Accelerating the pace of innovation in cell and gene therapy – how USP <72> is set to rewrite the rules of sterility testing

With the introduction of new guidances and the endorsement of USP has not only provided a clear support for rapid microbiological methods, but it has also issued a challenge to the wider industry – pushing pharmaceutical companies are encouraged to innovate beyond current expectations by embracing processes that can deliver much faster testing results without compromising on safety and compliance. 

Trends towards more personalized treatment have led to an explosion in Advanced Therapy Medicinal Products, which have become increasingly established over recent decades. For example, this year marks twenty years since the first clinical usage of CAR T-cells, paving the way for the range of CAR T-cell therapies available today that can treat patients using their own immune cells. 

While the adoption of advanced therapies continues to grow, regulatory frameworks and manufacturing practices are evolving to keep pace with increasing product complexity. Traditional sterility testing methods, designed for conventional drugs, are often too slow and rigid for certain cell and gene therapies or short-life products that require rapid access to patients. USP <72> provides a framework for implementing rapid microbiological methods, reducing validation burdens and opening the door to non-traditional, easier-to-adopt approaches. While this does not directly address the high cost of these therapies, it helps remove a critical bottleneck in time-to-patient—especially for life-saving treatments—by enabling faster, more flexible release processes.

By their very nature, cell and gene therapies are deeply reliant on precision and quality control to not only deliver efficacy, but to ensure the ongoing safety of the patients who receive them. If undetected, microbial contamination in cell and gene therapy products can lead to severe infections and even fatalities in some cases. 

Effective sterility testing is therefore a vital element of the manufacturing process for these treatments, guaranteeing that the final product is free of harmful contaminants, protecting efficacy and meeting standards for regulatory compliance.

The foundations of modern sterility testing were established in the 1930s, when regulators stepped in to implement new standards, marking the pivotal moment that sterility assurance became a legal requirement rather than merely an aspiration of good practice.

Traditionally, sterility testing has harnessed culture-based methods, such as membrane filtration or direct inoculation, which can be used to detect the absence of viable microorganisms within samples. Although effective and reliable, these traditional processes were defined at a time before modern treatment approaches such as cell and gene therapy were even a consideration. 

Traditional sterility methods are therefore not ideal to test cell and gene therapies as they were not designed with the purpose of analyzing products that contain living cells or viral vectors: their presence within samples would affect the accuracy of testing results, and the 14-day incubation period would create problematic delays where rapid delivery to the patient is vital.

The limitations of culture-based methods for cell and gene therapy sterility testing have led manufacturers to explore alternative options, such as new Rapid Microbiological Methods (RMMs). RMMs are more effectively designed to meet the demands of cell and gene therapy manufacturing as they can provide results in a matter of hours, enabling the release of products in real time and avoiding unnecessary delays. 

This industry-led shift towards RMMs has placed pressure on regulatory bodies to evolve their standards in response. The first meaningful step towards this came with the introduction of European Pharmacopoeia chapter 2.6.27, which officially recognized a growth-based rapid method as compendial for cell-based products. 

The publication of USP <72> marks another defining moment. Not only does this new guidance relax the global validation requirements for RMMs, but it also offers much-needed flexibility in determining the incubation time for the product to be examined, acknowledging the realities of modern manufacturing and release-testing for advanced therapies and opening the doors to sterility results in less than 7 days. This incubation time is based on the time-to-detection of the slowest organism targeted with the addition of a safety margin.

When considering the end-to-end manufacturing of cell and gene therapy products, the benefits of integrating RMMs for sterility testing are clear, but taking a broader view suggests that uptake of these methods could lead to greater benefits at an industry-wide level. 

By providing easier-to-use and rapid sterility solutions, manufacturers can reduce their time-to-release and ultimately improve patient outcome.