Continuous Manufacturing of Active Pharmaceutical Ingredients: Current Trends and Perspectives

Abstract

The pharmaceutical industry has traditionally employed batch processing as a means of synthesizing active pharmaceutical ingredients (APIs) on a commercial scale. Batch manufacturing enables API synthesis in large quantities in order to meet regulations. Yet, this strategy remains cumbersome, is labor‐intensive, and creates complex logistical networks. In recent decades, batch API processing has gradually eroded American economic competitiveness and has led to the off‐shoring of API manufacturing from the United States. Today it is estimated that +80% of APIs are manufactured overseas. Meanwhile, disruptions from the Coronavirus Disease (SARS‐CoV‐2) have exacerbated weaknesses in the global supply chain, culminating with widespread shortages of critical life‐saving drugs. These shortages have emphasized the importance of reshoring drug manufacturing to the U.S. and fostered a regulatory landscape that seeks advanced methods of API manufacturing in order to bolster America’s supply chain resiliency. Recently, increased attention has been directed towards continuous drug manufacturing to enable nonstop API production within modular stand‐alone flow systems. Continuous manufacturing (CM) facilitates modular automation, offers new avenues towards process intensification, and even enables in‐line analytical monitoring from raw materials to packaged products. This strategy offers better conversion, increased safety, reduced waste, and overall cost savings versus traditional batch‐style processing. The rise of advanced API manufacturing, coupled with the current regulatory landscape, offers a rare window of opportunity to convert traditional batch pharmaceutical processes into continuous, streamlined production systems to on‐shore API manufacturing and eliminate drug shortages. This review will outline the current state‐of‐the‐art in the CM of APIs and will highlight the translation of chemistry and unit operations from batch processes to modular CM systems.

Development of Continuous Additive-Controlled MSMPR Crystallization by DoE-Based Batch Experiments

“…In turn, the advantages of continuous technologies, such as improved productivity, constant product quality, and technological flexibility, make them more economical compared to their batch equivalents. 25,26 In addition, these benefits fit well with the idea of additive-controlled crystallization to simplify downstream formulation by targeted morphology alteration to make solid API production more efficient and economical. Continuous crystallization is a well-established research field with two basic operational implementations, which are the mixed suspension mixed product removal (MSMPR) crystallizers 27,28 and different tubular crystallizers (TC).…”

“…All at the same, there are numerous examples of additive-controlled crystallization which are dominantly performed in batch mode, and only a few publications discuss the adaptation of continuous technologies. In turn, the advantages of continuous technologies, such as improved productivity, constant product quality, and technological flexibility, make them more economical compared to their batch equivalents. , In addition, these benefits fit well with the idea of additive-controlled crystallization to simplify downstream formulation by targeted morphology alteration to make solid API production more efficient and economical.…”

Reshoring Fine Chemical and Pharmaceutical Productions

“…9 From the manufacturing technology viewpoint, chemists and chemical engineers have long suggested that successful reshoring goes through industry's adoption of digitally controlled, efficient continuous manufacturing (CM) in fluidic reactors. 10 CM employing homogeneous and heterogeneous catalysis, 11 in other words, would ensure the required economic competitiveness. The higher yields, much smaller size ("footprint"), and larger mass and heat transfer in fluidic reactors would lower inasmuch the cost of the "production campaigns", as to allow repatriation of fine chemicals production in countries where the cost of labor and energy is far higher than in Asian countries.…”

“…As shown in the following, Austria already repatriated penicillin production, and France is near to successful relocation of acetaminophen production . From the manufacturing technology viewpoint, chemists and chemical engineers have long suggested that successful reshoring goes through industry’s adoption of digitally controlled, efficient continuous manufacturing (CM) in fluidic reactors . CM employing homogeneous and heterogeneous catalysis, in other words, would ensure the required economic competitiveness.…”