Abstract Summary (Max 250 words)
The monitoring of suspension, deposition, and re-suspension phenomena of aluminium-based adjuvants in pharmaceutical formulation tanks represents a significant technological and regulatory challenge, particularly when operating at low solid volume fractions. Aluminium phosphate adjuvants are widely used in vaccine formulations due to their immunostimulatory properties; however, they exhibit complex physicochemical behaviour in aqueous environments. These materials are electrically non-conductive and tend to form cohesive, gel-like sediment layers upon settling. Once deposited, such layers may undergo structural consolidation over time, leading to the formation of dense cakes whose mechanical strength and re-suspension behaviour depend strongly on formulation parameters. In particular, buffer composition, pH, ionic strength, protein adsorption onto particle surfaces, and storage duration have all been shown to significantly affect interparticle interactions and sediment strength. As a consequence, ensuring homogeneous suspension during manufacturing and prior to filling remains a critical quality attribute in pharmaceutical processing. Traditional methods for monitoring solid-liquid dynamics in stirred tanks, such as visual inspection, off-line sampling, or intrusive probes, are often inadequate for aluminium-based adjuvants. These approaches can be disruptive, lack spatial resolution, or fail to capture transient phenomena such as partial suspension or localized deposition near the vessel bottom. In this context, Electrical Resistance Tomography (ERT) offers a promising alternative as a non-intrusive Process Analytical Technology (PAT) capable of providing real-time, spatially resolved information on solid distribution and dynamics within opaque systems. ERT operates by injecting low-amplitude electrical currents through arrays of electrodes positioned on or within the vessel walls and measuring the resulting voltage differences. In solid-liquid systems containing non-conductive particles dispersed in a conductive liquid phase, local changes in solids concentration translate directly into measurable variations in electrical conductivity. In the present work, a bespoke ERT configuration was developed to enhance sensitivity to deposition and re-suspension phenomena occurring near the tank bottom, which are of primary relevance for pharmaceutical formulation processes. Experimental investigations were conducted at two different vessel scales to assess the robustness and scalability of the technique. A laboratory-scale vessel with a working volume of 7 L and a scale-down system of 300 mL were employed. Both vessels were equipped with a custom-designed linear electrode probe mounted at the tank bottom. The use of geometrically similar probes across scales allowed for direct comparison of ERT responses and facilitated the evaluation of scale-dependent effects. A systematic experimental campaign was performed to investigate aluminium phosphate settling, deposition, and re-suspension under a range of operating and formulation conditions. Impeller rotational speed was varied to explore different suspension regimes, from complete off-bottom suspension to partial suspension and full sedimentation. Deposition time was controlled to assess the evolution of sediment structure and packing density, while protein adsorption conditions were modified to mimic realistic pharmaceutical formulations in which antigens are adsorbed onto the adjuvant surface. The ERT measurements revealed distinct conductivity signatures associated with each regime, enabling clear discrimination between suspended, partially settled, and fully deposited states. The results demonstrate that ERT can reliably capture both the kinetics of aluminium phosphate settling and the progressive consolidation of the sediment layer over time. During re-suspension experiments, ERT was able to detect the onset of particle mobilization, the gradual erosion of the sediment bed, and the eventual restoration of a homogeneous suspension as impeller speed increased. Importantly, differences in re-suspension behaviour arising from protein adsorption and extended deposition times were clearly reflected in the conductivity maps, highlighting the sensitivity of the technique to subtle changes in particle-particle and particle-fluid interactions. Overall, this study confirms Electrical Resistance Tomography as a robust, non-intrusive PAT tool capable of providing both qualitative and quantitative insight into critical solid-liquid mixing phenomena under realistic pharmaceutical processing conditions. By enabling real-time monitoring of suspension quality, sediment formation, and re-suspension dynamics, ERT has the potential to support improved process understanding, enhanced control strategies, and more reliable scale-up of formulation operations involving aluminium-based adjuvants.
