In-Depth Evaluation of Data Collected During a Continuous Pharmaceutical Manufacturing Process: A Multivariate Statistical Process Monitoring Approach.

The present work presents an in-depth evaluation of continuously collected data during a twin-screw granulation and drying process performed on a continuous manufacturing line. During operation, the continuous line logs 49 univariate process variables, hence generating a large amount of data. Three identical 5-h continuous manufacturing runs were performed. Multivariate data analysis tools, more specifically latent variable modeling tools such as principal component analysis, were used to extract information from the generated data sets unveiling process trends and drifts. Furthermore, a statistical process monitoring strategy is presented. The approach is based on the application of multivariate statistical process monitoring to model the variables that remain around a steady state.

Evaluation of combination therapy for Burkholderia cenocepacia lung infection in different in vitro and in vivo models.

Burkholderia cenocepacia is an opportunistic pathogen responsible for life-threatening infections in cystic fibrosis patients. B. cenocepacia is extremely resistant towards antibiotics and therapy is complicated by its ability to form biofilms. We investigated the efficacy of an alternative antimicrobial strategy for B. cenocepacia lung infections using in vitro and in vivo models. A screening of the NIH Clinical Collection 1&2 was performed against B. cenocepacia biofilms formed in 96-well microtiter plates in the presence of tobramycin to identify repurposing candidates with potentiator activity. The efficacy of selected hits was evaluated in a three-dimensional (3D) organotypic human lung epithelial cell culture model. The in vivo effect was evaluated in the invertebrate Galleria mellonella and in a murine B. cenocepacia lung infection model. The screening resulted in 60 hits that potentiated the activity of tobramycin against B. cenocepacia biofilms, including four imidazoles of which econazole and miconazole were selected for further investigation. However, a potentiator effect was not observed in the 3D organotypic human lung epithelial cell culture model. Combination treatment was also not able to increase survival of infected G. mellonella. Also in mice, there was no added value for the combination treatment. Although potentiators of tobramycin with activity against biofilms of B. cenocepacia were identified in a repurposing screen, the in vitro activity could not be confirmed nor in a more sophisticated in vitro model, neither in vivo. This stresses the importance of validating hits resulting from in vitro studies in physiologically relevant model systems.

Blend uniformity evaluation during continuous mixing in a twin screw granulator by in-line NIR using a moving F-test.

This study focuses on the twin screw granulator of a continuous from-powder-to-tablet production line. Whereas powder dosing into the granulation unit is possible from a container of preblended material, a truly continuous process uses several feeders (each one dosing an individual ingredient) and relies on a continuous blending step prior to granulation. The aim of the current study was to investigate the in-line blending capacity of this twin screw granulator, equipped with conveying elements only. The feasibility of in-line NIR (SentroPAT, Sentronic GmbH, Dresden, Germany) spectroscopy for evaluating the blend uniformity of powders after the granulator was tested. Anhydrous theophylline was used as a tracer molecule and was blended with lactose monohydrate. Theophylline and lactose were both fed from a different feeder into the twin screw granulator barrel. Both homogeneous mixtures and mixing experiments with induced errors were investigated. The in-line spectroscopic analyses showed that the twin screw granulator is a useful tool for in-line blending in different conditions. The blend homogeneity was evaluated by means of a novel statistical method being the moving F-test method in which the variance between two blocks of collected NIR spectra is evaluated. The α- and ß-error of the moving F-test are controlled by using the appropriate block size of spectra. The moving F-test method showed to be an appropriate calibration and maintenance free method for blend homogeneity evaluation during continuous mixing.

Linking granulation performance with residence time and granulation liquid distributions in twin-screw granulation: An experimental investigation.

