What are the main differences between the original USP <73> and the latest update released this year?
The main difference is the level of detail in the new USP <73>. As a chapter with a two-digit number, it contains some methodology and details that were missing in the original publication. For instance, it contains an equation to calculate the incubation time before ATP bioluminescence detection is performed. These factors in the exponential growth of the slowest growing organism of concern are used to calculate an appropriate time to detection (TTD) based on the speed of microbial growth. Furthermore, a new sample interference section was created from content that was previously part of the membrane filtration section, now rearranged for better flow and clarity.
Can you explain how USP <1071> and USP<73> work together?
Both chapters describe risk-based approaches to rapid microbial testing of short-life products. USP <1071> deals with such methods in general, mentioning several different rapid technologies. It provides guidance on, for example, test sample sizes, taking into consideration the probability of detection. USP<73>, on the other hand, is wholly focused on ATP bioluminescence technology, while referencing USP <1071> as an informational chapter on how to select and validate rapid methods for short shelf-life products. Both chapters address methods for achieving Rapid sterility testing results for short shelf-life products that would normally take 14 days to result with the compendial USP <71> method.
There is an equation for incubation time in the new USP <73>. What is it for?
The equation should be used to determine the minimum incubation time of the sample when performing rapid sterility tests based on ATP bioluminescence. This mathematical procedure aims to prevent premature reading of test results and thus maximize the possibility of detecting ATP bioluminescence at the appropriate time.
How should an ATMP manufacturer balance speed and sensitivity when using a rapid sterility testing method?
Manufacturers of such advanced therapy medicinal products (ATMPs) should take a risk-based approach. They should consider technology that is both fast and sensitive enough to find low levels of contamination. They should assess which of the two criteria is more critical for patients’ health and safety. If a patient needs treatment within 24 hours, they should consider a technology that can deliver results within that period. However, if more time is available, a more sensitive test may be better suited from a patient safety perspective.
Manufacturers also need to consider how the product is administered. In cases of, for example, intravenous or another invasive means of delivery, they might want to consider a more sensitive technology.
Patients often need ATMP treatments as soon as possible. How does a rapid method help make that possible?
By delivering faster sterility test results, rapid methods allow doctors to administer an ATMP earlier. Speed can be critical from a patient health or a product stability perspective, or both. The choice of test method should depend on result reliability and on the available time. Patients who are on several courses of antibiotics, for example, would need their ATMP treatment as early as possible. Faster test results allow doctors to make earlier and better decisions on patients’ health.
What are the differences between a rapid sterility test for a classical aseptic preparation and an ATMP preparation?
Rapid sterility testing is used for both classical aseptic and ATMP preparations. However, ATMPs tend to have very short shelf lives, often just a few days, so the key aspect is how quickly the manufacturer can release the batch of cells or injectables to treat a usually very small number of individual patients who are waiting. There may also be a business case to use rapid sterility testing for classical aseptic injectable preparations. It would allow manufacturers to release their product faster to a market waiting for their product, possibly saving storage capacity, allowing for increased production capacity. For both types of preparation, earlier results lead to better outcomes.
What are the differences between a rapid sterility test for autologous and for allogeneic cells?
Autologous cells are a patient’s cells, often available in only small quantities and many cases, viable only for a short time. Allogenic cells are donor cells and tend to have larger sample sizes. Rapid sterility testing should consider the risks associated with both. The sample size required for testing may also vary between the two cell types based on batch size. In almost all cases, autologous treatments need a rapid sterility testing result because the patient requires immediate treatment. Many allogeneic treatments could use classical USP testing for a 14-day release test, but there are also cases where such therapeutics may require a faster result.
Learn more or request more info on SigmaAldrich.com/milliflex-rapid.
Author Details
Lamin Jallow- Microbiology Technology Specialist, MilliporeSigma; Burlington; MA; USA, An affiliate of Merck, KGaA Darmstadt, Germany
Publication Details
This article appeared in American Pharmaceutical Review:
Vol. 28, No. 3
April 2025
Page: 57
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