Medical Device Sterilization Modality Selection Decision Process

The process of choosing a sterilization modality for a medical device is an important element of development of the product, and an important aspect of an effective and efficient end-to-end sterility assurance process. Choosing a nonoptimal sterilization modality can lead to several problems, including failure to ensure adequate product/device/drug or biological component sterilization that could result in harm to patients. Compromised functionality may also occur, which could negatively impact the ability of the device/drug or biological component to deliver the desired clinical outcomes or therapy. Nonoptimal sterilization processes could also involve complex validations, which could translate to wasted resources and delays in product launches. All of these issues could lead to extended, expensive regulatory review and potential nonacceptance in various regions.

This article explores the main considerations for selecting a sterilization modality and demonstrates the modality selection process through various examples. More detailed considerations of sterilization modality selection—including specific details of product design, logistical, and safety concerns of various modalities, speed to market, and economic considerations—are left to a future publication.

To optimize development time and costs, sterilization modalities contained in the Food and Drug Administration (FDA) guidance titled Submission and Review of Sterility Information in Premarket Notification (510(k)) Submissions for Devices Labeled as Sterile¹  are highly recommended. These modalities include established Category A (dry heat, ethylene oxide, moist heat, and radiation), established Category B (hydrogen peroxide, ozone, and flexible bag systems), and novel sterilization modalities, such as vaporized peracetic acid, high-intensity or pulsed light, microwave radiation, sound waves, and ultraviolet light. Considering the advent of more complex products and combination products, new novel sterilization modalities and the combination of sterilization technologies may need to be considered.

Several key considerations must be evaluated when selecting a sterilization modality. The first question that must be asked is “How is this product used?” Understanding the intended use of the product, and how it comes into contact with a patient, determines whether or not the product requires sterilization. This determination is based on the risk of transmission of infection from the device under consideration. For example, a product that only comes into contact with uncompromised skin, such as a skin electrode or stethoscope, are classified as noncritical and may not require sterilization, but may only need validated processes for cleaning and disinfection.²  A product that comes into contact with the bloodstream or other sterile areas of the body requires sterilization.² 

Detailed understanding of the product materials and design features is necessary to enable selection of an appropriate sterilization modality. Conditions present in various sterilization modalities can negatively impact product and packaging functionality; therefore, thorough understanding of sensitivities to heat, moisture, ionizing radiation, certain chemicals, oxidation, and pressure changes is critical when selecting a sterilization modality. Ultimately, the potential for a sterilization process to negatively impact the ability of the device to provide its intended patient care needs to be completely understood.

Understanding how the product is manufactured (e.g., extruded, 3D printed, injection molded, chemical processing) is also key to understanding potential sensitivities. For example, devices containing polymers manufactured with a high degree of residual stress from manufacturing may be more susceptible to damage from the effects of sterilization.³  Chlorine-containing chemicals used in manufacturing may result in high levels of residual ethylene chlorohydrin for ethylene oxide–sterilized products. For devices that are reprocessed, impacts related to multiple cleaning and sterilization cycles must also be understood.

Ideally, the person responsible for selecting the sterilization modality should begin to work closely with the product design engineers early in the design process to ensure proper evaluation of all potential product sensitivities. If the product design is conceived with sterilization in mind, this can minimize design failures and rework later during the product development process. The person responsible for selecting the sterilization modality should request a sample device or sample components/materials as they become available in order to have hands-on interaction with the device and its packaging. This hands-on interaction allows for a better understanding of features of the device that may pose a challenge to and/or be impacted by sterilization. The person responsible for selecting the sterilization modality should also gain a clear understanding of whether there is opportunity to change the design of the product, if necessary, to ensure that the device can be sterilized. Early involvement by sterilization experts is key to avoiding time-consuming and costly design changes later in the development process, such as when a sterilization modality is determined to negatively impact the product's intended use after the design elements have been selected.

