HAZARDOUS PROPERTIES OF BROMINATED, PHOSPHORUS, CHLORINATED, NITROGEN AND MINERAL FLAME RETARDANTS IN PLASTICS WHICH MAY HINDER THEIR RECYCLING

Flame retardants are numerous and some of them are (re)classified with time as hazardous for the man and the environment. A list of 69 flame retardants used in EU was set from three sources and their chemical properties were searched in their registration dossier at ECHA. Substance self-classifications (hazard statement assignment by the registrant) frequently indicate no hazard or data not available, while for the same substances a re-evaluation by ECHA is underway as persistent, bioaccumulative, toxic or endocrine disruptor. When the substance has hazard statement(s), the concentration that triggers the classification of a plastic as hazardous when it is a waste can be compared to the functional concentration, when available. Registration dossiers should be completed for the many “non-available” information. Of these 69 substances, 12 (= 17%) are used at concentrations greater than those making plastic waste hazardous and 13 (= 19%) are under re-evaluation by ECHA. These 12 or 13 substances should not become “legacy” substances which hinder the recycling of plastics. The sorting (mainly by density) and management options of these flame-retarded plastics are discussed. The technical concentration limit of 2000 mg total Br/kg for sorting should not be modified as it includes all organobromine substances currently reassessed by ECHA. A two-step sorting process is necessary to avoid the loss of non-hazardous dense plastics.

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.

THE SUBSTITUTION OF REGULATED BROMINATED FLAME RETARDANTS IN PLASTIC PRODUCTS AND WASTE AND THE DECLARED PROPERTIES OF THE SUBSTITUTES IN REACH

Plastics containing brominated flame retardants (BFR) currently contain both “legacy” regulated and non-regulated BFR (R-BFRs and NR-BFRs), as evidenced by the increasingly lower correspondence over time between total bromine and R-BFRs content. The portion of substitutive NR-BFR present in the plastics and their toxicity and ecotoxicity properties are documented. Data relating to plastics and foam present in electrical and electronic equipment (EEE), waste EEE, vehicles, textiles and upholstery, toys, leisure and sports equipment show how 88% of plastic waste contains bromine from NR-BFRs. BFR substances mentioned in the catalogs of the three main producers (Albemarle, ICL, Lanxess) and BFR on the official used list of 418 plastic additives in the EU were gathered and the toxic and ecotoxic properties of these compounds as listed in their ECHA registration dossier were compiled. Fifty-five preparations using 34 NR-BFRs substances, including polymers and blends, were found. Seventeen of these substances featured an incomplete dossier, 12 were equipped with a complete dossier, whilst 11 substances (including 2 ill-defined blends) should be reassessed. Eight substances have been notified for assessment by the ECHA as persistent, bioaccumulative and toxic, or as endocrine disruptors, including decabromodiphenylethane; 3 substances display functional concentrations (the concentration of additives that retards flame) exceeding the concentration limits classifying a waste as hazardous but are “reactive” (they bind to the polymer). The technical limit of 2 000 mg total Br/kg indicated for further recycling (EN 50625-3-1) relates to all brominated substances and is relevant in the sorting of all poorly classified new substances.

RULES FOR DETERMINING THE ORDER OF DISPENSING DRUGS IN THE EURASIAN ECONOMIC UNION: APPLICATION, FEATURES

The article is devoted to the rules of determining the order for dispensing drugs in the Eurasian Economic Union (hereinafter - the Union). It is shown that when registering drugs and making changes to the registration dossier in the Member States of the Union prescription drugs with conventional, special (containing narcotic or psychotropic substances in the composition), limited (used exclusively at a hospital or causing very serious adverse reactions) prescription may be sorted out. Active ingredients in prescription drugs are also classified depending on the possibility of re-sale using the same recipe. Over-the-counter drugs are those meeting relevant criteria based on their safety profile. In addition, over-the-counter drugs may be those containing prescription active ingredients but with the lower dosage, the number of doses in the package and another route of administration.

