SIST EN ISO 18153:2003
(Main)In vitro diagnostic medical devices - Measurement of quantities in biological samples - Metrological traceability of values for catalytic concentration of enzymes assigned to calibrators and control materials (ISO 18153:2003)
In vitro diagnostic medical devices - Measurement of quantities in biological samples - Metrological traceability of values for catalytic concentration of enzymes assigned to calibrators and control materials (ISO 18153:2003)
This EN specifies how to assure the traceability of values assigned to calibrators and control materials intended to establish or verify trueness of measurement of the catalytic concentration of enzymes, and provided by the manufacturers as part of, or to be used together with, in vitro diagnostic medical devices. This EN describes requirements for the selection and properties of enzyme calibration materials appropriate to their use as elements of a calibration hierarchy of measurement procedures and calibrators.
In-vitro-Diagnostika - Messung von Größen in Proben biologischen Ursprungs - Metrologische Rückführbarkeit von Werten der katalytischen Konzentration von Enzymen, die Kalibratoren und Kontrollmaterialien zugeordnet sind (ISO 18153: 2003)
Diese Europäische Norm legt fest, wie die metrologische Rückführbarkeit der Kalibratoren und Kontrollmaterialien zugeordneten Werte sichergestellt wird, die ihrerseits dafür vorgesehen sind, die Richtigkeit einer Messung der katalytischen Konzentration von Enzymen zu etablieren oder zu verifizieren. Kalibratoren und Kontrollmaterialien sind solche Materialien, die von den Herstellern als Teil der In-vitro-Diagnostika oder zur gemeinsamen Verwendung mit diesen geliefert werden.
Nicht zum Anwendungsbereich dieser Norm gehören
a) Anforderungen an die Entwicklung oder die Auswahl eines Referenzmessverfahrens;
b) Größen, welche die Masse oder die Immunreaktivität von Enzymen betreffen;
c) Kontrollmaterialien, die keinen Zielwert besitzen und nur zur Bewertung der Präzision eines Messverfahrens, entweder von dessen Wiederholpräzision oder dessen Vergleichpräzision, verwendet werden (Präzisionskontrollmaterialien);
d) Kontrollmaterialien, die zu Qualitätskontrollzwecken innerhalb eines Laboratoriums vorgesehen sind und mit Akzeptanzbereichen bereitgestellt werden, wobei jeder Bereich durch Übereinkunft zwischen verschiedenen Laboratorien in Bezug auf ein festgelegtes Messverfahren erhalten wurde, und mit Grenzwerten, die nicht metrologisch rückführbar sind;
e) die metrologische Rückführbarkeit von Routineergebnissen auf den Produktkalibrator und deren Bezug zu medizinischen Entscheidungsgrenzen;
f) Eigenschaften, die mit Nominal- und Ordinalskalen beschrieben werden.
Dispositifs médicaux de diagnostic in vitro - Mesurage des grandeurs dans des échantillons d'origine biologique - Traçabilité métrologique des valeurs de concentration catalytique des enzymes attribuées aux agents d'étalonnage et aux matériaux de contrôle (ISO 18153:2003)
La présente Norme européenne spécifie la maniere dont on garantit la traçabilité métrologique des valeurs attribuées aux agents d'étalonnage et aux matériaux de contrôle destinés a établir ou vérifier la justesse de mesurage de la concentration catalytique des enzymes. Ces agents d'étalonnage et ces matériaux de contrôle sont fournis par les fabricants en tant que parties intégrantes des dispositifs médicaux de diagnostic in vitro ou comme éléments a utiliser conjointement avec ces derniers.
Les points suivants ne relevent pas du domaine d'application de la présente Norme :
a) les exigences relatives a la conception ou a la sélection d'un mode opératoire de référence ;
b) les grandeurs ayant un rapport avec la masse de l'enzyme ou l'immunoréactivité des enzymes ;
c) les matériaux de contrôle qui n'ont pas une valeur attribuée et qui sont utilisés uniquement pour l'évaluation de la fidélité d'un mode opératoire de mesure, en termes de répétabilité ou de reproductibilité (matériaux de contrôle de la fidélité) ;
d) les matériaux de contrôle destinés a la maîtrise de la qualité intralaboratoire et fournis avec des intervalles de valeurs acceptables proposées, chaque intervalle ayant fait l'objet d'un consensus interlaboratoire pour un mode opératoire de mesure spécifié avec des valeurs limites sans traçabilité métrologique ;
e) la traçabilité métrologique de résultats de routine par rapport au matériau d'étalonnage produit par un fabricant et leurs relations a une limite de décision clinique ,
f) les propriétés qui impliquent des échelles nominales et ordinales.
