Facility Design — Balancing Stainless-Steel, Single-Use, And Continuous Approaches To Manufacturing
By Madhu Raghunathan
The key factor driving change in today’s pharmaceutical industry is the impressive rise in biologic drugs, which now make up 25 percent of the total pharmaceutical market.1 Companies targeting biologics face a new frontier in development and manufacturing, as these drugs are complex, diverse, and difficult to produce. This complexity and the emergence of biosimilars are driving cost efficiency, as well as promoting the adoption of more modern bioprocessing technologies. Compounding the challenge of biologic drug development is that manufacturers must gain approval from regulatory agencies on not just the biologic drug itself, but also the process used to manufacture it. This makes changing the production process after a drug and its process are approved both risky and costly, which is why some biopharmaceutical manufacturers are hesitant to try new and potentially more efficient technologies. Nonetheless, manufacturers may have to embrace change to remain competitive in this growing market. Several modern downstream technologies available today can improve efficiency and even quality, such as single-use technology (SUT). It is important to understand the benefits of each these options and how they can be used to forge a path toward bioprocessing excellence.
Weighing The Options
Choosing a facility design and unit operation requires a balance among many factors. That is why no two unit operations are identical. Each has different goals from a process standpoint. For example, the operating costs for a capture step are not the same as the operating costs for a virus inactivation step, due to the difference in tools, buffers, and other equipment used in each process. Some questions to consider during the decision-making process are:
- Is this a startup or a large, established biopharma?
- What type of product is being manufactured?
- What is the scale of operations?
- What is the in-house knowledge and capability?
- What level of demand is expected and, therefore, how much capacity is needed?
The answers to these questions will help determine the most suitable facility design and unit operation for the project. There are specific considerations, though, when reviewing upstream options versus downstream options. With upstream processing, there is a higher processing volume, a growth environment, a greater presence of in-process impurities, and, consequently, a higher risk of bioburden. As a result, the cleaning-in-place (CIP) and sterilization-in-place (SIP) requirements are more complex. In downstream processing, the value of the biologic drug and the burden of demonstrating purity of the drug increase exponentially. Because of this, the complexity of the analytical instrumentation needed also increases, which is reflected in the cost of consumables for a bioreactor versus the cost of consumables for an SUT flow kit.
In many instances, it makes sense to apply SUT upstream. In others, it may not make equal sense to apply it downstream, especially at a commercial scale when manufacturing several batches of the same product. There may be other scenarios, such as preclinical or clinical manufacturing or switching frequently between molecules, where SUT makes sense also downstream. Even though the analytical burden is still there, other drivers, such as getting to market faster, have a greater weight than cost. In this case, operating cost may be sacrificed in lieu of other considerations. At commercial scale, though, the cost profile becomes more important, and other trade-offs may be made that a manufacturer was not willing to make at a smaller scale.
One design option to consider is to start out small and then scale out over time instead of scaling up. The risk being that, if there is not enough capacity when it is time to scale out, the result could be costly production delays as well as a possible loss of market share. Another design option is to make the facility flexible enough to accommodate different types of molecules. This creates its own challenges, as a flexible facility can be difficult to accommodate because it drives up the complexity. An equipment and solutions provider becomes a great resource in this situation, as they can assist in selecting processing tools that fit a project’s needs based on the objectives.
The Benefits Of SUT In The New Era Of Biomanufacturing
When looking at the industry’s current pipeline, the vast majority of registered biological drugs have an annual volume between 100 and 500 kilograms. SUT’s ability to produce small batch volumes such as these is one of its major benefits, especially in an era when manufacturers are targeting more niche drugs for smaller patient populations. In addition, future upstream titers are anticipated to be 5 grams per liter and above. At lower volumes and higher titers, the cost benefits shift more toward SUT, although this is not a black-and-white conclusion.
The biggest driver of its popularity is the ability to build out a facility using SUT as opposed to building the entire facility up front and expecting (or hoping) the demand will come at some point in the future. In the case of stainless steel, a facility takes from three to five years to build. It is challenging to know that far ahead what the demand of a drug will be. And when determining which type of facility to build, it is important that capacity matches the demand profile for the drug being produced. The timeline for SUT is much shorter (12 to 18 months). While this does not mean SUT is always the best option, it does offer a distinct advantage in terms of demand forecasting. Other major advantages of SUT include decreased capital investment, smaller footprint, reduced cleaning requirements, and increased process flexibility.
Managing An SUT Cost Profile
One way to manage an SUT cost profile is to use disposable technology in earlier clinical phases and then shift over to stainless steel once a project moves to commercial scale. Also, SUT does not have to be for only one particular unit operation. It can be combined among unit operations by using a single-use chromatography step combined with a single-use filtration step. This is achieved by using the method queue feature in system control software, which combines different unit operations under one automation method. Such a setup eliminates interactions when moving from one unit operation to another, and there are no intermediate pool vessels or holdup vessels. There are also a number of advantages to not focusing on one unit operation but extending the same principle to connecting a few unit operations.
