An entrepreneur can have a lasting influence on a company, and this has been the case with Jack Bush, who founded Millipore in 1954 to make use of his expertise in membrane filtration. Over the following decades, the company developed products under the Steritest® brand that significantly improved the reliability of sterility testing results by reducing false positives and false negatives, with the ultimate goal of ensuring that patients are administered microbiologically safe drugs. In the 50 years since the first Steritest® product was introduced, we have continued Bush’s legacy, improving on user safety, time-to-result, and more recently data integrity, mostly in small steps and occasionally in big leaps forward.
The need to reduce false positives and negatives
In the early 1970s, the pharmaceutical industry was struggling with the release testing of products that needed to be sterile. Sterility tests were performed openly under a laminar flow hood, which led to many false positive results, often more than 30%. Each time this happened, additional tests and controls had to be performed, and frequently production lots were discarded and manufacturing delayed, leading to significant financial consequences and sometimes even drug shortages. The development of these new canisters, with integrated cellulose membranes, eliminated many of the manipulations previously required, resulting in a reduction of false positives, making Steritest® the standard for sterility testing.
Testing antibiotics and products with antimicrobial properties, however, still proved difficult. While cellulose ester membranes are perfectly suited for most pharmaceutical products, permitting high filtration flow rates, their many analyte-interacting functional groups that also bind antimicrobial substances frequently led to false negative results. In 1984 Millipore introduced canisters with membranes made of low adsorption polyvinylidene fluoride (PVDF) to address this need. We have since added a third type of canister with a broader chemical compatibility spectrum for testing viscous products such as creams and ointments, which are usually diluted in solvents like isopropyl myristate to improve filterability.
Meeting today’s need for rapid results and data integrity
A challenge for the pharmaceutical industry has long been the time-to-result of the compendial sterility test. It takes two weeks to complete and is thus too long, particularly for the manufacturers of novel cell and gene therapeutics. As rapid microbial detection methods emerged, we developed the Milliflex® Rapid system which uses ATP bioluminescence to detect minute colonies long before they can be seen by the naked eye. Like the compendial Steritest® method, it is based on membrane filtration, making it easier to compare and validate as an alternative method. In addition to rapid sterility testing, the Milliflex® Rapid system, now in its second generation, can also serve to perform rapid bioburden testing, which opens up new strategies to increase confidence in the microbiological safety of ATMPs (see earlier interview).
In recent years, automation and digitalization have opened up opportunities to improve microbiological QC tests about traceability and data integrity, two requirements to which regulatory authorities are giving more and more attention. This has led us to develop a solution that helps guide operators through their sterility testing workflow: the M-Trace® software, launched in 2023. It gives instructions on the Steritest® Symbio pump’s display or by voice, while it records all relevant test data contemporaneously and automatically to ensure full traceability, data integrity, and regulatory compliance. The software can be integrated into a manufacturer’s existing digital QC environment, allowing the reports it generates to be transferred to a LIMS. Its step-by-step guidance principle also reduces the likelihood of handling errors by the operator.
Striving to improve remains a constant
What we have learned from Jack Bush is to engage closely with the pharmaceutical manufacturers we serve, and this helps us to learn where we need to refine our solutions or adapt them to new testing needs and settings. To cater to an ever wider spectrum of pharmaceutical compounds, containers to sample from, and contaminant strains, we have steadily expanded our portfolio of accessories, fluids, and culture media over the decades. As testing gradually moved from the laminar flow hood to the isolator, we first introduced double, then triple packaging of consumables. Quality control demands continue to rise, so we want to ensure that the documentation we make available fulfills not just some, but all requirements. The same conviction guides the manufacture of our consumables: we test not just some, but all sterility testing canisters for integrity, in addition to stringent in-process controls along the way. Innovative ideas and an eye for detail spurred Bush and his team of pioneers to success as membrane filtration became the gold standard of sterility testing. Their approach has instilled a culture of continuous improvement into the company that still inspires us half a century on.
Take a look at the vast portfolio of instruments, accessories, culture media, fluids, and application notes we maintain for sterility testing. SigmaAldrich.com/sterilitytesting
Author Details
Michel van Musschenbroek, BioMonitoring Commercial Applications Field Support MilliporeSigma; Burlington; MA; USA, An affiliate of Merck, KGaA Darmstadt, Germany; Yoann Mainguy, Global Product Manager, Sterility testing, Mycoplasma testing, Millipore SAS, Molsheim, France, An affiliate of Merck, KGaA Darmstadt, Germany
Publication Details
This article appeared in American Pharmaceutical Review: Vol. 27, No. 4May/June 2024Pages: 40-41
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