Step-change Experiments Research Articles

Evaluating the Improvement of Blend Potency Measurements in the Feed Frame of a Rotary Tablet Press Using Combined NIR and Raman Spectroscopy.

This study investigated the added value of combining both near-infrared (NIR) and Raman spectroscopy into a single NIRaman Combi Fiber Probe for in-line blend potency determination in the feed frame of a rotary tablet press. A five-component platform formulation was used, containing acetylsalicylic acid as the Active Pharmaceutical Ingredient (API). Calibration models for the determination of 1 and 5%w/w label claim tablets were developed using NIR and Raman spectra of powder blends ranging from 0.75 to 1.25%w/w and 3.75 to 6.25%w/w API, respectively. Step-change experiments with deliberate 10% deviation steps from the label claims were performed, from which the collected spectra were used for model validation. For model development and validation, low-level data fusion was explored through concatenation of preprocessed NIR and Raman spectra. Mid-level data fusion was also evaluated, based on extracted features of the preprocessed data. Herewith, score vectors were extracted by transforming preprocessed spectra through Principal Component Analysis, followed by critical feature selection through Elastic Net Regression. Partial Least Squares regression was applied to regress singular, low-level or mid-level fused data versus blend potency. It could be concluded that irrespective of the data fusion technique, an increase in Step-Change Sensitivity (SCS) and decrease in Root Mean Squared Error (RMSE) was observed when predicting the 5%w/w step-change experiment. For the prediction of the 1%w/w step-change experiment, no added benefit with regard to SCS and RMSE was observed due to the addition of the noisy NIR spectra.

Analytical deconvolution of smearing effect for inversion of scanning mobility particle sizer data

The scanning mobility particle sizer (SMPS) is a key instrument for aerosol studies that enables rapid measurement of particle size distribution. When SMPS data are inverted, the smearing effect needs to be considered. Previous studies used numerical methods to deconvolute the smearing effect. In this paper, to reduce the complexity of SMPS data inversion, we derive an analytical formula for de-smearing, and include our de-smearing formula into a full SMPS data inversion scheme. We also propose the voltage step change experiment to characterize the smearing effect of an SMPS. The effectiveness and robustness of our de-smearing approach were demonstrated using experimental data.

Four kinds of body temperatures and their relationships with thermal perception

Body temperature serves as the principal factor in thermal perception determination. Current thermal comfort researches mainly focused on skin temperature, while other kinds of body temperatures were often ignored. In laboratory with strictly controlled environment, 26 subjects (13 males and 13 females) remained seated for a duration of 130 min in two thermal environments (19 °C and 35 °C), arranged in a particular order; four kinds of body temperatures (skin temperature, oral temperature, auditory canal temperature and breath temperature) and three kinds of thermal perception votes (thermal sensation, thermal comfort and thermal acceptable) were regularly collected. The analysis results showed that, skin temperature and breath temperature significantly changed with ambient temperature (p < 0.001); the difference between average value of core temperature in two conditions was small (≤0.3 °C), but a significant difference was almost observed in auditory canal temperature of males (p = 0.07). Both skin temperature and breath temperature were significantly related with three subjective votes (p < 0.001), meanwhile, the prediction accuracy of breath temperature for thermal perception was in no way inferior to skin temperature. Although oral temperature and auditory canal temperature had partial significant correlations with thermal perception, they were difficult to be carried out in practical application due to their weak explanatory powers (correlation coefficient <0.3). In summary, this research tried to establish correlation laws between body temperatures and thermal perception votes during a temperature step-change experiment, while finding the potential of utilizing breath temperature for thermal perception prediction, which is expected to be further promoted in the future.

Elucidation of the powder flow pattern in a twin-screw LIW-feeder for various refill regimes

The importance of residence time distribution modeling is acknowledged as a tool for enabling material tracking and control within a continuous manufacturing line in order to safeguard both product quality and production efficiency. One of the first unit-operations into a continuous direct compression line (i.e. CDC-line) worthwhile doing extensive RTD-analysis upon are the LIW-feeders since they dose the ingredients in a controlled way following the label claim and hence can directly influence critical quality attributes like content uniformity. An NIR measurement method was developed determining the RTD of selected powders at specific feeder settings. Step-change experiments using sodium saccharin as a tracer were conducted. In order to gain and in depth understanding of the material flow, spatial samples throughout the hopper were taken at predefined timepoints during the step change experiments. This revealed the presence of a bypass trajectory along the edges of the agitator, while in the center of the agitator an inner mixing volume in which the tracer concentration lags behind seemed to be present. Finally, a model based on a plug flow and continuous stirred tank reactor was evaluated. The fitted model was not able to capture this complex flow behavior and shows the need for an extended compartmental model distinguishing between a bypass trajectory formed by the agitator and an inner mixing volume.

