Development Of Continuous Process Research Articles

Averaging Level Control to Reduce Off-Spec Material in a Continuous Pharmaceutical Pilot Plant

The judicious use of buffering capacity is important in the development of future continuous pharmaceutical manufacturing processes. The potential benefits are investigated of using optimal-averaging level control for tanks that have buffering capacity for a section of a continuous pharmaceutical pilot plant involving two crystallizers, a combined filtration and washing stage and a buffer tank. A closed-loop dynamic model is utilized to represent the experimental operation, with the relevant model parameters and initial conditions estimated from experimental data that contained a significant disturbance and a change in setpoint of a concentration control loop. The performance of conventional proportional-integral (PI) level controllers is compared with optimal-averaging level controllers. The aim is to reduce the production of off-spec material in a tubular reactor by minimizing the variations in the outlet flow rate of its upstream buffer tank. The results show a distinct difference in behavior, with the optimal-averaging level controllers strongly outperforming the PI controllers. In general, the results stress the importance of dynamic process modeling for the design of future continuous pharmaceutical processes.

ON THE CLINICS AND DIAGNOSIS OF EPILEPTIC ENCEPHALOPATHY

Early childhood is characterized by a continuous process of development of structures and functions of organism, especially central nervous system. The concept of epileptic encephalopathy is based on the assumption that the aggressive epileptic activity during the maturation of the brain is the main causal factor in cognitive and neuropsychological impairment or regress. With age, EEG signs of evolving consistent with the transition into each another. Currently the diagnosis criteria are not well developed and the treatment options are very limited, whereby patients cannot receive adequate treatment that further aggravates encephalopathy. Unfortunately clinicians are often unable to diagnose also benign epileptic syndromes.

KEY FACTORS FOR A CONTINUOUS IMPROVEMENT PROCESS

The goal of this work was to examine the content of continuous improvement processes, taking into account its inclusion in modern organizationsstrategies. Continuous improvement plays an important role in ISO 9000 norms and excellence models. This paper argues that several specific issues must be taken into account in order to reach successful outcomes. This work starts with a literature review on the matter. On this basis we designed a survey of a group of 30 large companies, selected according to their billing, its market share, its membership to quality institutions and the existence of a certified management system. Finally, we compared the development of continuous improvement process in companies with very effective results and with scarce results. Differences that emerged from this comparison enabled us to identify critical factors for achieving a successful improvement process.

ECO-FRIENDLY PROCESSES FOR BIODIESEL PRODUCTION FROM NON-EDIBLE OILS

At present, edible vegetable oils are most often used feedstocks for industrial biodiesel production. In this paper, the various non-edible oils and usually used processes for biodiesel production are analyzed from the ecological and economic aspects. The aim of the paper is to present the possibilities for improving the biodiesel synthesis by employing the heterogeneous catalysts, the novel catalysts obtained from waste materials and continuous process development, especially taking into account their impact on the environment. Key words:alcoholysis, biodiesel, non-edible oils.

Humanização na teoria e na prática: a construção do agir de uma equipe de enfermeiros

doi: 10.5216/ree.v15i2.17916 - http://dx.doi.org/10.5216/ree.v15i2.17916.RESUMOPesquisa descritiva exploratória de abordagem qualitativa, desenvolvida em uma Unidade de Terapia Intensiva (UTI) pública de Goiânia-GO, cujo objetivo foi descrever como o saber e o fazer (conceito e prática) humanização da assistência vêm sendo constituídos pelos enfermeiros desta UTI, que integram uma equipe em processo contínuo de formação e estudo científico. A coleta de dados ocorreu em 2011, com sete dos enfermeiros da UTI, por meio de entrevistas semiestruturadas gravadas, transcritas e categorizadas por análise de conteúdo, resultando nas categorias “O Conceito de humanização” e “O fazer no cotidiano da terapia intensiva”. Os enfermeiros conhecem o conceito e sabem como realizar a prática humanizada mas ainda não aplicam esse conhecimento a todas as situações, atribuindo a responsabilidade por isso a fatores externos a si mesmos. É necessário identificar os pontos de estrangulamento nesse processo para ajudar no planejamento das intervenções necessárias para produzir mudanças efetivas no comportamento desses profissionais. Descritores: Humanização da Assistência; Enfermagem; Unidade de Terapia Intensiva.

