Establishing metrological traceability of measurement is essential to improve the accuracy and comparability of measurement results. With increasing recognition of the importance of traceability, some regulatory policies have been applied to enforce its implementation. Technology advancement also provides more tools for improving measurement traceability. During the assay development on the Mindray CL-2000i Chemiluminescence Immunoassay System, well recognized highest reference methods or reference materials were used in assigning the values of master calibrators; the accuracy of product calibrators was guaranteed through an unbroken metrological traceability chain.
by Xiang Yu and Ke Li
Introduction
With the advancement in automation over the past 20 years, most of the immunoassays have been shifted from traditional manual assays to fully automatic systems leading to an overall improvement of the quality of measurements. The accuracy and comparability of testing results have been emphasized, since they are the keys to defining and using common clinical decision values and reference intervals, following constant standards and practice guidelines, pooling data from different studies based on different analytical systems to facilitate clinical research.
One critical mechanism to improve the accuracy and comparability of clinical testing results is to make the testing results traceable to higher reference materials or methods in calibration hierarchy. Briefly, the testing results should have metrological traceability. The general principles and features have been described in the document of the International Organization for Standardization (ISO) 17511:2003 [1].
Ideally, results produced by different routine methods for the same measurand should be metrologically traceable to the highest level of calibration hierarchy – the International System of Units (SI units), with an estimated measurement uncertainty. However, only a limited number of analytes, including some metabolites, electrolytes, steroid hormones, has reference materials available with traceability to the SI unit. Most of the clinical analytes still have no primary and secondary reference measurement procedures and are not traceable to the SI unit. They are not well defined and have only traceability to an international conventional standard or manufacturers’ internal standard, such as tumour markers and viral antigens [2].
The EU directive on in vitro diagnostic devices (IVDD) enacted in 1998 stated “The traceability of values assigned to calibrators and/or control materials must be assured through available reference measurement procedures and/or available reference materials of a higher order” [3]. Therefore, for all the IVD analytical system (reagents), manufacturers must ensure their products are standardized against available reference materials or methods in order to be distributed in the EU market.
Traceability chain and value assignment procedure on Mindray CL-2000i System
Mindray CL-2000i system is a closed system composed of a fully automatic immunoanalyser, related reagents and calibrators. The calibration hierarchy was established and documented strictly based on EN ISO 17511:2003 [1]. Mindray’s traceability procedure is indicated in figure 1, ensuring the establishment of metrological traceability between the testing results and the highest standard available. Based on the characteristics of different analytes, three major traceability chains have been used: traceable to an SI unit, traceable to an international conventional calibrator, and traceable to manufacturers’ selected procedure.
Measurements traceable to the SI unit
If the chemical and physical properties of an analyte are well defined, there should be a primary reference measurement procedure with the measurement traceable to the SI unit (mole). CL-2000i total T3, total T4, progesterone, testosterone and estradiol are traceable to this highest level of calibration hierarchy. Mindray has performed the traceability of the above measurements in collaboration with the Reference Institute for Bioanalytics (RfB), a German reference laboratory certified by the Joint Committee for Traceability in Laboratory Medicine (JCTLM) [4]. Thirty Mindray master calibrators at different levels covering the whole detection range were assigned values for each analyte at RfB with the reference measurement procedure of Isotope dilution mass spectrometry (ID-MS). The calibrator values with uncertainty were then applied to define the values of Mindray working calibrators and product calibrators, and the metrological traceability between the testing results of CL-2000i end-users’ routine measurement procedure and the SI unit was finally established. The assays that are traceable to the SI unit are indicated in Table 1.
Measurements traceable to an international conventional calibrator
The reference materials, such as WHO standards and some national standard materials are defined by convention or consensus, without traceability to the SI unit; the assigned values are in arbitrary units (e.g. WHO international unit). Most of assays for tumour markers, hormones, and viral antigen/antibody of the CL-2000i system are traceable to this kind of reference materials, indicated in Table 1.
Measurements traceable to manufacturers’ selected procedure
For analytes that are either not traceable to the SI unit, or for which no reference method and reference material are available, a commercial certified measurement procedure with traceability, high accuracy and analytical specificity was selected for Mindray master calibrator value assignment; the measurement accuracy of the Mindray routine measurement procedure is ensured and also indicated in Table 1.
