Clinical manufacturing of cGMP-compliant mammalian cell culture processes is a complex and resource-intensive effort that presents several challenges, including variability, regulatory compliance, capacity limitations, cost, productivity, and quality control.
Scorpius BioManufacturing was born out of the recognition that the industry needed a new kind of biologics CDMO, specifically a partner that can guide emerging biotechs throughout their product’s lifecycle and accelerate time to market.
To understand more about Scorpius BioManufacturing’s operations, we stepped behind the scenes with Brian O'Mara, Senior Director of Manufacturing, Sciences & Technology at Scorpius BioManufacturing.
Brian has more than 23 years of experience in the biotech industry. Throughout his career, he has focused on the downstream processes at all phases of the product lifecycle. Scorpius BioManufacturing offers two protein expression platforms, mammalian and microbial. However, our conversation with Brian focused on Scorpius’ mammalian clinical manufacturing capabilities—specifically, monoclonal antibodies (mAbs), bispecifics, and recombinant proteins.
Brian: I know we are mainly talking about mammalian clinical manufacturing today, but I did want to briefly mention that we made the strategic decision to offer both mammalian and microbial expression system capabilities. The characteristics of a given therapeutic product dictate which expression system is required or desired, so offering both capabilities puts us in a great position to be as flexible as possible for clients.
From a facility and operational standpoint, we use almost 100% single-use processing systems (SUS). Many hybrid facilities are serving the market, but only a small number of biologics CDMOs are leveraging SUS entirely.
Leveraging SUS offers benefits and risk mitigation advantages to both the client and Scorpius. First, the use of SUS effectively eliminates the risks of product-to-product contamination, ensuring product integrity and safety. Secondly, Scorpius is able to reduce the amount of time between product changeovers through cleaning programs, which require the cleaning, testing, and release of fixed, non-disposable equipment.
The modular approach to our cleanrooms is another facility-based strength. If we execute a straightforward process, we likely will not have to adjust or modify our cleanroom setup. But, if we run a more complex, slightly unorthodox process, we can quickly adjust our cleanrooms to adapt.
This said, our approach and expertise are the heart of what differentiates Scorpius BioManufacturing from our competitors.
Between the senior management team and the technical scientists and engineers in the organization, there are many decades of industry experience in all aspects of the market. In fact, it's hard to find an area of expertise one of us doesn't have, and the opportunity to work with this team was the main reason I was so excited to join Scorpius.
Scorpius' former VP of Manufacturing Sciences, and I have a great history. He hired me directly out of school 23 years ago. When he told me about the Scorpius vision and the leadership team here, I had to be a part of it. Our senior management team is highly experienced, passionate about the science, and excited to help shape and support the industry's future.
We specialize in working with emerging companies with unique therapeutics and technologies; organizations that need our expertise. We treat their molecules as our own, setting the stage for great collaborations and delivering truly innovative therapeutics to the market.
Single-use technology is no longer new to the market, but facilities based entirely on SUS are still uncommon. Since Scorpius built a new facility instead of buying an existing CDMO and retrofitting it, we had the advantage of starting from the ground up and were not burdened with legacy systems—that certainly made SUS implementation easier.
A drastic reduction in cross-contamination risks is the number one advantage of SUS. Also, scaling production is much easier because SUS are highly flexible and avoid the need for significant capital equipment investments. I think these benefits are all well understood in the market.
Additionally, decreased changeover time is an incredible advantage that may not be top of mind for a lot of people. When a run is complete, all we need to do is clean and validate the cleanroom and, obviously, remove all product contact material.
There are extensive cleaning validation requirements, particularly in the later stages of development, so it can take weeks to change over and release a fixed equipment line. With single-use systems, that changeover time can be reduced to days.
Also, each product has unique detectability characteristics with varying potencies. This can introduce a lot of cleaning validation complexity at a significant cost to a CDMO that needs to change out its production lines frequently, given the variety of production runs at a multi-product facility.
Changing our production environments quickly means we can be more responsive to our clients, manage costs, and offer more production schedule flexibility.
