In Russia in the second half of the XIX century research schools, developing anthrax vaccines for agriculture were formed. Their level was highly competitive with the Western analogues. At the end of the 1930 Soviet military scientists were the first in the world to create the anthrax vaccine for medical use on the basis of the spores of unencapsulated live strains of B. anthracis. In the 1940-1960-ies Russian scientists determined the principles of the development of anthrax vaccines, which allowed to avoid failures of their Western colleagues, when developing the vaccines capable of protecting the population from biological weapons with anthrax spores as the harmful agent. Russian military scientists in the 1990s managed to keep the vaccine strains of anthrax bacteria and restore the technological capability for their manufacture, which helps to protect the population of the Russian Federation from natural anthrax outbreaks and from biological terror. At a time when there is a need in creating immunity in humans against infection caused by inhalation of anthrax spores, the most reasonable decision for the upcoming decades is to use the domestic combined vaccine that combines unencapsulated live strains of Bacillus anthracis and anthrax toxin protective antigen.

The problems of quality and safety products derived from human blood plasma and hyperimmune animal sera as well as recombinant blood products resolved strict government regulation of their production processes. The risk of implications is minimized by plasma fractionation and purification of a specific drugs from various impurities (immunoglobulin aggregates, protease, plasmin, plasminogen, prekallikrein activator, IgA and IgM etc.). Viral safety is achieved by multi-step manufacturing process that includes at least two independent methods (treatment with solvent/detergent + incubation at low pH or pasteurization, combined with polyethylene glycol processing). It was justified that for today the technological process of the development of plasma preparations and hyperimmune animal sera has reached its limit. Their further development is the most likely to refer to specific improvements. The improvements will relate to increasing the efficiency of manufacturing technologies and methods of clinical use (preparations for subcutaneous administration, combinations of different immunoglobulin preparations, etc.), viral safety, ways to eliminate component, that were previously not considered to be able to influence the outcome of clinical use (soluble molecules CD4, CD8, HLA, thrombin, trace amounts of blood clotting factors VIII, IX, X, XI, XII etc.). At the same time new genetic engineered preparations with well-characterized molecular composition and a high selectivity for target impact are expected to appear on the market because of these unsolved issues. These are recombinant blood factors with altered properties; cocktails of recombinant antibodies and Fab-fragments of IgG, highly affine for toxin epitopes, etc. Therefore, in the upcoming years it is necessary to create in Russia a new system for assessing the quality, efficacy and safety of blood products, taking into account the future course of their development.

Developing specific, effective and safe biomedical cell culture products (BCCP) assumes the following standard operating procedures: a) developing cell line with specific cell composition; b) obtaining a sufficient amount of cells of a specific cell line for therapeutic use as a part of BCCP; c) quality control and standardization of the developed cell line. Experts believe mesenchymal stromal cells (MSC) to be the first choice for the purpose of stem cell therapy. The development of a cell line with a specific cellular composition includes five sequential steps: selection of donors, sampling of biological material, cell isolation from donor material, preparation of standardized homogeneous population of cells, characterization of cell line composition of the cell line and its certification. The process of obtaining a sufficient amount of cells of a specific cell line for therapeutic use as a part of BCCP includes the selection of culture medium for cultivation of MSC, in special bioreactors for cultivation and culture control parameters. Quality control and standardization of the developed cell line assumes the elaboration of general requirements for quality parameters, characterizing all cell lines; as well as specific requirements for the assessment of therapeutic preparations in accordance with their proposed indications (for example, for the treatment of diabetes, bone grafting, restoration of blood supply to ischemic myocardium). The article describes typical procedures and identifies possible checkpoints for common technological methods used in BCCP manufacture and their quality assessment. It also outlines the requirements for the content of documents submitted by BCCP developer to an official authority in marketing authorization dossier as well as the expert evaluation procedure.

The article presents the practical assessment of the possibility of harmonization and standardization of methods for the determination of phenol in the immunebiological medicines. The evaluation of the statistical significance of differences in the results of determinations of phenol existing methods described in the standard documentation for foreign and domestic preparations: used ANOVA with Fisher’s exact test (F-test). The conclusion of the interchangeability of the studied methods for the determination of phenol in the immune-biological medicines and the opportunity of the development and certification of standard reference and sample validation measurements.

Quality evaluation of biologicals entails some specific considerations and problems associated with inherent variability of biological systems. This has implications not only for biological and immunological test methods, but for physical and physico-chemical methods as well. Usage of reference standards (RSs) has an important role to play in the improvement of evaluation of biologicals’ quality. Absence of some industry RSs, which have the status of national RSs, makes it impossible to standardize corresponding products and to assess comparability of test results obtained by different manufacturers for similar (similarly named) products. The first step in the creation of the national system of RSs for medicines is the analysis of the demand for RSs used in quality evaluation of medicines, including biologicals. The analysis of the range of RSs demonstrated that existing industry RSs are not sufficient for performing quality evaluation of available biologicals. At present new industry RSs are being developed.

