As more cell therapy products reach the “finish line” of U.S. Food and Drug Administration (FDA) approval and new regenerative medicine products begin the clinical development process, the need for expanded manufacturing capacity that can support long-term commercial business models is increasing.

Recently, David Smith, Alex Klarer, Thomas Heathman, Courtney LeBlon, Yasuhiko Tada and Brian Hampson of Hitachi Chemical Advanced Therapeutics Solutions (HCATS) co-wrote an article for Current Hematologic Malignancy Reports titled “Towards Automated Manufacturing for Cell Therapies.” In the report, the HCATS team outlined the:

1. Need to scale-out patient-specific cell therapies;
2. Different types of automation for therapeutic cell manufacturing;
3. Drivers of automation; and
4. Potential side effects of adopting automation in cell therapy manufacturing.

Here are a few highlights from the article:

The Challenge of Achieving Scalability with Patient-Specific Cell Therapy Products

In traditional biologics, where products have a long shelf life and there’s no need to match a donor to a recipient, the primary method of achieving scalability is to scale up production. However, as noted in the article, “Patient-specific therapies (autologous or matched donor allogeneic) will require companies to rethink manufacturing processes to facilitate scale-out methods as opposed to scale-up.”

Since patient-specific cell therapy (PSCT) products either come from the recipient or a matched donor, they have to be manufactured on a 1:1 basis. This eliminates “scaling up” as an option.

While integrating unit operations is one potential solution to achieving scalability, it may not always be the best option. The study cites challenges with this approach, stating that:

“This model has worked well in other industries with custom automation, but off-the-shelf, all-in-one systems need complete flexibility to map onto manufacturing processes, which make them inherently expensive and complex. Therefore, these simpler solutions often do not appropriately fit manufacturing processes, and often other devices are still required for specific unit operations, reducing the value of an all-in-one solution. Also, a single all-in-one system may be tied up for weeks during the culture process for example, whereby the majority of the instrument is not utilized, and cannot be utilized for another batch.”

Before integrating unit operations, the impact of trying to create an all-in-one solution should be weighed against the benefits of having a closed system. Additionally, the expected production load should be measured against the available production capacity.

Automation tools can also be used to improve process scalability and unify unit operations, but it’s important to use the right types of automation at the right times in order to achieve the best results.

The Types of Automation for Manufacturing Cell Therapy Products

The article outlines four broad categories of automation for manufacturing cell therapy products:

• Process Automation. Automation tools that employ closed-loop feedback/feedforward controls to react to changing parameters according to programmed boundaries. While this is not a replacement for human decision-makers, process automation can expand the work capacity of a decision-maker.
• Task Automation. Cited as “the most pervasive form automation currently incorporated into cell therapy processes,” task automation involves the automation of once-manual production activities. However, not all manual processes translate easily into automated tasks; some companies are working to “innovate new techniques to automate a unit step” rather than trying to recreate manual techniques.
• Test Automation. Quality control testing is crucial for following current good manufacturing practice (CGMP) standards. Test automation helps to streamline quality testing with inline processes—saving time while also increasing consistency.
• Operational/Factory Automation. Being able to efficiently manage information and monitor active processes can have an enormous impact on product quality and process consistency. Operational automation can be incredibly costly and complex, so a detailed examination of the return on investment (ROI) is required before adopting the automation.

While the different types of automation can be useful for cell therapy manufacturing operations, these solutions need to be implemented with a well-established plan in mind. Simply adopting the latest automation gadget does not guarantee an appropriate ROI.

What Drives Automation for Cell Therapy Manufacturing?

The primary drivers for adopting automation in cell therapy manufacturing processes are largely the same as the pillars of commercially-viable manufacturing. The four strategic drivers of automation identified in the article are:

1. Quality. One of the most important aspects of any cell therapy manufacturing process isachieving consistent quality. Automation helps eliminate the risk of human error, helping to ensure more consistent quality for manufacturing processes.
2. Cost of Goods. Automation can help reduce some direct costs, such as labor for cell therapy manufacturing processes, bringing down the cost of goods over time. However, the up-front investment in an automation solution may lead to a higher initial COG, though it can be minimized over time.
3. Scalability. This is closely related to cost of goods, but works differently in PSCT manufacturing when compared to over-the-counter products. Automation helps to improve process scalability by improving consistency and quality while minimizing cost of goods.
4. Sustainability. The ability to consistently manufacture a product at any given level of quality, COG, and scale. Automation may be able to improve sustainability by eliminating some of the need for high-skill labor to maintain newly-automated processes, ensuring such processes can be completed even when there is a shortage of skilled workers to carry out certain tasks.

The Potential Side Effects of Automation in Cell Therapy Manufacturing

While automation can be a powerful tool for improving scalability, sustainability, quality, and cost of goods for cell therapy manufacturing (both patient-specific and allogeneic), there is the potential for unintended side effects when adopting automation. Some of the specific scenarios identified in the article include:

• The “Black Box” Effect. There is a risk that some forms of task and process automation can reduce visibility into the process, creating a “black box” that hides the status of a product in progress. This is why automation systems need to be carefully designed and implemented to prevent variability.
• Amplified Failure Consequences. Automation can fail, especially if it isn’t properly configured and integrated. Assuming otherwise may lead to wasting time on failed product batches if there isn’t sufficient risk analysis and pre-confirmed process function. Failsafe protocols need to be considered to account for failed batches when setting up automated processes.
• Reduced Flexibility. While automated processes are more consistent, there’s less room forflexibility and adaptation. Manually-governed processes can be adapted in real time depending on the needs of the product. The best solution may be to defer integrating automation until the process is fully understood. 

Automation can be useful for cell therapy manufacturing processes, but these side effects need to be considered and addressed before adopting any automation solution.

You can read the full article in the Current Hematologic Malignancy Reports journal. If you have any questions about cell therapy manufacturing, CGMP issues, or how to improve your product’s commercial readiness, reach out to the HCATS team.

Citation

Smith, David, et al. “Towards Automated Manufacturing for Cell Therapies.” Current Hematologic Malignancy Reports. Volume 8, ISSN 1558-8211