The Experts below are selected from a list of 10011 Experts worldwide ranked by ideXlab platform
Peter Kleinebudde - One of the best experts on this subject based on the ideXlab platform.
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development and evaluation of an in line and on line monitoring system for Granule Size distributions in continuous roll compaction dry granulation based on laser diffraction
Journal of Pharmaceutical Innovation, 2021Co-Authors: Annika Wilms, Robin Meier, Peter KleinebuddeAbstract:Roll compaction/dry granulation is established in manufacturing of solid oral dosage forms and, within the context of continuous manufacturing, it has sparked interest as material is fed, processed, and ejected continuously while also providing large possible throughputs. However, this amount of material has to be adequately controlled in real time to assure quality. This research aimed at monitoring the critical quality attribute Granule Size distribution in continuous roll compaction/dry granulation (QbCon®; L.B. Bohle, Ennigerloh, Germany) using in-line and on-line laser diffraction. The influence of varying process parameters and excipient formulations was studied and evaluated with the prospect of using this technique to develop control loops. For this purpose, residence time parameters were assessed. In- and on-line data was compared with off-line laser diffraction and dynamic image analysis data. The system successfully monitored the Granule Size distribution in a variety of process parameters and throughputs (up to 27.5 kg/h). It was sensitive to changes in process parameters and changes in material blends, which could pose a potential threat to the final drug products’ quality. Average event propagation time from the compaction zone to the laser diffraction system of 17.7 s demonstrates the systems’ fast reaction time. Results highlight laser diffraction as a valuable method of in- and on-line Size determination and allow for the development of a control strategy using this principle.
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implementing feedback Granule Size control in a continuous dry granulation line using controlled impeller speed of the granulation unit compaction force and gap width
Journal of Pharmaceutical Innovation, 2020Co-Authors: Annika Wilms, Raphael Wiedey, Andreas Teske, Robin Meier, Peter KleinebuddeAbstract:In continuous manufacturing of pharmaceuticals, dry granulation is of interest because of its large throughput capacity and energy efficiency. In order to manufacture solid oral dosage forms continuously, valid control strategies for critical quality attributes should be established. To this date, there are no published control strategies for Granule Size distribution in continuous dry granulation. In-line laser diffraction was used to determine the Size of Granules in a continuous roll compaction/dry granulation line (QbCon® dry). Different process parameters were evaluated regarding their influences on Granule Size. The identified critical process parameters were then incorporated into control strategies. The uncontrolled and the controlled processes were compared based on the resulting Granule Size. In both processes, a process parameter was changed to induce a shift in median particle Size and the controller had to counteract this shift. In principle, all process parameters that affect the median particle Size could also be used to control the particle Size in a dry granulation process. The sieve impeller speed was found to be well suited to control the median particle Size as it reacts fast and can be controlled independently of the throughput or material. The median particle Size in continuous roll compaction can be controlled by adjusting process parameters depending on real-time Granule Size measurements. The method has to be validated and explored further to identify critical requirements to the material and environmental conditions.
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combination of a rotating tube sample divider and dynamic image analysis for continuous on line determination of Granule Size distribution
International journal of pharmaceutics: X, 2019Co-Authors: Annika Wilms, Klaus Knop, Peter KleinebuddeAbstract:Abstract The Granule Size distribution is a critical quality attribute of Granules. It has a great impact on further packaging or processing. Due to increasing interest in continuous manufacturing techniques, it is of high interest to develop an in-line or on-line tool to monitor the Granule Size distribution. However, development of an in-line measurement tool for Granule Size distribution was challenging since large throughput and inhomogeneous product stream are limiting factors for current particle Size analyzers. In this study, continuous sampling was tested in conjunction to a continuous on-line method of Size determination using dynamic image analysis. A rotating tube sample divider was used to split previously compacted material in representative samples at different ratios and the sample was directly conveyed to the particle Size analyzer where the Granule Size distribution was determined. The method was tested for different Granule Sizes to determine limits of detection and its ability to detect these changes immediately, as this enables real-time monitoring of the process. This research is the base for development of control tools concerning the Granule Size distributions for continuous granulation processes.
