Recommendations for the Contents of the “Glycan Profile” Part of a Product Specification File

“Glycan Profile” is a necessary part of manufacturers’ product specification files for monoclonal antibody active ingredients or final products and erythropoietin active ingredients. The expert of the Federal State Budgetary Institution “Scientific Centre for Expert Evaluation of Medicinal Products” of the Ministry of Health of the Russian Federation provides recommendations for a step-by-step presentation of the test procedure, which will allow applicants to align product specification files for Russian- and foreign-produced medicinal products, help experts to minimise or eliminate the need to request additional information from applicants, and will contribute to timely batch release of medicinal products.

Recommendations for the Contents of the “Peptide Mapping” Part of a Product Specification File

‘Identification. Peptide mapping’ is a necessary part of manufacturers’ product specification files for therapeutic proteins (active ingredients and final products of monoclonal antibodies, filgrastims, erythropoietins). The expert of the Federal State Budgetary Institution “Scientific Centre for Expert Evaluation of Medicinal Products” of the Ministry of Health of the Russian Federation provides recommendations for a step-by-step presentation of the test procedure, which will allow applicants to align product specification files for Russian- and foreign-produced medicinal products, help experts to minimise or eliminate the need to request additional information from applicants, and will contribute to timely batch release of medicinal products.

Current Approaches to Demonstration of Therapeutic Equivalence of Locally-Acting Gastrointestinal Drugs

Evolution of knowledge about pharmacokinetics and pharmacodynamics of locally acting products, and an increase in the number of generics and medicines under development have laid the ground for the development of new scientific approaches to planning and conducting of therapeutic equivalence studies of medicinal products acting locally in the gastrointestinal (GI) tract. To date, many international guidelines on planning and conducting of bioequivalence (BE) studies of locally acting GI products have been updated, however, there are still no such guidelines in the Russian Federation and the Eurasian Economic Union (EAEU). Therefore, elaboration of common methodological approaches to the planning of clinical studies of these products is of particular relevance for the EAEU. The aim of the study was to analyse foreign approaches to planning, conducting, and evaluation of therapeutic equivalence studies of locally acting GI products. The paper analyses the guidelines of the European Medicines Agency and the US Food and Drug Administration on the planning, conduct, and evaluation of BE studies of locally acting GI products. The analysis demonstrated that BE clinical trials are giving way to in vitro studies providing a sensitive and accurate assessment of the differences between a locally acting GI product and the reference product, based on careful consideration of the medicine’s mechanism of action, dosage form, and site of action. The paper gives examples of test methods applied to medicinal products with a complex biopharmaceutical profile whose bioequivalence assessment is challenging, with a special focus on mesalazine products. The results of the analysis may be used for elaboration of a harmonised methodological approach to planning and conducting therapeutic equivalence studies of locally acting GI products in the Russian Federation and EAEU.

Antibiotic Dosing in Chronic Kidney Disease

Infectious process is an important cause of morbidity and mortality among patients with chronic kidney disease. Prescription of antibacterial drugs should take into account the pharmacokinetic parameters of the medicine and the individual characteristics of the patient. Adequate antibiotic dosing is crucial for positive treatment outcome and minimisation of side effects. The aim of the study was to analyse scientific literature on factors affecting the dosing of antibacterials in patients with chronic kidney disease. Since most antibacterial medicines are eliminated by the kidneys, a decrease in glomerular filtration rate or kidney function should be followed by the dose adjustment in order to prevent the medicine accumulation and reduce the risk of side effects. Antibiotic dosing in such patients should be accompanied by kidney function assessment and be adjusted to ensure effective and safe treatment, as well as prevention of bacterial resistance. The review provides data on the dosing of some antibiotic groups (beta-lactams, aminoglycosides, fluoroquinolones) at different creatinine clearance rates. Extrarenal excretion of medicines does not usually require the dose adjustment in patients with chronic kidney disease.

