically revised.
ISO 8871 consists of the following parts, under the general title Elastomeric parts for parenterals and for
devices for pharmaceutical use:
Part 1: Extractables in aqueous autoclavates
Part 2: Identification and characterization
Part 3: Determination of released-particle count
Part 4: Biological requirements and test methods
Part 5: Functional requirements and testing
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SIST EN ISO 8871-1:2005
ISO 8871-1:2003(E)
Introduction
The elastomeric parts specified in the various parts of this International Standard are produced from a material
which is usually called “rubber”. However, rubber is not a unique entity, since the composition of rubber
materials may vary considerably. The base elastomer and the type of vulcanization have a major influence on
the principle characteristics of an individual rubber material, as do additives such as fillers, softeners and
pigments. These may have a significant effect on the overall properties. The effectiveness, purity, stability and
safe handling of a drug preparation may be affected adversely during manufacture, storage and administration
if the rubber part used has not been properly selected and validated (approved).
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SIST EN ISO 8871-1:2005
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SIST EN ISO 8871-1:2005
INTERNATIONAL STANDARD ISO 8871-1:2003(E)
Elastomeric parts for parenterals and for devices for
pharmaceutical use —
Part 1:
Extractables in aqueous autoclavates
1 Scope
1.1 This part of ISO 8871 defines procedures for classifying elastomeric parts for primary packs and
medical devices used in direct contact with preparations for parenteral use, including both aqueous
preparations and dry preparations which have to be dissolved before use.
It specifies a series of comparative test methods for chemical evaluation by the determination of extractables
in aqueous autoclavates (see Clause 4) and describes the various fields of application for elastomeric parts.
Dimensions and functional characteristics are specified in the relevant International Standards. Required
properties as specified in this part of ISO 8871 are regarded as minimum requirements.
1.2 This part of ISO 8871 is applicable for the categories of elastomeric parts given in Clause 3; specific
requirements, however, are laid down in the relevant International Standards dealing with the items or devices
listed in Clause 3.
Elastomeric parts for empty syringes for single use are excluded from the scope of this part of ISO 8871 as
they are not in contact with the injected preparation for a significant length of time.
1.3 Compatibility studies with the intended preparation have to be performed before the approval for final
use can be given; however, this part of ISO 8871 does not specify procedures for carrying out compatibility
studies.
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 8362-2:1988, Injection containers for injectables and accessories — Part 2: Closures for injection vials
ISO 8362-5:1995, Injection containers for injectables and accessories — Part 5: Freeze drying closures for
injection vials
ISO 8536-2:2001, Infusion equipment for medical use — Part 2: Closures for infusion bottles
ISO 8536-6:1995, Infusion equipment for medical use — Part 6: Freeze drying closures for infusion bottles
ISO 11040-2:1994, Prefilled syringes — Part 2: Plungers and discs for dental local anaesthetic cartridges
ISO 11040-5:2001, Prefilled syringes — Part 5: Plungers for injectables
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SIST EN ISO 8871-1:2005
ISO 8871-1:2003(E)
3 Classification
Elastomeric parts exist in various designs and sizes depending on the intended end-use. These parts serve
different purposes depending on the item or device in which they are incorporated. Elastomeric parts have,
therefore, been classified into the following categories:
elastomeric parts for injection vials (see ISO 8362-2);
elastomeric parts for infusion bottles (see ISO 8536-2);
elastomeric parts for prefilled syringes (see ISO 11040-2 and ISO 11040-5);
elastomeric parts for medical devices for pharmaceutical use (excluding gloves and probes);
elastomeric parts for freeze-dried products (see ISO 8362-5 and ISO 8536-6).
4 Requirements
4.1 Resistance to steam sterilization
Elastomeric parts shall not lose their required biological, chemical and physical properties after being sterilized
twice in saturated steam at (121 ± 2) °C for 30 min each time.
4.2 Chemical requirements
Elastomeric parts shall comply with the chemical requirements specified in Table 1.
Elastomers are divided into the following types:
Type I elastomer: this meets the strictest requirements and is the preferred type.