Strategies for Using Microreactors and Flow Chemistry: Drivers and Tools

AbstractAn innovative concept for the characterization of situations or problems (drivers) where the application of continuous flow processing, microreactor and/or other intensification technologies lead to the desired solutions is presented. An overview of techniques and equipment (tools) currently available for developing intensified processes is given as well as some examples of how they can be implemented in the engineering of chemical plants in kilo‐lab, pilot‐, and full‐size manufacturing scale. These drivers and tools are described and depicted by easy‐to‐understand icons, and strategies for the development of continuous processes are explained. Short summaries of three different case studies demonstrate the economic advantages and potentials of intensified flow processing in manufacturing scale. Finally, the current approach to avoid inflexibility of systems operated in continuous mode is reported and how pilot and manufacturing plants can be realized with a special focus on modularity and multi‐purpose functionality.

Model‐based design of a plant‐wide control strategy for a continuous pharmaceutical plant

The design of an effective plant‐wide control strategy is a key challenge for the development of future continuous pharmaceutical processes. This article presents a case study for the design of a plant‐wide control structure for a system inspired by an end‐to‐end continuous pharmaceutical pilot plant. A hierarchical decomposition strategy is used to classify control objectives. A plant‐wide dynamic model of the process is used to generate parametric sensitivities, which provide a basis for the synthesis of control loops. Simulations for selected disturbances illustrate that the critical quality attributes (CQAs) of the final product can be kept close to specification in the presence of significant and persistent disturbances. Furthermore, it is illustrated how selected CQAs of the final product can be brought simultaneously to a new setpoint while maintaining the remaining CQAs at a constant value during this transition. The latter result shows flexibility to control CQAs independently of each other. © 2013 American Institute of Chemical Engineers AIChE J, 59: 3671–3685, 2013

Developing Competence at Work

In this paper, we explore the relationship between differing conceptualisations of competence, and the implications of these differences for the enacted workplace curriculum and its pedagogical epistemologies. We argue that when competence is understood as a set of stand-alone attributes that reside within an individual, it limits and over simplifies understandings of work, the context of the work, and the vocation of which that work is a part. We propose that instead of a static end product, competence should be viewed as a continuous process of development, of becoming, and of understanding the work individually and collectively. Drawing on an analysis of two workplace learning case studies, we illustrate the ways in which the work itself structures the enacted workplace curriculum and facilitates or constrains learning. The Singaporean case studies, one of trainee chefs in a high-end hotel and the other of trainee healthcare assistants in a nursing home, for the elderly provide sharp contrasts of differing conceptualisations of competence. Data was collected through analysing organisational policies on training and development semi-structured interviews with trainees and their workplace supervisors, unstructured, nonparticipant workplace observations of the trainees and supervisors as they carried out their daily work tasks.

Design and Construction of a Batch Oven for Investigation of Industrial Continuous Baking Processes

AbstractA new batch oven has been constructed to mimic industrial convection tunnel ovens for research and development of continuous baking processes. The process parameters (air flow, air temperature, air humidity, height of baking area and the baking band velocity) are therefore highly controllable and adjustable over a wide range of settings. It is possible to monitor the product weight and temperature continuously during baking. The simultaneous measuring of mass and a window allowing for visual (e.g., by video recording) control is unique for this experimental batch oven. Two validation steps have been carried out. The uniformity of heating in the oven was assessed by measurements of local heat transfer coefficients and confirmed by baking tests. The methods showed that the oven is able to heat and bake uniformly across the baking area. Hereafter, the oven was validated against a commercial 10‐m tunnel oven, with a butter cookie as the test product. The investigated quality parameters for the butter cookies were mass loss and surface browning, where the uniformity of browning was evaluated subjectively against a scale of standards and objectively by L* value measurements. Good reproducibility of the baking was documented over a range of temperatures (160C to 190C).Practical ApplicationsThe purpose of this paper is to describe a new specially designed pilot scale batch oven. The batch oven is designed and constructed to imitate the baking processes in continuous tunnel ovens with forced convection. Experimental work in the new batch oven will increase knowledge of how the environment and baking conditions influence the quality of bakery products in continuous tunnel ovens.

