Updating the Toolbox
Batch production has traditionally been – and still is – the mainstay of the pharmaceutical manufacturing sector. However, the economic and technological advantages of continuous flow chemistry are driving adoption by API manufacturers.
Jonathan Knight, Shawn Conway |
This article was published in our sister publication, The Small Molecule Manufacturer, which celebrates the field of small molecule drug development and manufacturing with interviews and articles focusing on success stories, equipment, and new processing techniques.
Historically, continuous flow chemistry has been reserved primarily for highly energetic and/or hazardous reactions. In batch mode, these reactions have been limited to small vessels and minimal inventories to produce small quantities in facilities that may require bunkers and isolation in a location away from main manufacturing areas. In this way, if an uncontrollable event should occur during a reaction, the risk to personnel and the surrounding area could be minimized and any damage would be contained. Unfortunately, these facilities are expensive to build and maintain, and the small scale of the reactions limits their cost-effectiveness, with their remoteness adding additional logistical complexity, increasing headcount, time, and ultimately cost. For example, Cambrex has a long history of manufacturing and handling energetic compounds and reagents. The inherent explosive nature of these compounds and reagents meant that large scale production needed to be carried out in bunkered production facilities at a site in Karlskoga, Sweden, dating back to when the site was founded by Alfred Nobel in 1896.
In pharma, continuous flow chemistry has traditionally been limited to a specific subset of reactions and synthetic processes, driven by efficiency and cost-savings, with nitrations being among one of the most common processes undertaken. One of the biggest obstacles for companies looking to expand development capabilities in continuous flow, however, has been the lack of suitable commercially available equipment, but in recent years this has changed. Driven by the availability of new technologies and equipment, as well as the need to develop drugs faster, more cost-effectively and for smaller patient populations, there has been a growing movement towards replacing batch production with continuous flow operations. A number of large companies have invested in continuous flow operations for API production, as well as formulation, or both. For example, GSK has invested in continuous flow API development capabilities at its facilities in the UK, US and Singapore; while Vertex, Merck Sharp & Dohme, and Johnson & Johnson have invested in continuous flow formulation technology. Novartis, in collaboration with the MIT, has also spoken of its plans to combine continuous flow synthesis and continuous flow formulation.
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