Development of a pilot-scale manufacturing process for protein-coated microcrystals (PCMC): mixing and precipitation - part I.

A novel protein-coated microcrystal (PCMC) technology offers the possibility to produce dry protein formulations suitable for inhalation or, after reconstitution, for injection. Micron-sized particles are hereby produced by co-precipitation via a rapid dehydration method. Thus, therapeutic proteins can be stabilised and immobilised on crystalline carrier surfaces. In this study, the development of a continuous manufacturing process is described, which can produce grams to kilograms of PCMC. The process chain comprises three steps: mixing/precipitation, solvent reduction (concentration) and final drying. The process is published in two parts. This part describes the mixing and precipitation performed using continuous impingement jet mixers. Mixing efficiency was improved by dividing the anti-solvent flow into two or four jets, which were combined again inside the mixer to achieve an embracing of the aqueous solution (sandwich effect). The jets provided high energy dissipation rates. The anti-solvent jets (95% of the total volume) efficiently mixed the protein-carrier containing aqueous solution (5% of the total volume), which was demonstrated with computational fluid dynamics and the Villermaux-Dushman reaction. The improved mixing performance of the double jet impingement (DJI) or the quadruple jet impingement (QJI) mixers showed a positive effect on easily crystallising carriers (e.g. dl-valine) at laminar flow rates. The mixer and outlet tube bore size was 2.0-3.2 mm, because smaller sizes showed a high tendency to block the mixer. The mixing effect by impaction was sufficiently high in the flow rate range of 250-2000 mL/min, which corresponds to the transition from laminar to turbulent flow characteristics. At lower flow rates, mixing was enhanced by ultrasound. 50-80L PCMC suspension was readily produced with the QJI mixer.