The most important component of national health policy is the assurance of quality, efficacy, and safety of medicines entering the pharmaceutical market in the Russian Federation. In this interview, we have discussed the quality control of medicines; its interconnections with various branches of science, in particular, with analytical chemistry; and the matters of material and equipment supply with Elena L. Kovaleva (Doctor of Pharmaceutical Sciences, Deputy Director of the Centre for Medicinal Products Evaluation and Control of the Scientific Centre for Expert Evaluation of Medicinal Products of the Ministry of Health of the Russian Federation), Yuri A. Zolotov (Academician of the Russian Academy of Sciences, Full Professor, Doctor of Chemical Sciences), and Dmitry V. Somov (Candidate of Pharmaceutical Sciences, Acting Director General of the Information and Methodological Center for Expertise, Accounting, and Analysis of the Circulation of Medicinal Products of the Federal Service for Surveillance in Healthcare).

Scientific relevance. This article describes a risk-based analysis of the need for elaborating pharmacopoeial requirements for 6 therapeutic groups of medicines, including an evaluation of the range and number of batches of these medicines put into the stream of commerce in the Russian Federation and a comparison of the corresponding product specification files and quality standards. The  article presents a  set of criteria for planning the elaboration of monographs for the State Pharmacopoeia of the Russian Federation according to a risk-based approach, which is used in a variety of other fields.

Aim. The study aimed to develop a comprehensive multivariate risk-based system providing criteria for planning the  elaboration of monographs for the  State Pharmacopoeia of the Russian Federation.

Materials and methods. This study focused on medicines for human use under a  range of international non-proprietary names. The  authors analysed entries in the Russian State Register of Medicines, data on the number of batches released to the pharmaceutical market, and product specification files and quality standards. The study was conducted using literature search, data analysis, and system-oriented methods.

Results. According to the results, a multivariate risk-based analysis is needed for planning the elaboration of monographs for the State Pharmacopoeia of the Russian Federation and the subsequent prioritisation of therapeutic groups or individual medicines for their standardisation.

Conclusions. The  suggested risk-based system for planning the  elaboration of monographs for the  State Pharmacopoeia of the  Russian Federation includes the following criteria: the social significance of a medicinal product and its value for the  health care system; the  percentage of medicinal products not tested by the national regulatory authority at the level of active pharmaceutical ingredients; the substantial number of batches and the significant range of medicinal products and the  respective active pharmaceutical ingredients by different manufacturers present in the pharmaceutical market; and the analytical procedures and requirements established in product specification files and quality standards.

Scientific relevance. Hypromellose phthalate is used in enteric coatings for oral medicinal products. The proportion of phthalate groups in the polymer is standardised because it has a significant effect on solubility. Whereas, the molecular mass of hypromellose phthalate is not controlled, and its impact on solubility in media with different pH values is understudied.

Aim. The study aimed to employ NMR spectroscopy to investigate the effect the molecular mass of hypromellose phthalate may have on the dissolution kinetics at the pH value declared by the polymer manufacturer.

Materials and methods. The study analysed hypromellose phthalate isolated from proton-pump inhibitor enteric coatings and the hypromellose phthalate reference standard. The molecular mass of the polymer was estimated by diffusion-ordered NMR spectroscopy (DOSY) with polyethylene glycols of known molecular masses for calibration. The authors studied the dissolution profiles of hypromellose phthalates of different molecular masses using ¹H NMR spectra.

Results. The authors developed a procedure for estimating the average molecular mass of hypromellose phthalate by DOSY. The procedure showed variations in the molecular mass of the polymer in the test samples; the molecular mass scatter amounted to 10 kDa. The dissolution profile of the test samples in an aqueous buffer solution (pH 5.59) was described by a linear function during the first hour. The slope characterising the dissolution rate varied from 10° to 36°.

