Battlefield medicine, also called field surgery and later combat casualty care, is the treatment of wounded combatants and non-combatants in or near an area of combat. Studies of historical casualty rates have shown that about half of military personnel killed in action died from the loss of blood and that up to 80 percent died within the first hour of injury on the battlefield. This time period has been dubbed the “golden hour,” when prompt treatment of bleeding has the best chance of preventing death. Thus, developments in military medicine have focused on treatment to quickly stop bleeding and on the provision of immediate medical care. American soldiers fighting in remote places overseas do not always have the luxury of picking up the biopharmaceutical they need at a nearby pharmacy or hospital.
Battlefield logistics are a challenge regardless of the mission.Adversaries, terrain, and the environment all serve to complicate the process of delivering supplies to warfighters. The current Department of Defense (DoD) approach to medical supply logistics is limited in its reach to far-forward emergency settings, response to emergent in-theater threats, and utility for bio-preparedness stockpiling. It can often take weeks to months to manufacture and airlift organic pharmaceuticals and protein therapeutics to battlefield frontlines, meaning that critical medical supplies often do not arrive in time where they are needed most. Furthermore, the need to prepare medical supplies in advance based on an anticipated, specific threat can result in wasted materials, labor, and money when that threat is not realized. The DoD needs a new approach.
DARPA launched Battlefield Medicine program in 2016 to support military readiness in far-forward deployed settings by overcoming logistical obstacles to manufacturing and delivery of urgently needed pharmaceutical products used to treat emerging threats. Battlefield Medicine seeks to address this capability gap through two integrated research thrusts: the Pharmacy on Demand (PoD) and Biologically-derived Medicines on Demand (Bio-MOD) initiatives.
The combined efforts seek to develop miniaturized device platforms and techniques that can produce multiple small-molecule active pharmaceutical ingredients (APIs) and therapeutic proteins in response to specific battlefield threats and medical needs as they arise. PoD research is aimed at developing and demonstrating the capability to manufacture multiple APIs of varying chemical complexity using shelf-stable precursors, while Bio-MOD research is focused on developing novel, flexible methodologies for genetic engineering and modification of microbial strains, mammalian cell lines, and cell-free systems to synthesize multiple protein-based therapeutics. As a proof of concept, both PoD and Bio-MOD efforts will seek to develop platforms for manufacturing single-dose levels of FDA-approved APIs and biologics and demonstrate high purity, efficacy, and potency in short timeframes.
In developing a flexible, miniaturized synthesis and manufacturing platform, Battlefield Medicine will leverage continuous flow approaches that will, if successful, pave the path forward for enabling distributed, on-demand medicine manufacturing capabilities in battlefield and other austere environments. Additionally, the platform would have built-in flexibility to produce multiple types of therapeutics through its modular reaction design. The ultimate vision for Battlefield Medicine is to enable effective small-batch pharmaceutical production that obviates the need for individual drug stockpiling, cold storage, and complex logistics.
While the success of this project would certainly improve our ability to treat soldiers in the field or victims of natural disaster, it also would have a major effect on today’s pharma business model. The entire industry is looking for the most efficient and safest way to manufacture drugs. If Dr. Rao and his team can successfully build a system that has the ability to create an on-demand biopharmaceutical in less than 24 hours, would the large facilities of today even be necessary? The answer to that question is still very far away, but it’s definitely one that comes to the surface as the DARPA teams continue to move down this path.
Today, biopharmaceutical companies and regulators are also exploring different ways to bring drugs to market that do not have large commercial interest (i.e., orphan drugs). In this realm, the Bio-MOD system could thereby serve as a game changer for applications in personalized medicine. The beauty is that the economics become the same for individual doses for each product, whether it’s a blockbuster drug or a rare protein only a couple of hundred people need. What does the industry look like when market size becomes a non-issue?
Another area where Dr. Wood thinks Bio-MOD could have an impact is research. With this system, a scientist who discovers a new gene/target or wants to create a new drug can test it quickly. “Instead of having to create a completely new cell line for each protein, they can go straight from gene to purification of their target, and then find out if it’s active, amplify it, tweak it, and test it again,” he explains. “This device would allow them, within 24 hours, to have enough of a protein that they can experiment with it.” The ability of academia to quickly determine the potential of a therapeutic target that is still in the very early stages of testing would be huge for an industry that often looks to them for innovation. High-risk work such as this is often too much of a financial liability for many pharmaceutical companies. However, with enough funding, a university scientist can discover breakthroughs that today’s industry might never fathom.
The Bio-MOD project was divided into two phases. The first phase, which was recently completed, required a proof-of-concept to show that the team’s basic ideas would work. The second phase involves making the first integrated device that can produce six different model therapeutic proteins in a fully-formulated and ready-to-inject form. This is a challenge because in conventional large-scale systems, there is plenty of workaround and troubleshooting without any issues of water supply or pressure to push materials through a column. All of that changes when you are working at a millifluidic scale. An unexpected air bubble could choke the whole flow and stop the system, while being practically invisible to the operator.
