Stages Of Development Process Research Articles

Research Methodology for Microwave-Convective Processing of Grain

Studying the effect of microwave fields on the intensification of heat and moisture exchange processes in a granular layer is a rather complicated task, which cannot be effectively solved without an adequate research methodology. In presented materials, a system of principles and approaches for studying processes of microwave-convective grain treatment has been discussed. Based on the explicitly defined process target, functional-physical analysis has been performed that made it possible to specify the most essential factors of process. Morphological analysis of processes shall be performed in several stages. At each stage, targets of process have to be set by excluding combinations of factors that have no reason to be considered at this particular stage of process development. Application of mathematical simulation methods is advisable for selection of optimal options.

Influence of statistical activity variations in diluted catalyst beds on the thermal reactor behavior: Derivation of an a priori criterion

Catalyst bed dilution by mixing active and inert particles is common practice for highly exothermic gas phase reactions for balancing the heat generation and heat removal out of the reactor tubes. The predicted reactor performance is commonly calculated assuming a perfectly mixed bed. However, loading a particle mixture into a reactor tube is an inherently statistical process, and thus fluctuations in local activity cannot be avoided which can lead to the formation of local hotspots. We have analyzed the influence of non-uniform activity profiles on the reactor behavior by simulation studies using 1- and 2-dimensional reactor models. Based on the results, an a priori criterion using dimensionless numbers was derived for the prediction of maximum temperature variations. The general applicability has been successfully proven for several reaction systems and process conditions. The derived correlation allows for considering the non-idealities at an early stage of reactor and process development.

How can Belt and Road countries contribute to glocal low-carbon development?

In the context of global climate change, how to balance economic development and environmental protection has never been more vital. In response to this challenge, low-carbon economy development is undoubtedly endorsed worldwide. This paper proposes an improved low-carbon economy development index based on data envelopment analysis (DEA) for evaluating and analyzing the low-carbon economy development process of 56 Belt and Road Initiatives (BRI) countries in 2005–2015. The results show that: (1) The average value of green total factor productivity (GTFP) in BRI countries has increased slightly, due to the technological progress and improvement of pure technical efficiency; (2) Overall, BRI countries are still in the stage of energy-extensive economy. They have not achieved a development from “high-carbon” to “low-carbon” economy development. Although the low-carbon economy development index of BRI countries shows a rising trend, there is a general decline in 2015; (3) There is no obvious correlation between the low-carbon economy development and income levels; (4) The development processes of BRI countries are different, and most of them are in an unstable initial stage of development process. In view of this, this paper proposes that (1) improve technology to increase the growth rate of GTFP; (2) change development mode due to national policies; and (3) actively promote green BRI is of vital importance to BRI countries.

Recombinant β-Carotene Production by Yarrowia lipolytica - Assessing the Potential of Micro-Scale Fermentation Analysis in Cell Factory Design and Bioreaction Optimization.

The production of β-carotene has become increasingly interesting within the biotechnological industry due to a rising demand for safer and more natural colorants, nutritional supplements, and antioxidants. A recent study has described the potential of Yarrowia lipolytica as a β-carotene-producing cell factory, reporting the highest titer of recombinant β-carotene produced to date. Finding the best conditions to maximize production and scaling up the process to full scale, a costly and time-consuming process, it is often a bottleneck in biotechnology. In this work, we explored the benefits of using micro-fermentation equipment to significantly reduce the time spent on design and optimization of bioreaction conditions, especially in the early stages of process development. In this proof-of-concept study, a β-carotene producing Y. lipolytica strain was tested in micro-fermentations partly to assess the robustness of the cell factory design and partly to perform media optimization. The medium optimization led us to an improvement of up to 50% in the yield of β-carotene production in the best of the conditions. Overall, the micro-fermentation system had a high degree of reliability in all tests.

Characterization of Protein Aggregation Using Hydrogel-Encapsulated nIR Fluorescent Nanoparticle Sensors.