Preparation of a Nonclinical Overview Based on Scientific Literature

Current requirements for the registration dossier include submission of a preclinical (nonclinical) overview, including scientific literature data on preclinical studies and actual preclinical data on the medicinal product. For some groups of medicines, scientific literature data may be used instead of actual preclinical data, which may be redundant. One of the important functions of the scientific literature review is the analysis of updated preclinical information on the medicinal product, which reflects the product’s characteristics, supports conclusions on its efficacy or safety, and may affect the results of the benefit/risk assessment. The aim of the study was to determine the optimal format for presenting scientific literature data in a nonclinical overview that would reflect the methodological aspects of preclinical pharmacology and toxicology studies of medicines. The authors analysed the regulations of the Russian Federation and the Eurasian Economic Union containing requirements for the scientific literature review submitted instead of actual preclinical data as part of the registration dossier for a medicinal product. The authors also considered potential difficulties in preparing a nonclinical overview based on scientific literature. In order to systematise scientific literature data, it is recommended to provide pharmacodynamic, pharmacokinetic, and toxicological data using a format consistent with the common technical document. The proposed recommendations help to harmonise the process of preparation and design of a nonclinical overview which should contain data and facts enabling a reasoned assessment of the benefit/risk ratio. The standardised format of literature data presentation will help the developer prepare an adequate nonclinical overview and will speed up assessment of clinical trial or marketing authorisation applications.

Determination of Vancomycin B and Vancomycin Impurities by Liquid Chromatography

The preferred test methods for control of product-related impurities in medicinal products are high-performance liquid chromatography (HPLC) with a fine sorbent, and ultra-performance liquid chromatography (UPLC), which allow for better chromatographic separation of active substances and related impurities, reduction of time costs, and saving of material resources. The aim of the study was to develop HPLC and UPLC test procedures and assess the chromatographic separation capacity and efficiency in order to improve determination of the main vancomycin component and related impurities. Materials and methods: vancomycin hydrochloride lyophilisate for oral solution and solution for injection, and vancomycin hydrochloride reference standard (USP RS) were used as test objects. Agilent 1290 Infinity liquid chromatography system, and Chromolith® Performance RP-18e, Kinetex C18, Nucleodur C18 Isis, Zorbax RRHD Eclipse Plus C18, and LiChrospher® RP-18 columns were used for the testing. Results: HPLC analysis using a Chromolith® column (100×4.6 mm) reduces the testing time by 10 minutes compared to the USP test procedure, and by 15 minutes compared to the British Pharmacopoeia procedure. The proposed test procedure requires less eluent and increases chromatographic separation efficiency. UPLC analysis using a Kinetex C18 column (50×4.6 mm, 2.6 μm) made it possible to reduce the testing time by two thirds compared to the British Pharmacopoeia procedure. The use of isocratic elution greatly simplified the testing. The testing time under the proposed chromatographic conditions was 10 minutes. Conclusions: the selected HPLC and UPLC test conditions made it possible to significantly reduce the time of testing, minimise the use of expensive reagents, and increase efficiency of chromatographic separation in the determination of vancomycin impurities and the main component Vancomycin B.

Advanced Therapy Medicines Based on Oncolytic Viruses (Part II: Development and Authorisation of IMLYGIC®)

The only oncolytic virus-based product authorised in the US and EU—IMLYGIC®, a genetically modified herpes simplex virus type 1 (by BioVex Inc., a subsidiary of Amgen, Inc.)—was developed and approved for clinical use as monotherapy for recurrent unresectable melanoma. The aim of the study was to analyse materials on IMLYGIC® development and authorisation in order to be able to use the data on specific aspects of preclinical and clinical trials of oncolytic virus-based products in the development of regulatory framework for Russia and the EAEU. The publicly available preclinical and clinical trial results demonstrate a decrease in the size of both tumours being injected and remote tumours/skin lesions, which supports the local and systemic effects of IMLYGIC® due to the lysis effect of the virus on the tumour cells. The clinical trials of IMLYGIC® were the first to use the durable response rate, and not the overall survival, as the primary endpoint of the efficacy of the anticancer drug. Benefits of IMLYGIC® therapy were observed across all the secondary endpoints, except overall survival. Significant efficacy of the drug therapy was demonstrated only in patients without visceral lesions, which resulted in limitations of indications for use. There have been no serious or severe adverse effects associated with IMLYGIC®. If symptoms of viral infection develop, they can be neutralized thanks to the product’s sensitivity to acyclovir. At present, advanced therapy medicinal products derived from an oncolytic virus may be authorised in Russia for clinical use as monotherapy or combination therapy, according to the EAEU regulations.