Diagnostični medicinski pripomočki in vitro - Merjenje količin v vzorcih biološkega izvora – Meroslovna sleddljivost vrednosti za katalitične koncentracije encimov, dodeljenih kalibratorjem in kontrolnim materialom (ISO 18153:2003)
General Information
Standards Content (Sample)
SLOVENSKI STANDARD
SIST EN ISO 18153:2003
01-november-2003
'LDJQRVWLþQLPHGLFLQVNLSULSRPRþNLLQYLWUR0HUMHQMHNROLþLQYY]RUFLKELRORãNHJD
L]YRUD±0HURVORYQDVOHGGOMLYRVWYUHGQRVWL]DNDWDOLWLþQHNRQFHQWUDFLMHHQFLPRY
GRGHOMHQLKNDOLEUDWRUMHPLQNRQWUROQLPPDWHULDORP ,62
In vitro diagnostic medical devices - Measurement of quantities in biological samples -
Metrological traceability of values for catalytic concentration of enzymes assigned to
calibrators and control materials (ISO 18153:2003)
In-vitro-Diagnostika - Messung von Größen in Proben biologischen Ursprungs -
Metrologische Rückführbarkeit von Werten der katalytischen Konzentration von
Enzymen, die Kalibratoren und Kontrollmaterialien zugeordnet sind (ISO 18153: 2003)
Dispositifs médicaux de diagnostic in vitro - Mesurage des grandeurs dans des
échantillons d'origine biologique - Traçabilité métrologique des valeurs de concentration
catalytique des enzymes attribuées aux agents d'étalonnage et aux matériaux de
contrôle (ISO 18153:2003)
Ta slovenski standard je istoveten z: EN ISO 18153:2003
ICS:
11.100.10 'LDJQRVWLþQLSUHVNXVQL In vitro diagnostic test
VLVWHPLLQYLWUR systems
SIST EN ISO 18153:2003 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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SIST EN ISO 18153:2003
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SIST EN ISO 18153:2003
EUROPEAN STANDARD
EN ISO 18153
NORME EUROPÉENNE
EUROPÄISCHE NORM
August 2003
ICS 07.100.10
English version
In vitro diagnostic medical devices - Measurement of quantities
in biological samples - Metrological traceability of values for
catalytic concentration of enzymes assigned to calibrators and
control materials (ISO 18153:2003)
Dispositifs médicaux de diagnostic in vitro - Mesurage des In-vitro-Diagnostika - Messung von Größen in Proben
grandeurs dans des échantillons d'origine biologique - biologischen Ursprungs - Metrologische Rückführbarkeit
Traçabilité métrologique des valeurs de concentration von Werten der katalytischen Konzentration von Enzymen,
catalytique des enzymes attribuées aux agents die Kalibratoren und Kontrollmaterialien zugeordnet sind
d'étalonnage et aux matériaux de contrôle (ISO (ISO 18153: 2003)
18153:2003)
This European Standard was approved by CEN on 11 March 2003.
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 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 Management Centre has the same status as the official
versions.
CEN members are the national standards bodies of Austria, Belgium, Czech Republic, Denmark, Finland, France, Germany, Greece,
Hungary, Iceland, Ireland, Italy, Luxembourg, Malta, Netherlands, Norway, Portugal, Slovakia, 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
© 2003 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 18153:2003 E
worldwide for CEN national Members.