“We are entering a new realm of figuring things out,” says Dr. Rao. “Everything that happens today to manufacture a biopharmaceutical has to be miniaturized into this briefcase-sized device. There will be little chambers that are potentially at different temperatures with small amounts of fluid pumping through, all while ensuring that you don’t end up with something like running out of buffer. We are working through all of the calculations to understand any potential issue, in order to make sure that the scaled-down process is representative of what you successfully did in the lab and operates in a reproducible fashion.” He adds that this technology would also require regulatory authority approval, and the team has started discussions with the FDA to ensure that regulators are engaged early in the development process.
Three research teams whose proposals for the Bio-MOD project were awarded funding by DARPA, each with a different idea on how to approach it, the University of Maryland, Baltimore County (UMBC), Ohio State University (OSU), Thermo Fisher Scientific, and Latham Biopharm. The team’s founding member and principal investigator is Dr. Govind Rao, professor of chemical, biochemical, and environmental engineering at UMBC and director of the university’s Center for Advanced Sensor Technology.
Because the goal of the DARPA project is to make and purify proteins in a device the size of a laptop, Dr. Rao needed somebody who could address the need for protein purification. Through academic biotechnology journals, he was already aware of the innovative work by Dr. David Wood, associate professor of chemical and biomolecular engineering at Ohio State University. Dr. Wood is known for his research in the purification of recombinant proteins using a self-cleaving affinity tag technology based on small proteins known as inteins. As he describes it, inteins are mobile genetic elements that were discovered shortly before he started grad school in the mid-90s. Inteins (intervening proteins) are polypeptides that are found embedded in the middle of other proteins in nature. Once translated into a mature protein, inteins exhibit the remarkable ability to excise themselves from their host proteins through a self-splicing process. By re-engineering the intein’s self-splicing reaction into a self-cleaving reaction, Dr. Wood and his advisors generated a new tool for protein purification.
Dr. Rao’s Bio-MOD team is looking at an in-vitro translation system with the ability to produce complex glycosylated proteins. They will then use Dr. Wood’s intein-based purification platform to purify whatever protein is produced in the device. From there, some polishing steps will be developed, and a QbD approach and advanced process analytical technology (PAT) will be used to assess and ensure quality. Dr. Rao says the project includes a system design team to focus on the hardware, a protein expression team optimizing the expression system, a purification team to figure out how to purify the protein, and a regulatory team that offers guidance from industry advisors. The regulatory team includes partners from Merck, Pfizer, and Johnson & Johnson.
In Sep 2020, DOD and HHS Award $20 Million Contract to On Demand Pharmaceuticals to Develop Domestic Production of Critical Pharmaceutical Ingredients
The Department of Defense (DOD), in coordination and on behalf of the Department of Health and Human Services (HHS), signed a $20 million contract award with On Demand Pharmaceuticals (ODP) to develop a domestic production capability for critical active pharmaceutical ingredients (APIs) and final formulated medicines using their proprietary Pharmacy on Demand technology.
ODP’s device continuous flow chemistry to combine ingredients in a special tube or pipe, reducing the time and space needed for the multiple steps of traditional batch production. A process called continuous bioprocessing does something similar for biologics such as antibody therapeutics. ODP’s device can make both types of medicines. “These systems make drugs from starting materials to finished product in hours instead of weeks or months,” the company says on its Linkedin page. Such machines may prove useful far closer to home than DARPA originally
This investment will enable ODP to fully develop its small footprint pharmaceutical production technology, initially developed with funding from the Defense Advanced Research Projects Agency (DARPA). Critical APIs and their starting materials have long been sourced from overseas, and the collaboration with ODP is expected to increase the onshore production of three critical APIs that ultimately form the building blocks for final formulated medicines used to treat critically ill U.S. service members and COVID-19 patients.
This contract award is part of the ongoing collaboration between DOD’s Defense Assisted Acquisition (DA2) Cell and HHS Assistant Secretary for Preparedness and Response (ASPR) to apply HHS Coronavirus Aid, Relief, and Economic Security (CARES) Act funds to critical technology development projects to support the COVID-19 pandemic response. Execution of the award will be overseen by DARPA.
The pandemic has underscored how dependent the United States has become on foreign companies to supply various drugs and their components, called active pharmaceutical ingredients, or APIs. Lawmakers and others have expressed concern. “Critical APIs and their starting materials have long been sourced from overseas, and the collaboration with ODP is expected to increase the onshore production of three critical APIs that ultimately form the building blocks for final formulated medicines used to treat critically ill U.S. service members and COVID-19 patients,” notes the Monday statement from the Defense Department.
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