Biopharmaceuticals accounted for eight out of the top thirteen blockbuster drugs of 2021 by sales volume, accounting for 126.6B USD out 182.3B USD in global sales. However, the sustainability of biopharmaceutical manufacturing is poor. The cost of manufacture is high, with weak economic sustainability leading to increasing offshoring of manufacturing capacity. Further, the complexity of current manufacturing processes, which drives these costs, makes biopharmaceuticals highly vulnerable to supply chain disruption. The raw materials mass intensity of manufacture is high. For example, monoclonal antibodies, a key class of biopharmaceutical, typically require more than 10,000 kg of raw materials to produce 1 kg of drug substance. The vast majority of the raw materials need is accounted for by high-purity water, which is expensive to produce and whose sourcing in raw form may be a challenge for biotech hubs located in extreme drought areas such as California. Directly associated with raw materials usage is waste generation, with waste mass intensities mirroring raw material waste intensities. This leads to poor environmental sustainability. The costs of biopharmaceuticals are high, leading to poor social sustainability, limiting both domestic and global access. While manufacturing costs account for a small fraction of sales prices for biotherapeutics, e.g. for monoclonal antibodies the cost-of-goods for a drug product is typically 10-15% of the sales price, even selling a drug at cost puts these drugs out of reach for all but First World countries. As the COVID-19 pandemic has painfully demonstrated for highly communicable diseases, it is not sufficient to manage domestic access alone. And, of course, countries struggle to afford increasing drug costs. Recognizing fundamental differences in purity requirements and scale, biopharmaceutical manufacturers can draw on technologies developed for industrial biomanufacturing to improve sustainability.
CSB Members focused on Biopharmaceutical Research
The CSB focuses broadly on immuno-engineering directed toward immune modulation through manufactured products. These include biologics targeting the immune system, small molecules, and various products that “train” the immune system. mRNA technology and glycoengineering of protein therapeutics likely are at the top of the list of broad product classes. One major advantage for producing mRNA is that mRNA therapeutics can use a single standardized manufacturing process applicable across a range of targets. However, in the rush to manufacture mRNA vaccines and ensure mRNA integrity and high purity, several capital-intensive and time-consuming purification steps were needed.
Within mRNA processing technology, there is a critical need to reduce cost, develop a very large scale (100x vs. today), and enable distributed production of mRNA production. Cost is in three areas – 1) mRNA synthesis, which is performed in vitro; 2) purification of mRNA in a large scale; and 3) materials to protect the mRNA while allowing efficient transfection into target cells (for example, nasal delivery vs. systemic delivery of vaccines for respiratory infections). From a quantitative perspective, reducing the cost of mRNA synthesis 10-fold would enable more rapid development of vaccines, anticancer therapeutics, antimicrobial agents, etc. New materials built on the scaffolds of existing and inexpensive polymers and oligomers with functionalization for targeted delivery is critical, and a cost reduction of 5 to 10-fold is needed.
For protein therapeutics, moving toward mixed in vivo/in vitro methods to generate personalized biologics can be envisioned. This includes moving to microbial hosts for protein production (titers of 5-10x vs. mammalian cells) coupled to an in vitro methodology to glycosylate (or glycoengineered) protein products. This can be done in a single step or through templated glycan construction. The potential for purification coupled with glycan engineering to be performed in a single step will accelerate production times, reduce costs, and allow for distributed biomanufacturing (at least regionally). The scalability right now is poor, and substantial government investment in such scalable systems is needed. Moreover, how much can be done OUTSIDE cGMP so that costs and regulatory issues are reduced?
Supply chain issues will remain, which will become critical if we move to a more distributed biomanufacturing. The raw materials need to be developed internally (i.e., within the US) and depending on the raw material, can be synthesized on site. For example, for mRNA synthesis, the production of a range of unnatural nucleotides may aid in both stabilized mRNA and selected tissue targeting.
A number of new cancer therapeutics have been developed based on autologous blood treatment and engineering of a patient's cells to attack specific tumor characteristics. For example, CAR-T therapy has been used to treat lymphomas and leukemia, with several therapeutics approved by the FDA. Currently, therapeutics manufacturing is largely done by shipping the patient's cells to a centralized facility for processing, followed by shipment back to the hospital for infusion into the patient. This involves cryogenic processing and it is extremely important to keep track of the conditions of the "raw materials" and "final products" throughout the process. Ideally, hospitals would manufacture these therapeutics on-site, saving time and reducing the potential faulty material that must be wasted. A major challenge is that these decentralized manufacturing systems are unlikely to have as many operating personnel with manufacturing experience as those at centralized facilities, including with pharmaceutical analytical technologies. Thus, automation and control is even more important in these decentralized facilities. The major objective of this seed proposal is to initiate a collaboration between therapeutics researchers, cancer clinicians, bio-pharmaceutical engineers, and design and control engineers, to better understand the current limitations in the many steps from initial in-vitro and in-vivo studies, through various clinical trials, and implementing technology that can treat many patients at a time.
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