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The development and use of new methods of quality control of medicines involve the use of a lot of reference materials in quality control testing. Specialists of the Russian Research Antiplague Institute “Microbe” have proposed an alternative methodological approach to determination of potency of anti-rabies immunoglobulin in cell culture, which requires the development of an in-house reference standard (RS) certified against the biological reference preparation (BRP) of the European Pharmacopoeia human rabies immunoglobulin. The aim of the study was to develop and evaluate the metrological characteristics of an in-house RS for anti-rabies immunoglobulin potency, to be used in the virus neutralisation test in a Vero cell culture. Materials and methods: The following materials were used in the study: equine rabies immunoglobulin, Vero continuous cell culture, fixed rabies virus (Moscow 3253Vero strain), human rabies immunoglobulin BRP of the European Pharmacopoeia. The potencies of the candidate in-house RS and rabies immunoglobulin samples were determined in the neutralisation test in cell culture. The results were recorded using a fluorescent microscope. Statistical processing was carried out in accordance with general chapter 1.1.0014.15 of the State Pharmacopoeia of the Russian Federation, 14th edition. Results: the certified value of the in-house RS potency was 180.8±18.8 IU/mL. The confidence limits were determined at the 0.95 probability level. The shelf life of the in-house RS is 1.5 years (when stored according to the sanitary regulation SanPiN 3.3686-21). The certified in-house RS was assigned with the number 41-01-20. A set of technical and operational documentation was developed and approved for the in-house RS. The developed in-house RS can be used for in vitro determination of anti-rabies immunoglobulin potency, expressed in international units, to confirm its compliance with the product specification file. Conclusions: the authors developed an in-house RS for anti-rabies immunoglobulin potency, to be used in the virus neutralisation test in cell culture, certified against the human rabies immunoglobulin BRP of the European Pharmacopoeia.

At the moment, there are no scientific publications devoted to the technological aspects of production of immunoglobulin solid dosage forms. The aim of the study was to review Russian and foreign literature on production of immunoglobulin solid dosage forms, and present the results of the authors’ own research. The authors analysed data of the National Register of Medicines of the Russian Federation as of mid-2021 on the authorised medicines with a generic name ‘globulin in a solid dosage form’, and summarised their characteristics. They reviewed data on the qualitative and quantitative composition of excipients used in lyophilisation, preparation of tablets and capsules. A number of examples were used to illustrate the effect of technological parameters of immunoglobulin solid form production on the quality of the finished products. It was demonstrated that the production of solid forms of immunoglobulin products prevents aggregation and fragmentation of proteins during storage, which affect the product’s specific activity, and also help to preserve the product’s target characteristics for a longer period of time as compared to liquid dosage forms of immunoglobulins. The results of the study may be used as a basis for development of a manufacturing technology for solid forms of immunoglobulin products.

Introduction. This publication describes the design and implementation sequence of technological procedures for labeling immunobiological medicinal products produced by the FGHI RusRAPI "Microbe" of the Rospotrebnadzor. In light of meeting the requirements of the Federal Act "On the Circulation of Pharmaceutical Products", the materials of this study are undoubtedly relevant.Text. The paper presents a step-by-step sequence of introducing technological procedures for labeling and interaction with the system for monitoring the movement of pharmaceutical products (MMPP) into the production process of medicines. At the preparatory stage, the following main issues were addressed: verification of the identity of information about medicinal products in the State Register of Medicines and in the automatic identification system "UNISCAN/GS1 RUS"; determination of the method and possibility of applying the identification means onto the secondary packaging; amendments to the pharma-copoeial monographs of the enterprise for each type of drug. Stage 2 [development of requirements for the system of labeling, serialization, verification and aggregation (LSVAS)] included the following activities: development of a functional model of the labeling process in the FGHI RusRAPI "Microbe" and determination of the responsible for the implementation of this scheme units; determination of the method of secondary packaging (manual or automatic), as well as the required degree of aggregation and the required automation of the process, based on the analysis of the functional model and the technological process of labeling; analysis of the experience of introducing drug labeling systems; analysis of the existing IT-structure of the FGHI RusRAPI "Microbe"; monitoring of the market of hardware and software manufacturers; development of technical requirements for the created system of marking, serialization, verification and aggregation. Stage 3 (implementation of the labeling, serialization, verification and aggregation system at the production sites) included the following activities: equipment supply and commissioning; equipment qualification (IQ/OQ); training of the personnel; amendments to regulatory documents. In the materials devoted to the implementation of the final stage, the issues of validation of technological procedures for drug labeling and interaction with the system of labeling, serialization, verification and aggregation are considered.Conclusion. The works performed made it possible to produce medicines in accordance with the requirements of the Federal Act "On the Circulation of Pharmaceutical Products" and the Decree of the Government of the Russian Federation dated December 14, 2018 № 1556 "On Approval of the Regulation on the System for Monitoring the Movement of Drugs for Medical Use". The material presented may be of interest to manufacturers who produce medicines in small amounts.