Fouling of an anion exchange chromatography operation in a monoclonal antibody process: Visualization and kinetic studies

Fouling of chromatographic resins over their operational lifetimes can be a significant problem for commercial bioseparations. In this article, scanning electron microscopy (SEM), batch uptake experiments, confocal laser scanning microscopy (CLSM) and small-scale column studies were applied to characterize a case study where fouling had been observed during process development. The fouling was found to occur on an anion exchange (AEX) polishing step following a protein A affinity capture step in a process for the purification of a monoclonal antibody. Fouled resin samples analyzed by SEM and batch uptake experiments indicated that after successive batch cycles, significant blockage of the pores at the resin surface occurred, thereby decreasing the protein uptake rate. Further studies were performed using CLSM to allow temporal and spatial measurements of protein adsorption within the resin, for clean, partially fouled and extensively fouled resin samples. These samples were packed within a miniaturized flowcell and challenged with fluorescently labeled albumin that enabled in situ measurements. The results indicated that the foulant has a significant impact on the kinetics of adsorption, severely decreasing the protein uptake rate, but only results in a minimal decrease in saturation capacity. The impact of the foulant on the kinetics of adsorption was further investigated by loading BSA onto fouled resin over an extended range of flow rates. By decreasing the flow rate during BSA loading, the capacity of the resin was recovered. These data support the hypothesis that the foulant is located on the particle surface, only penetrating the particle to a limited degree. The increased understanding into the nature of the fouling can help in the continued process development of this industrial example.Scanning electron microscopy (SEM), batch uptake experiments, confocal laser scanning microscopy (CLSM) and small-scale column experiments were applied to characterize a case study where fouling had been observed on an anion exchange chromatography in a monoclonal antibody process. The results suggest the foulant is located on the particle surface, resulting in a minimal decrease in saturation capacity, but having a significant impact on the kinetics of adsorption, severely decreasing protein uptake rate.

Optimized Enzymatic Production of Waste Oil to Biodiesel

This study employed statistically based on experimental designs to optimize transesterification conditions for biodiesel production from waste oil via lipase-catalyzed in homoeothermy. Optimization of different reaction parameters were done by using response surface methodology. Results indicated optimum conditions including: alcohol to oil molar ratio 3:1, lipase concentration 58.38 U each gram of oil, water and n-hexane content were 24.59% and 13.28% respectively, reaction temperature at 20 °C , and reaction time for 24 h. Under these optimal conditions, 98.24% yield of biodiesel was obtained. This study will probably contribute to the development of continuous enzymatic processes, and maybe a suitable method for industrial production of biodiesel.

Development of continuous process enabling nanofibrillation of pulp and melt compounding