Study on the influence of hypobaric hypoxia on human thermal comfort under step change thermal environments

Given the meteorological conditions on the Tibetan plateau such as low temperatures and large diurnal range, people moving in and out of buildings are inevitably exposed to the transient, step change thermal environments. Significant temperature changes are closely related to humans' thermoregulatory processes, and the hypoxic environment may affect the thermoregulation process of sojourners in Tibet, which makes it difficult for people to adapt to temperature changes in time and increases the risk of disease. Nevertheless, most experimental studies on temperature step change were carried out in plain. Only a few experimental studies focused on the effect of temperature step change on human thermal comfort under low temperature and hypoxic environment. In order to understand the impact of this condition, the same temperature step change experiment was conducted in Xi'an and Lhasa, respectively. The results showed that the hypoxic environment of the plateau could cause decreasing of sojourners’ thermal sensation and skin temperature in Tibet under low temperature environment, and prolong the time needed for skin to rewarm. The results of this study can help provide a better thermal environment in buildings to ensure the health and thermal comfort of Tibetan sojourners.

An extended 3-compartment model for describing step change experiments in pharmaceutical twin-screw feeders at different refill regimes

Residence time distributions (RTDs) are a valuable tool for product tracking in the unit operations of a continuous line for manufacturing pharmaceutical oral solid dosage (OSD) and the integrated system itself. The first unit operation in such a continuous line in which extended intermixing can occur, is typically a feeder. The RTD of a feeder can be obtained by performing tracer experiments with a tracer material. A physical interpretation can be given to the observed tracer concentration responses by fitting a tanks-in-series (TIS) or compartmental model to it. Consequently, the internal mixing behaviour inside the feeder hopper can be rationalized. However, typically, a constant volume is assumed for the tanks or compartments in these models. This has led to several publications where the experimental set-up does not violate the constant volume assumption, i.e. one performs refills at a high hopper fill level. Here, we step away from this assumption and develop a set of differential equations for a 3-compartment model in order to account for a non-constant volume of the compartments. Moreover, the model distinguishes between a bypass trajectory formed by the agitator inside the feeder and an inner mixing volume, in which the tracer concentration lags on the tracer concentration in the bypass volume. This compartmentalization was inspired by the results obtained in a previous study using a spatial sampling method to assess the tracer concentration throughout the feeder hopper for different experimental runtimes. The developed model successfully describes the step responses for different refill regimes: the standard smooth first order plus dead time response (FOPDT) for a high refill regime and the more complex step response, including dips in the rising phase of the curve, for the low refill regime. As a consequence, a more thorough understanding of the complex mixing behaviour inside the feeder is obtained, which allows for an improved traceability. Next to that, the model delivers enhanced knowledge on the interaction between the residence time and the refill regime. The developed model was fitted to a data set, containing step change experiments for different pharmaceutical materials (Tablettose 80 (T80), Microcelac 100 (MCL), and Avicel PH101 (MCC)), different mass flow rates, and refill regimes. The experimentally observed phenomena could be reliably described by the proposed model. The model showed an improved transferability compared to typical TIS models.

Tracking raw material flow through a continuous direct compression line Part I of II: Residence time distribution modeling and sensitivity analysis enabling increased process yield

Continuous manufacturing (CM) offers advantages in quality and space–time yield compared to common batch manufacturing. However, higher yield losses due to the start-up procedure make a broad application uneconomical. This work discusses the possibility of reducing yield losses by adjusting the degree of back-mixing. Back-mixing of nonconforming material from disturbances or start-up will result in the contamination of subsequent material. Therefore, higher degrees of back-mixing cause the discharge of additional material. Choosing an advantageous setting of operational parameters may be a simple way to change the degree of back-mixing. Based on direct compression, this work demonstrates the identification of promising parameters. Therefore, step-change experiments using color-marked material in the feeder, blender, and tablet press quantify the impact of three operational parameters per device. Models for the devices and the entire process result from those measurements. Subsequently, a global variance-based sensitivity analysis identifies the most influential parameters. As a result, adjusting the minimal filling level of the feeder and the rotational feed frame speed of the tablet press reduces back-mixing by more than 30 %. At high costs of the raw materials, the resulting savings can significantly improve the economic performance of CM compared to batch manufacturing.

