Scale-down Model Research Articles

A Systematic Approach for Scale-Down Model Development and Characterization of Commercial Cell Culture Processes

The objective of process characterization is to demonstrate robustness of manufacturing processes by understanding the relationship between key operating parameters and final performance. Technical information from the characterization study is important for subsequent process validation, and this has become a regulatory expectation in recent years. Since performing the study at the manufacturing scale is not practically feasible, development of scale-down models that represent the performance of the commercial process is essential to achieve reliable process characterization. In this study, we describe a systematic approach to develop a bioreactor scale-down model and to characterize a cell culture process for recombinant protein production in CHO cells. First, a scale-down model using 2-L bioreactors was developed on the basis of the 2000-L commercial scale process. Profiles of cell growth, productivity, product quality, culture environments (pH, DO, pCO2), and level of metabolites (glucose, glutamine, lactate, ammonia) were compared between the two scales to qualify the scale-down model. The key operating parameters were then characterized in single-parameter ranging studies and an interaction study using this scale-down model. Appropriate operation ranges and acceptance criteria for certain key parameters were determined to ensure the success of process validation and the process performance consistency. The process worst-case condition was also identified through the interaction study.

Basic Concepts in Q Membrane Chromatography for Large-Scale Antibody Production

The large-scale production of recombinant human monoclonal antibodies demands economical purification processes with high throughputs. In this article we briefly describe a common antibody process and evaluate the Q membrane adsorber for process-scale antibody production as an alternative to a Q-packed-bed column in a flow-through mode. The scientific concepts underlining Q membrane technology and its application are reviewed. The disadvantages and advantages of using Q membrane chromatography as a purification unit in large-scale production are discussed, including problems initially seen with the Q membrane scale-down model but solved with the invention of a new scale-down model. The new Q-membrane unit operation has a process capacity greater than 3,000 g/m(2) or 10.7 kg/L with a LRV over 5 for four model viruses. In this Review, a cost analysis illustrates that Q membrane chromatography is a viable alternative to Q column chromatography as a polishing step in a flow-through mode for process-scale antibody production.

Two-compartment bioreactor as a scale-down model to study the effect of glucose overflow and anaerobiosis on large-scale recombinant protein production processes

Background In high-cell density fermentations the host cells are often subjects of transient changes in microenvironment around them. This is true especially in large-scale bioreactors. The changes can be for example substrate gradient, differences in oxygen availability and pH variations. Our aim is to obtain more information about physiological changes of E.coli W3110 and its recombinant variants in such conditions for better understanding of the bottlenecks in recombinant protein production processes.

308 コンクリート基礎の除振性能を向上させる振動制御システムの開発

Microvibration control technology has been rapidly becoming more important in a number of fields including superfine technology in semiconductor manufacturing and microgravity research experiments in space. In the paper, we propose the system which carries out vibration control of concrete foundation by using the piezoelectric actuator, to improve isolation performance. However, there were very few studies focused on the vibration control of concrete foundation in the past. We expect that it is difficult to realize the system in a nonlinear characteristic. In this study, the realization possibility of the proposed system is verified through the vibration isolation experiment using the scale-down model of the concrete foundation. In addition, a model matching controller is used as the control function.

Experimental study on superconducting fault current limiting transformer for fault current suppression and system stability improvement

We have been developing a superconducting fault current limiting transformer (SFCLT) with 3-phase, 500/275 kV, 625 MVA and optimized the main parameters by EMTP simulation. In this paper, we designed and fabricated an experimental scale-down model of SFCLT with 3-phase, 275/105 V, 6.25 kVA, using NbTi superconducting wire. We introduced the experimental model SFCLT into a transient network analyzer consisted of synchronous generators, transformers, transmission lines, circuit breakers and an infinite bus. It was revealed that experimental model had effective function-parameters as was simulated and experimental results clarified the effectiveness of SFCLT having both functions of the fault current suppression and the system stability improvement in a future superconducting power system.

Improvement of ventilation flow inside a large factory building using PIV velocity field measurements

Air movement in workplaces, whether resulting from a forced ventilation system or natural airflow, has a significant impact on occupational health. In a huge building of shipbuilding factory, typical harmful factors such as fume or vaporized gas from welding and cutting of steel plates give an unpleasant feeling. From field data survey, the yearly dominant wind directions around the factory building tested were north-west, north-east and south-east. Among the three wind directions, the ventilation improvement was the worst for the north-eastern wind. This study was focused on modification of opening vents in order to utilize the natural ventilation flow effectively. Instantaneous velocity fields inside the 1/1000 scale-down factory building model were measured using a 2-frame cross-correlation PIV method. The factory model was embedded in an atmospheric boundary layer simulated in a wind tunnel. The modified vents improved the internal ventilation flow with increasing the flow speed more than two times, compared with that of present vents.