Type II elastomer: this does not meet these severe requirements as a result of its different chemical
composition which is necessary to give the mechanical properties required for special applications (e.g.
multiple piercing).
The methods to be used to determine the chemical characteristics of the elastomeric parts are specified in
Annex A to Annex J.
5 Sampling
Take a random sample of the elastomeric parts which is representative of each delivery, with the parts in their
original state. The number of elastomeric parts taken shall be as specified in the relevant International
Standards (see Clause 3).
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SIST EN ISO 8871-1:2005
ISO 8871-1:2003(E)
Table 1 — Chemical requirements for testing aqueous autoclavates
Characteristic Requirements Test as described in
Clause/Annex
Turbidity Type l: Not more turbid than reference suspension II A.1
Type Il: Not more turbid than reference suspension III
Colour Type I and II: Not more intensely coloured than reference A.2
solution GY
5
Acidity/alkalinity Type I and II: B
u 0,3 ml sodium hydroxide solution, c(NaOH) = 0,01 mol/l
or
u 0,8 ml hydrochloric acid, c(HCI) = 0,01 mol/l
Absorbance Type l: u 0,2 AU across the whole range from 220 nm to 360 nm C
Type II: u 4,0 AU across the whole range from 220 nm to 360 nm
Reducing substances Type l: u 3,0 ml sodium thiosulfate solution, D
c(Na S O ) = 0,01 mol/l
2 2 3
Type II: u 7,0 ml sodium thiosulfate solution,
c(Na S O ) = 0,01 mol/l
2 2 3
Extractable heavy metals Type I and II: u 2,0 mg/l E
Extractable zinc Type I and II: u 5,0 mg/l F
Extractable ammonia Type I and II: u 2,0 mg/l G
Residue on evaporation Type I: u 2,0 mg/50 ml H
Type II: u 4,0 mg/50 ml
Volatile sulfides Type I and II: Black stain on acetate paper shall not be larger or I
2
darker than reference (0,154 mg Na S for every 20 cm of
2
stopper surface area.)
Conductivity (optional) Type I: u 15 µS/cm J
Type II: u 30 µS/cm
A blank may be prepared where appropriate for system control, but correction of the result using the blank result is only
allowed if mentioned in the corresponding annex.
6 Apparatus and reagents
6.1 Use only reagents of recognized analytical grade. For the preparation of standard solutions, see the
relevant annex.
6.2 Use purified water prepared by distillation or by any other suitable means.
Its conductivity shall be less than 3,0 µS/cm.
NOTE Purified water as specified in various national pharmacopoeias corresponds to grade 1 and grade 2 water as
specified in ISO 3696.
6.3 Glassware shall be made from borosilicate glass.
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SIST EN ISO 8871-1:2005
ISO 8871-1:2003(E)
7 Preparation of test solutions
7.1 Closures shall be processed in the as-delivered condition.
7.2 Place a suitable number of complete elastomeric parts in a wide-necked flask and add 300 ml of
2
purified water for every 150 cm of surface area of the elastomeric parts. Cover the mouth of the flask, e.g.
with aluminium foil or an inverted borosilicate glass beaker. Weigh the flask plus contents. Heat in an
autoclave so that a temperature of (121 ± 2) °C is reached within 20 min to 30 min and maintain this
temperature for 30 min. Cool to room temperature over about 30 min. Make up to the original mass with
purified water if necessary (if tightly closed containers are not used).
Shake this solution (solution S ) and immediately separate it from the elastomeric parts. Shake solution S
1 1
before each test.
7.3 Prepare a blank solution (solution S ) in the same way as for solution S except that 300 ml of purified
0 1
water are used without the elastomeric parts.
7.4 Use solutions S and S obtained as described to carry out the chemical tests.
1 0
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SIST EN ISO 8871-1:2005
ISO 8871-1:2003(E)
Annex A
(normative)
Appearance of solution
A.1 Turbidity of solution S
1
A.1.1 General
The determination may be carried out instrumentally using a turbidimeter or by visual comparison.
