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Rethinking Chemical Synthesis With Cell-free Biocatalysis

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Traditionally chemical synthesis is a lengthy, step-by-step, or rather "batch-by-batch", process. However, new technologies and approaches are driving the pharmaceutical manufacturing industry forward – with continuous processes now making the task of turning low-value materials into high-value therapeutics, quicker, more efficient and cost-effective, and cleaner. 

Technology Networks
recently had the pleasure of speaking with Debut Bio's CEO Dr Joshua Britton. We discuss the evolution of chemical manufacturing, key challenges faced by those working in the field, and
 the benefits of combining biocatalysis and continuous manufacturing. 

Laura Lansdowne (LL): For some of our readers that may be less familiar with Debut Bio, could you tell us a little more about the company?

Joshua Britton (JB):
Debut Bio creates therapeutic molecules in a faster and cheaper manner while avoiding toxic metals and resultant waste streams. Our core technology relies on the combination of immobilized enzymes with continuous manufacturing in a cell-free environment.

The company is built on the knowledge that nature has evolved enzymes for millions of years to perform bio-transformations to exacting specifications in a green and sustainable manner. To that end, we’ve created a platform for cell-free biocatalysis utilizing immobilized enzymes and continuous flow chemistry to help our customers rethink the way they perform chemical synthesis.

Our patented and scalable solutions help shift our partners away from batch manufacturing toward more sustainable, clean, and cost-effective methods of production.

By leveraging Debut Biotech's platform, pharmaceutical companies will no longer have to perform long and tedious syntheses when they want to create complex pharmaceuticals that resemble the molecules found in nature. Instead, they can simply use our enzyme-based system to turn low-value materials, such as glucose, into high-value therapeutics and intermediates in a sustainable manner.

When companies want to get the exact molecules found in nature with therapeutic benefits, they can again use our technology platform. As Debut Bio advances, we expect our platform capabilities to broaden to a large number of small molecule therapeutics that will allow quick, green, and cost-effective access to these value-added molecules.

LL: What does traditional chemical manufacturing look like and how has chemical manufacturing evolved over the years?

The grand challenge of the twenty-first century is the transition to greener, more sustainable manufacturing processes that efficiently use raw materials, eliminate waste, and avoid the use of toxic and hazardous substances. At present, the pharmaceutical industry relies on a production process known as batch manufacturing that has remained the status quo for 75+ years. This lengthy step-by-step “chemical vat” process often requires using oil products, scarce metals, and costly intermediates. In short, batch manufacturing is dirty, slow, and expensive. In fact, it is estimated that the pharmaceutical industry alone wastes nearly $50bn per year on inefficient batch manufacturing processes. To remain competitive, many incumbent manufacturers are interested in partnerships that will allow them to transition to bio-based chemical production.

Enter continuous manufacturing. In continuous manufacturing, a pump (or pumps) continuously passes a low value reactant solution through a reactor in which it is transformed. In our case, the reactor contains a large number of complex immobilized enzymes. After a set amount of time, the product exits the reactor and is collected. Continuous manufacturing often provides improved enzyme stability, reaction rates, selectivity, lifetime, and efficiency to cell-free systems, yet no continuous cell-free system exists. In general, continuous manufacturing is the distinct opposite to batch manufacturing.

In batch manufacturing, a reaction is started, it is run for a certain amount of time, and then the reaction is stopped. Then, the product is isolated and the whole process starts again. In continuous manufacturing, a solution is continuously passed through a reactor. As the solution enters one side of the reactor and then exits, it is transformed. In this sense, the reaction can run indefinitely and through a smaller infrastructure. Additionally, continuous manufacturing allows for quicker reaction times and better control, as well as the potential for analytical technology to follow the reaction in real time.

LL: What are some of the main challenges faced by those working in the area of pharmaceutical manufacturing?

As I mentioned earlier, the pharmaceutical industry wastes $50bn per year on inefficient batch manufacturing processes; this can be dramatically improved. As pharmaceutical cost drives innovation into the pharmaceutical sector, new and improved methods that can create cost competitive routes to molecules of interest are welcomed.

Additionally, while green chemistry principles are often emphasized as a driver, in our experience, this is often superseded by cost. If a company can offer better routes to pharmaceuticals with green chemistry at the core of its inception; that would be a welcomed advance.

In terms of continuous manufacturing and the pharmaceutical sector, there has been a lot of noise in this area over the past seven years. While there has been some great academic advances in continuous manufacturing that have been translated into industry (photochemical reactions, for example), many improvements published in continuous manufacturing systems offer only marginal advancements such as a reduction in reaction time or temperature; these have had less of an effect. We must remember that when researchers and companies talk about scale, many pharmaceuticals are created at a quantity that would not warrant continuous production.

In our experience, continuous manufacturing can offer consistency, stability, real-time monitoring and feedback and improved safety. While “new routes” are often created, the likelihood of a company changing its designated route to an active pharmaceutical ingredient is limited both by cost and regulatory reapproval; these systems must provide better benefits to see true adoption.

Finally, pharmaceuticals are becoming more complex as companies target both new and old diseases. As many of these molecules are adapted and inspired by natural products, synthetic chemistry and methodology must adapt and change to keep up with demand. While many of these transformations can (and will) be achieved in synthetic chemistry, what would it be like if these complex transformations could be achieved with enzymes? What happens if complex pharmaceuticals could be created by a simple enzyme sequence alone or coupled with a chemical step? What happens if we can make synthetic chemistry inferior to enzyme pathways for pharmaceutical creation - these questions drive us to new scientific levels.

What are the key benefits of combining biocatalysis and continuous manufacturing to create molecules?

When you combine an enzyme transformation with continuous manufacturing, you open a world of process benefits and consistency.

For example, in continuous manufacturing systems the product of the reaction can be removed and so that the enzyme always sees a fresh solution of substrate; this can drive reactivity to new levels.

Additionally, coupling enzyme systems in continuous manufacturing systems have shown a decrease in side reactions (byproducts). When we immobilize enzymes for their use in continuous systems, we offer a range of benefits including improved stability, recyclability, selectivity, reaction rates, and the enzyme does not have to be removed from the product.

Finally, continuous manufacturing allows the enzyme system to be scaled in an economical and effective way to meet a demand. Compared to the large typical enzyme reactors. A continuous system could save dramatically on reactor footprint and cost.

Joshua Britton was speaking to Laura Elizabeth Lansdowne, Senior Science Writer for Technology Networks.