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SIST EN ISO 15194:2009
01-julij-2009
'LDJQRVWLþQLPHGLFLQVNLSULSRPRþNLLQYLWUR0HUMHQMHNROLþLQYY]RUFLKELRORãNHJD
L]YRUD=DKWHYH]DFHUWLILFLUDQHUHIHUHQþQHPDWHULDOHLQYVHELQRSRGSRUQH
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In vitro diagnostic medical devices - Measurement of quantities in samples of biological
origin - Requirements for certified reference materials and the content of supporting
documentation (ISO 15194:2009)
In-vitro-Diagnostika - Messung von Größen in Proben biologischen Ursprungs -
Anforderungen an zertifizierte Referenzmaterialien und an den Inhalt der
Begleitdokumentation (ISO 15194:2009)
Dispositifs médicaux de diagnostic in vitro - Mesurage des grandeurs dans les
échantillons d'origine biologique - Exigences pour les matériaux de référence certifiés et
pour le contenu de la documentation justificative (ISO 15194:2009)
Ta slovenski standard je istoveten z: EN ISO 15194:2009
ICS:
11.100.10 'LDJQRVWLþQLSUHVNXVQL In vitro diagnostic test
VLVWHPLLQYLWUR systems
SIST EN ISO 15194:2009 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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SIST EN ISO 15194:2009
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SIST EN ISO 15194:2009
EUROPEAN STANDARD
EN ISO 15194
NORME EUROPÉENNE
EUROPÄISCHE NORM
May 2009
ICS 11.100.10
English Version
In vitro diagnostic medical devices - Measurement of quantities
in samples of biological origin - Requirements for certified
reference materials and the content of supporting
documentation (ISO 15194:2009)
Dispositifs médicaux de diagnostic in vitro - Mesurage des In-Vitro-Diagnostika - Messung von Größen in Proben
grandeurs dans les échantillons d'origine biologique - biologischen Ursprungs - Anforderungen an zertifizierte
Exigences relatives aux matériaux de référence certifiés et Referenzmaterialien und an den Inhalt der
au contenu de la documentation associée (ISO Begleitdokumentation (ISO 15194:2009)
15194:2009)
This European Standard was approved by CEN on 16 April 2009.
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 CEN Management Centre 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 CEN Management Centre has the same status as the
official versions.
CEN members are the national standards bodies of Austria, Belgium, Bulgaria, 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.
EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION
EUROPÄISCHES KOMITEE FÜR NORMUNG
Management Centre: Avenue Marnix 17, B-1000 Brussels
© 2009 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 15194:2009: E
worldwide for CEN national Members.
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SIST EN ISO 15194:2009
EN ISO 15194:2009 (E)
Contents Page
Foreword .3
Annex ZA (informative) Relationship between this International Standard and the Essential
Requirements of EU Directive 98/79 .4
2
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SIST EN ISO 15194:2009
EN ISO 15194:2009 (E)
Foreword
This document (EN ISO 15194:2009) has been prepared by Technical Committee CEN/TC 140 "In vitro
diagnostic medical devices", the secretariat of which is held by DIN, in collaboration with Technical Committee
ISO/TC 212 "Clinical laboratory testing and in vitro diagnostic test systems".
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 November 2009, and conflicting national standards shall be withdrawn
at the latest by November 2009.
Attention is drawn to the possibility that some of the elements of this document may be the subject of patent
rights. CEN [and/or CENELEC] shall not be held responsible for identifying any or all such patent rights.
This document has been prepared under a mandate given to CEN by the European Commission and the
European Free Trade Association, and supports essential requirements of EC Directive.
For relationship with EC Directive, see informative Annex ZA, which is an integral part of this document.
According to the CEN/CENELEC Internal Regulations, the national standards organizations of the following
countries are bound to implement this European Standard: Austria, Belgium, Bulgaria, 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 the United Kingdom.
