The article describes the historical and metrological aspects of the development of a system of metrological support of means and systems for measuring the flow and amount of liquid in the field of state regulation of ensuring the uniformity of measurements. The expediency of the method of indirect measurements in the transfer of units of flow and the amount of liquid for verification installations with weighing devices is substantiated, taking into account the sources of uncertainty due to dynamic influencing factors on the metrological characteristics of verification installations with weighing devices along with the methods of direct comparison and comparison using a comparison standard. The methodological approaches used in the presence of impacts on the static model of measuring the flow rate and amount of liquid due to dynamic changes in the main parameters of the liquid flow (fluctuations in the flow rate, temperature, pressure of the liquid in the pressure pipeline) and hydrodynamic features when the liquid flow flows out of the nozzle of the flow switch nozzle (formation a uniform velocity profile, and the degree of liquid filling of the nozzle exit).

Modern international requirements in the field of drug standardization determine the relevance of the development of reference materials (RMs) for quality control of medicinal products of various origins, including biological ones. Due to the complexity of monitoring the quality of biological products caused by the variability of the biological systems used, the development and certification of biological RMs is a priority. The purpose of this review is to describe the procedure for the development and certification of biological RMs, including consideration of the general principles for testing and calculating metrological characteristics based on an analysis of the domestic and foreign regulatory framework for RMs.

Isothermal titration calorimetry (ITC) allows studying the thermal effects of various chemical and physicochemical processes, including dissolution processes. This method is relatively new. Therefore, the active expansion of the scope of its application has revealed a number of problems. For instance, the article raises the problem of insufficient metrological support for isothermal titration calorimeters, which leads to inconsistency of the results obtained on different models of calorimeters, as well as their inconsistency with literature data. The current electrical and chemical calibration procedures for calorimeters are not universal and have a number of limitations in their application.

The purpose of the research is to develop basic approaches to the creation of certified reference materials with a certified value of heat of physicochemical interactions with established metrological traceability to the base SI units.

In the course of the study, the analysis of the state of metrological support in the field of ITC measurements was carried out, the main requirements for candidate substances to RMs were formulated; the target uncertainty of the value of the integral heat of dilution of propanol-1 solutions was estimated by analyzing the characteristics of working measuring instruments, which made it possible to establish requirements for the measurement method applied to characterize RMs. A method for determining the certified value of the integral heat of dilution that provides traceability to the State primary special standard of the unit of heat in the field of dissolution calorimetry and reactions GET 133 has been proposed and tested.

In order to implement the project, it is necessary to continue research in order to obtain experimental data on the characterization, assessment of the homogeneity and stability of the material, processing the obtained results, and estimating the uncertainty of the certified value, which will make it possible to complete the development of reference materials.

Metrological traceability of the research results of the nominal properties of biological substances is currently an unsolved problem. This is primarily due to the absence of CRMs for nominal properties, the lack of requirements and practices in the field of metrology for tools that ensure the traceability of the research results of nominal properties, such as the nucleotide sequence of nucleic acids, DNA, RNA, and the color of urine, and letter codes.

In the course of the research, the relevance of the development of the theory, requirements, and practice of using tools in Russian metrology to ensure the traceability of the research results of nominal properties is substantiated. Differences between the process of measurements and studies of nominal properties are given. A project of a metrological traceability chain of the research results of nominal properties to the international harmonization protocol is proposed, taking into account the fact that there are no primary standards of nominal properties, and there are no primary reference methods for measuring nominal properties. Methods for establishing the certified characteristics of reference materials of a fragment of human mitochondrial DNA and the inactivated strain «GK2020/1» of the coronavirus SARS-CoV-2, including additional characteristics of the nominal property «nucleotide sequence of nucleic acids», are presented. Thus, it has been established that the uncertainty of nominal properties can be expressed as a probability or level of confidence. In turn, reference materials of nominal properties are of high interest as a means of metrological assurance of the reliability of identification of the nominal properties of biological substances, which include the DNA nucleotide sequence (genes) of a human being. The main significance of the research is to create prerequisites for the application of the findings given in the work to create a new branch of metrology, which will be related to the creation of methods and means to ensure reliable results for determining the nominal properties of substances and materials.

Gas analytical measurements are one of the types of measurements of the physical and chemical composition and properties of substances, and cover a large amount of measurement tasks in various areas of human activity. The main means of calibration of gas analytical measuring instruments are working standards of the 1^st and 2^nd category: reference materials for the composition of gas mixtures in pressure cylinders, measures –  sources of microflows of gases and vapors, gas mixture generators.