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mcc mannitol mixtures after roll compaction dry granulation percolation thresholds for ribbon microhardness and Granule Size distribution
Pharmaceutical Development and Technology, 2017Co-Authors: Ana Perez Gago, Peter KleinebuddeAbstract:In roll compaction, the specific compaction force, the gap width and the roll speed are the most important settings as they have a high impact in the products obtained. However the mechanical properties of the mixture being compacted are also critical. For this reason, a multilevel full factorial design including these parameters as factors plus three repetitions of the center point was performed for microcrystalline cellulose, mannitol and five binary mixtures (15, 30, 50, 70 and 85% MCC). These two reference excipients were chosen in order to investigate the plastic/brittle behavior of mixtures for the roll compaction process. These materials were roll compacted in a 3-W-Polygran® 250/50/3 (Gerteis) and the ribbons obtained were collected and milled into Granules which were characterized regarding Granule Size distribution. After statistical evaluation, it was found that the most critical factors affecting the D10, D50, D90 and the fines fraction from the Granules were the gap width and the specific compaction force, as well as the proportion of MCC together with its quadratic effect and the interaction between force and proportion of MCC. The microhardness of the ribbons from the center point as well as the D10, D50, D90 and the fines fraction from the Granules produced at these same conditions were characterized. In all the cases, the proportion of MCC, i.e. the composition of the mixture, showed also an important effect on these properties measured. In this sense, the percolation theory was applied in order to study further the importance of the plastic/brittle ratio by calculating the percolation threshold or the limit over which the behavior of the system changes. This resulted in values of 34% for the HU (expression of microhardness), 27% and 28% for the D10 and fines, respectively (percolation of MCC) and 84% and 85% for the D50 and D90, respectively (percolation of mannitol).
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effect of roll compaction on Granule Size distribution of microcrystalline cellulose mannitol mixtures computational intelligence modeling and parametric analysis
Drug Design Development and Therapy, 2017Co-Authors: Pezhman Kazemi, Peter Kleinebudde, Mohammad Khalid, Jakub Szlek, Renata Jachowicz, Ana Perez Gago, Aleksander MendykAbstract:Dry granulation using roll compaction is a typical unit operation for producing solid dosage forms in the pharmaceutical industry. Dry granulation is commonly used if the powder mixture is sensitive to heat and moisture and has poor flow properties. The output of roll compaction is compacted ribbons that exhibit different properties based on the adjusted process parameters. These ribbons are then milled into Granules and finally compressed into tablets. The properties of the ribbons directly affect the Granule Size distribution (GSD) and the quality of final products; thus, it is imperative to study the effect of roll compaction process parameters on GSD. The understanding of how the roll compactor process parameters and material properties interact with each other will allow accurate control of the process, leading to the implementation of quality by design practices. Computational intelligence (CI) methods have a great potential for being used within the scope of quality by design approach. The main objective of this study was to show how the computational intelligence techniques can be useful to predict the GSD by using different process conditions of roll compaction and material properties. Different techniques such as multiple linear regression, artificial neural networks, random forest, Cubist and k-nearest neighbors algorithm assisted by sevenfold cross-validation were used to present generalized models for the prediction of GSD based on roll compaction process setting and material properties. The normalized root-mean-squared error and the coefficient of determination (R2) were used for model assessment. The best fit was obtained by Cubist model (normalized root-mean-squared error =3.22%, R2=0.95). Based on the results, it was confirmed that the material properties (true density) followed by compaction force have the most significant effect on GSD.
Ingmar Nopens - One of the best experts on this subject based on the ideXlab platform.
