Papers by Jurgen Vercruysse
European Journal of Pharmaceutics and Biopharmaceutics, 2015
Since small scale is key for successful introduction of continuous techniques in the pharmaceutic... more Since small scale is key for successful introduction of continuous techniques in the pharmaceutical industry to allow its use during formulation development and process optimization, it is essential to determine whether the product quality is similar when small quantities of materials are processed compared to the continuous processing of larger quantities. Therefore, the aim of this study was to investigate whether material processed in a single cell of the six-segmented fluid bed dryer of the ConsiGma™-25 system (a continuous twin screw granulation and drying system introduced by GEA Pharma Systems, Collette™, Wommelgem, Belgium) is predictive of granule and tablet quality during full-scale manufacturing when all drying cells are filled. Furthermore, the performance of the ConsiGma™-1 system (a mobile laboratory unit) was evaluated and compared to the ConsiGma™-25 system. A premix of two active ingredients, powdered cellulose, maize starch, pregelatinized starch and sodium starch glycolate was granulated with distilled water. After drying and milling (1000μm, 800rpm), granules were blended with magnesium stearate and compressed using a Modul™ P tablet press (tablet weight: 430mg, main compression force: 12kN). Single cell experiments using the ConsiGma™-25 system and ConsiGma™-1 system were performed in triplicate. Additionally, a 1h continuous run using the ConsiGma™-25 system was executed. Process outcomes (torque, barrel wall temperature, product temperature during drying) and granule (residual moisture content, particle size distribution, bulk and tapped density, hausner ratio, friability) as well as tablet (hardness, friability, disintegration time and dissolution) quality attributes were evaluated. By performing a 1h continuous run, it was detected that a stabilization period was needed for torque and barrel wall temperature due to initial layering of the screws and the screw chamber walls with material. Consequently, slightly deviating granule and tablet quality attributes were obtained during the start-up phase of the 1h run. For the single cell runs, granule and tablet properties were comparable with results obtained during the second part of the 1h run (after start-up). Although deviating granule quality (particle size distribution and Hausner ratio) was observed due to the divergent design of the ConsiGma™-1 unit and the ConsiGma™-25 system (horizontal set-up) used in this study, tablet quality produced from granules processed with the ConsiGma™-1 system was predictive for tablet quality obtained during continuous production using the ConsiGma™-25 system.
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International Journal of Pharmaceutics, 2015
Twin screw granulation (TSG) has been reported by different research groups as an attractive tech... more Twin screw granulation (TSG) has been reported by different research groups as an attractive technology for continuous wet granulation. However, in contrast to fluidized bed granulation, granules produced via this technique typically have a wide and multimodal particle size distribution (PSD), resulting in suboptimal flow properties. The aim of the current study was to evaluate the impact of granulator screw configuration on the PSD of granules produced by TSG. Experiments were performed using a 25 mm co-rotating twin screw granulator, being part of the ConsiGma™-25 system (a fully continuous from-powder-to-tablet manufacturing line from GEA Pharma Systems). Besides the screw elements conventionally used for TSG (conveying and kneading elements), alternative designs of screw elements (tooth-mixing-elements (TME), screw mixing elements (SME) and cutters) were investigated using an α-lactose monohydrate formulation granulated with distilled water. Granulation with only conveying elements resulted in wide and multimodal PSD. Using kneading elements, the width of the PSD could be partially narrowed and the liquid distribution was more homogeneous. However, still a significant fraction of oversized agglomerates was obtained. Implementing additional kneading elements or cutters in the final section of the screw configuration was not beneficial. Furthermore, granulation with only TME or SME had limited impact on the width of the PSD. Promising results were obtained by combining kneading elements with SME, as for these configurations the PSD was narrower and shifted to the size fractions suitable for tableting.
