As FDA and pharma warm to continuous manufacturing, generics stay skeptical
Though the Food and Drug Administration and large parts of the branded industry are increasingly turning to continuous manufacturing, generic drugmakers are seeking a slowdown.
FDA chief Scott Gottlieb touts the method as transformative, with the promise to "improve drug quality, address shortages of medicines, lower drug costs, and bring pharmaceutical manufacturing back to the United States," as he wrote in a July blog post.
Big pharma companies have already begun to move toward continuous manufacturing, albeit tentatively. Three original and one supplemental New Drug Applications have been OK'd by the FDA that use continuous manufacturing.
"I thought it would progress very slowly, and it has progressed very slowly," Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research, said in an interview with BioPharma Dive on Sept. 21. "I take the long view on things, and it is the future of manufacturing."
But while branded firms inch ahead, the generics industry sees a different calculus. Higher costs and risks to their slimmer margins loom large, as do worries pharma rivals will exploit the new technology to stymie competition. No generic drugs are currently approved using continuous manufacturing.
Before retiring last year from Eli Lilly, Ian Leavesley was the continuous manufacturing lead for the pharmaceutical giant, where he helped usher the technology from concept to real-world practice, culminating with the cancer drug Verzenio in 2017. Lilly makes Verzenio, as well as several experimental compounds, using continuous manufacturing.
"The generic industry and big pharma are in two different places," Leavesley said, who is now president of Modern Pharma Consulting. "I can see the same business drivers not being as profound."
Woodcock will be patiently waiting for broader adoption by all. She predicted the FDA will "probably not" provide additional incentives to businesses in the next few years to adopt continuous manufacturing, viewing business motivators as sufficient.
"If you still want your manufacturing to be like the 1940s, OK," she told BioPharma Dive. "If you can meet the standards, OK with us, because there's a lot of sunk costs [involved with shifting to continuous manufacturing]."
Technological advancement or tool for generic obstruction?
The generic drug industry is less enthusiastic about the new manufacturing process. The Association for Accessible Medicines, the primary U.S. trade group for generics, presented its case in an interview with BioPharma Dive.
David Gaugh, AAM's senior vice president for sciences and regulatory affairs, said that while his organization did not oppose continuous manufacturing, it has some unanswered questions and unaddressed concerns.
He said the "heat's been turned up at the FDA" on the topic in the past year.
According to Gaugh, the group is worried about the potential for continuous manufacturing to be used as another way for branded companies to potentially hinder generic competition.
He theorized companies could file citizen petitions and argue that any generic, in order to be fully equivalent to a continuous manufactured branded drug, would need to adopt the same production methods. Specifically, they could argue a narrower range of content uniformity makes it superior to batch processes.
Woodcock said she plans to address these concerns in a speech set for Oct. 3 at a conference in London. The CDER head said drugs simply have to be "fit for purpose" and the FDA won't force generics to use continuous to match a branded drug.
"Look, just because you can make [a drug] to this level of content uniformity, that doesn't mean it has to be made to that level of content," she said.
In an emailed statement to BioPharma Dive, the agency further pushed back on the concern of generic obstruction.
"Continuous manufacturing itself does not pose any barrier to generic entry," Sau Lee, deputy director of the Office of Research and Testing at FDA's Center for Drug Evaluation and Research said, "because FDA does not require use of specific manufacturing technologies, and all generic drugs are required to meet the same standards."
The issue, though, is a rare instance of opposition from the generic lobby to policies advanced by the FDA under Gottlieb.
"We work very well with him, very closely with him, we are a huge supporter of Dr. Gottlieb," Gaugh added. "So, this just happens to be the one area where we probably aren't as on board."
The FDA declined to comment on if they view the quality of drugs produced via continuous and traditional batch manufacturing to be equivalent.
"Efficient adoption of these approaches will require a paradigm change in the regulation of manufacturing."
Experts and executives in the field point to a hesitancy to embrace change as a key barrier to continuous manufacturing, particularly for generics.
Salvatore Mascia, the CEO of Continuus Pharmaceuticals, said adopting continuous "requires a transformation or change in mindset of the industry." Mascia is a former a strategic project manager at the Novartis-MIT Center for Continuous Manufacturing.
Mascia told BioPharma Dive his company will begin building a facility in the U.S. in 2019 for "one of the major generic companies" to begin using continuous manufacturing. Mascia declined to name the company or provide further details, but the agreement could make the firm a first adopter in the generic industry.
So far, AAM stated in a document provided to BioPharma Dive, generic companies exploring the concept "have found that the costs would exceed the benefits," citing a necessary "significant investment" in building or converting facilities.
"I think it's more about the pain of transition," said Douglas Hausner, who helps run an engineering center at Rutgers University that works on continuous manufacturing. "In the case of [the generic] industry, I think that their main concern would be from a capital standpoint. When they're already working with thin margins, how do they change over?"
Those questions are also present on the branded side, even as pharmas experiment with continuous manufacturing. Momentum looks set to grow, however, putting the generic industry at risk of being outflanked.
Leavesley, the former Lilly engineer, estimated that while less than 5% of total pharma product is now made with continuous manufacturing, roughly 80% of all product could be made with it over time.
He noted the main driver to adoption will be companies realizing the benefits, as was his case in convincing Lilly executives.
"The inflection point in all this was demonstrating we can develop a product faster, for less cost and using less material than anybody thought possible," Leavesley said in an interview with BioPharma Dive.
"Ultimately, it comes down to the business case," he added. "It's not about technology."
That optimism is shared by Mascia, although he conceded the journey to adoption remains marked with speed bumps and roadblocks for both generic and branded drugmakers.
"We still have a long way to go on this," Mascia said. "We have seen maybe 10% of the power continuous manufacturing can bring to to the pharmaceutical industry."
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