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modeling of semicontinuous fluid bed drying of pharmaceutical Granules with respect to Granule Size
Journal of Pharmaceutical Sciences, 2019Co-Authors: Michael Ghijs, Thomas Beer, Ashish Kumar, Elisabeth Schafer, Philippe Cappuyns, Ivo Van Assche, Fien De Leersnyder, Vaĺerie Vanhoorne, Ingmar NopensAbstract:In the transition of the pharmaceutical industry from batchwise to continuous drug product manufacturing, the drying process has proven challenging to control and understand. In a semicontinuous fluid bed dryer, part of the ConsiGma™ wet granulation line, the aforementioned production methods converge. Previous research has shown that the evolution of moisture content of the material in this system shows strong variation in function of the Granule Size, making the accurate prediction of this pharmaceutical critical quality attribute a complex case. In this work, the evolution of moisture content of the material in the system is modeled by a bottom-up approach. A single Granule drying kinetics model is used to predict the moisture content evolution of a batch of material of a heterogeneous particle Size, where it is the first time that the single Granule drying mechanism is validated for different Granule Sizes. The batch approach was validated when the continuous material inflow rate and filling time of the dryer cell are constant. The original single Granule drying kinetics model has been extended to capture the Granules' equilibrium moisture content. Finally, the influence of drying air temperature is captured well with a droplet energy balance for the Granules.
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on the modelling of Granule Size distributions in twin screw wet granulation calibration of a novel compartmental population balance model
Powder Technology, 2019Co-Authors: Daan Van Hauwermeiren, Thomas Beer, Maxim Verstraeten, Pankaj Doshi, Mary Am T Ende, Neil Turnbull, Kai Lee, Ingmar NopensAbstract:Abstract In recent years, novel developments in the continuous manufacturing of solid dosage forms using twin-screw wet granulation have grasped the attention of the pharmaceutical industry. In spite of this progress, there still exists a lack of fundamental knowledge on the physical processes occurring in the barrel of the twin-screw granulator. A major contributor to this knowledge gap has been the unavailability of measurements of Granule properties (particle Size, liquid content, porosity, etcetera) along the length of the barrel. Recently conducted tedious measurements at different barrel locations have been essential to build a hypothesis in terms of locally occurring mechanisms in twin-screw wet granulation. This paper proposes a novel kernel for modelling either the uni- or bimodal behaviour observed at different L/S ratios in the wetting zone, assuming pure aggregation only. Furthermore, a two stage (wetting and kneading zone) compartmental population balance model is constructed to successfully simulate Granule Sizes from preblend to the end of the granulator. This population balance model can simulate Granule Size distributions at a reasonable accuracy both in the case of single compartments as well as in the full two stage compartmental set-up. The proposed model in this paper is a first important step in knowledge build-up of twin-screw granulation and towards a general population balance model for twin-screw wet granulation.
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Experimental investigation of Granule Size and shape dynamics in twin-screw granulation
International Journal of Pharmaceutics, 2014Co-Authors: Ashish Kumar, Giacomo Bellandi, Jean Paul Remon, Jurgen Vercruysse, Chris Vervaet, Thomas Beer, Krist V. Gernaey, Ingmar NopensAbstract:A twin-screw granulator (TSG), a promising equipment for continuous high shear wet granulation (HSWG), achieves the desired level of mixing by a combination of the appropriate screw configuration and a suitable set of process settings (e.g. feed rate, screw speed, etc.), thus producing a certain Granule Size and shape distribution (GSSD). However, the primary sizing and shaping mechanism behind the resulting distribution is not well understood due to the opacity of the multiphase system in the granulator. This study experimentally characterised the GSSD dynamics along the TSG barrel length in order to understand the function of individual screw modules and process settings, as well as their interaction. Particle Size analysis of Granules collected at the outlet of the TSG suggested significant interaction between the process and screw configuration parameters influencing the heterogeneity in the GSSD. By characterising the samples collected along the screw length, a variable influence of the screw modules at different process conditions was observed. At low liquid-to-solid ratio (L/S), the first kneading module seemed to play a significant role in mixing, whereas the second kneading module was found to be more involved in reshaping the Granules. At high L/S and high throughput, aggregation mainly took place in the second kneading module changing the GSSD. The results obtained from this study will be further used for the calibration and validation of a mechanistic model and, hence, support future development of a more detailed understanding of the HSWG process in a TSG.
D.f. Long - One of the best experts on this subject based on the ideXlab platform.
