Maintaining a sterile environment is an absolute must for maintaining product sterility in cell therapy manufacturing. Although the cost of building cleanrooms has dramatically reduced recently due to modularization—estimates vary, but the statistics cited by labdesignnews.com state that “construction costs for an ISO 8 to ISO 7 cleanroom can range from $250/sf to $1,500/sf or more.” For a small cleanroom that’s 20 sq. ft. in size, this could make the room cost anywhere between $5,000 and $30,000 just to build—this doesn’t include the ongoing maintenance costs associated with air recycling/filtration systems, sanitation/sterilization, or labor. These maintenance costs can be astronomical and, unlike the build, are recurring costs.
Yet, as critical as cleanrooms are to the cell therapy development and manufacturing process, if your cell therapy product (CTP) is going to have a commercially-sustainable future, it’s vital for you to think beyond the cleanroom. You have to consider all of your resources and how you can make the most efficient and effective use of them—as well as when to add extra resources and which resources to acquire.
For example, if you were able to expand the number of processes you could have occurring simultaneously in a cleanroom by using closed processes, you would minimize your cost of goods (COGs) while increasing productivity by making more efficient use of the cleanroom. Another resource that has a significant impact on the cost of your CTP is the human labor that is used to run all of the manual processes that your cell therapy manufacturing process requires.
So, what can you do to go beyond the cleanroom to achieve commercial viability for your cell therapy product?
Here are a few things that cell therapy developers can do to improve efficiency for their cleanrooms and work towards achieving commercial viability:
Using Automation and Closed Systems
One of the most common strategies that the HCATS team employs for helping cell therapy developers achieve commercial viability is to use automation—both for cell production/modification and for process documentation. Using automation can have numerous benefits, such as:
- Eliminating Your Single Largest Contamination Risk. In any cleanroom process, the single biggest contamination risk is people. By automating processes, you can remove the human element from the room and reduce the risk of contamination.
- Reducing Documentation Deviations. By automating documentation processes, it is possible to reduce the impact of human error on your records. Considering that most such documentation deviations take around eight hours to investigate and correct, being able to reduce errors by just one per batch could save 8,000 hours of labor across 1,000 cell therapy batches.
- Improving Consistency Between Processes. Automated equipment can improve the batch-to-batch consistency of a cell therapy product, making it easier to establish and maintain your quality and safety standards.
In addition to integrating automation into the cell therapy manufacturing process, therapy developers can integrate closed processing systems to make their cleanrooms more efficient per square foot—especially for patient-specific cell therapies (PSCTs).
What is a closed system? In an article featured on The Cell Culture Dish, it is defined as “a process system with equipment designed and operated such that the product is not exposed to the room environment.” Having process systems in place that avoid exposing the product to the overall room environment offers a couple of distinct benefits.
First, a closed system allows multiple batches of different PSCTs to be manufactured concurrently in the same space—which has obvious benefits for the scalability of a cell therapy manufacturing process. This also helps you reduce your cost of goods by minimizing the amount of space that you need to establish for your projected demand.
Second, by creating a second closed environment in your cleanrooms, closed systems help to reduce the risk of contamination. This helps to improve quality and safety while reducing the batch rejection rate for a cell therapy product.
When Should You Automate Your Processes?
One of the biggest challenges for integrating automation is knowing exactly when and how to automate certain processes. Generally speaking, it’s usually better to make changes to your cell therapy development/manufacturing process earlier rather than later—especially when the changes introduce a high comparability risk because they significantly alter the journey of the cells.
This is because if you wait until you’re in phase three of your clinical trials to make such changes, you’ll have to repeat many late-phase trials to prove to regulators that the change doesn’t significantly alter the safety & potency of the cell therapy product.
However, introducing too much automation too early also carries some elements of risk. If you add some big, expensive automation technology to your development process too early, you could end up locking yourself into a single vendor to supply and maintain that technology—which can impact the flexibility of your supply chain and the sustainability of your cell therapy manufacturing process, as well as potentially increase costs.
Automation also has the potential to reduce the flexibility of your process and lead you to lock down aspects of the process which are not fully optimized. It is therefore important to consider the need for automation as a strategy with the view to the future of your therapy and/or pipeline.
Rather than trying to fully automate your entire production process with a single comprehensive technology solution, consider taking a marginal automation approach. Under such an approach, if you have 10 steps needed to complete your cell therapy product, you would find 10 different pieces of automation technology that are each relatively inexpensive to integrate. This way, your investment in any one solution isn’t so large, and you are able to switch technologies later if needed.
Also, consider automation technologies that are modular in nature, allowing you to add new features and tools as you need them. Many software programs have modular add-on options that you can purchase to enhance their functionality. For example, an office software might have a separate option for an automated cloud-based data backup feature to save your documents on a remote server and a control program for your manufacturing equipment might have an option for automated report generation detailing batch results.
Your anticipated production scale can also affect the decision of whether or not to automate. If your projected production demand is only a few dozen doses a month, then automation might not be as critical as it would be if your projected demand is a few thousand doses each month.
Where Should Your Product Be Made? Centralized vs. Decentralized Manufacturing
In the manufacturing of patient-specific cell therapies, one of the biggest challenges is transporting the unmodified cells to the manufacturing site for modification while maintaining the cells’ viability—and then transporting the modified treatment cells to the patient while upholding purity and potency standards. This is known as a “centralized” manufacturing method. Here, the cleanroom is the focus of your manufacturing efforts.
However, with the advent of closed systems and automation, cell and gene therapy developers have started to investigate the potential of using a decentralized (or distributed) manufacturing strategy. Under a decentralized manufacturing method, cell modification would occur at the “point of care,” where the treatment occurs. For cell therapy developers/manufacturers, this could provide a solution to the challenge of limited product shelf life—rather than having to preserve a product with short shelf life, it could be created onsite for near-immediate use.
Yet, despite the incredible promise of decentralized manufacturing, there are still numerous issues that cell therapy developers have to contend with:
- Decentralized manufacturing requires the point-of-care facility to maintain all of the personnel and equipment needed to successfully produce the therapy, therefore creating a larger capital investment.
- Testing for purity and potency can still take longer than the viable life of the cells—mandating a risk-based approach to CTP testing.
- Significant restructuring of the cell therapy developer’s organization may be required to enable a distributed manufacturing strategy.
- Moving manufacturing to the point-of-care means a reduction in the cell therapy developer’s ability to control the manufacturing process—increasing risks of deviations.
- Maintaining consistency of product is challenging.
- Any changes in a process now is carried out across multiple sites. Proving comparability becomes costly, along with changes in documentation, training, and validation being multiplied by the number of sites.
An alternative to the extreme of having point-of-care manufacturing would be for the cell therapy developer to set up (or acquire) extra manufacturing facilities and perform a technology transfer to replicate their cell therapy manufacturing process, termed “regional manufacturing.” This provides the benefit of expanding the reach of the therapy product while maintaining tighter control.
In the end, it’s usually best to speak with expert consultants to review your cell therapy manufacturing process and find out what is best for it.
If you need any more information about how to prepare your cell therapy product for manufacturing success, please download our free guide at the link below:
