Chemical Development From Cotton Candy To Pharmaceuticals

By Louis Garguilo, Chief Editor, Outsourced Pharma

“He Came, He Learned, He Taught.”

Sriram Naganathan, Senior Director, Chemical Development at Dermira, Inc., is such an upbeat and energetic professional, it’s a bit strange to start this article by quoting what he hopes will be his epitaph one day (far in the future).

That positive outlook and his future descriptor come together perfectly, for example, when he says, “I believe I ended up working at the two best places in the world for me to learn process chemistry, Pfizer and Roche.”

It’s also fitting that his first piece of advice to fellow drug developers is to really live by the concept of “phase appropriate.” He provides us more advice below. But first you’re probably wondering about that cotton candy.

The Sweet Smell Of Success

Speaking with Naganathan is, I’m sure, analogous to watching him work as a process chemist – there’s a methodical advancement, but with a retracing of sentences to ensure deliver of the most meaningful results.

He came out of the University of Kansas having demonstrated a proclivity in synthetic organic chemistry, and found himself under the tutelage of Professor Eric Block at University at Albany SUNY, studying organosulfur chemistry. This led to his joining what at that time was the food group at Pfizer-Groton – which “traces back directly to Charles Pfizer” – initially to help overcome challenges with a sulfur-containing artificial sweetener. “It was a lot of fun in my early days in industry,” he says. “You know the smell of cotton candy, right? That’s what I smelled for quite a while!”

Over the next decade and a half he moved on to other companies – including Roche (Bioscience) and Exelixis – before taking up his current position. Along the way he gained experiences outsourcing a variety of development and commercial products. Today his projects and products are in the dermatologic field, Dermira’s focus. At times that entails outsourcing fast-advancing process development projects; other times the manufacture of multi-tons of API and drug product. Dermira has grown to eighty-plus-employees, but has no labs of its own. Naganathan relies on outsourcing to move his projects and products through phase study to commercial.

So that’s how Naganathan “came.” We’ll talk specifically about his “teaching” soon – Outsourced Pharma readers are in for good news – but first he shares his lessons learned on becoming a better outsourcer.

A Million Dollars A Day

“The mantra is ‘phase appropriate,’” says Naganathan, knowing full well this is far from the first time readers have heard this. Yet he insists the concept is not applied fundamentally to decision-making. “I tell everyone to focus on your project status – early, middle or commercial phases – and consider immediate and long-term goals in the appropriate context,” he says. He offers the example of a drug developer trying to get to phase one; the paramount goal, he says, is getting there as quickly as possible.

“Let’s look for mathematical simplicity. You estimate you are looking at a drug with the commercial potential of generating $365 million a year. Every day you are not in the market, you are losing a million dollars. You can go through an elaborate evaluation and select that perfect CDMO to help you with early phase material, but if that takes you two additional months, will you really add $60 million dollars of value at this stage?”

Naganathan clarifies that he’s not advocating for signing up with “the first CDMO down the street.” He’s applying phase appropriate thinking, which in this case should be: get the drug into patients, and a “read out” on human data to determine if you will move forward to develop this product. “And one thing I’ve learned over these years,” he adds, “is you don’t want to be the bottleneck to your clinical people starting their clinical trial and getting your company that data as rapidly as possible. So for phase one, the key is speed. Your process at this point is probably not very well developed, and that is acceptable.”

Despite the need for speed, Naganathan does set down parameters for which CDMO a drug developer should work with. “You want to go to somebody specifically with a very strong chemistry and development expertise,” something that sounds obvious but not always followed, says Naganathan. Those professionals, he says, will quickly get you your phase one supply and into the clinic. “They also understand the strategy: There will be more time subsequently to develop a top-end, high-quality process, and work on goals like cost of goods. If you’re successful, think of these as good challenges to have later.”

I ask Naganathan if he tends to work with smaller CDMOs at this stage – despite the fact that one of those future challenges with dermatological products will be many tons of commercial material.

“In fact, yes,” he replies. “I do often go to an organization somewhere in the kilo-lab scale, because at this point I don’t need 1,500-liter vessels.” He then quickly supports his thesis with this: “But this doesn’t mean I’m not planning for success. Rather, at this phase, planning for success means when I am making my phase one material, I’ll make it together with volumes for phase two as well, and I’ll be sure to have materials for some formulation supply.”

In practice, Naganathan says it might look like this: If his clinical team estimates a need for one kilo of material for clinical use, he’ll typically attempt to make between five and ten kilos. He says “attempt to make” because in some cases, this might go against his golden rule: Do not hold up getting into the clinic. He also adds this caveat: “Also considering associated costs, I will not overdo it here. 

“In short,” he continues, “I’m planning for immediate success, and not hung up on the later stages, but staying strategic. A helpful CDMO goes a long way here. You need the partner that can mobilize quickly and can, obviously, look at multiple routes, take initial data, and pardon the cliché, take out all the low hanging fruit.”

Change For The Better

“Here’s my second thing,” says Naganathan. “When you are in phase one or two, never run the same process. Don’t make the material the same way two times in a row, because that means you’re not learning anything. You cannot tell me your process is so perfect that the second time you’re going to run it exactly the same way. You always want to learn from tweaking.”

Having hung around too many quality professionals, I instinctively ask him if that isn’t a risky proposition. Naganathan, with the air of somebody who also has hung around the quality team, takes no time to clarify his position. “Yes, if your QA group wants to get involved, and you’re thinking of changing controls, and that’s part of the strategy, they should actually come in and help you learn with each successive batch.”

He continues the change defense: “I’m not saying you change the whole route. But do look at alternatives, at streamlining, or telescoping. Do not give in by saying, ‘Oh, my goodness, this filtration is going to have to be terribly slow when we run it at scale.’ No … address that issue now. Don’t simply capitulate, and add those additional days to your plans for the next batch. Get that fixed now as much as possible.”

Finally, He Teaches

Here’s the news alluded to in the beginning of our article. Naganathan is excited about a new course he has designed and will teach at Stanford University, focused on process chemistry in phase one and two of pharmaceutical development. “Nobody really teaches process chemistry anymore,” he says. He’s also offered to provide OutsourcedPharma.com readers some help in this area. Professor Naganathan will contribute a quarterly article to these pages on the subject, and related to making better outsourcing decisions. We thank him for that offer, very much look forward to it … and let’s promise not to bring cotton candy to class.