Microfibrillated cellulose (MFC), a mechanically fibrillated pulp mostly consisting of nanofibrils, is a very attractive material because of its high elastic modulus and strength. Although much research has been done on composites of MFC and polypropylene (PP), it has been difficult to produce such composites at an industrial level because of the difficulties in using MFC in such composites are not only connected to the polarity (that can be improved with compatibilizers), but also with the challenge to make a homogeneous blend of the components, and also the low temperature stability of cellulose that could cause problems during processing. We developed a new processing method which enables continuous microfibrillation of pulp and its melt compounding with PP. Never-dried kraft pulp and powdered PP were used as raw materials to obtain MFC by kneading via a twin-screw extruder. Scanning electron microscopy showed nano to submicron wide fibers entangled in the powdered PP. MFC did not aggregate during the melt compounding process, during which the water content was evaporated. Maleic anhydride polypropylene (MAPP) was used as a compatibilizer to reinforce interfacial adhesion between the polar hydroxyl groups of MFC and non-polar PP. We investigated the effect of MAPP content on the mechanical properties of the composite, which were drastically improved by MAPP addition. Needle-leaf unbleached kraft pulp (NUKP)-derived MFC composites had better mechanical properties than needle-leaf bleached kraft pulp (NBKP)-derived MFC composites. Injection molded NUKP-derived MFC composites had good mechanical and thermal properties. The tensile modulus of 50 wt% MFC composite was two times, and the tensile strength 1.5 times higher than that of neat PP. The heat distortion temperature of 50 wt% MFC content composite under 1.82 MPa flexural load was increased by 53 °C, from 69 to 122 °C. This newly developed continuous process using powder resin has the potential for application at an industrial level.

General procedure to aid the development of continuous pharmaceutical processes using multivariate statistical modeling – An industrial case study

Streamlining the manufacturing process has been recognized as a key issue to reduce production costs and improve safety in pharmaceutical manufacturing. Although data available from earlier developmental stages are often sparse and unstructured, they can be very useful to improve the understanding about the process under development. In this paper, a general procedure is proposed for the application of latent variable statistical methods to support the development of new continuous processes in the presence of limited experimental data. The proposed procedure is tested on an industrial case study concerning the development of a continuous line for the manufacturing of paracetamol tablets. The main driving forces acting on the process are identified and ranked according to their importance in explaining the variability in the available data. This improves the understanding about the process by elucidating how different active pharmaceutical ingredient pretreatments, different formulation modes and different settings on the processing units affect the overall operation as well as the properties of the intermediate and final products. The results can be used as a starting point to perform a comprehensive and science-based quality risk assessment that help to define a robust control strategy, possibly enhanced with the integration of a design space for the continuous process at a later stage.

Process Development for a High-throughput Fine Line Metallization Approach Based on Dispensing Technology

In order to enhance prosperous dispensing technology towards an industrial application, besides a continuous process development, especially throughput rate has to be increased. In this study, paste rheology of two different dispensing pastes was transferred to CFD-simulation (CFD: Computational Fluid Dynamics) to investigate different nozzle geometries and print head designs. In the following, a single nozzle dispensing setup was used to verify simulative values by comparing them with those obtained from experimental investigations. Consequently, the single nozzle process was scaled to a parallel application, where a homogeneous pressure and flow distribution within the print head turned out to be crucial to achieve a homogeneous mass flow at all nozzles. In various iteration steps, the influence of fabrication tolerances especially concerning the nozzle geometry was isolated and print head designs were optimized based on CFD towards maximum process stability. Based on these results, a novel 10 nozzle fine line dispensing unit was designed and fabricated. Finally, successful cell production with resulting finger widths of less than 35μm could be demonstrated using the novel prototype.

Development of continuous processes for vegetable oil alcoholysis in microfluidic devices

Biodiesel can be produced from vegetable oils, animal fats, and waste cooking oils by transesterification with ethanol (also called ethanolysis) in order to substitute fossil fuels. In this work, we were interested in the transesterification reaction of sunflower oil with ethanol, which leads to ethyl esters, used to date for applications principally in food and cosmetic industry. To open the application field to biofuels (to substitute current fuels resulting from fossil resources), the process efficiency has to be developed to be economically profitable. The batch reaction of vegetable oil ethanolysis was transposed to a micro-scaled continuous device (PFA tube of 508 μm internal diameter), inducing better heat and mass transfer. Study of the influence of the operational conditions (reactants flow, initial ethanol to oil molar ratio, temperature. . .) revealed the favourable reaction parameters necessary to reach high conversions and yields. In these conditions, it is possible to acquire kinetics data at the first seconds of the reaction, which was not feasible in a conventional batch process. These data were used to model occurring phenomena and to determine kinetic constants and transfer coefficients. The model was subsequently used to simulate reactions with other operational conditions. To acquire these data in microreactors, an on-line analysis method by Near InfraRed (NIR) spectroscopy was developed by using gas chromatography as a reference method. PLS models were then set up to quantify on-line the major compounds contents during the reaction.