3
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SIST EN ISO 15194:2009
EN ISO 15194:2009 (E)
Annex ZA
(informative)
Relationship between this International Standard and the Essential Requirements
of EU Directive 98/79
This International Standard has been prepared under a mandate given to CEN by the European Commission
and the European Free Trade Association to provide one means of conforming to Essential Requirements of
the New Approach Directive 98/79.
Once this standard is cited in the Official Journal of the European Communities under that Directive and has
been implemented as a national standard in at least one Member State, compliance with the normative
clauses of this standard confers, within the limits of the scope of this standard, a presumption of conformity
with the corresponding Essential Requirements of that Directive and associated EFTA regulations.
WARNING: Other requirements and other EU Directives may be applicable to the products falling within the
scope of this standard.
4
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SIST EN ISO 15194:2009
INTERNATIONAL ISO
STANDARD 15194
Second edition
2009-05-01
In vitro diagnostic medical devices —
Measurement of quantities in samples of
biological origin — Requirements for
certified reference materials and the
content of supporting documentation
Dispositifs médicaux de diagnostic in vitro — Mesurage des grandeurs
dans les échantillons d'origine biologique — Exigences relatives aux
matériaux de référence certifiés et au contenu de la documentation
associée
Reference number
ISO 15194:2009(E)
©
ISO 2009
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SIST EN ISO 15194:2009
ISO 15194:2009(E)
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ii © ISO 2009 – All rights reserved
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SIST EN ISO 15194:2009
ISO 15194:2009(E)
Contents Page
Foreword. iv
Introduction . v
1 Scope . 1
2 Normative references . 1
3 Terms and definitions. 2
4 Systematic format of properties in the supporting documentation of a certified reference
material . 4
4.1 Format of properties. 4
4.2 Construction of systematic designations . 5
4.3 Trivial names . 5
5 Properties, production, and characterization of a certified reference material . 5
5.1 Hierarchical position . 5
5.2 Properties . 5
5.3 Production and characterization. 6
6 Content of supporting documentation . 6
6.1 Supporting documentation. 6
6.2 Label. 6
6.3 Certificate . 6
6.4 Certification report. 7
Annex A (informative) Certified reference materials with nominal properties or ordinal quantities. 15
Bibliography . 16
© ISO 2009 – All rights reserved iii
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SIST EN ISO 15194:2009
ISO 15194:2009(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 15194 was prepared by the European Committee for Standardization (CEN) Technical Committee
CEN/TC 140, In vitro diagnostic medical devices, in collaboration with Technical Committee ISO/TC 212,
Clinical laboratory testing and in vitro diagnostic test systems, in accordance with the Agreement on technical
cooperation between ISO and CEN (Vienna Agreement).
This second edition cancels and replaces the first edition (ISO 15194:2002), which has been technically
revised.
iv © ISO 2009 – All rights reserved
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SIST EN ISO 15194:2009
ISO 15194:2009(E)
Introduction
Reference measurement systems are needed to produce useful and reliable measurement results, whether in
science, technology or routine service, so as to be comparable and ultimately metrologically traceable to
measurement standards and/or measurement procedures of the highest metrological level.
Substances or devices that are used to obtain this metrological traceability, through time, distances and
different measurement procedures, are reference materials. Certified reference materials are needed at the
higher metrological levels of a calibration hierarchy.
A given certified reference material is supported by documentation containing sources of material,
descriptions, measurement results, metrological traceability, instructions for use, stability data and storage
conditions, as well as health and safety warnings. This International Standard specifies the quality
requirements for such materials and the content of their supporting documentation.
Reference materials are used for one of three main purposes:
a) calibration of quantity values indicated by a measuring system or assigned to another reference material;
b) validation or control of trueness of measured values in a given laboratory, or in a group of laboratories;
NOTE In ISO terminology “trueness” is related to “bias”, “systematic effect” and “systematic error”, whereas
“accuracy” is related both to “trueness” (with its relations) and “precision”, where the latter is related to “standard deviation”,
“coefficient of variation ”, “random effect” and “random error”.
c) evaluation of the performance of a new measurement procedure.
