Measurement traceability and US IVD manufacturers: the impact of metrology

A goal of clinical laboratory science is to produce accurate and comparable patient test results for a specimen independent of analytical methodology. The In Vitro Diagnostics Directive in Europe has provided the impetus for the U.S. in vitro diagnostic (IVD) industry to adapt the concepts of Metrology, the science of measurement, including measurement traceability and measurement uncertainty. The joint committee for traceability in laboratory medicine has provided a valuable database of internationally recognized reference materials and methods and reference laboratories. Much of the responsibility for measurement traceability falls on IVD manufacturers, but all global stakeholders, including the clinical laboratory profession, government Regulatory bodies, metrology institutes, and the providers of EQA/PT surveys, must cooperate to progress toward this goal. The adaptation of the concepts of Metrology to the clinical laboratory is an appropriate and logical development and it will continue in the twenty-first century.     

Establishing measurement traceability in clinical chemistry

Measurement traceability is probably the most important tool for achievement of comparability in clinical chemistry. As stipulated by the In Vitro Diagnostica Directive of the European Union and several ISO standards, values assigned to calibrators and control materials must be traceable to reference materials and/or reference procedures of higher order. In the German proficiency testing system, statutory use of reference measurement procedures for several measurands has been in force since 1988. As a result, reference procedures are now regularly applied for the setting up of target values in the control samples of internal and external quality assessment and for assigning values to the manufacturers calibrator and control materials. Noticeably, the comparability of results obtained by different diagnostic tests has greatly improved for the measurement of many metabolites and substrates, e.g. creatinine, cholesterol, uric acid, total glycerol and urea. For many measurands in laboratory medicine the implementation of the concept of traceability proves to be much more difficult; this mainly concerns the measurement of proteins, in particular enzymes, proteo-hormones, tumour markers and cardiac markers. For such measurands the analyte must first of all be distinctively defined before a reference system can be established which comprises reference procedures, reference materials and networks of reference laboratories.Presented at the CCQM Workshop on Traceability 16–17 April 2002 at the BIPM, Sèvres, France     

Metrological traceability in laboratory medicine

 The establishment of a reference examination system necessary for metrological traceability of the many types of sophisticated examination result in laboratory medicine is a daunting task, which has been made mandatory by the EU Directive on in vitro diagnostic medical devices and the requirements for accreditation. Following a definition of examinand and allowed examination uncertainty, a dedicated calibration hierarchy is established from stated reference through alternating reference examination procedures and calibrators providing a traceability chain from examination result to the reference, often a definition of a measurement unit. The various types of possible calibration hierarchy are outlined in EN ISO Standards. Recent efforts by national and international stakeholders to establish a global reference examination system have led to the creation of a Joint Committee on Traceability in Laboratory Medicine with the International Committee for Weights and Measures, International Bureau of Weights and Measures, International Federation of Clinical Chemistry and Laboratory Medicine, International Laboratory Accreditation Cooperation, and World Health Organization as the principal promoters. This structure will identify reference procedures, reference materials, and reference laboratories, and seek support for further prioritised and coordinated development of the system. Received: 1 August 2002 Accepted: 22 November 2002 Based on a lecture at an IUPAC Seminar, EC JRC Institute for Reference Materials and Measurements, Geel, BE, 2001–12–18 Correspondence to R. Dybkaer     

Current best practice for traceability in testing laboratories,when certified reference materials are unavailable

Since the implementation of ISO/IEC 17025 in 2002, all accredited laboratories (at the least) need to establish traceability in all their tests and calibration methods. Traceabilty, though well understood in the calibration field (through an unbroken chain of comparisons to the International System of Units —SI), is less straight forward and not so well understood in the testing laboratories. Traceability in analytical and biological testing is found through the use of reference materials, and the validated steps of a test method. This article describes the possibilities to comply with the traceability requirement of ISO/IEC 17025 in testing laboratories , when certified reference materials are unavailable.Presented at the Second International Conference on Metrology—Trends and Applications in Calibration and Testing Laboratories, 4–6 November, 2003, Eilat, Israel     

Quality in point-of-care testing: what drives the system—personnel, regulatory standards, or instrumentation?

