EXPERT OPINION
The paper presents recommendations on describing analytical procedures for evaluation of medicinal products in terms of sterility and microbiological quality in accordance with the State Pharmacopoeia of the Russian Federation and the Pharmacopoeia of the EAEU. These quality attributes should be covered in Product specification files for any medicinal product. The paper describes specific considerations for preparation of the corresponding sections of the Russian or EAEU Product specification files. It is necessary to provide and justify quality requirements, refer to or describe the recommended analytical procedure and indicate differences, if any, from the standard one. Standardisation of the approach to microbiological quality control of medicinal products will allow analysts to accurately perform the tests, get reliable results and ensure the safety of medicinal products.
Abnormal toxicity testing helps to detect unexpected toxic impurities in medicinal products for parenteral use and in the corresponding active pharmaceutical ingredients of natural origin. In accordance with the requirements of the State Pharmacopoeia of the Russian Federation and in order to obtain reliable results, all test parameters, the most important of which is the test dose, should be correct. In this paper, the experts of the Scientific Centre for Expert Evaluation of Medicinal Products offer their recommendations on range finding. A correct test dose will provide reliable analytical results and ensure the safety of the evaluated medicinal products.
MAIN TOPIC: CURRENT APPROACHES TO EVALUATION OF HERBAL MEDICINES
Currently experts are actively working on Russian specifications for herbal drugs, herbal drug preparations, and herbal medicinal products, and specifically on analytical procedures to evaluate the quality of these medicines. The aim of this study was to provide a scientific basis for improving the procedures of qualitative and quantitative analysis of herbal drugs, herbal drug preparations and herbal medicinal products containing phenolic compounds. It was shown that the chemical nature, physicochemical and spectral characteristics of biologically active compounds should be considered a basis for the development of new methodological approaches to standardisation of plant raw materials and herbal medicines. The study used an example of herbal drugs and herbal medicinal products containing flavonoids, phenylpropanoids, and anthracene derivatives to justify the feasibility of standardisation using TLC, HPLC, spectrophotometry, as well as indicative reference standards as criteria of identity and quality. The study substantiated the necessity of a state system for development and registration of reference standards for pharmacopoeial analyses.
Global interest in herbal medicinal products is growing, thus increasing the demand for medicinal plant raw materials. However, the growth in sales of raw materials entails the risk of a wider spread of counterfeit and substandard medicinal products. The use of such products can lead to serious complications and even death. This brings to the forefront the studies aiming at identification and quality control of herbal drugs. In addition, the relevance of these studies stems from the need for harmonisation of test methods for identification of related plant species as acceptable foreign elements in herbal medicinal products. The aim of the study was to determine the most widely used methods for identification of closely related plant species and to analyse the possibility of aligning the requirements of Russian standards and foreign pharmacopoeial monographs. According to the analysis of identification requirements, the main test method for identification of related plant species is thin-layer chromatography; morphological and anatomical characteristics of plants are also used. Methodological approaches of the European Pharmacopoeia to identification of closely related species in herbal medicinal products have found application in updating compendial standards of the Russian Pharmacopoeia. Russian standards are harmonised with the requirements described in monographs of leading pharmacopoeias and provide for the detection of unacceptable impurities in herbal medicinal products by morphological, anatomical and chromatographic characteristics.
Native herbal medicinal products (NHMPs) are medicinal products derived from plant raw materials. NHMPs are characterised by a complete transfer of contaminants from raw materials to finished products and comparability of therapeutic doses to daily consumption of many foods. The aim of the study was to develop an approach to assessing the content of elemental contaminants in NHMPs, based on public health risk assessment methods, and exemplify its use by applying it to pumpkin seeds. Materials and methods: the study analysed national and international regulatory documents governing the control of elemental contaminants in medicinal products and food, as well as literature on the ability of pumpkin seeds to accumulate such contaminants. In order to determine permitted concentrations, hazard quotients and cancer slope factors, the authors used internationally accepted risk assessment criteria. Results: the study identified the elemental contaminants to be controlled during risk assessment of NHMPs (i.e., As, Cd, Co, Cr, Pb, Hg, Ni, and V). The authors calculated permitted concentrations of the elements for a therapeutic dose of pumpkin seeds; hazard quotients for the essential (Co, Cr, Cu, Fe, Mn, Mo, Se, Zn), probably essential (As, Ni, V) and toxic (Al, Cd, Hg, Pb, Sr, Tl) elements consumed with the dose; and individual cancer risks associated with As, Cd, Cr, Pb. Conclusions: the total health impact of the studied elements in a therapeutic dose of pumpkin seeds is permissible, and there is no risk of non-carcinogenic effects. The content of each carcinogenic element in pumpkin seeds corresponds to the acceptable level of maximum individual cancer risk. These risk levels are to be controlled at all times. The results of this study may support the development of a compendial monograph on pumpkin seeds.
