ISO 17511:2003
(Main)In vitro diagnostic medical devices — Measurement of quantities in biological samples — Metrological traceability of values assigned to calibrators and control materials
In vitro diagnostic medical devices — Measurement of quantities in biological samples — Metrological traceability of values assigned to calibrators and control materials
ISO 17511:2003 specifies how to assure the metrological traceability of values assigned to calibrators and control materials intended to establish or verify trueness of measurement. The calibrators and control materials are those provided by the manufacturers as part of, or to be used together with, in vitro diagnostic medical devices. External quality assessment (survey) samples, with proven commutability, whose values have been assigned by means of internationally agreed reference measurement systems or internationally agreed conventional reference measurement systems fall within the scope of ISO 17511:2003. ISO 17511:2003 is not applicable to control materials that do not have an assigned value and are used only for assessing the precision of a measurement procedure, either its repeatability or reproducibility (precision control materials); control materials intended for intralaboratory quality control purposes and supplied with intervals of suggested acceptable values, each interval obtained by interlaboratory consensus with respect to one specified measurement procedure, and with limiting values that are not metrologically traceable; correlation between results of two measurement procedures at the same metrological level, purporting to measure the same quantity, because such "horizontal" correlation does not provide metrological traceability; calibration derived from correlation between the results of two measurement procedures at different metrological levels, but with quantities having analytes of different characteristics; metrological traceability of routine results to the product calibrator and their relations to any medical discrimination limit; and properties involving nominal scales, i.e. where no magnitude is involved (e.g. identification of blood cells).
Dispositifs médicaux de diagnostic in vitro — Mesurage des grandeurs dans des échantillons d'origine biologique — Traçabilité métrologique des valeurs attribuées aux agents d'étalonnage et aux matériaux de contrôle
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Standards Content (Sample)
INTERNATIONAL ISO
STANDARD 17511
First edition
2003-08-15
In vitro diagnostic medical devices —
Measurement of quantities in biological
samples — Metrological traceability
of values assigned to calibrators and
control materials
Dispositifs médicaux de diagnostic in vitro — Mesurage des grandeurs
dans des échantillons d'origine biologique — Traçabilité métrologique
des valeurs attribuées aux agents d'étalonnage et aux matériaux
de contrôle
Reference number
ISO 17511:2003(E)
©
ISO 2003
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ISO 17511:2003(E)
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ISO 17511:2003(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 17511 was prepared by the European Committee for Standardization (CEN) 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).
Throughout the text of this document, read ".this European Standard." to mean ".this International
Standard.".
For the purposes of this International Standard, the CEN annex regarding fulfilment of European Council
Directives has been removed.
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ISO 17511:2003(E)
Contents
page
Foreword.v
Introduction .vi
1 Scope .1
2 Normative references .1
3 Terms and definitions.1
4 Metrological traceability chain and calibration hierarchy .7
4.1 Principles.7
4.2 Structure and nomenclature.8
4.3 Considerations in establishing metrological traceability.12
4.4 Functions of reference materials .13
5 Calibration transfer protocols .13
5.1 Availability and structure.13
5.2 Cases with primary reference measurement procedure and primary calibrator(s) giving
metrological traceability to SI.14
5.3 Cases with international conventional reference measurement procedure (which is not
primary) and international conventional calibrator(s) without metrological traceability to SI.15
5.4 Cases with international conventional reference measurement procedure (which is not
primary) but no international conventional calibrator and without metrological traceability to
SI.16
5.5 Cases with international conventional calibrator (which is not primary) but no international
conventional reference measurement procedure and without metrological traceability to SI .17
5.6 Cases with manufacturer's selected measurement procedure but neither international
conventional reference measurement procedure nor international conventional calibrator and
without metrological traceability to SI.18
5.7 Trueness control materials.19
6 Expression of uncertainty of measurement.19
7 Validation of metrologically traceable calibration.20
8 Information on metrological traceability to be given in the instructions for use of an in vitro
diagnostic medical device .21
Bibliography .23
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ISO 17511:2003(E)
Foreword
This document (EN ISO 17511:2003) 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 EN ISO 17511:2003 including the Amendment shall be given the status of a national
standard, either by publication of an identical text or by endorsement, at the latest by February 2004, and
conflicting national standards shall be withdrawn at the latest by February 2004.
