The Rapid Microbial Testing Methods Consortium: Enabling Safe, Effective and Timely Advanced Therapies

What is an advanced therapy, and how does it differ from traditional medicine?

The term “advanced therapy” typically refers to biologically based, next-generation therapies to treat disease. These can include cell therapy, gene therapy, tissue engineered products and microbial cell therapy. One example is CAR T-cell therapy for treating cancer, which you may have read about in the news. It involves taking a patient’s own immune cells, modifying them to target the cancer, and then injecting those cells back into the patient. There’s been remarkable clinical success.

Traditional medicine is often based on small molecule drugs like ibuprofen, for example, that are chemically defined — we know exactly what they are and how to measure them. They’re produced in very large lots with a long shelf life, and they serve as a more general treatment. There's no special ibuprofen for you, no special ibuprofen for me. We all get the same ibuprofen.

Because advanced therapies like CAR-T are harnessing the power of biology to treat disease, they are typically much more complex than traditional medicines, often consisting of biological entities such as cells or DNA, and we can’t come close to defining every aspect of them. Some of these therapies also fall into the realm of precision medicine, in which case they are manufactured in small, patient-specific lots.

As such, advanced therapies are very different from traditional drugs and require a whole new set of measurement methods that must be developed and validated.

What are some of the challenges associated with producing these advanced therapies?

All therapies must be safe and efficacious. On the safety side, one important aspect is testing for microbial contamination before and during the manufacturing process and in the final product. Current culture-based methods for detecting bacteria require 14 days. For a traditional drug with a long shelf life, like ibuprofen, this isn’t a problem. But many advanced therapies have a shelf life far shorter than 14 days, as these are often live products. Also, culture-based methods aren’t perfect. Not all bacteria readily grow in a culture dish, so some contaminant bacteria may go undetected.

That’s not to mention the fact that waiting 14 days before administering the therapy can mean the difference between life and death for a critically ill patient who needed the life-saving treatment yesterday. They can’t afford to wait an additional two weeks for release testing. Rapid, reliable microbial testing methods will help them receive their treatment safely and more quickly.

Then there is quality control to consider. Quality control for each advanced therapy product requires robust measurements and confidence in the measurement results to make decisions. For instance, being able to quickly, let’s say within an hour — which is a lofty goal — assess the level of contamination in a cell therapy product during manufacturing would support corrective steps. Stopping or modifying production of a contaminated, unsafe product saves money and time. Again, time is of the essence when it comes to these life-saving therapies.

Why do we need a consortium to develop a rapid microbial testing method? Why can't NIST or industry do this on their own? What are the things that NIST can and cannot do in this space?

The consortium is needed because the challenge of rapid microbial testing requires an organized community response. Our partner, the Standards Coordinating Body, has done a fantastic job coordinating efforts to identify gaps related to rapid microbial testing, and they are leading the development of documentary standards particularly with respect to a risk-based approach. Through their work, it has become apparent that an extended collaborative effort to generate data and validate testing strategies is needed for the field to advance. We at NIST have a lot of experience organizing interlab studies and developing reference materials, including our latest microbial cell-based reference materials, the first of which should be released later this year. We can bring this expertise to the stakeholders.

However, we need continuing input from industry and other stakeholders — their firsthand experience of the needs and challenges in testing for microbial contamination as well as their understanding of what is feasible on their end. Any efforts toward a reference material, interlab study, testing method or documentary standard would likely be less relevant and less impactful without input from stakeholders throughout the whole conception and development process.

Industry comes to the table because they trust NIST as a neutral third party who is really seeking to act in their best interest. This truly speaks to our NIST mission to support industry. Without a collaborative effort with an impartial convener, the transition to the much-needed rapid testing will be slow and expensive as each company independently establishes, validates and applies their own rapid microbial test, likely with one trailblazer leading the way. However, even larger companies can be hesitant to take on the risks associated with being first, including navigating the regulatory landscape. As my colleague says, it’s a race to be second. Developing and validating a new method and demonstrating its comparability or superiority to existing methods is daunting. Our consortium can take the lead, and together we can pave a path for the community to follow.

What's the consortium’s final goal or goals? Are you solving a shorter-term problem or are you looking to create a permanent presence?

Ideally, we would work ourselves out of a job, right? We would end up with the ability to do routine, rapid microbial testing throughout an advanced therapy’s production and release. That’s a large ask, so we’re starting smaller. Overall, we’d like to provide what we call “measurement assurance strategies” to support and enable the industrywide adoption of one or more rapid microbial testing methods that are acceptable to and recognized by regulatory agencies. These strategies could include best practices for testing based on interlaboratory study results, the use of control materials — perhaps NIST-developed reference materials — to enable comparability, or method validation schema. The beauty of these types of strategies, and standards in general, is that they promote measurement innovation by laying the foundation to compare new methods to existing ones.

Developing these strategies within the consortium would go a long way toward helping stakeholders demonstrate and validate their own methods. If we identify one or more methods that appear promising, we could validate them within the consortium, if it made sense to do so. That would be a longer-term effort.

We also recognize that the advanced therapy industry isn’t the only sector that needs rapid microbial testing. I believe the efforts and results from this consortium can be leveraged to support other communities, from biosurveillance to food safety to pathogen detection. In that sense, I do see an enduring presence in this area of rapid microbial detection, identification and quantification.

What kinds of collaborators are you looking for? What will you be asking of them?

We are really interested in hearing from subject matter experts in areas such as microbial detection, advanced therapy and regenerative medicine, and regulatory science, representing manufacturers, contract research organizations, nonprofits, government and academia. I think that covers pretty much everyone! We would like consortium members to actively engage in the consortium, not just listen. We need to understand their challenges in terms of using the current methods and in applying rapid methods. What’s fast enough for them? What sensitivity do they need? What specificity do they need? What does fit-for-purpose mean for them?

We want and need them to help direct the path forward and to walk along that path with us.  Practically, this would involve helping design prototype reference materials, providing microbial strains to NIST to build a repository of relevant contaminant microbes, helping design and participating in interlaboratory studies, providing insight into detection methods, and so on. Besides being able to provide input into the consortium activities and helping to prioritize efforts, consortium members will also get a first look at the materials, interlaboratory data and conclusions.

Is there anything else you'd like to add?

Just that as with most NIST efforts, this is really a team effort. That’s one of the great things about working at NIST. The NIST team spearheading the consortium consists of myself, Scott Jackson, Tara Eskandari and Sheng Lin-Gibson. Given the interdisciplinary nature of the consortium and the level of effort it takes to establish and maintain what we hope will be a vibrant, impactful consortium, it truly does take a team. Sheng brings the big picture perspective of standards for regenerative medicine, Scott has great expertise in microbial detection methods, and Tara is an expert in managing partnerships. I’m confident that the combination of our NIST team, the stakeholder community and partners such as the Standards Coordinating Body will make the consortium successful, and that our efforts will result in tangible improvements in the use of rapid microbial testing methods and greater confidence in their results. When it’s all said and done, that’s the impact we’re hoping for.