The global demand for monoclonal antibodies (mAbs) therapeutics is not waning any time soon. In fact, the global mAbs market was valued at $147 billion in 2020, according to the market analyst firm ResearchAndMarkets, and is projected to reach $390 billion by 2030.
This continued growth in the mAbs market has led to demand for large capacity requirements that single-use facilities can’t support cost-effectively. Consequently, there has been very little choice but to return to stainless steel for these larger capacity facilities.
Of course, contract manufacturing organizations are taking up some of this slack as manufacturing demand outstrips current capacity. But there will still be innovator companies that continue to make investments in their facilities.
The design and construction of a new manufacturing facility can be a costly proposition. And for those manufacturing organizations that must continually balance capital expenditures (CapEx) against product delivery, some process design considerations might be overlooked.
The following are four factors that any organization must keep in mind during the design of mAbs facilities and the production of therapeutics being manufactured in those facilities. They can reduce an organization’s CapEx and OpEx costs considerably.
1. Design accommodations for reprocessing the downstream batches to minimize or eliminate the lost batches
Often during design development for a mAb process, we might think of equipment failure, but we always think of what that does to the product sitting there at risk.
To put a finer point on it: What do you do when you have millions of dollars worth of product sitting in a tank, and you have had a post-use filter integrity test failure or an elevated bioburden sample that triggers an action limit, and you must reprocess to save the batch?
Remember, mAbs facilities run like railroad trains. There is a set schedule with typical facilities producing batches every three or four days. If the train goes off the tracks, every other train is held up unless there is a mechanism for working around the problem. If there’s no well-engineered system to go back upstream to reprocess, the entire batch will be lost.
Manufacturing managers are sometimes faced with the choice of taking the time to implement whatever quick fix they may have versus the risk of losing all the upstream batches that are coming. It can be a strenuous time because there is a considerable amount of money at risk no matter which choice is made. And more importantly, it puts the patients at risk of low supply.
Consequently, it is essential to make accommodations in overall equipment design that preserve optimal process performance under normal conditions while also integrating mechanical, automation, and cleaning strategies that enable speedy and successful reprocessing when disruptions occur. The considerations can be as simple as incorporating a swing elbow or flex hose solution to transfer the product back upstream.
More complex solutions could involve permanent valving with associated automation. Even more difficult and costly solutions could entail redundant tanks at critical steps with cold hold accommodations to mitigate bioburden accumulation during processing delays.
2. Optimize for filtration requirements at a large scale to minimize the consumables changeout
Implementation of process intensification technologies such as perfusion to achieve ever-higher titers has resulted in high cell densities that are a challenge for harvest and clarification operations. With extracellular mAbs proteins, you must remove the harvested cells from the process stream as the broth contains your product.
The most efficient technology for separating the cell debris from the product is a centrifugation cell separation step, which removes roughly 95% of the solids. The residual cells and cell debris that breakthrough centrifugation must be filtered. Because of the multi-product nature of manufacturing and the need to always consider what new product must be accommodated down the road, some organizations are very conservative in sizing their filtration capacity.
That often leads to large rooms filled with depth filters and their holders. And because filters themselves are single-use, there can be a massive flow of consumables coming in and going out. It is extremely operator intensive and cumbersome.
Unfortunately, there is no real solution other than to be more aggressive with filtration sizing, optimize the process, and thereby reduce the number of consumables that must be managed.
3. Operating advantages of a single-use bioreactor seed train may not outweigh stainless steel’s initial capital cost
Some companies are so invested in a single-use seed train that they don't consider anything else. It is hard to know exactly where the actual crossover point is in cost versus performance. This decision is not just a function of CapEx but of the number of batches that may go through their facility in a year. In some cases, a company simply trades capital expenses for operating expenses.
It is not always easy to make the single-use seed train fit within the layout of a large-scale stainless steel facility. An organization may think it’s saving money on bioreactors, skids, and fixed stainless tanks. Still, there are many expensive challenges associated with implementing the single-use seed train in a large-scale facility, the most significant of which is correctly handling the logistics design for both new and waste single-use components.
Additionally, single-use equipment also carries a potential for leaks. It is essential to have closed connections, although this can be challenging with single-use equipment because tube welders are no longer commonplace, and aseptic connectors can be expensive for additions. Some organizations opt for redundancy in single-use components to reduce the risk of not being able to run. However, this can lead to supply chain issues and increased warehousing requirements.
All of this boils down to each organization needing to perform its own economic and logistical analysis to determine whether it makes sense for your building and your design. The answer may surprise you.
4. Involve operators in the design process to reduce or eliminate the human error risk
This is many ways, a continuation of the previous point. With a single-use seed train, operators have to interface with the stainless at some point — ultimately transferring to the next stainless steel bioreactor. If an operator makes a mistake in the transfer, it could lead to considerable problems with production. There is much more risk in getting the product into the next stainless steel bioreactor than there may be in having used a full stainless train.
That is because the most significant risk in any mAbs facility is the people. If they do not follow standard operating procedures, or if they are not adequately trained, a simple mistake could be compounded into a costly production problem.
The earlier operators are involved in the facility’s design and construction, the more successful the outcome will be. It is not uncommon, however, to launch a project and not see any operations people until the die has been cast. And making changes amid a detailed design phase can be expensive.
This consideration does not just apply to operations people. It extends to maintenance, validation, and commission and qualification personnel. Of course, at the end of the day, the operators are responsible for the quality of that product — and unfortunately, there’s a high degree of turnover in those roles. If people are not trained correctly, or an organization gives engineering access to contractors filling the gap, it creates considerable risk.
Of course, it is a cumbersome task to anticipate and address all the potential pitfalls at every step of the project, from design to production. Still, the more you can rationalize expectations, the more successful your organization will be at balancing your costs and risks.