Scale‐down model to simulate spatial pH variations in large‐scale bioreactors

For the first time a laboratory-scale two-compartment system was used to investigate the effects of pH fluctuations consequent to large scales of operation on microorganisms. pH fluctuations can develop in production-scale fermenters as a consequence of the combined effects of poor mixing and adding concentrated reagents at the liquid surface for control of the bulk pH. Bacillus subtilis was used as a model culture since in addition to its sensitivity to dissolved oxygen levels, the production of the metabolites, acetoin and 2,3-butanediol, is sensitive to pH values between 6.5 and 7.2. The scale-down model consisted of a stirred tank reactor (STR) and a recycle loop containing a plug flow reactor (PFR), with the pH in the stirred tank being maintained at 6.5 by addition of alkali in the loop. Different residence times in the loop simulated the exposure time of fluid elements to high values of pH in the vicinity of the addition point in large bioreactors and tracer experiments were performed to characterise the residence time distribution in it. Since the culture was sensitive to dissolved oxygen, for each experiment with pH control by adding base into the PFR, equivalent experiments were conducted with pH control by addition of base into the STR, thus ensuring that any dissolved oxygen effects were common to both types of experiments. The present study indicates that although biomass concentration remained unaffected by pH variations, product formation was influenced by residence times in the PFR of 60 sec or longer. These changes in metabolism are thought to be linked to both the sensitivity of the acetoin and 2,3-butanediol-forming enzymes to pH and to the inducing effects of dissociated acetate on the acetolactate synthase enzyme.

Improvement of Natural Ventilation in a Factory Building Using a Velocity Field Measurement Technique

Air movement in wokplaces, whether resulting from a forced ventilation system or naturally occurring airflow, has a significant impact on occupational health. In a huge shipbuilding factory building, typical harmful factors such as fume or vaporized gas from welding and cutting of steel plates, and dusts from grinding give unpleasant feeling. From field data survey, the yearly dominant, wind directions for the shipbuilding factory building tested were northwest, northeast and southeast Among the three wind directions, the ventilation improvement was the worst for the northeastern wind. This study was focused on location of the opening vents in order to utilize the natural ventilation effectively. Instantaneous velocity fields inside the 1/1000 scale-down factory building model were measured using a 2-frame PIV system. The factory building model was embedded in an atmospheric boundary layer simulated in a wind tunnel. The modified vents improve the internal Ventilation flow with increasing the flow speed more than two times, compared with that of present vents.

Evaluation of the Thin-Layer Method Used for Measuring Single Particle Drying Kinetics

One method employed to measure drying kinetics for small particles is the thin layer method (TLM). In this method, the drying rate of a layer of particles is measured and the single particle kinetics must then be extracted from this data. This scale down process is rather complex since the gas phase changes through the bed which means that the drying conditions vary both in space and time. This paper is essentially a theoretical evaluation of the method. The validity of some of the assumptions made in the scale-down model (e.g. about transfer coefficients and the omission of the heat balance) are tested. Different expected problems such as the effects of the number of transfer units (NTU) and the degree of complexity of the internal drying kinetics on the quality of the results are also addressed.

Studies on Sway Control Systems for Rotary Cranes. Sway Control of a Scale-Down Model during Boom Hoisting Operations.

This paper is concerned with the sway control system for rotary cranes during boom hoisting operations. The sway control system in lever operations has been performed by developing a sway angle sensor and a sway controller, and the load sway is regulated by a feedback control, as reported previously. A sway control system during boom hoisting operations is developed by applying the regulator theory to a linearized crane model, which consists of the feedback of boom hoisting and sway angles, and their derivatives. It is confirmed by comparison of analytical and experimental results that the proposed sway system during boom hoisting operations shows excellent control performance.

Studies on Sway Control Systems for Rotary Cranes. Development of a Sway Angle Sensor and Sway Control of a Scale-Down Model during Swing Operation.

This paper is concerned with the sway control system for rotary cranes during swing operation. The sway control system in lever operation is successfully performed by developing a sway angle sensor and a sway controller. The proposed sensor is composed of strain gauges and a FIR filter which can measure the sway angle with time-lag using boom strain. The load sway is regulated by applying the regulator theory to a linearized crane model. It is confirmed by comparison of analytical and experimental results that the proposed sway system shows excellent performance and allows easy operation from a practical viewpoint.

An investigation of fluidized-bed scaling: heat transfer measurements in a pressurized fluidized-bed combustor and a cold model bed

A method is proposed for predicting heat transfer coefficients in hot fluidized-bed combustors by translating results measured in a scaled-down, cold model bed. Provided the beds are scaled to hydrodynamic similarity, local heat transfer coefficients measured in the cold model bed can be translated into local hot-bed convective coefficients with the aid of existing correlations for the gas and particle convective components. To obtain the total hot-bed-to-surface coefficients, a radiative component is then added. The chief advantages of the proposed method are that existing convective heat transfer correlations can be applied locally in a bed, and that no a priori knowledge of the voidage close to the transfer surface is required. In a previous paper by Almstedt and Zakkay, measurements of the bubble activity in a pressurized fluidized-bed burning coal and in a scale-down pressurized model bed operating at room temperature showed that a good hydrodynamic similarity can be obtained between the beds. The heat transfer translation method proposed here has been validated by comparing heat transfer coefficients measured in the same two beds, operating under scaled conditions. Average heat transfer coefficients for four different horizontal tube bundles, as well as local coefficients measured with probes in four different positions were compared. The results indicate good agreement between the hot-bed results measured and the results translated from the model bed measurements employing the proposed method. Furthermore, the present paper presents heat transfer measurements from the cold model bed for three different bed materials, at pressures of 0.1, 0.24 and 0.5 MPa and fluidization velocities ranging from 0.15 to 1.3 m/s. The results are in good accordance with existing theory, but indicate that the gas convective component (as well as the particle convective component) is significantly dependent on the fluidization velocity.