Personalized healthcare is the goal that a great deal of technological research in the medical industry is working towards. This includes research in everything from artificial intelligence and smart devices, to medical implants and drug production and delivery.
One of the fastest-growing sectors in the pharmaceutical industry is that of biopharmaceuticals, a class of drugs comprising proteins such as antibodies and hormones. These drugs are increasingly important for “precision medicine,” which are drugs and treatments specifically tailored toward the genetic or molecular profiles of particular individuals or groups of patients.
Biopharmaceutical drugs are typically manufactured at large facilities that are dedicated to producing a single product, often using processes that are difficult to reconfigure. This rigidity of processes and equipment results in manufacturers focusing on producing the drugs needed by the largest number of patients. Most of the time, this means drugs that could help smaller populations of patients may not be made, or will be produced rarely and availability will suffer between production runs.
A team of MIT chemical engineers and researchers set out to make more of these drugs available, and have developed a new way to rapidly manufacture biopharmaceuticals on demand. Their system is easy to reconfigure to produce different drugs, which enables flexible switching between products as needed.
“Traditional biomanufacturing relies on unique processes for each new molecule that is produced,” says J. Christopher Love, a professor of chemical engineering at MIT and a member of MIT’s Koch Institute for Integrative Cancer Research. “We’ve demonstrated a single hardware configuration that can produce different recombinant proteins in a fully automated, hands-free manner.”
The researchers have used this manufacturing system, which can fit on a lab benchtop, to produce three different biopharmaceuticals, with comparable quality to commercially available versions.
Streamlining the Process
Most biopharmaceuticals are injected drugs, and are often used to treat diseases including cancer, cardiovascular disease and autoimmune disorders. The majority of these drugs are produced in “bioreactors” where bacteria, yeast, or mammalian cells churn out large quantities of a single drug. These drugs then need to be purified before use, which means the entire production process can include dozens of steps—many of which require human oversight or intervention. As a result, most production processes take weeks to months to produce a single batch of a single drug.
The research team at MIT wanted to create a more agile system—one that was easy to reprogram and able to quickly produce a variety of different drugs on demand. They also wanted this system to require very little human oversight, while still maintaining the high quality of protein required for use in patients.
“Our goal was to make the entire process automated, so once you set up our system, you press ‘go’ and then you come back a few days later and there’s purified, formulated drug waiting for you,” said Laura Crowell, a graduate student on the research team.
One key element of the new system is the use of a different type of cell in the bioreactors — a strain of yeast called Pichia pastoris. Yeast can begin producing proteins much faster than mammalian cells, and they can grow to higher population densities. Additionally, the purification process for drugs produced by Pichia pastoris is much simpler, as Pichia pastoris secretes only about 150 to 200 proteins of its own, compared to about 2,000 proteins for Chinese hamster ovary (CHO) cells, which are often used for biopharmaceutical production.
The team also worked to greatly reduce the size of the system, with the ultimate goal of making it portable. Their system consists of three connected modules: the bioreactor, where yeast produces the desired protein; a purification module, where the drug molecule is separated from other proteins using chromatography; and a module in which the protein drug is suspended in a buffer that preserves it until it reaches the patient.
The researcher team used their technology to produce three different drugs: human growth hormone; interferon alpha 2b, which is used to treat cancer; and granulocyte colony-stimulating factor (GCSF), which is used to boost the immune systems of patients receiving chemotherapy.
They found that for all three molecules, the drugs produced with the new process had the same biochemical and biophysical traits as the commercially manufactured versions. The GCSF product behaved comparably to a licensed product from Amgen when tested in animals.
Reconfiguring the system to produce a different drug requires simply giving the yeast the genetic sequence for the new protein and replacing certain modules for purification. With colleagues at Rensselaer Polytechnic Institute, the researchers also designed software that helps to come up with a new purification process for each drug they want to produce.
Using this approach, they can come up with a new procedure and begin manufacturing a new drug within about three months. In contrast, developing a new industrial manufacturing process can take 18 to 24 months.
Decentralized Drug Manufacturing
A system that easily switches between production of different drugs could be used in many different applications. For example, it could be useful for producing drugs to treat rare diseases. Currently, many rare diseases have few treatments available, because it isn’t worthwhile for drug companies to devote an entire factory to producing a drug that’s not widely needed. The new MIT technology could easily achieve small-scale production of such drugs, and the same machine could be used to produce a wide variety of drugs.
Another potential use is producing small quantities of drugs for “precision medicine,” which involves treating patients who have cancer or other diseases with drugs that are specific to a genetic mutation or other feature of their particular disease. Many of these drugs are also needed in only small quantities.
“This paper is an important breakthrough in the possibility to produce and develop biotherapeutics at the point of care, and makes personalized medicine a reality,” says Huub Schellekens, a professor of medical biotechnology at Utrecht University in the Netherlands, who was not involved in the research.
These machines could also be deployed to regions of the world that do not have large-scale drug manufacturing facilities, including developing nations and those areas adversely affected by war and other conflict.
“Instead of centralized manufacturing, you can move to decentralized manufacturing, so you can have a couple of systems in Africa, and then it’s easier to get those drugs to those patients rather than making everything in North America, shipping it there, and trying to keep it cold,” said Crowell.
This type of system could also be used to rapidly produce drugs needed to respond to an outbreak such as Ebola.
The researchers are currently working on making their device more modular and portable, as well as experimenting with producing other therapies, including vaccines. The system could also be deployed to speed up the process of developing and testing new drugs, the researchers say.
“You could be prototyping many different molecules because you can really build processes that are simple and fast to deploy. We could be looking in the clinic at a lot of different assets and making decisions about which ones perform the best clinically at an early stage, since we could potentially achieve the quality and quantity necessary for those studies,” said Kerry Routenberg Love, one of the team’s research assistants.
The research was funded by the Defense Advanced Research Projects Agency, SPAWAR Systems Center Pacific, and the Koch Institute Support (core) Grant from the National Cancer Institute.
Love is the senior author of the study, which appears in the XX issue of the journal Nature Biotechnology. The paper’s lead authors are graduate students Laura Crowell and Amos Lu, and research scientist Kerry Routenberg Love.
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Source: MIT News Office