Metrological traceability a concept for standardization in laboratory medicine

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1 DOI /cclm Clin Chem Lab Med 2013; 51(5): Opinion Paper Lothar Siekmanna, * Metrological traceability a concept for standardization in laboratory medicine Abstract: The concept of measurement traceability provides the most important strategy in achieving standardization in laboratory medicine aimed at equivalent measurement results regardless of the principle of measurement, the method, the actual (test kit) and the laboratory where analyses are carried out. Keywords: measurement traceability; reference materials; reference s; reference measurement services; standardization. a Previous chair of the IFCC Committee on Traceability in Laboratory Medicine (C-TLM). *Corresponding author: Prof. Dr. Lothar Siekmann, Institute for Clinical Chemistry and Clinical Pharmacology, Sigmund Freud Strasse 25, Bonn, Germany, Lothar.Siekmann@ukb.uni-bonn.de Hierarchical scheme of measurement traceability Measurement traceability (defined as property of a measurement result whereby the result can be related to a reference through a documented unbroken chain of calibrations, each contributing to the measurement uncertainty according to VIM 2008) [ 1 ] forms the basis for standardization in laboratory medicine which is described in detail in ISO [ 2 ]. The strategy of traceability in laboratory medicine is described in detail in ISO [ 2 ]. As demonstrated in Figure 1, a result of measurement in a patient sample should be traceable along a cascade of mea surement procedures and calibrators/reference materials of increasing metrological order up to the highest level represented by the definition of the measurand in SI units. This hierarchical scheme represents a sequence of s and materials of increasing metrological order from the routine sample obtained from a patient applying the end-user s routine (test kit) to the highest level: the definition of the measurand in SI units. The increasing uncertainty μ c (y) from the top level down to the result in a patient sample is symbolized by the horizontal bars. The responsibilities for the procedures and materials at different levels lie, on the top, with the International Bureau for Weights and Measures (BIPM), which serves as a functional unit for the General Conference on Weights and Measures (CGPM); this is followed by the National Metrology Institutes (NMI), the Accredited Reference (Calibration) Laboratories (AR), the Manufacturer s Laboratories () down to the basic level of the enduser s routine (testing) laboratories. In many situations, it is acceptable to skip pairs of materials and procedures. However, it is important to maintain the highest levels in the scheme, e.g., the primary reference of outstanding specificity and trueness to assign values to secondary matrix reference materials. The hierarchical scheme for the measurement of catalytic concentrations of enzymes shows some differences as, in this case, the top level cannot be described by a primary calibrator and its certification. Instead, the enzyme measurand has to be defined by an exactly described conventional reference. This concept is described in ISO [ 3 ] and the respective primary reference s have been published by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) for a series of enzymes [ 4 ]. Requirements for establishing the concept of traceability The implementation of the traceability concept obviously requires the establishment of internationally accepted: reference s; reference materials; and reference measurement laboratory services.