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the evolution of Granule fracture strength as a function of impeller tip speed and Granule Size for a novel reverse phase wet granulation process
International Journal of Pharmaceutics, 2015Co-Authors: Jonathan B. Wade, Gary P. Martin, D.f. LongAbstract:Abstract The feasibility of a novel reverse-phase wet granulation process has been established previously and several potential advantages over the conventional process have been highlighted ( Wade et al., 2014a , Wade et al., 2014b , Wade et al., 2014b ). Due to fundamental differences in the growth mechanism and Granule consolidation behaviour between the two processes the reverse-phase approach generally formed Granules with a greater mass mean diameter and a lower intragranular porosity than those formed by the conventional granulation process under the same liquid saturation and impeller tip speed conditions. The lower intragranular porosity was hypothesised to result in an increase in the Granule strength and subsequent decrease in tablet tensile strength. Consequently, the aim of this study was to compare the effect of impeller tip speed and Granule Size on the strength and compaction properties of Granules prepared using both the reverse-phase and conventional granulation processes. For the conventional granulation process an increase in the impeller tip speed from 1.57 to 4.71 m s −1 (200–600 RPM) resulted in an increase in the mean Granule strength ( p p p > 0.05) on mean Granule strength whereas, like the conventional process, an increase in Granule Size fraction from 425–600 to 2000–3350 μm resulted in a decrease ( p p > 0.05) for either granulation approach. These data support the rejection of the original hypothesis which stated that an increase in Granule strength may result in a decrease in the tablet tensile strength. The similar tablet tensile strength observed between the conventional and reverse-phase granulation processes indicated that while mechanistic differences exist in the formation of the Granules, which resulted in significant Granule-scale fracture strength differences, the Granule compaction properties at pharmaceutically relevant tableting pressures were unaffected.
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Controlling Granule Size through breakage in a novel reverse-phase wet granulation process: the effect of impeller speed and binder liquid viscosity.
International Journal of Pharmaceutics, 2014Co-Authors: Jonathan B. Wade, Gary P. Martin, D.f. LongAbstract:Abstract The feasibility of a novel reverse-phase wet granulation process has been established previously highlighting several potential advantages over the conventional wet granulation process and making recommendations for further development of the approach. The feasibility study showed that in the reverse-phase process Granule formation proceeds via a controlled breakage mechanism. Consequently, the aim of the present study was to investigate the effect of impeller speeds and binder liquid viscosity on the Size distribution and intragranular porosity of Granules using this novel process. Impeller tip speed was found to have different effects on the Granules produced by a conventional as opposed to a reverse-phase granulation process. For the conventional process, an increase in impeller speed from 1.57 to 3.14 m s−1 had minimal effect on Granule Size distribution. However, a further increase in impeller tip speed to 3.93 and 4.71 m s−1 resulted in a decrease in intragranular porosity and a corresponding increase in mean Granule Size. In contrast when the reverse-phase process was used, an increase in impeller speed from 1.57 to 4.71 m s−1 resulted in increased Granule breakage and a decrease in the mean Granule Size. This was postulated to be due to the fact that the granulation process begins with fully saturated pores. Under these conditions further consolidation of Granules at increased impeller tip speeds is limited and rebound or breakage occurs. Based on these results and analysis of the modified capillary number the conventional process appears to be driven by viscous forces whereas the reverse-phase process appears to be driven by capillary forces. Additionally, in the reverse-phase process a critical impeller speed, represented by the equilibrium between centrifugal and gravitational forces, appears to represent the point above which breakage of large wet agglomerates and mechanical dispersion of binder liquid take place. In contrast the conventional process appears to be difficult to control due to variations in Granule consolidation, which depends upon experimental variables. Such variations meant increased impeller tip speed both decreased and increased Granule Size. The reverse-phase process appears to offer simple control over Granule porosity and Size through manipulation of the impeller speed and further evaluation of the approach is warranted.
Cunxu Wei - One of the best experts on this subject based on the ideXlab platform.
