Even the most promising and innovative API is going to be of little value unless it can be affordably manufactured at scale. One approach to achieve that goal that is gaining significant support from pharmaceutical manufacturers is the use of engineered enzymes for the biocatalytic production of increasingly complex synthetic molecules.

A wide variety of catalysts occur in nature, and they have long been used in various ways to enable or to speed up reactions. Until today, the vast majority of catalysts were metallic species, and have been constrained in their catalytic ability or selectivity in a chemical process by nature and structure. They are often not very optimizable beyond their initial performance.

On the other hand, biocatalysts or enzymes can be manipulated significantly through the process of protein engineering. Therefore, we can modify biocatalysts to
enhance specific performance characteristics and refine them to achieve their full potential.

Manufacturing efficiency
When a pharmaceutical company identifies a development candidate, it must also determine a way of manufacturing it cost-effectively and reproducibly at scale. It is very important that the route of synthesis be efficient, flexible and ideally not require extreme or specialized conditions. Most importantly, the process must robustly meet quality standards and deliver desired long-term economics. Protein engineering makes it possible to optimize API manufacturing processes and improve product quality and streamline production in ways that are impossible with chemical catalysts and naturally occurring enzymes.

For example, imagine that to achieve a desired outcome, a reaction required unusual conditions such as high temperature, organic solvent or high acidity that are hostile to a natural enzyme. Through protein engineering, designer enzymes can perform their biocatalytic function in these non-natural conditions, creating unique and efficient processes that could not otherwise be envisaged. Steps can be eliminated and productivity improved because of the unique ability to tailor properties of the enzyme catalyst.

The evolutionary process
Pharmaceutical scientists developing a drug with a biocatalytic route often start with an existing enzyme. During early development, where speed to produce API is typically more important than optimal performance, that reaction may work fine. As additional quantities of drug are required, however, many are now turning to a process of accelerated evolution to further optimize the enzyme.

The key benefit of designing a biocatalytic route with protein engineering in mind is that the route of synthesis and the API impurity profile can be relatively locked early on, confident that process and economic performance can be greatly optimized later.

Beginning with a target performance objective, the rapid evolution process comprises in silico screening, the introduction of function-driven mutations, high-throughput screening, machine learning to identify a productive combination of mutations and, finally, the human expertise of our scientific team. Each iterative cycle produces compounded improvements that can be refined until the targeted performance is achieved.

One particular advantage of processes using engineered enzymes is that they are typically simple and scalable. They use standard equipment, operate in normal temperature and pressure ranges, and don’t require complex controls. This flexibility is a huge advantage for companies that outsource manufacturing to contract manufacturers.

Although engineered enzymes are mostly used today to improve API manufacturing processes, they are increasingly being applied in drug discovery. Sometimes chemical reactions can’t happen without an appropriate catalyst. A chemist may be able to imagine an innovative molecule and envision the best enabling chemistry using an enzyme. This enzyme may be unavailable in nature or of too low activity but—through protein engineering—an enzyme can be quickly evolved to generate the desired molecule.

The future of biocatalysis
Sophisticated protein engineering is still a relatively new technology, and the tools we use in our accelerated evolution process have been developed and perfected only recently. Our process is highly automated and depends on the meticulous coordination of key components.

Because it is a new and significantly different approach, pharmaceutical developers and manufacturers are still gaining an understanding of what protein engineering does and the truly remarkable benefits it can achieve.

The chemistry in modern APIs is getting more complicated as we understand more about disease, how it can be treated, and how one can intervene in the disease process. As these molecules get more complex, the pharmaceutical industry will need ever more sophisticated catalysts to manufacture them, and that’s where engineered enzymes will certainly play an increasingly important role. 

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Michael Aldridge
Codexis

Michael Aldridge is senior vice president of corporate and strategic development at Codexis. He manages all aspects of the company’s growth initiatives, including the CodeEvolver protein-engineering platform that enables the development of custom-designed enzymes. An industry veteran with more than 25 years of experience in the healthcare and investment banking industries, he previously served as a senior pharmaceutical executive for several companies including as founder, president and CEO of Sirona Therapeutics.