Conclusions. The variation in the molecular mass of hypromellose phthalate significantly affects the dissolution rate of the test samples. The function of the dissolution rate against the molecular mass of hypromellose phthalate is non-linear. The article provides a compelling reason for further research to derive a correlation equation for the dissolution rate of hypromellose phthalate as a function of two variables (molecular mass and proportion of phthalate groups in the polymer).

Scientific relevance. Zinc content is a quality attribute of insulin products. The State Pharmacopoeia of the Russian Federation requires that it should be determined by flame atomic absorption spectrometry (FAAS). However, many pharmaceutical manufacturers currently prefer inductively coupled plasma mass spectrometry (ICP-MS), which is considered the most promising method for pharmaceutical and biomedical elemental analysis.

Aim. The study aimed to develop and validate an ICP-MS-based analytical procedure for zinc content determination in insulin products.

Materials and methods. The study focused on human insulin, insulin lispro, insulin aspart, and insulin glargine in the form of active substances, suspensions for subcutaneous injection, and solutions for injection from different manufacturers. Zinc content was determined on an Agilent 7900 ICP-MS; the analysis included 66Zn signal intensity registration.

Results. The study compared the results of zinc content determination in test samples with either hydrochloric or nitric acid used as the solvent for sample preparation. The authors selected the experimental conditions to achieve relative standard deviations (RSDs) of not more than 2.5% for the measurements. The ICP-MSbased analytical procedure was validated for its specificity, linearity, accuracy, and precision in the range of 0.4–1.6 mg/L. The authors compared the measurements of zinc content made using FAAS and ICP-MS.

Conclusions. The ICP-MS-based analytical procedure for zinc content determination in insulin products meets the validation criteria. This analytical procedure, as developed and validated, may be used in the quality control of medicinal products in the Russian healthcare system and at the batch release stage of pharmaceutical manufacturing.

Scientific relevance. Zinc quantification in insulin active substances and preparations by atomic absorption spectrometry requires a sample preparation procedure using hydrochloric acid, a narcotic and psychotropic precursor. The exclusion of precursors from laboratory practice significantly reduces labour costs during analysis.

Aim. This study aimed to modify the pharmacopoeial method for quantifying zinc in insulins with a view to eliminating drug precursors and to evaluate the applicability of the modified method across different insulin preparations.

Materials and methods. The study considered insulin active substances and preparations of various types, dosage forms, and strengths. Zinc content determination involved using an Agilent 240FS atomic absorption spectrometer at a characteristic wavelength of 213.86 nm.

Results. The authors selected the conditions for elemental analysis (nitric acid concentration, monochromator slit width, and flame stabilisation time) corresponding to the pharmacopoeial requirements for quantifying zinc in insulins (RSD ≤1.4%, standard zinc solution with a concentration of 0.8 mg/dm³, and calibration curve correlation coefficient ≥0.99). The study compared zinc content measurements in the studied insulin samples with hydrochloric acid or nitric acid as a solvent; it did not reveal any significant differences between the results obtained by the pharmacopoeial method and the modified method.

Conclusions. The modified method enables analysts to quantify zinc in insulin preparations in various dosage forms without drug precursors.

Scientific relevance. Deuterated analogues of test substances, when used as internal standards, enable analysts to determine traces of residual pesticides in a medicinal plant raw material by gas or liquid chromatography coupled with mass spectrometry. This prompts the search for an undemanding method for the synthesis of deuterated reference standards, with the ultimate goal of expanding the range of reference standards produced in Russia.

Aim. The study aimed to synthesise deuterated reference standards (malathion-D₆, chlorophos-D₆, dichlorophos-D₆, and their precursors) and determine their spectral characteristics using ¹Н, ²Н, ¹³С and ³¹Р nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectrometry.