The aim of this review is to consider the literature data on methods and engineering solutions for decontamination of gases vented from equipment, containing microorganisms, during the cultivation process. Methodological approaches and engineering solutions for the removal or inactivation of microorganisms contained in a biological aerosol are addressed. A number of examples demonstrate the advantages and disadvantages of biological aerosol decontamination systems used. Presented is the information about modern, non-moisture-absorbing membrane filters, announced by manufacturers as elements that allow for sterilization of air supplied for oxygen saturation of the culture medium in bioreactors and neutralization of the gas removed from them. Discussed in detail are designed by specialists of the Institute “Microbe” system for purification of exhaust gases from the bioreactor, where hydrophobic filters based on sintered mass of nickel powders are the main element. Requirements for the construction of systems for the neutralization of microorganisms in gases drawn off from equipment in which biotechnological processes take place are formulated.

Objective: to study the possibility of applying electro-optical analysis for the assessment of cell viability of tularemia microbe vaccine strain at different stages of experimental live tularemia vaccine production.Materials and methods. The research object was a cell culture of Francisella tularensis 15 NIIEG. Investigations were carried out at all stages of experimental live tularemia vaccine (ELTV) manufacturing according to an advanced technology: cultivation, concentrating, diafiltration, mixing with drying media, stabilization, and storage (two-year period of observation). Electro-optical analysis by the parameter “polarizability anisotropy” of bacterial cell was conducted with the help of EloTrace (EloSystems, Germany). Total concentration of cells was evaluated using density metering at 590 nm and spectrometry – at 650 nm. Viability was assessed through inoculation of plates with FT-agar.Results and discussion. The experiment has demonstrated that the change in polarizability anisotropy of the cell at the frequencies of 900 kHz and 2100 kHz, reflecting the state of cytoplasm and cytoplasmic membrane, respectively, is the earliest response to changes in vital indicators of bacterial culture in the process of cultivation. Thereby, the decrease in viability of F. tularensis cells occurrs well before the decrease in cell concentration. We have shown the preservation of viability of F. tularensis 15 NIIEG cells at all stages of experimental live tularemia vaccine production. Electro-optical analysis allows for registering the changes in vital parameters of microorganism cells in real-time mode, while the assessment of viability applying bacteriological method takes up to 5 days. Different stages of tularemia vaccine manufacturing have impact on the vital indicators of F. tularensis cells, and electro-optical analysis is a prospect method of control of such parameter as “Specific activity (the number of live microbial cells)”.

Introduction. The inevitable of post-registration variations due to the improvement of production processes and quality control related to the integration of the modern technological solutions, replacement of equipment, suppliers of raw, consumables and packaging materials, improvement of form release or composition, administrative changes, as well as obtaining new data on clinical efficacy and safety of immunobiological medicinal products (IMP) during post-marketing studies.Text. The purpose of this work is to analyze the post-registration changes in the life cycle of IMP «Сholera bivalent chemical Vaccine» produced by Russian State anti-plague Research Institute «Microbe», reflecting the harmonization of the documents of the registration dossier with the innovations of the Russian legislation, the optimization of production and quality control. First of all, the changes made to the registration documentation for IMP concerned the updating of the dossier in accordance with the adopted Federal laws and Resolutions of the government of the Russian Federation. The following changes related to the optimization of methods for controlling the limit content of impurities of substances used at different stages of antigen production. Also, the changes were associated with the improvement of consumer properties of the drug, namely the introduction of modern polymer packaging and several drug’s form release, convenient for use in practical health care institutions. The latest change of Pharmacopoeia enterprise article (PEA) R N001465/01-111119 regulates the application of identification means in the form of a two-dimensional bar code (QR-code) on the packaging of medicines, which is due to compliance with the requirements of article 67 «Information on medicines. The system of monitoring the movement of medicines» Federal law N 61 «Оn medicines circulation».Conclusion. Maintaining the required level of quality of IMP when changing production technology or control requires a comprehensive analysis of the proposed changes in order to make them in the documents of the registration dossier. At the same time harmonization of documents of the registration dossier with novelties of the Russian legislation is a necessary condition for implementation of production activity within the legal field.