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 EU Directive(s).
The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC), the European Confederation of
Laboratory Medicine (ECLM), and the European Diagnostic Manufacturers Association (EDMA) have contributed to
its preparation.
This standard includes a Bibliography.
According to the CEN/CENELEC Internal Regulations, the national standards organizations of the following
countries are bound to implement this European Standard: Austria, Belgium, Czech Republic, Denmark, Finland,
France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Luxembourg, Malta, Netherlands, Norway, Portugal,
Slovakia, Spain, Sweden, Switzerland and the United Kingdom.
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ISO 17511:2003(E)
Introduction
For measurements of quantities in laboratory medicine, it is essential that the quantity is adequately defined and
that the results reported to the physicians or other health care personel and patients are adequately accurate (true
and precise) to allow correct medical interpretation and comparability over time and space.
NOTE In this European Standard the concept "accuracy of measurement" (see 3.1) is related to both "trueness of
measurement" (see 3.33) and "precision of measurement" (see 3.23) whereas the Directive 98/79/EC on in vitro diagnostic
medical devices uses the term ‘’accuracy'’ instead of ‘'trueness’'.
To allow 'correct medical interpretation' involves more than the metrological (analytical) aspects of the traceability
chain. As the measurement results are eventually used by the physician for the benefit of the patients, the
physician should gather information on a number of other aspects, such as knowledge about the pre- and post-
analytical phase, the diagnostic sensitivity and specificity, and relevant reference interval(s). The present European
Standard deals only with the analytical aspects of measurements in Laboratory Medicine (see also 1 e)).
The measurement of quantities in biological samples requires reference measurement systems including:
- the definition of the analyte in the biological sample with regard to the intended clinical use of the measurement
results;
- a reference measurement procedure for the selected quantity in human samples;
- suitable reference materials for the selected quantity, e.g. primary calibrators and secondary matrix-based
calibrators that are commutable.
The trueness of measurement of a value assigned to a defined quantity of a calibrator or trueness control material,
depends on the metrological traceability of the value through an unbroken chain of alternating measurement
procedures and measurement standards (calibrators), usually having successively decreasing uncertainties of
measurement (see Figure 1). The uncertainty of the value assigned to a given calibrator or trueness control
material depends on the stated metrological traceability chain and the combined uncertainties of its links.
The ideal end-point of a metrological traceability chain is the definition of the relevant unit of the International
System of Units (SI), but the selection of steps and the level at which metrological traceability for a given value
stops, depend on the availability of higher order measurement procedures and calibrators. In many cases, at
present, there is no metrological traceability above the manufacturer's selected measurement procedure or the
manufacturer's working calibrator. In such cases, trueness is referred to that level of the calibration hierarchy until
an internationally agreed reference measurement procedure and/or calibrator becomes available.
The objective of a chosen metrologically traceable calibration is to transfer the degree of trueness of a reference
material, and/or reference measurement procedure, to a procedure that is of a lower metrological order, e.g. a
routine procedure. Metrological traceability of calibration requires that the reference and routine measurement
procedures measure the same measurable quantity with an analyte of the same pertinent characteristics.
In this context, it is important to recognize that different procedures purporting to measure the same quantity may in
fact give different results when applied to a particular sample or reference material. This may arise, for example,
when two or more immunoprocedures purporting to measure the concentration of a hormone such as thyrotropin
(thyroid stimulating hormone, TSH) are applied to a reference material of the hormone, because the respective
reagents recognize and react to different extents with various epitopes in the material, thus leading to results for
different although related quantities.
Laboratory medicine routinely provides results for 400 to 700 types of quantity. For most of these, the metrological
traceability of the assigned value for a product calibrator stops after only one metrologically higher step consisting
of a (reference) measurement procedure, or after two steps consisting of a measurement procedure and a
(reference) calibrator. The reason is that many of such quantities are related to mixtures of molecular species with
clinically relevant properties in common, but with different structures and molecular masses in varying proportions,
e.g. glycoproteins.
