Quality Management in Pharmaceutical Development of Biotechnology-Derived Medicinal Products: Implementation and Evaluation

Scientific relevance. One of the challenges associated with the development of medicines lies in creating a quality management system (QMS) and tools to assess its performance.Aim. The study aimed to propose a QMS model for the development of biotechnology-derived medicinal products and a performance evaluation tool for this QMS universally applicable in the research centre of the company regardless of the specific activities of its individual divisions.Materials and methods. The study analysed internal audit outcomes, non-compliance responses, and the document flow of the research centre. Parameter values for quality index (QI) calculations were entered into validated Microsoft Excel spreadsheets. Data analysis and visualisation involved using the Microsoft Power Business Intelligence (BI) business analytics platform (mainly, the Power BI Desktop and Power BI Service components).Results. The QMS was implemented, and the authors proposed their QMS performance evaluation tool universally applicable to all the divisions of the research centre.Conclusions. The authors proposed their QMS model for the development of biotechnology-derived medicinal products and the QI tool for collecting digital data, carrying out standardised monitoring, and tracking QMS status changes. The QI tool is universal for all company departments regardless of their requirements, easy to use, and customisable by adding individual company-specific quality parameters. This makes the QI tool applicable not only to drug development departments but also to other research units

Behavioral Sequence Analysis Reveals a Novel Role for ß2* Nicotinic Receptors in Exploration

Nicotinic acetylcholine receptors (nAChRs) are widely expressed throughout the central nervous system and modulate neuronal function in most mammalian brain structures. The contribution of defined nAChR subunits to a specific behavior is thus difficult to assess. Mice deleted for ß2-containing nAChRs (ß2−/−) have been shown to be hyperactive in an open-field paradigm, without determining the origin of this hyperactivity. We here develop a quantitative description of mouse behavior in the open field based upon first order Markov and variable length Markov chain analysis focusing on the time-organized sequence that behaviors are composed of. This description reveals that this hyperactivity is the consequence of the absence of specific inactive states or “stops”. These stops are associated with a scanning of the environment in wild-type mice (WT), and they affect the way that animals organize their sequence of behaviors when compared with stops without scanning. They characterize a specific “decision moment” that is reduced in ß2−/− mutant mice, suggesting an important role of ß2-nAChRs in the strategy used by animals to explore an environment and collect information in order to organize their behavior. This integrated analysis of the displacement of an animal in a simple environment offers new insights, specifically into the contribution of nAChRs to higher brain functions and more generally into the principles that organize sequences of behaviors in animals

Optimisation of induction conditions for a bacterial strain producing proinsulin aspart

Diabetes poses a serious threat to the health of people around the world. Therefore, in 2021, the World Health Organisation launched the Global Diabetes Compact, an initiative aimed at improving the management and prevention of diabetes. The rapid growth in the number of diabetic patients has increased the need for insulin. Rapid-acting human insulin analogues, including insulin aspart, improve the efficacy of insulin therapy. Methods for insulin aspart production include its biosynthesis in the proinsulin form in Escherichia coli. However, the yield of the recombinant protein largely depends on the optimisation of the production process.The aim of the study was to optimise the induction conditions for an E. coli strain expressing recombinant proinsulin aspart through applying the Design of Experiment (DoE) approach to enhance bacterial cell productivity.Materials and methods. The study focused on a strain of E. coli producing proinsulin aspart. The authors planned the experiment using MODDE software and the reduced face-centred central composite design (CCF) enabling the assessment of factor interactions and the creation of design spaces. The authors carried out fermentations of the producing strain in a 5 L Biostat® B bioreactor and measured proinsulin aspart concentrations by capillary gel electrophoresis. The results were analysed using GraphPad Prism 6.Results. Using the DoE approach, the authors optimised the conditions for the growth of the producer strain and the biosynthesis of proinsulin aspart. Based on data from response surface plots for wet biomass concentration, specific productivity, and volumetric productivity, as well as plotted models, the authors established design spaces for the induction of proinsulin aspart expression in E. coli. The plotted models demonstrated high predictive power and high reproducibility of the results. The authors successfully validated the induction process for the synthesis of proinsulin aspart in a bioreactor under optimised conditions. The volumetric productivity of the strain producing proinsulin aspart increased from 3.06±0.16 g/L (conventional conditions) to 4.93±0.80 g/L (optimised conditions).Conclusions. The authors achieved a 60% increase in the volumetric yield of proinsulin aspart. The study results may be used to intensify the industrial production of insulin aspart

Analysis of the Trajectory of Drosophila melanogaster in a Circular Open Field Arena

