« Previous article
A Way to Reconcile E...

10th June 2024  Content supplied by: Merck

A History of Overcoming the Challenges Associated With Sterility Testing

Over the half-century since Millipore brought the first Steritest® product to market, sterility testing has become much more reliable, easier to perform, and faster. The industry-leading products under the Steritest® brand have managed to vastly improve result reliability by reducing false positive and false negative results, thus ensuring microbiologically safer drugs for patients. A string of innovations over the years has helped to boost user safety, time-to-result, and data integrity. This was achieved mostly in small steps and occasionally in big leaps forward with new products being launched, for example:

  • 1974: a closed canister with a cellulose membrane
  • 1986: a canister with a low-binding PVDF membrane
  • 2004: an ATP bioluminescence-based rapid detection system
  • 2023: a digital workflow companion for error-free data recording


It is worth looking closer at the challenges that the pharmaceutical industry faced and how they were overcome.

Secondary contamination drastically reduced
Fifty years ago, sterility tests were performed openly under a laminar flow hood, which is one of the main reasons why pharmaceutical companies struggled with the reliability of product release testing. Up to 30% of positive sterility test results were estimated to have been false. In each such case, further tests and controls had to be performed. As a consequence, production lots were often rejected and manufacturing delayed. This led to painful financial losses and sometimes even drug shortages. The development of a closed sterility testing canister with an integrated cellulose membrane avoided the need for many of the handing steps previously required, resulting in an industry-wide drop in false positives. These Steritest® canisters eventually became the standard for sterility testing. 

Solutions for challenging sample types 
While cellulose ester membranes proved perfectly suited for most pharmaceutical products, permitting high filtration flow rates, it remained challenging to test antibiotics and other products with antimicrobial properties. The reason for this is that cellulose membranes host many analyte-interacting functional groups with the ability to bind antimicrobial substances, and this frequently gave rise to false negative results. This issue was solved in 1984 when Millipore introduced canisters with membranes made of low-adsorption PVDF (polyvinylidene fluoride). Some years later, a third type of canister was launched that possesses a broader scope of chemical compatibility with viscous products, for example, creams and ointments. These must usually be diluted in solvents such as isopropyl myristate (IPM) to improve filterability. 

When rapid sterility testing reached maturity 
An issue that pharmaceutical manufacturers have long had to deal with is the time needed for the compendial sterility test, which takes two weeks to complete. In particular, biologics such as cell and gene therapeutics cannot wait on hold that long. When rapid microbial detection techniques matured, Millipore developed the Milliflex® Rapid system. It uses ATP bioluminescence to detect tiny colonies long before they become visible to the naked eye. In common with the compendial Steritest® method, the rapid method is based on membrane filtration, which makes it easier to compare and validate as an alternative method. In addition to rapid sterility testing, the Milliflex® Rapid system, which is now in its second generation, can also be used for rapid bioburden testing along the entire processing chain to boost confidence in the sterility of short-life drugs.

Software-based guidance for full data integrity and traceability
More recently, automation and digitalization have opened up opportunities to improve microbiological QC tests with regard to traceability and data integrity, two requirements to which regulatory authorities are giving more and more attention. This led to the development of 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 and stores all relevant test data contemporaneously and automatically, ensuring 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 also reduces the likelihood of handling errors by the operator. The 21 CFR 11 compliant solution supports electronic documentation conforming to the ALCOA+ principles. This improves the workflow thanks to the digitalization features (barcode scanner, voice command) and reduces the burden that operators shoulder to avoid handling and documentation mistakes.

In addition, many smaller improvements
The culture that Bush and his pioneers established within the company is to stay on top of customer and regulatory demands by engaging closely with the pharmaceutical industry. Solutions are constantly being refined or adapted to new testing needs and settings. To cater for an ever wider spectrum of pharmaceutical compounds and containers to sample from, the past decades have seen an expansion of the portfolio of contaminant strains, accessories, fluids, and culture media. As sterility testing moved from the laminar flow hood to the isolator, initially double and then triple packaging of consumables was introduced. A cutting clamp was introduced to avoid scissor use in the isolator, and the canisters have been made accessible to safe sampling during incubation. Quality control demands are still increasing, so a key focus today is to ensure that the documentation made available to customers fulfills all requirements. It is similar for the manufacture of consumables: all sterility testing canisters are checked for their integrity, and additional in-process controls flank the manufacturing process—an example of how the Millipore pioneers’ philosophy of assuring reliability still guides their successors 50 years later.

Discover a complete solution

Share on:


Date Published: 10th June 2024

Source article link: View

View full company details

« Previous article
A Way to Reconcile Early





Tel: +[49] 6151 72-0

Email Supplier

View full company details

Related news from Merck