The maximum acceptable measurement uncertainty of the assigned value of a reference material depends on
the requirements of the measured quantity values obtained by a measurement procedure involving the
reference material.
As the proper use of a reference material depends on its description, it is important to apply rules for the
documentation of reference materials.
The advantages of having standards available are listed in ISO/IEC Guide 15.
In Clause 3 of this International Standard, concepts are indicated by italicized text.
© ISO 2009 – All rights reserved v
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SIST EN ISO 15194:2009
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SIST EN ISO 15194:2009
INTERNATIONAL STANDARD ISO 15194:2009(E)
In vitro diagnostic medical devices — Measurement of
quantities in samples of biological origin — Requirements for
certified reference materials and the content of supporting
documentation
1 Scope
This International Standard specifies requirements for certified reference materials and the content of their
supporting documentation, in order for them to be considered of higher metrological order in accordance with
ISO 17511. It is applicable to certified reference materials classifiable as primary measurement standards,
secondary measurement standards and international conventional calibrators that function either as
calibrators or trueness control materials. This International Standard also provides requirements on how to
collect data for value determination and how to present the assigned value and its measurement uncertainty.
This International Standard applies to certified reference materials with assigned values of differential or
rational quantities. Annex A provides information on nominal properties and ordinal quantities.
This International Standard does not apply to reference materials that are parts of an in vitro diagnostic
measuring system, although it is possible that many elements are helpful.
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.
1)
ISO 31 (all parts) , Quantities and units
ISO 5725-2, Accuracy (trueness and precision) of measurement methods and results — Part 2: Basic method
for the determination of repeatability and reproducibility of a standard measurement method
ISO 17511:2003, In vitro diagnostic medical devices — Measurement of quantities in biological samples —
Metrological traceability of values assigned to calibrators and control materials
ISO 18153, In vitro diagnostic medical devices — Measurement of quantities in biological samples —
Metrological traceability of values for catalytic concentration of enzymes assigned calibrators and control
materials
ISO Guide 31, Reference materials — Contents of certificates and labels
ISO Guide 34, General requirements for the competence of reference material producers
ISO Guide 35, Reference materials — General and statistical principles for certification
ISO/IEC Guide 98-3:2008, Guide to the expression of uncertainty in measurement (GUM:1995)
ISO/IEC Guide 99:2007, International vocabulary of metrology — Basic and general concepts and associated
terms (VIM)
1) The ISO 31 series is currently being replaced progressively by the ISO 80000 series and the IEC 80000 series.
© ISO 2009 – All rights reserved 1
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SIST EN ISO 15194:2009
ISO 15194:2009(E)
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO/IEC Guide 99 and the following
apply.
3.1
primary measurement standard
primary standard
measurement standard whose quantity value and measurement uncertainty are established using a primary
measurement procedure
EXAMPLE Primary measurement standard of amount-of-substance concentration prepared by dissolving a known
amount of substance of a chemical component to a known volume of solution.
NOTE 1 Adapted from ISO/IEC Guide 99:2007, 5.4.
NOTE 2 The concept of “primary measurement standard” is equally valid for base quantities and derived quantities.
NOTE 3 Further explanation of the role of primary measurement standards within a calibration hierarchy can be found
in ISO 17511 and ISO 18153.
3.2
secondary measurement standard
secondary standard
measurement standard whose quantity value and measurement uncertainty are assigned through calibration
with respect to a primary measurement standard for a quantity of the same kind
NOTE 1 The relation can be obtained directly between the primary measurement standard and the secondary
measurement standard, or involve an intermediate measuring system calibrated by the primary standard and assigning a
measurement result to the secondary standard.
NOTE 2 Adapted from ISO/IEC Guide 99:2007, 5.5.
EXAMPLE NIST Standard Reference Material 1951b, Lipids in Frozen Human Serum is a secondary measurement
standard that is calibrated using NIST Standard Reference Material 1911c, Cholesterol of known purity.
