Esther Welterlin- R&D Validation Expert BioMonitoring, Millipore SAS, Molsheim, An affiliate of Merck KGaA, Darmstadt, Germany; Dr. Anne-Grit Klees- Lead Expert, Product & Portfolio Manager, BioMonitoring Environmental Monitoring, Merck KGaA, Darmstadt, Germany
The COVID-19 pandemic once again highlighted the fact that compendial sterility testing is a critical bottleneck in getting pharmaceutical products purporting to be sterile to the market. Due to the slow growth of some microorganisms, a sterility test according to 21 CFR 610.12 and USP <71>takes at least 14 days to complete, during which the manufactured product must remain on hold. The resulting delay in shipment not only puts patients’ health at risk, it also increases costs and affects sales revenues on the manufacturer side, in particular with respect to biologicals with a short shelf life such as mRNA corona vaccines. Certain therapeutics, for example the so-called advanced therapy medicinal products (ATMPs) for cell or gene therapy, are mostly so short-lived that there is no way around administering them before the final result of the compendial sterility test becomes available.
New regulation to facilitate rapid test methods
To meet these challenges, regulation to support the introduction of novel microbiological methods for earlier results is being introduced around the globe. USP <1071>, titled “Rapid Microbial Tests for Release of Sterile Short-Life Products: A Risk-Based Approach”, gives an overview of the available technologies, outlines the user’s requirements for a rapid test, and discusses important issues to consider when planning to validate a rapid method as a replacement for the compendial method. In Europe, the recently revised EU GMP Annex 1 has seen changes that open the door to alternative rapid sterility testing methods, both for short-life products and, more generally, to expedite the detection of microbial contamination and reduce the risk to an injectable.
What is keeping many manufacturers from implementing rapid sterility tests is the requirement to validate the alternative method by demonstrating its equivalency or superiority over the established compendial method, a procedure that USP <1223>and PDA TR 33 describe. This perceived drawback is why it makes sense to look closer into what validation involves. As a supplier, our strategy at MilliporeSigma is to minimize the validation and qualification work for our customers by performing as much ourselves as is possible and reasonable, as well as offering documentation and services that make it easier for customers to carry out validation at their own facility.
Validating an alternative sterility testing method
A recent example of this is the validation of our Milliflex® Rapid System 2.0, a platform for both rapid sterility and rapid bioburden testing based on membrane filtration, luminescence-based detection of emerging microcolonies’ ATP, and software-based image analysis. We performed separate validation studies for both applications and as a worldwide supplier made sure they covered both the USP and the Ph. Eur. guidelines. For compendial sterility testing of filterable pharmaceutical products, membrane filtration is the method of choice. It can thus serve as the reference method to demonstrate equivalence or superiority of an alternative method. As a pioneer in membrane filtration for sterility testing since we made this technology available in the 1970s, we found ourselves in the fortunate position to have a proven reference platform of our own that we could use for validation: the Steritest® closed filtration system, now in its fourth generation.
While the Milliflex® Rapid System 2.0 can deliver quantitative results, the compendial sterility test is a qualitative, non-enumerative application that yields a yes/no result, which is why regulation involves fewer parameters to be tested to validate a corresponding rapid method. We devised and performed tests to determine the detection limit, robustness, ruggedness and specificity of the Milliflex® Rapid System 2.0 method, comparative tests for equivalence with the compendial test, as well as tests to prove the absence of bacteriostasis and fungistasis, as the rapid sterility test is performed in an isolator, where consumables might come into contact with the VHP used for decontamination. The panel of microorganisms included the bacteria and fungi specified in the USP and Ph. Eur. sterility test chapters, but also two anaerobes as well as seven further strains to represent the method’s full spectrum of incubation conditions. All performed tests confirmed the equivalence or superiority of the rapid method. Validation for bioburden testing, being a quantitative application, required additional testing. This study was also concluded successfully.
What this means for the user
Customers must still qualify the alternative method based on their own risk assessment, using their own product and, probably, in-house strains of theirs. Our validation studies offer a model system that might suit their needs, offer ideas, simplify their qualification tasks and save them some tests altogether, for example to assess the ruggedness of the instrument and consumables. For further support, users can call upon or expert services to make validation succeed and thus to benefit from reducing the time-to-result of their sterility testing from 14 to 5 days, as the Milliflex® Rapid System 2.0 does.
Find out more about the Milliflex® Rapid System 2.0 and get in touch with our sterility testing experts.
www.SigmaAldrich.com/milliflex-rapid
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