The approximation of a well mixed reactor is prevalent when it comes to the modeling of a crystallization process. Since temperature, concentration, and mass content vary due to inhomogeneous mixing, this approximation is a very loose one. The continuously operated seeded tubular crystallizer system developed in our group overcomes obstacles like a slow response to changes in the outer parameters and inhomogeneous mixing. Therefore the applicable well mixed assumption facilitates detailed modeling of the crystallization process by means of population balance equations (PBE) coupled with mass and energy balances. Modeled results were validated by means of experiments. The amount of aggregation events during the crystallization could be quantified and it was proven that the growth of seeded crystals is almost exclusively responsible for solid mass uptake if the reactor is operated appropriately. The performed sensitivity analysis exposed which process settings should be maintained most accurately to avoid fluctuations in the product crystals' quality attributes and to limit undesired nucleation events.

Moving toward continuous manufacturing in the pharmaceutical industry offers new possibilities, such as reducing costs and improving flexibility and product quality. However, this paradigm change requires new small-scale continuous manufacturing technologies. Since drying is one of the crucial elements of pharmaceutical production, we performed an evaluation of existing drying technologies suitable for continuous production. We focused on small-scale equipment for handling preconcentrated slurries at the kg/h scale. Lactose (soluble) and ibuprofen (poorly soluble) suspensions were dried, first, in two fluidized bed spray dryers, second, in a small-scale spray dryer, third, in a spin flash dryer, fourth, in a paddle dryer, and, finally, in a corotating twin-screw extruder. During these trials we evaluated the performance of the equipment and its advantages and disadvantages with regard to pharmaceutical production. An analysis was performed to compare the different technologies. Our findings confirm that there is a need for improved continuous small-scale systems for drying crystalline products without causing agglomeration and/or attrition in order to preserve crystal properties originating from careful engineering during the crystallization phase. The aim of this study was to provide information regarding operational capabilities of continuous small-scale drying equipment.

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Near infrared (NIR) spectroscopy is a versatile, non-invasive and non-destructive tool that is often used for process monitoring in the pharmaceutical industry. Often, equipment window fouling or probe fouling of in-situ NIR probes occurs, leading to biased spectra and wrong interpretations (e.g. process-state estimation). Physical countermeasures, including self-cleaning probes and geometrical considerations, are called for. This paper presents a mathematical solution to the problem of window fouling for an NIR-monitored process: by determining the distance to the particles, we established which part of the signal was missing owing to the coating accumulation on the probe window. The proposed approach is illustrated with the example of hot-melt coating in a fluidised bed, during which coating buildup on substrate particles was monitored despite window fouling.

In a previous study, a small-scale dynamic filtration device (SFD) was analyzed and the basic mechanisms governing the filtration process were characterized. The present work aims at improving the device's performance in terms of actual production. Various operation modes were tested in order to increase permeate flow and concentration factors (CF), while maintaining a fully continuous production mode. Both, a vacuum-enhanced and a pulsating operation mode, proved to be superior to the currently implemented open-operation mode. For example, for lactose, an increase of the CF could be achieved from 1.7 in open mode to 7.6 in pulsating operation mode. The investigated operation strategy enables process control systems to rapidly react to fluctuating feeds that may occur due to changes in upstream manufacturing steps. As a result, not only filtration performance in terms of permeate rate but also process flexibility can be significantly increased. Overall, vacuum-enhanced operation was shown to be most promising for integration into an industrial environment. The option to elevate achievable concentration factors, ease of flow monitoring as well as the ability to react to changes in the feed conditions allow for effective and efficient continuous small-scale filtration.

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Abstract. The aim of the present work was to develop a PAT strategy for the supervision of hot melt coating processes. Optical fibers were placed at various positions in the process chamber of a fluid bed device. Experiments were performed to determine the most suitable position for in-line process monitoring, taking into account such requirements as a good signal to noise ratio, the mitigation of dead zones, the ability to monitor the product over the entire process, and reproducibility. The experimental evidence suggested that the position at medium fluid bed height, looking towards the center, i.e., normal to particle movement, proved to be the most reliable position. In this study, the advantages of multipoint monitoring are shown, and an in-line-implementation was created. This enabled the real-time supervision of the process, including the fast detection of inhomogeneities and disturbances in the process chamber, and the compensation of sensor malfunction. In addition, a model for estimating the particle size distribution via NIR was successfully created. This ensures that the quality of the product and the endpoint of the coating process can be determined correctly.

This study aimed to apply quality risk management based on the The International Conference on Harmonisation guideline Q9 for the early development stage of hot melt coated multiparticulate systems for oral administration. N-acetylcysteine crystals were coated with a formulation composing tripalmitin and polysorbate 65. The critical quality attributes (CQAs) were initially prioritized using failure mode and effects analysis. The CQAs of the coated material were defined as particle size, taste-masking efficiency, and immediate release profile. The hot melt coated process was characterized via a flowchart, based on the identified potential critical process parameters (CPPs) and their impact on the CQAs. These CPPs were prioritized using a process failure mode, effects, and criticality analysis and their critical impact on the CQAs was experimentally confirmed using a statistical design of experiments. Spray rate, atomization air pressure, and air flow rate were identified as CPPs. Coating amount and content of polysorbate 65 in the coating formulation were identified as critical material attributes. A hazard and critical control points analysis was applied to define control strategies at the critical process points. A fault tree analysis evaluated causes for potential process failures. We successfully demonstrated that a standardized quality risk management approach optimizes the product development sustainability and supports the regulatory aspects.