Pharmacopoeial analytical methods involving reference standards (RS) are used for manufacture and quality control of medicinal products, including biologicals, these RS should now to be called pharmacopoeal. The introduction of the mentioned term reflects special drug characteristics, which are regulated not by the State Union Standards but by the Russian State Pharmacopoeia in terms of quality control. Drug and RS special characteristics require the establishment of legal and methodological framework. The recommendations stated in ISO REMCO are general do not fully cover the special aspects of the certification of reference standards for each specific area. The documents of the Federal Agency for Technical Regulating and Metrology (Rosstandart) on reference standards can not be used for biological medicinal products due to their specificity as the test methods do not allow to separate systematic and random components of uncertainty of test results, as required by Rosstandart. The regulatory framework for biological RS should be developed on the basis of WHO and ICH Guidelines. The classification of drug reference standards and the list of priority documents required for the elaboration of normative and procedural framework regulating their development, certification, approval and use is considered in the article. The development of the documents for the mentioned system is exemplified by a new pattern for an RS certificate.

The analysis of patent and scientific literature on the production of biomedical cell-based products (BMCP) showed that the main patentable developments in this sphere are focused on organ and tissue recovery, preventing transplant rejection and characterization of cell line viability. The researchers have revealed recent tendency for replacing the clinical use of BMCP based on unmodified cells and human cell lines by their genetically modified derivatives. Several dozens of Western companies are the principal developers, holding key patents in this field. At the same time, the analysis of patent activity showed that the technology of BmCp reached its peak of the development in 2000-2010, but many issues related to their safety clinical practice has not been solved yet. The examples of the mentioned issues are low efficiency of implanted cell differentiation maintanance; the possibility of BMCP contamination with infectious agents; nonspecific immunosuppressive effect on recipient organism; poor control of gene expression in transplant cell lines differentiated in a target organ and some

Reference standards, including pharmacopoeial reference standards, are widely used for quality assessment of drug substances. Leading global pharmacopoeias contain monographs regulating the requirements for the classification, attestation, and use of reference standards. The drug standardization system in the Russian Federation, which includes drug substances, requires revision for the creation and attestation of national reference standards, including pharmacopoeial ones.

Pharmacopoeial analytical methods involving reference standards (RS) are used for manufacture and quality control of medicinal products, including biologicals, these RS should now to be called pharmacopoeal. The introduction of the mentioned term reflects special drug characteristics, which are regulated not by the State Union Standards but by the Russian State Pharmacopoeia in terms of quality control. Drug and RS special characteristics require the establishment of legal and methodological framework. The recommendations stated in ISO REMCO are general do not fully cover the special aspects of the certification of reference standards for each specific area. The documents of the Federal Agency for Technical Regulating and Metrology (Rosstandart) on reference standards can not be used for biological medicinal products due to their specificity as the test methods do not allow to separate systematic and random components of uncertainty of test results, as required by Rosstandart. The regulatory framework for biological RS should be developed on the basis of WHO and ICH Guidelines. The classification of drug reference standards and the list of priority documents required for the elaboration of normative and procedural framework regulating their development, certification, approval and use is considered in the article. The development of the documents for the mentioned system is exemplified by a new pattern for an RS certificate.

Standard samples constitute one of the key elements in the medicines standardization system. In pharmacopeia analysis in the Russian Federation and many foreign countries, the use of standard samples is regulated by the corresponding normative documents and pharmacopeia monographs. There are different classifications for standard samples and, depending on purpose, certification programs. Standard samples used in compliance with the requirements of pharmacopeia articles or monographs in international, regional and national pharmacopeias are generally termed pharmacopeia standard samples.

Одним из ключевых элементов системы стандартизации лекарственных средств являются стандартные образцы. В фармакопейном анализе Российской Федерации, а также стран ближнего и дальнего зарубежья применение стандартных образцов регламентируется соответствующими нормативными документами и монографиями фармакопей. Существуют различные классификации стандартных образцов и, в зависимости от назначения, программы их аттестации. Стандартные образцы, используемые в соответствии с требованиями фармакопейной статьи или монографии международной, региональной или национальной фармакопеи, как правило, называются фармакопейными стандартными образцами.