Principle of the traceability of Mindray CL-2000i end-user’s measurement results
The immunoanalyser is calibrated by measuring three levels of product calibrators and relative light units (RLUs) generated. The corresponding concentration of each calibrator was used to adjust the master calibration curve stored in the barcode of each lot of reagents.
The value of end-user’s product calibrators and the master curve stored in the barcode are both defined by the Mindray routine measurement procedure that is calibrated by Mindray working calibrators in the manufacturer’s laboratory. The working calibrators have roughly 12 concentration levels and have the same matrix as the end-user’s product calibrators.
It is the Mindray standard measurement procedure that determines the values of Mindray working calibrators. The Mindray standard measurement procedure makes use of the Mindray standard CL-2000i automatic immunoassay analyser, standard reagents, and Mindray master calibrators. Mindray master calibrators are composed of a series of human serum at different concentration levels. They are stored at -70°C and represent the highest accepted standard available.
The values of the Mindray master calibrators are fixed, and the measurement standard established by the Mindray standard measurement procedure is preferably not variable and should be kept as consistent as possible. On the other hand, the value of working calibrators and end-user’s product calibrators can be flexible within a certain range. The assigned values of calibrators will be adjusted according to the results of internal QC and method comparison so as to ensure the traceability between the reference and end-user’s routine measurement procedures.
Discussion
We have made our best efforts for the traceability of the Mindray CL-2000i system, eventhough the implementation of traceability is challenging, especially the traceability in immunoassays.
Firstly, majority of analytes lack a primary reference measurement procedure and thus are not traceable to the SI units. The chemistry and physical properties of these analytes still require more accurate definition.
Secondly, the international conventional calibrators have played an important role in harmonizing testing results. However, there are still some issues with using the international standards, such as the long term stability of WHO standards, the matrix effect, the difference between different generations of the standards, and difference between the source of the standards and the real sample in the clinic.
Thirdly, some of the analytes have neither reference materials nor reference methods available, and are only traceable to manufacturers’ in-house standards. The harmonization of clinical results could not be fully implemented [5].
References
1. ISO 17511:2003. In vitro diagnostic medical devices –measurement of quantities in biological samples – metrological traceability of values assigned to calibrators and control materials. Geneva, Switzerland: ISO
2. Database of higher-order reference materials and reference measurement methods/procedures. http://www.bipm.org/en/committees/jc/jctlm/jctlm-db
3. Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on in vitro diagnostic medical devices. Off J Eur Union 7 December 1998; L 331:1–37.
4. JCTLM: Joint Committee for Traceability in Laboratory Medicine. http://www.bipm.org/en/committees/jc/jctlm/
5. Danni L. Meany and Daniel W. Chan Comparability of tumor marker immunoassays: still an important issue for clinical diagnostics? Clin Chem Lab Med 2008; 46(5):575–576.
The authors
Xiang Yu*, MSc and Ke Li, PhD
Immunoassay Department, Shenzhen
Mindray Bio-Medical Electronics Co. Ltd., Nanshan, Shenzhen, 518057 China
*Corresponding author
Email: yuxiang@mindray.com
Looking at ANA testing from a different perspective
, /in Autoimmunity & Allergy, Featured Articles /by 3wmediaby James D. Peele, PhD The HEp-2 immunofluorescence assay (IFA) for ANA screening is excellent for ruling out many connective tissue diseases, but a positive result seldom translates into a clinically meaningful diagnosis. A new automated, efficient, enzyme immunoassay for ANA screening provides reliable, objective information that can be applied clinically with confidence.
Building trustful partnership in In Vitro Diagnostics
, /in Featured Articles /by 3wmediaMedical care has been undergoing tremendous advances in the Middle East, not least in diagnostic testing. Roche Diagnostics Middle East (RDME) is a pioneer in leading this development in in vitro diagnostics (IVD), by supporting laboratories to achieve a higher level of performance, efficiency and sustainability. IVD testing directs over 60% of clinical decision-making and accounts for a small fraction of global healthcare spending. Whether it is in oncology, virology, blood screening, or research on infectious diseases, autoimmunity, inflammation, women’s health or metabolism, RDME has supported a large number of leading and prominent healthcare institutions to move from multiple analyzers and workflows to comprehensive, integrated laboratory solutions, meeting international standards and certifications.