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International Journal of Pharmaceutics, 2014
According to the quality by design principle processes may not remain black-boxes and full proces... more According to the quality by design principle processes may not remain black-boxes and full process understanding is required. The granule size distribution of granules produced via twin screw granulation is often found to be bimodal. The aim of this study was to gain a better understanding of binder distribution within granules produced via twin screw granulation in order to investigate if an inhomogeneous spread of binder is causing this bimodal size distribution. Theophylline-lactose-polyvinylpyrrolidone K30 (PVP) (30-67.5-2.5%, w/w) was used as a model formulation. The intra-granular distribution of PVP was evaluated by means of hyperspectral coherent anti-Stokes Raman scattering (CARS) microscopy. For the evaluated formulation, no PVP rich zones were detected when applying a lateral spatial resolution of 0.5 μm, indicating that PVP is homogenously distributed within the granules.
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European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, Jan 16, 2015
Twin-screw granulation is a promising continuous alternative for traditional batchwise wet granul... more Twin-screw granulation is a promising continuous alternative for traditional batchwise wet granulation processes. The twin-screw granulator (TSG) screws consist of transport and kneading element modules. Therefore, the granulation to a large extent is governed by the residence time distribution within each module where different granulation rate processes dominate over others. Currently, experimental data is used to determine the residence time distributions. In this study, a conceptual model based on classical chemical engineering methods is proposed to better understand and simulate the residence time distribution in a TSG. The experimental data were compared with the proposed most suitable conceptual model to estimate the parameters of the model and to analyse and predict the effects of changes in number of kneading discs and their stagger angle, screw speed and powder feed rate on residence time. The study established that the kneading block in the screw configuration acts as a ...
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International journal of pharmaceutics, Jan 20, 2014
A twin-screw granulator (TSG), a promising equipment for continuous high shear wet granulation (H... more 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 influen...
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International journal of pharmaceutics, Jan 30, 2015
The International Conference on Harmonisation (ICH) states in its Q8 'Pharmaceutical Developm... more The International Conference on Harmonisation (ICH) states in its Q8 'Pharmaceutical Development' guideline that the manufacturer of pharmaceuticals should have an enhanced knowledge of the product performance over a range of material attributes, manufacturing process options and process parameters. The present case study evaluates the effect of unspecified variability of raw material properties upon the quality attributes of granules; produced using a continuous from-powder-to-tablet wet granulation line (ConsiGma™ 25). The impact of different material attributes of six samples of microcrystalline cellulose (MCC) was investigated. During a blind study the different samples of MCC were used separately and the resulting granules were evaluated in order to identify the differences between the six samples. Variation in size distribution due to varying water binding capacity of the MCC samples was observed. The cause of this different water binding capacity was investigated and ...
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Pharmaceutical Development and Technology, 2013
There exists the intention to shift pharmaceutical manufacturing of solid dosage forms from tradi... more There exists the intention to shift pharmaceutical manufacturing of solid dosage forms from traditional batch production towards continuous production. The currently applied conventional quality control systems, based on sampling and time-consuming off-line analyses in analytical laboratories, would annul the advantages of continuous processing. It is clear that real-time quality assessment and control is indispensable for continuous production. This manuscript evaluates strengths and weaknesses of several complementary Process Analytical Technology (PAT) tools implemented in a continuous wet granulation process, which is part of a fully continuous from powder-to-tablet production line. The use of Raman and NIR-spectroscopy and a particle size distribution analyzer is evaluated for the real-time monitoring of critical parameters during the continuous wet agglomeration of an anhydrous theophylline- lactose blend. The solid state characteristics and particle size of the granules were analyzed in real-time and the critical process parameters influencing these granule characteristics were identified. The temperature of the granulator barrel, the amount of granulation liquid added and, to a lesser extent, the powder feed rate were the parameters influencing the solid state of the active pharmaceutical ingredient (API). A higher barrel temperature and a higher powder feed rate, resulted in larger granules.