The European Commission (EC) Directive on in vitro diagnostic medical devices requires—amongst other obligations—manufacturers to establish metrological traceability of values assigned to calibrators to available measurement procedures and/or available reference materials of a higher order. Manufacturers use different procedures to accomplish this task and to indicate uncertainties of assigned values. Medical laboratories may want to calculate the uncertainties of their results or accreditation bodies may require them to do so. For this purpose some practical approaches are presented and some examples discussed.Presented at the Roche Diagnostic Workshop on In Vitro Diagnostics Directive: A Nordic event about the implication of traceability and uncertainty in practice, 13–15 February, 2003, Helsinki, Finland. Organized in connection with Labquality Days, 13 February, 2003, Helsinki.     

The increasing demands of quality assurance in chemical testing

The chemical and microbiological testing community is going through a rather difficult period of change. Publication of ISO/IEC 17025 (General requirements for the competence of Calibration and Testing Laboratories, 1999) [1] is placing additional demands on testing laboratories to ensure traceability and estimate uncertainty in their measurements. At the same time, laboratories must remain mindful of the need to provide relevant, timely and economic services to their clients. International Accreditation New Zealand (IANZ) and its accredited laboratories are currently focussing on establishing realistic methods for ensuring traceability to national and international standards and estimating measurement uncertainty. To this end, IANZ recognizes that it has an important role in providing as much advice and assistance as possible, not only to its accredited chemical laboratories but also to all those contemplating accreditation in New Zealand.

Traceability and uncertainty – A comparison of their application in chemical and physical measurement

 Establishment of the traceability and the evaluation of the uncertainty of the result of a measurement are essential in order to establish its comparability and fitness for purpose. There are both similarities and differences in the way that the concepts of traceability and uncertainty have been utilised in physical and chemical measurement. The International Committee of Weights and Measures (CIPM) have only in the last decade set up programmes in chemical metrology similar to those that have been in existence for physical metrology for over a century. However, analytical chemists over that same period have also developed techniques, based on the concepts of traceability and uncertainty, to ensure that their results are comparable and fit for purpose. This paper contrasts these developments in physical and chemical metrology and identifies areas where these two disciplines can learn from each other.     

Integration of metrological principles in a proficiency-testing scheme in the field of water analysis

Measurement traceability is universally recognised as one of the basic prerequisites for comparability of results obtained in different laboratories and is a basic aspect of metrological sciences such as analytical chemistry. This requirement is underscored by the increasing adoption of standards and measurement quality systems, such as laboratory accreditation against ISO/IEC 17025. Testing laboratories ensure traceability of their measurement results by using appropriate reference standards for calibration of instruments and control of measurement processes. For routine work in the field of water analysis, these standards are usually commercial solutions or in-house solutions prepared from pure products. Therefore, laboratories should demonstrate that their use of reference standards is appropriate and sufficient, which can be done by participation in an appropriate proficiency-testing scheme. The paper reports how measurement traceability of results from field laboratories (nitrite nitrogen, nitrate nitrogen, chloride and sulphate; all in water) can be demonstrated by participation in a proficiency-testing scheme based on reference values.     

Interlaboratory comparison for the determination of pesticide residues in Chinese cabbage

The results of and findings from an interlaboratory comparison among laboratories carrying out food testing of pesticide residues in the APEC (Asia–Pacific Economic Cooperation) region are presented and discussed to show critical roles of chemical metrology infrastructure in establishing traceability of measurements and in supporting existing measurement capability in safety and quality of food trade. The study material, which was prepared and certified by Korea Research Institute of Standards and Science (KRISS), was freeze-dried Chinese cabbage powder fortified with two organophosphorous pesticides (diazinon and chlorpyrifos). Among 14 participants, 12 laboratories were accredited based on ISO/IEC17025 and one laboratory was under assessment for the accreditation at the time of this study. Though all participants demonstrated very good intra-day repeatability and inter-day intermediate precision, many of them showed a large bias from the certified values. It is suggested that in addition to the accreditation system, economies are encouraged to develop appropriate chemical metrology infrastructure, which could effectively support laboratories to assure measurement traceability to SI, for which NMIs could play significant roles through their metrological services recognized in Mutual Recognition Arrangement (MRA) of the International Committee for Weights and Measures (Comité International des Poids et Mesures, CIPM).     