NOTE 3 “Measurement standard” includes “reference material”.
NOTE 4 Further explanation of the role of secondary measurement standards within a calibration hierarchy can be
found in ISO 17511 and ISO 18153.
3.3
international conventional calibrator
international conventional calibration material
calibrator whose quantity value is not metrologically traceable to the SI but is assigned by international
agreement
NOTE 1 The quantity is defined with respect to the intended application.
NOTE 2 Adapted from ISO 17511:2003, 3.11.
3.4
reference material
RM
material, sufficiently homogeneous and stable regarding one or more properties, used in calibration,
assignment of a value to another material, or quality assurance
NOTE 1 “Reference material” comprises materials embodying quantities as well as nominal properties.
NOTE 2 Adapted from ISO/IEC Guide 99:2007, 5.13.
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SIST EN ISO 15194:2009
ISO 15194:2009(E)
EXAMPLE 1 Human serum with an assigned quantity value for the amount-of-substance concentration of cholesterol,
used only as a calibrator, embodies a quantity.
EXAMPLE 2 DNA compound containing a specified nucleic acid sequence embodies a nominal property.
NOTE 3 In this definition, value covers both “quantity value” and “nominal property value”.
NOTE 4 Some reference materials have quantities which are metrologically traceable to a measurement unit outside a
system of units. Such materials include those containing antibodies to which International Units (IU) have been assigned
by the World Health Organization.
NOTE 5 A reference material is sometimes incorporated into a specially fabricated device, e.g.
⎯ glass of known optical density in a transmission filter holder,
⎯ spheres of uniform particle size mounted on a microscope slide, and
⎯ calibration plate for microtiter plate reader.
3.5
certified reference material
CRM
reference material, accompanied by documentation issued by an authoritative body and referring to valid
procedures used to obtain a specified property value with uncertainty and traceability
NOTE 1 Adapted from ISO/IEC Guide 99:2007, 5.14.
EXAMPLE Human serum containing cholesterol with assigned quantity value and associated measurement
uncertainty stated in an accompanying certificate, used as calibrator or trueness control material.
NOTE 2 In this definition, uncertainty covers both “measurement uncertainty” and “uncertainty of nominal value”, such
as for identity and sequence, expressed as probabilities. Traceability covers both “metrological traceability” of a quantity
value and “traceability of nominal value”.
NOTE 3 “Certified reference material” is a specific concept under “reference material”.
3.6
matrix
〈material system〉 components of a material system, except the analyte
3.7
matrix effect
influence of a property of the sample, independent of the presence of the analyte, on the measurement and
thereby on the measured quantity value
NOTE 1 A specified cause of a matrix effect is an influence quantity.
NOTE 2 A matrix effect depends on the detailed steps of the measurement as described in the measurement
procedure.
EXAMPLE The measurement of the amount-of-substance concentration of sodium ion in plasma by flame emission
spectrometry can be influenced by the viscosity of the sample.
3.8
commutability of a reference material
property of a given reference material, demonstrated by the closeness of agreement between the relation
among the measurement results for a stated quantity in this material, obtained according to two measurement
procedures, and the relation obtained among the measurement results for other specified materials
NOTE 1 The reference material in question is usually a calibrator and the other specified materials are usually routine
samples.
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SIST EN ISO 15194:2009
ISO 15194:2009(E)
NOTE 2 The measurement procedures referred to in the definition are the one preceding and the one following the
reference material (calibrator) in question in a calibration hierarchy.
NOTE 3 Adapted from ISO/IEC Guide 99:2007, 5.15.
3.9
report
document giving detailed information on a reference material, supplementary to that contained in a certificate
4 Systematic format of properties in the supporting documentation of a certified
reference material
4.1 Format of properties
4.1.1 System
The system is the material itself or a specified part of the material.
