Corporate Partner Spotlight: EMD Millipore Corporation
Author: Anne Connors
Regional Marketing Manager-Environmental Monitoring/Media Fill Testing
EMD Millipore Corporation
290 Concord Road
Billerica, MA 01821 USA
Phone: +1 781.533.5438
Testing Final Products to Ensure Sterility and Patient Safety
Sterility and media fill testing are critical elements of quality control (QC) microbiology programs for compounding pharmacies. The tests are used to identify contamination of final products, which can be introduced in the production process by infected personnel, unclean surfaces and poor air quality. As such, robust sterility and media fill testing procedures should be implemented to minimize risk of product recall and ensure consumer safety.
Sterility testing is vital for monitoring all products that are purported to be sterile or need to be qualified for beyond-use-dating, according to USP <797>. A variety of sterility testing solutions exist, but test quality can vary and affect credibility of findings. False negative results may lead to the release of contaminated products, with potentially severe consequences for both patients and manufacturers. In addition, false positive results can result in lengthy and costly investigations, as well as possible product hold or rejection.
Membrane filtration is the traditional method for sterility testing of filterable products. The test is used for samples containing preservative, bacteriostatic or fungistatic compounds, which inhibit microbial growth of potential contaminants. When performing membrane filtration, microorganisms are retained by a 0.45-micron pore size filter and all inhibiting compounds are rinsed using an appropriate solution. Media are selected based on their ability to support the growth of anaerobic and aerobic microorganisms, and are transferred to the membrane filters.
One membrane filtration method, the Steritest™ system (EMD Millipore, Billerica, MA) allows the entire testing process, from aliquoting to reading, to be performed without exposure to the environment. There are no open containers or membrane manipulations, which eliminates bacteriostatic, fungistatic or bactericidal agents from being present in product formulation. The system therefore decreases the risk of adventitious contamination and false positive results.
The Steritest™ system can be used with standard Mixed Cellulose Esters (MCE) membranes for regular products, special low-binding Durapore® membranes (EMD Millipore, Billerica, MA) for products with inhibitory properties (e.g. antibiotics) or for applications with high chemical compatibility which require the presence of solvents.
Although standard membrane filtration is recommended for sterility testing, there are certain products that are not filterable or deformable. These products are normally tested using direct inoculation, which allows the test sample to be added directly into the required media, ensuring that the amount of sample is below ten percent of the total media volume.
The drawback of traditional microbiological methods for sterility testing is that they require a 14-day incubation period to obtain final test results. When releasing a product to market is dependent on a positive test result, a faster method is needed. One such method, the Milliflex® Rapid System (EMD Millipore, Billerica, MA) delivers sterility test results within five days. The system is based on the detection of adenosine triphosphate (ATP) with a bioluminescence reaction. When evaluated by the FDA Center for Biologics Evaluation and Research (CBER) in comparison with two other rapid sterility methods, results showed that the Milliflex® system was the most sensitive.1
Media Fill Trials
Media fill trials simulate the actual filling process as closely as possible, using media in place of the liquid pharmaceutical ingredients. The trials are performed to help validate or revalidate the robustness of aseptic manufacturing processes, demonstrating whether a product is likely to become contaminated in the filling process.
During trials, the media comes into contact with the same production line components that the product will eventually touch. In these studies, use of animal-based peptone media increases the risk of bovine spongiform encephalopathy (BSE) and transmissible spongiform encephalopathies (TSE), which can damage the product and affect consumer safety. As a result, use of vegetable media, which is guaranteed to be free of BSE/TSE, is increasing. Vegetable media allow growth of a broad range of microorganisms, similar to that of animal-based peptone media.
Preparation of culture media has traditionally been a cumbersome process. Culture media that is in powder form is difficult to handle and hard to dissolve, and increases exposure to airborne toxins and health risks. Dehydrated and granulated culture media are specifically formulated to minimize dust formation, component separation and clumping – even under warm or humid conditions. Granulation minimizes airborne toxins and allergens, results in enhanced personnel safety and protects facilities from contamination.
To further reduce risk, all media and rinse solutions used in the sterility testing process should be manufactured to the most stringent requirements. All Steritest ™ media and solutions have been formulated and tested to meet the requirements of the United States, European and Japanese pharmacopeias. Additionally, the solutions are manufactured in an ISO® 9001, environmentally controlled production center. Each lot is certified for pH, sterility and growth promotion using ATCC® strains specified by the United States Pharmacopeial Convention (USP), European Pharmacopoeia (EP) and Japanese Pharmacopoeia (JP).
Sterility and media fill testing are an essential part of any QC microbiology program to maintain the highest level of product quality and patient safety. The tests help ensure the final product is contaminant-free before it is released to market. Sterility and media fill testing are two of the strategies discussed in this four-part article series that compounding pharmacies can utilize as part of a robust QC microbiology program to effectively minimize risk and help support patient safety and positive outcomes.
Part one of the series
discussed the evolving regulations for compounding pharmacies and strategies companies can take to increase control in the sterile compounding process. USP <797> guidelines were written to allow for flexibility, which can be challenging when an organization is trying to define the right approach to QC. Additionally, the regulations governing compounding pharmacies are undergoing unprecedented change. To effectively deal with this evolving landscape, compounding pharmacies should identify the most stringent requirements possible and adhere to them to ensure final products comply with varying guidelines across states or countries.
In part two
, establishing and maintaining a robust microbiology sampling and testing program was discussed. An effective approach is one that includes a formal risk assessment and intimate knowledge of the product and processes that the compounding pharmacy is working with. Standard operating procedures, validation protocols and Corrective Actions/Preventative Actions (CAPA) must also be implemented and communicated to all employees.
The third part of the series
described the latest environmental monitoring technologies, which are an essential part of a QC microbiology program. Air and surface monitoring enable companies to identify contamination sooner and release products to market faster.
It is ultimately up to the company responsible for the final product to comply with laws and regulations, and observe industry standards. However, by establishing a more robust QC microbiology program, from identifying requirements through implementing environmental monitoring and sterility testing, companies can effectively increase control in the sterile compounding process, identify contamination faster, and improve the sterility testing of final products.
1 Parveen, S., Kaur, S., Wilson David, S.A., Kenny, J.L., McCormick, W.M, Gupta, R.K., Evaluation of Growth Based Rapid Microbiological Methods for Sterility Testing of Vaccines and Other Biological Products. Vaccine. 2011. 29: p. 8012-8013.