1. What steps has your company taken to ensure the reliability and accuracy of your rapid sterility testing methods? How do you validate the results to meet regulatory requirements?
In its overview of rapid technologies, USP outlines user requirements and discusses issues to consider when planning to validate a rapid method. It explicitly contains information on the ATP bioluminescence detection technology that our Milliflex® Rapid System 2.0 uses for rapid sterility testing. What we have done to facilitate validation according to USP and Ph. Eur. guidelines is to complete as much as makes sense for a supplier to do, for example, studies on detection limit, robustness, ruggedness, specificity as well as proving the absence of bacteriostasis and fungistasis. Of course, there remains validation work to be performed by the end-users, particularly relating to the specific nature of the sample. However, Milliflex® Rapid validation can conveniently reference the compendial filtration method for sterility testing because the method is likewise based on membrane filtration and microbial growth.
Validation must include not just the microorganisms specified in the regulations but also the in-house strains of a facility. Most rapid methods can detect the fastest growers overnight, or even within a few hours, but that is not relevant. It is the time-to-result that matters, which depends on the slowest growing organisms to consider, often Cutibacterium acnes or certain Methylobacterium species, and this will take any rapid method several days. This is why our internal validation included several slow growers as well as the three incubation conditions (aerobic at 20-25 °C and 30-35 °C, anaerobic at 30-35 °C) the FDA’s CBER deems necessary.
2. What strategies did you employ to minimize both false positive and negative results to provide consistent, trustworthy results?
Both false positives and false negatives can have profound consequences for manufacturers, so we do our utmost to develop workflows for our methods that minimize these risks during testing in an isolator or ISO 5 laminar flow hood. We offer full feasibility and method development before validation to reduce the potential for false results. All reagents, media, and other consumables we recommend for use with our systems are QC tested and released for their intended applications to ensure no inhibitory effects or background signals are observed.
3. Data integrity is critical in the pharmaceutical industry. How do you ensure the data generated by your rapid sterility tests maintains a high level of traceability and meets all regulatory standards for data integrity?
Regulatory authorities are giving more and more attention to traceability and data integrity, so these are key objectives to fulfill for us as a supplier. The software for the Milliflex® Rapid System 2.0 was developed according to GAMP5, FDA 21 CFR Part 11, and European GMP EudraLex Volume 4 Annex 11 requirements, along with all necessary audit trail functions, user accessibility levels, and tracking. A third-party consultancy subsequently conducted an independent compliance audit, and its document also gives recommendations to guide our customers through procedural and organizational requirements and guidelines. The Milliflex® Rapid System’s electronic edits, e-approvals, and sign-offs as well as compliant storage and data communication further improve data integrity and traceability.
4. Rapid sterility testing is evolving fast. What new technologies or methodologies are your company exploring to further improve the speed, accuracy, and efficiency of your sterility testing capabilities?
We are always looking for the next technology that will allow faster detection of all potential microbial contaminants without affecting result reliability. Validation must be as straightforward as possible, which puts growth-based rapid methods at a clear advantage. Furthermore, lab staff with the usual expertise and skill levels must be able to operate the system and perform the tests. With the automation of microbial QC on the industry’s horizon, we might see in-line detection become a reality. Much will depend on how technologies and regulations evolve.
5. Which key factors are driving the adoption of rapid sterility testing methods in the pharmaceutical industry? How are you working to educate and support your customers in transitioning from traditional sterility testing?
Recent years have seen a surge in cell and gene therapeutics being developed. For these biologics, rapid methods are a must because patients and doctors do not have the time to wait 14 days for the results of a classical compendial sterility test. Manufacturers of other drugs and injectables stand to benefit, too. A delay in shipment not only puts patients’ health at risk, it also increases storage costs and affects sales revenues. Fortunately, regulatory acceptance of rapid methods has improved, with new regulations giving manufacturers more clarity about the requirements for validation.
Since pioneering the first Steritest® membrane filtration products 50 years ago, we have gained an in-depth understanding of compendial and rapid microbial testing. We share this wealth of knowledge in webinars and directly with our customers in a variety of ways such as providing application notes, validation studies, SOPs, and e-protocols as well as training on best practices in aseptic handling and processing.
Learn more about the 21 CFR Part 11 compliant Milliflex® Rapid System 2.0 for rapid sterility and bioburden testing & get in touch with our microbial QC testing experts. www.SigmaAldrich.com/milliflex-rapid
Author Details
Lamin Jallow- Microbiology Technology Specialist, MilliporeSigma; Burlington; MA; USA, An affiliate of Merck, KGaA Darmstadt, Germany; and Nicolas Lelievre, PhD- BioMonitoring Regional Application & Commercial Tactics Manager, Millipore SAS, Molsheim, France, An affiliate of Merck, KGaA Darmstadt, Germany.
Publication Details
This article appeared in American Pharmaceutical Review: Vol. 27, No. 5July/Aug 2024Pages: 46-47
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