The economic benefits of continuous flow

The rising trend of continuous flow is bringing economic and safety benefits to manufacturers, says Dr Shawn Conway, engineering R&D director for Cambrex.

The economic and safety benefits of implementing continuous flow retrospectively on a commercial scale for a single process step are widely known and have been well documented, with the replacement of traditional batch-based manufacturing by continuous flow chemistry continuing apace. Many major pharmaceutical corporations, including Lilly, GSK and Novartis, are actively investigating and investing significant sums in the use of continuous flow.

There is also an emerging use of continuous flow processes in early clinical development, where the need is to manufacture enough of a drug compound so that the development process can begin. 

Introducing continuous flow at this point enables the use of specific types of reactions that are very difficult to accommodate with the traditional batch process. This means that a compound can typically be obtained in a quicker, cleaner manner; it also makes it possible to start building a process that can be commercially viable from the outset, reducing the potential multiple iterations of a development cycle as the compound progresses from phase to phase.

The ability to optimise the process from the outset is a major advantage as it means that the best route can be used, rather than one best suited to a batch operation. Commercial scale batch processing imposes limitations in terms of the types of equipment that may be available and the processes that could be used. With continuous flow, all routes can be explored to find the most appropriate synthesis that can then be progressed through all the different stages of development.

In general, continuous flow offers a process that is scalable from the beginning, allowing the manufacture of a few hundred grams or perhaps a kilogram of a compound, and this can be quickly increased to larger quantities of material for a later phase, by increasing the scale of the equipment, or by extending the processing time. This scale up can be done multiple times through to commercial quantities, as opposed to batch manufacturing, where process optimisation would have to be carried out each time production is scaled up.

Applying continuous flow in early phase development also allows greater control over the reaction. A batch reaction can introduce significant variations within the vessel that can lead to incomplete conversion, side reactions and degradation, whereas with continuous flow, parameters such as residence time, temperatures, pressures, concentration and pH, can all be tightly controlled resulting in a high degree of consistency. Avoiding these impurities gives a more streamlined process that is easier to take on to subsequent phases.

Similarly, the increased monitoring of the process and the ability to take samples in real time increases the understanding of what is happening during the synthesis. Monitoring the process across a range of time points creates a much better picture of the reaction compared with leaving a batch to process for 12 or 16 hours and then sampling the result. 

Although cost savings cannot be quantified precisely, making an intermediate sized batch of product could be in the region of hundreds of thousands of dollars, so any technology that can streamline this process and reduce or remove this spend is obviously advantageous. Furthermore, reducing the development timeline and shortening the development phases can mean that a compound reaches the market faster, bringing forward the time when a drug gets to the patient and the company starts to make a return on its investment.

There is increasing demand for drug substances with higher potencies which require, smaller doses and therefore, potentially smaller manufacturing campaigns. Smaller volume batches can be relatively expensive using traditional batch production, due largely to the overhead costs of the facility, so lend themselves well to continuous flow technology where capital costs tend to be much lower. Rather than converting a batch process into a continuous flow-based analogue, exploring flow synthesis in the early development stages allows for the subsequent steps to be streamlined, saving time and money in the long run, as previously noted.

Multiple process steps in flow, such as reactions, work-up, extractions, crystallisations and distillations with different equipment requirements can be developed and connected in a small footprint facility as opposed to over several large assets in a production facility with the associated handling challenges and costs.

Eli Lilly's highly potent oncology drug Prexasertib demonstrates the practice of employing continuous flow in early phase development, where the technology was adopted for the final four steps of the synthesis throughout clinical scale manufacture, and now on to commercial production at a rate of three kilograms a day. Specific challenges that needed to be addressed, that have been published and discussed, included the use of hydrazine at elevated reaction conditions to drive purity and performance, as well as avoiding issues surrounding isolation and handling of potent toxic intermediates. Concurrent analytical monitoring also enabled rapid trouble-shooting during the manufacturing process.

The recognised benefits of this process were numerous and allowed eight continuous operations to take place in series, within small continuous reactors, extractors, evaporators, crystallisers and filters. A continuous reactor type was developed and utilised, as was a method for in-process filtration and redissolution. The process included the ability to operate at high temperature in a low-boiling solvent, afforded improved safety for a hazardous reaction, better yield and an improved impurity profile. The containment of highly potent materials was achieved through the use of dedicated and disposable equipment; and synthetic efficiencies were seen with enhanced product stability, the elimination of one isolation step, and the elimination of solids handling in another isolation step.

The advantages described above and illustrated in the example from Eli Lilly demonstrate that continuous flow drastically minimises, if not eliminates, safety and quality complications that arise from inhomogeneity and it should therefore be regarded as a truly enabling technology and a powerful development tool.