The monitoring of biopharmaceutical critical quality attributes in-process, at both the process development and manufacturing stages, is necessary for the implementation of process analytical technology and quality-by-design principles. Among these attributes, it is important to monitor and control protein aggregation during the manufacturing of biological therapeutics to prevent adverse immunogenic responses and minimize negative impacts on drug deliverability. In this work, we explore hydrogel-encapsulated, label-free fluorescent nanosensors for the characterization of protein aggregation. A mathematical model is used to describe the diffusion and binding of a series of stressed pharmaceutical samples to such sensors, describing their dynamic response. We use mathematical modeling to map the influence of hydrogel properties on the separation performance, given the composition of UV-stressed IgG1 samples. Using this modified model, the compositions of light-stressed IgG1 samples were fit to experimental data and correlated with size-exclusion chromatography data. The results demonstrate the ability to detect the presence of high-molecular-weight protein species at a concentration as low as 1%. This work represents a significant step toward the development and deployment of rapid process analytical technologies for biopharmaceutical characterization.

СПЕЦИФИКА ПОСТКОЛОНИАЛЬНОГО ТЕКСТА ПЕРЕСЕЛЕНЧЕСКИХ ОБЩЕСТВ АВСТРАЛИИ И НОВОЙ ЗЕЛАНДИИ: СРАВНИТЕЛЬНЫЙ АСПЕКТ

A brief comparative review of English-language literatures of Australia and New Zealand is given in the article. The aim of the article is to highlight the similarities and differences at the stages of the literary process development from the point of view of postcolonial studies. The historical genesis specificity of the region and the uniqueness of national identity formation at the juncture of colonial and colonized cultures stipulate the definition of Australia and New Zealand as settler societies. Tasks needed to be resolved are to disclose the notion “settler societies”, to determine common characteristics of the studied national literatures as postcolonial ones, to give their comparative outline, to make a textual analysis of a number of literary works which are indicative for each stage of the literary process development. In the course of the study, the authors refer to a comparative historical method of scientific enquiry to highlight similarities in the literary process development and the degree of influence of metropolitan literature on it. They also use a sociological method to estimate the impact of the settler societies development on the literary process and a hermeneutic interpretative method in textual analysis to interpret the transformation of a typical hero at various stages of the literary process in Australia and New Zealand. The article is divided into theoretical and practical parts. In the theoretical part, the authors define “settler societies”, overview the place of “settler” countries in the postcolonial space, and note factors allowing to review the national literatures comparatively as postcolonial ones. In the practical part, the authors characterize three stages of the literary process development observed in the national literatures of Australia and New Zealand, conduct an interpretative analysis of the works in which the prolific features of a typical hero are shown. On conducting the research the authors come to the following conclusions. The national literatures of Australia and New Zealand are under the influence of the metropolitan culture and literaturel, but the relation started to loosen at a contemporary stage of the literary process development due to the formation of the national identities of Australians and New Zealanders. The impact of colonized indigenous peoples’ cultures on the literary process defines the difference between the national literatures. For the countries, the national identity formation is characteristic in the cultural sphere, which makes the further study of identification processes presentation in literary text promising.

Taguchi method application in the pilot production phase-a case study

This work comes at the product and process development stage in a medical device company, namely the bone substitute. The production of bone substitutes has high regulatory requirements, also the consumer of these products has high-quality requirements. In the pilot production phase, a quality problem was detected in the bone substitute blocks. The work presented was developed in a real context requiring an understanding of the production process and the product. Through a multidisciplinary analysis allowed to direct the problem to the impregnation process. The study of the impregnation process was developed according to the DOE through the Taguchi method. For the experiment, six factors and one interaction allocated in an L8 array were identified. Results obtained show that the process variability is clearly superior to the effect of the studied factors. For future work, the removal of non-significant factors is recommended, adding new factors not included in the study.