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European Journal of Pharmaceutics and Biopharmaceutics, 2014
Twin-screw granulation is a promising continuous alternative for traditional batch high shear wet... more Twin-screw granulation is a promising continuous alternative for traditional batch high shear wet granulation (HSWG). The extent of HSWG in a twin screw granulator (TSG) is greatly governed by the residence time of the granulation materials in the TSG and degree of mixing. In order to determine the residence time distribution (RTD) and mixing in TSG, mostly visual observation and particle tracking methods are used, which are either inaccurate and difficult for short RTD, or provide an RTD only for a finite number of preferential tracer paths. In this study, near infrared chemical imaging, which is more accurate and provides a complete RTD, was used. The impact of changes in material throughput (10-17 kg/h), screw speed (500-900 rpm), number of kneading discs (2-12) and stagger angle (30-90°) on the RTD and axial mixing of the material was characterised. The experimental RTD curves were used to calculate the mean residence time, mean centred variance and the Péclet number to determine the axial mixing and predominance of convective over dispersive transport. The results showed that screw speed is the most influential parameter in terms of RTD and axial mixing in the TSG and established a significant interaction between screw design parameters (number and stagger angle of kneading discs) and the process parameters (material throughput and number of kneading discs). The results of the study will allow the development and validation of a transport model capable of predicting the RTD and macro-mixing in the TSG. These can later be coupled with a population balance model in order to predict granulation yields in a TSG more accurately.
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European Journal of Pharmaceutics and Biopharmaceutics, 2014
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European Journal of Pharmaceutics and Biopharmaceutics, 2014
Continuous manufacturing gains more and more interest within the pharmaceutical industry. The Int... more Continuous manufacturing gains more and more interest within the pharmaceutical industry. The International Conference of Harmonisation (ICH) states in its Q8 'Pharmaceutical Development' guideline that the manufacturer of pharmaceuticals should have an enhanced knowledge of the product performance over a range of raw material attributes, manufacturing process options and process parameters. This fits further into the Process Analytical Technology (PAT) and Quality by Design (QbD) framework. The present study evaluates the effect of variation in critical raw material properties on the critical quality attributes of granules and tablets, produced by a continuous from-powder-to-tablet wet granulation line. The granulation process parameters were kept constant to examine the differences in the end product quality caused by the variability of the raw materials properties only. Theophylline-Lactose-PVP (30-67.5-2.5%) was used as model formulation. Seven different grades of theophylline were granulated. Afterward, the obtained granules were tableted. Both the characteristics of granules and tablets were determined. The results show that differences in raw material properties both affect their processability and several critical quality attributes of the resulting granules and tablets.
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European Journal of Pharmaceutics and Biopharmaceutics, 2012
The aim of the current study was to screen theophylline (125 mg) tablets manufactured via twin sc... more The aim of the current study was to screen theophylline (125 mg) tablets manufactured via twin screw granulation in order to improve process understanding and knowledge of process variables that determine granule and tablet quality. A premix of theophylline anhydrate, α-lactose monohydrate and PVP (ratio: 30/67.5/2.5,w/w) was granulated with demineralized water. Experiments were done using the high-shear wet granulation module (based on twin screw granulation) of the ConsiGma™-25 unit (a continuous tablet manufacturing system) for particle size enlargement. After drying, granules were compressed using a MODUL™ P tablet press (compression force: 10 kN, tablet diameter: 12 mm). Using a D-optimal experimental design, the effect of several process variables (throughput (10-25 kg/h), screw speed (600-950 rpm), screw configuration (number (2, 4, 6 and 12) and angle (30°, 60° and 90°) of kneading elements), barrel temperature (25-40°C) and method of binder addition (dry versus wet)) on the granulation process (torque and temperature increase in barrel wall), granule (particle size distribution, friability and flowability) and tablet (tensile strength, porosity, friability, disintegration time and dissolution) quality was evaluated. The results showed that the quality of granules and tablets can be optimized by adjusting specific process variables (number of kneading elements, barrel temperature and binder addition method) during a granulation process using a continuous twin screw granulator.
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European Journal of Pharmaceutics and Biopharmaceutics, 2012
Manufacturers of pharmaceutical solid dosage forms aim for a reduced production time and a shorte... more Manufacturers of pharmaceutical solid dosage forms aim for a reduced production time and a shorter "time-to-market." Therefore, continuous manufacturing gains increasing interest in the pharmaceutical industry. For continuous manufacturing, the quality of produced pharmaceuticals should be assessed in real-time (in-line, on-line, and at-line) and not via the traditional off-line, often destructive and time-consuming analysis methods that supply the desired information only hours after sampling. This research paper evaluates three Process Analytical Technology (PAT) tools for the real-time at-line analysis of granules, which were produced using a continuous wet twin-screw granulator being part of a from powder-to-tablet production line (ConsiGma™-25). A Raman and NIR spectrometer were used together with a photometric imaging technique in order to acquire solid-state information and granule size data. These multivariate data were then used to predict the granules' moisture content, tapped and bulk density, and flowability. The three PAT tools provided complementary information for predicting these quality attributes of the continuously produced granules. The residual moisture content was mostly correlated with the spectroscopic data, whereas the imaging data had the highest predictive capability for the flowability of the granules.
