ISO/TC 212/WG 2 - Reference systems

This document specifies requirements for a protocol implemented by an international body to achieve equivalent results among two or more IVD MDs for the same measurand for cases where there are no reference measurement procedures and no fit-for-purpose certified reference materials or international conventional calibrators. In this case, the harmonisation protocol defines the highest level of metrological traceability for the stated measurand. This document can be applied in cases when certified reference materials or international conventional calibrators exist but are not fit-for-purpose because, for example, they are not commutable with human samples. NOTE This document addresses one case of traceability of assigned and measured values described in 5.6 in ISO 17511:2020.

This document specifies technical requirements and documentation necessary to establish metrological traceability of values assigned to calibrators, trueness control materials and human samples for quantities measured by IVD MDs. The human samples are those intended to be measured, as specified for each IVD MD. Metrological traceability of values for quantities in human samples extends to the highest available reference system component, ideally to RMPs and certified reference materials (CRMs). All parties having a role in any of the steps described in a calibration hierarchy for an IVD MD are subject to the requirements described. These parties include but are not limited to manufacturers (of IVD MDs), RMP developers (see ISO 15193), RM producers (see ISO 15194), and reference/calibration laboratories (see ISO 15195) supporting calibration hierarchies for IVD MDs. NOTE 1 Producers of RMs intended for use in standardization or calibration of IVD MDs include commercial and non-commercial organizations producing RMs for use by many end-users of IVD MDs and/or calibration laboratories, or for use by a single end-user medical laboratory, as in the case of a measurement standard (calibrator) intended to be used exclusively for calibration of a laboratory-developed MP. This document is applicable to: a) all IVD MDs that provide measurement results in the form of numeric values, i.e. rational (ratio) and/or differential (interval) scales, and counting scales. b) IVD MDs where the measurement result is reported as a qualitative value established with a ratio of two measurements (i.e. the signal from a specimen being tested and the signal from a RM with a specified concentration or activity at the cut-off), or a counting scale, with corresponding decision threshold(s). This also includes IVD MDs where results are categorized among ordinal categories based on pre-established quantitative intervals for a quantity. c) RMs intended for use as trueness control materials for verification or assessment of calibration of IVD MDs, i.e. some commutable CRMs and some external quality assessment (EQA) materials (if so indicated in the RM's intended use statement). d) IVD MD-specific calibrators and trueness control materials with assigned values, intended to be used together with a specified IVD MD. e) IVD MDs as described in a) and b), where no end-user performed calibration is required (i.e. when the manufacturer performs a factory calibration of the IVD MD). This document is not applicable to: a) calibrators and trueness control materials for IVD MDs which, due to their formulation, are known to have zero amount of measurand; b) control materials that are used only for internal quality control purposes in medical laboratories to assess the imprecision of an IVD MD, either its repeatability or reproducibility, and/or for assessing changes in IVD MD results compared to a previously established calibration condition; c) control materials that are used only for internal quality control purposes in medical laboratories and which are supplied with intervals of suggested acceptable values that are not metrologically traceable to higher order reference system components; d) properties reported as nominal scales and ordinal scales, where no magnitude is involved. NOTE 2 Nominal scales are typically used to report e.g. identity of blood cell types, microorganism types, identity of nucleic acid sequences, identity of urine particles. NOTE 3 Ordinal scales are often applied to results differentiated into dichotomous groupings (e.g. ?sick' vs. ?healthy'), and occasionally to results differentiated into non-dichotomous categories where the result categories are rank-ordered but the rank-ordered categories cannot be differentiated in terms of relative degree of difference, e.g. negative, +1, +2, +3 for grading of presence of haemoglobin in urine specimens by visual observation.

This document specifies the requirements for competence to carry out reference measurement procedures in laboratory medicine, using the requirements of ISO/IEC 17025:2017 as a normative reference and listing additional requirements for calibration laboratories to perform their tasks adequately. The relationship between clauses in this document and ISO/IEC 17025:2017 are summarized in Annex A. Examinations of properties with results reported on a nominal or ordinal scale are not included. This document is not applicable to medical laboratories. NOTE Requirements for medical laboratories are specified in ISO 15189[1].

ISO 15194:2009 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. ISO 15194:2009 also provides requirements on how to collect data for value determination and how to present the assigned value and its measurement uncertainty. ISO 15194:2009 applies to certified reference materials with assigned values of differential or rational quantities. Annex A provides information on nominal properties and ordinal quantities. ISO 15194:2009 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.

ISO 15193:2009 specifies requirements for the content of a reference measurement procedure for in vitro diagnostic medical devices and medical laboratories. ISO 15193:2009 applies to reference measurement procedures providing values of differential or rational quantities. Annex A provides information on nominal properties and ordinal quantities. ISO 15193:2009 is valid for any person, body or institution involved in one of the various branches of laboratory medicine whose intention is to write a document to serve as a reference measurement procedure.

ISO 18153:2003 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 ISO 18153:2003: requirements for the design or selection of a reference measurement procedure; quantities involving mass of enzyme or immunoreactivity of enzymes; 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; metrological traceability of routine results to the product calibrator and their relations to any medical discrimination limit; properties involving nominal and ordinal scales.

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).

ISO 15193:2002 specifies requirements for the drafting of a reference measurement procedure. It is applicable to any person, body, or institution, involved in one of the various branches of laboratory medicine, intending to write a document to serve as a reference measurement procedure.

ISO 15194:2002 specifies requirements and formats for the description of reference materials. It is applicable to reference materials of higher metrological order, classifiable as primary measurement standards and secondary measurement standards that function either as calibrators or control materials for reference measurement procedures. ISO 15194:2002 is not applicable to reference materials that are parts of an in vitro diagnostic measuring system. ISO 15194:2002 also provides instructions on how to collect basic data for value assignment and how to present the assigned value as well as specifies the format for a certificate. ISO 15194:2002 is not applicable to the production of the reference materials.