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effect of Granule Size on the properties of lotus rhizome c type starch
Carbohydrate Polymers, 2015Co-Authors: Lingshang Lin, Z Wang, Jun Huang, Lingxiao Zhao, Juan Wang, Cunxu WeiAbstract:Lotus rhizome C-type starch was separated into different Size fractions. Starch morphologies changed from irregular to elongated, ellipsoid, oval, and spherical with decreasing Granule Size. The small- and very-small-Sized fractions had a centric hilum, and the other Size fractions had an eccentric hilum. The different Size fractions all showed C-type crystallinity, pseudoplasticity and shear-thinning rheological properties. The range of amylose content was 25.6 to 26.6%, that of relative crystallinity was 23.9 to 25.8%, that of swelling power was 29.0 to 31.4 g/g, and that of gelatinization enthalpy was 12.4 to 14.2J/g. The very-small-Sized fraction had a significantly lower short-range ordered degree and flow behavior index and higher scattering peak intensity, water solubility, gelatinization peak temperature, gelatinization conclusion temperature, consistency coefficient, hydrolysis degrees, and digestion rate than the large-Sized fraction. Granule Size significantly positively influenced short-range ordered structure and swelling power and negatively influenced scattering peak intensity, water solubility, hydrolysis and digestion of starch (p<0.01).
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different structural properties of high amylose maize starch fractions varying in Granule Size
Journal of Agricultural and Food Chemistry, 2014Co-Authors: Canhui Cai, Z Wang, Lingshang Lin, Lingxiao Zhao, Jianmin Man, Cunxu WeiAbstract:Large-, medium-, and small-Sized Granules were separated from normal and high-amylose maize starches using a glycerol centrifugation method. The different-Sized fractions of normal maize starch showed similar molecular weight distribution, crystal structure, long- and short-range ordered structure, and lamellar structure of starch, but the different-Sized fractions of high-amylose maize starch showed markedly different structural properties. The amylose content, iodine blue value, amylopectin long branch-chain, and IR ratio of 1045/1022 cm(-1) significantly increased with decrease of Granule Size, but the amylopectin short branch-chain and branching degree, relative crystallinity, IR ratio of 1022/995 cm(-1), and peak intensity of lamellar structure markedly decreased with decrease of Granule Size for high-amylose maize starch. The large-Sized Granules of high-amylose maize starch were A-type crystallinity, native and medium-Sized Granules of high-amylose maize starch were CA-type crystallinity, and small-Sized Granules of high-amylose maize starch were C-type crystallinity, indicating that C-type starch might contain A-type starch Granules.
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Different Structural Properties of High-Amylose Maize Starch Fractions Varying in Granule Size
2014Co-Authors: Canhui Cai, Z Wang, Lingshang Lin, Lingxiao Zhao, Jianmin Man, Cunxu WeiAbstract:Large-, medium-, and small-Sized Granules were separated from normal and high-amylose maize starches using a glycerol centrifugation method. The different-Sized fractions of normal maize starch showed similar molecular weight distribution, crystal structure, long- and short-range ordered structure, and lamellar structure of starch, but the different-Sized fractions of high-amylose maize starch showed markedly different structural properties. The amylose content, iodine blue value, amylopectin long branch-chain, and IR ratio of 1045/1022 cm–1 significantly increased with decrease of Granule Size, but the amylopectin short branch-chain and branching degree, relative crystallinity, IR ratio of 1022/995 cm–1, and peak intensity of lamellar structure markedly decreased with decrease of Granule Size for high-amylose maize starch. The large-Sized Granules of high-amylose maize starch were A-type crystallinity, native and medium-Sized Granules of high-amylose maize starch were CA-type crystallinity, and small-Sized Granules of high-amylose maize starch were C-type crystallinity, indicating that C-type starch might contain A-type starch Granules
Thomas Beer - One of the best experts on this subject based on the ideXlab platform.
