Improving Quality Control in Cell Therapy Manufacturing
George Bitar, Executive Director, Quality | February 5, 2018
Quality control is a major issue for any therapeutic cell production process. Deviations in the manufacturing process not only waste materials and time—adding to the cost of goods for the therapy—they can create health risks for the patient if affected cells are infused.
Finding ways to maximize quality and prevent deviations can help improve the commercial viability of a cell therapy product in the long term—as well as help meet phase-appropriate quality requirements in the short term.
Some strategies for improving quality control—and thus the quality and safety of cell therapy manufacturing—include automation of both production and of documentation, and the selection of quality and safety testing methods, both detailed below.
Automation of Both Production and of Documentation
Strong quality control in cell and gene therapy requires extraordinarily precise and accurate control over conditions in the laboratory itself. Technological solutions, such as manufacturing automation and process documentation software, can help improve quality control processes and minimize risk of deviations.
Using robotic manufacturing tools is a key means of maximizing sterility in cell therapy manufacturing processes. Humans, even after undergoing thorough delousing/sterilization processes and putting on cleanroom suits, can massively increase the risk of contamination simply by being in the same room that the therapeutic cells are being manufactured in.
By automating manufacturing, you remove one of the single largest contamination risks in the entire process—which makes controlling quality easier and more consistent.
Automation of documentation can also help improve quality control processes. For example, say that you have one record entry error per batch when you use a manual documentation process caused by human error when copying or moving data. Using electronic batch record systems would remove the human error, improving documentation and reducing deviations.
Why do documentation deviations matter?
Every deviation noted in the records takes an average of 8 hours of labor to investigate and correct. If using electronic batch records cuts the error rate in half, then that could save 4,000 hours of labor over the course of 1,000 cell therapy batches—time that can be spent on more productive activities than double-checking paperwork.
Selecting Quality & Safety Testing Methods
Another major challenge for any manufacturing process is finding the right way to handle quality control and safety testing—an issue that becomes even more difficult when using an outsourced manufacturing partner. In many cases, cell therapy developers may want to use one set of tools, but the manufacturing partner may not have expertise in those particular quality control systems.
Ideally, the analysts running the quality control tests should be experts in the equipment necessary for those tests. It takes time to teach a new process to the quality control team, which delays production and may compromise results.
However, there may be instances where a new testing method is more effective and efficient than the current testing method—so making a switch is beneficial.
For example, say that you were running a compendial test that takes two or more weeks to verify the sterility/safety of the cell therapy. While useful during a purely exploratory trial phase, this is not as useful for actual manufacturing because most cell therapies are only viable for a few days after production—by the time the test is finished that verifies the safety of the therapeutic cells, they would be useless to patients.
Here, switching to an endotoxin analysis method, such as Limulous Amoebocyte Lysate (LAL), can significantly reduce the time required for testing down to 1 day. An automated PCR test for mycoplasma can also reduce testing time from 14 days to 1 day. With cryopreservation, this may allow for the sterility testing finish before the therapeutic cells lose their potency.
Additionally, automated testing equipment, such as the BACT/Alert System, can help further speed up testing by automatically initiating tests of each cell batch immediately after production.
Ultimately, the goal of quality testing is to achieve “best in class” status for both results and time efficiency. So, it’s important to balance the accuracy of the testing method and how familiar analysts with a process (which can affect testing accuracy) with the speed of the testing method.
Other quality testing considerations include:
Harmonizing Testing Across Multiple Sites. When using multiple production sites for cell therapy, it’s important to harmonize testing methods across all of those sites so each one is using the same types of tests and equipment. This makes it easier to transfer processes from one site to another while making quality control efforts more consistent across the board.
The Current Production Phase. When assessing quality testing methods, the current production phase can impact the requirements for the testing. For example, a Phase 1 trial phase therapy doesn’t require a fully validated testing method. However, later phases, such as Phase 3, will require a validated process.
Quality Control in Cell Collection
Quality control standards for cell collection in patient-specific cell therapy are still evolving as cell therapy developers experiment with collection techniques, storage solutions, and transportation of cells.
Right now, one of the most common solutions is to use a complete blood count collection method and store the collected cells in a sealed Grade A or Class 100 environment for shipping. Some developers are working on conducting sterility tests of cells prior to the cells coming into the production facility—which can help prevent contamination of cell therapy products and facilities, improving quality.
Currently, this sterility testing is done using a risk-based approach which happens concurrently with cell therapy modification/development because of time constraints imposed by normal testing methods. This means that if the test comes back positive for contamination, the modified cells will have to be disposed of and the process repeated from the initial collection phase.
One of the big challenges is that the actual collection of cells is typically handled by a third party—not someone in the cell therapy manufacturer’s/developer’s organization. Because of this, enforcing uniform standards for cell collection can be a challenge.
As quality control processes for cell collection continue to evolve, we can expect to see new standards come to the fore.
If you have questions about how to improve quality control for your cell therapy development, please contact PCT! We have years of experience in helping cell therapy developers meet their phase-appropriate quality standards in preparation for commercialization, as well as optimizing quality control processes for reliability and efficiency.
George Bitar, Executive Director, Quality
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