How Early Communication with FDA Sped Up One RMM Implementation
Rapid Microbial Methods (RMMs) offer another tool that can facilitate Lean Manufacturing in biologics and pharmaceutical manufacturing, and taking the industry a few steps closer to parametric product release. Proactive communication with FDA reviewers was instrumental in getting approval for one RMM implementation project at a major pharma company. Rich Boehler discusses how his team at a previous (unnamed) employer went about the implementation.
By Agnes Shanley, Editor in Chief
We did some research and found that Dr. Reilly had already published a document that addressed those issues. If we hadn’t done a thorough review of the literature, we might have duplicated work that had already been done, unnecessarily. Research is essential to supporting a strong scientific case to present to senior management.
Ph.M – What is the most important aspect of the validation studies?
R.B. – Setting acceptance criteria is extremely important. With ATP Bioluminescence, a baseline must first be established, based on non-microbial ATP. A reading two times that amount or greater should be considered a positive bioluminescence result; other levels (i.e. less than two times the baseline luminometer measurement) would mean that the material has passed testing and can be released.
Extensive studies performed by Celsis support the calculation (two times the baseline luminometer measurement) of a positive bioluminescence result. However, in-house validation work needed to be performed to analyze, interpret and confirm this acceptance criteria.
All that information must be spelled out clearly in your documentation. Each product should undergo this validation process, and it should be written up in all summary reports submitted to management for review, including reports for QA and in-house regulatory specialists.
The question of how to set these criteria is an obstacle for some companies. People usually wind up saying, “The old way works.” Some also worry that with new, more sensitive methods, they’ll get false positives.
Ph.M – But what do you do when you get a positive result?
R.B. – We established a two-tier approach. If you get a positive RMM reading on a sample, you revert back to traditional testing methods for that specific sample.
Ph.M – But doesn’t reverting imply that RMMs aren’t that effective?
R.B. – Actually, the two-tiered approach with RMMs is extremely effective. 95% of the time our products tested negative for contamination and we could release those products within 18-48 hours. For the 5% that we found a positive reading, we’d need to revert back to traditional testing methods for end product release. This way, we only needed to delay release on a very small percentage of our products.
Ph.M – What additional in-house tests were required to support validation documents?
R.B. – We generated test data after we had a solid validation plan in place, and we also ran additional support studies, and in this case, it was important to keep an open mind. For instance, why use TAT and not Latheen? One could reference literature, but we also performed tests to demonstrate whether the two broths exhibited different levels of organism recovery.
In addition, mold studies were extremely important. Although they weren’t required in addressing questions of potential risk, by doing these studies we were able to demonstrate recovery of mold within 48 hours.
Other support studies looked at incubation time and temperature, and controls. Additional studies provided relevant support for our RMM initiative.
Ph.M – What would be a realistic time frame to expect for a project like this?
R.B. – You meet with FDA to discuss an initial proposal and you have a strong validation plan in place, approval is possible in a little over a year. But success requires ensuring that technical and regulatory professionals on the team are communicating well and often, and that even minor issues are addressed proactively before they can snowball. The keys to success are ongoing communication and establishing a dialogue with FDA.