Advanced Therapy Medicines Based on Oncolytic Viruses (Part I: Development and Authorisation of Products in China)

One of the promising areas in the development of innovative products for the treatment of cancer is the use of oncolytic (native or genetically modified) viruses (OLVs) for selective targeting of tumour cells and their destruction, especially as part of combination therapy. At present, there are three OLV-based products approved for medical use (two in China and one in the USА and EU). The aim of the study was to analyse data on specific aspects of OLV-based products’ development, preclinical and clinical research, and authorisation process in China. The authors analysed data freely available on the manufacturers’ websites, in public reports and documents of the Chinese regulatory authorities, in international clinical trial registries, and scientific publications. The products Gendicine® (SiBiono GeneTech Co., Ltd.) and Oncorine® (Shanghai Sunway Biotech Co., Ltd.) were originally developed and approved in China for clinical use as part of combination therapy. The analysis demonstrated long product development periods (Gendicine had been studied for 14 years before the start of the authorisation procedures), complex preclinical trial designs, and potential use of the products for several medical conditions with different tumour localisation. The identified specific aspects of OVL-based products’ development and authorisation in China could be taken into account in the regulatory practice of the Russian Federation.

Analysis of Vitamin A in Multivitamin Products

Vitamin A is present in multivitamin products mainly in the form of retinol esters: retinyl acetate, retinyl palmitate, and beta carotene—retinol precursor (dimer) found in plants, which is capable of converting into retinol in liver cells. Retinol is determined in medicinal products primarily by high performance liquid chromatography (HPLC), with preliminary purification and vitamin isolation by liquid-liquid extraction. However, scientific literature also describes other methods of sample preparation and analysis of such compounds. An important issue is differentiation of vitamin A from other fat-soluble vitamins often included as components in multivitamin products. The aim of the study was to analyse and summarise data on current methods used for determination of vitamin A and its derivatives in medicinal products. The authors analysed the range of vitamin A products authorised in the Russian Federation, and the test methods described in their product specification files. The study demonstrated that the test method most often used for determination of retinol esters was HPLC with isocratic elution mode using octadecylsilyl packing in the reverse-phase mode, and, less frequently, aminopropylsilyl packing in the normal phase mode. Determination of beta carotene in medicinal products is most often performed using spectrophotometry.

Determination of Folic Acid in Multivitamin Preparations by Reversed Phase HPLC

A great variety of components in multivitamin preparations containing folic acid, and a variety of test methods and conditions of folic acid determination proposed by manufacturers, require alignment of test procedures for products with similar composition.The aim of the study was to compare the results of experimental verification of folic acid determination procedures which use reversed phase high-performance liquid chromatography (RP HPLC) with isocratic elution mode. Materials and methods: The Agilent 1260 Infinity II LC system with a diode array detector (280 nm), isocratic elution mode, C8- and C18-bonded silica gel chromatographic columns, model mixtures containing folic acid, cyanocobalamin, ferrous sulfate, and potassium iodide, were used in the study.Results: The lowest relative standard deviation of the folic acid peak area (RSD=0.09%), and the lowest asymmetry factor (As=1.04) for folic acid were observed for the model mixture “ferrous sulfate+folic acid+cyanocobalamin” and the following test conditions. Column: 250×4.0 mm, silica gel for chromatography, octylsilyl (C8), endcapped; mobile phase: methanol‒phosphate buffer (12:88), pH 6.6; column temperature: 25ºС. The study demonstrated the feasibility of using these conditions for determination of pteroic acid impurity with simultaneous precipitation of interfering ferrous ions, using ethylenediaminetetraacetic acid solution, pH 9.5, as a solvent.Conclusions: RP HPLC can be recommended as an optimal aligned test procedure for determination of folic acid in combination products. It is recommended to use a solution containing folic and pteroic acids for system suitability testing.