The article presents materials on processing and interpretation of the results of microbiological analysis of the quality of medicines in accordance with the State Pharmacopoeia of the Russian Federation and the Pharmacopoeia of the Eurasian Economic Union. It exemplifies the use of the rules for processing test results and counting aerobic microorganisms and microscopic fungi on agar culture media in Petri dishes and on membrane filters. The author discusses the possibility of and prospects for applying various sample inoculation methods, as well as using calculation factors when interpreting their results. The text covers approaches to repeating microbiological testing of medicines to verify the reliability of a non-compliant first result.

Depending on the class of toxicity, organic solvents used or formed during the production of active substances may pose risks to human health. Therefore, residual Depending on the class of toxicity, organic solvents used or formed during the proorganic solvents must be controlled, and limits for their content must be established. The article covers requirements and approaches to the assessment and establishment of maximum permissible quantities of residual organic solvents in active substances. This will help applicants decide on the need to either include the residual solvent control into product specification files or justify its absence in order to ensure the safety of medicines.

The main quality attributes of radiopharmaceuticals that ensure their effectiveness and safety and are unique to their specifications are activity, radionuclide identity, radionuclide purity, and radiochemical purity. The aim of this study was to analyse the possibility of formation and methods for determination of various impurities in radiopharmaceuticals based on radionuclides of several groups: technetium-99m and rhenium-188; iodine and fluorine-18 isotopes; and gallium-68 and some other metallic radionuclides used in theranostic schemes combining radionuclide diagnostics and radionuclide therapy. The article analyses the sources for the formation of radionuclide, radiochemical, and chemical impurities; the influence of these impurities on visualisation quality and dosimetric characteristics of radiopharmaceuticals; various approaches to the methods of impurity detection and quantification; compendial requirements to the quality of radiopharmaceuticals; and research results reported in publications. The article demonstrates the need for the development and certification of Russian reference standards for testing quality attributes of radiopharmaceuticals as part of harmonisation of the State Pharmacopoeia of the Russian Federation with the Pharmacopoeia of the Eurasian Economic Union and the European Pharmacopoeia.

In 2012, the European Medicines Agency (EMA) adopted a guideline, which divided all antibiotics into groups according to the manufacturing process and established acceptance criteria for organic impurities for each of the groups.

The aim of the study was to justify the requirements and methodological approaches to setting the limits for organic impurities in semisynthetic antibiotics.

Materials and methods: the authors analysed the requirements established by the leading world pharmacopoeias and the State Pharmacopoeia of the Russian Federation regarding the control of organic impurities in semisynthetic antibiotics, using the example of four semisynthetic antibiotics: doxycyline hyclate, clarithromycin, meropenem, and ceftriaxone. The study used the methods of comparative analysis and content analysis.

Results: the study demonstrated that the organic impurity profiles of the analysed active substances and the corresponding finished medicinal products often differ significantly across the leading pharmacopoeias, either qualitatively or quantitatively. The Russian, European, and United States pharmacopoeias provide for the use of impurity reference standards in the test procedures for the determination of impurities in active substances of the semisynthetic antibiotics in question, whereas the Japanese Pharmacopoeia allows the use of non-compendial reference substances in the assessment of the chromatographic system separation power.

Conclusions: the ability of a pharmacopoeial text to cover a variety of medicinal products coming to the Russian market from different countries has become a vital issue. This includes covering the impurity determination procedures, reference standards, and limits used, because general-purpose methods and limits do not always allow for correct assessment of impurity profiles in substances produced by different manufacturing processes. The current USP practice is to include various impurity control procedures in monographs on medicinal products, and the limits may also vary. This approach may be applied in the State Pharmacopoeia of the Russian Federation as well.