Much interest is taken in identification of Aloe arborescens Mill. medicines by a major class of bioactive compounds (anthracene derivatives), as well as in quantitative determination of the compounds belonging to the class, with the same unified method for the entire spectrum from herbal drugs to herbal medicinal products. The aim of the study was to develop a methodological approach and select unified conditions for the identification and assay of anthracene-derived compounds in herbal drugs, herbal drug preparations and herbal medicinal products of Aloe arborescens Mill., observing the principle of holistic, end-to-end standardisation. Materials and methods: analytical conditions were unified using literature data and a comparison of reference values and requirements of the Russian and other pharmacopoeias. The subsequent practical evaluation of the selected conditions used three batches of the herbal medicinal product “Aloe Juice” by Vifitech (batches 131217, 030318 and 070618). The identification was carried out using a silica gel plate for high-performance thin-layer chromatography (HPTLC Silica Gel 60 HX85224933 1056330001 by Merck). The results were examined in daylight before and after spraying with a 2% alcohol solution of sodium hydroxide. The quantification was carried out using a Cary-100 spectrophotometer by Agilent at 512 nm and 0.5% magnesium acetate in methanol as a developing solvent. Results: the authors developed a unified approach to identification and quantification of anthracene-derived compounds in herbal drugs, herbal drug preparations and herbal medicinal products of Aloe arborescens Mill. and suggested using aloe-emodin as a reference standard. The authors established reference values for anthracene-derived compounds in herbal drugs, herbal drug preparations and herbal medicinal products of Aloe arborescens Mill. and drafted the corresponding monographs for the State Pharmacopoeia of the Russian Federation. Conclusions: the developed procedures allow for comprehensive identification and quantification of anthracene-derived compounds in herbal drugs, herbal drug preparations and herbal medicinal products of Aloe arborescens Mill. by the same class of biologically active compounds.
To ensure the safety of herbal medicinal products, particularly in liquid dosage forms, it is necessary to control environmental toxins to acceptable levels. However, there is no methodology for individual elemental impurities in tinctures. The aim of the study was to select sample preparation conditions for quantitative determination of heavy metals and arsenic in tinctures. Materials and methods: the study used tinctures of anomalous peony, motherwort and valerian sampled from pharmacies. Sample preparation involved microwave-assisted digestion of pre-concentrated aliquots. Quantitative determination of 16 elemental impurities (As, Cd, Co, Cr, Cu, Fe, Mn, Mo, Ni, Pb, Sb, Sr, Ti, V, Zn, Hg) was carried out using inductively coupled plasma–atomic emission spectrometry. Results: according to the study results, quantitative analysis of most elemental impurities requires sample concentration at the preparation step. Due to the method sensitivity, direct quantification of individual elements in a sample is possible only at levels of not less than 0.1 mg/kg. The optimal volume of a tincture for concentration is 25 ml, both in terms of time efficiency and recovery of toxic elements. Conclusions: the proposed procedure showed the possibility of quantification of 16 elemental impurities in the tinctures. The concentrations of heavy metals and arsenic in the tinctures of anomalous peony, motherwort and valerian did not exceed 0.722 mg/kg. Zinc and manganese were the most abundant elemental impurities in the studied samples.