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ISO 17511:2003(E)
Depending on the possibility of metrological traceability to SI and on the availability of various metrological levels of
measurement procedures and calibrators, the following five typical upper ends of the metrological traceability chain
can be identified.
a) Quantities for which results of measurements are metrologically traceable to SI.
A primary reference measurement procedure and one or more (certified) primary reference materials (used as
calibrators) are available. These levels exist for approximately 25 to 30 types of quantity having well defined
components, e.g. some electrolytes, metabolites, steroid hormones, and some thyroid hormones. These types
of quantity cover a large proportion of the routine results provided by medical laboratories (see 4.2.2, 5.2,
Figures 1 and 2).
b) Quantities for which results of measurements are not metrologically traceable to SI.
1) An international conventional reference measurement procedure (see 3.12) (which cannot be called a
primary reference measurement procedure) and one or more international conventional calibration materials
(see 3.11) with values assigned by that procedure are available. These conditions apply for quantities with
components such as HbA (see 5.3 and Figure 3).
1c
2) An international conventional reference measurement procedure is available but no international
conventional calibration materials. These conditions apply for about 30 types of quantity with components such
as haemostatic factors (see 5.4 and Figure 4).
3) One or more international conventional calibration materials (used as calibrators) with a protocol for value
assignment are available, but no international conventional reference measurement procedure. These
conditions apply for over 300 types of quantity, e.g., for quantities referred to World Health Organization's
International Standards, such as protein hormones, some antibodies, and tumour markers (see 5.5 and
Figure 5).
4) Neither reference measurement procedure nor reference materials for calibration are available. The
manufacturer can establish 'in-house' measurement procedure(s) and calibrator(s) to support value
assignment to his product calibrator. These conditions apply for about 300 types of quantity with components
such as tumour markers and antibodies (see 5.6 and Figure 6).
The principles of the respective transfer protocols (calibration hierarchies) are presented, given the provisions of
the European Standards EN 12286 on presentation of reference measurement procedures and EN 12287 on the
description of reference materials.
It is the aim of metrology in laboratory medicine to improve metrological traceability for results of a type of quantity
from the conditions described under b2), b3), and b4) to those of b1) by providing the missing reference
measurement procedures and reference materials, based on international consensus.
The special problems of metrological traceability for values of catalytic concentration of enzymes are considered in
prEN ISO 18153.
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ISO 17511:2003(E)
1 Scope
This European Standard specifies how to assure the metrological traceability of values assigned to calibrators and
control materials intended to establish or verify trueness of measurement. The calibrators and control materials are
those provided by the manufacturers as part of, or to be used together with, in vitro diagnostic medical devices.
External quality assessment (survey) samples, with proven commutability, whose values have been assigned by
means of internationally agreed reference measurement systems or internationally agreed conventional reference
measurement systems fall within the scope of this European Standard.
This European Standard is not applicable to:
a) control materials that do not have an assigned value and are used only for assessing the precision of a
measurement procedure, either its repeatability or reproducibility (precision control materials);
b) control materials intended for intralaboratory quality control purposes and supplied with intervals of suggested
acceptable values, each interval obtained by interlaboratory consensus with respect to one specified
measurement procedure, and with limiting values that are not metrologically traceable;
c) correlation between results of two measurement procedures at the same metrological level, purporting to
measure the same quantity, because such 'horizontal' correlation does not provide metrological traceability;
d) calibration derived from correlation between the results of two measurement procedures at different
metrological levels, but with quantities having analytes of different characteristics;
e) metrological traceability of routine results to the product calibrator and their relations to any medical
discrimination limit;
f) properties involving nominal scales, i.e. where no magnitude is involved (e.g. identification of blood cells).
2 Normative references
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).
EN 375:2001, Information supplied by the manufacturer with in vitro diagnostic reagents for professional use.