EXAMPLES Reconstituted lyophilized plasma (as a system) for which there is a certified amount-of-substance
concentration and measurement uncertainty of 17β-Estradiol (as a component); reconstituted lyophilized haemolysate (as
a material) containing Haemoglobin β chains (as a system) for which there is a certified amount-of-substance fraction and
measurement uncertainty of N-(1-deoxyfructos-1-yl) haemoglobin β chains (as a component).
4.1.2 Component(s)
Any relevant component(s), also called analyte(s), of the system shall be named according to an
internationally accepted nomenclature, including for example any necessary indications of elementary entity,
relative molecular mass or molar mass, oxidation state, multiple forms comprised and, for enzymes, the EC
number.
EXAMPLES Aliphatic carboxylate(C10 to C26, non-esterified); Fibrinogen(340 000); Iron(II+III); Lactate dehydro-
genase (E.C.1.1.1.27) isoenzyme 1; Basic fibroblast growth factor(human, rec. DNA).
4.1.3 Kind-of-quantity
The kind-of-quantity, e. g. mass, amount-of-substance, number fraction, amount-of-substance concentration,
shall always be stated. If no simple relationship between component and system can be expressed, reference
shall be made to the measurement procedure.
NOTE Appropriate names and symbols for kind-of-quantities are given in ISO 31 and in publications by IFCC and
IUPAC.
4.1.4 Quantity value
4.1.4.1 If the property is a differential quantity (e.g. Celsius temperature) or a rational quantity (e.g.
thermodynamic temperature), it shall have a value consisting of a product of numerical value and
measurement unit, together with a measurement uncertainty.
4.1.4.2 The number of significant figures of a quantity value shall be chosen so that the measurement
uncertainty lies on the last or, if the first significant figure of the uncertainty measure is 1 or 2, on the two last
figures. For numerical values with more than four figures on either side of the decimal mark, these should be
separated by a space in groups of three, counting from the mark to the left or right.
4.1.4.3 The measurement unit chosen shall be an SI unit, whenever possible, or other internationally
accepted measurement unit.
4.1.4.4 The measurement uncertainty shall be calculated and expressed consistent with
ISO/IEC Guide 98-3.
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SIST EN ISO 15194:2009
ISO 15194:2009(E)
4.2 Construction of systematic designations
A systematic name and value shall consist of elements as specified in 4.1.
EXAMPLE 1 A systematic name of a calibrator for a haematology analyser can be secondary reference material for
calibration (Responsible body NN; Product no 4132), for example:
12
⎯ Erythrocytes; number concentration = (4,71 ± 0,09) 10 /l; average and expanded uncertainty (k = 2, with level of
confidence 0,95);
9
⎯ Leukocytes; number concentration = (6,52 ± 0,25) 10 /l; average and expanded uncertainty (k = 2, with level of
confidence 0,95);
9
⎯ Thrombocytes; number concentration = (240 ± 12) 10 /l; average and expanded uncertainty (k = 2, with level of
confidence 0,95).
EXAMPLE 2 Certified reference material (Human serum; BCR; CRM 303)--Calcium(II); amount-of-substance
concentration (reconstituted) c = 2,472 mmol/l (U = 0,019 mmol/l; k = 2), where U is the expanded uncertainty of
measurement using the coverage factor k.
4.3 Trivial names
A trivial name shall be constructed by omitting from the systematic name elements that are not necessary for
the understanding of the function of the CRM in the measurement.
EXAMPLE The trivial name in general form for the material given in 4.2, EXAMPLE 1, can be:
⎯ “Calibrator(Responsible body NN; Product no 4132)--Erythrocytes, Leukocytes and Thrombocytes”; or
⎯ “Calibrator(Responsible body NN; Product no 4132)--Blood cells”.
The trivial name for the corresponding industry product can be:
⎯ “Calibrator(Company NN; Product no 4132; Batch no 4132-2)--Blood cells”.
5 Properties, production, and characterization of a certified reference material
5.1 Hierarchical position
“Reference material” is regarded as a type of “measurement standard”, and reference materials of higher
metrological order shall be classified as measurement standards, in accordance with their positions in the
refer
...