Optimizing machining parameters of carbon steel EN24 to minimize surface roughness and tool wear

EN 24 (817M40) is used for creating punches and dies due to its hardenability, it's very tough to machine, so we investigate the parameters affecting the surface roughness produced within the turning process for the carbon steel EN24. Design of experiments was conducted for the analysis of the influence of the turning parameters like cutting speed, feed rate, tool wear and depth of cut on the surface roughness. The results of the machining experiments were accustomed characterize the most factors affecting surface roughness by the Analysis of Variance (ANOVA) method Taguchi’s parametric design is that the effective tool for robust design it offers an easy and systematic qualitative optimal design to a comparatively low cost. The Taguchi method of quality control encompasses all stages of product and process development. However, the key element for achieving prime quality at low cost is Design of Experiments (DOE). during this Analysis Taguchi’s (DOE) approach used to analyze the effect of process parameters like cutting speed, feed rate, tool wear and depth of cut on Surface Roughness and to get an optimal set of those parameters which will lead to good surface finish.

Microbioreactors for Process Development and Cell-Based Screening Studies.

Microbioreactors (MBRs) have emerged as potent cultivation devices enabling automated small-scale experiments in parallel while enhancing their cost efficiency. The widespread use of MBRs has contributed to recent advances in industrial and pharmaceutical biotechnology, and they have proved to be indispensable tools in the development of many modern bioprocesses. Being predominantly applied in early stage process development, they open up new fields of research and enhance the efficacy of biotechnological product development. Their reduced reaction volume is associated with numerous inherent advantages - particularly the possibility for enabling parallel screening operations that facilitate high-throughput cultivations with reduced sample consumption (or the use of rare and expensive educts). As a result, multiple variables can be examined in a shorter time and with a lower expense. This leads to a simultaneous acceleration of research and process development along with decreased costs.MBRs range from simple miniaturized cultivations vessels (i.e., in the milliliter scale with limited possibilities for process control) to highly complex and automated small-scale microreactors with integrated sensors that allow for comprehensive screenings in very short time or a precise reflection of large-scale cultivation conditions. Progressive developments and improvements in manufacturing and automation techniques are already helping researchers to make use of the advantages that MBRs offer. This overview of current MBR systems surveys the diverse application for microbial and mammalian cell cultivations that have been developed in recent years.

A simple and efficient model for calculating fixed capital investment and utilities consumption of large-scale biotransformation processes

Environmental concerns and the depletion of fossil resources are the major factors that boost modern society towards bio-based and circular economy. To this end, the development of mathematical tools that can be used to perform rapid comparative analysis across multiple technology options is necessary. The aim of this work is to present a simple and accurate mathematical model, which describes the economics of the bioreaction section of a typical biotransformation technology. The functional dependency of fixed capital investment (FCI) and utilities consumption from parameters determined experimentally is developed using a regression model. The proposed model, which consists only of three equations, can be used to compare the economic performance of different bio-based technologies that could potentially reach commercialization. More specifically, it can be used to estimate, at the early stages of process development, the effect of final broth concentration (titer), fermentation time and aeration rate on overall process economics.

In silico model-based characterization of metabolic response to harsh sparging stress in fed-batch CHO cell cultures

Mammalian cell culture platform has been successfully implemented for industrial biopharmaceutical production through the advancements in early stage process development including cell-line engineering, media design and process optimization. However, late stage developments such as scale-up, scale-down and large-scale cell cultivation still face many industrial challenges to acquire comparable process performance between different culture scales. One of them is the sparging strategy which significantly affects productivity, quality and comparability. Currently, it is mainly relying on the empirical records due to the lack of theoretical framework and scarcity of available literatures to elucidate intracellular metabolic features. Therefore, it is highly required to characterize the underlying mechanism of physiological changes and metabolic states upon the aeration stress. To this end, initially we cultivated antibody producing CHO cells under mild and harsh sparging conditions and observed that sparging stress leads to the decreased cell growth rate, viability and productivity. Subsequent in silicomodel-driven flux analysis suggested that sparging stress rewires amino acid metabolism towards the enriched H2O2 turnover rate by up-regulated fluxes of amino acid oxidases. Interestingly, many of these H2O2-generating reactions were closely connected with the production of NADH, NADPH and GSH which are typical reducing equivalents. Thus, we can hypothesize that increased amino acid uptake caused by sparging stress contributes to restore redox homeostasis against oxidative stress. The current model-driven systematic data analysis allows us to quickly define distinct metabolic feature under stress condition by using basic cell cultivation datasets.

