Eli Lilly’s breast cancer med Verzenio may look like your standard drug tablet—ovular, off-white, emblazoned with the dosage on the front and Lilly’s logo on the reverse—but behind that modest façade is a high-tech manufacturing approach that pharma has been inching toward for more than a decade.
To make the drug, Lilly's workers feed powdered raw materials into a continuous system. Inside, the materials are continuously fed, blended and pressed into uncoated Verzenio tablets, which come tumbling out like coins from a slot machine.
It’s called a continuous direct compression process, and Lilly’s hoping to apply the same approach to other products.
“[O]ur continuous platform is our preferred platform for any new products in development, so we are targeting its use for additional new products in the future,” David Pappa, technical services and manufacturing sciences director for Lilly’s dry products network, said in an interview.
The method might not work for all drugs just yet—the industry's biggest successes have been tablets—but Pappa said Lilly plans to continue expanding continuous manufacturing “as much as possible.”
The technique has had the industry buzzing for years, but, despite efforts from a handful of pharmas and researchers, continuous drug production has suffered on the uptake. The tide may be changing, though. The COVID-19 pandemic exposed cracks in the U.S. pharmaceutical supply chain, and a handful of companies are flush with government cash to bring continuous manufacturing to the fore.
The winding road to continuous
In 2019, Janet Woodcock, M.D., then-director of the FDA’s Center for Drug Evaluation and Research (CDER), wrote that just 28% of manufacturers producing drug ingredients for the U.S. market were based in the U.S.
But, she conceded, local manufacturers using batch-based production “could never offset the labor and other cost advantages” enjoyed by contractors in China and India.
Continuous manufacturing, where production steps play out in an unbroken stream—unlike the stop-and-start batch process the industry has depended on for decades—would prove vital to the U.S.’ future manufacturing independence, she said.
The idea is not lost on experts in the field.
"People in the industry understand if we could snap our fingers and the whole industry were continuous, that would have tremendous benefits,” said Bernhardt Trout, director and principal investigator of the Novartis-MIT Center for Continuous Manufacturing—a now-concluded research collaboration to transform drug production. “The problem is the hurdle to get there."
Continuous manufacturing is faster than batch processing and easier to scale. It offers greater control and eliminates the need to stop and handle drugs between steps, potentially improving quality and consistency. The equipment involved takes up less space, is more environmentally friendly and, in some cases, can be moved between facilities—and those are just a few of the perks.
But “mindset and mental inertia” have proved two major stumbling blocks for the industry, to hear Trout tell it, along with “a lot of perceived regulatory hurdles.”
Those hurdles exist, to be sure, but the FDA has specifically set out to develop regulatory standards, harmonize them with guidelines abroad and ease the entry of early adopters.
MIT itself proved the approach was feasible in 2011 when it successfully ran the first end-to-end continuous pharmaceutical process with automated, model-based control at the bench scale.
This marked “the first time and really the only time for small molecules, even on the bench scale, in which there’s been end-to-end process from chemical precursor all the way to coated tablets, integrated, with automation and control,” Trout said.
“That showed the world that this could be done, and doing so was a big challenge of the Center,” he added. Former CDER director Woodcock even spoke at the center’s inauguration, sounding the continuous manufacturing call as far back as 2007.
A tablet here, a tablet there
Since then, at least six drugs that partially incorporate continuous manufacturing have been approved in the U.S. or abroad, according to a white paper published in the Journal of Pharmaceutical Sciences in 2019. Vertex Pharmaceuticals kicked off the trend with its cystic fibrosis med Orkambi in 2015. Vertex’s Symdeko, one of Orkambi's sister drugs, also uses the approach, as does Johnson & Johnson’s HIV med Prezista.
Clinical supplies of Pfizer’s acute myeloid leukemia drug Daurismo, meanwhile, were initially made the same way most drugs are: raw ingredients moved through mixing and compression in discrete steps using a traditional, small batch process.
But with proof of concept in hand, the company pivoted to development on its Portable, Continuous, Miniature and Modular (PCMM) oral solid-dose technology, a Pfizer spokesperson said via email.