Residence time distribution as a traceability method for lot changes in a pharmaceutical continuous manufacturing system

Residence time distribution (RTD) models were developed to track raw material lots and investigate batch transitions in a continuous manufacturing system. Two raw materials with similar physical properties (granular metformin and lactose) were identified via Principal Component Analysis (PCA) from a library of bulk material properties and used to simulate the switching of lots during production. In-line near-infrared (NIR) spectra were collected with the powder flowing through a chute in a continuous manufacturing system to monitor metformin and lactose concentration in step-change experiments with Partial Least Squares (PLS) models. RTD provided an understanding of raw material propagation through the continuous manufacturing system. Transition times between raw material changes were identified using the results of two multivariate approaches PLS and PCA. The methodology was implemented to discriminate the transition zone in a raw material change, contributing to design control strategies for acceptance and diverting mechanisms.

Modelling of kinetics, mass transfer and flow pattern on open foam structures in tubular reactors: Hydrogenation of arabinose and galactose on ruthenium catalyst

Open foam structures are very beneficial as heterogeneous catalysts for three-phase processes, because they have high efficiency and low pressure drop. A mathematical model for open foam catalyst structures was developed. It was based on the concept of axial dispersion as flow pattern, on liquid-solid mass transfer effects and intrinsic kinetics on the active sites of the catalyst. Rate equations were presented for the hydrogenation of individual sugars and binary sugar mixtures on Ru/C catalysts and they were implemented in the mass transfer and flow models of the open foam catalyst. The flow pattern in the foam structure was confirmed with step change experiments with an inert tracer. The multiphase model was applied on the hydrogenation of arabinose and galactose in a laboratory-scale open foam catalyst bed. The model was able to reproduce the main features of the experimental observations, both for individual sugars and binary sugar mixtures.

Residence time distribution modelling and in line monitoring of drug concentration in a tablet press feed frame containing dead zones

The presence of a ‘significant dead zone’ in any continuous manufacturing equipment may affect the product quality and need to be investigated systematically. Dead zone will affect the residence time distribution (RTD) of continuous manufacturing and thus the mixing and product quality. Tablet press (feed frame) is one of unit operations that directly influence the critical quality attributes (CQA’s). However, currently no systematic methods and tools are available to characterize and model the feed frame dead zone. In this manuscript, the RTD of the tablet press feed frame containing dead zone is investigated. Step-change experiments revealed that the feed frame could be expressed as a traditional continuous stirred tank model. The volume fractions of the dead zones are determined experimentally as well as using RTD model. In addition, an in-line NIR method for drug concentration monitoring inside the feed frame is also developed. The developed NIR calibration model enables to monitor the drug concentration precisely and detect the variation immediately with the probe positioned right above the left paddle. It is also found that the feed frame paddle speed slightly affects the predictive accuracy of NIR, while the die disc speed has no significant effect.

“Bristle-State” Friction: Modeling Slip Initiation and Transient Frictional Evolution From High-Velocity Earthquake Rupture Experiments

Lamont-Doherty Fellowship in Earth and Environmental Sciences National Science Foundation (NSF) 1615203 National Research Center for Integrated Natural Disaster Management ANID/FONDAP/15110017 Andean Geothermal Center of Excellence, CEGA 15090013

Mixing experiments in 3D-printed silos; the role of wall friction and flow correcting inserts

The mixing of particles during silo discharge is of high industrial significance, yet quantitative studies of this process in literature are few. Here we present experimental measurement of particle mixing in 3D-printed silos during complete discharge, accounting for hopper half angle, the wall condition, and the addition of flow correcting inserts. Mono-sized mustard seed are dyed one of two colours (yellow or blue) to enable them to be distinguished during a step-change experiment. The silo is partially filled with yellow particles, followed by an equal mass of blue, then discharged onto a rotating table apparatus which automatically collects particle samples for proportion analysis. The experiments are repeated for six hopper half angles, and for three different wall conditions of different smoothness. Finally, three flow correcting inserts are added to a silo to quantify their influence. It is found that, while the wall condition has a large influence on the mixing and the size of the stagnant “pocket” region (the non-flowing region in a funnel-flow silo), the addition of flow correcting inserts has the greatest effect in reducing mixing and pocket region size. Our method of completely discharging the silo has the advantage that the pocket region mass can be easily quantified, in contrast to classical continuous flow residence-time experiments.

