Medicina Laboratorial - Ano 2016 - Volume 52 - Número 3
Rastreabilidade metrológica no laboratório clínico
Metrological traceability in clinical laboratory
1. Instituto Nacional de Metrologia, Qualidade e Tecnologia (Inmetro), Rio de Janeiro, Brazil
2. Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
Endereço para correspondência
Maria Cristina Ferreira Pessoa
Rua Prefeito João Felipe, 537, apto 103; Santa Teresa
CEP: 20251-140; Rio de Janeiro-RJ, Brasil
Primeira Submissão em 25/02/2016
Última Submissão em 25/03/2016
Aceitado para sua publicação em 06/04/2016
Publicado em 20/06/2016
INTRODUÇÃO: Rastreabilidade metrológica é um tema da metrologia pouco conhecido e discutido nos laboratórios clínicos, apesar de ser a base para resultados comparáveis; associa-se a material de referência certificado (MRC) e a método de referência (MetR). Quando usada na cadeia de suprimentos pelos fabricantes de conjuntos diagnósticos, atua na garantia da exatidão dos resultados produzidos pelos laboratórios.
OBJETIVO: Apresentar a disponibilidade das informações sobre rastreabilidade metrológica fornecidas pelos fabricantes de conjuntos diagnósticos.
MÉTODO: O estudo foi feito com as informações obtidas nos conjuntos diagnóstico de glicose (GLI), ureia (URE), creatinina (CRE), ácido úrico (AU) e colesterol (COL) participantes de um programa de ensaio de proficiência ao longo de 2012 e 2013.
RESULTADOS E CONCLUSÃO: Na pesquisa sobre produtores de materiais de referência (MRs) e de produtos disponibilizados, foram encontrados 18 produtores e 204 analitos para a área de laboratórios clínicos. No estudo sobre rastreabilidade metrológica, foi demonstrado o uso preferencial de MRC pelos fabricantes de conjuntos diagnósticos (GLI 60%; URE 69%; CRE 60%, AU 50% e COL 43%), bem como o dado importante de que há um número expressivo de conjuntos diagnósticos que não informa rastreabilidade (GLI 16%; URE 19%; CRE 16%, AU 13% e COL 5%), embora ela seja requisito em norma nacional que regulamenta o registro de produtos. Esperamos que este estudo contribua para sensibilizar a comunidade laboratorial da necessidade de conhecimento mais abrangente acerca deste assunto e que estimule as instituições relacionadas com a disseminação de conhecimento na área de laboratório clínico a promover discussões sobre o tema.
Palavras-chave: reagentes de laboratório; bioquímica.
INTRODUCTION: Metrological traceability is a little-known and little-discussed metrology theme in clinical laboratories, although it is the basis for comparable results. It is associated with certified reference material (CRM) and reference method (RMet). When it is used in the supply chain by diagnostic kit manufacturers, it ensures accuracy of the results yielded by laboratories.
OBJECTIVE: This study shows the availability of information on metrological traceability provided by diagnostic kit manufacturers.
METHOD: It was done with the information obtained in kits of glucose, urea, creatinine, uric acid and cholesterol participants in a proficiency testing program throughout 2012 and 2013.
RESULTS AND CONCLUSION: In the research, 18 producers of reference materials (RMs) and 204 measurands available for laboratory medicine were found. In the study of metrological traceability, the preferential use of CRM was demonstrated by kit manufacturers (glucose 60%, urea 69%, creatinine 60%, uric acid 50%, and cholesterol 43%). An important factor is that there are a significant number of kits that do not report traceability (glucose 16%, urea 19%, creatinine 16%, uric acid 13%, and cholesterol 5%), although it is a requirement for product registration in Brazil. We hope that this study will contribute to sensitize the laboratory community to the need for a more comprehensive knowledge of this subject, and that it will stimulate institutions involved in the dissemination of knowledge in laboratory medicine to hold discussions on this topic.