STAGES OF EXPERTISE OF EXTERNAL APPEARANCE OF VETERINARY PRODUCTS

The long moratorium on state control (supervision) over the activities of business entities has led to an increase in the volume of unregistered, low-quality, counterfeit and counterfeit veterinary products on the Ukrainian market. Violations by manufacturers regarding the entry into circulation of dangerous products are also due to the long absence of licensing of production and sale of products for veterinary medicine and animal husbandry. In these circumstances, there are numerous complaints from consumers about the low quality and safety of veterinary drugs, feeds, feed additives and premixes. The article covers the issues of examination of product appearance, labeling, primary (group) and secondary (transport) packaging, which is carried out in order to establish the conformity of manufactured products to the requirements declared in the regulatory documentation, which will identify dangerous products on the domestic market. In carrying out the examination of veterinary goods presented by consumers and other enterprises or institutions, the general procedure for its conduct shall be established. They check the completeness of the sent materials and check their availability with the corresponding list in the cover letter, open the sealed samples by commission and find out whether the veterinary drug has been registered in Ukraine. Then the data presented in the materials are compared with the registration materials and normative documentation, and a protocol of product inspection for compliance with the requirements declared in the dossier, registration certificates, technical conditions, quality certificates, etc. is drawn up. Examination of the appearance of the label is carried out visually, comparing with the original or with the materials of the relevant registration dossier. Check the correct labeling and packaging of products, and it is important to pay attention to the statement of the summary product of characteristics. As a result of the procedures for assessing the correctness and reliability of the appearance of veterinary products in accordance with the original sample, registration dossier and regulatory documentation, a conclusion is issued, which provides a detailed description of the research and the conclusions drawn from their results.

Expert Evaluation of Pharmacovigilance System Documents Included in the Registration Dossier

The Russian Federation and the member states of the Eurasian Economic Union (EAEU) are working on the creation of a common pharmaceutical market. EAEU marketing authorisation may be granted to those pharmaceutical companies whose activities comply with the Good Pharmacovigilance Practice (GVP). The aim of the study was to analyse pharmacovigilance system documents submitted as part of registration dossiers of medicines and to identify problems that may arise during preparation of the pharmacovigilance system master file (PSMF). The authors analysed the PSMF, which makes part of the registration dossier, for compliance with the EAEU GVP requirements for submission, content, and completeness of all sections of the document. They identified the most common types of errors in PSMF preparation and analysed conditions when a PSMF is required or, alternatively, when a brief summary of the pharmacovigilance system of the marketing authorisation holder will suffice. The paper summarises specific aspects of incorporating pharmacovigilance system documents in regulatory submissions, as well as aspects of presenting pharmacovigilance system data when bringing the registration dossier in line with the EAEU requirements. This information may be useful for marketing authorisation holders who are the main stakeholders in the medicine authorisation process and who are directly involved in the pharmacovigilance system management during the authorisation and post-authorisation stages of the drug life-cycle.

The Modern Concepts of Pharmaceutical Development in the Context of the Transition to a Uniform Regulation of Medicinal Products Circulation

Introduction. At the stage of transition from national to a uniform of circulation of pharmaceutical products regulation at the Eurasian Economic Union (EAEU) framework, harmonization of requirements for the development of medicines determines the need of use modern approaches, including the use of new methods and tools, thus to assure EAEU and other integration associations markets entry for effective and safe medicinal products. The new medicinal products development model, described in the ICH guidelines (The International Conference of Harmonization), involves a science-based approach to developing, using appropriate tools, such as defining a target product profile, establishing of critical quality indicators, risk assessment, establishment of design space, development of control strategy, drug lifecycle management and continuous improvement of existing processes. These approaches and techniques are not a part of the traditional paradigm of pharmaceutical development; although they are poorly understood and expensive, they are ensure the market entry of effective products with the desired quality parameters.Aim. Main purposes of this work are to compare two concepts of pharmaceutical developmentof medicinal products: traditional and improved, and to consider the necessity of new model usingin generic products development.Materials and methods. Research materials of this study were available literature sources, regulatory documents and guidelines regarding pharmaceutical products development, registration dossier documents, reports of regulatory authorities, pharmaceutical development reports. The achieving of study purposes was carried out on the basis of scientific research methods in the framework of comparative and logical analysis, and through the analysis and interpretation of the obtained data regarding pharmaceutical development of medicinal products.Results and discussion. On the basis of the data provided, author assess that modern concept it is a new, improved tool for development of medicinal products with specified quality parameters.Conclusion. The modern paradigm requires new expensive methods, stuff special knowledge and skills, investment and time, but it is effectively oriented on development of effective and safe medicinal products.

