Bioresorbable polymers for medical devices encompass a broad class of materials with two of the more common materials being poly(L-lactic acid) and poly(lactic-co-glycolic acid). Some terminal sterilization processes may result in changes in materials properties, thereby significantly impacting the functional behavior of bioresorbable implants. Matching a terminal sterilization method to a bioresorbable implant requires the materials properties of the device to be considered as part of the product development process. Currently, there are several types of terminal sterilization processes in use for these polymers, including gamma radiation, e-beam radiation, and ethylene oxide (EtO). Sterilization with nitrogen dioxide (NO2) gas provides a room-temperature alternative that should be considered for this class of materials.
Sterilization of a bioresorbable device should be considered early in the product development process. Gas processes, like NO2 and EtO, require gas access to all surfaces of the bioresorbable device, which is typically achieved by incorporating a Tyvek® header or lid in the packaging. Mated surfaces may also affect the choice of a sterilization process. Additionally, the effects of any sterilization method on active pharmaceutical ingredients incorporated into the bioresorbable implant should be thoroughly understood. For any sterilization method, the factors that need to be tested during validation include, at a minimum, product sterility, device functionality (bioresorption rate and mechanical performance), and device biocompatibility.
Some of the more common changes in materials properties that are observed during terminal sterilization, include: reductions in molecular weight, in creased rates of hydrolysis (bioresorption), dimensional in stabilities, and measureable residual sterilant contamination. Radiation sterilization methods (gam ma and e-beam) commonly lead to a decrease in molecular weight, which, in turn, can affect the bioresorption rate of a device. Ethylene oxide sterilization can leave sterilant residuals in the polymer that require lengthy aeration, and the elevated temperature and humidity of EtO sterilization can lead to hydrolysis and heat-related damage. An alternative to EtO and radiation is nitrogen dioxide (NO2) sterilization, which provides a rapid, room temperature sterilization process. Several feasibility studies have demonstrated the benefits of NO2 sterilization for bioresorbable materials. The results from some of these studies are briefly presented here.
The principle objective of the sterilization process is the controlled reduction of contaminating microorganisms. A thorough review of this topic is provided by Byron J. Lambert, et al., in the article “Radiation and Ethylene Oxide Terminal Sterilization Experiences with Drug Eluting Stent Products,” published by the American Association of Pharmaceutical Scientists in AAPS PharmaSciTech, Vol. 12, No. 4, December 2011, in which they discuss the target sterility assurance level (SAL) for bioresorbable polymers. The demonstration of the SAL with the NO2 process is based on the population reduction of 106 spores of Geobacillus stearothermophilus (most resistant organ ism). For this test, approximately 106 microorganisms were directly applied to the bioresorbable polymer poly(L-lactic acid), PLLA, prior to exposure. As can be seen in Figure 1, the number of recovered viable spores was reduced as the duration of the NO2 exposure was increased. Furthermore, a concentration of 10 mg/L NO2 resulted in a more rapid rate of reduction in spore population as compared to a concentration of 3 mg/L NO2. These results indicate that the total duration of the NO2 exposure would be about 10 to 20 minutes for a complete sterilization process.
The NO2 gas sterilization process is carried out at room temperature, which is below the glass transition temperatures of bioresorbable polymers. This results in better dimensional stability than sterilization processes carried out at elevated temperatures. It has also been shown that the NO2 process does not alter the molecular weight or bioresorption time of the bioresorbable polymers. Devices made from PLLA that were exposed to the NO2 process exhibited no change in molecular weight, whereas similar samples exposed to radiation sterilization exhibited a significant reduction in molecular weight (roughly 50 percent reduction). The rate of bioresorption was evaluated by immersing samples of PLLA films in saline solution and recording film weights versus immersion time. PLLA samples exposed to the NO2 sterilization process did not exhibit a significant difference in the rate of mass loss as compared to unexposed control samples.
Given the results presented here, the NO2 sterilization process offers an alternative to EO and radiation methods. The rapid, room temperature, NO2-based process is an effective sterilant and is generally compatible with the bioresorbable implants. Furthermore, the low temperature of the NO2 process does not cause changes in the physical properties of the implant materials or in the dimensions of implants made from these materials.
This article was written by David Opie, PhD, Senior Vice President, R&D, Noxilizer, Inc., and Evan Goulet, PhD, Technical Applications Manager, Noxilizer, Inc., Baltimore, MD. For more information, Click Here
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