The purpose of the research was to summarize the many years of experience of the specialists of the Research Department of State Standards in the field of Physical and Chemical Measurements, D. I. Mendeleyev Institute for Metrology, in terms of the use of reference materials-imitators for metrological support of gas analytical measuring instruments, identification and analysis of the main factors that allow the use of imitators in testing and calibration of measuring instruments.

The research considered the main features of the use of reference materials for the composition of gas mixtures in pressure cylinders as imitators of real environments in the metrological support of gas analytical measuring instruments. The main differences between imitators in terms of their equivalence with a real environment were described. Approaches have been developed to assess the possibility of using imitators, the features of testing for the purpose of type approval and verification of measuring instruments using imitators.

The practical significance of the research is the possibility of using the research results by metrologists in solving practical problems that arise during tests for the purpose of type approval, and calibration of gas analytical measuring instruments.

The present article presents comparative characteristics of domestic and international approaches to estimating the instability of reference materials, and describes the proposed changes in R50.2.031-2003. A mathematical apparatus and an algorithm of actions for estimating the standard uncertainty due to instability, and the shelf life of a reference material are proposed. Approaches to estimating the uncertainty due to instability in the cases of absence and presence of a significant trend in the certified characteristic of a reference material over time are considered. It is shown that there is a rationale for the minimum number of measurements to study the stability of a reference material. It has been established that the smoothing of the measurement results when estimating the stability of a reference material leads to the appointment of an overestimated shelf life. 

Production, characterization and certification of reference materials (RMs) are key activities in ensuring the metrological traceability of measurement results in various industries. One of the sources of RM uncertainty is the standard uncertainty due to heterogeneity. Estimation of the standard uncertainty is based on the analysis-of-variance method in accordance with GOST 8.531-2002, ISO Guide 35:2017.

The main difference between the developed algorithms and ISO Guide 35:2017 is the elaboration of specific algorithms suitable for calculation and automation, the main difference from GOST 8.531-2002 is the updating of the calculation of the standard uncertainty due to heterogeneity when it is comparable to the standard measurement uncertainty of type A. The developed algorithms have been tested on various examples, and their applicability has been proven on model data.

The aim of the study was to develop algorithms for calculating the standard uncertainty due to heterogeneity of the RM for the composition and properties of dispersed and solid materials.

The objectives of the study were to analyze the algorithms set forth in GOST 8.531-2002 and ISO Guide 35:2017, and to develop and test new algorithms for calculating the standard uncertainty due to heterogeneity based on these algorithms.

The research results have shown that it is more efficient to use the approach set out in ISO Guide 35:2017 to estimate the uncertainty due to heterogeneity, modernized and taking into account the mass of the smallest representative sample. Separately, it should be noted that the developed algorithm is applicable both for studying the indicators of the composition, and properties of solid and liquid substances, and materials.

Thus, the updated algorithms will be used in the revision of GOST 8.531-2002 to harmonize GOST 8.531-2002 and ISO Guide 35:2017, as well as to increase confidence in the results of determining the metrological characteristics of RMs in Russia and ensure the uniformity of measurements at the international level.

In this work, algorithms for the characterization of reference materials are developed based on the data model of an interlaboratory experiment containing hidden uncertainties. These algorithms make it possible to evaluate hidden uncertainties, and, taking into account these estimates, adjust the data and obtain an agreed value of the certified characteristics. The Monte Carlo method was used to study the properties of estimates of hidden uncertainties, as well as the study of new algorithms in comparison with traditional ones.

The establishment and control of the metrological characteristics of the determination of trace elements in biological materials is an urgent task due to the wide application of these measurements in medical laboratory diagnostics. In the course of the research, the process of developing a primary reference procedure for measuring the mass fraction and molar concentration of copper and zinc in biological materials by isotope dilution mass spectrometry is presented. The optimal conditions for sample preparation and measurements by isotope dilution and mass spectrometry with inductively coupled plasma are determined in order to increase the accuracy. The sources of uncertainty are studied; the contribution of each source to the uncertainty budget is estimated. During the certification of the developed measurement procedure, the following metrological characteristics were determined: the measurement range of the mass fraction of copper and zinc is from 1 ∙ 10^–6 to 1,5 ∙ 10^–3 %, the measurement range of the molar concentration of copper and zinc is from 2 to 20 µmol/dm³, the relative expanded measurement uncertainty of the mass fraction of copper is (7.1–7.5) %, the relative expanded uncertainty of the mass fraction of zinc is (8.9–9.2) %, the relative expanded uncertainty of the molar concentration of copper is 8.8 %, the relative expanded uncertainty of the molar concentration of zinc is 8.6 %.