The problems of quality and safety products derived from human blood plasma and hyperimmune animal sera as well as recombinant blood products resolved strict government regulation of their production processes. The risk of implications is minimized by plasma fractionation and purification of a specific drugs from various impurities (immunoglobulin aggregates, protease, plasmin, plasminogen, prekallikrein activator, IgA and IgM etc.). Viral safety is achieved by multi-step manufacturing process that includes at least two independent methods (treatment with solvent/detergent + incubation at low pH or pasteurization, combined with polyethylene glycol processing). It was justified that for today the technological process of the development of plasma preparations and hyperimmune animal sera has reached its limit. Their further development is the most likely to refer to specific improvements. The improvements will relate to increasing the efficiency of manufacturing technologies and methods of clinical use (preparations for subcutaneous administration, combinations of different immunoglobulin preparations, etc.), viral safety, ways to eliminate component, that were previously not considered to be able to influence the outcome of clinical use (soluble molecules CD4, CD8, HLA, thrombin, trace amounts of blood clotting factors VIII, IX, X, XI, XII etc.). At the same time new genetic engineered preparations with well-characterized molecular composition and a high selectivity for target impact are expected to appear on the market because of these unsolved issues. These are recombinant blood factors with altered properties; cocktails of recombinant antibodies and Fab-fragments of IgG, highly affine for toxin epitopes, etc. Therefore, in the upcoming years it is necessary to create in Russia a new system for assessing the quality, efficacy and safety of blood products, taking into account the future course of their development.

Стандартные образцы, в том числе фармакопейные стандартные образцы, широко используются в оценке качества фармацевтических субстанций. В ведущих фармакопеях мира содержатся монографии, регламентирующие требования, предъявляемые к классификации, аттестации и применению стандартных образцов. Система стандартизации лекарственных средств в Российской Федерации, к числу которых относятся и фармацевтические субстанции, нуждается в возобновлении работ по созданию и аттестации отечественных стандартных образцов, в том числе и фармакопейных.

Intravenous immunoglobulin (IVIG) preparations are polyclonal IgG antibodies, obtained from donor blood plasma. Modern IVIG have high IgG purity with normal subclass distribution and the monomer and dimer content of more than 95 % of the total volume of a preparation. The activity of Fc-fragment of IgG molecule reaches almost 100 %. The article describes the evolution of the approaches to obtaining IVIG, safety measures and quality control in the production of IVIG and the characteristics of various IVIG generations and quality parameters. Quality and safety issues of IVIG are resolved under strict state regulation of the processes of collection and fractionation of donor plasma and monitoring of manufacture. Resolving the issues specific for IVIG is carried out by a thorough purifying of an IVIG preparation form immunoglobulin aggregates, proteases, plasmin, plasminogen, prekallikrein activator, impurities of IgA and IgM. Viral safety is achieved by a multi-step manufacturing process that includes at least two independent methods (solvent-detergent treatment + incubation at low pH or pasteurization, combined with the polyethylene glycol processing). It is assumed that for today the development limit for the whole field of obtaining IVIG from donor plasma has been achieved. Certain improvements will be related to upgrading the efficiency of manufacturing technologies and methods of IVIG clinical applications (preparation for subcutaneous administration, combination of different immunoglobulin preparations, etc.), their viral safety, methods of eliminating the impurities from the components that have previously not been considered to be able to influence the outcome of clinical use (soluble molecules CD4, CD8, HLA, thrombin, trace amounts of blood clotting factors VIII, IX, X, XI, XII and others). However, up till now the technologies ensuring viral safety have not been developed a 100 % yet. Any combination of these factors can provide only «maximum level of viral safety» in the obtaining of IVIG. It is also not possible with the existing approach to obtaining IVIG (as a pool of IgG with a high purity derived from thousands of donors plasma) to achieve reproducible results and their clinical application. The unresolved problems limits clinical use of IVIG and their further improvement. At the same time another type of immunoglobulin preparations are assumed to appear on the market: genetically engineered preparations that are well-characterized in terms of molecular composition, having a high selectivity for the target exposure.

The analysis of patent and scientific literature on the production of biomedical cell-based products (BMCP) showed that the main patentable developments in this sphere are focused on organ and tissue recovery, preventing transplant rejection and characterization of cell line viability. The researchers have revealed recent tendency for replacing the clinical use of BMCP based on unmodified cells and human cell lines by their genetically modified derivatives. Several dozens of Western companies are the principal developers, holding key patents in this field. At the same time, the analysis of patent activity showed that the technology of BmCp reached its peak of the development in 2000-2010, but many issues related to their safety clinical practice has not been solved yet. The examples of the mentioned issues are low efficiency of implanted cell differentiation maintanance; the possibility of BMCP contamination with infectious agents; nonspecific immunosuppressive effect on recipient organism; poor control of gene expression in transplant cell lines differentiated in a target organ and some