The global anthropogenic load on the biosphere results in a potentially unmanageable problem of ecosystem pollution with organic and inorganic impurities, which may carry significant risks for human health. Therefore, the development and production of medicinal products from raw materials of animal origin require a careful risk-based assessment of impurities that may be found in the finished product. The aim of the study was to categorise the impurities in animal-derived medicines, identify and characterise specific impurity groups, and suggest a control methodology. The article reviews the factors that allow grouping impurities in animal-derived medicines, namely, the origin (anthropogenic or natural), type (process- or raw material-related), nature (product-related or foreign), and presence (inherent or potential impurities). The authors note the necessity of considering the specific production conditions, the origin of raw materials, and the intended use of medicinal products to determine an optimal control strategy for each impurity group and to justify the level at which a specific impurity should be controlled (the raw material, active substance, or finished product). A product’s marketing authorisation application must contain comprehensive data on the choice of the control strategy for potential impurities, including a justification of the selected control level and the established limits, details of the chosen control procedures, and risk-assessment reports.

An important indicator of the safety of plant raw materials and herbal medicinal products is the content of residual pesticides. Its determination is particularly difficult in aromatic plants characterised by a diverse composition of terpenoids co-extracting with organochlorine pesticides and forming numerous degradation products that interfere with the analysis.

The aim of the study was to develop and validate an analytical procedure for the quantification of organochlorine pesticides in plant raw materials containing terpenoids, compliant with the requirements of the State Pharmacopoeia of the Russian Federation.

Materials and methods: the study analysed samples of morphologically different raw materials from 21 plant species containing terpenoids. The analysis was carried out by GLC-MS on a 450-GC gas chromatograph coupled to a 220-MS ion-trap mass spectrometer (Varian, USA) using a FactorFour VF-5ms quartz capillary column (30 m × 0.25 mm).

Results: the authors developed the analytical procedure for organochlorine pesticides in medicinal plant raw materials containing terpenoids. Its specificity was confirmed by retention times and mass spectra for all the tested analytes. The recovery of pesticides was studied on model mixtures of a plant raw material and ranged from 70.04 to 99.27%. The authors established the linearity using a calibration curve for internal standard (4,4'-dibromodiphenyl) concentrations from 1.0 to 18.1 µg/mL. The procedure was linear across the entire studied range; the correlation coefficient equalled 0.999. The trueness and precision of the analytical procedure met the acceptance criteria.

Conclusions: the analytical procedure has been put into use at the Testing Centre of VILAR. From 2018 to 2020, 63 samples of 21 types of medicinal plant raw materials were analysed and found to be corresponding to the safety requirements for the organochlorine pesticide content. Residual pesticides were detected in the medicinal plant raw materials in few sporadic cases.

The manufacture of different medicinal products in shared facilities creates a risk of cross-contamination. One of the approaches to select the limits for possible contaminants is based on calculating the permitted daily exposure (PDE), i.e. the dose of an active pharmaceutical ingredient or any other substance contaminating a medicinal product that will not be associated with any adverse events in a human in the case of lifetime exposure. The aim of this study was to provide practical guidance on selecting adjustment factors for calculating PDEs to establish limits for potential contaminants in multi-purpose pharmaceutical facilities. The authors analysed the regulatory requirements and literature needed to establish critical effects of contaminants, outlined possible assumptions in the use of quantitative indicators for measuring toxicity, and described the relationship between the PDE and other indicators of the safety of chemical compounds for human health. The article presents an example of PDE calculation for an investigational hypoglycemic medicinal product using a limited amount of open-source literature data. Thus, the article demonstrates the role of information on the primary pharmacodynamic effects of medicinal products in the assessment of their critical effects, which is necessary to implement the most conservative approaches to PDE calculation. The example of PDE calculation presented in the article may be used to assess cross-contamination risks associated with non-dedicated manufacturing facilities.

The assessment of the quality of 93% oxygen obtained from the air by pressure swing adsorption (PSA) presents an important challenge for applied research. Such an assessment provides a possibility to guarantee the safety of oxygen therapy using both stationary and portable PSA-based oxygen concentrators. In this article, the experts of the Scientific Centre for Expert Evaluation of Medicinal Products and S.M. Kirov Military Medical Academy offer their recommendations for the implementation of monograph 2.2.0037.22 Oxygen (93 per cent) in civil healthcare organisations or military medical units. The publication of this monograph, which was approved by order No. 126 issued by the Ministry of Health of the Russian Federation on 01.03.2022, became the endpoint of the experts’ cooperation aimed at the inclusion of 93% oxygen into the Russian State Register of Medicinal Products.