A.1.2 Visual comparison with standards
A.1.2.1 Reagents
A.1.2.1.1 Hydrazine sulfate solution
Dissolve 1,0 g of hydrazine sulfate in water and dilute to 100 ml with water. Allow to stand for 4 h to 6 h.
A.1.2.1.2 Hexamethylenetetramine solution
Dissolve 2,5 g of hexamethylenetetramine in 25,0 ml of water in a glass-stoppered 100 ml flask.
A.1.2.1.3 Stock suspension
To the solution of hexamethylenetetramine in the flask add 25,0 ml of hydrazine sulfate solution. Mix and allow
to stand for 24 h. This suspension is stable for 2 months, provided it is stored in a glass container free from
surface defects. Discard if the suspension adheres to the glass. Mix well before use.
A.1.2.1.4 Standard suspension
Dilute 15,0 ml of the stock suspension to 1 000 ml with water. This suspension shall be freshly prepared and
may not be stored for longer than 24 h.
A.1.2.1.5 Reference suspensions
Prepare reference suspensions in accordance with Table A.1. Mix well before use.
Table A.1
I II III
Standard suspension 5,0 ml 10,0 ml 30,0 ml
Water 95,0 ml 90,0 ml 70,0 ml
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SIST EN ISO 8871-1:2005
ISO 8871-1:2003(E)
A.1.2.2 Procedure
Use identical test tubes made of colourless, transparent, neutral glass, and with a flat base and an internal
diameter of 15 mm to 25 mm. Fill one tube to a depth of 40 mm with solution S and three others to the same
1
depth with the reference suspensions (see Table A.1). Compare the solutions in diffuse daylight 5 min after
preparation of the reference suspensions, viewing vertically against a black background. The light conditions
shall be such that reference suspension I can be readily distinguished from water, and that reference
suspension II can be readily distinguished from reference suspension I.
A.1.3 Instrumental determination by turbidimeter
The reference suspensions prepared in A.1.2.1.5 represent the following limits:
1)
Reference suspension II: 6 FTU (type I elastomers)
Reference suspension III 18 FTU (type II elastomers)
Check the instrument on a regular basis to ensure that it defines these limits correctly.
A.1.4 Expression of results
Report the result as “complies”/“does not comply” with type I or type II requirements (see Table 1).
A.2 Colouration of solution S
1
A.2.1 Reagents
A.2.1.1 Stock yellow solution
Dissolve 46 g of ferric chloride in about 900 ml of a mixture of 25 ml of concentrated hydrochloric acid
(∼ 36 %) and 975 ml of water and make up to 1 000 ml with the same mixture. Titrate (see A.2.1.2) and adjust
the concentration of the solution to 45,0 mg of FeCl ⋅6H O per millilitre by adding the same mixture. Protect
3 2
the solution from light.
A.2.1.2 Titration
Into a 250 ml conical flask fitted with a ground-glass stopper, place 10,0 ml of the stock solution, 15 ml of
water, 5 ml of concentrated hydrochloric acid and 4 g of potassium iodide. Close the flask, allow to stand in
the dark for 15 min and then add 100 ml of water. Titrate the liberated iodine with 0,1 mol/l sodium thiosulfate,
using 0,5 ml of starch solution (A.2.1.8), added towards the end of the titration, as indicator.
1 ml of 0,1 mol/l sodium thiosulfate is equivalent to 27,03 mg of FeCI ⋅6H O.
3 2
A.2.1.3 Stock red solution
Dissolve 60 g of cobalt chloride in about 900 ml of a mixture of 25 ml of concentrated hydrochloric acid and
975 ml of water and make up to 1 000 ml with the same mixture. Titrate (see A.2.1.4) and adjust the
concentration of the solution to 59,5 mg of CoCl ⋅6H O per millilitre by adding the same mixture.
2 2
1) Formazine turbidity units.