Various design changes to improve compatibility and potentially enable sterilization should be considered when compatibility issues arise. This consideration may include changes in:

• Design: E.g., packaging devices in a low-oxygen environment to reduce impacts of oxidative degradation during sterilization, or packaging devices in a low-temperature environment (e.g., ice packs) to reduce thermal degradation during sterilization.

• Material: Consider removing, replacing, or altering materials impacted by sterilization (e.g., including additives such as antioxidants or stabilizers to enhance radiation resistance of certain materials; this may be accomplished by working with material suppliers).⁴ –⁶ 

• Manufacturing: E.g., reduction of bioburden to enable lower radiation dose.

An alternate sterility assurance level may also be considered, per AAMI/ANSI ST67,⁷  to reduce the impact of sterilization on product functionality. Such consideration is based on an assessment of the risk of harm due to a nonsterile product compared to the benefit the product provides.

The following section provides six examples of product evaluation for sterilization modality selection as described above. The flowchart in Figure 1 provides a decision tree for choosing commonly used sterilization modalities. While sterilization modality selection involves more complexity than shown in Figure 1, this flowchart presents a high-level thought process for sterilization modality selection. Figures 2 to 7 show examples of how the flowchart in Figure 1 may be used to select a sterilization modality for various devices. The functionality aspects listed in these examples are not exhaustive and do not go into detail regarding potential design changes that could enable successful sterilization, but are meant to provide examples of the connection between patient care and device characteristics impacted by sterilization.

The example shown in Figure 2 demonstrates the modality selection process for a chemical ice pack. The product is used for treatment of swelling due to injury, and only has contact with intact skin. Therefore, based on the intended use and mode of patient contact, sterilization for this device is not required.

The example shown in Figure 3 demonstrates the modality selection process for a silicone breast implant. This product is used for breast augmentation and/or reconstruction through implantation in a patient. Because of the mode of patient contact, sterilization is required. The device materials consist of a silicone shell filled with silicone gel. The product can withstand temperatures of up to 250°C for up to 48 hours and can withstand pressures as low as seven pounds per square inch (absolute). The critical functional aspects of this product include joint integrity, breaking strength, and elongation, which are negatively impacted by ionizing radiation. Therefore, moist or dry heat may be selected. Gaseous sterilization may be an option, but pressure limitations will restrict the modality or cycle parameters.

The example shown in Figure 4 demonstrates the modality selection process for a ureteral stent and delivery system. This product is delivered through the urethra and bladder and implanted in the ureter to maintain flow of urine between the kidney and bladder. Key requirements of this device include flexibility and lubricity to enable navigation of the stent and delivery system through the relevant anatomy. The stent portion of this device is implanted within a patient's ureter, thus requiring sterilization. The stent delivery system also requires sterilization as it is used to place the stent within the ureter. The product materials include three polymers and a hydrophilic coating. Moist or dry heat sterilization is not possible, as polymers comprising the device experience softening at temperatures above approximately 50°C, and the coating functionality is negatively impacted by high humidity. Radiation sterilization is not possible because of the risk that the polypropylene component flexibility will be negatively impacted at the radiation doses of 25 kGy to 50 kGy typically used in medical device sterilization.³  Ethylene oxide sterilization is selected as a suitable method, with temperature and humidity conditions confirmed not to impact product functionality.

The example flowchart for a prefilled vaccine syringe is illustrated in Figure 5. Because the vaccine is intended for parenteral use, product sterility of both the syringe and contained vaccine is a strict requirement. While the materials of the syringe components could withstand various sterilization modalities, the prefilled vaccine syringe in its final configuration could not undergo a terminal sterilization process because all the terminal sterilization modalities (heat, ionizing radiation, gas) would negatively impact the quality of the vaccine. Heat and ionizing radiation, for instance, could cause degradation of the drug substance. Gaseous sterilization would not be able to penetrate the prefilled syringe. As a result, aseptic processing is the sole viable option to reach a sterile product.