Metrological concept for comparable measurement results under the European water framework directive: demonstration of its applicability in elemental analysis

Within the scope of a project of the “European Association of National Metrology Institutes??(EURAMET), a European metrological dissemination system (network) providing traceable reference values assigned to matrix materials for validation purposes is described and put to the test. It enables testing laboratories (TL) to obtain comparable results for measurements under the “EU Water Framework Directive 2000/60/EC??(WFD) and thus, to comply with a core requirement of this very directive. The dissemination system is characterized by the fact that it is available to all laboratories throughout Europe which intend to perform measurements in the context of the WFD and that it can ensure sustainable metrological traceability to the International System of Units (SI) as a reference point for the measurement results. This dissemination system is set up in a hierarchical manner and links up the level of the national metrology institutes (NMI) with that of the TLs via an intermediate level of calibration laboratories (CL) by comparison measurements. The CLs are expert laboratories with respect to the measurement of the analytes considered here (within the project, the CLs are called potential calibration laboratories (PCL)) and are additionally involved in the organization of comparison measurements within the scope of regional quality assurance (QA) systems. Three comparison measurements have been performed to support the approach. A total of about 130 laboratories participated in this exercise with the focus on the measurement of the priority substances Pb, Cd, Hg, and Ni defined in the WFD. The elemental concentrations in the water samples roughly corresponded to one of the established environmental quality standards (EQS), the annual average concentration (AA-EQS), which is defined in the daughter Directive 2008/105/EC of the WFD. It turned out that a significant number of TLs still need to improve their measurement methods in order to be able to fulfill the minimum requirements of the WFD, in particular, with regard to the elements Cd and Hg probably due to their low EQS values. Furthermore, it became obvious that the hierarchical dissemination system suggested here actually corresponds to the measuring capabilities of the three participating groups (NMIs, PCLs, and TLs).     

Metrology for metalloproteins—where are we now, where are we heading?

The use of the amount of certain proteins in biological samples as markers for distinguishing between a healthy and a diseased state has become increasingly important in clinical diagnosis. As about 30 % of all proteins contain metals in one form or another, either as a cofactor or covalently bound as part of the protein, some of these proteins are regularly analyzed in clinical laboratories. With the increasing number of measurements of those proteins performed all over the world, the necessity of obtaining reliable and comparable results is becoming a focal point for scientists and politicians. Directives such as the EC directive covering in vitro diagnostic medical devices (Directive 98/79/EC) and standards such as EN ISO 17511:2003 demand the traceability of the results obtained for analytes in samples of human origin. However, no reference measurement procedures with results traceable to the SI exist for many metalloproteins. In this article, the situation for a few important metalloproteins, such as hemoglobin, transferrin, superoxide dismutase, ceruloplasmin, and C-reactive protein, for which specific efforts have been made in recent years to achieve comparable and traceable results worldwide, is discussed. These proteins also serve as examples of the difficulties scientists face when they wish to quantify proteins and the pitfalls they should avoid to achieve reliable results.

Reference material requirements for laboratories and the role of accreditation bodies

It is now over two years since ISO/IEC 17025 General requirements for the competence of testing and calibration laboratories was published. The standard places increased emphasis on the demonstration of traceability of measurements made by laboratories. In the areas of chemical and biological metrology, the introduction of this standard has brought new challenges for laboratories to grapple with. This paper will examine the requirements regarding traceability for chemical and biological measurements, with specific reference to the use of reference materials by laboratories. This will be explored from the perspective of both accreditation bodies and a laboratory which is both a user and producer of certified reference materials. Moreover, the paper will describe mechanisms that are being used to improve the use of reference materials by accredited laboratories and hence the traceability of measurements. Finally the role of accreditation programs for reference material producers in assisting with this aspect will be examined.Electronic Supplementary Material Supplementary material is available for this article if you access the article at . A link in the frame on the left on that page takes you directly to the supplementary material.Presented at BERM-9—Ninth International Symposium on Biological and Environmental Reference Materials, June 15–19, 2003 Berlin, Germany.     

