The article demonstrates that bioequivalence studies of generic drugs whose active substances are analogues of endogenous compounds found in the human body in natural concentrations present a major challenge as compared to other products and call for a specific regulatory approach. In the absence of available scientific data demonstrating that the product intake can increase the general concentration of the endogenous compound, conducting bioequivalence studies can be economically impractical in contrast to a standard comparative clinical trial, because first it would be necessary to demonstrate a significant increase in the compound concentration in blood plasma. The article analyses Russian legislation and international law with respect to evaluation of medicinal products that are analogues of endogenous compounds, i.e. vitamins, hormones, enzymes, amino acids and salts. It was demonstrated that correction for endogenous compound concentration in blood plasma and control of its dietary intake are required in order to obtain accurate bioequivalence results. The article summarises the experience gained at the FSBI «SCEEMP» of the Ministry of Health of the Russian Federation with respect to evaluation of medicines that are analogues of endogenous compounds, and outlines the most frequent mistakes in testing protocols. It substantiates the need for an individual approach tailored for each particular product, since there is no single solution to the problem of background concentration of endogenous compounds. The authors of the article developed some key solutions that can help minimize the impact of background concentrations of test samples on the results of bioequivalence assessment. Based on the results of the analysis performed and accumulated experience the authors of the article suggested some ways to resolve the problem.

Expansion of the range of new medicines leads to a significant increase in healthcare spending and, consequently, to the appearance of more affordable generic drugs. A drug can be recognised as generic if there is sufficient evidence of equivalent structural characteristics of the active substance and therapeutic characteristics of the drug. However, for a number of substances which are multicomponent mixtures of sister compounds it is quite difficult to demonstrate absolute similarity of the chemical structure and to determine a substrate for bioavailability evaluation. Therefore, a separate group of non-biological complex drugs has been singled out. The present article summarises the requirements of the leading regulatory agencies for demonstration of equivalence between the reference product and such medicines as glatiramoids, liposome-encapsulated doxorubicin and iron-based nanosized colloidal products. It has been shown that preclinical and clinical studies are still necessary for these types of products, and the amount of testing will depend on the results of comparability assessment.

The efficacy and safety of purine receptor agonists in patients with chronic pain have been analysed. The data on the clinical application of purine analgesia in the management of pain syndrome are reviewed. The use of purine analgesia for the treatment of patients with chronic neuropathic pain is scientifically justified. The central mechanisms of purine receptor agonists and their analgesic activity are described in detail. It has been shown that purine receptor agonists have a strong analgesic effect and a narrow range of side effects, and they effectively relieve neuropathic pain by influencing the purinergic regulatory mechanism. The mechanisms of the analgesic effect of B vitamins (B₁, B₆, B₁₂) that have their own analgesic potential are considered — which is of great importance in the pharmacotherapy of polyneuropathies. It should be noted that the prescription of B vitamins is pathogenetically justified in diabetic polyneuropathy, and a combination of B vitamins is more efficacious than a monotherapy.

The article reviews literature data on development and clinical use of biomedical cell products (BCPs) — a new class of medicines which could be approved for distribution and use only after their specific activity and safety have been thoroughly examined at the stage of experimental research. The article describes main characteristics of BCPs approved in the Russian Federation, as well as specific aspects of their formulation and use. It analyses the main stages of preclinical studies (requirements for animal models, testing of general toxicity, immunogenicity, oncogenicity, tumorigenicity, etc.) that do not cover medicine quality evaluation. The article also dwells upon requirements for the clinical stage of BCPs development. It was shown that the choice of clinically relevant efficacy and safety endpoints could be substantiated by respective preclinical data and accumulated experience of the clinical use of medicines for a particular condition.

The article describes the main stages of introduction of the Good Distribution Practice (GDP) in Russia following the adoption of new laws making it mandatory for wholesalers to comply with requirements for storage and transportation of medicinal products. The article compares the regulatory requirements of the European Union, Eurasian Economic Commission and the Russian Federation for GDP system development by entities involved in medicines circulation. It highlights the main activities that help a wholesaler create an efficient GDP system. The key role in the implementation of GDP principles is played by the director of the company and the employee in charge. The article analyses the risk-oriented approach that the Federal Service for Surveillance in Healthcare relies upon when supervising wholesalers of medicinal products. It was demonstrated that the compliance of a product with efficacy and safety criteria can only be assured if GDP standards are met.

The assessment of allergic risk at the preclinical stage of drug development has been a debatable issue due to the integration of national requirements for medicines authorisation with those of the Eurasian Economic Union (EAEU). The article summarises mechanisms and factors involved in the development of drug hypersensitivity, as well as the main national and foreign regulatory requirements. It also cites the results of allergic risk assessment studies involving standard guinea pig tests, such as systemic anaphylactic reactions and active cutaneous anaphylaxis, for a number of medicines with the molecular weight of the active substance of more than 1000 Da and less than 1000 Da. Data analysis confirms that the number of positive reactions for high molecular weight compounds (>1000 Da) is significantly higher than the number of positive reactions for low molecular weight compounds (<1000 Da). There were some false-positive results detected. The results of foreign studies confirm the lack of correlation between the experimental data obtained in similar tests in guinea pigs and the clinical data. Thus, standard tests in guinea pigs cannot adequately predict the risk of immediate hypersensitivity reactions to new medicines in clinical practice. Negative or positive results should not be regarded as confirmation of potential absence or presence of anaphylactic reactions in clinical practice.

The article investigates the applicability of the amino column XBridge Amide 150×4.6 mm for separation of 4-hydroxybenzoic acid esters (parabens) — based on experience with hydrophilic interaction liquid chromatography used for analysis of various compounds. The study analysed the retention times, elution order and resolution between the peaks of parabens and impurity A (4-hydroxybenzoic acid) while using acetonitrile : phosphate buffer mobile phases containing 7–10 % of acetonitrile and acetonitrile : water mobile phases containing 96–99 % of acetonitrile, and the above-mentioned column. It was demonstrated that reversed-phased chromatography was preferable for separation of paraben homologues, while hydrophilic interaction chromatography was preferable for analysis of 4-hydroxybenzoic acid impurity. When analysing potential mechanisms of retention of compounds by the XBridge Amide column it was suggested that, unlike amino groups, amide groups of the sorbent do not have affinity for phenolic hydroxyl groups of parabens in hydrophilic interaction liquid chromatography.

The article compares test methods and levels of requirements laid out in the world’s leading pharmacopoeias and in manufacturers’ specifications with regard to the quality of levonorgestrel and ethinyl estradiol containing medicinal products used as oral contraceptives. The study analysed medicines containing a combination of levonorgestrel and ethinyl estradiol (Vezantra, Melleva, Microgynon, Minisiston, Modelle Libera etc.) that were tested at the FSBI «SCEEMP» of the Ministry of Health of the Russian Federation as part of premarketing evaluation. The comparison of the obtained data revealed that the test methods recommended by foreign pharmacopoeias and manufacturers’ specifications for quality control of medicines containing levonorgestrel and ethinyl estradiol are in line with the current trends in the pharmaceutical analysis and make it possible to adequately assess the quality of this group of medicines that are authorised in the Russian Federation. Manufacturers’ specifications include additional parameters, such as «Related impurities», «Microbiological purity», and, in some cases, «Identification of colouring agents» (titanium dioxide, iron oxide), «Average weight», «Disintegration», «Water», and «Residual organic solvents». The study showed that the requirements included into manufacturers’ specifications meet the requirements of the world’s leading pharmacopoeias or even exceed them, as in the case of the «Assay» parameter.