In 2016, the (bio)pharmaceutical industry continues to face escalating demands to improve productivity, build pipelines faster, streamline infrastructure, reduce costs, and shorten time to market. At the same time, sponsor companies must meet increasingly rigorous regulatory expectations and conduct more complex clinical trials. Although the industry has traditionally been slow to embrace new processes and technologies, effective methods to accomplish these objectives are extremely valuable.
One way to help satisfy these demands is to employ custom-engineered enzymes as catalysts in novel, efficient manufacturing processes — a technology introduced to the industry over a decade ago. Since then, advances in genetics, high throughput biochemistry, and computational methods have enabled the creation of highly improved — and even completely novel — biocatalysts which improve efficiency and reduce cost in the discovery, development and manufacturing of active pharmaceutical ingredients (APIs) and drug products.
In this article, Codexis, Inc., a world leader in the field of protein engineering, biocatalytic process development services and enzyme production, highlights how technological advancements over the past decade have met many critical industry needs, and how long-held preconceptions about the use (and usefulness) of enzymes in the synthesis of APIs have been eroded.
Biocatalysis is the acceleration of a chemical reaction by an enzyme. Until quite recently (the 1990s), biocatalysis was limited to enzymes found in nature. The limited utilization of biocatalysis as an effective option within chemical manufacturing processes was in part due to misconceptions about yield, reliability, scalability, specificity, and cost — all of which are now readily addressable with focused and directed enzyme engineering and process development.
Codexis deploys state-of-the-art protein engineering technology to create completely novel, customized enzymes and processes to reduce the number of steps involved in API manufacture, thereby optimizing efficiency and reducing cost. The company leverages the latest breakthroughs in genomics and proteomics, along with data analytics, high throughput robotics and computational modeling to rapidly develop highly efficient enzymes, customized for specific molecules and optimized for challenging process conditions.
A common and significant challenge in the manufacture of pharmaceutical products is their increasing level of structural complexity, requiring many steps in the synthesis of a given molecule.
Improving Process Efficiency
“Time is of the essence” has never been more applicable than in today’s drug development process environment, due to fierce industry competition and pressures to build pharmaceutical pipelines more efficiently and more rapidly advance drug candidates to market.2 In the past, enzymes were not often incorporated into the development and manufacturing process because developing new enzymes for each different molecule was believed to take too long. Indeed, the application of enzymes in commercial manufacturing processes was often relegated to second- or third-generation developments that only the most highly resourced pharmaceutical companies could afford to implement and develop.
A common and significant challenge in the manufacture of pharmaceutical products is their increasing level of structural complexity, requiring many steps in the synthesis of a given molecule. Processes found in traditional chemical synthesis can often involve 8 to 12 steps. Enzymes developed by Codexis can revolutionize synthesis routes and often eliminate steps from these processes, resulting in more streamlined, cleaner processes for the manufacture of pharmaceutical products.
Much has changed over the last decade. The unique combination of breakthrough technologies in gene synthesis, molecular biology, high throughput analytics and bioinformatics has resulted in the rapid development of high-performing and cost-effective custom enzymes. This has provided solutions to problems that classical biocatalytic approaches would never have been able to overcome. Today, by using these highly advanced technologies, enzymes from a rapidly growing toolbox can more quickly and easily be identified and customized to particular uses. Codexis’ access to a substantial database of enzymes and structure-activity data provides an excellent starting point for customization. This rich informational baseline is leveraged in combination with molecular modeling and advanced high throughput screening methods, as well as powerful, proprietary data analytics to yield rapid and dramatic improvements in enzyme performance.
Another benefit provided by using customized enzymes in biocatalysis is that these enzymes can be developed to provide much higher volumetric productivity than natural variants. Thus, a much smaller quantity of custom enzyme can produce more product in less time as compared to alternative options. Engineered biocatalysts also can enable much higher throughput. Due to enzyme limitations, typical biocatalytic processes often operate in the range of 1%–5% product produced per reactor volume. In contrast, using engineered biocatalysts can result in between 15% and 30% of the reactor being filled with the molecule of interest. Additional benefits include cleaner reactions, with the production of a smaller proportion of impurities, water, solvent, and extraneous protein. As a result, modern biocatalysis can enable a very significant increase in manufacturing efficiency and throughput — often delivering at least 10- to 20-fold productivity improvement.
Optimizing Enzymes With CodeEvolver®
Codexis engineers custom enzymes utilizing its proprietary CodeEvolver® protein engineering platform. This platform incorporates many advanced technologies to speed the process of enzyme optimization for use in pharmaceutical production processes. The technology relies upon implementation of complex methods coordinated between various aspects of the workflow, including in silico modeling and molecular dynamic simulations to assess the ability of candidate enzymes to catalyze a reaction of interest.
Through the use of its proprietary technology and protein engineering knowledge, Codexis is able to respond to industry demands for cost reduction, helping its customers bring improved products to market much more rapidly and in a much more environmentally friendly manner. Codexis’ products and services are helping the (bio)pharmaceutical industry to advance innovation, and develop greener manufacturing processes that bring better medicines to patients more rapidly, more cost-effectively, and more efficiently. Codexis is also leveraging its technology to reach into additional, related markets.
- Tufts Center for the Study of Drug Development. Cost to Develop and Win Marketing Approval for a New Drug Is $2.6 Billion. Nov 18, 2014.http://csdd.tufts.edu/news/complete_story/pr_tufts_csdd_2014_cost_study.
- Agres T., New Life for Old Drugs. Drug Discovery & Development. Jul 29, 2011.http://www.dddmag.com/articles/2011/07/new-life-old-drugs.