Introduction. Documentation is an integral part of the quality management system, a key element of production and quality control of medicines. A necessary condition for the Rules of good manufacturing practice and guaranteed production of quality products is compliance with the requirements set out in the documents of the registration dossier for the drug. During the life cycle of a drug, post-registration changes in the dossier may be required.Text. This work is an analytical review of changes in the documents of the registration dossier for the drug «Immunoglobulin antirabic from horse blood serum liquid», solution for injections, reflecting the improvement of biotechnology of drug production and methods of its control in the post – registration period. The first post-registration changes in the regulatory documentation were administrative in nature and did not require examination of samples of the drug. The next group of changes in the documents of the registration dossier was due to the expansion of production, reconstruction of technological sites and the introduction of innovative technologies in order to comply with the requirements of GMP, as well as improving the consumer properties of the drug. The last group of changes concerned the revision of methods of quality control of finished products associated with the introduction of modern analytical equipment, expanding the list of standards and bringing into compliance with the requirements of the state Pharmacopoeia XIII edition.Conclusion. The timely introduction of changes into documents of the registration dossier allows you to optimize the procedure for the conduct of internal and external control of rabies immunoglobulin, as well as to avoid violations related to the actualization of the technological documentation. The analysis of changes in the documents of the registration dossier for the drug «Immunoglobulin antirabic from horse blood serum liquid», solution for injections, reflecting the improvement of biotechnology of drug production and methods of its control in the post-registration period. Timely changes in the documents of the registration dossier allow to optimize the procedure of internal and external quality control of anti-rabies immunoglobulin, as well as to avoid violations associated with the updating of technological documentation.

The paper contains the data on the development of quality control sample (QCS) for determination of specific activity of heterologous anti-rabies immunoglobulin in neutralization test on white mice. Given are the results on QCS attestation in reference to international standard samples of human immunoglobulin against rabies. The quality control sample is put on the register of QCSs approved for application in experimental-production subdivisions and in the department of biological and technical control. It is deployed for final quality control of anti-rabies immunoglobulin preparation in commercial batches.

The possibility of applying sedimentation, centrifuge, and filtration techniques for concentration of F. tularensis 15 NIIEG suspensions obtained after submerged cultivation has been evaluated. It is established that realization of tangential ultrafiltration as part of technological process of live tularemia vaccine production is of distinct advantage. Characteristics of Francisella tularensis 15 NIIEG concentrate stored under different temperature/time-dependent conditions have also been studies. It is demonstrated that it is practical to preserve them at 4 °C within ≤6 days.

Abstract. In modern conditions for passenger complex of Russian Railways, important tasks include improvement of transportation quality, maintenance of stable positions in a competitive environment and increasing demand. To address these issues, a customer-oriented approach is applied based on the segmentation of transport market in relation to certain groups of passengers. Performance of children's transportation is of particular relevance and social significance. Railways are charged with a huge range of work, including sale of travel documents, preparation and equipping of passenger cars, provision of food during the trip, instructing workers, ensuring security during the embarkation/disembarkation of passengers, etc. Children can travel as individually with accompanying persons and as part of organized groups. Processes of planning, organizing, monitoring the transportation of this age category of passengers are associated with the analysis of a large amount of reference and regulatory and reporting documentation. On the basis of the ACS “Express-3”, a program-analytical complex “Children's transportation” was developed and implemented, which allows to receive data at the regional and network levels in the operational (train number, day) and statistical (period of dates, month) modes. This information technology provides analytical support for key transportation management functions — planning, control, analysis. Planning of transportation of organized children's groups is carried out on the basis of a study of the dynamics of data on the number of applications received and travel documents issued, determining the routes of trains, periods of the highest intensity of passenger traffic, obtaining information about the stations of embarkation and disembarkation. To perform the functions of monitoring the embarkation and disembarkation at the destination station of groups of children, the employees involved receive information on the train number, car number, date and time of arrival, number of children in the group using the Children's Transportation software. For the analysis of transportation of children's age categories, a functional has been developed that ensures the construction of aggregated reporting based on trains data that completed the trip. Users receive reporting information in table form, including “strict” (designed according to the approved layout) and “flexible” forms (construction is performed according to specified parameters). Software and analytical complex is designed for managers and specialists of the passenger unit of the JSC “Russian Railways”, has a modular principle of increasing functionality and provides a solution to current problems in the system of organizing children's transport service.

