Authors
Chuntian Hu, Christopher J. Testa, Wei Wu, Khrystyna Shvedova, Dongying Erin Shen, Ridade Sayin, Bhakti S. Halkude, Federica Casati, Paul Hermant, Anjana Ramnhat, Stephen C. Born, An automated modular assembly line for drugs in a miniaturized plant, Thomas F. O'Connor, Xiaochuan Yang, Sukumar Ramanujam, An automated modular assembly line for drugs in a miniaturized plant
INTRODUCTION
Currently, most pharmaceuticals are still manufactured via fragmented batch processes, which are very time-intensive and expensive. Active pharmaceutical ingredients (APIs) are often produced at one site, and then shipped to a completely different facility for the formulation and final transformation into tablets, capsules or other final dosage forms. This inefficient process can require up to 12 months, and cause drug shortages as a result of long lead times or quality defects. The pharmaceutical manufacturing sector is transitioning from batch to continuous operations, due to inefficiencies and lower quality as compared to other process industries. For example, semiconductors run 6 sigma quality processes (B0.0003% defects), whereas pharmaceutical manufacturing typically provides 2–3 sigma quality (B6.7–30.9% defects). Increased interest in continuous manufacturing of APIs and drug products stems fromthis need to increase the quality assurance, while enabling rapid production of these pharmaceuticals in a significantly reduced footprint, and at a lower cost.
Five continuous manufactured drug products have been approved in the US (i.e., Vertex’s Orkambi and Symdeko, Johnson & Johnson’s Prezista, Eli Lilly’s Verzenio, and Pfizer’s Daurismo) and four in the EU (i.e., Vertex’s Orkambi and Symkevi, Johnson & Johnson’s Prezista, and Eli Lilly’s Verzenios). However, there is still no example of a commercial end-to-end integrated continuous manufacturing (ICM) process (a first-of-kind research demonstration was unveiled at MIT in 2011) with a modular design. Here, we report the first fully automated end-to-end commercial ready ICM pilot plant, in which the synthesis of the API and the final dosage forms are integrated into a single continuous process with no interruptions. The elimination of the stop-and-start sequences, with reduced human intervention, combined with the implementation of in-line sensors to determine product quality real-time, offers better assurance of the final product quality.
ABSTRACT
The US healthcare system is facing unprecedented challenges with unaffordable drug prices and shortages of critical small-molecule drugs. More than 60% of these shortages are due to quality issues, most of which stem from the ‘step-by-step, batch’ manufacturing process that pervades the industry. As a paradigm-shifting approach, we report here a fully automated, end-to-end, integrated continuous manufacturing (ICM) process for a small-molecule generic medication with built-in quality assurance. The entire ICM process has a 30.7 m2 modular footprint and a total residence time of < 24 h, with a throughput up to 4,800 tablets/h, or 40.3 × 106 tablets/year. The commercialization of this innovative ICM process will lead to a more efficient and sustainable manufacturing sector, and could significantly improve the affordability and accessibility of pharmaceuticals on a global scale.
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