SUT does have its limitations, though. The technology’s flow kits have physics-based restrictions on what they can support, such as on maximum pressure rating and flow rate. In terms of sensors, single-use sensors are less sensitive than traditional sensors. In addition, SOPs are often written for the use of traditional sensors and technologies, so it may not be possible to switch to a single-use sensor without changing the SOPs. There is also the consideration of other important factors, such as extractables and leachables, integrity (i.e., bag leakage), and the ordering and management of single-use consumables. Overall, SUT requires more trust with a vendor to make sure there is security of supply in order to have the consumables necessary (Fig. 1). If SUT is selected, understanding its benefits and challenges is critical. That knowledge can facilitate implementation and, if applicable, ensure a smoother transition, so the full benefits of SUT can be realized in the unit operation.
Intensification Of Traditional Approaches
While SUT offers appealing benefits, there may be resources or capacity already in use. This does not mean one must abandon those legacy processes and implement single-use processing tools instead. There are a number of ways to intensify traditional technologies.
In-line conditioning
One option is in-line conditioning or in-line buffer formulation. With this technology, the buffer is manufactured by manually combining the necessary components in real time. This can be done in a buffer kitchen, and the buffers are then transported into the unit operations in a single-use bag. Another method is to manufacture the buffers at the point of usage in a chromatography or filtration step. The benefit of this technology is that manual operation and concerns for out-of-spec buffers are minimized.
It is important to remember that buffer conditioning is essentially diluting the buffer concentration to the concentration needed with the addition of Water for injection (WFI), which is not the same as in-line buffer dilution. Even though buffer conditioning is preferred over manual preparation, it still presents several challenges, such as managing, storing, and cleaning the large tanks where buffers and raw material are stored. With in-line buffer formulation, there is no need for tanks or manual intervention. The system dynamically prepares buffers to the required specifications based on the desired "recipe." If the buffer falls outside of those specifications, the in-line conditioning system automatically detects the deviation and makes necessary adjustments or executes a fallback strategy. By considering buffer preparation early, a manufacturer has enough freedom to make those changes and arrive at their desired endpoint (Fig. 2). It also allows them to prepare their own stock concentrates or even go further back in the value chain to secure the stock concentrates directly from a vendor.
Buffer preparation is not often thought about up front, but instead only after something has gone wrong. Once that happens, a facility or process has already been designed so inefficiently that the entire process becomes a bottleneck.
Prepacked, disposable columns
The universal benefits of SUT solutions also hold true for prepacked columns. For example, many steps are required today before a clean-and-reuse column can be applied to a purification step. It can take up to several days to complete these steps. During preclinical or clinical manufacturing, time is precious, and the process for a clean-and-reuse column is very inefficient. A prepacked column comes pre-validated with documentation to demonstrate sanitization and that it is packed within the specified tolerance. This eliminates the time to pack the column and complete the necessary validation activities. It also minimizes the possibility of any cross-contamination risks. A prepacked column can be ready to use as soon as it is plugged in and connected to the system and buffers (Fig. 3).
Continuous chromatography
There is a lot of buzz about continuous chromatography. Some see it as a valuable process intensification technology, while others are skeptical about its viability. Just as with SUT, there are situations when applying continuous chromatography makes the most sense, such as when dealing with low annual production. In this case, continuous processing can lower the initial capital investment needed and reduce facility footprint.
From a technical perspective, continuous processes could be considered when working with sensitive molecules or low selectivity operations, wherein a choice needs to be made between yield or productivity. High titers, in combination with periodic counter-current chromatography (PCC) dynamic control functionality, can improve process robustness with fewer safety margins. Preclinical or clinical manufacturing is also a sweet spot for continuous chromatography, as chromatography resins at this scale are not typically utilized to their full life cycle. However, with continuous chromatography, that can be overcome by cycling the purification step more often at smaller resin volumes.
A Proper Evaluation For A Successful Step Forward
In summary, several drivers affect how the appropriate facility design and unit operations for a process are selected. No universally accepted template works across the board, irrespective of business objectives, process outcomes, and resource/knowledge footprint. Regardless of how the process is designed, though, it is clear that many technologies today offer improved functionality and even new benefits. Therefore, while change can be intimidating, this disruptive innovation allows manufacturers to achieve the increased efficiency and quality needed in an industry that is quickly evolving. That is why it is imperative that each option is properly evaluated. This makes it possible to choose the one(s) that can sustainably deliver your desired results and offer the best chance of success in the new and exciting world of biomanufacturing.
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