Keywords: laboratory chemicals; indicators and reagents.
Metrology is the area of knowledge that deals with measurement; it is also known as science of measurement(1, 2). The word comes from the Greek métron, which means measure or evaluate; and logos, reason, study(3). Metrological traceability is a topic in metrology that links a measurement result with a chain of comparisons at the highest level of metrological reliability, promoting comparability of results(1, 4).
Issues related to metrological traceability, such as reference material (RM), certified reference material (CRM) and reference method (RMet) are little known or discussed in Brazilian clinical laboratories. However, the use of these concepts is associated with the results of measurements made by the laboratory, and is the basis for comparable results between laboratories(4-6).
In clinical laboratories, the term traceability is usually related to quality. In this regard, it is associated with the origin of diagnostic kits, inputs, sample custody chain, or identification of professionals involved in the different steps of the analytical process. As already mentioned, another concept of traceability, metrological traceability, is not related to quality, but to measurement(7).
In the context of laboratory medicine, metrological traceability links measurement results of a patient's sample with a reference, and, thus, makes these measurements comparable among different systems (or assays), places, and times in which they were conducted(4, 8). Metrological traceability is a requirement in all international standards intended for use in clinical laboratories, such as the International Organization for Standardization (ISO) 15189(9), ISO 22870(10) and ISO 17025(11). We can ensure metrological traceability of a test result obtained by a diagnostic kit is by means of CRM or RMet when input and/or diagnostic kits are produced.
These terms have specific definitions. RMet is defined in the International Vocabulary of Metrology (VIM)(1) as a measurement procedure considered capable of providing measurement results adequate for veracity assessment(2). The ISO Guide 30(12) defines RM as "material, sufficiently homogeneous and stable with respect to one or morespecified properties, which has been established to be fit for its intended use in a measurement process"; and, CRM as "RM characterized by a metrologically valid procedure for one or more specified properties, accompanied by an RM certificate that provides the value of the specified property, its associated uncertainty, and a statement of metrological traceability".
RM is a more general term that comprises materials for use in quality control (QCM) and also the CRMs. RMs have several uses and applications (Table 1), according to its characteristics and purpose of use, as calibration of a measurement system, evaluation of a measurement process, validation, verification, method development, quality assurance, among others(2, 12-15). CRM is a term included in the RM category, with a more specific use. CRMs are more elaborate materials, characterized by their chemical structures or microbiological species, and by their property values defined by a metrologically valid procedure(15).
It is important to note that the terms standard, measuring standard, analytical standard, calibration standard, and calibrator used in the clinical laboratory are synonymous with RM(15, 16).
The increasing demand for reliability and accuracy in the results obtained by analytical and metrological techniques have increased the demand for CRM for use in the validation of measurement methods and calibrations(17).
There are currently two international databases that offer information on RM producers and RMets: the Code d'Indexation des Matériaux de Référence (COMAR)(18) and the Bureau International des Poids et Mesures (BIPM)(19). COMAR is a free-of-charge database aimed at disseminating information about RMs available in the world. It maintains cooperation with ISO/REMCO Committee on reference materials, and international metrology institutes. BIPM(19) is an institution aimed at supplying the basis for a worldwide unique and coherent system of measures, which are traceable to the International System of Units (SI). It works through the International Committee of Weights and Measures (CIPM), which cooperates with other international organizations responsible for metrology, accreditation, and normalization, such as ISO, International Laboratory Accreditation Cooperation (ILAC) and International Organization of Legal Metrology (OIML). In 2012 BIPM created the Joint Committee for Traceability in Laboratory Medicine ( JCTLM), which is responsible for the area of clinical laboratories. In its webpage this committee lists CRM producers and their respective measurands, besides reference methods(20, 21).
