Knowledge Center

Article / 2021

Flow Chemistry

Panel Discussion with Rudi Oliveira, Scientist – R&D Process Engineering and Scale-up at Hovione

  • Rudi Oliveira
Chimica Oggi-Chemistry Today, May/June 2021


2021, the year where all expectations are set on leaving the pandemic behind us. It follows a very intensive 2020 where the world’s community focused their attention on the pharmaceutical companies expecting them to deliver in record timelines, efficient and safe drugs and vaccines. On the blind side of this media attention is the supply chain that feeds the development and manufacturing of drugs. The globalization which characterizes the modern world, made easy the acquisition of raw materials in different continents and ship them to where these were needed. With the pandemic, especially in the beginning, the availability and sometimes the transport of raw materials gained a new level of uncertainty, as a result of sudden lockdowns in countries or companies and increased scrutiny in the shipment of materials. This made governments more aware that the industry was highly dependent on the global market and started thinking to gain more control on the supply chain.

This is an opportunity for continuous manufacturing to show one of its strengths – small footprint to produce on demand. Dividing high tonnage bulk manufacturing by regional manufacturing is not economically attractive, but the small footprint of continuous systems may facilitate the replication of smaller units in different areas of the globe. Looking more into the future, if medicine evolves into personalized medicine then having small local manufacturing units will likely become the standard approach.

At Hovione, continuous flow chemistry is seen as an alternative to batch manufacturing, not a replacement technology. Continuous flow is more advantageous for reactions that are not efficient or simply dangerous to handle in a large manufacturing setting. Reactions that have very high exotherms (e.g. hydrogenations, organometallic chemistry) or use highly toxic reagents (e.g. corrosive gas) are among the most suited chemistries to perform in continuous. Chemistries that work well in batch and don’t present clear benefits to be performed in continuous, these remain as such.

Flow chemistry is developed at Hovione in both commercial systems as well as home-built systems. Commercial systems are great starting points to get into flow chemistry, these are generally user-friendly, thought to be plug-and-play and often count with the support from the vendor. However, these may become expensive to complement or customize to fit projects in early development or new projects that appear in the pipeline. Home-built systems are most useful in these early stages of development but require users with adequate knowledge to configure the system appropriately to study the reaction. For instance, changes to the placement of temperature probes, exploration of different mixing geometries or the impact of doing additions at different points can maximize the knowledge captured. When processes are more characterized, then commercial systems became more attractive because you get a system built for your need and often you get the benefit of seamless scale-up. This feature may well save effort later in the project since there is the opportunity to acquire a system where the development can be completed but also where it is possible to produce material to supply the first clinical stages. Most commercial systems cover well the productivity range from grams of product to multiple kilos, so the scale-up is generally straightforward not requiring further development, which all together contribute to accelerate time to market.

Continuous flow also provides a safer supply chain. In batch, if something goes wrong you risk losing the entire pack of starting materials, causing you to delay the supply chain while an intermediate or product needs reprocessing or fully redone. For fast track molecules like most ones for oncology or those planned for COVID, this is terrible news. In continuous, the ability to divert any material at risk and idle your process until the system is back in order, brings a significant advantage in securing the supply of product in time.

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