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SIST EN ISO 18153:2003
EN ISO 18153:2003 (E)
Contents
page
Foreword.3
Introduction .4
1 Scope .6
2 Normative references .6
3 Terms and definitions.6
4 Metrological traceability chain and calibration hierarchy .8
4.1 Principles.8
4.2 Structure .9
5 Validation of metrologically traceable calibration.11
5.1 Principles.11
5.2 Analytical specificity of measurement procedures.11
5.3 Commutability of calibrators .12
5.4 Commutability of control materials.12
Annex A (informative) List of IFCC primary reference measurement procedures .13
Annex B (informative) List of certified reference materials (CRM).14
Annex ZA (informative) Clauses of this European Standard addressing essential requirements or other
provisions of EU Directives .15
Bibliography .16
2
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SIST EN ISO 18153:2003
EN ISO 18153:2003 (E)
Foreword
This document (EN ISO 18153:2003) 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 18153:2003 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).
For relationship with EU Directive(s), see informative annex ZA, which is an integral part of this document.
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.
Annexes A and B are informative.
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.
3
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SIST EN ISO 18153:2003
EN ISO 18153:2003 (E)
Introduction
The Directive 98/79/EC on in vitro diagnostic medical devices requires that the metrologically traceability of values
assigned to calibrators and control materials be assured through available reference measurement materials and
reference measurement procedures of higher order. Following this concept, the European Standard
prEN ISO 17511 on "traceability" has been elaborated which describes a hierarchical order of measurement
procedures and calibration materials. The general rules expressed in that standard also apply to quantities
involving catalytic activity. Whenever possible, metrological traceability should be demonstrated to the SI unit which
forms the top of the calibration hierarchy.
For the measurement of the catalytic activity concentration of enzymes (hereafter called 'catalytic concentration'), a
hierarchy of calibrators and measurement procedures is described in the present standard. For enzyme
measurements, the definition of the derived coherent SI unit "mole per second cubic metre", given the special
name "katal per cubic metre" by the General Conference on Weights and Measures, is the top of the hierarchy
followed by a primary reference measurement procedure to which lower level measurement procedures,
calibrators, and control materials should be traced whenever possible.
Enzymes in blood or other biological fluids can be measured for diagnostic purposes in terms of their catalytic
concentrations. The analytical principle of the measurement of the catalytic rate of conversion of substrate has
considerable advantages of speed, low limit of detection, analytical specificity, and low cost. Results of catalytic
concentration measurements are only comparable if the enzyme activities are measured under the same
conditions. Therefore, an enzyme measurand cannot be described only by kind-of-quantity (e.g. catalytic
concentration), name of enzyme and of system, but requires also the specified measurement procedure and
especially the indicator component of the measured reaction. At the top of the calibration hierarchy, the
measurement procedure should be internationally agreed, e.g. 'creatine kinase measured by the conversion rate of
NADH in the IFCC reference measurement procedure'.
Thus, the primary reference measurement procedure is an integral part of the definition of the measurand and has
to be followed in all detail, e.g. as concerns:
kind of substrate (where the specificity of the enzyme allows this to be varied) and its concentration,
activators and their concentrations,
direction of catalysed reaction,
indicator component,
buffer system and pH,
temperature,
pre-incubation time,
material used for starting the reaction,
lag time,
reaction time.
4
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SIST EN ISO 18153:2003
EN ISO 18153:2003 (E)
The disadvantage of the procedure-dependence of the definition of the enzyme measurand and therefore of the
results of the measurements are well known: problems are caused in external quality assessment (EQA) and in
assessing the transferability of methods; a multiplicity of biological reference intervals exists with the consequent
risk of clinical misinterpretation of enzyme results. The standardization of routine enzyme measurements is
important to laboratory medicine, to improve the clinical utility and comparability of results through the elimination of
existing differences in biological reference intervals.
Two approaches can be considered:
a) the exclusive routine use of a recommended or standardized procedure for each enzyme;
b) calibration of one or more routine procedures by commutable enzyme calibration materials with values
assigned by a chosen reference measurement procedure.
The "recommended procedure" approach (a)) has been pursued vigorously for more than twenty years. It has had
considerable success in improving the quality and comparability of enzyme measurements and in discouraging the
use of analytically unsatisfactory procedures. However, the recommended-procedure-approach to standardization
appears to have reached the limits of its usefulness. Its disadvantages include: absence of a consensus of choice
among a number of differing recommendations; intentional or unintentional modification of recommended
procedures in routine use; unresponsiveness of recommended procedures to analytical and technical
improvement; and partly non-adaptability of recommended procedures to preferred automation. As a change in
routine enzyme procedures, whether recommended or not, inevitably entails a change of biological reference
values, it is understandably unwelcome to clinicians.