Development of Continuous Crystallization Processes Using a Single-Stage Mixed-Suspension, Mixed-Product Removal Crystallizer with Recycle

An ideal pharmaceutical crystallization process produces a pure product at a high yield while minimizing energy input, the process equipment footprint, and its complexity. A good candidate for such a process is a single-stage mixed-suspension, mixed-product removal (MSMPR) crystallizer with recycle (SMR) system, where the characteristics of the refined crystal are controlled by the crystallization conditions of the MSMPR and the yield is manipulated by the recycle ratio. In this study, two continuous SMR systems, for the cooling crystallization of cyclosporine and the antisolvent-cooling crystallization of deferasirox, were developed. Both systems were designed to maintain the desired operating conditions inside the MSMPR crystallizer. For cooling crystallization, the recycle stream was concentrated via vacuum evaporation. For antisolvent-cooling crystallization, the desired solvent to antisolvent ratio was maintained by controlling the flow rates of feed, antisolvent, and recycle streams. The maximum exp...

Development of continuous ingot casting process for uranium dendrites in pyroprocess

A continuous ingot casting process was developed to improve the productivity of ingot fabrication. A supplemental charge method in which uranium dendrites were additionally added into molten uranium was introduced for the first time, and a tilting system of a melting crucible to mold was developed. The feasibility of these processes was confirmed by a uranium melting test at the laboratory scale, successfully obtaining a uranium ingot in about 4.6 kg. Based on the results, we scaled up the ingot casting processes at the engineering scale. A rotating continuous feeder was installed for the ceaseless feeding of the dendrites into molten uranium. The tilting system and eight mold crucibles on a turn-table were adopted. The operability of the continuous ingot casting process at the engineering scale was successfully confirmed by a melting test of copper. We consider that the engineering scale equipment can cast above a 50 kg U/batch with the continuous casting processes.

Stereoselective Chemoenzymatic Synthesis of Enantiopure 2-(1H-imidazol-yl)cycloalkanols under Continuous Flow Conditions

The development of continuous flow processes for the synthesis of chiral enantiopure 1-(2-hydroxycycloalkyl)imidazoles is reported. For the ring-opening reaction microwave batch processes and continuous flow reactions have led to similar results in terms of conversion, although the productivity is clearly improved under flow. The use of continuous flow systems for the lipase-catalyzed kinetic resolution of the racemic 2-(1H-imidazol-yl)cycloalkanols with either immobilized CAL-B or PSL-C has been demonstrated to be significantly more efficient than the corresponding batch processes. The continuous flow biotransformations have allowed us to easily increase the production of these chiral imidazoles, adequate building blocks in the synthesis of chiral ionic liquids.

Development of Continuous Pharmaceutical Production Processes Supported by Process Systems Engineering Methods And Tools

Development of Continuous Pharmaceutical Production Processes Supported by Process Systems Engineering Methods And Tools

History and future of world's most advanced biorefinery in operation

Running a biomass biorefinery based on lignocellulosic feedstock is challenging both from a processing point of view as well as from a market point of view. Continuous process and product development is needed to meet the dynamics in the markets. Borregaard in Sarpsborg Norway is one of the most advanced biorefineries in operation today and has more than 40 years experience of running such a biorefinery. Based on this experience and presence in many markets, new strategies for converting lignocellulosic biomass to biochemicals and biofuels in a sustainable and profitable way has been implemented. The company is loyal to the biorefinery strategy of making the maximum amount of valuable products out of the biomass. Examples of potential new product lines are microfibrillar cellulose (MFC), water soluble specialty lignins from other sources than wood, lignocellulosic ethanol, proteins and sugar based chemicals. Both experience from the long history of running a biorefinery as well as the main development routes for future new bioproducts is analyzed and discussed.