Current areal of anthrax among live stock and wild animals covers almost all the continents. The cause of human infection is conventionally considered to be the contact with diseased animals in the process of carrying for an animal, forced slaughter or further trimming of carcasses, as well as contact with infected raw materials of animal origin. Licensed vaccines has made an invaluable contribution to the improvement of epidemiological situation on anthrax, however, development of the vaccines complying with current scientific progress remains relevant. We have constructed a vaccine prototype containing recombinant protective antigen and S-layer EA1 protein and added state-of-the-art CpG 2006 adjuvant to the formulation. We have demonstrated the advantage of the lyophilized form of the preparation. Objective — obtainment of anthrax vaccine prototype in lyophilized state and assessment of the prototype compliance with the requirements to vaccine preparations. Materials and methods. Isolation of rPA and EA1 protein was carried out using producer-strain B. anthracis 55ΔTПА-1Spo– on an integrated end-to-end manufacturing line, including concentration, diafiltration and two-phase chromatography. CpG 2006 adjuvant was synthesized according to known sequences. Components were mixed and lyophilized in sublimation unit. Combination of 1% sucrose and 3% glycine was used as cryoprotector. Effectiveness and safety of the preparation were evaluated on the model of BALB/c mice and guinea pigs applying immunological, morphometric, and histological assays. Antibody titers in sera of immunized animals were evaluated using standard ELISA procedures. Protective properties were investigated through LD50 values for the test-strain used on immunized and control animals and immunity index. Results. We have performed complex investigation of the anthrax vaccine prototype, containing B. anthracis 55ΔTПА-1Spo– proteins as main and supplementary antigens, as well as CpG 2006 adjuvant, stabilizers and preservative agent. The prototype meets the requirements to immunobiological medicinal drugs by all physical-chemical properties. Our preparation does not have a toxic effect on the organism of laboratory animals in case of subcutaneous and intraperitoneal administration of single human dose. Pathomorphological study of guinea pigs’ organs immunized with double dose of the vaccine prototype has not revealed any evidence of damaging effect on the cells and tissues of macroorganism. The prototype protects BALB/c mice from the infection with B. anthracis 71/12 test-strain.

The paper contains the results of the development of mathematical models for O-antigen synthesis by atoxigenic cholera vibrio strains KM 262 biovar El Tor serovar Ogawa, KM 263 biovar El Tor serovar Inaba, and M 377 O139 serogroup based on the modeling of the synthesis of O-antigen, produced in the course of cultivation of the virulent Vibrio cholerae M 41 strain belonging to classical biovar, serovar Ogawa. The data obtained provide the possibility to successfully perform the task of up-scaling the designed pilot technology for cultivation of atoxigenic cholera vibrio strains to be utilized on commercial-scale bioreactors.

Steady requirements of consumers to the quality of to the development of automated systems, make it necessary to the information provided, on the basis of which the control actions constantly process or create higher quality products. The require-are carried out, as well as the acceleration of technical means related ment to improve the basic information solutions using modern technical resources offered by industry was the reason for the rework of the existing business process for managing the fleet of passenger cars implemented in the automated system for managing operation and repair of the passenger car fleet (ASUPV). The article gives a brief analysis of the 20-year work of the linear enterprises (LP) with the ASUPV - (ASUPV LP) subsystem, with the help of which the source documents are entered into the car park, trains are formed and the passenger car fleet maintenance is monitored. This subsystem is the main supplier of information for obtaining analytical data at all levels of passenger car fleet management. The article also outlines the main goal of the new information technology - obtaining, through single processing of primary data, new quality information, on the basis of which optimal management solutions should be developed. The purpose of the newly developed ASUPV LP-2 system is to automate the technological processes of centralized management of the passenger fleet of linear enterprises to improve performance and efficiency of the industry, which will allow optimizing the work of passenger line enterprises, monitoring compliance with technological processes and ensuring the availability of reliable information to interested users. The article describes the main tasks of the developed system: ensuring the need for the necessary and sufficient number of passenger cars for the fulfillment of the transportation plan at the linear enterprise; creating of guaranteed traffic safety of the formed passenger trains; improving the quality of repairs and maintenance. It is noted that the sources of increased complexity of managing the passenger car fleet are the constantly increasing complexity of business processes automated at the linear enterprise, which conflicts with the existing regulatory and technological base, as well as increasing requirements for the speed and accuracy of execution of all operations with cars. It is also indicated that automatic monitoring of the input sequence of source documents and its information interconnection should be created in the developed system and a system of automated control and prevention of conscious violations performed by users should be developed in order to improve the performance of their own work. The system should control the user's actions as much as possible and check the information entered by the user for compliance with regulatory requirements.