Improvement of the design and analytical performance of enzyme measurements will, and should, continue.
However, this should follow the normal practice of development and dissemination of scientific advances. Attempts
to develop and promote further standardized procedures for universal use are neither practicable nor desirable.
The "reference measurement procedure and calibration material" approach (b)) has, in contrast, received relatively
little attention. Among the objections that have been raised are:
1. lack of stable enzyme reference materials in appropriate matrices to serve as calibrators;
2. dissimilarity between candidate enzyme calibrators and the analyte enzymes in human samples, including
differences in isoforms;
3. absence of a constant inter-procedure ratio between a calibrating (reference) procedure and calibrated
(routine) procedure(s), for both the enzyme calibrator and patients' samples containing the analyte enzyme
(also described as a lack of commutability).
The converse of these objections constitutes a list of specifications, both for higher order enzyme reference
materials and for families of measurement procedures between which calibration is proposed. The calibrator should
be stable and have an analyte enzyme that is close in its catalytic properties within its matrix to those of the analyte
enzyme in the routine samples. The procedures themselves should have the same specificity for the catalytic
activity of the target enzyme.
Harmonization of the results of routine enzyme measurements can thus be achieved by selecting a reference
measurement procedure and identifying a family of related procedures for each clinically important enzyme.
Results obtained by any procedure included within such a family will be metrologically traceable to the chosen
reference measurement procedure.
5
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SIST EN ISO 18153:2003
EN ISO 18153:2003 (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 of the catalytic concentration of enzymes.
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.
The following subjects are outside the scope of this standard:
a) requirements for the design or selection of a reference measurement procedure;
b) quantities involving mass of enzyme or immunoreactivity of enzymes;
c) 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);
d) 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;
e) metrological traceability of routine results to the product calibrator and their relations to any medical
discrimination limit;
f) properties involving nominal and ordinal scales.
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).
prEN ISO 17511, In vitro diagnostic medical devices - Measurement of quantities in biological samples -
Metrological traceability of values assigned to calibrators and control materials: (ISO/FDIS 17511:2002)
nd )
1
International Vocabulary of Basic and General Terms in Metrology, 2 edition, Geneva: ISO, 1993
) )
2 3
Guide to the Expression of Uncertainty in Measurement, 1st edition, Geneva:ISO, 1993
3 Terms and definitions
For the purposes of this European Standard, the following terms and definitions apply.
3.1
analyte
component indicated in the name of a measurable quantity
1) The abbreviation VIM:1993 is used in this standard
2) 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)
3) The abbreviation GUM:1993 is used in this standard
6
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SIST EN ISO 18153:2003
EN ISO 18153:2003 (E)
EXAMPLE In the type of quantity "catalytic concentration of lactate dehydrogenase isoenzyme 1 in plasma", "lactate
dehydrogenase isoenzyme 1" is the analyte. The long phrase designates the measurand (see 3.5).
3.2
catalytic activity
z
E
property of a component corresponding to the catalysed substance rate of conversion of a specified chemical
reaction, in a specified measurement system
NOTE 1 Adapted from IUPAC/IFCC 1995:9.101.3.
NOTE 2 In this standard the "component" is an enzyme.
NOTE 3 The quantity "catalytic activity" relates to an amount of active enzyme, not its concentration, see 3.3.
-1
NOTE 4 The coherent derived SI unit is "katal" (kat), equal to "mole per second" (mol s ).
NOTE 5 The measurement procedure is an essential element of the definition of the measurand.
NOTE 6 In many instances, instead of the conversion rate of the substrate ascribed in the short name of the enzyme analyte,
e.g. "creatine" in "creatine kinase", the conversion rate of an indicator substance as substrate of a combined reaction is
measured. Then the measurand should be defined as 'catalytic activity of the enzyme as measured by the conversion rate of an
indicator substance in a specified system according to a given measurement procedure', e.g. 'catalytic activity of creatine kinase
+
as measured by the rate of conversion of NADP in the IFCC reference procedure in human serum'.
3.3
catalytic-activity concentration
catalytic concentration
b
E
catalytic activity of a component divided by volume of the original system
NOTE 1 Adapted from IUPAC/IFCC 1995:9.104.2.