Key parameters of autologous biomedical product for cartilage tissue repair

Repair of cartilage defects associated with injury or pathology is a clinically relevant problem. Chondral tissue, especially articular cartilages, has a poor regenerative potential. Inflammation triggers the growth of connective tissue, which cannot exert the normal function of the hyaline cartilage. This contributes to the progression of the pathology and eventually raises the need for surgery. At present, there are no pharmaceutical drugs capable of restoring the damaged cartilage. However, advances in cell-based technology hold promise for regenerative medicine. Reports describing fabrication of autologous cartilage transplants pose a special interest. A registration dossier of a biomedical cell product must contain the product’s specifications, presenting the basic characteristics of the product that can be used to assess its quality. This review looks at a few basic parameters that can be used to verify the authenticity of the cell product derived from autologous chondrocytes and describe its specifications.

Polysaccharide Vaccines. Current Approaches to Quality Assessment Issues

Relevance. Polysaccharide vaccine quality assessment must, on the one hand, comply with modern domestic and international regulatory documents, and on the other hand, reflect the characteristics of newly developed drugs. The list of drugs registered on the Russian market is constantly expanding due to the development of new effective vaccines and the introduction of new production sites. Thus, the expert requirements for assessing the quality of these drugs and the information content of the documents submitted as part of the registration dossier need to be updated.Aims. The aim is to update the expert assessment of quality in preclinical and clinical studies of polysaccharide vaccines, as well as to revise the evaluation of quality parameters depending on the composition and structure of the finished product.Conclusions. We highlight the key problematic aspects of assessing the protective properties of purified polysaccharides: in particular, the problems related to the natural immunity of animals to diseases caused by bacterial species that are relevant to humans and, as a result, the lack of an adequate experimental model. Modern trends in the characterization and subsequent confirmation of the structure authenticity of purified and conjugated polysaccharides are taken into account. An analysis of the latest international and domestic pharmacopoeial requirements for the quality of polysaccharide vaccines is carried out. The disadvantages of selected methodological approaches to the evaluation of quality parameters such as «Identification» and «Molecular mass distribution» are noted. It is shown that it is necessary to generate recommendations for the examination of polysaccharide vaccines which would unify the recommendations for completing registration dossiers and forming specification files by taking into account each individual peculiarity of this type of drugs.

Robustness Optimization of an Existing Tablet Coating Process Applying Retrospective Knowledge (rQbD) and Validation

The objective of these studies is to verify and validate the improvement in the inter-tablet coating uniformity for an industrially commercialized coated tablet, without involving changes in the approved registration dossier. Using the CPP (critical process parameters) determined from previous retrospective statistical analysis, the recommended working ranges are identified. Retrospective analysis showed that the design of experiments (DoE) provided an improved process variable configuration. Therefore, it is decided to study two critical parameters: Product temperature and drum speed, with an additional 22 experimental design. The quality results of the samples analyzed show that the aesthetic defects of the batches made with the new working ranges have been reduced. These results have also been corroborated with the 42 industrial batches manufactured with the new ranges. With the optimized parameters, tablets have been coated and the suitability of the model determined. The results demonstrated the overall reliability and effectiveness of the proposed Quality by Design approach and provides a useful tool to help optimize the industrial coating process. This study confirms that it is possible to optimize and validate the manufacturing process of an existing commercial product by means of a DoE with retrospective data. Therefore, no variation in the dossier is required.