Objective of the study is to experimentally substantiate the possibility of production of anti-cholera immune-enterosorbent in the pharmaceutical form of a pill.Materials and methods: experimental antitoxic immune-enterosorbent against cholera, stabilized using cool dehumidification. Residual moisture of enterosorbent lyophilizate was determined by means of Sartorius MA 150 moisture meter. Screen assay of the powders and granulates was performed applying the sieving of bulk material samples through screen set with sieve openings of various sizes. Specification of tap density was carried out with the help of SVM-10 unit. Granulation of specific enterosorbent was done using GPCG 2 LabSystem. The pills were manufactured in tablet press, MiniTabT. The hardness of the pallets was carried out by means of TBH 125 TD tester. The test for friability of the pills was performed in GTA 120.Results and conclusions. Utilization of cellulose microcrystalline and polyvinyl pyrolidone as pharmaceutical aids for granulation of lactose monohydrate is experimentally substantiated. It is established that the obtained granulate with passable values of technological parameters can serve as the basis for pharmaceutical dosage form of specific enterosorbent. Identified has been optimum mass of anti-cholera enterosorbent tablet cores. Demonstrated has been the possibility of Acryl-eze enteric coating application as protective shell of the pills. Studied has been specific activity of the pelleted enterosorbent in vitro, verified is its resistance capacity under conditions modeling gastrointestinal tract. In consequence of the performed trials and tests, technology for the production of antitoxic enterosorbent against cholera – enteric-coated tablet – has been developed. Long-term trials: the storage of the constructed preparation at 4–8°C within 24 months period (the observation time) – have revealed retention of enterosorbent activity, which testifies to its stability and defined the shelf life of specific tableted anti-cholera immune-enterosorbent.

The intraoperative radiation therapy (IORT) in combined therapy of soft tissue sarcoma in a single dose 10–20 Gy is the method, which can optimize the role of radiation therapy in treatment of this nosology. This method allows exact localization of the irradiation zone in the frames of «tumor bed», thereby minimizing the damage of normal tissues and critical organs. The aim of the study was the influence of IORT on the rate and structure of postoperative complications and long-term results of treatment in the group under study (n=49) in comparison with the group of combined treatment without IORT (n=57) and the group of surgical treatment. No statistically reliable difference in the rate of postoperative complications in groups (p=0.57) was obtained and there was no influence on the structure of postoperative complications. At the same time the statistically reliable increase of general survival rates (p=0.025) and the survival without relapse in the main group (p

Objective of the study is experimental substantiation of possibility to produce new presentation form of cholera diagnostic sera – lyophilizate in bottles. Materials and methods. Cholera diagnostic sera. Liophylization was performed in Martin Christ Epsilon 2-6D. Residual moisture of dry sera was determined using humidity meter Sartorius MA 150. Solubility of experimental samples was assessed visually. pH was evaluated by potentiometry with the help of PK SevenExcellence-475 Mettler Toledo device, measuring pH/ORP/Ion content/conductivity/concentration. Specific activity and specificity was analyzed through expanded agglutination reaction, using relevant control strains of cholera vibrio. Results and conclusions. Experimentally justified is the possibility to lyophilize cholera diagnostic sera in flasks. Specified are the optimum parameters of lyophilization. It is determined that lyophilization does not result in deterioration of properties, as judging by the quality indicators they meet the requirements of regulatory documentation. Using accelerated aging test, it is demonstrated that the new presentation form of cholera diagnostic sera – lyophilizate in flasks – maintains their specific activity within five years term (the set out shelf life), which fully conform to normative standards.

Objective of the study was to develop and test new biotechnological approaches for live tularemia vaccine production.Materials and methods: Francisella tularensis 15 NIIEG strain was used as producer-strain; Francisella tularensis 503 strain – as test infecting one. Producer strain was cultivated on solid and liquid nutrient media. Tangential ultrafiltration was performed with the help of microfiltration module “Viva-flow”. Lyophilization was conducted using drying installation – Free Zone 2.5 L.Results and discussion: Application of the designed liquid nutrient medium on the basis of enzymatic fibrin hydrolysate and submerged cultivation of the producer-strain has allowed for a significant biomass yield increment. At the stage of tularemia microbe culture concentration via microfiltration through filtering membranes with pore size of 0.2 μm, in the mode of tangential liquid flow, increased has been the content of microbe cells; the nutrient media residues – removed. Comparative analysis of the obtained in accordance with experimental technique laboratory series of the vaccine and commercial preparation of live tularemia vaccine has demonstrated their conformity with the specific normative properties. It is established that application of modified liquid nutrient medium, submerged cultivation conditions, methods of biomass concentration and separation has no negative influence on the main properties of live tularemia vaccine and will provide for considerable produce-ability increase in the future.