BACKGROUND: Obtaining a complete phenotypic characterization of a freely moving organism is a difficult task, yet such a description is desired in many neuroethological studies. Many metrics currently used in the literature to describe locomotor and exploratory behavior are typically based on average quantities or subjectively chosen spatial and temporal thresholds. All of these measures are relatively coarse-grained in the time domain. It is advantageous, however, to employ metrics based on the entire trajectory that an organism takes while exploring its environment. METHODOLOGY/PRINCIPAL FINDINGS: To characterize the locomotor behavior of Drosophila melanogaster, we used a video tracking system to record the trajectory of a single fly walking in a circular open field arena. The fly was tracked for two hours. Here, we present techniques with which to analyze the motion of the fly in this paradigm, and we discuss the methods of calculation. The measures we introduce are based on spatial and temporal probability distributions and utilize the entire time-series trajectory of the fly, thus emphasizing the dynamic nature of locomotor behavior. Marginal and joint probability distributions of speed, position, segment duration, path curvature, and reorientation angle are examined and related to the observed behavior. CONCLUSIONS/SIGNIFICANCE: The measures discussed in this paper provide a detailed profile of the behavior of a single fly and highlight the interaction of the fly with the environment. Such measures may serve as useful tools in any behavioral study in which the movement of a fly is an important variable and can be incorporated easily into many setups, facilitating high-throughput phenotypic characterization

Внедрение и оценка системы менеджмента качества в области фармацевтической разработки биотехнологических лекарственных препаратов

Scientific relevance. One of the challenges associated with the development of medicines lies in creating a quality management system (QMS) and tools to assess its performance.Aim. The study aimed to propose a QMS model for the development of biotechnology-derived medicinal products and a performance evaluation tool for this QMS universally applicable in the research centre of the company regardless of the specific activities of its individual divisions.Materials and methods. The study analysed internal audit outcomes, non-compliance responses, and the document flow of the research centre. Parameter values for quality index (QI) calculations were entered into validated Microsoft Excel spreadsheets. Data analysis and visualisation involved using the Microsoft Power Business Intelligence (BI) business analytics platform (mainly, the Power BI Desktop and Power BI Service components).Results. The QMS was implemented, and the authors proposed their QMS performance evaluation tool universally applicable to all the divisions of the research centre.Conclusions. The authors proposed their QMS model for the development of biotechnology-derived medicinal products and the QI tool for collecting digital data, carrying out standardised monitoring, and tracking QMS status changes. The QI tool is universal for all company departments regardless of their requirements, easy to use, and customisable by adding individual company-specific quality parameters. This makes the QI tool applicable not only to drug development departments but also to other research units.Актуальность. Важными задачами при создании лекарственных средств являются формирование в области фармацевтической разработки системы менеджмента качества (СМК) и разработка инструментов оценки ее эффективности.Цель. Предложить модель системы менеджмента качества в области фармацевтической разработки биотехнологических препаратов, а также разработать механизм оценки эффективности функционирования данной системы в различных подразделениях научно-исследовательского центра.Материалы и методы. В работе представлены данные о результатах внутренних аудитов научно-исследовательского центра, результаты работы с несоответствиями и данные о документообороте. Значения параметров для расчета индекса качества регистрировали в валидированных Excel-файлах. Для анализа и визуализации данных использовали программный продукт Microsoft Power BI (Business Intelligence), предназначенный для бизнес-анализа данных. Основными используемыми компонентами платформы Power BI являлись Power BI Desktop и Power BI Service.Результаты. Внедрена СМК и разработан механизм, позволяющий проводить оценку эффективности работы СМК в подразделениях научно-исследовательского центра вне зависимости от индивидуальных требований к каждому подразделению.Выводы. Предложены модель организации СМК в области фармацевтической разработки биотехнологических препаратов и инструмент (индекс качества) для сбора оцифрованных данных, проведения унифицированного мониторинга и отслеживания динамики изменения состояния СМК вне зависимости от индивидуальных требований к каждому подразделению. Отмечено, что индекс качества может быть применен не только в отношении подразделений разработки лекарственных препаратов, но и в отношении других научных подразделений ввиду его универсальности, простоты и возможности модификации за счет введения дополнительных индивидуальных показателей качества

Mouse Cognition-Related Behavior in the Open-Field: Emergence of Places of Attraction

Spatial memory is often studied in the Morris Water Maze, where the animal's spatial orientation has been shown to be mainly shaped by distal visual cues. Cognition-related behavior has also been described along “well-trodden paths”—spatial habits established by animals in the wild and in captivity reflecting a form of spatial memory. In the present study we combine the study of Open Field behavior with the study of behavior on well-trodden paths, revealing a form of locational memory that appears to correlate with spatial memory. The tracked path of the mouse is used to examine the dynamics of visiting behavior to locations. A visit is defined as either progressing through a location or stopping there, where progressing and stopping are computationally defined. We then estimate the probability of stopping at a location as a function of the number of previous visits to that location, i.e., we measure the effect of visiting history to a location on stopping in it. This can be regarded as an estimate of the familiarity of the mouse with locations. The recently wild-derived inbred strain CZECHII shows the highest effect of visiting history on stopping, C57 inbred mice show a lower effect, and DBA mice show no effect. We employ a rarely used, bottom-to-top computational approach, starting from simple kinematics of movement and gradually building our way up until we end with (emergent) locational memory. The effect of visiting history to a location on stopping in it can be regarded as an estimate of the familiarity of the mouse with locations, implying memory of these locations. We show that the magnitude of this estimate is strain-specific, implying a genetic influence. The dynamics of this process reveal that locations along the mouse's trodden path gradually become places of attraction, where the mouse stops habitually

Regulatory evaluation of Glybera in Europe-two committees, one mission

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