Design and Commercialization of an End-to-End Continuous Pharmaceutical Production Process: A Pilot Plant Case Study

Traditionally, pharmaceuticals have been produced by batch processes despite technical disadvantages,1 quality control issues, and supply chain inefficiencies. These problems, coupled with a challenging industrial landscape (e.g., increasing R&D costs, effectively shortened patent lives, increased competition, uncertainty for drug approvals) have compelled the industry to upgrade its production methods with more innovative and efficient ones. Integrated continuous manufacturing (ICM) has gained attention from industry, academia, and regulatory agencies. It is a streamlined approach to production characterized by a series of integrated unit operations, where material input and output flows are concurrent (i.e., raw materials enter and final products leave the system simultaneously). The continuous production of small-molecule active pharmaceutical ingredients (APIs) and oral solid dosage (OSD) forms can include reaction, crystallization, separation, filtration, drying, downstream processing (e.g., blending, milling, sieving, granulation), and dose formation steps. Integrated continuous processes are hallmarked by their use of plant-wide control systems, which generally include model-based control features and process analytical technologies (PATs). ICM provides advantages with regard to process robustness, product quality, improved economics, sustainability, facilitated scale-up, and increased efficiency in the supply chain.

Most recent research directed toward the advancement of continuous processing technologies has been performed on individual unit operations, PATs, and control systems. There has been limited work focused on the design and commercialization of end-to-end (i.e., starting from commercially available raw materials, through drug substance, to the final dosage form) continuous processes (e.g., ICM). One such example is the $85 M research project called the Novartis-MIT Center for Continuous Manufacturing, which succeeded in the development and operation of the first end-to-end continuous line able to produce a pharmaceutical product. This work demonstrated the technical feasibility of applying ICM to pharmaceutical production processes and the associated benefits. The current paper details another end-to-end continuous manufacturing process, though with more commercially intended objectives. Regulatory bodies (i.e., the US Food and Drug Administration (FDA), European Medicines Agency (EMA), and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA)) are now supporting the shift from batch to continuous production. For example, the FDA is interested in mitigating drug shortages by upgrading outdated manufacturing processes, facilities, and equipment. Increased regulatory support and guidance, coupled with the advancement of continuous processing technologies, has led to the commercialization of continuous processes. Vertex’s Orkambi (US and EU) and Symdeko/Symkevi (US/EU), Johnson & Johnson’s Prezista (US and EU), Eli Lilly’s Verzenio/Verzenios (US/EU), and Pfizer’s Daurismo (US) are all examples of approved drug products manufactured with continuous processes. These processes are “hybrids” (i.e., the downstream processes are continuous, while the upstream remains batch). There is not yet an example of a commercial end-to-end ICM pharmaceutical process.

Herein, the design and operation of an end-to-end ICM pilot plant and the factors critical to enabling future commercial implementation are described. The plant produces both API and tablets of a marketed generic drug (currently manufactured via a batch process). It has an approximately 30.7 m2 footprint, a total residence time of <30 h, and a throughput of up to 4800 tablets/h. It is comprised of six main process areas:

1. Feeding, dissolution, and clarification bypass,
2. Reactive crystallization,
3. Filtration and resuspension,
4. Drying
5. Extrusion molding coating (EMC)
6. Solvent recovery

The aim is to scale-up the process to a commercial cGMP manufacturing line. QbD-based design principles, product quality specifications, the results of economic analysis, and several attractive commercial features (e.g., use of cheaper raw materials, dial-up/down capability, real-time release (RTR), and solvent recovery) are the focus of this work.