In 2000, the metrology institute of the United States, the National Institute of Standards & Technology (NIST), RM producer, published a study over the economic impact of CRM use in cholesterol assays(22). This study demonstrates the importance and the necessity of CRM use by manufacturers of diagnostic kits to ensure accuracy and quality of the results yielded by clinical laboratories. Additionally, the use of CRM decreases production costs of measurement systems, besides ensuring metrological traceability in the supply chain.
Considering this scenario, this work aims at listing the institutions that produce RM for clinical laboratories, and verify the existence of information on metrological traceability of diagnostic kits commercialized in Brazil for the measurands glucose, urea, creatinine, uric acid, and cholesterol.
Sources of information about MRC producers and RMet
For information about MR producers, the international data bases COMAR (www.comar.bam.de) and BIPM (www.bipm.org) were consulted. For information about RMets, JCTLM (www.bipm.org/jctlm) was consulted.
Sources of information about products (CRM)
Consultations on CRM products available for clinical laboratories were hold on the websites of JCTLM (www.bipm.org/jctlm), COMAR (www.comar.bam.de) and American Type Culture Collection (ATCC) (www.atcc.org).
Information on metrological traceability of diagnostic kits
Instructions for use of diagnostic kits or calibrators were used to obtain information about metrological traceability. These documents are available on the manufacturers' websites or were provided by the scientific advisory body of the diagnostic companies.
Selection of measurands
The option for the measurands glucose, urea, creatinine, uric acid and cholesterol as object of the study was taken because these are biochemical tests ordered in large numbers in clinical laboratories. A second criterion was the ascertainment of the variety of different diagnostic kits commercialized in the diagnostic market for these measurands.
Selection of diagnostic kits
We selected the analytical systems and/or diagnostic kits reported by laboratories participating in a proficiency testing program of ControlLab, to whom we thank for the courtesy of providing these pieces of information. This study was carried out during 2012 and 2013, when results of eight cycles of the program were compiled.
For analysis purposes, the analytical systems and/or diagnostic kits were classified according to categories of metrological traceability, as follows:
CRM category - diagnostic kits that use CRM in their manufacturing;
RMet category - diagnostic kits that use RMet in their manufacturing;
CRM + RMet category - diagnostic kits that use CRM and RMet in their manufacturing;
N-Info category - diagnostic kits that did not have metrological traceability or about which it was not possible to obtain information.
Finally, in order to make the article clearer, we presented the definition of some terms used in this text:
measurand - means "what is intended to be measured"(1). Synonymous with "analyte";
diagnostic kit(23) - group of reagents (kit) that permits the detection or the quantification of a certain measurand;
analytical system(9) - group that comprises equipment and a diagnostic kit.
Table 2 lists the institutions producers of RMs; Table 3, the analytes (measurands) produced by these institutions.
Table 4 displays the RMets, besides the principles of the methods listed by JCTLM for the studied measurands. Table 5 shows the methods chosen by producers for the investigated analytical systems.
Table 6 presents the informed metrological traceability reported by the laboratories participating in the proficiency testing program of ControlLab, in 2012 and 2013, for the studied measurands. The Figure is a summary of Table 6, presenting the percentages of analytical systems that use CRM, RMet, CRM + RMet, and N-Info.
Figure - Traceability of the analytical systems reported by the laboratories participating in the proficiency testing program of ControlLab, for determinations of glucose, urea, creatinine, uric acid, and cholesterol, during 2012 and 2013
CRM: certified reference material; RMet: reference method; N-Info: no information on the use of CRM or RMet.
In the survey of RM producers and products made available for the area of clinical laboratory, 18 institutions (Table 2) and 204 analytes (Table 3) produced by these institutions were found, but not all RM products are registered in the databases COMAR and/or BIPM. For these cases, the survey was conducted directly on the producers' websites, for example, on ATCC.