Generally, preclinical studies of medicines conducted in accordance with national and international regulatory recommendations allow minimising the risks of detecting serious adverse events in patients at the stage of clinical trials. Nevertheless, current analytical trends motivate the development of new prognostic approaches aimed at improving the reliability and accuracy of safety assessments.

The aim of this study was to develop and test methodological approaches to comprehensive preclinical assessment of the key risk factors associated with the use of medicinal products in humans and to mathematical prediction of the corresponding benefits and risks.

Materials and methods: the study combined information analysis and statistics; it used consolidated preclinical data on the protective properties of fabomotizole and national and international regulatory documents describing the principles and methods of evidence-based medicine, in particular, Bayesian statistics and prognostic research methods.

Results: The article presents mathematical approaches developed to confirm the statistical reliability and prognostic significance of the results of preclinical assessment of the safety of medicines, based on Bayesian statistics, in particular, the concepts of weight of evidence (WoE), information value (IV), and normalised density (ND). Depending on the volume of the evaluated data, the WoE can be used to determine the weight of evidence of single variables, as well as entire groups of variables from individual tests or whole test panels, considered in the studies of general toxic effects, reproductive toxicity, genotoxicity and other studies characterising the condition of vital organs when evaluating the safety of medicines.

Conclusions: The developed methodology allows evaluating the entire volume of information obtained in preclinical studies of medicinal products. The criteria in the form of WoE and IV in preclinical safety assessment of medicines can be used to estimate the benefits and risks of using medicines, including the products developed specifically for children and pregnant women.

The relationship between dissolution and bioavailability is an example of the interdependency between the quality of a medicinal product and its safety and efficacy. The uniqueness of thioctic acid is that it can exist in an oxidised and a reduced form, showing lipophilic (lipoic acid) and hydrophilic (dihydrolipoic acid) properties. Bioavailability studies of thioctic acid are necessary to evaluate the expected therapeutic effect and mitigate side effects of the medicinal product.

The aim of the study was to carry out equivalence dissolution testing to compare the release of thioctic acid from medicinal products produced by several manufacturers.

Materials and methods: the study used a reference medicinal product and three multisource medicinal products by different manufacturers; more specifically, film-coated tablets containing 600 mg of thioctic acid. The experiment was carried out in dissolution media at pH of 6.8±0.05 and 1.2±0.05. Statistical analysis was performed by calculating the average amounts of the substance dissolved, the standard deviation (SD), and the relative standard deviation (RSD, %) using Microsoft Office Excel 2007.

Results: The authors chose the testing conditions (dissolution media pH values of 6.8±0.05 and 1.2±0.05) taking into account the nature and characteristics of thioctic acid. The comparison of thioctic acid release profiles based on the calculation of the similarity factor (f2) showed that the dissolution profiles of multisource medicinal products 2 and 3 at pH 6.8 were equivalent to that of the reference medicinal product (more than 85% of the active pharmaceutical ingredient released within 15 minutes) and the dissolution profile of multisource medicinal product 1 was not equivalent to it (with f2 of 28).

Conclusions: the established differences in the rate and degree of active ingredient release from the studied medicinal products may indicate possible differences in their pharmacological effectiveness in vivo.

The legislation of the Eurasian Economic Union (EAEU) includes all the necessary requirements and tools to implement a unified approach to preparing Module 1 of the electronic Common Technical Document (eCTD) for the concerned member states (CMSs). However, the approaches to the matter and the recommendations provided to applicants differ across member states. This causes significant ambiguity and imposes an excessive burden on the applicants. Drafting of a guideline on preparation of eCTD Module 1 for the CMSs will allow for tackling this important grey area in the EAEU regulatory framework, as regulatory authorities are lacking consensus on country-specific submissions. Currently, pharmaceutical industry stakeholders consider the Russian experience of implementing the legislation in question the most successful, so it is proposed to convey this experience to the common market of the EAEU.