During the last decade, the push within the biopharmaceutical industry has been three-fold: increase capacity, gain flexibility, and decrease costs. All of these factors have led to the adoption of single-use systems (SUS) in biopharmaceutical manufacturing; however, complete adoption of an SUS may not be the best plan. There are still situations in which stainless steel has advantages. We have also noticed that hybrid systems have become more common these days, and there are good reasons for this.
We thought that it might be fun to look at the details of these different types of systems to understand the relative pros and cons.
The Costs of Cleaning
Remembering back ten years, the primary rationale for the development of SUSs was to decrease the time, cost, and water usage associated with CIP/SIP. It is true, stainless steel equipment requires cleaning after every use. Ten years ago, when the average process took 20-30 days, spending one day cleaning the equipment was reasonable. Today, when many processes take under five days, the relative downtime of the plant for cleaning has grown tremendously. Cleaning feels nearly continuous, and it ends up that water usage is a huge component of a permanent system’s ecological footprint.
Being able to “throw away” (actually incinerate) the SUS processing equipment after each batch greatly reduces the need for water. It also eliminates or reduces the use of harmful cleaning chemicals. All in all, eliminating the need to clean is extremely beneficial for the environment.
Figure 1. Single-use bioreactor
Or is it? How about the disposal of all these throw-away SUSs? What are the ecological ramifications of either putting them in landfill or incinerating them? Is burning plastic a good thing for the environment? How about the energy required to incinerate the single-use materials?
Several reputable sources say that the best choice depends upon the circumstances. In some situations, SUSs are clear ecological winners, but this is not always the case, and each facility needs to analyze their particular situation to determine the right choice.
The Capital Outlay for Processing Equipment
No one can deny that building a stainless steel plant is extremely expensive. And after it has been built, making changes is also very expensive. The cost of SUSs is directly tied to the number of batches made, because they are single use. We have even seen customers reuse their SUSs to cut down on the purchase and disposal expense of SUSs; however, that means that they have to be cleaned, eliminating the major SUS advantage. Logically, it seems that the right choice of SUSs versus stainless systems depends on the frequency of batches and the number of years that the process will continue without modification.
Validation and Extractables
The validation cost of SUSs is also lower, because there is no need to validate the cleaning process. This saves time and significant money up front. However, moving to new plastics and resins in new process conditions requires reassessment. Information about leachables and extractables is also still in the process of being collected by vendors. The BPSA has developed an initial set of disposables best practices, but more work still needs to be done. For example, there is no consensus among countries or standard-setting organizations, such as the FDA and EMA.
Flexibility, Reproducibility, and Scalability
SUSs have been pushed heavily due to their flexibility. Because there are no physical changes that have to be made to the plant for a different process, under the right circumstances SUSs can increase plant capacity and provide significant production schedule flexibility. Changes to process flow, size, and layout are easier, cheaper, and faster, which speeds up product changeover and turnaround. Some industry experts point out that if the correct subunits exist, a plant can evolve a “plug-and-play” approach to process configurations.
The need to produce biopharmaceutical products around the world has also pushed SUSs to the forefront. Companies are finding it easier to reproduce their plants on foreign shores using disposable components. They can also start with small production amounts and scale to larger amounts, as needed, with little to no change to the plant.
Figure 2. Examples of BioPure disposable components
It all sounds amazing, but at the present time, there are some limitations. The biggest one is that the processes are limited to 2,000 liters. For small batches, this is not an issue; however, some processes rely on 5,000 or even 10,000 liter batches to attain the required capacity.
Second, the availability of some components is still limited—not every sub-process has a disposable alternative. For example, until recently chromatography in SUSs was extremely limited. New chromatography processes are now available; however, they don’t handle all situations.
Current Issues with Disposables
Why aren’t disposable systems dominating biopharmalogical processing? Mostly because there are significant issues that still need to be addressed, and although progress is being made on many fronts, the SUS industry is not yet mature and is undergoing constant change:
- Limited to 2,000 liter bioreactor capacity. This is a deal breaker for some processes.
- There are still questions concerning the compatibility of process chemicals and SUS materials. Vendors are working on compatibility, extractables, and leachables data for SUS components that use new materials. There is a lot of work to do.
- There have been product containment failures; however, vendors are working feverishly to address all known issues.
- Not all components are available. For example, not all types of mixing can be done in SUSs and centrifugation is not yet available.
- It takes time to find the right SUS vendors for the different system components, if they exist. For many of these components, there is currently only one vendor. This creates an uncomfortable dependence on a single vendor.
- Companies are still working out how to best use disposable components for each of their processes. Novel engineering and process flow layout designs are emerging; however, only a few experienced consultants are creating those innovative designs.
- Not only does a plant have to dispose of the SUS after a process has run, but they have to store the SUS components until they are used. These components can take significant space, and many companies are still figuring out how much SUS inventory they need to have on hand to ensure that production is not interrupted.
- The standards for disposable systems are just now being developed, which leaves some companies feeling vulnerable, because there are no universal standards to use to evaluate the SUS components.
As you can, see both stainless and disposable systems have their benefits and limitations. This leads us to hybrid systems. We see that hybrid systems are steadily becoming more popular. Stainless and disposable systems can be mixed in two ways. First, a plant might have some processes that are strictly carried out in stainless systems, while other processes might be performed entirely in an SUS. Second, we are seeing, with increasing frequency, a mix of single-use and traditional components within a given process. This hybridization might occur due to capacity needs, the availability of a component, chemical reactivity issues, the cost of a component (either in stainless or disposable), or the cost of cleaning a particular component.
Figure 3. BioPure hybrid plant
It seems to us that creating hybrid systems might actually be an economical and prudent way to incorporate disposable systems into your process, especially until there are more vendors, more components, and universal standards with which to evaluate the components and vendors. Additionally, using hybrid systems gives you the most flexibility to design and optimize your process, enabling you to lower your costs and make your process as efficient as possible.
Because of their flexibility and outstanding cleanability, many of ASEPCO’s products, especially our Sample and I-Sample valves, are excellent components for a hybrid system.