Estimating capital investment and facility footprint in cell therapy facilities

Estimations of the facility footprint and fixed capital investment (FCI) of cell therapy (CT) facilities need to consider the unique features of the single-use technologies (SUTs) selected for CT manufacture (e.g. cleanroom containment requirement, capacity, automation) and the product nature that impacts scale-out versus scale-up approaches. A novel detailed factorial methodology is proposed for estimating FCI and footprint for bespoke stick-built cell therapy facilities that accounts for technology-specific factors for key cell culture technologies as well as the implications of SUTs, open versus closed operations and the commercialisation scenario selected. This was used to derive benchmark values for short-cut cost and area factors for typical cell therapy facilities according to the technologies selected. The results provide project-specific ratios for equipment purchase costs to facility footprint (area factor) and for FCI to total equipment purchase costs (cost factor or “Lang” factor). Area factors ($/m2) were 675-6,815 and the cost factors were 2.3–8.5 for a greenfield project in a medium-developed country. The case study shows that for the same output, facility footprints and FCI values are on average 6 times higher for autologous processes than allogeneic processes. This is attributed to economies of scale achieved with scale-up for allogeneic cell therapy manufacture. This study can be used to predict the commercial FCI and facility footprint during early stages of process development.

Large-Scale Manufacturing of CMV-CD19CAR T Cells and Characterization of Their Biologic and Immunologic Properties

We have successfully established a clinical platform for CD19 chimeric antigen receptor (CAR) T cells and evaluated its safety and efficacy in a series of pilot clinical trials following autologous hematopoietic cell transplantation (HCT) for treatment of high-risk non-Hodgkin lymphoma (NHL) and acute lymphoblastic leukemia (ALL). However, the full potential of this therapy has been limited by the lack of engraftment and persistence of CAR T cells in patients, most likely due to the inadequate antigen drive to stimulate robust expansion and long-term persistence of the infused CAR T cells. Additionally, CD19+ NHL seems less responsive to current CAR T cell technology than does CD19+ ALL that might be explained by lower engraftment and persistence of CAR T cells in NHL. To improve the efficacy and durability of CAR T cells in these disease settings, we sought to examine a novel approach based on properties of cytomegalovirus (CMV)-specific T cells. Specifically, we select CMV pp65-specific T cells for ex vivo modification with a CAR targeting CD19. After in vitro expansion, CMV-CD19 bi-specific T cells will be infused into the patient. A second round of expansion will be done in vivo, using a CMV vaccine (Triplex), developed and clinically evaluated multiple clinical sites including City of Hope. Triplex is a multi-antigen recombinant modified vaccinia Ankara (MVA) virus vaccine expressing pp65, IE1 and IE2, that has proven safe and immunogenic in Phase I trials in healthy volunteers and transplant patients and was highly tolerable and efficacious in a completed Phase II vaccine trial in allogeneic HCT recipients. We hypothesis that shorter ex vivo expansion time will prevent CAR T cell exhaustion that results in better in vivo expansion, especially after Triplex vaccination. Thus far, we have performed six large-scale manufacturing process development (PD) runs of CMV-CD19 CAR T cells using T cells from healthy donors. Briefly, peripheral blood mononuclear cells (PBMCs) were collected and processed in the CliniMACS Prodigy® system, in which PBMCs were first stimulated with a GMP-grade PepTivator® overlapping CMV pp65 peptide pool, then enriched for CMV-responsive IFNɣ+ T cells using the IFNγ Catchmatrix reagent (Miltenyi Biotec Inc.). CMV-responsive IFNɣ+ T cells were next transduced with a lentiviral vector encoding EGFRt/CAR, and finally expanded for approximately 15 days in vitro. As summarized in Table 1, we consistently recovered 4.8%+/-1.4 ×106 CMV specific T cells with 78.3%±2.9 purity from 1×109 PBMC input, which is the maximum input number suggested by the CCS program associated with the Prodigy system (Miltenyi Biotec Inc.). During the early stage PD runs, we noticed that red blood cell contamination in the PBMC layer after ficoll separation could negatively impact the yield of CMV-specific T cells. Thus, we optimized the separation process by performing a second ficoll whenever a red buffy coat was observed, and increased the yield of CMV-specific T cells from 2.8 ×106 to 9.25×106 (Table 1, HD 187.2 PBMCs underwent 2 subsequent ficolls). Phenotypic analysis demonstrated that freshly isolated CMV-specific T cells consisted of four different memory subsets (TEMRA, Tscm, Tcm and effector memory T cells). After in vitro expansion for 15 days, CMV-CAR bi-specific T cell expansion was significantly improved from 60×106 cells in the early stage runs to 200×106 in the late stage optimized runs (Figure 1). The CMV-CD19CAR T cells expressed CD62L, though not exhaustion markers such as PD1. Bispecific T cells exhibited bi-functionality upon stimulation with CD19+ tumor cells or CMVpp65 antigen, as indicated by secretion of IFNγ. Interestingly, we detected stronger effector function against CD19+ tumor cells from CMV-CD19CAR T cells compared to conventional CD19CAR T cells that were derived from the same donor (Figure 2). To validate our manufacturing process, we are currently conducting IND-enabling studies using patient-derived PBMC as the starting population and will initiate our first clinical trial in early 2020 for patients with intermediate/advanced-grade B cell NHL post lymphodepletion or autologous/allogeneic HCT followed by Triplex vaccination 28 days after T cell infusion for in vivo expansion of bi-specific CAR T cells. The primary objectives of these two trials are to examine safety and persistence/expansion of CMV-CD19CAR T cell before and after Triplex vaccine boost. Disclosures Nakamura: Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: support for an academic seminar in a university in Japan; Alexion: Other: support to a lecture at a Japan Society of Transfusion/Cellular Therapy meeting ; Kirin Kyowa: Other: support for an academic seminar in a university in Japan.

