How to Make Biopharmaceuticals Quickly in Small Batches

Posted on October 8th, 2018 by Dr. Francis Collins

Diagram showing three components of InSCyT system

Caption: InSCyT system. Image shows (1) production module, (2) purification module, and (3) formulation module.
Credit: Felice Frankel Daniloff, Massachusetts Institute of Technology, Cambridge

Today, vaccines and other protein-based biologic drugs are typically made in large, dedicated manufacturing facilities. But that doesn’t always fit the need, and it could one day change. A team of researchers has engineered a miniaturized biopharmaceutical “factory” that could fit on a dining room table and produce hundreds to thousands of doses of a needed treatment in about three days.

As published recently in the journal Nature Biotechnology, this on-demand manufacturing system is called Integrated Scalable Cyto-Technology (InSCyT). It is fully automated and can be readily reconfigured to produce virtually any approved or experimental vaccine, hormone, replacement enzyme, antibody, or other biopharmaceutical. With further improvements and testing, InSCyT promises to give researchers and health care providers easy access to specialty biologics needed to treat rare diseases, as well as treatments for combating infectious disease outbreaks in remote towns or villages around the globe.

In today’s commercial manufacturing facilities, biologic therapies used to treat cancer, cardiovascular disease, and many other disorders are made in huge vats, in which harmless bacteria, yeast, or mammalian cells churn out large quantities of a single product. But researchers, led by NIH grantee J. Christopher Love, Massachusetts Institute of Technology (MIT), Cambridge, have recognized a growing need to design a new kind of manufacturing system, capable of producing a wide variety of clinical-grade products on an as-needed basis.

Their InSCyT platform completes a manufacturing process using three interconnected modules. They are:

Production module, where harmless, genetically engineered yeast rapidly synthesize and secrete a desired biologic product.
Purification module, separating therapeutic biomolecules from other proteins secreted by the yeast, using an easily adaptable approach.
Formulation module, which bottles purified drug in the desired dosage before it’s suspended in a buffer to preserve its quality until needed, immediately or weeks later.

As a first demonstration, the researchers used InSCyT to produce human growth hormone (hGH), a well-established biologic medicine commonly used to treat growth deficiencies. The extensive knowledge about hGH made it an ideal choice to evaluate their new system.

After inoculating three independent InSCyT systems with a harmless yeast genetically engineered to churn out hGH, they produced more than 100 doses of formulated product in just one week. Even better, the process was fully automated and hands free. Careful analysis of the final product showed their InSCyT-produced hormone was of comparable quality in purity and potency to commercially available hGH.

To demonstrate the system’s agility in transitioning from one drug to another, the researchers produced two other biologic drugs, both used to stimulate the immune system: interferon-alpha 2b and granulocyte colony-stimulating factor (G-CSF). Overall, the test runs confirmed InSCyT rapidly and consistently produced a high-quality product. In subsequent tests on an animal model, their G-CSF appeared to work as well as a commercially available version.

The researchers report that it took them about 12 weeks to devise the processes needed to produce each drug. That’s compared to the year or two that is normally required to get a more traditional, large-scale manufacturing operation up and running.

Even more encouraging, Love and his colleagues say the process is now taking even less time as they’ve gotten more familiar with the system. As protocols and modules tailored to the production of more and more drugs are devised, adapting the system to produce similar products will become even more straightforward

Looking ahead, the system could help researchers and practitioners do a lot of things that they can’t right now do. InSCyT promises to speed up production of experimental treatments for clinical testing. It might also become possible to produce biologic treatments specially tailored to attack the cancer of a particular individual. Rather than stockpiling medications, hospitals might equip themselves for on-site production. With a distributed network of such automated, high quality manufacturing systems in place, the researchers say there also may be cost advantages.

While today’s version of InSCyT includes an array of bottles, vials, and machines linked with plastic tubing, Love’s team ultimately envisions a machine similar in appearance to a large inkjet printer. With this in mind, they’re now working to make their device more modular and portable.

They’re also working hard on the manufacture of vaccines. In fact, Love’s team is now engaged in the Bill and Melinda Gates Foundation’s Grand Challenge called ULTRA to develop low-cost vaccines for those in need around the world. They’ve already made and purified components of the first target vaccine for rotavirus, the leading cause of death for kids under age 5, on the InSCyT benchtop systems. So stay tuned to this exciting work.

Reference:

[1] On-demand manufacturing of clinical-quality biopharmaceuticals. Crowell LE, Lu AE, Love KR, Stockdale A, Timmick SM, Wu D, Wang YA, Doherty W, Bonnyman A, Vecchiarello N, Goodwine C, Bradbury L, Brady JR, Clark JJ, Colant NA, Cvetkovic A, Dalvie NC, Liu D, Liu Y, Mascarenhas CA, Matthews CB, Mozdzierz NJ, Shah KA, Wu SL, Hancock WS, Braatz RD, Cramer SM, Love JC. Nat Biotechnol. 2018 Oct 1.

Links:

Drug Discovery, Development, and Deployment (National Center for Advancing Translational Sciences/NIH)

J. Christopher Love (MIT, Cambridge, MA)

Video: Inside the Lab: J. Christopher Love (Koch Institute, MIT)

MIT Undertakes Grand Challenge for Innovation in Global Vaccine Manufacturing (MIT News)

NIH Support: National Cancer Institute; National Institute of General Medical Sciences