The example flowchart for a flexible irrigation bag is illustrated in Figure 6. The saline irrigation solution is used to exert a mechanical cleansing action for the irrigation of body cavities, tissues, or wounds and for washing, rinsing, or soaking surgical dressings, instruments, and laboratory specimens. Because the irrigation solution is used to clean and irrigate open wounds, or to rinse other sterile medical devices, the sterility of the product is strictly required. The final product includes the solution on one side and the container-closure system, made of flexible polymeric materials, on the other side. Because of the nature of the polymeric container material, the product is not suitable for dry heat sterilization as the high temperature ranges (typically 150°C to 250°C) encountered in a dry heat sterilization process would impair the functionality of the container-closure system. While dry heat temperatures are not suitable for this product, the temperature (typically 110°C to 135°C), moisture, and pressure ranges encountered in a moist heat sterilization process are confirmed not to affect product functionality.

The product configuration of the flexible irrigation bag includes an impermeable, nonbreathable primary packaging. Therefore, gaseous sterilization is not possible for this product because the gas would not be able to reach the solution.

While the relatively high density of the flexible irrigation bag might make this product unsuitable for sterilization with all ionizing radiation sterilization processes (electronic beam in particular might be a challenge), the dose ranges encountered in various ionizing sterilization processes are suitable for the polyvinyl chloride container material and the saline solution. An ionizing radiation sterilization process such as gamma or X-ray could be selected for the sterilization of the flexible irrigation solution bag. While both moist heat and ionizing radiation modalities provide the same level of sterility assurance, sterilization by heat has a lower risk for impacting the materials (e.g., moist heat does not introduce radiolysis impurities). For these reasons, moist heat is given priority over ionizing radiation in the decision process.

The example shown in Figure 7 demonstrates the modality selection process for a reusable flexible endoscope that is used for therapeutic and diagnostic applications. Because these devices are reusable, the healthcare facility is responsible for processing them through cleaning, disinfection, and/or sterilization per validated methods provided by the manufacturer. It should be noted that device compatibility with cleaning and disinfection methods must be considered along with compatibility with sterilization modalities.

As flexible endoscopes contact nonsterile pathways such as the mouth, throat, and colon, sterilization is not strictly required, and cleaning and high-level disinfection may be acceptable. However, the classification of these devices is a subject of ongoing debate. Because of the potential for exposure to blood and tissue during critical applications, sterilization may be pursued for these devices. If sterilization is selected over disinfection, only low-temperature gas sterilization methods are possible (including ethylene oxide, vaporized hydrogen peroxide, and vaporized hydrogen peroxide with ozone) because these devices are temperature sensitive. Radiation sterilization typically is not available for sterilizing reusable devices in healthcare settings.

Each low-temperature gas modality presents potential issues for sterilization of reusable flexible endoscopes. Ethylene oxide is not commonly used for reusable devices because of relatively long cycle times, safety concerns around sterilant residuals left on the device, and material compatibility issues resulting in loss of required device flexibility.⁸  Vaporized hydrogen peroxide methods present material compatibility problems with flexible endoscopes after several reprocessing cycles; so, while these methods may be an option, the number of times a device is reprocessed may be limited. Therefore, there is a need to explore additional, potentially novel, sterilization modalities or changes in device design in order to improve material compatibility if sterilization is to be pursued.

The ability of a medical device to provide its intended patient care—including the intended use and functional requirements of the device—is the foundation for all decisions concerning sterilization modality selection. It is therefore critical to gain a detailed understanding of how the product interacts with the patient, as well as how the sterilization modality will interact with the product. Understanding key elements of the product design, such as details of the materials and design configuration, is critical in making this assessment.

The author thanks Andre Tuggles, Emily Craven, Phil Cogdil, Vu Le, Patrick Weixel, Alpa Patel, George Ngatha, Neville Niessen, Melissa Escobeda, Brian McEvoy, Joyce M. Hansen, and Jeff Nelson for their contributions to this article.