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Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.
Collaboration provides pharmaceutical industry customers with access to enzyme expertise and assets resulting in cost-effective, green processing at all phases of development, from preclinical to commercial manufacturing scale.
Application of biocatalysis
Catalysis is critical to the synthesis of pharmaceutical intermediates and APIs. Catalysts make important synthetic reactions proceed more rapidly and often enable the formation of complex structures in fewer steps with greater selectivity. Biocatalysts, typically enzymes, offer additional advantages. They catalyze reactions under mild conditions and thus consume less energy. They do not require the use of heavy or toxic metals, and in some cases enable the avoidance of hazardous raw materials. In addition, such reactions can often be carried out in water rather than organic solvents, and they tend to generate less waste.
Until recently, pharmaceutical companies tended to consider biocatalytic routes only in later development stages. “Biocatalysts have not frequently been considered in the design of manufacturing processes for drug candidates in early stage development, such as candidate selection in preclinical development, according to Daniel Mink, corporate scientist, biocatalysis, from DSM. “Generally, biocatalysis has been treated as a viable cost-saving alternative only in late-phase clinical stages (i.e., Phase II and III).
Biocatalysis is now being applied throughout the pharmaceutical development process, beginning with the synthesis of compounds for structure activity relationship studies through initial route development and for commercial scale production, according to Tom Moody, head of biocatalysis with the Almac Group.
Rationale for the collaboration
Recognizing the growing need for biocatalytic expertise, Almac established a biocatalysis group in 2007 that has since doubled in size. The company recently invested £2.5 million ($3.75 million) in biocatalyst R&D and launched its own selectAZyme biocatalyst technology platform. “The biocatalysis group is now an integral part of the Almac Sciences’ business unit, which focuses on the development phase. Furthermore, Almac has successfully introduced biocatalysis in manufacturing processes for candidates in preclinical development that immediately resulted in substantial savings in terms of processing time, quantity of starting materials required, and quality of end product, with no impact on the development time, according to Moody.
DSM, meanwhile, has a proven track record with over 30 commercial bioprocesses run on a multiton scale with experience in the manufacturing of intermediates, APIs, and enzymes, according to Mink. “As a result, this collaboration on biocatalysis fits strategically and technically for both companies. Our manufacturing assets are complementary, and together we can offer a true one-stop-shop for biocatalytic solutions.”
As importantly for Moody, with the partnership in place, Almac now has the opportunity to screen the collection of DSM enzymes at Almac, while DSM has access to Almac’s proprietary enzymes. “Together, we now offer the pharma industry the largest enzyme platform for structural diversification and commercial scale production,” he explains. Each company has the entire platform of enzymes in house and available for screening but will continue to handle the sale of enzymes or transformations individually. “With such a large platform that offers many complementary enzyme chemistries, we have a much higher chance of finding a hit as the result of our enzyme screens,” Moody states.
Specific enzyme technologies of note include pig liver esterase (PharmaPLE) for sterically demanding esters, aldolases for carbon–carbon bond formation, and epimerases and oxidoreductases that make it possible to investigate different chiral spaces, which is critically important in pharmaceutical synthesis.
Collaboration at work
The goal of this partnership is to increase the services that both companies can offer to their customers. “Via this agreement, we maintain our commitment to the future of pharma manufacturing, adding to our green-chemistry toolbox. Working with the Almac Group marks further advancement of DSM's stated strategy towards strategic partnerships to excel in providing new customer solutions,” says Alexander Wessels, president and CEO of DSM Pharmaceutical Products.Notably, the agreement is nonexclusive. “The relationship with the customer is very open, and it is the customer who drives the entire process,” Moody says. Almac will always discuss manufacturing options in good faith with the client. If the process fits within Almac’s scale of manufacture, Almac will likely keep the project. If it exceeds Almac’s capacity, Almac will and recommend DSM where appropriate.
In addition, customers can choose from several different business models. “From the earliest stage of discussions, the clients’ strategy for commercial supply will be discussed and defined, and a range of options will be offered to them,” notes Mink.
If a customer is only interested in material delivery, Almac or DSM, as appropriate, will develop the process and supply the product at an agreed price. Alternatively, customers can pay for the process development work and own the process intellectual property, but still have Almac or DSM manufacture the product. Clients can also choose to have full control over the process, own the enzyme for the particular transformation (such as one that has been evolved at the behest of the customer to perform specific chemistry using the customer’s substrate), and transfer the manufacture to an external third party. Customers that choose to scale up their processes with DSM will benefit from a seamless transition. “Almac has an experienced and dedicated technical transfer team that has already transferred multiton scale manufacturing processes to commercial facilities in Europe and the Far East,” Moody observes. “Furthermore,” he adds, “Almac and DSM share the same approach to process development and have complementary production capacities, which should make the transition even smoother.”
Initial project work
The collaboration, announced in the fall of 2012, has already born fruit. The first project, for which Almac developed the process and has proven it at the pilot scale, will shortly be transferred to DSM for commercial-scale production. While the companies cannot provide details of the API due to confidentiality agreements, Moody has indicated that the compound is a natural product, and the process involves a multistep synthesis.
“We are excited about this collaboration and the fact that it will help increase our chances of finding the right enzymes for our customers and make it possible to access new and varied structures,” says Moody. “Both Almac and DSM are and will remain very active in the discovery and development of new enzymes that will further widen the spectrum of bioreactions possible and offer even more diversity to the pharma industry, adds Mink.”