The End of the Wait for Climate Sensitivity?

AbstractThe Earth system responds on a range of timescales to a change in radiative forcing, and full equilibration takes centuries to millennia in many models. In their recent paper, Saint‐Martin et. al (2019, https://doi.org/10.1029/2019GL083031) propose a technique for reaching a faster equilibrium temperature response to alternative CO2 concentration levels by briefly overshooting the desired concentration level to warm the deep ocean faster than a conventional step change experiment. Understanding how these timescales interact is essential for better representing the relationship between transient climate change and the warming which should be expected as greenhouse gas concentrations stabilize. But the technique also raises new possibilities about how Earth System Models could be developed and whether we could gain the capacity to spin‐up alternative model configurations such as perturbed parameter simulations or alternative control states to explore historical forcing uncertainty.

On the Transient Thermal Characteristics of Silicon Carbide Power Electronics Modules

The transient performance of power semiconductor devices relates directly to their available power rating, reliability, and operating lifetime. This paper examines the transient thermal performance of liquid-cooled, silicon carbide power devices subjected to different unsteady electrical loads. The first part uses infrared thermography to examine an observed asymmetrical device thermal time constant when subjected to step-change increases and decreases in current. A theoretical analysis connects this behavior to the dependence of mosfet on-resistance on junction temperature. It also identifies three time constants that characterize junction transient response, one each for the die, the module, and the cold plate. The second part extends the transient thermal evaluation to half-sine wave periodic excitations that emulate real-application operating conditions. These experiments show that thermal ripple increases with increasing excitation amplitude but decreases with increasing excitation frequency. They also connect the observed thermal response to the time constants inferred from the step-change experiments. Both parts of the study show the importance of considering transient loads when designing power electronics cooling systems and the role that electrical properties play in determining unsteady thermal response.

Combining tracer studies and biomimetic design principles to investigate clogging in constructed wetlands

In this study, we suggest a clogging maintenance strategy and design alteration for constructed wetlands. Such a system could benefit rural communities who rely solely on constructed wetland systems for provision of household and agricultural water and for whom regular system shut-down for maintenance is essentially not viable. A newly established, pilot-scale horizontal subsurface flow constructed wetland was investigated by means of step-change tracer experiments. Sampling was carried out at multiple points down the length of the wetland and at three depths for each location. The mean residence time datawere used to generate velocity profiles. This methodology enabled the development of a three-dimensional hydraulic model to identify dead zones and regions of short-circuiting within the system. Biomimetic principles were then incorporated to propose improvements to conventional constructed wetland design, which would potentially allow for better clogging management and continuous operation. In particular, modularizing the regions of the wetland most prone to clogging (those containing dead space) would accommodate isolation, removal and replacement of such sections, while still allowing treatment of wastewater in adjacent sections.

A system identification approach for developing model predictive controllers of antibody quality attributes in cell culture processes.

As the biopharmaceutical industry evolves to include more diverse protein formats and processes, more robust control of Critical Quality Attributes (CQAs) is needed to maintain processing flexibility without compromising quality. Active control of CQAs has been demonstrated using model predictive control techniques, which allow development of processes which are robust against disturbances associated with raw material variability and other potentially flexible operating conditions. Wide adoption of model predictive control in biopharmaceutical cell culture processes has been hampered, however, in part due to the large amount of data and expertise required to make a predictive model of controlled CQAs, a requirement for model predictive control. Here we developed a highly automated, perfusion apparatus to systematically and efficiently generate predictive models using application of system identification approaches. We successfully created a predictive model of %galactosylation using data obtained by manipulating galactose concentration in the perfusion apparatus in serialized step change experiments. We then demonstrated the use of the model in a model predictive controller in a simulated control scenario to successfully achieve a %galactosylation set point in a simulated fed‐batch culture. The automated model identification approach demonstrated here can potentially be generalized to many CQAs, and could be a more efficient, faster, and highly automated alternative to batch experiments for developing predictive models in cell culture processes, and allow the wider adoption of model predictive control in biopharmaceutical processes. © 2017 The Authors Biotechnology Progress published by Wiley Periodicals, Inc. on behalf of American Institute of Chemical Engineers Biotechnol. Prog., 33:1647–1661, 2017

Lab-scale experimental studies of Fischer–Tropsch kinetics in a three-phase slurry reactor under transient reaction conditions

Fluctuating electricity can be converted into hydrocarbon fuels via hydrogen as intermediate, thus replacing fossil fuels and possibly be attractive as a long-term storage in excess electricity generation situations. In this context, flexible operation of the chemical synthesis reactor may be motivated by the possibility of reducing the size of the hydrogen storage and the investment needed. The present study has the aim to identify general aspects and limitations of flexible Fischer–Tropsch reactor operation considering catalyst behavior and reactor operation in a three-phase system. In this contribution, methodology and first results of lab-scale experiments with a stirred slurry reactor are presented. Results of step-change experiments can be described by a mathematical model of the lab-scale setup, using steady-state kinetics determined in separate experiments. During periodic-change experiments, average rates of CO consumption and CH4 formation are not affected by period length. In contrast, analysis of periodic-change experiments with emphasis on hydrocarbon product distribution indicate that long chain hydrocarbon molar flows cannot follow forced oscillation as fast as methane molar flow.

Simulation the flow of semi-solid steel alloy using an enhanced model

Simulating steel semi-solid metal forming close to a real industrial forming is necessary to reduce potential run-time errors and costs. Simulating requires modeling of semi-solid behaviour. In this work a model based on micromechanical analysis with consideration the viscoplastic response along with an enhanced Herschel-Bulkley model has been proposed to predict the flow behaviour of semi-solid M2 high speed steel. This model is introduced to overcome the limitations of the previously used models. The extracted model parameters from the steady state flow stress and step-change of shear rate experiments were then calculated and fitted to the experimental rheology results of continuous cooling. The model was then implemented linking into the computational fluid dynamics software (FLOW 3D Ver.9.3). A T-Shape die used to investigate the flow front of semisolid alloy. Also the extracted parameters at low shear rate in the step change experiments used for simulation of the compression process of M2 tool steel at high solid fraction by the proposed model and in the ABAQUS 6.9 software. The experimental results of compression test shows a well agreement with simulations results indicative of the performance of the proposed model to predict rheological properties and flow behaviour of semi-solid states especially for the tool steel systems in the wide range of liquid fraction.

Fischer‐Tropsch Synthesis with H2/CO2 – Catalyst Behavior under Transient Conditions

AbstractCatalytic reactors are usually operated under steady‐state conditions; however, transient operation may lead to benefits for the overall process. Two different methodologies are presented to study catalyst activity under transient operation conditions: (i) step change experiments combined with mathematical modeling and (ii) periodic changes. Fischer‐Tropsch synthesis using iron‐based catalyst is the selected example reaction. According to both methods, the catalyst activity under transient operation can be described in the range of validity of the selected rate equation and parameter values determined under steady‐state conditions.

Determination of air-to-air heat wheel sensible effectiveness using temperature step change data

The determination of the effectiveness of large heat wheels using standard measured data and test conditions can be very expensive and time consuming. The main contribution of this paper is that it tests heat wheel components rather than the wheel itself. In addition, this paper deals directly with the question of what accuracy can be achieved for the determination of sensible energy effectiveness by using a transient step change method for the exchanger matrix materials in a test cell. In this study, the sensible effectiveness of heat wheels is predicted by performing a number of cyclic and single step change transient experiments on a parallel-plate heat exchanger. A new experimental facility is developed to cause a step change for the inlet air temperature of the exchanger. In the cyclic tests, the heat exchanger is exposed to a periodic inlet temperature steps; afterward, the sensible effectiveness of parallel-flow and counter-flow heat wheel, comprised of the same material as parallel-plate exchanger, is determined using the obtained temperature profiles. It is find that this method can be used to determine the sensible effectiveness of parallel-flow heat wheel. However, the high uncertainty found in the sensible effectiveness of counter-flow heat wheel, ±32%, makes the results unreliable. In the single step-change test, a time constant is assigned to the exchanger response when it is subjected to a step change in inlet temperature. The time constant is obtained by fitting the experimental data to a first order exponential time response curve. An analytical solution posits that the effectiveness of the heat wheel depends only on the product of the time constant and the wheel angular speed, or angle ratio. Comparing values of the sensible effectiveness calculated through available empirical correlations and the ones obtained by single step change experiment showed less than 3% difference in results when the heat capacity rate ratio is greater than 5. It is concluded that due to simplicity, accuracy, and low cost of the single step change experiments, it is the preferred method to determine the effectiveness of heat wheels operating at a specified rotary speeds, provided the flow channel geometries and Reynolds numbers for both the wheel and the small-scale test cell.