The review provides information on the major outcomes of research and development work, performed within the frames of the Federal Target Program “National system of chemical and biological safety” (2009-2014), aimed at elaboration and introduction of cultural techniques into the manufacturing of anti-rabies immunoglobulin. Described are the key phases in methodology engineering, deployed for the large-scale cultivation of fixed rabies virus, concentration of cultural liquid, quantitation of rabies virus using PCR, and immunization of producers. Obtained pilot batches of the enhanced anti-rabies immunoglobulin, complying with normative requirements to commercial formulations, testify to the effectiveness of the developed biotechnological and methodological procedures, as well as of the designed engineering-manufacturing project documentation.

Objective of the study was to substantiate experimentally the possibility to enhance efficiency of manufacturing process through application of novel engineering solutions in the course of freeze-drying of vaccine immunogens. Materials and methods. Choleragen-anatoxin and O-antigens, Inaba and Ogawa, served as specific immunogenic components of the vaccine. Identified were temperature values for O-antigen eutectics (approx. -35 ºC). At reaching -55 ºC choleragen-anatoxin froze incompletely (fractionally). Full solidification of the preparation was achieved by means of the “annealing”. Revealed was non-effect of the tested freeze modes on the properties of antigen components of chemical cholera vaccine. Desired values of technological parameters for primary drying and desorption were specified by trial. Investigations of activity of chemical cholera vaccine immunogen lyophilizates testified to the compliance with the rated critical requirements. Results and conclusions. Results of the study provided for significant time expenditure reduction and obtainment of high-quality preparations at once.

Represented is domestic and foreign literature review dedicated to usage of ultrafiltration for concentrating and purification of antigens. Discussed are the issues of deployment of various ultrafiltration techniques. It is determined that filtering in the tangential mode by means of modules with flat-frame filtering elements is among the prospective ones. Demonstrated is the impact of such technological specifications as concentration rate, pressure, temperature, and membrane nominal cut-off on molecular mass on the quality of target products, the time elapsed, and preparation losses decrease (increase). Literature data analysis proves to be useful for the selection of the proper procedure for concentrating and purification of protective antigens of bacterial and viral origins. In addition, it allows for taking into account the parameters under discussion when developing specific manufacturing technologies for diagnostic and preventive medical immunobiological preparation production.

Experimentally substantiated is the possibility to apply tangential ultrafiltration for desalting antigen components of the tableted bivalent chemical cholera vaccine. Specified are the technological parameters of the process. It is demonstrated that the properties of choleragen-anatoxin (produced by Vibrio cholerae strain 569B Inaba) and O-antigens (produced from V. cholerae 569B Inaba and M-41 Ogawa strains) obtained using the designed methodology are as efficient as the ones manufactured using certified procedure and satisfy regulatory requirements. Experimentally substantiated technology for the desalting of antigen components of chemical cholera vaccine provides for the reduction of the time elapsed up to 5-6 hours from the original 3 to 4 days. It also allows for the manufacturing under controlled conditions. This hard-ware controlled method of desalting has been implemented into the vaccine production practice.

Objective of the study is to experimentally substantiate the possibility to improve manufacturing efficiency by means of mass reduction of a vaccine tablet from 300 to 100 mg. Materials and methods. Inaba O-antigen lyophilizate serves as the specific immunogenic component of the vaccine. Results and conclusions. It is identified that it is expedient to produce tablets of 6 mm in diameter. Justified is the quantitative content of additive substances (lactose monohydrate, micro-crystal cellulose, and polyvinylpyrolidone). Moreover, the studies have specified target values for technological parameters of such processes as fluid bed granulation of the formula with overfeed of the binder, tablet compression and enteric-coating (Acryl-eze) application to finished dosage form. Using Inaba O-antigen lyophilizate manufactured has been model experimental series of the vaccine. Investigated have been its characteristics. Verified vaccine quality indicators testify to the compliance of the product with the requirements of manufacturer’s pharmacopoeial monograph. The studies exercised showed the possibility in principle to enhance manufacturing efficacy through the decrement of additives amounts, and thus the mass of a vaccine tablet from 300 up to 100 mg.

Consideration is given to implementation of state-of-the-art filtration technologies for up-scaled manufacturing of cholera toxin B-subunit, produced by recombinant Vibrio cholerae non O1 KM93 strain. Selected are micro- and ultra-filtration membranes to be incorporated into manufacturing method. Investigated are the properties of cholera toxin B-subunit, obtained applying the pilot technology. The engineered method for up-scaled manufacturing of cholera toxin B-subunit makes the procedure easier-to-maintain due to tangential micro- and ultra-filtration, performed at the stage of purification and concentration. It excludes labor-consuming chromatographic purification, while retaining B-subunit properties. The studies undertaken make it possible to manufacture cholera toxin B-subunit with the same characteristics as in the case of the pilot technology, but under production conditions, and use it as a component for chemical cholera vaccine.

Presented is mathematical model of kinetics of the process of O-antigen and cholera toxin synthesis during periodical submerged cultivation of V. cholerae 569В Inaba with limitation as regards carbonic substrate. The proposed model is based upon analysis of experimental data on V. cholerae 569В Inaba biomass and antigens accumulation, rate of growth and antigens release, and glucose utilization. Using Mathcad 15.0 software calculated are coefficients of differential equations entering into the mathematical model. Comparison of predicted and experimental data demonstrates that relative error of determination of concentrations of the synthesized substances, glucose and cholera vibrio is between 5 and 20 %. The proposed model permits to determine maximum output of final products and specify the parameters of cultivation process performance at different initial conditions.

Displayed is the review of domestic and foreign literature sources devoted to matters of cholera vibrio cultivation. Discussed is the information concerning the following methods utilized in the technological process of vibrio growth stimulation: batch cultivation, fed-batch, fermentation and dialysis, periodic and continuous cultivation. Analyzed is the impact of such parameters as dissolved oxygen concentration, count of carbon nutrition source, medium pH, temperature rate , concentration and physiological condition of inoculate, duration of technological process, affecting the growth of this microorganism and synthesis of its antigens. Consequently, literature data analysis has contributed to the selection of proper method for cholera vibrio cultivation and consideration of the factors mentioned above for the development of manufacture technology applied to the production of medical immunoglobulin preparations for diagnostics and prophylaxis of cholera.

We evaluated immunochemical, physical and biochemical properties of Vibrio cholerae 569B INABA protective antigenes, derived on industrial and own-developed bioreactors as well as by technology of its concentration by tangential ultrafiltration. We detected, protease, twinase and. lysophospholipase in all samples. Also, dotimmunoanalysis showed equal concentration, of cholerogen-anatoxine and. O-antigen in all samples too. Using chromatography and. electrophoresis, we found their properties as similar. Thus, we suppose to be possible using developed bioreactor as well as technology of Vibrio cholerae 569B INABA protective antigens concentration by tangential concentration during a process of synthetic oral cholera vaccine production.

The data on exploration of biological properties of experimental solid and liquid media on the basis of dry enzymatic hydrolysate of fibrinobtained from production waste of anti-rabies immunoglobulin is presened here. The culture media engineered meets the requirements of normative documents and. is highly competitive with the test medium in their qualitative characteristics. Suggested media can be used for V. cholerae cultivation, including submerged cultivation, in production of cholera preventive and. diagnostic preparations.

week after immunization (specific activity is identified using neutralization reaction on the model of white mice and dot-blot immunoassay). This level of activity is sufficient for the fractioning of immune serum and extraction of anti-rabies immunoglobulin. Physicochemical and biological properties of the anti-rabies immunoglobulin, obtained with the help of cultural antigen technique, meet the requirements stated in the normative documentation on anti-rabies immunoglobulins extracted from equine blood serum. Specific activity level of experimental batches of anti-rabies immunoglobulin, obtained with the help of cultural technologies, corresponds to 242 and 214 IU/ml.

Studied is the kinetics of major antigen accumulation at growing of Vibrio cholerae M-41 Ogawa and 569 B Inaba strains in industrial and engineered reactors. Demonstrated is the possibility to obtain conditional native protective antigens in the engineered bioreactor. Shown is the identity of physiological and morphological properties of industrial Vibrio cholerae strains during their submerged cultivation in industrial and engineered bioreactors. Cholera bivalent chemical vaccine obtained using engineered bioreactor possesses quality indices meeting the requirements of normative documents and equal to those of preparation received by traditional approach.

Justified is the possibility of application of fixed rabies virus Moscow 3253, reproduced on the cell culture Vero, as an antigen for heterologous anti-rabies immunoglobulin production. Application of the adjuvant - aluminium hydrate - is determined to be effective. Herein, by the day 73 post immunization, specific antibodies titer is ≥ 1:500 (wherein specific activity has been identified by means of neutralization test, carried out on white mice, and dot-blot immunoassay). The level of specific activity in experimental samples of anti-rabies immunoglobulin, isolated from rabbit immune serum, corresponds to 332 and 347 ME/ml. Physicochemical and biological properties of anti-rabies immunoglobulin, produced with the help of cultural antigen, fully comply with regulatory requirements specified for commercial preparation of heterologous anti-rabies immunoglobulin.