When we compare RMets and the principles of methods for the measurands glucose, urea, creatinine, uric acid and cholesterol listed by JCTLM (Table 4) with the methods chosen by producers when metrological traceability was conferred by the use of RMet (Table 5), one can observe that the methods of the Clinical and Laboratory Standards Institute (CLSI) and of the American Association for Clinical Chemistry (AACC) do not appear in the JCTLM list, despite this is the choice by producers of the analytical systems Advia and Ebram. The survey conducted in the information of RMets supplied by diagnostic enterprises demonstrated that there is no standardization in the way to inform metrological traceability when one uses RMet. Some manufacturers inform the method principle, such as, for instance, isotope dilution mass spectrometry (ID-MS); others, the institution that developed the method, for example, the Centers for Disease Control and Prevention (CDC). We could also observe that there are package inserts with outdated information, such as that of the analytical system Advia for the measurand glucose, which refers to CLSI mentioning the old acronym NCCLS.
In the metrological traceability informed through the use of CRM, RMet, CRM + RMet, and N-Info of analytical systems for determinations of glucose, urea, creatinine, uric acid, and cholesterol (Table 6 and Figure), we could observe that metrological traceability was presented at a higher percentage by the use of CRM (glucose 60%, urea 69%, creatinine 60%, uric acid 50%, and cholesterol 43%), and that an expressive number of analytical systems (glucose 16%, urea 19%, creatinine 16%, uric acid 13%, and cholesterol 5%) do not inform traceability.
Nowadays there is an international movement for the development of a measurement system reference, which encompasses CRM and RMet. Metrological traceability is considered one of the most important tools for the support of this process(24), what stimulates us to know and discuss this subject further.
Most of the 18 CRM producers are metrology institutes, and the number of RMs made available for clinical laboratories (a total of 204 measurands) is small contrasted with the number of conducted tests.
Concerning information on metrological traceability, most suppliers use CRM. There is an expressive number, ranging from 5% to 19%, of commercialized products in Brazil, which do not inform traceability, what reveals the little importance given to this piece of information by some diagnostic enterprises.
The laboratory community, including professionals that are part of them, is badly acquainted with the terms and concepts of metrological traceability and with its importance in laboratory results - although metrological traceability is a requirement in international guidelines applied to laboratories and in the national norm that rules product registration (RDC nº 206/2006).
This theme should be further discussed and studied by all the involved groups; and institutions related to the dissemination of knowledge in the area of clinical laboratories should make an effort to promote discussions about this issue.
We hope this study contributes to sensitize the laboratory community to the need for a more encompassing knowledge of the process of laboratory result production. We call special attention to the prior critical analysis of the diagnostic kits chosen by laboratories for routine use and the implications of this choice in their results.
1. Instituto Nacional de Metrologia, Qualidade e Tecnologia (Inmetro). Brasil. Vocabulário Internacional de Metrologia - conceitos fundamentais e gerais e termos associados (VIM 2012) [Internet]. 1 ed. Luso-Brasileira; 2012. Available at: http://www.inmetro.gov.br/inovacao/publicacoes/vim_2012.pdf
2. International Organization for Standardization (ISO). ISO Guide 33:2015 - Reference materials - Good practice in using reference material; 2015.
3. Instituto Nacional de Metrologia, Qualidade e Tecnologia (Inmetro). Brasil. História e Evolução da Metrologia. Programa de integração de servidores; 2011: 6.
4. Vesper HW, Thienpont LM. Traceability in laboratory medicine. Clin Chem. 2009; 55(6): 1067-75.
5. Zakaria O, Rezali MF. Reference materials as a crucial tools for validation and verification of the analytical process. Procedia - Social and Behavioral Sciences. 2014; 121: 204-13.
6. Bureau International des Poids et Mesures (BIPM), Joint Committee for Traceability in Laboratory Medicine ( JCTLM). Paris. Available at: http://www.bipm.org/jctlm/JCTLM_Database_Leaflet.pdf.
7. Associação Brasileira de Normas Técnicas (ABNT). ABNT NBR ISO 9000:2005. Sistemas de gestão da qualidade - Fundamentos e vocábulos; 2005.