Early integration of Design of Experiment (DOE) and multivariate statistics identifies feeding regimens suitable for CHO cell line development and screening.

In Chinese Hamster Ovary (CHO) cell lines, the establishment of the ideal fed-batch regimen promotes metabolic conditions advantageous for the bioproduction of therapeutic molecules. A tailored, cell line-specific feeding scheme is typically defined during process development (PD) activities, through the incorporation of Design of Experiment (DOE) and late stage cell culture approaches. The feeding during early stage cell line development (CLD) was a simplified "one-fits-all" design, inherited from PD lab, that didn't account for CLD needs of throughput and streamlined workflow. The "one-fits-all" efficiency was not routinely verified when novel technologies were incorporated in CLD and sub-optimal feeding carried the risk of not selecting the most desirable cell lines amenable to late stage PD. In our work we developed the DOE-feed method; a streamlined, three-stages framework for identifying efficient feeding schemes as the CLD technologies evolved. We combined early stage cell culture input data with late-stage techniques, such as statistical modelling, principal component analysis (PCA), DOE and Prediction Profiler. Novel in our DOE-feed work, we deliberately anticipated the application of statistics and approached the method development as an early-stage, continuously updated process, by building iterative datasets and statistically interpreting their responses. We capitalized on the statistical models defined by the DOE-feed methodology to study the influence of feeds on daily productivity and growth and to extrapolate feeding-schemes that improved the cell line screening. The DOE-feed became a methodology suited for CLD needs at AbbVie, and optimized the early stage screening, reduced the operational hands-on time and improved the overall workstream efficiency.