) )
1 2
International Vocabulary of Basic and General Terms in Metrology, 2nd edition, ISO, Geneva, 1993.
ISO Guide 35:1989, Certification of reference materials - General and statistical principles.
3 Terms and definitions
For the purposes of this European Standard, the following terms and definitions apply:
3.1
accuracy of measurement
closeness of the agreement between the result of a measurement and a true value of the measurand
)
1
This monograph has been prepared simultaneously in English and French by a joint working group consisting of experts appointed by: BIPM
(International Bureau of Weights and Measures), IEC (International Electrotechnical Commission), IFCC (International Federation of Clinical
Chemistry and Laboratory Medicine), ISO (International Organization for Standardization), IUPAC (International Union of Pure and Applied
Chemistry), IUPAP (International Union of Pure and Applied Physics), OIML (International Organization of Legal Metrology)
)
2
The abbreviation VIM:1993 is used in this standard
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ISO 17511:2003(E)
[VIM:1993, 3.5]
NOTE 1 Accuracy of measurement is related to both trueness of measurement and precision of measurement.
NOTE 2 Accuracy cannot be given a numerical value in terms of the measurand, only descriptions such as 'sufficient' or
'insufficient' for a stated purpose.
NOTE 3 An estimator of an inverse measure of accuracy is "deviation", defined as 'value minus a conventional true value'.
NOTE 4 ISO 3534-1, instead of "a true value" in the definition above, uses the concept "the accepted reference value", which
can be a theoretical (true), assigned, consensus, or procedure-defined value.
NOTE 5 In this standard the concept "accuracy of measurement" is related to both "trueness of measurement" (see 3.33)
and "precision of measurement" (see 3.23) whereas the Directive 98/79/EC on in vitro diagnostic medical devices uses the term
'accuracy' instead of 'trueness'.
3.2
analyte
component represented in the name of a measurable quantity
EXAMPLE In the type of quantity "mass of protein in 24-hour urine", "protein" is the analyte. In "amount of substance of
glucose in plasma", "glucose" is the analyte. In both cases the long phrase represents the measurand (see 3.17).
3.3
analytical specificity
ability of a measurement procedure to measure solely the measurand
3.4
bias of measurements
difference between the expectation of the results of measurement and a true value of the measurand
NOTE An estimator is the "statistical sample bias of measurements" which is the 'average minus its reference value'.
3.5
calibration
set of operations that establish, under specified conditions, the relationship between values of quantities indicated
by a measuring instrument or measuring system, or values represented by a material measure or a reference
material, and the corresponding values realized by standards
[VIM:1993, 6.11]
NOTE The term ''standard'' here refers to "measurement standard" (see 3.19), not a written standard.
3.6
calibration transfer protocol
transfer protocol
detailed description for assigning a value of a quantity to a reference material using a specified sequence of
measurement procedures calibrated by higher-order reference materials for the same type of quantity
3.7
calibrator
calibration material
reference material whose value is used for the independent variable in a calibration function
3.8
certified reference material
CRM
reference material, accompanied by a certificate, one or more of whose property values are certified by a
procedure which establishes metrological traceability to an accurate realization of the unit in which the property
values are expressed, and for which each certified value is accompanied by an uncertainty at a stated level of
confidence
[slightly adapted from VIM:1993, 6.14]
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ISO 17511:2003(E)
3.9
commutability of a material
closeness of agreement between the mathematical relationship of the measurement results obtained by two
measurement procedures for a stated quantity in a given material, and the mathematical relationship obtained for
the quantity in routine samples
3.10
influence quantity
quantity that is not the measurand but that affects the result of the measurement
[VIM:1993, 2.7]
3.11
international conventional calibrator
international conventional calibration material
calibrator whose value of a quantity is not metrologically traceable to the SI but is assigned by international
agreement
NOTE The quantity is defined with respect to the intended clinical application.
3.12
international conventional reference measurement procedure
measurement procedure yielding values that are not metrologically traceable to the SI but which by international
agreement are used as reference values for a defined quantity
NOTE The quantity is defined with respect to the intended clinical application.
