With scientific and medical communities now poised to deliver on the promise of cell and gene therapies, learn how manufacturers of advanced therapy medicinal products (ATMPs) are evolving their processes to meet unique challenges and a drastically increased quality control burden.
Irving Ford is a leading quality assurance and quality control (QA/QC) professional with extensive experience driving quality programs for cell and gene therapies. In this question-and-answer session, Ford shares his expert perspective and personal opinions on the state of QC microbiology in cell and gene therapy manufacturing and the role of rapid microbial methods (RMMs). Questions and answers have been lightly edited for brevity and clarity.
How does QC microbiological testing differ in cell & gene therapies compared with other biologic modalities?
For traditional pharmaceutical biologics, everything is done with compendial methods and standard turnaround times. But in cell therapy, everything is done with rapid methods. Because of the nature of the product and the disease state of the patients, testing must be done quick, fast, and in a hurry. Companies don’t have the luxury of waiting 28 days for traditional mycoplasma tests or 14 days for compendial sterility tests.
How do automated RMM systems, like the Growth Direct® System, benefit a company’s cell & gene therapy manufacturing process?
It benefits the work tremendously because if rapid methods didn’t exist, a company would be stuck. Taking away the human aspect and letting robotics take over is a huge advantage. Currently, most cell therapy treatments are either the third or fourth line of defense. If the patient is getting this treatment, it’s often their last hope for survival. So, clinicians want the therapy back as soon as they can get it. If a company had to wait on traditional micro testing, it would only add to the time it takes to get it back to the patient, which would not be good.
What is the average “vein-to-vein” time at the moment?
Typical cell therapy manufacturing processes are between eight to ten days, but it does depend on the type of process that they're using. For the ones currently on the market, the vein-to-vein time can be anywhere from 20 to 30 days or even longer, which includes both manufacturing and QC.
How are new technologies speeding up cell therapy manufacturing?
Some new cell therapy technologies [in early R&D stages] are not really dependent upon cell expansion at the manufacturing site. With most of the products on the market, you expand patient cells in the manufacturing facility. For some newer approaches, you do the initial work at the manufacturing site, but the cell expansion will occur within the patient's own body. For those technologies, rapid micro testing is going to be even more critical because the manufacturing time is so short.
What was the decision-making like on your end to adopt the Growth Direct® System, or any other automated RMM system? When did you realize increased automation would be a requirement in the QC microbiology lab?
It was actually a decision from day one. The key motivation was to have a completely functional paperless laboratory and systems that can integrate with LIMS and talk to each other. With cell therapy manufacturing, each process is segregated, and you can have up to 20 batch records for one active cell therapy process. You can just imagine that if all of those records are paper, you’ve created this mound of paper you have to track, review, and verify. That is not sustainable for cell therapy.
Would you say implementing automated RMMs on day one comes with advantages?
You have to remember that when you’re going from compendial methods to rapid methods, there’s a whole change control, and you have to interact with regulatory agencies. So, you have to change your filing, and you have to do an amendment. It’s a whole lot of time you can’t afford to lose, if you start with non-automated processes.
Since you have adopted the Growth Direct® System into your QC microbiology labs, how has it worked for you? What have been some of the advantages?
Growth Direct® helps a lot and not just with the manufacturing process. It’s especially helpful for personnel training and monitoring, like when doing aseptic operator qualifications, media fills for aseptic process simulations, and controlling more manual processes.
Would you say that this common dependence on manual processes in cell therapy manufacturing makes personnel monitoring especially important? Are there higher testing volumes as a result?
Right. It’s key for gowning qualification, especially if employees are wearing full body suits. In traditional filling lines, you probably only have two people in the room per shift. In cell therapy manufacturing, you could have significantly more personnel in the room due to the manual nature of the process. With more people, there's more personnel monitoring but you still need rapid time to result. Some of those manual processes involve critical aseptic manipulations, and those are the steps where you really want results back fast.
Organizations often use rapid sterility tests as interim assessments to speed up lot release. Do you think that environmental and personnel monitoring help to support those efforts? How do they work together?
Sterility is not the be all, end all. Regulatory bodies expect you to have an overall contamination control program. The sterility test is just one point in the overall process. The better control you have over the process from start to finish, the better it is for your end result.
I think more companies are now trying to determine how they can get away from sterility testing at the end. They want to try to implement controls upstream of the final product, so that they can say, “We tested at these points, and we didn't have any chance of introducing contamination afterwards. So, do we really need this test at the end?” They're trying to be more strategic and take a risk-based approach, so that they don't have to wait at the very end. This is referred to as “just in time release.”
Want to learn more from Irving Ford and other experts about the unique challenges posed by new life-altering therapies? Download our whitepaper, Adapting QC Microbiology Labs for the Demands of Cell & Gene Therapies.