Case study of a method of development of a selection process for community health workers in sub-Saharan Africa

BackgroundChoosing who should be recruited as a community health worker (CHW) is an important task, for their future performance partly depends on their ability to learn the required knowledge and skills, and their personal attributes. Developing a fair and effective selection process for CHWs is a challenging task, and reports of attempts to do so are rare. This paper describes a five-stage process of development and initial testing of a CHW selection process in two CHW programmes, one in Malawi and one in Ghana, highlighting the lessons learned at each stage and offering recommendations to other CHW programme providers seeking to develop their own selection processes.Case presentationThe five stages of selection process development were as follows: (1) review an existing selection process, (2) conduct a job analysis, (3) elicit stakeholder opinions, (4) co-design the selection process and (5) test the selection process. Good practice in selection process development from the human resource literature and the principles of co-design were considered throughout. Validity, reliability, fairness, acceptability and feasibility—the determinants of selection process utility—were considered as appropriate during stages 1 to 4 and used to guide the testing in stage 5. The selection methods used by each local team were a written test and a short interview.ConclusionsWorking with stakeholders, including CHWs, helped to ensure the acceptability of the selection processes developed. Expectations of intensiveness—in particular the number of interviewers—needed to be managed as resources for selection are limited, and CHWs reported that any form of interview may be stressful. Testing highlighted the importance of piloting with CHWs to ensure clarity of wording of questions, interviewer training to maximise inter-rater reliability and the provision of guidance to applicants in advance of any selection events. Trade-offs between the different components of selection process utility are also likely to be required. Further refinements and evaluation of predictive validity (i.e. a sixth stage of development) would be recommended before roll-out.

Selection of High Producers From Combinatorial Libraries for the Production of Recombinant Proteins in Escherichia coli and Vibrio natriegens.

The optimization of recombinant protein production in bacteria is an important stage of process development, especially for difficult-to-express proteins that are particularly sensitive or recalcitrant. The optimal expression level must be neither too low, which would limit yields, nor too high, which would promote the formation of insoluble inclusion bodies. Expression can be optimized by testing different combinations of elements such as ribosome binding sites and N-terminal affinity tags, but the rate of protein synthesis is strongly dependent on mRNA secondary structures so the combined effects of these elements must be taken into account. This substantially increases the complexity of high-throughput expression screening. To address this limitation, we generated libraries of constructs systematically combining different ribosome binding sites, N-terminal affinity tags, and periplasmic translocation sequences representing two secretion pathways. Each construct also contained a green fluorescent protein (GFP) tag to allow the identification of high producers and a thrombin cleavage site enabling the removal of fusion tags. To achieve proof of principle, we generated libraries of 200 different combinations of elements for the expression of an antimicrobial peptide (AMPs), an antifungal peptide, and the enzyme urate oxidase (uricase) in Escherichia coli and Vibrio natriegens. High producers for all three difficult-to-express products were enriched by fluorescence-activated cell sorting. Our results indicated that the E. coli ssYahJ secretion signal is recognized in V. natriegens and efficiently mediates translocation to the periplasm. Our combinatorial library approach therefore allows the cross-species direct selection of high-producer clones for difficult-to-express proteins by systematically evaluating the combined impact of multiple construct elements.

Forced Degradation Studies to Identify Critical Process Parameters for the Purification of Infectious Measles Virus.

Oncolytic measles virus (MV) is a promising treatment for cancer but titers of up to 1011 infectious particles per dose are needed for therapeutic efficacy, which requires an efficient, robust, and scalable production process. MV is highly sensitive to process conditions, and a substantial fraction of the virus is lost during current purification processes. We therefore conducted forced degradation studies under thermal, pH, chemical, and mechanical stress to determine critical process parameters. We found that MV remained stable following up to five freeze–thaw cycles, but was inactivated during short-term incubation (< 2 h) at temperatures exceeding 35 °C. The infectivity of MV declined at pH < 7, but was not influenced by different buffer systems or the ionic strength/osmolality, except high concentrations of CaCl2 and MgSO4. We observed low shear sensitivity (dependent on the flow rate) caused by the use of a peristaltic pump. For tangential flow filtration, the highest recovery of MV was at a shear rate of ~5700 s−1. Our results confirm that the application of forced degradation studies is important to identify critical process parameters for MV purification. This will be helpful during the early stages of process development, ensuring the recovery of high titers of active MV particles after purification.

