Manufacturing therapeutic proteins such as monoclonal antibodies, while potentially lucrative, is fraught with uncertainty. A company can have a number of biologics in the pipeline, each requiring an estimate of future need for a variety of indications, a different competitive landscape, and none with a guarantee of regulatory approval.
“It can be extremely challenging for companies to estimate manufacturing capacity to support their market projections,” said Matthew Kennedy, a bioprocess specialist and senior associate at CRB in Philadelphia, Pennsylvania, US, and an ISPE member since 2001. “They have to invest in manufacturing capability long before they know the definitive outcome of clinical trials.”
This is a challenge Kennedy loves to meet. He is a champion of applying innovations in facility and equipment design—namely continuous, closed processing and single-use technology—to the facility of the near future. The benefits include a reduced footprint, lower capital and ongoing utility costs, greater speed to market, and the capability to scale up or scale out from clinical production through launch capacity.
Matthew Kennedy is a Bioprocess Specialist and Senior
Associate at CRB in Philadelphia, Pennsylvania, US
In 2015 Kennedy was named a “Top 20 under 40” award winner for the Engineering News Record Mid-Atlantic Chapter for his work in design and construction. He studied chemical engineering at the University of Delaware, US. After graduating, he worked at Biokinetics, where he first got exposure to the design, construction, and validation of equipment used in biopharmaceutical manufacturing. He continues to build on that experience at CRB, where he focuses on holistic design to align the investment in the manufacturing facility with the business objectives of the company.
Kennedy sees continuous closed processing as key to dealing with demand uncertainty and, when combined with single-use technology, to transforming the biologics industry.
“Combining single-use, closed, and continuous manufacturing dramatically compounds the effects of each of these innovations,” he said. “While each holds the potential to reduce the footprint, when you have all three, the size of the facility collapses. Single-use technology eliminates or reduces process utility systems, while the process closure reduces the number and size of air handlers, and thereby the demand for chilled water, steam, and electricity. Continuous processing then amplifies these effects and reduces the cost of consumables making a dramatic impact on the cost of goods.”
This end-to-end manufacturing connects upstream and downstream processes, both of which have seen enhanced efficiency in the past decade.
“As we get up to higher cell densities and higher protein expression rates upstream, then single-use manufacturing becomes attractive for large-scale protein production,” Kennedy said. “Instead of a $1 billion, 60,000-liter bioreactor facility, you can make the same quantity of a therapeutic protein using much smaller, simpler pieces of equipment like 2,000-liter single-use bioreactors operating in intensified batch or perfusion mode. The process becomes cheaper, faster, and better.”
This pushes the bottleneck downstream to harvesting cells and the desired proteins they express. But here, too, innovations such as multicolumn chromatography have improved productivity, coupling high-yield protein production upstream with an efficient purification process. It is now possible to purchase one train of equipment that has a bioreactor operating in a perfusion mode, couple it to continuous purification, and make it all single use.
“This overcomes a downside of single-use technology which, despite a low capital cost, is expensive in the long run. When you couple single-use technology with continuous manufacturing, connecting upstream and downstream processes, you reap the benefits of both innovations. The cost incurred from frequent and rapid changeover usually associated with batch-based single-use systems goes away.
“If you need to switch to another product, you can simply reconfigure some tube sets, swap out a series of chromatography resins and filters, and quickly change the suite to begin production of another protein. Not only can you produce a large amount of protein with a well-architected platform of manufacturing technology, you can change the protein you’re making with a modest changeover time. If you need to double production, you can quickly scale out by adding a second set of equipment.
“Innovation can be beneficial while being disruptive.”
We welcomed 2023 with high hopes and dreams of what Women in Pharma® could eventually be. As I prepare to conclude my time as the Chair of ISPE’s International Women in Pharma Steering Committee, I do so with immense gratitude.
This is my last column in Pharmaceutical Engineering®. It has been my real pleasure and an honor to serve as your International Board Chair. Thank you for your support and I, like you, look forward to another phenomenal year for ISPE in 2024.