The platform encloses the continuous process in a portable, autonomous space that Pfizer calls a POD. Around 60% to 70% smaller than a traditional manufacturing line, Pfizer’s modular factory is compact enough to fit on the back of a semi-truck and can be set up in about a year versus the two, three or more needed to build a fixed plant.
Pfizer’s PODS can be broken down and redeployed, and they use the same equipment for development, clinical trials and commercial manufacturing alike. Perhaps most crucially, the technology can help slash production timelines from weeks to mere minutes.
Pfizer in 2017 switched to PCCM for Daurismo’s development at its R&D center in Groton, Connecticut, and started using the technology for commercial supply of the drug from its Freiburg, Germany, plant in 2019, the spokesperson said. Much like Verzenio, Pfizer uses continuous mixing and continuous direct tablet compression to make its Daurismo tablets.
Like Lilly, Pfizer’s spokesperson said its PCMM platform "has been the direction and priority for our drug product manufacturing technology over the last five years." The company expects to leverage continuous processing for “a number” of immediate release tablets in the future and is building out investment and science plans to bolster PCMM, he said.
COVID's "onshoring" impetus
Whether it was the COVID-19 pandemic itself, the federal funding poured into manufacturing because of it or the recent emphasis on “onshored” drug production, continuous manufacturing has reached a tipping point.
Woodcock’s 2019 appeal to wean the U.S. off its foreign active pharmaceutical ingredient habit came months before COVID-19 touched down and reignited discussions about a lack of domestic drug manufacturing. Through the Trump administration and its Operation Warp Speed initiative, the U.S. government dumped billions of dollars into companies—some established and others little-known—over the course of 2020.
It's unclear how those “onshoring” efforts will play out under President Joe Biden, but a February executive order that called for a 100-day review of American supply chains—including those for drug ingredients—suggests the new administration will continue to keep an eye on the nation's homegrown drugmaking prowess. In recent decades, more than 70% of API makers supplying the U.S. have moved offshore, according to a prepared fact sheet from the White House.
Meanwhile, 2021 has already seen at least two companies tap the continuous approach to bring production of critical meds stateside. While the pandemic certainly isn't the only culprit behind continuous manufacturing's rise, "COVID-19 is a major aspect because it brought to the fore the importance of manufacturing," MIT’s Trout said.
Continuus Pharmaceuticals, itself a spinout of the Novartis-MIT team-up, nabbed a $69.3 million government contract in January to set up the country’s first FDA-approved, end-to-end continuous production facility using its integrated continuous manufacturing (ICM) technology. The plant will be kitted out to produce APIs for small-molecule drugs as well as finished products.
The contract, awarded by the U.S. departments of Defense and Health and Human Services, will see Continuus leverage ICM to onshore production of three key meds for intensive care patients, including those with COVID-19. The company aims to turn out 100 million doses per year at the plant, which should be up and running in the next two years, founder and CEO Salvatore Mascia, Ph.D., told Fierce Pharma at the time.
In February, fledgling Phlow Corporation—previously awarded a $354 million contract to build a generic medicine and API plant in Richmond, Virginia—said it would adopt a similar tack.
The company is teaming up with United States Pharmacopeia—a nonprofit that sets quality, purity, strength and identity standards for drugs—to develop a new laboratory to certify and validate continuous manufacturing processes. The goal, to hear Phlow and USP tell it, is to supply the U.S. with “affordable, high-quality, U.S.-manufactured essential medicines.”
The methods the partners develop will be made available to other U.S. generics makers to encourage broader adoption of the continuous approach and, ideally, bolster the U.S. supply chain.
Continuous manufacturing is especially well-suited to crises like the current COVID-19 pandemic, Ronald Piervincenzi, Ph.D., CEO of USP, said in a release. Advantages over batch manufacturing “include the availability and use of real-time data to accelerate manufacturing scale-up and help improve medicine quality, enabling more efficient and nimble production of essential medicines and strengthening the overall supply chain,” he said.