Ask star antibody developer and Medicxi partner Kevin Johnson to name the biggest challenge in bringing a new antibody into the clinic, and his immediate answer has only three letters: CMC. Everyone knows how big a challenge it is to get the manufacturing piece right for an antibody. And many promising projects stumble due to insufficient focus on the deceptively simple process of actually making the drug.
The difficulties are obvious to most drug developers – almost all of whom have a biology background. Proteins are orders of magnitude more complex than a typical small molecule chemical drug. They can vary in structure (for example due to glycosylation), be unstable (thanks to oxidation of methionine or deamidation of glutamine), change conformation and so lose activity, aggregate and fall out of solution – in short, the challenge of making reproducible lots of any protein is transparently substantial.
Contrast that, though, the with attention typically paid small molecule manufacturing. “Chemistry is just cooking” one biologist and biotech CSO once told DrugBaron dismissively – only to discover a year and £2million later that his company’s deceptively simple lead compound was every bit as challenging to make at scale as any antibody.
“Making a small molecule drug at scale is indeed ‘just cooking’” according to David Fox, who heads up chemistry for RxCelerate, ‘but like cooking, most of the skill is in finding the right recipe in the first place, rather than just following it. Fundamentally, finding a suitable route to manufacture any novel molecule on a kilo, or larger, scale is a chemistry research activity – and in research outcomes are never guaranteed.”
That’s quite different from the usual perception. To a biology-trained drug developer, if you can make a gram of your molecule, the task of making kilos or tons seems like an engineering problem rather than a chemistry one. And that misperception often leads to trouble, when they engage a contract manufacturer staffed by chemical engineers, who know very well how to drive the plant, but fail to properly understand the details of the underlying chemistry. “Chemical engineers are engineers who work with chemicals – not chemists” says Fox.
“Finding a good, scalable manufacturing route for a new compound has more in common with medicinal chemistry than with engineering. In a medicinal chemistry project, we are looking to choose one molecule out of an almost infinite set of possibilities that has a particular set of properties. In a scale-up project, we are looking to choose one route, one process out of a similarly large number of plausible variations.”
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