2 954 Siekmann: Metrological traceability in laboratory medicine SI-Unit Definition of the measurand Certification of a reference material (purity) μ c (y) Uncertainty BIPM, CGPM NMI ISO (modified) Primary calibrator NMI, AR Secondary calibrator Primary reference NMI, AR AR, BIPM: International Bureau of Weights and Measures Traceability Manufacturer s working (master) calibrator Mf. s product calibrator Secondary reference Manufacturer s standing End-user s routine, AR Manufacturer and/or end-user CGPM: General Conference on Weights and Measures NMI: National Metrology Institute AR: Accredited Reference Measurement Laboratory Routine sample End-user : Manufacturer s Laboratory Result End-user Figure 1 Hierarchical scheme of traceability in laboratory medicine (modified according to ISO 17511). With respect to these requirements, the Joint Committee for Traceability in Laboratory Medicine (JCTLM) [ 5 ], established by the BIPM, the IFCC and the International Laboratory Accreditation Cooperation (ILAC), has launched two projects in its working groups (WG). WG-1 lists tables of reference materials and reference procedures on the JCTLM website [ 5 ]. The materials and procedures are first inspected by review teams dedicated to different groups of measurands on the basis of criteria defined in the International Standards ISO [ 6 ] and [ 7 ]. The criteria for listing reference measurement materials and s are described in detail in the respective procedure manuals on the JCTLM website [5 ]. The list of materials and methods is updated annually according to the decisions made by the JCTLM Executive Committee. The identification of reference measurement laboratories is the objective of JCTLM WG-2. Establishing networks of reference laboratories is in addition to reference s and reference materials one of the biggest challenges in implementing the concept of measurement traceability. Each individual proposal of a reference laboratory for a particular measurement service (measurand) is first inspected by a review team dedicated to the appropriate group of measurands and then approved by the JCTLM Executive Committee according to the rules of the corresponding WG-2 procedure manual [ 5 ]. There is general agreement now that reference laboratories should be identified: according to the metrological level of the procedures applied; on the basis of accreditation as calibration laboratory according to ISO [ 8 ] and ISO [ 9 ]; and on the basis of their ability to demonstrate performance in regular inter-laboratory comparisons (ring trials). With respect to the metrological level the measurement principle [e.g., isotope dilution-mass spectrometry (IDMS)] is probably one of the most important criteria to accept a method as reference in view of its outstanding specificity and trueness. In addition, the use of a primary reference material as calibrator is essential. Furthermore, all gravimetric and volumetric steps must be carefully calibrated gravimetrically using certified test weights. Each certified measurement result achieved after a campaign of at least three independent measurement occasions must be accompanied by an individual uncertainty statement. Also, extensive quality assessment of each analytical campaign is obligatory. Matrix control materials with certified target values must be included in each series of measurements.

3 Siekmann: Metrological traceability in laboratory medicine 955 Laboratories must show their accreditation as a reference (calibration) laboratory to demonstrate adherence to the requirements of ISO standards and In order to support the JCTLM activities regarding inter-laboratory comparisons, the IFCC has launched a ring trial program for reference laboratories (RELA) particularly dedicated to reference measurement laboratories for some 30 different measurands [ 10 ]. Ring trial results not only demonstrate the competence of individual laboratories, they also reveal the equivalence of individual laboratory results or, in some cases, the bias of different reference procedures. In this special issue of Clinical Chemistry and Laboratory Medicine, the article External Quality Assessment Scheme for reference laboratories review of eight years experience [ 11 ] describes the details. Hierarchical scheme of laboratories In summary, a hierarchical scheme of laboratories has been established as demonstrated in Figure 2. At the top, we find the NMIs; they must demonstrate their competence in key comparisons and are listed in the CIPM-MRA-Key-Comparison-Data-Base (International Committee on Weights and Measures Mutual Recognition Arrangement Key Comparison Data Base). Their services include certification of primary and secondary Outline of the Calibration and Measurement Hierarchy in Laboratory Medicine CIPM MRA Key Comparisons Data Base (KCDB) CIPM National Metrology Institutes Listed: CIPM KCDB list (Appendix C) of National Metrology Institutes providing Calibration and Measurement Capabilities (CMCs) Realizations of the SI units providing: a) Certified values for reference materials, b) Calibration and measurement capabilities on the highest metrological level for comparative measurements e.g. in Ring Trials for Reference Laboratories Reference (Calibration) Laboratories JCTLM a) Accreditation as Calibration Laboratories according to ISO and 15195, b) Use of JCTLM listed reference methods, c) Participation in Ring Trials for Reference Laboratories Listed: JCTLM list of reference laboratories Reference measurement service for a) Diagnostica manufacturers, b) Regulatory bodies c) Proficiency testing organisations, certifying reference method values for ring trials for routine laboratories Routine (Testing) Laboratories National Regulatory Bodies a) Accreditation according to ISO 15189, b) Participation in ring trials of proficiency testing organisations, Reference method certified by reference laboratories Measurement service for patient samples Figure 2 Hierarchical scheme of laboratories for calibration and measurement in laboratory medicine.