8. Associação Brasileira de Normas Técnicas (ABNT). ABNT NBR NM ISO 17511:2010. Produtos médicos para uso em diagnóstico in vitro - medição de quantidades em amostras biológicas - rastreabilidade metrológica de valores designados a calibradores e materiais de controle (ISO 17511:2003, IDT); 2010.
9. Associação Brasileira de Normas Técnicas (ABNT). ABNT NBR ISO 15189:2015. Laboratórios clínicos: requisitos de qualidade e competência; 2015.
10. Associação Brasileira de Normas Técnicas (ABNT). ABNT NBR NM ISO 22870:2006. Laboratórios clínicos - teste laboratorial remoto (TLR) - requisitos para a qualidade e competência; 2006.
11. Associação Brasileira de Normas Técnicas (ABNT). ABNT NBR ISO/IEC 17025:2005. Requisitos gerais para a competência de laboratórios de ensaio e calibração; 2005.
12. International Organization for Standardization (ISO). ISO Guide 30:2015. Reference materials -- Selected terms and definitions; 2015.
13. Moura SS, Costa SRR. Estudo da utilização de materiais de referência nas análises de água por laboratórios envolvidos no sistema de acreditação. Production. 2009; 19(2): 304-16.
14. European Cooperation for Accreditation. EA-4/14 INF:2003. The selection and use of reference materials; 2003.
15. Instituto Nacional de Metrologia, Qualidade e Tecnologia (Inmetro). Coordenação Geral de Acreditação (Cgcre) - Brasil. DOQ-CGCRE-016. Orientação para seleção e uso de materiais de referência. Revisão 2; 2010. Available at: http://www.inmetro.gov.br/credenciamento/organismos/doc_organismos.asp?tOrganismo=AvalLAB
16. Emons H. The 'RM family' - Identification of all of its members. Accreditation and Quality Assurance. 2006; 10(12): 690-1.
17. Associação Brasileira de Normas Técnicas (ABNT). ABNT ISO GUIA 31. Materiais de Referência - conteúdo de certificados e rótulos. 2 ed; 2004.
18. COde d'Indexation des MAtériaux de Référence (COMAR). Alemanha. Available at: http://www.comar.bam.de/home/login.php.
19. Bureau International des Poids et Mesures (BIPM), Joint Committee for Traceability in Laboratory Medicine ( JCTLM). Paris. Available at: http://www.bipm.org/jctlm/.
20. Bureau International des Poids et Mesures (BIPM), Joint Committee for Traceability in Laboratory Medicine ( JCTLM). Paris. JCTLM Database Newsletter [internet]. Issue 1; April, 2014. Available at: http://www.bipm.org/en/committees/jc/jctlm/#newsletter.
21. Armbruster D, Miller RR. The Joint Committee for Traceability in Laboratory Medicine ( JCTLM): a global approach to promote the standardisation of clinical laboratory test results. Clin Biochem Rev. 2007; 28(3): 105.
22. National Institute of Standards & Technology (NIST). USA. Planning, Strategic. The Economic Impacts of NIST Cholesterol Standards Program. Economic Analysis; 2000. Available at: http://www.nist.gov/director/planning/upload/report00-4.pdf.
23. Ministério da Saúde. Agência Nacional de Vigilância Sanitária (ANVISA). Secretaria de Vigilância em Saúde, Departamento de DST, Aids e Hepatites Virais. Manual técnico para o diagnóstico da infecção pelo HIV. 2013. Available at: http://www.aids.gov.br/sites/default/files/anexos/publicacao/2013/55594/_p_manual_tecnico_hiv_final_pdf_p__23462.pdf.
24. Panteghini M. Traceability, reference systems and result comparability. Clin Biochem Rev. 2007; 28(3): 97. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1994107/pdf/cbr28_3p097.pdf.