The developed procedure is intended to establish the metrological characteristics of reference materials for the composition of lyophilized blood serum and reconstituted lyophilized blood serum, control the accuracy of the measurement results obtained using other procedures (methods) of measuring similar values, perform high-precision measurements of mass fractions and molar concentrations of copper and zinc in lyophilized blood serum and reconstituted lyophilized blood serum for referee purposes.

Isotopic analysis is an efficient method for quality control and detection of counterfeit food products. The method of elemental analysis isotope ratio mass spectrometry (hereinafter referred to as EA-IRMS) is traditionally used in the field of isotopic analysis of food products and is regulated in the relevant regulatory documents. The method of combustion module-cavity ring-down spectroscopy (hereinafter referred to as CM–CRDS) is a rapidly developing method for measuring the carbon isotope ratio with a number of advantages; currently, this method is of most interest for the isotope analysis of food products. However, studies of the metrological characteristics of the CM–CRDS method as part of the analysis of the isotopic composition of vanillin have not been carried out. The purpose of the research was to develop a procedure for measuring the carbon isotope ratio in vanillin by the CM–CRDS method with an expanded uncertainty (at k = 2) of less than 0.1 ‰.

The development of the measurement procedure was carried out in preparation for the international key comparison CCQM-K167 «Carbon isotope delta measurements of vanillin» (2019–2022) organized by the international Working Group on Isotope Ratios of the Consultative Committee for Amount of Substance of the International Bureau of Weights and Measures. The experimental part of the research was carried out on a reference installation, which is part of the State primary standard of units of molar part, mass part and mass concentration of components in gas and gas condensate environs GET 154-2019.

The expanded uncertainty (at k = 2) of this procedure for measuring the carbon isotope ratio in vanillin by the CM–CRDS method is less than 0.1 ‰. The following tasks were solved to achieve the set goal: the factors that form the measurement uncertainty budget were identified, some of which were eliminated or minimized by developing a procedure for preparing equipment and samples, a procedure for performing and controlling the measurement accuracy, and a procedure for processing measurement results.

The results of international comparisons CCQM-K167 confirmed the possibility of measuring the carbon isotope ratio in vanillin by the CM–CRDS method using the developed procedure with an expanded uncertainty (at k = 2) of 0.09 ‰, which corresponds to the best measurements performed by the EA-IRMS method.

The achieved result is of practical importance, because it confirms the possibility of applying the CM–CRDS method for quality control and detection of counterfeit vanillin.

Further research will be aimed at developing procedures for measuring the carbon isotope ratio using the CM–CRDS method in other substances and materials analyzed in the food industry, including for quality control and safety confirmation of juice products according to TR CU023/2011 and alcoholic products according to TR EAEU047/2018.

In accordance with TR CU022/2011 «Food products in terms of their labeling», the content of allergens in food products is subject to mandatory control. Work on the creation of a metrological support complex for the identification and quantitative determination of the content of non-infectious food allergens of animal or plant protein origin in food products includes the development and certification of methods for identification and quantitative determination; conducting interlaboratory comparisons; creation and testing for type approval of reference materials.

Within the framework of this research, work was carried out on the development and certification of methods for identifying and quantifying the content of non-infectious food allergens of plant (gluten, peanuts, nuts, soybeans) and animal (cow’s milk, chicken eggs, fish and seafood) protein origin in samples of all kinds of food products and objects related to the requirements for food products, swabs taken from work surfaces during production control using reagent kits for enzyme-linked immunosorbent assay produced by XEMA LLC.

Certification of quantitative analysis methods in accordance with legal requirements in the field of ensuring the uniformity of measurements was conducted using imported reference materials of food allergens. The lowest sensitivity limits (detection limits) of the presence or absence of antigens by allergen protein weight ranged from 0.001 ppb to 5 ppm. The developed methods make it possible to ensure the safety of food products when establishing the conformity of products with the requirements of the legislation on technical regulation.