Mixing Cell: a Device to Mimic Extent of Lubrication and Shear in Continuous Tubular Blenders.

Continuous manufacturing (CM) has clear potential for manufacturing solid oral dosages. It provides several advantages that may aid the manufacturing and quality of drug products. However, one of the main challenges of this technology is the relatively large amount of knowledge required and the amounts of material needed to develop the process during the early stages of development. Early process development evaluations of continuous manufacturing equipment often require larger amounts of material compared with batch, which hinder CM prospect for drugs during the early stages of process development. In this work, a small-scale evaluation of the mixing process occurring in a continuous mixing system was performed. The evaluation involved the use of a small-scale "mixing cell" which was able to replicate the lubrication process of a continuous mixer. It is worth mentioning that we designed the mixing cell by reconfiguration of an existing continuous tubular blender. The extent of lubrication evaluation was performed for three example formulations and was done by mimicking the amount of shear provided to a formulation by means of matching the number of paddle-passes that a formulation experiences within a continuous blending process in the batch mixing cell. The evaluation showed that the small-scale mixing cell was able to replicate the extent of lubrication-evaluated by measuring the tensile strength of compacts being made with both the continuous and mixing cell experiments-occurring in the continuous mixer using a fraction of the amount of materials needed to perform the same evaluation in the continuous blending process.

Overcoming Challenges in Process Development of Cellular Therapies

Cellular therapy using chimeric antigen receptor (CAR) T cells as a treatment option for patients with lymphoma and leukemia has proven to be remarkably efficacious. This success has sparked the development of new cellular therapy products for numerous indications. Similar to pharmaceutical products, challenges exist at nearly every stage of process development; however, the unique nature of a cellular therapy product can present exceptional challenges that are just beginning to emerge. The purpose of this review is to explore some of the most common challenges experienced during the early phases of development of CAR T cell products and to provide suggestions for navigating these challenges. Recent articles focused on CAR T cells are highlighted with special attention on aspects that relate to CAR T cell process development and clinical manufacturing. We examine the various stages of process development for CAR T cells and outline some of the obstacles that must be overcome in order to move from pre-clinical development into clinical manufacturing. As the field of CAR T cell therapy continues to grow, it is important to quickly move new CAR T cell products into and through early phase clinical trials and to ensure that the result of these trials can be adequately compared. Having laboratory and clinical investigators and GMP manufacturing facilities aligned on the numerous aspects of new product development will facilitate this process.

ПРОБЛЕМЫ КОММЕРЦИАЛИЗАЦИИ ИННОВАЦИЙ В МЕДИЦИНСКОЙ ПРОМЫШЛЕННОСТИ

The article highlights the problems associated with improving quality, reducing costs and increasing availability of medical care with limited funding in Russia. The necessity to ensure a greater consistency of transformation of medical services into cost-effective products has been substantiated. The main engine of progress is innovations whose development and introduction into the medical industry can provide a new level of medical care for the population. It has been stated that at present in the Russian Federation there are no large industrial enterprises in the medical industry that are able to enter the world market with their innovative developments. Development of medicine requires the complex long-term research, clinical trials and significant financial and resource costs, which in most cases leads to unrealized implementation. Medical industry is one of the most high-tech industries characterized by a high level of research and innovations. The structure of production of medical products and equipment is considered. The stages of the innovation process (development of innovation and its commercialization) have been designated. The elements of the innovation system in health care have been shown. The factors constraining the innovative development of the medical industry in Russia, including insufficient state participation, are investigated. The comparative analysis of the current costs on health care in different countries has been carried out; Russia is found to rank 35th place among 44 countries under study. The state federal programs of the Russian Federation aimed at creating a national innovation system in the medical industry, changing the structure of spending on medicine and approaching the level of spending of developed countries have been considered. The problems of commercialization in the Russian medical industry, which lead to a slowdown in production growth, are formulated, and possible solutions are proposed.