The principle of consistent, end-to-end standardisation builds upon the fact that qualitative and quantitative analysis of bioactive compounds in herbal drugs, herbal drug preparations, and corresponding herbal medicinal products involves the same methods of analysis. The possibility of such standardisation should be considered at the stage of specification development. The aim of the study was to explore approaches to analysing of Eucalyptus viminalis leaves and chlorophyllipt medicinal products, observing the principle of end-to-end standardisation. Materials and methods: the authors analysed Eucalyptus viminalis as a herbal drug (leaves), a herbal drug preparation (chlorophyllipt soft extract), and herbal medicinal products (Chlorophyllipt®, 1% alcohol solution for oral, cutaneous, rectal, and vaginal use; 2% oil solution for cutaneous and vaginal use; and 25 mg orodispersible tablets) by direct UV spectrophotometry, thin-layer chromatography (TLC), and qualitative reactions. Results: the study demonstrated the possibility of using a herbal reference standard of eucalimin to analyse the Eucalyptus viminalis herbal drug and chlorophyllipt preparations and medicinal products in different dosage forms by TLC. Conclusions: procedures for determination of total phenolic aldehydes, if included into specifications and production technology of chlorophyllipt preparations and products, ensure compliance with the principle of end-to-end standardisation and allow for quantitative determination and control of active ingredients throughout the product lifecycle: from the acceptance of raw materials, through in-process controls, to testing and monitoring of finished products’ quality.
Mint is a medicinal herbal drug; and its leaves are also widely used in the food and cosmetic industries. Medical literature states that mint is naturally resistant to toxic elements and capable of accumulating them in significant amounts. The aim of the study was to compare heavy metals, arsenic, and aluminum contents in mint leaves and products. Materials and methods: the study covered peppermint leaves, tinctures, and oils, as well as teas and dietary supplements made of different varieties of mint. Elemental analysis was performed according to the procedure of inductively coupled plasma mass spectrometry (ICP-MS) developed by the authors. Results: the authors studied the compliance of the experimentally established contents of heavy metals, arsenic, and aluminum in peppermint leaves and products to the requirements of Russian and foreign regulatory documentation. Nonparametric Spearman correlation coefficients were calculated to characterise the interaction between chemical elements. Conclusions: arsenic contents in mint leaves may exceed the limit given in the State Pharmacopoeia of the Russian Federation, 14th ed. It is supposed that the increased contents are not a result of the anthropogenic factor, but a specific characteristic of this plant. The study demonstrated synergistic absorption of aluminum, iron, and vanadium, as well as copper and zinc by mint. It was established that manganese had an antagonistic effect on the absorption of nickel, lead, and cobalt by mint.
CLINICAL PHARMACOLOGY
One of the most promising trends in clinical pharmacology is pharmacometrics, a combination of pharmacology and statistics that implements quantitative approaches for characterising dose–response relationships and predicting the variability of these relationships attributable to patient-specific characteristics (covariates). The aim of the study was to evaluate the significance of quantitative clinical pharmacology and discuss opportunities for its development in the context of health systems moving towards the value-based care model. The study showed that two key prerequisites for pharmacometrics development were the advancements in mathematical and statistical methodology based upon non-linear mixed effects regression modelling and the emergence of a personalised medicine paradigm aimed at creation of strategies for individualised prescribing of medicinal products. The study demonstrated the necessity for using the dose–response relationship information obtained by exploratory analysis of data stored in existing and newly created bases. Further integration of pharmacostatistical modelling and real-world data processing technologies, as well as their incorporation into clinical and economic evaluation of health technologies, will streamline decision making and, thus, facilitate the transition of health systems to the value-based model.
LEGAL ASPECTS OF MEDICINES EVALUATION AND REGISTRATION
The economic sanctions imposed on the Russian Federation in 2022 create a potential risk of shortages or absence of a range of medicines demanded by the Russian healthcare system. The article describes the legislative measures by the Russian Government aimed at prevention of inventory shortages of medicinal products and, in particular, the special requirements to expert evaluation and registration of the medicines that could be affected by the risk. The article pays special attention to the time frames of assessment and registration procedures.
Registration of medicines under the EAEU procedure
The article presents a comprehensive analysis of the main changes to the Rules of marketing authorisation and assessment of medicinal products for human use in the Eurasian Economic Union (EAEU). The reflection of regulatory procedures in the legislation is quite a significant systemic feature that makes it possible to establish common requirements for the medicines present in the EAEU and to ensure the possibility of unified regulation of the matter within the national economies of the member states.
RETRACTION
ISSN 3034-3453 (Online)