Source: Life Science Leader

When I first saw the name Frank Gupton, Ph.D., it was on the agenda for a session I was attending at the 2016 ISPE conference. Listed as a professor at Virginia Commonwealth University (VCU), I expected his contribution to the panel to be that of an academic and, likely, more theoretical than some of the other industry panelists. I quickly found out how wrong I was.

Gupton started by explaining that being a professor and a department chair was actually his second career, one that started in 2007. Previously he spent 30 years in pharmaceutical manufacturing. “I was happily retired,” stated the former executive director of process development for Boehringer Ingelheim Pharmaceuticals. “I got recruited out of retirement to come to VCU, and the pitch I will make to you is: Academia is a great second career — an opportunity to give back knowledge to those young chemists and chemical engineers who can get value from your industry experience.”

Gupton and I connected after that session, and since then we’ve kept in touch routinely, though I haven’t written about any of our subsequent conversations — until now. After all, as he joked during one of our recent calls, “I’ve gotten more press during the last six and a half months than in my 68 years on this Earth.”

Can an old dog teach young dogs some new tricks?

One of the first things Gupton did when he arrived on VCU’s campus as the chair of the chemical engineering department was to take the chair of the chemistry department out to lunch. In his experience, he had recognized a gap in need of filling. “My research groups in industry were about a 50/50 mix of chemists and chemical engineers. And as they cross-pollinated with each other, they became much more valuable.” Together, the two department chairs mapped out how students could get a double major undergraduate degree in chemistry and chemical engineering in just four years. “We have to be able to ‘prime the pump’ regarding personnel, because what is needed today is a hybrid between a chemist and a chemical engineer,” he says. According to Gupton, 70% of VCU chemical engineering students today graduate with double majors. “Not only are those the first ones to get jobs, they get the highest paying jobs, because they can be used in more areas.” Gupton says that cross-pollination is something academics typically tend to avoid. “My research group where chemists and chemical engineers cohabitate and learn from each other is the exception to the rule.”

That research group is the VCU Medicines For All Institute (M4ALL), which was established in 2017 to develop a more cost-effective way to manufacture drugs used to treat HIV and AIDS. “When you think about the life cycle of a drug, there is about an 18-month window to do process development on the APIs,” Gupton explains. Looking at the cost structure of drugs (i.e., APIs only make up between 5% to 10% of new patented products), there is very little incentive to make improvements, as companies are focused on getting the drug to market as quickly as possible. As such, the API process is locked down prior to when clinical trials start. And when you consider the approximate life cycle of a patented pharmaceutical to be roughly 20 years, you realize a lot of new chemistry is developed during a small molecule’s lifetime. “The problem is, when you go for an ANDA approval for a generic, the criteria the FDA uses is equivalency. Generic companies are disincentivized from making changes to the process for fear they will not get an FDA approval,” he explains. “So, this 20-yearold process, developed for a complex molecule very early in its development, with no incentive to reduce costs, is not only perpetuated over the entire branded life of the drug, but continues on into its generic life cycle as well, often for decades.” This was something Gupton hoped to change, so he tasked his students with figuring how it could be done. Why? Because while APIs may be a small percent of the cost to manufacture a branded product, they can constitute about half of the cost when producing generics, and therein lies the opportunity.

M4ALL began by looking at some basic principles and common-sense ideas on changing the chemistry and doing yield optimization on some older compounds. “We looked at common solvents, reagents, and commodity-based starting materials in the processes, so we could drop the cost, reduce waste, and increase access to a lot of WHO-essential drugs.” The approach taken by his group allowed them to “telescope steps” — eliminate unneeded operations and improve yields. What they do from there is develop batch and continuous process modes to be agnostic regarding the molecule’s mode of manufacturing. According to Gupton, just a 10% improvement in one HIV/AIDS drug would result in an annual savings of approximately $7 million, thereby allowing the Gates Foundation to treat 150,000 more patients.

The first drug M4ALL investigated was Nevirapine, a compound for which Gupton had developed the process while in industry. This was the first nonnucleoside reverse transcriptase inhibitor approved by the FDA for people with HIV infections, and Gupton says he was very proud of the process he had developed. The first-generation Nevirapine commercial process consisted of six steps and 21-unit operations. With a yield of 59%, the cost of doing it the way he had originally developed it was somewhere in the range of $135 to $225/kg of produced Nevirapine. But by making a few simple changes in the starting materials (a strategy that allows you to make a change without having to reregister the process), M4ALL developed a process that was about one-third the size of the original and provided a 92% yield. And, the finished product not only meets all the United States Pharmacopeia (USP) purity specifications for the drug, the cost of the raw materials is under $60/kg. But what’s really striking is the first-generation process required about 58kg of starting material to produce 1kg of product, while the new M4ALL process requires only 4kg of starting material to produce the same amount. This success led his research group to evaluate other commercial processes (e.g., Tenofovir disoproxil, an antiretroviral medication used to prevent and treat HIV/ AIDS and chronic hepatitis B). “When we priced the cost of the asymmetric center that was being put in, it was about $600/kg,” he says. So, Gupton asked his students how this could be done differently. One suggestion led to them using threonine, which costs about 15 cents/kg. “I thought, ‘How could that be?’” he says incredulously. Turns out threonine is a poultry additive. “Basically, we are making a molecule from chicken feed,” he laughs.

How Professor Gupton became involved with restoring U.S. pharma manufacturing

During his time at VCU, Gupton has been responsible for amassing various grants, publications, and patents. In 2018 he also received the American Chemical Society (ACS) award for affordable green chemistry from Dow Chemicals and the Presidential Green Chemistry award from the EPA. Suddenly, Gupton’s name was showing up on a lot of people’s radars.