Materials and methods. The study involved methanol-D₄, phosphorus pentasulfide, phosphorus trichloride, maleic acid diethyl ether, triethylamine, hydroquinone, and chloral hydrate. The authors recorded ¹H, ²H, ¹³C, and ³¹P NMR spectra using a QONE AS400 NMR spectrometer operating at a temperature of 298 °K and respective frequencies of 399.83, 61.38, 100.55, and 161.85  MHz. Mass spectra were obtained using an analytical system comprising an Agilent Infinity 1260 liquid chromatograph equipped with an automatic sample injector and coupled with a Thermo Scientific Orbitrap Fusion Lumos high-resolution mass-selective tandem spectrometer operating in electrospray ionisation mode.

Results. The authors used existing methods for the synthesis of organophosphate pesticides as a basis and developed synthesis routes to produce the deuterated analogues malathion-D₆, chlorophos-D₆, and dichlorophos-D₆. The synthesised compounds were identified by NMR spectroscopy and high-resolution mass spectrometry.

Conclusions. The synthesised compounds are highly pure and suitable for use as internal standards in the determination of organophosphate pesticides in medicinal plant raw materials. The synthesis methods developed by the authors can be used to produce reference standards in Russia.

Scientific relevance. The State Pharmacopoeia of the Russian Federation, edition XIV, requires the identification of aniseed and fennel fruits by the same thin-layer chromatography (TLC) procedure using Sudan III and menthol. These markers are neither specific nor related to the therapeutic effects of these herbal drug products. The visual interpretation of chromatograms is complicated because of the low intensity of adsorption zones. Moreover, the corresponding compendial monographs do not characterise the adsorption zones specific to each of the plants. The most abundant component in aniseed and fennel essential oils, trans-anethole, would make a better reference standard from a methodological point of view.
Aim. This study aimed to optimise the TLC procedure for essential oil determination in herbal drugs and herbal medicinal products of aniseed and fennel fruits and subsequently recommend it for inclusion in the relevant compendial monographs.
Materials and methods. The study examined samples from several batches of herbal drugs, including aniseed and common fennel fruits, sourced from Russian manufacturers. The reference standards comprised commercial reagents, including trans-anethole, anise oil, and linalool, as well as fresh essential oils that had been steam distilled from the test samples in a Clevenger apparatus. The study was conducted by TLC. Sample preparation involved using Merck aluminium TLC plates, an IKA KS-501 digital orbital shaker, and a CAMAG Linomat 5 semi-automatic sample application system. The authors heated the plates in either a Binder ED53 drying oven or a CAMAG TLC plate heater. For visualisation, the authors selected a CAMAG TLC VISUALIZER 2 UV imaging and documentation system.
Results. The informational and experimental research showed the feasibility of using trans-anethole as an identification reference standard for common anise and fennel fruits. The authors selected the optimal solvent for extracting active substances from the test products (hexane) and a detection reagent for improving visual evaluation of the chromatograms (1% sulfovanillin). The authors established characteristic adsorption zones for differentiating between aniseed and fennel fruits.
Conclusions. The optimised procedure identifies the main components in the essential oils of aniseed and fennel fruits with a specific reference standard. This procedure may be recommended for inclusion in draft monographs for the corresponding herbal medicinal products.

Scientific relevance. When harmonising conditions for qualitative and quantitative analysis of bioactive compounds in herbal medicines, the Institute of Pharmacopoeia and Medicinal Product Standardisation has discovered that horse-chestnut products lack national quality standards.
Aim. This study aimed to review international quality standards in order to identify the most promising testing methods for the main groups of bioactive compounds in horse-chestnut seeds and draw upon these methods when drafting national pharmacopoeial monographs for horse-chestnut seed products.
Discussion. The authors compared the requirements established by leading world pharmacopoeias for the identification and assay of herbal drugs and herbal drug preparations derived from horse-chestnut seeds.
Conclusions. The study results show that, predominantly, identification tests are based on thin-layer chromatography, assays rely on spectrophotometry, and aescin is used as a pharmacopoeial reference standard. The authors drafted a pharmacopoeial monograph for the medicinal product Horse-Chestnut Seed Dry Extract + Thiamine Hydrochloride, Oral Solution, which requires using thin-layer chromatography and spectrophotometry for qualitative and quantitative testing.

