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-en-gineering 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.
Biocatalysis for APIs
Engineered enzymes pave easier, faster road to scalable API manufacturing
Even the most promising and innova- tive 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 op-timizable 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.
When a pharmaceutical company identi-
fies 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 manu-
facturing 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 intro-
duction of function-driven mutations,
high-throughput screening, machine
learning to identify a productive combi-
nation of mutations and, finally, the hu-
man expertise of our scientific team. Each
iterative cycle produces compounded im-
provements 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 stan-
dard equipment, operate in normal temper-
ature 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. CP