Martin VanTrieste, president and CEO of Civica Rx, a newly founded nonprofit generic drug manufacturer (see our July 2019 article, “Ending Generic Drug Shortages At Hospitals: A Capitalist Goes Nonprofit”), was one of the first to seek out Gupton’s expertise. “He was worried that they were purchasing their APIs from China and formulating over here,” Gupton explains.

Next came Rosemary Gibson, a senior advisor to The Hastings Center. Author of several books, including China Rx: Exposing the Risks of America’s Dependence on China for Medicine, she, too, expressed concern over the industry’s reliance on China. Gibson also expressed support for what Gupton was doing with M4ALL, as its mission had evolved to include improving access to safe, effective, and affordable medicines — for all.

Finally, Gupton was visited by Marshall and Karen Summar, both M.D.s. Marshall is the division chief of genetics and metabolism and director of the rare disease institute at Children’s National Hospital (Washington, D.C.), while his wife, Karen, also a pediatrician, is the health policy director at the U.S. Senate. They educated Gupton on a rather sad state of U.S. affairs. “Did you know that every newborn in the U.S. now gets tested for genetic deficiencies?” he asks. “The problem is that when a deficiency is found, they don’t have the drugs to treat it, as the volumes to manufacture are so low, and shelf lives so short, they’ve become cost-prohibitive to produce.” According to Gupton, these are very simple drugs (i.e., small molecule), like food additives in sodas and preservatives. “And because we currently aren’t able to produce the necessary APIs cost-effectively here in the U.S., every day, somewhere in the U.S., a pediatrician has to inform parents that their child has a genetic deficiency, and though there’s a drug to treat it, they can’t get it, and their child is going to die.” Gupton describes this and other U.S. shortages of healthcare basics (e.g., saline solution) as “Third-World problems” happening right here in the states. “Marshall asked if we could set up a repository in Richmond, VA, to store the active ingredients and have them shipped to the various children’s hospitals around the country so they could formulate on demand as needed.” So, Gupton began helping to pull together a consortium of pharmaceutical manufacturers, initially just to address the U.S. pediatric drug supply chain issue.

Gupton credits Gibson and Karen Summar with socializing the VCU M4ALL research initiative around Washington. He soon was contacted by the White House amid concerns China might hold U.S. healthcare hostage by restricting access to APIs. “COVID-19 has really shined a light on how broken the U.S. pharmaceutical supply chain actually is, and they were asking what I’d recommend as a solution.” Gupton put together a proposal, they liked it, and now he finds himself the recipient of one of the largest grants awarded by America’s Biomedical Research and Development Authority (BARDA) — $354 million. He also has become a cofounder of Phlow, the newly formed pharma in Virginia, which will use those funds to manufacture affordable, high-quality, essential medicines for the U.S. (For more info on Phlow, see the articles written by Louis Garguilo, chief editor of OutsourcedPharma.com.)

In other words, not only is Gupton playing a major role in the reshoring of American pharmaceutical manufacturing, he’s building a major industrial pharmaceutical manufacturing hub in Virginia, as he noted other important industry players will soon be announcing their plans to also co-locate to the area.

But Gupton is involved in so much more. For example, he has been working with the Gates Foundation on the two antiviral drugs that hold promise for treating COVID-19 (i.e., Gilead’s Remdesivir, and EIDD-2801, an antiviral in collaborative development by Ridgeback Biotherapeutics [a Nov. 2020 Company To Watch] and Merck). Recall hearing about the Remdesivir shortage this past summer? Guess who was pivotal in figuring out how to fix it? And Gupton continues to work with the USP in trying to address the drug supply chain issues in Africa. “We [M4ALL] plan to help them stand up their own manufacturing capabilities and train them on how to run these processes. Then, they can take that knowledge back to their respective countries and make their own HIV and AIDS medications much more cost-effectively.”

Near the end of one of our recent conversations, Gupton shared some interesting personal anecdotes that, given his impressive career and current industry status, many people may find surprising. “I don’t know if I’ve ever told you this, but I got a ‘D’ in chemistry in high school,” he reveals. Further, he admits that without his scholarship to play basketball at the University of Richmond, he would not have been able to afford to go to college. “Just goes to show you, it’s not how you start, it’s how you finish,” the professor wisely concludes.

Sidebar 1

Preparing the next pharmaceutical manufacturing generation

Learning from his students is one of the things Frank Gupton, Ph.D., enjoys most about his role as professor and department chair of chemical and life sciences engineering at Virginia Commonwealth University (VCU). “They seem to teach me something new in the lab almost every day,” he contends. And while collaborating with pupils provides the professor with the motivation to stay sharp, he is now gaining fulfillment from seeing the fruits of his labor starting to impact industry. For example, two of his former VCU students have played a significant role in refining the manufacturing process that he developed while in industry for Nevirapine, the first nonnucleoside reverse transcriptase inhibitor approved by the FDA for people with HIV infections. One is Jensen Verghese, who completed a master’s, Ph.D., and post doc at VCU. He’s now working with Joel Hawkins, who is senior research fellow for global R&D at Pfizer. Another former student of Gupton’s is Caleb Kong, who completed his Ph.D. at VCU in 2019, and now works in process development chemistry at AMPAC Fine Chemicals. “From the time you hire somebody coming out of academia, there tends to be a bit of an induction period — a slow start,” the professor analogizes. “Our job as teachers is to make that period as short as possible, so our students can hit the ground running and add value almost immediately.” How does he do it? By enabling chemistry and chemical engineering students to not only cohabitate and collaborate on real-world problems, but to come up with and implement real-world, cost-saving solutions via VCU’s Medicines For All Institute (M4ALL). To learn more, check out the M4ALL website at https://medicines4all.vcu.edu/