Scientific relevance. Laminariae thalli are a native herbal preparation used to prevent or treat multiple diseases. To achieve the optimal effect, this herbal preparation is usually taken for several weeks or months. The control of Laminariae thalli should extend beyond the element content in the herbal drug limited by specifications; additionally, it is important to assess the health risks of ingesting heavy metals with the medicinal product during the exposure period.

Aim. The study aimed to assess the carcinogenic and non-carcinogenic risks of consuming elemental contaminants with therapeutic doses of herbal medicinal products based on Laminariae thalli.

Materials and methods. The study investigated the content of elemental contaminants (Al, As, Cd, Cr, Co, Cu, Fe, Hg, Mn, Mo, Ni, Se, Pb, Sr, V, and Zn) in Laminaria saccharina and Laminaria japonica. The content of inorganic arsenic was determined by solid-phase extraction using inductively coupled plasma mass spectrometry (ICP-MS).

Results. When averaged at the 90th percentile level, the mean concentrations of the specified elements did not exceed the limits for seaweed and seagrass foods. The total hazard index from exposure to all analysed elements amounted to 0.173 at the median level and 0.616 at the 90^th percentile level. The leading contributors to the total hazard index were As, Fe, Cd, and Sr. The individual carcinogenic risk (CR) values for the potential carcinogens (As, Cd, Pb, and Cr) fell within the range of 1×10^-6<CR<1×10^-4.

Conclusions. If the elements analysed are ingested with a daily therapeutic dose of Laminariae thalli for the exposure period, their total negative effect will not cause harm to the human body. To eliminate the risk of developing neoplasms when the studied medicinal product (Laminariae thalli) is taken at its maximum recommended therapeutic dose for a month or more, the Cr content should be controlled along with the elements limited by specifications for herbal medicines.

Scientific relevance. In the context of pharmacopoeial harmonisation, the available methods for quantifying the total heavy metal content in tinctures are not sufficient to demonstrate the safety of liquid dosage forms based on herbal drugs. However, the establishment of individual limits for the heavy metal content requires analysing the patterns of environmental toxicant transitions from plant raw materials to herbal medicinal products in finished dosage forms.

Aim. This study aimed to analyse the trans-environmental transitions of heavy metals and arsenic from the soil through plants to herbal medicinal products using a case study of aqueous and alcoholic extracts of valerian and motherwort herbal drugs.

Materials and methods. The study focused on motherwort herb and valerian rhizomes with roots, the corresponding herbal medicinal products, and the rhizospheric soil. The elemental composition of the studied samples was determined by inductively coupled plasma mass spectrometry.

Results. The authors determined the content of 15 elements (Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Sr, Cd, Sb, Hg, and Pb) in plant raw materials, the rhizosphere, and herbal drug infusions and tinctures. The concentrations of elements were 0.002–109.884 mg/kg in motherwort herb samples and 0.017–866.618 mg/kg in the samples of valerian rhizomes with roots. Pb, Cd, and As were detected in all plant raw materials, while Hg was found only in 25% of the study samples. The content of these elements was within acceptable limits. Valerian and motherwort infusions contained all elements, except for Hg; valerian tinctures were free from Fe and Hg; and motherwort tinctures included no Fe, Hg, Sr, Cd, and Pb. The concentrations of elements in the infusions did not exceed 3.169 mg/kg, while the concentrations of elements in the tinctures were below 1.27 mg/kg. In the tinctures, Zn, Cu, Mg, and Ti were the most abundant elements, and Sb and Cd were present in minimum amounts.

