Life Science Leader Magazine Supplements

CMO 2017

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LIFESCIENCELEADER.COM THE CMO LEADERSHIP AWARDS 2017 12 By L. Garguilo SOME STRAIGHT TALK TO CMOs ACHAOGEN Leaders and consistency from your CMO." Larson makes clear that sponsors like Achaogen are looking for continued modernization — implementa- tion of up-to-date equipment and technologies — to produce material reliably and consistently. However, she says the disconnect is when CMOs bring ideas and the sponsor has to respond: "Yes, we want better titer output, and higher purification, but that's not the key drivers of our business. We'd need more foundational innovation to make a real business difference." So what would a foundational innovation be? One example, says Larson, is dramatically rethinking how to work with cell lines. "Maybe it's cell-expression systems, or something like cell-free synthesis that Jim Swartz [Stanford University's James H. Clark professor at the School of Engineering, and professor of chemi- cal engineering and bioengineering] has been working on for years. Others have looked at E. coli expression systems, although here the purification is still quite challenging. I think that the foremost opportunity for game-changing innovation today is basically cleaning up the expression systems, although that's obviously not going to be easy." She believes that the bottom line is that high-yield manufacturing gets completely disconnected with the overall business. "Look at the wider industry today, particularly as we move to more personalized medi- cine, high-potency products, and advanced delivery systems, all meaning less volume," she explains. "I have worked on products where all the material needed for a decade could be produced by just doing the qualifica- tion batches. More than ever, sponsors and their service providers have to keep an eye on the evolving business CMOs: Improvement in titers drives down the cost of goods. "This isn't unlike other industries with sup- ply chains and strong competition between service providers," she says. "In the chemical industries, if you figure out how to get a 10 percent improvement in your distillation column, you can practically retire on that. However, a CMO's idea to double the titer for one of my processes isn't necessarily going to drive down the cost of my goods, and it certainly won't induce us to make a business decision. Actually, in some situ- ations, you could be offered 200 percent more mate- rial out of a biologics manufacturing process, but who cares? Honestly, I hate to say that, but that's not the real target." So what is? Fundamentally, throughout the entire pipeline, this business is all about speed to market. "That's the busi- ness driver. It's not about manufacturing," says Larson emphatically. "It is about being the first one to get a product to market and as fast as we can. Our process is essentially locked at market application for this pur- pose. This is the context for that 200-percent improve- ment in output. Any post-filing innovation of that sort will be offset by the cost of new filings, potentially even redoing a clinical trial, and specifically our speed to market. It simply is not worth it." She adds that, even premarket, you need to decide if you are talking about improving a process that in any way could slow you down from getting to your filings. "If so, it's probably not worth it. I mean, I see an under- estimation of speed to market as being the key driver of this industry for most products. CDMOs, CMOs, and our own process-development folks need to take this to heart." Larson provides an example where a service provider was pushing for an improved titer, but that increase consequently resulted in a different quality profile and more variants; the material would end up harder to purify with less consistent production. "We've seen companies push levels up to multiple grams per liter, but they actually never ran that at commercial scale," she explains. "There's this tendency to become obsessed with cell-culture yield because it's an easy metric. But if you lose one or two runs in manufacturing, the cost completely wipes out your titer improvement." "For years we've focused on the drug substance, but increasingly the differentiation is in other areas, for example on device and delivery," she continues. "So you are focusing on getting your drug substance down to $10 a dose from the antibody production, but then you put that in a device that brings your dose closer to $50. You're focusing on the wrong place. You might want to be looking at things like the likelihood of delivery by sterile, prefilled syringes, and simply the best quality Small molecule manufacturing has the potential to be so much more elegant. Manufacturers have just lacked the business drivers to modernize.

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