Investigated are immunochemical, chemical and biochemical properties of the O-antigen preparations obtained from Vibrio cholerae M41 classical biovar, serotype Ogawa strain using standard manufacturing and improved technologies of their concentrating. The preparations have been concentrated by ultrafiltration in the mode of tangential liquid flow with membranes of various cut-off levels for a particular molar weight. ELISA has revealed equal O-antigen load in all of these preparations. Studies of specific fractures by means of chromatographic and electrophoretic methods have demonstrated their properties to be alike. Chemical composition analysis has also identified coincidence in the load of components under specification. Thus, it has been proved that application of the improved V. cholerae protective antigen concentrating technology for manufacturing cholera chemical bivalent palletized vaccine is justified.

Developed is the system of differential equations that characterize kinetics of biomass growth, glucose utilization and O-antigen accumulation in the process of submerged cultivation of V. cholerae strain M-41 Ogawa. The parameters of the mathematic model are identified. Using the developed software in Mathcad 15.0 determined are kinetic constants and coefficients. The mathematical model is demonstrated to describe adequately O-antigen biosynthesis process. The received data can be used in large-scale technology of V. cholerae strain M-41 submerged cultivation.

Determined are the key bio-kinetic indexes of submerged cultivation of Vibrio cholerae non-toxigenic strains, producers of O-antigens. Evaluated is the technology of O-antigen concentration using tangential ultrafiltration technique. The results suggest the principal possibility of using these strains for biologically safe production of chemical cholera vaccines.

Worked out is the experimental technology for protective antigens of Vibrio cholerae 569 B Inaba (cholera-anatoxin and O-antigen) concentrating by means of tangential ultrafiltration. Optimization of concentrating technological process is carried out. This technique makes it possible to obtain cholera vaccine components meeting all regulatory requirements.

Demonstrated is possibility to apply cross-flow ultrafiltration method for O antigen of Vibrio cholerae M-41 Ogawa concentrating from germ-free centrifugate. Technological process of concentrating was optimized. Worked out were the regimes of conservation and cleaning of the ultrafiltration device. The prospects of cross-flow ultrafiltration method introduction in technology of cholera chemical bivalent vaccine production were determined.

Graphene applications in electronics require experimental study of the formation of high-quality Ohmic contacts and deeper understanding of electron transport mechanisms at metal/grapheme contacts. We have studied carrier transport in twisted CVD graphene decorated with electrodeposited Co particles forming Ohmic contacts with graphene layers. We have compared layer resistivity as a function of temperature and magnetic field R□(T, B) for as-synthesized and decorated twisted graphene on silicon oxide substrates. Experiments have proven the existence of negative (induction < 1 Tl) and positive (induction > 1 Tl) contributions to magnetoresistance in both specimen types. The R□(T, B) functions have been analyzed based on the theory of 2D quantum interference corrections to Drude conductivity taking into account competition of hopping conductivity mechanism. We show that for the experimental temperature range (2–300 K) and magnetic field range (up to 8 Tl), carrier transport description in test graphene requires taking into account at least three interference contributions to conductivity, i.e., from weak localization, intervalley scattering and pseudospin chirality, as well as graphene buckling induced by thermal fluctuations.

Objective. To analyze mathematical model of the efficiency of the compensatory mechanism of the deformed spine. Material and Methods. The developed basic kinematic model of the spine was used. The restoration of the position of the projection of the general center of mass (GCM) was mathematically modeled, and mechanogenesis of the spinal deformity and possibility of its compen- sation were evaluated. To assess the reliability of the mathematical model, spinal skiagrams taken from patients with clinically confirmed pathology and sagittal imbalance were used. Results. On the basis of quantitative characteristics of the primary spine deformity of a certain clinical case and using the developed algo- rithm, it is possible to create a model of both a primary deformity and a compensatory response from intact segments of the spine taking into account the influencing factors. This makes it possible to use the proposed kinematic model in scientific research on predicting the course of various types of spinal deformities. Conclusion. The proposed algorithms simulating the development of spinal deformities based on the restoration of the position of the GCM projection reflect their mechanogenesis and can be used to model various pathological conditions of the spine. A complete correc- tion of the deformity does not mean a complete cure, since the required spinal fusion creates a new, prognostically less significant, but pathological situation.

The results of the first statistical studies of the mechanical properties of the new construction material of MONICA are presented. The statistical parameters of the strength and yield strength, the relative elongation, Young’s modulus and hardness are established. The interrelations of the strength — plasticity and strength — hardness characteristics for this material are analyzed.