A key enabler for the future success of continuous manufacturing in pharmaceutical and fine chemical production processes is the control of product quality. Since approx. 90% of all small molecular active pharmaceutical ingredients produced involve a crystallization step, a holistic view on its process chain is crucial in order to ensure a defined particle size distribution, high purity, and specific polymorphic form. Different concepts for small-scale continuous crystallization are available, improving the product qualities in comparison to batch. Continuous solid–liquid separations, on the other hand, are rather scarce. Therefore, we designed and characterized an innovative continuous vacuum screw filter (CVSF) for solid–liquid separation, washing, and drying of suspensions in a small scale (up to 10 g of solid per minute). This contribution shows the general working principle of the CVSF as well as a systematic investigation of varying operating parameters on the particle size distribution (PSD), residual moisture, and residence time distribution of the solid phase. As a model system, l-alanine/water is used. The results show that the PSD can be entirely maintained while ensuring a narrow residence time distribution of the solid phase with axial dispersion numbers between 18.7 and 76.2. The residual moisture is for all experiments in a good range of 20–25%. Furthermore, it could be shown that the operability is possible over 8 h. Summarizing, the modular setup of the CVSF offers a maximized flexibility and thus rapid adaptability to changing market demands and product requirements.

A novel apparatus concept for integrated, small-scale continuous filtration, washing, and drying is presented. The continuous vacuum screw filter (CVSF) allows obtaining dried and free-flowing product particles from the continuously fed suspension. While the first study presented the CVSF concept in detail and focused on the characterization with respect to the product quality control and solid-phase residence time distribution (RTD S ) during sole filtration, the modular extension with washing modules and a vacuum-induced (pre-) drying setup is now presented here. For this purpose, a wash module was designed and implemented. The influence of single-stage and two-stage washing on the particle size distribution (PSD) and RTD S was investigated for the L-alanine/water model system. Single-stage washing increased the particle size of d 90,3 by 120 μm (+19%) due to a higher agglomeration degree, while using two-stage washing could completely preserve the particulate properties of the inlet suspension. To identify favorable operating conditions for efficient (pre-) drying, the effect of varying throughputs and mean residence times on the residual moisture of the product particles was quantified. High filling degrees (>30%) and increased mean residence times (>11 min), in combination with two-stage washing and efficient vacuum-induced airflow, ensured completely isolated, free-flowing, and almost dry particles with residual moistures of 1% and an entire maintenance of the PSD. Measurements of the RTD S showed a slight broadening due to the wash liquid used, still ensuring a narrow RTD S and thus almost plug-flow-like behavior. In summary, the CVSF offers unique features, such as its modularity and rapid start-up behavior, providing a promising concept for integrated continuous particle isolation from suspensions.

The continuous vacuum screw filter (CVSF) for small-scale continuous product isolation of suspensions was operated for the first time with cuboid-shaped and needle-shaped particles. These high aspect ratio particles are very common in pharmaceutical manufacturing processes and provide challenges in filtration, washing, and drying processes. Moreover, the flowability decreases and undesired secondary processes of attrition, breakage, and agglomeration may occur intensively. Nevertheless, in this study, it is shown that even cuboid and needle-shaped particles (l-alanine) can be processed within the CVSF preserving the product quality in terms of particle size distribution (PSD) and preventing breakage or attrition effects. A dynamic image analysis-based approach combining axis length distributions (ALDs) with a kernel-density estimator was used for evaluation. This approach was extended with a quantification of the center of mass of the density-weighted ALDs, providing a measure to analyze the preservation of the inlet PSD statistically. Moreover, a targeted residual moisture below 1% could be achieved by adding a drying module (Tdry = 60 °C) to the modular setup of the CVSF.

Integrated continuous manufacturing processes of active pharmaceutical ingredients (API) provide key benefits concerning product quality control, scale-up capability, and a reduced time-to-market. Thereby, the crystallization step, which is used in approximately 90% of API productions, mainly defines the final API properties. This study focuses on the design and operation of an integrated small-scale process combining a continuous slug flow crystallizer (SFC) with continuous particle isolation using the modular continuous vacuum screw filter (CVSF). By selective adjustment of supersaturation and undersaturation, the otherwise usual blocking could be successfully avoided in both apparatuses. It was shown that, during crystallization in an SFC, a significant crystal growth of particles (Δd50,3≈ 220 µm) is achieved, and that, during product isolation in the CVSF, the overall particle size distribution (PSD) is maintained. The residual moistures for the integrated process ranged around 2% during all experiments performed, ensuring free-flowing particles at the CVSF outlet. In summary, the integrated setup offers unique features, such as its enhanced product quality control and fast start-up behavior, providing a promising concept for integrated continuous primary manufacturing processes of APIs.