The Rapid Micro Blog

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FDA Perspectives on RMMs

Following comment from the Australian TGA, two FDA staff members provided their
perspectives on RMMs. CDER's Dr. David Hussong stated that RMMs are very important for meeting Quality by Design (QbD) principles, smart processing and Process Analytical Technology (PAT). CDER actively encourages the use of new technologies, and the regulatory mechanisms for implementation of RMMs are evolving. For QbD, ongoing analysis of your processes is expected, and continuous improvement strategies should be utilized, in order to facilitate defining and revision of your design space and understanding what changes in your processes are acceptable. For RMMs, current policy provides for the use of comparability protocols and a number of post-approval change strategies, including prior-approval supplements, annual reports and Special Reports.

Next, Dr. Rajesh Gupta (CBER) discussed the use of RMMs as an alternative for sterility testing for biologics. The USP sterility test has been around for decades, and for many years, the test has had a good track record for ensuring product safety. So, why would there be a need for an alternative sterility test for biologics? From a manufacturing perspective, RMMs can provide faster resolution of process problems, screening of raw materials, and implementation of corrective actions. Some biologics have a very short shelf life (e.g., less than 14 days, which is the timing for the incubation phase of the sterility test), are manufactured in small quantities, and immediately required for emergency use (e.g., pandemic vaccines).

CBER’s considerations for a RMM for biologics are viewed on a case-by-case situation depending on the product. The RMM should preferably be a non-destructive technology (the expectation is that a sterility test contaminant can be identified), or use the same/comparable technology as the current methods *i.e., growth-based. The RMM should also be shown to detect VBNC organisms. Some non-acceptable practices when validating a RMM test includes the use of 10-99 CFU of test organisms as cited in the USP and CFR. However, the expectation is that you use less than 10 CFU, and include environmental isolates and stressed organisms. Furthermore, you should look for product interference and run the existing and RMM in parallel. The FDA labs compared the MilliFlex Rapid, BACTEC FX and BacT/ALERT systems as potential RMMs for sterility testing. Dr. Gupta stated that the MiliFlex system shows promise as an alternative sterility test for filterable products, and that the other two methods were not as sensitive with regard to a lower spike of organisms and in products containing thimerosol. In these cases, modifications may need to be made to the latter two RMMs.

In summary, CBER supports the application of RMMs for sterility testing. However, because there are not many applicants coming forward, this is the reason why the FDA labs have conducted their own validation and comparability studies.

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