-3
NOTE 2 The coherent derived SI unit is "katal per cubic metre" or "mole per second cubic metre" (kat m
-1 -3
= mol s m ). In laboratory medicine, the unit of volume can be chosen to be "litre" (l).
NOTE 3 In this standard the "component" is an enzyme and the "original system" can be, e.g., the plasma of a blood sample.
3.4
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
3.5
measurand
particular quantity subject to measurement
[VIM:1993, 2.6]
NOTE See 3.1, Example.
3.6
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 achieved 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.
7
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SIST EN ISO 18153:2003
EN ISO 18153:2003 (E)
4 Metrological traceability chain and calibration hierarchy
4.1 Principles
4.1.1 The nomenclature and basic principles of calibration and of metrological traceability of values obtained by
measurement of quantities in biological samples as given in prEN ISO 17511 shall also apply when the analyte is
an enzyme and the measurand is the derived kind-of-quantity "catalytic activity" (or a further derived kind-of-
quantity, e.g., "catalytic concentration" or "catalytic content"). A typical number of levels in a calibration hierarchy is
shown in Figure 1. The primary reference measurement procedure shall assign a value to a primary calibrator
which is used for calibration of the next lower measurement procedure and so on to the results obtained by the
end-user for a routine sample.
NOTE The term 'primary reference measurement procedure' as used here refers to a fully detailed set of measurement
instructions whereas the term 'primary method of measurement' as defined by the Consultative Committee for Amount of
Substance (CCQM) is a generic description of a measurement principle or a measurement method covering various procedures.
4.1.2 It is a prerequisite for the applicability of such a transfer protocol that the measurement procedures used
in descending order in the hierarchical scheme measure the same quantity. Therefore, it shall be demonstrated
that procedures subordinate to the primary reference measurement procedure in the calibration hierarchy measure
the same measurands, e.g. the catalytic concentration of a particular isoenzyme or a group of isoforms to the same
relative extent in a given system.
NOTE 1 Since the kind-of-quantity catalytic activity is defined by the rate of conversion of a specified substance in a
specified reaction mixture (specified, e.g., as to substrate concentration, co-factors, volume fraction of analytical portion,
temperature), the measurement conditions should be sufficiently similar throughout the descending order of measurement
procedures. Deviations from those reaction conditions that will increase the uncertainty of the result assigned to a calibrator or
control material should be avoided.
NOTE 2 The moderate catalytic specificity of some enzymes allows the nature of the substrate to be varied, but if the chosen
substrate in a hierarchically lower measurement procedure varies from that in the reference measurement procedure, additional
experimental evidence is needed to demonstrate that the same quantity is being measured in the modified procedure.
4.1.3 In principle, the primary reference measurement procedure and the manufacturer's product calibrator shall
be required if metrological traceability to SI is to be claimed for the value assigned to a manufacturer's product
calibrator.
NOTE To reduce uncertainty, it is desirable to omit as many pairs of consecutive levels (calibrator and procedure) of a
calibration hierarchy as practicable.
8
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SIST EN ISO 18153:2003
EN ISO 18153:2003 (E)
CALIBRATION
VALUE ASSIGNMENT
MATERIAL PROCEDURE IMPLEMENTATION u (y)
c
1
definition of
SI unit by CGPM
a
IOs
2
primary reference
3
primary
measurement procedure
a
calibrator
IOs
4
secondary reference
ARML, ML
measurement procedure
5
secondary
ARML, ML
b
calibrator
6
manufacturer’s selected
ML
measurement procedure
7
manufacturer’s
ML
working calibrator
8
manufacturer’s standing
ML
measurement procedure
9
manufacturer’s
ML
product calibrator
10
end-user’s routine
Manufacturer
measurement procedure
and/or end-user
routine sample
End-user
End-user
RESULT
The index numbers correspond to the third place decimal numbers in subclause 4.2. Further explanations are
found in prEN ISO 17511.
Abbreviations: ARML Accredited reference measurement laboratory (such a laboratory may be an independent or a
manufacturer's laboratory); BIPM International Bureau of Weights and Measures; CGPM General Conference on
Weights and Measures; IOs International scientific organizations (e.g. IFCC); ML Manufacturer's laboratory; NMI
National metrology institute.
