Innovative Biopharma Manufacturing Models
Bugs, biologics and a new way to make small molecule drugs drove the discussion at a break-out session focused on advanced biopharmaceutical manufacturing in Massachusetts at the MassBio 2016 Annual Meeting.
“Massachusetts is an established global leader in biopharma research and development, but now the expansion of drug targets and the advent of new classes of therapeutics is also driving growth and innovation in manufacturing here, across many platforms,” said Kamal Rashid, PhD, director of the Biomanufacturing Education & Training Center and research professor of biology and biotechnology at Worcester Polytechnic Institute (WPI) who moderated the session.
More than 100 people attended the session on March 31, the first day of the two-day annual meeting held at the Royal Sonesta Hotel in Cambridge. They heard presentations from a panel of manufacturing experts at Biovolutions, Seres Therapeutics and Vertex Pharmaceuticals, then engaged the panel with questions.
Traditionally, manufacturing of biologics and small molecule pharmaceuticals has been done in large-scale, fed-batch systems. The companies on the advanced manufacturing panel, while working in different fields, are integrating new technologies, or working on novel platforms that do not depend on large batch systems.
“The only way we could compete with Asia was to come up with an advanced, low-cost solution,” said Maurizio Cattaneo, PhD, CEO of Biovolutions, a service provider and contract manufacturer of proteins and monoclonal antibodies for research and clinical studies. “So we thought, let’s take some ideas from Toyota and make biologics like making a car.”
Cattaneo said his team applies the principles of lean manufacturing, and the just-in-time flow of materials along an auto production line to build a continuous process for making biologics.
“We started from the bottlenecks, which are downstream, and worked backwards,” he said. “We want to synchronize upstream and downstream, so what comes out of the perfusion reactor should match what you can take into purification.”
Advantages to Biovolutions’ continuous system, starting with a low-flow perfusion reactor, include less media required upstream and less Protein A resin downstream, Cattaneo said. Critical to the platform, he noted, are advanced process analytics to monitor key parameters in real time to maintain quality. “Our goal is end-to-end continuous manufacturing, but we’re not there yet,” Cattaneo said. “Right now we’re focused on upstream and synching that with capture.”
Patricia Hurter, PhD, senior vice president of CMC and preclinical development at Vertex Pharmaceuticals said the company was an early adopter of Quality By Design methodology and that “is not a good fit for big batches.”
Moving to a continuous platform for production, the Vertex team can quickly make adjustments to various aspects of manufacturing to improve efficiency and maintain quality, Hurter said.
The continuous model crystalized at Vertex when the company was considering the needs of an antiviral medication in development for pandemic flu, Hurter said. “In a pandemic year, you’ll want tons of product available really fast, and in a normal year, not so much. So that calls out for a continuous process that can be ramped up quickly.”
When Vertex made a major breakthrough with its cystic fibrosis program and focus turned to production of that small molecule, the company stuck with a continuous model and built out a proprietary production facility in Boston, she said
That system currently has a maximum capacity of seven ingredients. The API (active pharmaceutical ingredient) in the formulation needs to be suitable for movement by a screw feeder. The system combines the ingredients through a series of unit operations that end with a finished drug coming out the other end. “It’s quite a machine, three stories tall,” Hurter said.
At Seres Therapeutics, the goal is to modulate the human microbiome and treat diseases that arise from imbalances or deficiencies in the broad population of microorganisms that populate the human GI tract. Seres’ R&D focuses on the key microbes and pathways involved in a particular disease, and once targets are identified, the manufacturing team uses a proprietary technology platform to culture the commensal microbes as a potential therapeutic for patients.
“My business model, essentially, is to contaminate my plant by growing bugs,” said John Aunins, PhD, executive vice president of bioprocess & Manufacturing and CTO at Seres, drawing laughter from the audience.
Growing those beneficial microbes, many of which die in the presence of oxygen and need nutrients from other microbes or factors from the host’s body, in a controlled environment is a major challenge, Aunins noted. So the company is building a novel manufacturing platform to handle the production. “We are trying to cultivate microbes that have historically been considered, uncultivatable,” he said.
The company’s lead drug candidate targets the bacterium Clostridium difficile, or C. diff which can cause serious, sometimes life-threatening diarrhea in hospitalized patients. The therapy is now in clinical trials. See: http://www.serestherapeutics.com/pipeline/ser-109.
Most healthy people who carry C. diff don’t get sick because the bug is kept in check by a healthy gut microbiome. When the GI tract is thrown out of balance by illness, a depressed immune system, or use of antibiotics to treat other infections, C. diff can grow out of control and secrete toxins that damage the intestinal wall.
“This is an ecological problem. So what we’re trying to do is create an ecology of beneficial microbes that can co-exist with the gut microbiome and provide a set of beneficial functions,” Aunins said.
At the close of the session, Rashid thanked the panelists and the audience for their questions. He also echoed remarks made by Governor Charlie Baker at the morning plenary session about the need for continued STEM education and workforce training to fill the pipeline with qualified employees to help Massachusetts biotech companies grow. “Industry and academia must continue to work in partnership to focus on giving our students and our employees the education and hands-on training they need to drive the success of biopharmaceutical manufacturing in this state," Rashid said.
Photo Credit: Sean Browne