Twin-screw granulation is a promising wet granulation technique for the continuous manufacturing of pharmaceutical solid dosage forms. A twin screw granulator displays a short residence time. Thus, the solid-liquid mixing must be achieved quickly by appropriate arrangement of transport and kneading elements in the granulator screw allowing the production of granules with a size distribution appropriate for tableting. The distribution of residence time and granulation liquid is governed by the field conditions (such as location and length of mixing zones) in the twin-screw granulator, thus contain interesting information on granulation time, mixing and resulting sub-processes such as wetting, aggregation and breakage. In this study, the impact of process (feed rate, screw speed and liquid-to-solid ratio) and equipment parameters (number of kneading discs and stagger angle) on the residence time (distribution), the granulation liquid-powder mixing and the resulting granule size distributions during twin-screw granulation were investigated. Residence time and axial mixing data was extracted from tracer maps and the solid-liquid mixing was quantified from moisture maps, obtained by monitoring the granules at the granulator outlet using near infra-red chemical imaging (NIR-CI). The granule size distribution was measured using the sieving method. An increasing screw speed dominantly reduced the mean residence time. Interaction of material throughput with the screw speed and with the number of kneading discs led to most variation in the studied responses including residence time and mixing capacity. At a high screw speed, granulation yield improved due to high axial mixing. However, increasing material throughput quickly lowers the yield due to insufficient mixing of liquid and powder. Moreover, increasing liquid-to-solid ratio resulted in more oversized granules, and the fraction of oversized granules further increased at higher throughput. Although an increasing number of kneading discs was found to be critical for achieving a uniform distribution of the granulation liquid, the granulation performance was hampered due to insufficient solid-liquid mixing capacity of the current kneading discs which is essential for wet granulation. Thus, a balance between material throughput and screw speed should be strived for in order to achieve a specific granulation time and solid-liquid mixing for high granulation yield. Additionally, more efforts are needed both in modification of the screw configuration as well as the geometry of the mixing elements to improve the mixing capacity of the twin-screw granulator. The results from the current experimental study improved the understanding regarding the interplay between granulation time and the axial and solid-liquid mixing responsible for the granulation performance in twin-screw wet granulation.

Conceptual framework for model-based analysis of residence time distribution in twin-screw granulation.

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 plug-flow zone inside the granulator. Furthermore, it was found that a balance between the throughput force and conveying rate is required to obtain a good axial mixing inside the twin-screw granulator. Although the granulation behaviour is different for other excipients, the experimental data collection and modelling methods applied in this study are generic and can be adapted to other excipients.

Impact of microcrystalline cellulose material attributes: a case study on continuous twin screw granulation.

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 was caused by a different degree of crystallinity. Afterwards, an experimental design was conducted in order to evaluate the effect of both product and process variability upon the granule size distribution. This model was used in order to calculate the required process parameters to obtain a preset granule size distribution regardless of the type of MCC used. The difference in water binding capacity and its effect on granular properties was still present when combining the MCC grades with different binders.

Experimental investigation of granule size and shape dynamics in twin-screw granulation.

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.

Mixing and transport during pharmaceutical twin-screw wet granulation: experimental analysis via chemical imaging.

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.

Moisture and drug solid-state monitoring during a continuous drying process using empirical and mass balance models.

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 determination model, the classical approach by means of indirect parameters and the mass balance model were then compared. Our conclusion is that the PAT-based method is most suited for use in a production set-up. Secondly, the different size fractions of the dried granules obtained during different experiments (fines, yield and oversized granules) were compared separately, revealing differences in both solid state of theophylline and moisture content between the different granule size fractions.

Influence of raw material properties upon critical quality attributes of continuously produced granules and tablets.

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.

Distribution of binder in granules produced by means of twin screw granulation.

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.

Visualization and understanding of the granulation liquid mixing and distribution during continuous twin screw granulation using NIR chemical imaging.

Over the last decade, there has been increased interest in the application of twin screw granulation as a continuous wet granulation technique for pharmaceutical drug formulations. However, the mixing of granulation liquid and powder material during the short residence time inside the screw chamber and the atypical particle size distribution (PSD) of granules produced by twin screw granulation is not yet fully understood. Therefore, this study aims at visualizing the granulation liquid mixing and distribution during continuous twin screw granulation using NIR chemical imaging. In first instance, the residence time of material inside the barrel was investigated as function of screw speed and moisture content followed by the visualization of the granulation liquid distribution as function of different formulation and process parameters (liquid feed rate, liquid addition method, screw configuration, moisture content and barrel filling degree). The link between moisture uniformity and granule size distributions was also studied. For residence time analysis, increased screw speed and lower moisture content resulted to a shorter mean residence time and narrower residence time distribution. Besides, the distribution of granulation liquid was more homogenous at higher moisture content and with more kneading zones on the granulator screws. After optimization of the screw configuration, a two-level full factorial experimental design was performed to evaluate the influence of moisture content, screw speed and powder feed rate on the mixing efficiency of the powder and liquid phase. From these results, it was concluded that only increasing the moisture content significantly improved the granulation liquid distribution. This study demonstrates that NIR chemical imaging is a fast and adequate measurement tool for allowing process visualization and hence for providing better process understanding of a continuous twin screw granulation system.

Real-time assessment of critical quality attributes of a continuous granulation process.

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.

Prediction of quality attributes of continuously produced granules using complementary pat tools.

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.

Mechanistic modelling of the drying behaviour of single pharmaceutical granules.

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, ß. 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 ß on the drying behaviour. Experimental data with the six-segmented fluidised bed dryer were collected to calibrate ß. An exponential dependence on the drying air temperature was found. Independent experiments were done for the validation of the drying model.