Finally, SUS offers system design flexibility, which is increasingly essential for many of the novel products making their way through the pipeline. You can customize systems as needed, easily connecting different SUS from multiple vendors, which may be difficult and expensive with fixed equipment or hybrid facilities.
There are many challenges that the client can face as they prepare to move into the clinic. One difficulty is navigating the rigor of designing and developing robust processes for Phase 1 clinical manufacturing through the scale-up and transition to a highly regulated and controlled GMP production environment.
If the process used to advance the asset was performed at the ‘bench’ to generate small quantities of material, the tools used might not be scalable or amenable to a manufacturing environment. There are unit operations or process steps that can be easily scaled using different technologies, such as substituting dialysis for tangential flow filtration (TFF).
However, to meet the client’s clinical needs, some unit operations may need to be changed for the process to be considered manufacturable. For example, using a transient transfection versus a stable production cell line or small bead chromatography resins versus larger and rigid beads with superior pressure-flow characteristics may prohibit efficient scaling to commercial quantities.
In our discussions with the client, the needed or recommended process adjustments are always thoroughly discussed and included in the work statement. There are no surprises; we are always fully aligned with our clients before work begins. We help drive progress for the client’s program with data-driven decisions that build highly efficient and scalable processes, with product quality always at the forefront of the decision-making.
There is a critically important interplay between upstream and downstream process development, and there is a balance between quality and quantity. Quality considerations always win, but it is also important to maximize yield.
Our upstream and downstream process development teams work closely together because you can only make final data-based upstream decisions once the downstream process development team gets involved. After the full picture is assembled, the ramifications of upstream process decisions are understood.
Our downstream development team is involved early on, and concurrent development is often required to meet the project timeline. The team evaluates the completed experiments of the upstream group to understand quality-influencing characteristics and how yield objectives influence quality. Once verified, each functional area’s process is ‘locked.’
This collaboration helps us make the best end-to-end decisions for the client's product—assuring quality and maximizing yield and efficiency.
Many of our early-phase clients are not yet thinking about the commercial-scale cost considerations of their process. For instance, utilizing standard, off-the-shelf consumables is often more cost-effective and less likely to have lead time delays because we either maintain a healthy stockpile or have reasonable and predictable lead times for standard consumables.
Most of the opportunities for cost reduction need to be addressed as early in the development process as possible. For instance, chromatography resin selections and the column packing approach are substantial opportunities for cost savings.
In regard to Protein A chromatography resins, the patent protection has expired, so several new suppliers have developed very productive and cost-effective resins increasing competition, ultimately reducing costs and increasing availability of this material.
Additionally, oftentimes, changing the column size and cycling strategy can reduce the resin cost by maximizing the column utilization. Perhaps you reduce the column volume to 30-50% of its capacity and cycle the product three or four times back-to-back.
Yet another COGs consideration is the batch strategy at different clinical stages of the program.
For example, suppose the client and our organization are confident in the product and process, and it is known that a single 1000-L or 2000-L batch can provide sufficient material to enable multiple clinical trial phases. In that case, the decision might be made to run all the needed product as one batch.
The projection for commercial production may also influence the client’s decision. For instance, if commercial production is anticipated at the 2000-L scale, minimizing process changes and scale effects may reduce some of these important studies and activities at a later stage.
On the other hand, cost and speed are critical drivers that should be scrutinized in the IND-enabling stage. If the batch productivity or cell culture titer is sufficient to generate material from a smaller bioreactor, a reduced scale may be employed to enable the early, Phase 1 clinical program. Also, if process adjustments and improvements are likely, producing only the product quantities needed for early-phase trials may be the ideal strategy from a COGs perspective.
Each strategy has pros and cons, but we analyze and present the options, and the decision is ultimately up to the client.
In a follow-on conversation, Brian will share his insights on manufacturing innovations in mammalian systems for biologics. Please get in touch with us if you would like to discuss how Scorpius BioManufacturing might support your program.