Roche, with its unique privilege of having both pharmaceutical and diagnostics research under one roof, aims to improve healthcare and make a difference in patients’ lives. The medical solutions start from the stages of early detection and prevention of disease, to diagnosis, treatment selection and treatment monitoring. Roche Diagnostics is leading the industry by addressing unmet medical needs with new or medically enhanced diagnostic tests, supporting doctors and patients with an improved information basis for better medical decisions and treatment selection. Roche’s IVD test menu is one of the broadest in the industry and is continually being expanded based on the latest scientific advances.
Pioneering in Personalized Healthcare
Personalized Healthcare systematically uses patient characteristics, disease biology and diagnostic tests to tailor medicines to patients and improve disease management. Cooperating in the early development of new drugs is integral for the implementation of Personalized Medicine. Roche Diagnostics supports throughout the patient care chain, from screening, early detection, diagnosis and classification to therapy monitoring. Roche Diagnostic’s breakthrough HPV DNA test truly shows how Personalized Medicine works in practice, as it has offered clinicians the ability to detect the presence of specific HPV genotypes. Notably, having such a targeted test has enabled clinicians to choose the most appropriate treatment for their patients, rather than treating every HPV-infected individual with equal and aggressive therapy. This development has also given more confidence to patients, who are re-assured that the treatment they receive is tailored to their specific needs.
Leading in optimizing performance
Optimizing performance, automation and information technology are simplified with a common architecture that delivers tailor-made solutions for diverse workloads and testing requirements. Roche Diagnostics offers platforms that are designed to reduce the complexity of laboratory operation and provide efficient and compatible solutions for network cooperation. For example, Roche Diagnostics has developed medical diagnostic tests based on the Nobel prize-winning polymerase chain reaction (PCR; which exponentially amplifies small amounts of target DNA), that would otherwise be too time-consuming or impossible to perform.
Providing superior workflow solutions, including blood screening
Superior workflow solutions such as Task Targeted Automation (TTA) and Total Lab Automation (TLA) are designed to meet the needs of today’s fast developing healthcare systems. In RDME, a regional project management team is an added value to customers by providing consultancy and implementation support. TLA is customized to the specific needs of individual customers and, thanks to the modular system landscape, can be configured in 90 layouts, differing in size and shape. Roche Diagnostics is successfully delivering best in class Total Lab Solutions for Pathology and Cytology Laboratories to substantially improve the workflow with a unique and complete solution. Another example of superior workflow solutions and automation is with blood screening. Roche Diagnostics has been the preferred partner in the Blood Bank Industry by safeguarding patients through industry-leading assays and technologies. Besides offering Nucleic Acid Testing (NAT), Roche Diagnostics launched Roche Blood Safety Solutions (RBSS), which introduced serology testing of blood samples in an automated manner. As such, Roche Diagnostics is the only provider of a complete Blood Safety Solution to blood banks of any size. Fully integrated automation is offered; these standardized processes reduce manual steps, which guarantees the safety of the blood supply and offers state-of-the-art assay sensitivity and genotype coverage.
Improving therapeutic monitoring
Roche’s IVD offering can be used for treatment selection, response prediction and therapeutic monitoring once a condition has been identified. One of the best examples of this is in hepatitis, qualitative immunoassays (e.g. surface antigen; HBsAg II assay) screen for the presence of hepatitis B virus (HBV) skin, while other assays verify the existence of viral antigens or antibodies. The viral load, the amount of virus in the body, can be determined by quantitative tests. This test shows if therapy has effectively controlled the virus and whether it is replicating or not allowing doctors to monitor the stage and progression of the disease. The continual innovation in therapeutic monitoring is demonstrated in hepatitis C, where Roche Diagnostics has developed Elecsys anti-HCV II, a new state of the art diagnostic test that has an increased seroconversion sensitivity compared to other assays.
Enhancing centralization of data
Similarly, Roche offers centralization of data which is achieved with rapid and easy-to-operate systems that facilitate immediate healthcare decisions, thus placing an emphasis on patient-oriented diagnosis. One example of such a system is the Cobas IT 1000, a point-of-care IT solution that provides complete remote management of and access to all point-of-care diagnostic systems from just one hospital workstation. This automation and centralization of data management into just one workstation frees staff time and enhances the diagnostic service offered to patients.