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modeling of semicontinuous fluid bed drying of pharmaceutical Granules with respect to Granule Size
Journal of Pharmaceutical Sciences, 2019Co-Authors: Michael Ghijs, Thomas Beer, Ashish Kumar, Elisabeth Schafer, Philippe Cappuyns, Ivo Van Assche, Fien De Leersnyder, Vaĺerie Vanhoorne, Ingmar NopensAbstract:In the transition of the pharmaceutical industry from batchwise to continuous drug product manufacturing, the drying process has proven challenging to control and understand. In a semicontinuous fluid bed dryer, part of the ConsiGma™ wet granulation line, the aforementioned production methods converge. Previous research has shown that the evolution of moisture content of the material in this system shows strong variation in function of the Granule Size, making the accurate prediction of this pharmaceutical critical quality attribute a complex case. In this work, the evolution of moisture content of the material in the system is modeled by a bottom-up approach. A single Granule drying kinetics model is used to predict the moisture content evolution of a batch of material of a heterogeneous particle Size, where it is the first time that the single Granule drying mechanism is validated for different Granule Sizes. The batch approach was validated when the continuous material inflow rate and filling time of the dryer cell are constant. The original single Granule drying kinetics model has been extended to capture the Granules' equilibrium moisture content. Finally, the influence of drying air temperature is captured well with a droplet energy balance for the Granules.
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on the modelling of Granule Size distributions in twin screw wet granulation calibration of a novel compartmental population balance model
Powder Technology, 2019Co-Authors: Daan Van Hauwermeiren, Thomas Beer, Maxim Verstraeten, Pankaj Doshi, Mary Am T Ende, Neil Turnbull, Kai Lee, Ingmar NopensAbstract:Abstract In recent years, novel developments in the continuous manufacturing of solid dosage forms using twin-screw wet granulation have grasped the attention of the pharmaceutical industry. In spite of this progress, there still exists a lack of fundamental knowledge on the physical processes occurring in the barrel of the twin-screw granulator. A major contributor to this knowledge gap has been the unavailability of measurements of Granule properties (particle Size, liquid content, porosity, etcetera) along the length of the barrel. Recently conducted tedious measurements at different barrel locations have been essential to build a hypothesis in terms of locally occurring mechanisms in twin-screw wet granulation. This paper proposes a novel kernel for modelling either the uni- or bimodal behaviour observed at different L/S ratios in the wetting zone, assuming pure aggregation only. Furthermore, a two stage (wetting and kneading zone) compartmental population balance model is constructed to successfully simulate Granule Sizes from preblend to the end of the granulator. This population balance model can simulate Granule Size distributions at a reasonable accuracy both in the case of single compartments as well as in the full two stage compartmental set-up. The proposed model in this paper is a first important step in knowledge build-up of twin-screw granulation and towards a general population balance model for twin-screw wet granulation.
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Experimental investigation of Granule Size and shape dynamics in twin-screw granulation
International Journal of Pharmaceutics, 2014Co-Authors: Ashish Kumar, Giacomo Bellandi, Jean Paul Remon, Jurgen Vercruysse, Chris Vervaet, Thomas Beer, Krist V. Gernaey, Ingmar NopensAbstract:A twin-screw granulator (TSG), a promising equipment for continuous high shear wet granulation (HSWG), achieves the desired level of mixing by a combination of the appropriate screw configuration and a suitable set of process settings (e.g. feed rate, screw speed, etc.), thus producing a certain Granule Size and shape distribution (GSSD). However, the primary sizing and shaping mechanism behind the resulting distribution is not well understood due to the opacity of the multiphase system in the granulator. This study experimentally characterised the GSSD dynamics along the TSG barrel length in order to understand the function of individual screw modules and process settings, as well as their interaction. Particle Size analysis of Granules collected at the outlet of the TSG suggested significant interaction between the process and screw configuration parameters influencing the heterogeneity in the GSSD. By characterising the samples collected along the screw length, a variable influence of the screw modules at different process conditions was observed. At low liquid-to-solid ratio (L/S), the first kneading module seemed to play a significant role in mixing, whereas the second kneading module was found to be more involved in reshaping the Granules. At high L/S and high throughput, aggregation mainly took place in the second kneading module changing the GSSD. The results obtained from this study will be further used for the calibration and validation of a mechanistic model and, hence, support future development of a more detailed understanding of the HSWG process in a TSG.