Implementation of traceability – needs and perspective of the in-vitro-diagnosticum industry

Manufacturers support the concept of traceability. However, only a small number of the medically relevant measurands can be traced to the highest metrological order. In many cases, the measured substances are heterogeneous mixtures where traceability can be established only to either an international conventional reference measurement procedure or to a manufacturers own in-house reference system. The traceability concept needs to be seen in the context that the results of medical laboratories are not an aim per se, but are meant to provide useful medical information to clinicians, and that pre- and post-analytical steps may also contribute significantly to errors. There is a need for the further development of suitable reference measurement systems, but in view of the multitude of tasks and limited resources, priorities need to be set.Presented at BERM-9 – 9^th International Symposium on Biological and Environmental Reference Materials, 15–19 June 2003, Berlin, Germany     

The use of certified reference materials in the Romanian traceability scheme

 For ensuring the traceability and uniformity of measurement results, the main objectives of national metrology programmes in chemistry are to calibrate and verify measuring instruments, to evaluate the uncertainty of measurement results and to intercompare the analytical results, etc. The concept of traceability has developed recently in chemical measurements, thus, an attempt to implement the principles of metrological traceability especially by appropriateness calibration using composition certified reference materials (CRMs) is underlined. Interlaboratory comparisons are also a useful response to the need for comparable results. The paper presents some aspects and practices in the field of spectrometric measurement regarding the metrological quality of the traceability by calibrating the instruments using suitable and reliable CRMs. The uncertainty of results, as a measure of the reliability that can be placed on them, has been adequately described in different documents and, as a consequence, some examples of evaluating the measurement uncertainty are described. The relationship between uncertainty and traceability, as two fundamental concepts of metrology which are intimately linked, is underlined. Received: 12 November 1999 / Accepted: 10 December 1999     

Achieving traceability in chemical measurement—a metrological approach to proficiency testing

ISO/IEC 17025 requires that testing laboratories establish the traceability of their measurements, preferably to the SI units of measurement. The responsibility for establishing traceability lies with each individual laboratory and must be achieved by following a metrological approach.The results of measurements made in such a way are traceable to the standards used in method validation and to the calibration standards used during the measurement process. If these standards are traceable to SI then the measurements will also be traceable to SI.Participation in appropriate proficiency studies (an ISO/IEC 17025 requirement) enables laboratories to demonstrate the comparability of their measurements. If the materials used for the studies have traceable assigned values, then proficiency testing also provides information about measurement accuracy and confirms, or otherwise, that appropriate traceability has been established. This paper will report on a new approach for the establishment of traceable assigned values for chemical testing proficiency studies. The work is conducted at a "fit for purpose" level of measurement uncertainty, with costs contained at a level similar to previous "consensus" based proficiency studies. By establishing traceable assigned values in a cost effective way, NARL aims to demonstrate the added value of the metrological approach to participant laboratories.     

Physiological reference values: a shared business? Report of the second European symposium on clinical laboratory and in vitro diagnostics industry

The Catalan Association of Clinical Laboratory Sciences, with the support of its corporative members, organized the second European symposium devoted to physiological reference values, in Barcelona. The objectives were: (i) to discuss ways to develop a common strategy among clinical laboratories and the in vitro diagnostic (IVD) industry for the generation of physiological reference values related to biological quantities of medical interest; and (ii) to establish consensus between both groups regarding the interpretation of the requirements related to physiological reference values contained in the European (EU) Directive 98/79-EC and in the EN-ISO 15189:2003 standard. The symposium was divided into four parts in which different aspects of the reference values were discussed: legal and normative aspects, alternatives to the production of own reference values, methodology, and diffusion and teaching. The main conclusions were the need to clarify the requirements described by the EU Directive 98/79-EC and EN-ISO 15189:2003 regarding reference values, and the need for cooperation between industry, clinical laboratories, and health authorities to achieve common reference intervals, including multicentric reference intervals.     

Interlaboratory comparison for the determination of five residual organochlorine pesticides in ginseng root samples by gas chromatography

An interlaboratory comparison study for the determination of 5 residual organochlorine pesticides (hexachlorobenzene and 4 hexachlorocyclohexane isomers) in ginseng root was performed. This program [Asia Pacific Laboratory Accreditation Cooperation (APLAC) T049] was the first of its kind for an herbal matrix and involved the participation of 70 laboratories from 26 countries worldwide. Consensus mean values were computed statistically from the reported results, which were eventually used to assess the performance of individual laboratories in terms of the z-scores. The distribution of analytical data was found to be widespread, with standard deviation ranging from 43.9 to 55.9%, and the result patterns obtained were similar to those residue pesticide programs using other matrixes. Although the estimation of measurement uncertainty is a crucial requirement for all quantitative tests for laboratories that meet the requirements of International Organization for Standardization/International Electrotechnical Commisssion (ISO/IEC) 17025, some laboratories in this program had difficulties and showed unfamiliarity with respect to that quality criterion. It was recommended that laboratories review and rectify the situation promptly so that they would have a better understanding of measurement uncertainty or the test service provided.     