4 956 Siekmann: Metrological traceability in laboratory medicine reference materials and provision of calibration and measurement capabilities on the highest metrological level, e.g., by participating in Ring Trials for Reference (Calibration) Laboratories. Thereby, they provide the link to the second level of laboratories in the hierarchical order. The Reference (Calibration) Laboratories have to demonstrate their competence: by accreditation as calibration laboratories according to ISO [8 ]; by using JCTLM accepted reference measurement procedures; and by regular participation in ring trials dedicated to reference/calibration laboratories. Once the requirements for particular services (measurands) are fulfilled, these laboratories will be listed by the JCTLM on the respective website. The service of the reference/calibration laboratories is to support diagnostic kit manufacturers and regulatory bodies in the establishment and control of traceability of diagnostic test kits. Furthermore, they provide certified reference method target values for External Quality Assessment Schemes (EQAS), thus linking to the basic group of routine/testing laboratories. These may demonstrate their competence by accreditation according to ISO [ 12 ] and by participation in ring trials where target values are certified by reference/ calibration laboratories. Obviously, their service is the analysis of samples from patients. Implementation of the concept of measurement traceability The implementation of the concept of traceability improves standardization in laboratory medicine as evident from the results of EQAS for routine laboratories using reference method target values. The concept of traceability as described here has to date become available for only a limited number of measurands for which certified primary reference materials and/or reference s are available. Up to now, the JCTLM has listed 241 reference materials, 156 reference s and 63 reference measurement services from eight reference laboratories. Extension of the concept of traceability to include further measurands by developing new reference materials and reference s and establishing reference measurement services is scheduled for the future. Nevertheless, it can be estimated that in the current situation, about 65% of all measurements in a typical clinical chemical laboratory can be covered by the concept of traceability. For measurements where the concept is not applicable another approach has been proposed based on harmonization. This has been discussed extensively in recent years [ 13 ]. However, it must be emphasized that harmonization should not be applied when the metrological concept of traceability can be implemented. Conflict of interest statement Author s conflict of interest disclosure: The author stated that there is no conflict of interest regarding the publication of this article. Research funding: None declared. Employment or leadership: None declared. Honorarium: None declared. Received June 27, 2012; accepted October 9, 2012; previously published online November 12, 2012 References 1. International vocabulary of metrology Basic and general concepts and associated terms (VIM). 3rd ed version with minor corrections. JCGM 200, In vitro diagnostic medical devices Measurement of quantities in biological samples Metrological traceability of values assigned to calibrators and control materials, ISO 17511, 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 18153, Siekmann L, Bonora R, Burtis CA, Ceriotti F, Clerc-Renaud P, Ferard G, et al. IFCC primary reference procedures for the measurement of catalytic activity concentrations of enzymes at 37 C, Part 1. The concept of reference procedures for the measurement of catalytic concentrations of enzymes. Clin Chem Lab Med 2002;40: Joint Committee for Traceability in Laboratory Medicine (JCTLM). Available from: Accessed 15 October In vitro diagnostic medical devices Measurement of quantities in samples of biological origin Requirements for content and presentation of reference s, ISO 15193, 2009.

5 Siekmann: Metrological traceability in laboratory medicine 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, Laboratory medicine Requirements for reference measurement laboratories, ISO 15195, General requirements for the competence of testing and calibration laboratories, ISO 17025, RELA surveys. Available from: shtml. Accessed 15 October Kessler A, Siekmann L, Weykamp C, Geilenkeuser WJ, Dreazen O, Middle J, et al. External Quality Assessment Scheme for reference laboratories review of eight years experience. Clin Chem Lab Med 2013;51: Medical laboratories Particular requirements for quality and competence, ISO 15189, Miller WG, Myers GL, Gantzer, Kahn SE, Sch ö nbrunner ER, Thienpont LM, et al. Roadmap for harmonization of clinical laboratory s. Clin Chem 2011;57: