The current trend in the pharmaceutical industry for the manufacture of small-molecule therapeutic agents is moving toward continuous flow processes. In 2007, the Novartis–MIT Center for Continuous Manufacturing was established with $65 million in funding from the drug company. The center is proposing a "Blue Sky" concept where there is a continuous process from the start of a chemical synthesis through final pharmaceutical dosage form (1, 2). The Blue Sky program is an ambitious goal but is gaining ground rapidly among thought leaders in the pharmaceutical industry and US Food and Drug Administration. Consequently, the momentum for this concept is likely to have a trickle-down effect for contract manufacturers (CMOs) that design and develop early-stage manufacturing processes for clients developing innovator small-molecule drugs.

Continuous-flow technology

Continuous-flow technology involves the continuous introduction of a stream of chemical reactants into a flow or microreactor to yield a desired reaction product on a continuous basis. The versatility and usefulness of continuous-flow reactor (CFR) technology is expanding rapidly with an ever broadening scope of applicable chemistries and the development of new flow technologies (3). Champions of continuous-flow technology cite a wide range of potential advantages compared with traditional batch manufacturing of pharmaceuticals. In general, the greater optimization and control achievable with CFR technology can translate to significant savings in time and costs and can have a favorable safety and environmental impact. Furthermore, the small-reaction volume, broad operating pressure and temperature ranges, and mixing efficiencies of flow reactors extends the repertoire of chemistries beyond that of the safety and technical limitations of batch reactors. The capital investment for CFR technology is also substantially less as is the footprint required in the plant than a similar capacity batch-reactor system. However, even though the potential advantages of CFR technology can be significant, the technology is currently not applicable or practical in all situations.

Adapting CFR technology to early-stage development projects has significant merit, but also significant challenges. CMOs work with numerous sponsor clients, diverse chemistries, and projects in all stages of development. Many of the projects CMOs encounter are very early stage with the development candidate being licensed out of an academic laboratory or coming directly from the sponsor company's discovery laboratories. These early-stage projects more often than not require various degrees of process research and/or process development to make the discovery synthesis amenable to current good manufacturing practice (cGMP) scale-up. Also, to receive additional funding or secure a development partner, the sponsor company has a strong sense of urgency to enter the clinic and achieve proof-of-concept as soon as possible. This puts pressure on the CMO to rapidly develop a scalable process to meet the near-term active pharmaceutical ingredient (API) goals of the sponsor company and at the same time enable the process to further scale-up to meet later stage API demands.