A key content of Directive 98/79/EC of the European Union on in vitro diagnostic products is the traceability requirement for in vitro diagnostic products: “Traceability of calibration substances and/or quality control substances must be guaranteed by existing high-level reference methods and/or reference substances”. These guidelines are legal instruments which must be applied by member States. The implementation of eu guidelines on in vitro diagnostic products means that the traceability of the value of in vitro diagnostic products has been raised to a legal height. In 1999, the International Organization for Standardization (ISO) drafted 5 relevant ISO standard documents to coordinate with the implementation of the Eu guidelines on in vitro diagnostic products. Among them, closely related to manufacturers and clinical laboratories are ISO/CD 17511 “Metrological traceability of the value of calibration substances and quality control substances” and ISO/CD 18153 “metrological traceability of the value of enzymatic concentration calibration substances and quality control substances”. In view of the emergence of these EU guidelines and ISO standards and their potential international impact, the National Institute of Standards and Technology (NIST), a metrology authority in the United States, in collaboration with the National Committee on Clinical Laboratory Standards (NCCLS), With the support of CENTERS for Disease Control and Prevention (CDC), The Association for Advanced Medical Technology (AdvaMed), the Society of Pathology (CAP), and the Society of Clinical Chemistry (AACC), we convened a panel of experts from the United States and Europe to discuss the traceability of clinical laboratory tests and in vitro diagnostic test systems. The purpose of the symposium was to demonstrate the need for value traceability in order for manufacturers to implement international standards, and to improve the comparability of clinical test data, thereby promoting the effectiveness of clinical diagnosis and treatment.
1. Traceability of quantity value
ISO defines traceability as follows: an attribute that enables a measurement result or standard value to be linked to a given standard through a continuous comparison chain, usually a national or international standard, with a given uncertainty for each step of comparison in the chain.
Traceability is to solve the problem of the correctness of the measured results, that is, the degree of consistency between the measured mean value and the true value. Theoretical traceability does not solve measurement quality problems beyond correctness.
At present, the traceability requirements of clinical test values are mainly reflected in two aspects, one is the calibration value of products, the other is the clinical test results, which are the product manufacturers and clinical laboratories respectively. At present, most clinical laboratories use commercial kits, so the traceability of the calibration products produced by enterprises is more important. The traceability requirements of the Eu guidelines on in vitro diagnostic products and ISO17511 and ISO18153 are aimed at manufacturers. The guidelines require that “the determination of the standard or calibration product must pass the existing higher level reference measurement procedures and/or reference materials to ensure its traceability.”
Second, the structure and working principle of quantity traceability chain
There may be different modes of quantitative traceability for clinical tests, but the central content of which is to correlate the measurement values of each measurement method with an accepted standard. Traceability of the measurement results of a sample or calibrated substance is established through a series of comparative measurements, in which the measurement process and calibration characteristics of the measurement are measured in a continuous chain from low to high (traceability chain). The top of the chain is the International System of Units (SI) (basic or derived unit). The first level reference measurement process is the reference measurement process with the highest metrological characteristics. It must be based on a specific, low-uncertainty measurement principle that can be traced to SI units without the need for the same amount of calibration. At present, only isotope dilution/mass spectrometry (ID/MS), Coulomb, gritmetric, titration and colligative (freezing point reduction) measurements are considered to be applicable to the first-level reference measurement process. The primary reference material is the embodiment of the unit of measurement and has the lowest possible measurement uncertainty. It can be determined directly by the primary reference measurement process or indirectly by reliable impurity analysis. The primary reference material is generally a highly purified substance under test. The secondary reference measurement process is a measurement process that has been fully demonstrated and its uncertainty can meet specific requirements and can be used for the evaluation of the lower level measurement process and the identification of reference materials. The secondary reference measurement process is calibrated with the primary reference materials. Level 1 and level 2 reference substances are generally certified reference substances (CRM) certified by metrological authority or administrative body.
Iii. Status of clinical laboratory reference system
Clinical test samples are biological samples with a high degree of complexity. Currently, there are about 400 to 600 clinical tests, and only 25 to 30 can be traced to SI units. They are mainly small molecule compounds that are well defined chemically. Including electrolyte substances (such as potassium, sodium, chlorine, magnesium, calcium, lithium ions, etc.), metabolites (such as cholesterol, triglyceride, glucose, muscle liver, uric acid, urea, etc.) and some steroid hormones and thyroid hormones. These items, though small in number, constitute a major component of routine clinical testing programs.
In addition to a small number of items mentioned above, most of the other clinical test items are very difficult to establish the first-level reference measurement process and prepare the first-level reference materials due to the complexity of the tested substances (mainly biological macromolecules) (such as mixtures, isomers, etc.), and their value traceability can only stay at a low level. Such inspection items currently has the following several ways in the world, is a kind of international reference measurement process (not a primary reference measurement procedure), fixed value is also useful to the reference measurement process of the international reference materials, such as hemoglobin a1c, another is the international reference measurement process, a sweeping the reference material, there are about 30 inspection items belong to this kind of situation: The third case is that there are international reference materials and fixed value scheme, but there is no international reference measurement process, about 250 inspection items belong to this case; About 300 others have no international reference measurement process or reference material.
Advanced reference systems (primary and secondary reference measurement processes, primary reference materials and high accuracy matrix reference materials) for the above tests traceable to SI units are mostly established and maintained by NIST, DCKC and BCR. There are also some universities, hospitals, research institutions and professional laboratories of manufacturers to establish their own reference measurement process, engaged in reference measurement work for many years, to a high level of metrology. Reference systems (mainly reference substances) for test items that cannot be traced to SI units are mainly from relevant international organizations, such as the World Health Organization (WHO) and international Society of Clinical Chemistry (IFCC). Some of the measurement processes and substances are likely to become international level I reference measurement processes and level I reference substances.
At present our country according to the quantitative determination of hepatitis b virus surface antigen of medicine management kit and hepatitis b virus surface antibody quantitative determination of the standard kit is by the world health organization (WHO) to establish a standard, China academy of pharmaceutical and biological products verification to establish a secondary standard and traced to the WHO, the production enterprise to set up their own standard, And must be traced to the National Institute for Pharmaceutical and Biological Products testing.
As an important means to improve the quality of test, traceability of test results has been paid more and more attention. Traceability of test results may become an important quality indicator in the production of in vitro diagnostic reagents and clinical laboratory tests. Developers of in vitro diagnostic reagents should attach great importance to the traceability of clinical tests. At the beginning of developing quantitative determination kits, they should fully investigate the traceability of standard products related to the determination items and carefully study relevant literatures, such as ISO/CD 17511 and ISO 18153, so as to truly improve the quality level of the products developed.
Post time: Apr-07-2022