Roche Diagnostics’ ongoing commitment to developing new analytical tools greatly benefits patients, and its technological innovations create a big impact on the healthcare development in the Middle East. As well as the analytical and technological advances described above, RDME has worked hard to establish the relevant infrastructure in the Middle East with a logistics hub, continual training for employees and a customer support center. These factors combined make RDME the leader in IVD and allow healthcare professionals to benefit from reliable, accurate and immediate results, which directly impact their diagnoses. RDME provides the deepest industry know-how and aims to become the region’s trusted IVD partner.
Measurement traceability of Mindray CL-2000i Chemiluminescence Immunoassay System
, /in Featured Articles /by 3wmediaEstablishing metrological traceability of measurement is essential to improve the accuracy and comparability of measurement results. With increasing recognition of the importance of traceability, some regulatory policies have been applied to enforce its implementation. Technology advancement also provides more tools for improving measurement traceability. During the assay development on the Mindray CL-2000i Chemiluminescence Immunoassay System, well recognized highest reference methods or reference materials were used in assigning the values of master calibrators; the accuracy of product calibrators was guaranteed through an unbroken metrological traceability chain.
by Xiang Yu and Ke Li
Introduction
With the advancement in automation over the past 20 years, most of the immunoassays have been shifted from traditional manual assays to fully automatic systems leading to an overall improvement of the quality of measurements. The accuracy and comparability of testing results have been emphasized, since they are the keys to defining and using common clinical decision values and reference intervals, following constant standards and practice guidelines, pooling data from different studies based on different analytical systems to facilitate clinical research.
One critical mechanism to improve the accuracy and comparability of clinical testing results is to make the testing results traceable to higher reference materials or methods in calibration hierarchy. Briefly, the testing results should have metrological traceability. The general principles and features have been described in the document of the International Organization for Standardization (ISO) 17511:2003 [1].
Ideally, results produced by different routine methods for the same measurand should be metrologically traceable to the highest level of calibration hierarchy – the International System of Units (SI units), with an estimated measurement uncertainty. However, only a limited number of analytes, including some metabolites, electrolytes, steroid hormones, has reference materials available with traceability to the SI unit. Most of the clinical analytes still have no primary and secondary reference measurement procedures and are not traceable to the SI unit. They are not well defined and have only traceability to an international conventional standard or manufacturers’ internal standard, such as tumour markers and viral antigens [2].
The EU directive on in vitro diagnostic devices (IVDD) enacted in 1998 stated “The traceability of values assigned to calibrators and/or control materials must be assured through available reference measurement procedures and/or available reference materials of a higher order” [3]. Therefore, for all the IVD analytical system (reagents), manufacturers must ensure their products are standardized against available reference materials or methods in order to be distributed in the EU market.
Traceability chain and value assignment procedure on Mindray CL-2000i System
Mindray CL-2000i system is a closed system composed of a fully automatic immunoanalyser, related reagents and calibrators. The calibration hierarchy was established and documented strictly based on EN ISO 17511:2003 [1]. Mindray’s traceability procedure is indicated in figure 1, ensuring the establishment of metrological traceability between the testing results and the highest standard available. Based on the characteristics of different analytes, three major traceability chains have been used: traceable to an SI unit, traceable to an international conventional calibrator, and traceable to manufacturers’ selected procedure.
Measurements traceable to the SI unit
If the chemical and physical properties of an analyte are well defined, there should be a primary reference measurement procedure with the measurement traceable to the SI unit (mole). CL-2000i total T3, total T4, progesterone, testosterone and estradiol are traceable to this highest level of calibration hierarchy. Mindray has performed the traceability of the above measurements in collaboration with the Reference Institute for Bioanalytics (RfB), a German reference laboratory certified by the Joint Committee for Traceability in Laboratory Medicine (JCTLM) [4]. Thirty Mindray master calibrators at different levels covering the whole detection range were assigned values for each analyte at RfB with the reference measurement procedure of Isotope dilution mass spectrometry (ID-MS). The calibrator values with uncertainty were then applied to define the values of Mindray working calibrators and product calibrators, and the metrological traceability between the testing results of CL-2000i end-users’ routine measurement procedure and the SI unit was finally established. The assays that are traceable to the SI unit are indicated in Table 1.