Conclusions. Valerian and motherwort plants can concentrate Cu, Cr, Fe, and V from the soil. The transition of heavy metals and arsenic into infusions did not exceed 65% of the content of these elements in herbal drugs, while tinctures contained less than 30% of the content of heavy metals and arsenic in herbal drugs. Some elements passed into infusions 1.5–5 times more efficiently than into tinctures.

Scientific relevance. In December 2020, the Russian Federation adopted the Eurasian Economic Union (EAEU) requirements. This has significantly changed the certification procedure for qualified persons (QPs) of manufacturers of medicinal products for human use in the Russian Federation. To accommodate these changes, the Russian regulatory framework needs further improvement.

Aim. This study aimed to review the changes made to the mechanism of state regulation of medicines and to evaluate the impact on the pharmaceutical industry two years after the adoption of the current QP certification procedure.

Discussion. This review compares two QP certification procedures established by Order No. 7n of the Ministry of Health of the Russian Federation dated 12 January 2021. The first is an abbreviated one for QPs certified under the previous procedure, and the second is an initial one for QPs being certified for the first time, having an expired certificate, or wishing to extend their professional qualification profiles. The article illustrates common mistakes made by certification applicants when preparing their documents. Furthermore, the authors describe the most prevalent knowledge gaps identified by testing. The abbreviated certification procedure ensured a sufficiently smooth transition to the EAEU requirements. For example, by 1 February 2023, 506 QPs were recertified for the next five-year period according to this procedure. This accounts for slightly more than half of all QPs certified in the Russian Federation according to the previous requirements. The total number of QPs certified according to the EAEU requirements in Russia in 2021–2022 is approximately 1.5 times higher than the number of QPs certified during the same period in 2014–2015.

Conclusions. The updated procedure for QP certification has noticeably changed the occupational group of QPs formed in the Russian Federation in the last decade. The implementation of the new QP certification procedure has revealed several procedural issues that require additional explanation and clarification by the Ministry of Health of the Russian Federation.

Scientific relevance. Medicinal products formulated as aerosols and sprays are increasingly used in clinical practice, which makes the control of their quality, including microbiological testing, a highly topical issue. The current regulatory standards for microbiological testing of medicines provide little information on the quality control of metereddose aerosols. Proper microbiological sampling of these medicinal products can be difficult because of their primary packaging. The specialised analytical procedures set forth in international standards require verification and standardisation before use. Medicinal products in the form of sprays, despite being free from the disadvantages of aerosols, are more susceptible to the risk of microbial contamination.

Aim. The study aimed to describe specific aspects of sampling, to analyse the results of microbiological testing of aerosols and sprays, and to study the spectrum of microbial contaminants in these dosage forms.

Materials and methods. The authors retrospectively analysed the microbiological quality and sterility data for 181 batches of sprays, aerosols, and other inhalation dosage forms. The data were obtained at the Scientific Centre for Expert Evaluation of Medicinal Products of the Ministry of Health of Russia in 2020–2022. The Microbiology Laboratory tested the dosage forms according to the specifications provided by the manufacturers. The analysts used well-established testing procedures outlined in the current pharmacopoeias of the Russian Federation and the Eurasian Economic Union.

Results. The microbial counts exceeded the acceptable limits in 2.8% of the batches tested. The authors identified the microbial species that contaminated the medicinal products found to be non-compliant with regulatory requirements. Most of the non-compliant sprays that contained benzalkonium chloride as an antibacterial preservative were contaminated with Burkholderia cepacia complex species.

Conclusions. The authors consider it relevant to conduct research aiming at using the findings on potential contaminants to improve microbiological testing procedures for aerosols and sprays.

This article provides recommendations for documenting an analytical procedure for the determination of related substances by high-performance liquid chromatography in a product specification file (PSF). The article contains a description of specific aspects and a template for the typical contents and layout of the PSF section dedicated to related substances. A unified approach to the PSF content and layout will ensure error-free testing, reliable results, and streamlined regulatory assessments.