When Pierre Lemieux and his team at Acasti Pharma went looking for a pharmaceutical manufacturing partner, they had a surprising amount of trouble finding one.
Out of the sea and into the factory
The reason was the type of drug they are developing. The active ingredient in Acasti’s lead product, which lowers triglyceride levels in people at risk of cardiovascular disease, is an extract from krill oil, and not everyone wants to work with krill oil.
For starters, natural product extraction is an art not widely practiced among drug outsourcing firms. In addition, krill are shrimplike crustaceans, and some potential partners were concerned about contaminating their facilities with shellfish allergens. On top of that, extracting the active ingredient involves acetone, a flammable solvent some companies weren’t prepared to handle. A krill oil plant operated by Acasti’s then parent company exploded in 2012, killing three people.
But Acasti kept looking. It was having success in early trials of its drug and would soon need a partner with facilities approved by the U.S. Food & Drug Administration so it could pursue larger-scale trials in North America.
Clinical-stage manufacturing of its active ingredient would be one more step in a journey for Acasti that began a decade ago when the Canadian company now called Neptune Wellness Solutions spawned the drug firm.
▸ Sources: Fatty fish, krill, fermentation
▸ Current therapeutic market: ~$1.5 billion per year
▸ Current supplement market: ~$3.0 billion per year
▸ CaPre’s competitors: Amarin’s Vascepa, AstraZeneca’s Epanova, GSK’s Lovaza
At the time, Neptune was selling krill oil rich in omega-3 fatty acids to the dietary supplement market, and it saw an opportunity to move into the regulated pharmaceutical arena. Lovaza, a fish-oil-based drug now sold by GlaxoSmithKline, had won U.S. approval in 2005 and was rapidly racking up sales. Lemieux came aboard in 2010 to help lead Acasti’s effort to launch a competitor to Lovaza. Neptune is now a minority shareholder in Acasti.
The firm’s advantage, Lemieux says, is that its oil comes from krill rather than fish. In the Lovaza manufacturing process, the omega-3s—eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)—are converted into ethyl esters to provide stability during purification. Acasti points to tests showing that the esterified oils are most effective when ingested with high-fat meals—not ideal for people with heart conditions.
In contrast, the EPA and DHA in Acasti’s product, called CaPre, are either free fatty acids or bound to phospholipid esters. Acasti’s Phase I and II clinical trials show that CaPre’s bioavailability is far less affected when it’s taken on an empty stomach or with a low-fat meal than is Lovaza’s.
Moreover, says Lemieux, a Ph.D. biochemist who is Acasti’s chief operating officer, trial data show that CaPre lowers triglycerides while also benefiting both good and bad cholesterol. The firm’s scientists don’t fully understand why, he says, but they suspect it has to do with the role that phospholipids play in how the body manages cholesterol. Two Phase III clinical trials of CaPre are ongoing, and Acasti expects to be able to report data by the end of 2019.
Although several contract manufacturers looked at the Acasti job and said, “No thank you,” CordenPharma welcomed the challenge. Formed in 2006, CordenPharma is a pharmaceutical services firm composed of facilities cast off by large drug companies. Its strategy is to buy the unwanted plants at a discount and continue manufacturing some products for their former owners while gradually bringing in outside customers.
One of CordenPharma’s first acquisitions was a facility in Chenôve, France, that had several past owners, including Merck & Co. and Solvay Pharmaceuticals. Stephen Houldsworth, CordenPharma’s global director for small molecules and antibiotics, says the plant was a good candidate for the Acasti job. It had experience with natural products and was already producing an extract from tree bark.
But in evaluating the potential contract, the CordenPharma team saw a problem: Daily doses of the omega-3s are measured in grams, not milligrams like many small-molecule drugs. Extracting the required amount of EPA and DHA a batch at a time would involve large vessels and large amounts of solvent. “Phase III supply would be a challenge,” Houldsworth says, “and commercial was never going to be able to be done at Chenôve.”
That’s when engineers at the plant, led by site director Yves Michon, realized the solution might be to move from a traditional batch-manufacturing process to a smaller and safer continuous one. “They did a quick proof-of-concept experiment with very crude equipment and presented it to Acasti,” Houldsworth says.
CordenPharma had previously tried to convince customers to adopt continuous manufacturing, Houldsworth recounts. But as is often the case in the drug industry, conservatism prevailed. It was an easier sell for Acasti, according to Lemieux, because some people on his team, aware of the Neptune accident, were thinking along the same lines.
After the contract was signed, the partners worked with a process equipment firm to design a continuous decantation system. The equipment firm then built it, shipped it to Chenôve, and installed it on skids. “The footprint is a fraction of what the batch process would require,” Houldsworth says. The amount of solvent in the system at any given time is similarly reduced.
The partners’ adoption of a continuous-flow process comes at a time when FDA is advocating for more continuous production in the drug industry. It released several bulletins last year championing the approach. Not surprisingly, Lemieux says the agency responded supportively when informed of the plan to go continuous.
In addition to cost and safety improvements, a continuous process can offer better analytical control. In a batch process, Houldsworth notes, the analytical testing required for product release happens after making a batch. “In continuous processing, you push a lot of analytical testing into the process,” he says. “You get continuous data feedback and know almost instantly what the process is doing and how it’s performing.”
Continuous processes do involve batches, but they are defined by time or volume. To date, CordenPharma has made a number of such batches for Acasti’s Phase III trials. Houldsworth says the plant is now gearing up to start the process validation that is required before the company files a New Drug Application with FDA.
Lemieux and his team are already starting to think about what comes next. The current facility can produce about 20 metric tons of the CaPre active ingredient per year—enough, he figures, for the drug’s first few years on the market. But if CaPre is as successful as Acasti hopes it will be, the firm will need a second, 200-metric-ton facility. Houldsworth would love to see it get built in Chenôve.
Today, Acasti ships the purified omega-3s from France to Canada for encapsulation, sealing, and packaging by other manufacturing partners. “It would be nice to have all the steps under one roof,” Lemieux says. A one-shop process would further extend the Acasti-CordenPharma partnership and mean even more business for the once-unwanted plant in Chenôve.