Measurements traceable to an international conventional calibrator
The reference materials, such as WHO standards and some national standard materials are defined by convention or consensus, without traceability to the SI unit; the assigned values are in arbitrary units (e.g. WHO international unit). Most of assays for tumour markers, hormones, and viral antigen/antibody of the CL-2000i system are traceable to this kind of reference materials, indicated in Table 1.
Measurements traceable to manufacturers’ selected procedure
For analytes that are either not traceable to the SI unit, or for which no reference method and reference material are available, a commercial certified measurement procedure with traceability, high accuracy and analytical specificity was selected for Mindray master calibrator value assignment; the measurement accuracy of the Mindray routine measurement procedure is ensured and also indicated in Table 1.
Principle of the traceability of Mindray CL-2000i end-user’s measurement results
The immunoanalyser is calibrated by measuring three levels of product calibrators and relative light units (RLUs) generated. The corresponding concentration of each calibrator was used to adjust the master calibration curve stored in the barcode of each lot of reagents.
The value of end-user’s product calibrators and the master curve stored in the barcode are both defined by the Mindray routine measurement procedure that is calibrated by Mindray working calibrators in the manufacturer’s laboratory. The working calibrators have roughly 12 concentration levels and have the same matrix as the end-user’s product calibrators.
It is the Mindray standard measurement procedure that determines the values of Mindray working calibrators. The Mindray standard measurement procedure makes use of the Mindray standard CL-2000i automatic immunoassay analyser, standard reagents, and Mindray master calibrators. Mindray master calibrators are composed of a series of human serum at different concentration levels. They are stored at -70°C and represent the highest accepted standard available.
The values of the Mindray master calibrators are fixed, and the measurement standard established by the Mindray standard measurement procedure is preferably not variable and should be kept as consistent as possible. On the other hand, the value of working calibrators and end-user’s product calibrators can be flexible within a certain range. The assigned values of calibrators will be adjusted according to the results of internal QC and method comparison so as to ensure the traceability between the reference and end-user’s routine measurement procedures.
Discussion
We have made our best efforts for the traceability of the Mindray CL-2000i system, eventhough the implementation of traceability is challenging, especially the traceability in immunoassays.
Firstly, majority of analytes lack a primary reference measurement procedure and thus are not traceable to the SI units. The chemistry and physical properties of these analytes still require more accurate definition.
Secondly, the international conventional calibrators have played an important role in harmonizing testing results. However, there are still some issues with using the international standards, such as the long term stability of WHO standards, the matrix effect, the difference between different generations of the standards, and difference between the source of the standards and the real sample in the clinic.
Thirdly, some of the analytes have neither reference materials nor reference methods available, and are only traceable to manufacturers’ in-house standards. The harmonization of clinical results could not be fully implemented [5].
References
1. ISO 17511:2003. In vitro diagnostic medical devices –measurement of quantities in biological samples – metrological traceability of values assigned to calibrators and control materials. Geneva, Switzerland: ISO
2. Database of higher-order reference materials and reference measurement methods/procedures. http://www.bipm.org/en/committees/jc/jctlm/jctlm-db
3. Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on in vitro diagnostic medical devices. Off J Eur Union 7 December 1998; L 331:1–37.
4. JCTLM: Joint Committee for Traceability in Laboratory Medicine. http://www.bipm.org/en/committees/jc/jctlm/
5. Danni L. Meany and Daniel W. Chan Comparability of tumor marker immunoassays: still an important issue for clinical diagnostics? Clin Chem Lab Med 2008; 46(5):575–576.
The authors
Xiang Yu*, MSc and Ke Li, PhD
Immunoassay Department, Shenzhen
Mindray Bio-Medical Electronics Co. Ltd., Nanshan, Shenzhen, 518057 China
*Corresponding author
Email: yuxiang@mindray.com
CytoBead Assays
, /in Featured Articles /by 3wmediaSimplexa Direct Chemistry
, /in Featured Articles /by 3wmediaRIQAS – Randox Int’l Quality Assessment Scheme
, /in Featured Articles /by 3wmediaAlfred 60 AST: strong time reduction in urine culture
, /in Featured Articles /by 3wmediaIMMULEX S. pneumoniae Omni
, /in Featured Articles /by 3wmediaCL-2000i Chemiluminescence Immunoassay System
, /in Featured Articles /by 3wmediaNova StatStrip Cited As Most Accurate Glucose Meter
, /in Featured Articles /by 3wmedia