A Continuous Rotary Filtration for the Separation and Purification of an API

Introduction

Continuous manufacturing offers many advantages over batch manufacturing. Several studies have demonstrated that continuous manufacturing can improve product quality and decrease production cost, reduce process footprint, increase flexibility in production capacity, reduce raw material usage, and improve process safety. Moreover, regulatory agencies have published guidelines for the industry, some of which highlight key advantages of continuous processing, including decreased variability, improved efficiency, and easier scale-up. Several pharmaceutical companies have already received approval for drug products that contain significant continuous manufacturing components, including fluticasone propionate API production (GSK), Orkambi and Symdeko (Vertex), Prezista (Johnson & Johnson), Verzenio (Eli Lilly), and Daurismo (Pfizer).

Recently, the design and operation of an end-to-end integrated continuous manufacturing (ICM) pilot plant producing a small-molecule API and its oral solid dosages (tablets) was reported. Significant reductions in capital investment (92%) and operating costs for the API (33.6%) and final drug product (29.4%) were projected based on experimental results. However, a key challenge for manufacturing final dosage forms starting from raw materials is the isolation of the API, which is studied in this article.

In the current study, the continuous operation of this rotary filter for a slurry containing a commercially available API and two main impurities is presented. The impact of the feed material crystallization temperature, impurity concentration, rate of the first cake wash, and cake residence time (on the filter plate) on the final cake impurity levels was investigated. The combined yields of crystallization and filtration processes were calculated at different crystallization temperatures and cake wash rates. The continuous rotary filter was initially tested as a stand-alone unit operation and then incorporated into an ICM line, where it processed the slurry from a crystallizer and then transferred the resulting wet cake into the downstream process. The positive results (e.g., product consistently within the required specifications, low usage of wash solvent, and minimum yield loss due to wash) confirm the effectiveness and robustness of the novel filtration unit.

Abstract

As pharmaceutical manufacturers are looking for ways to shift toward continuous manufacturing, one of the biggest challenges has been the continuous separation and purification of active pharmaceutical ingredients (APIs). To address these challenges, a continuous rotary filter was developed, and its design space was investigated using a commercially available API. The filtration unit consists of a rotatable plate that receives a continuous flow of feed material that is distributed along the radius of the plate, forming a thin cake. The cake is continuously filtered, washed, and removed from the plate. An additional plate wash continually cleans the filter medium, enabling long-term operations. A slurry containing the selected API and two main impurities was processed by a continuous rotary filter. The performance of the unit was assessed both as a standalone entity and as a component of an integrated continuous manufacturing line. We observed that longer cake residence times (3.25 vs 2.5 min) on the filter plate and higher wash rates (among 12, 9, 6, and 3 mL/min) improved purification performance, though the latter plateaued above certain levels. Elevated crystallization temperatures (up to 70 °C) also increased the purification efficiency while not significantly impacting the yield. Finally, feed material with lower impurity concentrations resulted in a reduction in residual impurity ratio (down to 0.001). Yield studies demonstrated that the final crystallization temperature and cake wash rate impact the overall filtration yield (98.05% yield was obtained). In both settings, the rotary filter isolated and purified the cake to the required quality specifications, proving its effectiveness and robustness during continuous operations.

A Continuous Rotary Filtration for the Separation and Purification of an API

Introduction

Abstract

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