The symbol u (y) stands for combined standard uncertainty of measurement.
c
The horizontal bars at the extreme right under u (y) are not to scale.
c
a
In collaboration with BIPM, NMIs, ARMLs, and manufacturers
b
The calibrator can be an appropriate surrogate reference material or a human sample.
Figure 1 – Extensive calibration hierarchy and metrological traceability to SI
4.2 Structure
4.2.1 The coherent derived SI unit of measurement "katal per cubic metre" or "mole per second cubic metre",
-3 -1 -3
symbolized kat m (= mol s m ) shall be the top of any calibration hierarchy for catalytic concentration of an
enzyme when a primary reference measurement procedure is available.
NOTE 1 The kind–of-quantity "catalytic concentration" is catalytic activity of component in katal (or mole per second) divided
by volume of (original) system sampled in cubic metres.
NOTE 2 In laboratory medicine, the denominator can be chosen to be "litre", giving the non-coherent derived unit "katal per
-1 -1 -1
litre", symbolized = kat l = kat/l = mol s l = (mol/s)/l.
NOTE 3 Another, non-coherent unit used is based on the unit for catalytic activity "enzyme unit" (or "international unit"),
-1 -9 -9
symbolized U, with the conversion equation, 1 U = 1 μmol min 16,667 10 kat. Consequently, 1 U/l 16,667 10 kat/l.
9
METROLOGICAL TRACEABILITY
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SIST EN ISO 18153:2003
EN ISO 18153:2003 (E)
The unit of measurement is independent of the measurement procedure.
4.2.2 A primary reference measurement procedure, which by a description of the measuring system, including the
reaction conditions, defines the measurand, especially the enzymatic component, shall preferably be the next level
of a given calibration hierarchy, and the first operational level.
The results of measurement shall be given directly as catalytic concentration, e.g. in the derived SI unit katal per
litre or mole per second litre, or one of its mutiples or submultiples as appropriate.
Each step of the measurement shall be clearly defined so that a standard uncertainty can be estimated. The
function for calculating the value of the output quantity, the measurand, from all input quantities shall be given
explicitly so that the combined uncertainty can be calculated preferably according to GUM:1993.
NOTE 1 The estimation of uncertainty requires that each measurement step is clearly described and controllable by
experiment, which is not always the case for automated measurement procedures.
NOTE 2 The primary reference measurement procedure preferably should be recommended by international consensus, e.g.
by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). If there is no internationally approved
primary reference measurement procedure, a national metrology institute or scientific society can be encouraged to develop
such a procedure for subsequent international endorsement.
NOTE 3 The IFCC is currently updating its reference measurement procedures to allow a reaction Celsius temperature of 37
o o
C instead of 30 C. New 37° C reference measurement procedures for ALT, AST, CK, y-GT and LDH have already been
published. A list of primary reference measurement procedures is given in annex A.
4.2.3 A primary calibrator shall have its value and uncertainty of measurement assigned by a primary reference
measurement procedure (see 4.2.2), through a formal interlaboratory certification exercise including evaluation of
commutability.
NOTE 1 The preparation and certification of primary calibration materials should be undertaken on behalf of international
organizations.
)
4
NOTE 2 Examples of primary calibrators are the BCR ® certified reference materials, developed within the "Measurement
and Testing, Infrastructure" of the European Commisssion or by cooperation between the "Institute of Reference Materials and
Measurements" (IRMM) of the European Union and the "IFCC". They are listed in annex B.
4.2.4 A secondary reference measurement procedure shall describe a measuring system calibrated by one or
more primary calibrators (see 4.2.3). The reaction conditions shall be such that the measurand is the same as that
of the primary reference measurement procedure. The principles of description as well as of calculation of values
and uncertainties given in 4.2.2 shall apply.
NOTE 1 For ease of operation, a secondary reference measurement procedure can be more mechanized than a primary
one, but 4.2.2, Note 1 still applies.
NOTE 2 A secondary reference measurement procedure can be described and implemented by a reference measurement
laboratory or by the manufacturer.
4.2.5 A secondary calibrator shall have its value assigned according to a secondary reference measurement
procedure (see 4.2.4).
NOTE 1 A secondary calibrator can be accompanied by a certificate.
NOTE 2 The value assignment
...
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