3.13
international measurement standard
international standard
standard recognized by an international agreement to serve internationally as the basis for assigning values to
other standards of the quantity concerned
[VIM:1993, 6.2]
3.14
matrix of a material system
matrix
totality of components of a material system except the analyte
[EN 12287:1999, 3.3]
3.15
matrix effect
influence of a property of the sample, other than the measurand, on the measurement of the measurand according
to a specified measurement procedure and thereby on its measured value
NOTE 1 A specified cause of a matrix effect is an influence quantity.
NOTE 2 The term 'matrix effect' is sometimes erroneously used for the lack of commutability due to a denatured analyte or
an added non-genuine component ('surrogate analyte') meant to simulate the analyte.
3.16
measurable quantity
quantity
attribute of a phenomenon, body or substance that may be distinguished qualitatively and determined quantitatively
[VIM:1993, 1.1]
NOTE 1 Properties that are expressed on a nominal scale are not measurable quantities.
NOTE 2 "Measurable quantity" is not to be confused with "analyte", see 3.2.
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ISO 17511:2003(E)
3.17
measurand
particular quantity subject to measurement
[VIM:1993, 2.6]
NOTE See 3.2, Example.
3.18
measurement procedure
set of operations, described specifically, used in the performance of particular measurements according to a given
method
[VIM:1993, 2.5]
3.19
measurement standard
material measure, measuring instrument, reference material or measuring system intended to define, realize,
conserve or reproduce a unit or one or more values of a quantity to serve as a reference
[VIM:1993, 6.1]
NOTE 1 A given measurement standard with an assigned value for one quantity can sometimes serve as a reference
material for measurement procedures yielding values for more than one type of quantity. (For example, a reference material for
cholesterol also serving for cholesterol esters that are measured after hydrolysis as cholesterol).
NOTE 2 The term 'standard' is used with two meanings: "measurement standard" and "written standard". The full terms
should be used when doubt can arise.
3.20
method of measurement
logical sequence of operations, described generically, used in the performance of measurements
[VIM:1993, 2.4]
NOTE A method of measurement, due to its generalized description, does not have numerically specified performance
characteristics. A given method can be the basis of one or more measurement procedures, each with inherent numerical values
for its performance characteristics.
3.21
metrological traceability
property of the result of a measurement or the value of a standard whereby it can be related to stated references,
usually national or international standards, through an unbroken chain of comparisons all having stated
uncertainties
[VIM:1993, 6.10]
NOTE 1 Each comparison is effected by a (reference) measurement procedure defined in a calibration transfer protocol.
NOTE 2 There are several types of traceability. Therefore the term 'metrological traceability' is used in the present text.
3.22
metrology
science of measurement
NOTE Metrology includes all aspects both theoretical and practical with reference to measurements, whatever their
uncertainty, and in whatever fields of science or technology they occur.
[VIM:1993, 2.2]
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ISO 17511:2003(E)
3.23
precision of measurement
closeness of agreement between independent results of measurements obtained under stipulated conditions
[ISO 3534-1:1993, 3.14]
NOTE 1 Precision of measurement cannot be given a numerical value in terms of the measurand, only descriptions such as
'sufficient' or 'insufficient' for a stated purpose.
NOTE 2 The degree of precision is usually expressed numerically by the statistical measures of imprecision of
measurements, such as standard deviation and coefficient of variation, that are inversely related to precision.
NOTE 3 "Precision" of a given measurement procedure is subdivided according to the specified precision conditions.
"Repeatability" relates to essentially unchanged conditions and is often termed "withinserial" or "within-run precision".
"Reproducibility" relates to changes in conditions, e.g. time, different laboratories, operators, and measuring systems (including
different calibrations and reagent batches).
3.24
primary reference material
reference material having the highest metrological qualities and whose value is determined by means of a primary
reference measurement procedure
NOTE 1 The concept "primary calibrator" is subordinate to "calibrator" (see 3.7) and to "primary reference material".
NOTE 2 See 3.26, Note.
3.25
primary reference measurement procedure
reference meas
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