Improvements in organic synthesis, reaction vessels, and more promise to speed up manufacturing of small-molecule pharmaceuticals.

An SAFC Pharma employee works in the R&D Lab in Manchester UK, which specializes in early-stage development manufacturing. (Source: SAFC Pharma)

Building new structures has always been a desire of human beings. From the beginning of recorded history, humans used these new structures to provide shelter, education, as well as places to work, play, and worship, for their fellow man. In the 19th and 20th centuries, man combined his intellect and desire to build things to create new structures of a different scale: new chemical structures. Such endeavors gave rise to the modern manufacturing processes of small molecules as we know them today. And pharmaceutical companies, large and small, established and emerging—as well as contract manufacturers—have all lent a hand in that development.

Michael Harris, PhD, vice president for sales and manufacturing, SAFC Pharma, a contract manufacturer based in Poole, UK, deals with pharmaceutical companies that run the gamut from the emerging to the very established and everything in between. For the emerging companies, which may only have one or a few compounds in the pipeline, Harris says: “The success of that early-stage clinical phase manufacture and clinical phase testing is really going to define whether that company grows and creates a lot of value or whether it falls over before it is even started.” And for that early-stage manufacture, Harris explains that speed without loss of quality is the most important factor. Whether a drug company is large or small, the objective nowadays is to weed out, as early as possible, those compounds that are not going to pass through early development into clinical trials. And speed is a key factor in this weeding out process as well.

Marcello DiMare, who heads up the small-molecule active pharmaceutical ingredient (API) group for contract manufacturer Aptuit in Kansas City, Mo., agrees that the most important concern for supplying Phase 1 and Phase 2 clinical trials is speed. “People want to do their first-in-man studies. They want to get proof-of-concept that their API is doing what they hope it does and that it is safe. So in Phases 1 and 2, the emphasis is all about speed—rapid manufactured material that is suitable for human use,” says DiMare. “In that early stage, everybody is starved for their API, meaning they have been making gram quantities and now they know that they need kilogram quantities, typically, but they don’t have kilogram quantities on the shelf. So API is often rate-determining.”

An SAFC employee performs Pharmorphix Solid State studies at SAFC’s facility in Cambridge, UK. (Source: SAFC Pharma)

ORGO soup
Manufacturing API requires typical organic chemistry reactions and processes that, quite frankly, have not generated a lot of new technologies lately. However, according to DiMare, one of the newer trends in API manufacturing involves the use of continuous processing, which has been used in the production of gasoline for many years. DiMare describes this process as follows. “Imagine how most chemistry is conducted to make multi-kilo amounts in a batch mode. It is like you are making soup. You put everything into a big pot, you cook it up, and then you get your product out of it. Where there is some real interest these days is in continuous processing, which means you don’t throw everything together, you sort of continuously produce the product of interest in what is called a microreactor.” Although Aptuit does not use microreactors or continuous processing, DiMare says that other major pharmaceutical houses and competing contract manufacturers are exploring these options. He also points out that other measures needed in the scale up steps of small-molecule manufacturing include using larger glassware to reduce workers’ exposure to toxic reagents or explosion hazards, and reducing solvent waste in chromatography steps. 

And speaking of organic synthesis, Don M. Coltart, PhD, assistant professor, Department of Chemistry, Duke University, Durham, N.C., has developed a new approach to performing asymmetric synthesis with ketones. “There is a striking gap in the technology available to synthetic chemists with respect to asymmetric alpha-alkylation or the alpha-functionalization of ketones,” says Coltart. The original idea of asymmetric ketone alkylation was derived mainly by chemist Dieter Enders over 25 years ago. “There were some fundamental issues with the chemistry though. In particular, the technical requirements and the practical considerations were somewhat limiting.”

Coltart’s belief is that his new chemistry will be applicable to the organic synthetic processes used by medicinal chemists to build small-molecule pharmaceuticals. “I would say if you look at a list of the 100 top-selling drugs, you’ll find a good representation of chiral ketones and derived compounds in them.” He explains that some of these compounds are currently being marketed as racemates, possibly because the manufacturers could not afford to process them in single enantiomer form. “I am not privy to this inside info,” says Coltart. “But if that is the case (and I suspect it is), well then you can imagine that if a drug company has the opportunity to do what is referred to in the field as a chiral switch and start producing a single enantiomer of a drug, it could lead to an additional period of exclusivity on their patent. So I would say there is probably a market for it.”

In contrast to early-phase manufacturing, the focus of manufacturing for Phase 3 clinical trials and for commercial production is quality and efficiency of process. “Until there is a problem, it’s possible to forget how important regulatory compliance is. But there have been enough large stories recently where maybe the quality aspects of pharmaceutical products have not been as good as companies would like them to be. And that has obviously caused issues,” says Harris. And there are still other important concerns. “The environmental aspects of running a chemical manufacturing plant are getting stricter. Manufacturing processes and routes of chemical synthesis are being looked at because if you could reduce waste, conserve energy, and increase your yield and efficiency today, then … you are much more able to compete in the marketplace, regardless of location.”

As pressures to develop more efficient manufacturing processes mount, academic chemists and contract manufacturers are working to keep up with industry demands. Newer, more efficient chemical synthesis, coupled with improvements in reaction vessel technology and continuous processing are just some of the measures being taken. But there surely will be more to come.

This article was published in Drug Discovery & Development magazine: Vol. 11, No. 7, July, 2008, pp. 33-34.