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SIST EN ISO 8871-1:2005
ISO 8871-1:2003(E)
A.2.1.4 Titration
Into a 250 ml conical flask fitted with a ground-glass stopper, place 5,0 ml of the stock solution, 5 ml of dilute
hydrogen peroxide solution and 10 ml of a 300 g/l solution of sodium hydroxide. Boil gently for 10 min, allow to
cool and add 60 ml of dilute sulfuric acid (A.2.1.7) and 2 g of potassium iodide. Close the flask and dissolve
the precipitate by shaking gently. Titrate the liberated iodine with 0,1 mol/l sodium thiosulfate, using 0,5 ml of
starch solution (A.2.1.8), added towards the end of the titration, as indicator. The end-point is reached when
the solution turns pink.
1 ml of 0,1 mol/l sodium thiosulfate is equivalent to 23,79 mg of CoCl ⋅6H O.
2 2
A.2.1.5 Stock blue solution
Dissolve 63 g of copper sulfate in about 900 ml of a mixture of 25 ml of concentrate hydrochloric acid and
975 ml of water and make up to 1 000 ml with the same mixture. Titrate (see A.2.1.6) and adjust the
concentration of the solution to 62,4 mg of CuSO ⋅5H O per millilitre by adding the same mixture.
4 2
A.2.1.6 Titration
Into a 250 ml conical flask fitted with a ground-glass stopper, place 10,0 ml of the stock solution, 50 ml of
water, 12 ml of dilute acetic acid (∼ 12 %) and 3 g of potassium iodide. Titrate the liberated iodine with
0,1 mol/l sodium thiosulfate, using 0,5 ml of starch solution (A.2.1.8), added towards the end of the titration, as
indicator. The end-point is reached when the solution shows a slight pale-brown colour.
1 ml of 0,1 mol/l sodium thiosulfate is equivalent to 24,97 mg of CuSO ⋅5H O.
4 2
A.2.1.7 Sulfuric acid, dilute
Prepare a solution containing 98 g of sulfuric acid per litre of water.
A.2.1.8 Starch solution
Triturate 1,0 g of soluble starch with 5 ml of water and, whilst stirring, pour the mixture into 100 ml of boiling
water containing 10 mg of mercuric iodide.
A.2.1.9 Standard solution
From the three stock solutions, prepare a standard solution as follows:
Table A.2 — Standard solution GY
Volumes in millilitres
Stock yellow Stock red Stock blue
Standard solution
solution solution solution
GY (greenish-yellow) 9,6 0,2 0,2
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SIST EN ISO 8871-1:2005
ISO 8871-1:2003(E)
A.2.1.10 Reference solution
From the standard solution, prepare a reference solution as follows:
Table A.3 — Reference solution GY
5
Volumes in millilitres
Hydrochloric acid
Reference solution Standard solution GY
(10 g/l HCI)
GY 3,0 97,0
5
Prepare the reference solution immediately before use.
A.2.2 Procedure
Use identical test tubes made of colourless, transparent, neutral glass, and with a flat base and an internal
diameter of 15 mm to 25 mm. Fill one tube to a depth of 40 mm with solution S and another to the same
1
depth with the reference solution (see Table A.3). Compare the solutions in diffuse daylight, viewing vertically
against a white background.
Using identical tubes of colourless, transparent, neutral glass with a flat base and an external diameter of
15 mm to 25 mm, compare the liquid to be examined with the reference solution (see Table A.3). The depth of
the layer being 40 mm. Compare the colours in diffuse daylight, viewing vertically against a white background.
A.2.3 Expression of results
Report the result as “complies”/“does not comply” with the requirement (see Table 1).
8 © ISO 2003 — All rights reserved
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SIST EN ISO 8871-1:2005
ISO 8871-1:2003(E)
Annex B
(normative)
Acidity or alkalinity
B.1 General
Depending on their composition, some types of closure formulation contain ingredients which may act as
acids or alkalis. If acidic or alkaline material is extracted, a change in the pH-value, which may adversely
affect the stability of a pharmaceutical product, may occur. Such a change in the pH-value can be determined
by potentiometric measurement of the aqueous extract using a pH electrode. However, the potentiometric
determination may lead to misleading results when measurements are performed in unbuffered systems
around pH 7. Therefore, it is recommended that a titration method be used to determine acidity or alkalinity.
B.2 Reagents
B.2.1 Bromothymol blue solution
Dissolve 50 mg of bromothymol blue in a mixture
...
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