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European Journal of Pharmaceutics and Biopharmaceutics, 2012
The trend to move towards continuous production processes in pharmaceutical applications enhances... more The trend to move towards continuous production processes in pharmaceutical applications enhances the necessity to develop mechanistic models to understand and control these processes. This work focuses on the drying behaviour of a single wet granule before tabletting, using a six-segmented fluidised bed drying system, which is part of a fully continuous from-powder-to-tablet manufacturing line. The drying model is based on a model described by Mezhericher et al. and consists of two submodels. In the first drying phase (submodel 1), the surface water evaporates, while in the second drying phase (submodel 2), the water inside the granule evaporates. The second submodel contains an empirical power coefficient, β. A sensitivity analysis was performed to study the influence of parameters on the moisture content of single pharmaceutical granules, which clearly points towards the importance of β on the drying behaviour. Experimental data with the six-segmented fluidised bed dryer were collected to calibrate β. An exponential dependence on the drying air temperature was found. Independent experiments were done for the validation of the drying model.
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European Journal of Pharmaceutics and Biopharmaceutics, 2013
The aim of this study was to investigate the process transfer of a commercially available product... more The aim of this study was to investigate the process transfer of a commercially available product from the current batch fluid bed granulation and drying production method to an innovative continuously operating "from powder to tablet" production line using twin screw granulation as an intermediate granulation step. By monitoring process outcomes (torque, water temperature at the granulator jacket inlet, differential pressure over the dryer filters, and temperature mill screen) and granule and tablet quality in function of process time, the stability and repeatability during long production runs were determined. Three consecutive 5h "from powder to tablet" production runs were performed using the ConsiGma™-25 system (GEA Pharma Systems, Collette™, Wommelgem, Belgium). A premix of two active ingredients, powdered cellulose, maize starch, pregelatinized starch, and sodium starch glycolate was granulated with distilled water. After drying and milling (1000 μm and 800 rpm), granules were in-line blended with magnesium stearate and directly compressed using a Modul™ P tablet press (tablet weight: 430 mg, main compression force: 12 kN). Granule (loss on drying, particle size distribution, friability, flow) and tablet (weight uniformity, hardness, thickness, friability, content uniformity, disintegration time, and dissolution) quality was evaluated in function of process time. For each of the logged process outcomes, a stabilization period was needed to reach steady-state conditions. Slightly deviating particle size distribution and friability results for milled granules were observed during start-up due to initial layering of the mill screen. However, no deviating tablet quality was detected in function of process time. For multiple hours, granule and tablet quality was constant in function of process time. Furthermore, process data trends were highly repeatable. Consequently, the ConsiGma™-25 system can be considered as a stable and repeatable system for the continuous production of tablets via wet granulation.
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European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft für Pharmazeutische Verfahrenstechnik e.V, 2014
Classically, the end point detection during fluid bed drying has been performed using indirect pa... more Classically, the end point detection during fluid bed drying has been performed using indirect parameters, such as the product temperature or the humidity of the outlet drying air. This paper aims at comparing those classic methods to both in-line moisture and solid-state determination by means of Process Analytical Technology (PAT) tools (Raman and NIR spectroscopy) and a mass balance approach. The six-segmented fluid bed drying system being part of a fully continuous from-powder-to-tablet production line (ConsiGma™-25) was used for this study. A theophylline:lactose:PVP (30:67.5:2.5) blend was chosen as model formulation. For the development of the NIR-based moisture determination model, 15 calibration experiments in the fluid bed dryer were performed. Six test experiments were conducted afterwards, and the product was monitored in-line with NIR and Raman spectroscopy during drying. The results (drying endpoint and residual moisture) obtained via the NIR-based moisture determinati...
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Papers by Jurgen Vercruysse