Determination of dissolved bromate in drinking water by ion chromatography and post column reaction: interlaboratory study

A collaborative study, International Evaluation Measurement Programme-25a, was conducted in accordance with international protocols to determine the performance characteristics of an analytical method for the determination of dissolved bromate in drinking water. The method should fulfill the analytical requirements of Council Directive 98/83/EC (referred to in this work as the Drinking Water Directive; DWD). The new draft standard method under investigation is based on ion chromatography followed by post-column reaction and UV detection. The collaborating laboratories used the Draft International Organization for Standardization (ISO)/Draft International Standard (DIS) 11206 document. The existing standard method (ISO 15061:2001) is based on ion chromatography using suppressed conductivity detection, in which a preconcentration step may be required for the determination of bromate concentrations as low as 3 to 5 microg/L. The new method includes a dilution step that reduces the matrix effects, thus allowing the determination of bromate concentrations down to 0.5 microg/L. Furthermore, the method aims to minimize any potential interference of chlorite ions. The collaborative study investigated different types of drinking water, such as soft, hard, and mineral water. Other types of water, such as raw water (untreated), swimming pool water, a blank (named river water), and a bromate standard solution, were included as test samples. All test matrixes except the swimming pool water were spiked with high-purity potassium bromate to obtain bromate concentrations ranging from 1.67 to 10.0 microg/L. Swimming pool water was not spiked, as this water was incurred with bromate. Test samples were dispatched to 17 laboratories from nine different countries. Sixteen participants reported results. The repeatability RSD (RSD(r)) ranged from 1.2 to 4.1%, while the reproducibility RSD (RSDR) ranged from 2.3 to 5.9%. These precision characteristics compare favorably with those of ISO 15601. A thorough comparison of the performance characteristics is presented in this report. All method performance characteristics obtained in the frame of this collaborative study indicate that the draft ISO/DIS 11206 standard method meets the requirements set down by the DWD. It can, therefore, be considered to fit its intended analytical purpose.     

Quality management, certification and accreditation in medical laboratories – the view of ECLM

 Increasing demands from health care planners and industrialists conducting clinical trials, as well as general competition, are forcing medical laboratories to seek third-party recognition of their quality management systems. There is a tendency to move from certification of a laboratory director, via certification of the laboratory quality system (ISO 9000 family), to accreditation needing proof of professional and technical competence in laboratory tasks. The requirements of accreditation are presented in several national schemes and in the European Standards series (EN 45 000) and the International Organization for Standardization's guide, ISO/IEC 25, to be amalgamated soon. The latter system provides transnational recognition through participation of the accrediting bodies in the European co-operation for Accreditation. Necessary supplementary guidelines exist for chemical laboratories (Eurachem) and medical laboratories CEAC/ECLM). Traceability and reliability of results are obtained by utilizing a global reference examination system and by participating in transdisciplinary work. The costs of achieving accreditation are considerable and mainly involve the production of quality handbooks and written work procedures by personnel. The rewards are an open system, smoother work, emphasis on prevention of mistakes, and satisfied stakeholders. Received: 5 October 1998 · Accepted: 20 October 1998     

Conformity assessment and metrology: update on the state of affairs

A couple of years ago, ISO CASCO launched a major project of transforming all the existing ISO Guides on conformity assessment to a comprehensive series of ISO standards 17000 being now in various stages of development. As the concept of traceability underpinning all measurements has been a basic mission of metrology, a number of these standards have a direct bearing on metrology. The series is logically based on a definition standard, ISO 17000, giving, among others, a guidance which activities fall under conformity assessment. The fact that calibration does not, might have important consequences which must yet be assessed. A controversial discussion on some issues has been in progress concerning ISO 17011 on accreditation bodies which touches both on national metrology institutes (NMIs) with an accreditation function and on calibration labs at large. ISO 17040 on peer review could be used with an advantage to support mutual recognition arrangements among a limited number of bodies of a specialized expertise (e.g., CIPM MRA among NMIs under the Metre Convention). ISO 17025 has been the most important standard for the metrology community and has undergone a major overhaul taking on board the uncovered requirements from ISO 9001:2000. In general, the paper will give an update on the developments outlined above and discuss the consequences and further steps from the viewpoint of metrology.