Rethinking Sterility Assurance for Short-Life Cell Therapies

For short-life ATMPs, sterility is assured throughout the entire manufacturing process, not by a single test at the end.

Short-life advanced therapy medicinal products (ATMPs) put real pressure on a deceptively simple question: when, where, and how do you test for sterility? 

The traditional 14-day compendial sterility test does not always align with a product that may be infused into a patient within hours/days of release. Much of the existing guidance predates these types of processes. That leaves developers to interpret, adapt, and lean harder on a well-designed contamination control strategy (CCS). 

Irving Ford, VP & Head of Quality and Compliance at Made Scientific, recently joined leaders from Novartis, Roche-Genentech, AstraZeneca, and others for a virtual roundtable to discuss sterility challenges and opportunities for ATMPs, hosted by BioPharma Webinars. In this informative session, Irving shared his approach to building a successful CCS for short-life cell therapies. Irving brings more than three decades of experience in pharmaceutical quality and has supported four cell therapy products from clinical development through commercial approval. His conviction is a practical one: in short-life manufacturing, sterility assurance must be engineered into the process, not inspected in afterward.

Sterility assurance is bigger than the sterility test 

Irving’s recurring point is that the final sterility result is used for release of the product, however it is supported by everything that happens before it. 

A robust CCS depends on controls built in across the process. That starts with understanding where contamination could realistically occur and how those risks can be detected, controlled, and documented before the final-product result is available. 

For short-life products, that means teams should be prepared to: 

• map the process from start to finish 

• identify critical manufacturing steps and higher-risk interventions 

• understand which organisms may reasonably be expected 

• build in-process testing at appropriate points 

• ensure the final sterility result is supported by process-wide controls 

The goal is to distribute confidence across the process, rather than concentrating it at a single end point. 

Test where the risk is 

Irving has long advocated just-in-time release of cell therapy products. Even when a process is not fully closed, risk analysis should pinpoint where contamination is most likely and which organisms may reasonably be expected. 

Those organisms, not only the compendial panel, should inform rapid-method validation. In many cases, growth-based detection methods may be able to detect relevant organisms within 24–48 hours. The practical upshot is in-process testing at higher-risk or open steps, so teams are building evidence throughout manufacturing. 

Validate at the temperature you manufacture at 

Temperature is another important consideration for sterility testing strategy. 

For growth-based methods, compendial approaches specify incubation in the range of roughly 20–25°C and 30–35°C. Cell therapy products are typically cultured at 37°C, and that difference can affect what organisms are recovered and how quickly they are detected. 

Irving recommends validating rapid methods at both the compendial temperatures and the actual process temperature. Manufacturing-temperature incubation can support faster recovery and may provide a more process-relevant view of the organisms likely to be encountered. 

For teams working with short-life products, validation that reflects manufacturing conditions can provide a clearer view of process risk. 

When the patient is waiting: releasing with results pending 

For short-life products, the timeline may create scenarios where the product needs to be released and infused before sterility testing is complete, with the result reported afterward. 

Irving noted that, in certain short-life product scenarios, release with sterility results pending may be considered when supported by a sound contamination control strategy, appropriate manufacturing controls, and clear regulatory justification. 

The strategy, not a single end-point assay, is what makes the approach defensible. 

Vendor data helps, but the sponsor owns acceptability 

On rapid-method validation, Irving was direct about where accountability sits. 

Vendors increasingly provide robust primary validation packages, and those data can be genuinely useful to draw on. But the sponsor holds the ultimate responsibility to demonstrate that any system is acceptable for its intended use. 

That means doing the due diligence, completing the necessary follow-up, and working collaboratively with the vendor without outsourcing accountability to them. 

Do not overlook the starting material 

Regulatory expectations increasingly emphasize understanding the quality of incoming starting materials, particularly those derived from a patient donor. For short-life products, this can be especially important for traceability.

If a failure occurs at the end of the process, teams need to understand whether the source may have been the starting material, the manufacturing process, or another point of entry.

Irving framed incoming material testing as part of a broader CCS. How far a team takes that testing depends on the process, the product, and what is deemed sufficient for detection and traceability.

He also offered a useful reframe: when contamination is traceable to the patient starting material, the risk profile may differ from contamination introduced during manufacturing. That makes traceability and clinically relevant isolate testing especially important, alongside the traditional compendial recommended panel.

The takeaway 

It all comes back to one idea: build a comprehensive contamination control strategy with controls throughout the process, and make sure the method you adopt is genuinely fit for your process, not chosen simply because it is the newest option on the market. 

For teams developing short-life cell therapies, sterility strategy assurance must be built into the process from the beginning. Made Scientific’s quality and manufacturing teams can help support that work, from process mapping and method validation through regulatory engagement.