Chemical reaction

Despite the multistep processes and ungainly equipment required to meet global demand for drugs, batch manufacturing has become the firmly settled status quo in pharma.

This is due, in no small part, to a lack of sustainability among classical stirred tank reactors.

In contrast, continuous flow (CF) reactors differ in the performance of chemical reactions within pipes or tubes. With an increased surface-area-to-volume ratio they offer improved heat-transfer and reaction mixing efficiency. These key differences lead to a variety of important advantages such as improved safety, reaction selectivity and yield but – pivotally – they reduce environmental impact.

While the polymer and petrochemical industries have efficiently used continuous technologies for many years, surprisingly, pharma has been relatively slow in the uptake of continuous methods. Recently, however, the winds of change have been stirring.

Batch of the day

Quality control in batch processes is typically performed during pauses between each synthetic step. During hold time, material may enter storage or be shipped to other facilities for subsequent steps. This slows production which risks degradation of sensitive compounds and can impact the flexibility with which the manufacturing processes can meet changes in demand.

Drugs made using CF methods are moved non-stop within the same facility, reducing or eliminating hold time between steps. By feeding material through an assembly line of integrated components time is saved, the likelihood of human error is reduced, and the production pipeline can respond to market changes with greater agility. For example, changing demand can be met by running a process for a longer or shorter period, with no change in the size of manufacturing equipment.

Significantly, quality control can be automated with more frequent sampling. Such monitoring can help to detect issues with equipment long before a failure occurs, leading to proactive maintenance and reduced facility downtime. Continuous manufacturing can also permit more flexible product tracking. A quantity of material can be delineated by a time stamp, amount of drug produced, or the amount of raw input material. All of this means that in the event of a process failure the manufacturer can isolate a smaller amount of defective material which leads to less waste.

Furthermore, CF reactors can be adapted to reaction chemistry – 3D printed mixers and microreactor chambers provide increasingly expansive ways in which flow equipment can be arranged.

Temperature adjustment

Merck – an early adopter of CF in the pharma space – has developed a process to produce 2-fluoroadenine, a key fragment of the nucleoside reverse transcriptase translocation inhibitor, islatravir. The chemical transformation typically results in an extremely rapid and highly exothermic reaction, but by moving to a CF set-up the temperature can now be tightly controlled through tube diameter at the point of mixing.

Overall, the CF method led to a reduction in the financial and environmental cost of the process by reducing the amount of reagents required, increasing production and circumventing the need for resource intensive chromatographic purification.
Clearly, pharma’s reaction to the new age of reactors will represent a vital step on the path to increased sustainability.