Ethylene Oxide Depyrogenation vs. Sterilization For Medical Devices
What is sterilization, why is it essential for medical products, What Is Ethylene Oxide Sterilization, And What is ethylene oxide depyrogenation?
Sterilization keeps patients safe from toxins and microbial illnesses when therapies or devices are consumed or used. Sterilization is any process that removes, kills, or deactivates all forms of life. Under the strictest definition of sterility, an item or product is sterile when there is the complete absence of viable microorganisms (bacteria, yeasts, viruses, and molds). For regulatory purposes, sterility is defined by acceptance criteria based on calculated contamination probability. An acceptable level of contamination risk for most items is the probability of a single contaminated product out of a million manufactured products. However, sterility criteria may be more stringent or lax depending upon the intended use of the medical device or product. Sterile products that undergo sterilization are often chemical (ethylene oxide sterilization), heat, or filter sterilized. Sterilization kills any microorganisms products collect during manufacturing. For chemical and heat sterilization, sterilization occurs after the product is placed in its final packaging. The product is often filtered and then aseptically filled into a sterile container for sterilization by filtration. So what is ethylene oxide sterilization and depyrogenation? Ethylene oxide sterilization processes involve the use of ethylene oxide gas, some pressure, and some humidity to chemically kill any viable microbes. Ethylene oxide gas at increased humidity and pressure can also remove endotoxins from products (a process called depyrogenation). While ethylene oxide is useful, ethylene oxide sterilization danger exists because ethylene oxide is toxic and carcinogenic to the human body at certain levels.
What is depyrogenation, and why is depyrogenation needed for sterile products?
Parenteral products must be sterile and pyrogen-free. Even if a product is sterile, it can still contain pyrogens. Depyrogenation is a process that removes pyrogens. The most prevalent and problematic pyrogens are the bacterial endotoxins found in the outer cell walls of gram-negative bacteria. Thus, depyrogenation is a process that will either destroy or remove bacterial endotoxins. Products can accumulate pyrogens from raw materials or other parts of the manufacturing process. The best pyrogen removal or destruction processes are product-dependent. Standard depyrogenation methods are dry heat, rinsing, and filtration.
What are pyrogens, endotoxins, and lipopolysaccharide (LPS)?
Pyrogens are any molecules or substances that cause a feverous reaction when they enter the human body. There are two primary pyrogen types. The most common pyrogen type is exogenous pyrogens, such as endotoxins from the cell walls of gram-negative bacteria. The endotoxins themselves are molecules with both fat components and complex sugar components. The presence of fat and sugar components is why endotoxins are also known in scientific literature as lipopolysaccharides (LPS). LPS is the biologically active portion of an endotoxin. In other words, LPS is the part of the endotoxin that triggers the innate immune system and causes illness in humans. Parenteral products and devices are contaminated with endotoxin through Gram-negative bacterial cells or cell wall fragments containing LPS. Lipopolysaccharide’s structure allows it to stick to hydrophobic (water-repellant) and hydrophilic (water-loving) surfaces. Thus, LPS components easily attach to molecules and proteins in solutions or material surfaces, causing endotoxin contamination. LPS also sticks to itself to form LPS chains known as aggregates.
What is ethylene oxide sterilization?
Let’s better understand ethylene oxide to further answer the question of what is ethylene oxide sterilization. Ethylene oxide (EO or ETO) is a gas commonly used to sterilize medical devices and products chemically. Ethylene oxide is a potent and highly penetrating alkylating agent. These characteristics make it an extremely effective sterilizing agent. However, at certain levels, ethylene oxide is also capable of causing cancer. Thus, there are real ethylene oxide sterilization dangers for patients if ethylene oxide residuals are not assessed. Sterilization by ethylene oxide kills microorganisms through exposure to ethylene oxide gas under vacuum and humidity. EO is used either as one hundred percent EO, a carbon dioxide mixture, or a mixture with other gasses.
How common is ethylene oxide sterilization?
Approximately 20 billion medical devices are sterilized with an ethylene oxide sterilization process each year. Thus, ethylene oxide sterilization processes account for about half of sterilized medical supplies in the United States.
What items can be sterilized by ethylene oxide?
Due to its low-temperature conditions, ethylene oxide sterilization processes are well suited for medical devices with embedded electronics and medical devices that cannot withstand steam (autoclave) sterilization. Ethylene oxide is also used to sterilize the personal protective equipment and drapes used by doctors and healthcare workers. Medical device types that are sterilized with ethylene oxide range from external wound dressings to implantable stents. Other devices include heart valves, vessel closure devices, catheters, and guidewires. Products combining devices, drugs, and biologics within a single item may also be sterilized using ethylene oxide. Ethylene oxide can sterilize almost every type of plastic. Standard materials sterilized with ethylene oxide are plastics, heat-labile materials (e.g., electronics), elastomer polymeric materials, and biomaterials.
What items cannot be sterilized with ethylene oxide, or are ethylene oxide resistant?
Ethylene oxide is not recommended for medical devices with embedded batteries due to the vacuum used during sterilization. Ethylene oxide sterilization processes are not recommended for materials sensitive to temperatures ranging from 30°C to 60°C or for medical devices made with materials that are sensitive to humidity. Polymers that are resistant to ethylene oxide sterilization are polyolefin resins such as polypropylene (PP), high-density polyethylene (HDPE), and low-density polyethylene (LDPE). Ethylene oxide resistant polymers often require higher levels of ethylene oxide exposure to be sterilized and thus pose a greater ethylene oxide sterilization danger to patients.
What is depyrogenation by ethylene oxide (EtO)?
Depyrogenation by ethylene oxide destroys endotoxins through lengthy exposure to an ethylene oxide gas combination under 50% humidity and low pressure. An example protocol for ethylene oxide depyrogenation is exposure to 12% ethylene oxide and 88% Freon at 50% humidity and 3.5 PSI gauge pressure for 6.5 hours.
Should you use ethylene oxide sterilization or depyrogenation for your sterile product?
The primary ethylene oxide sterilization danger is its absorption into certain materials and its reaction with water or other material components to form toxic residual compounds (ethylene oxide, ethylene glycol, and ethylene chlorohydrin). These residual compounds are hazardous both to people and to the environment. Ethylene glycol is an ethylene oxide sterilization danger formed from ethylene oxide and water reaction, while ethylene chlorohydrin is formed from the interaction of ethylene oxide and chloride compounds. Products sterilized with ethylene oxide must meet strict EO residual limits to keep patients safe during medical device and product use. Current ISO 10993-7 EO residual limits can be found here.
As mentioned earlier, ethylene oxide is not recommended for medical devices with embedded batteries due to the vacuum used during sterilization. Further, ethylene oxide should be avoided for materials sensitive to temperatures ranging from 30°C to 60°C or for medical devices made with materials that are sensitive to a humidity of less than 40%.
What are the similarities and differences between ethylene oxide sterilization and depyrogenation processes?
Ethylene oxide sterilization has fewer requirements and more flexibility than ethylene oxide depyrogenation processes. Traditional EtO sterilization methods may use EtO-carbon dioxide mixtures with an 8.5% concentration of EtO or EtO-hydrochlorofluorocarbons mixture of 8.6-10% EtO. In some instances, high pressures of 29 psi gauge are needed for sterilization protocols. Resting times for EtO sterilization range from 1-6 hours, and humidity ranges from 40-80%. With EtO sterilization, gas concentration can be increased to reduce EtO processing time. However, longer hold times at higher EtO concentrations are needed for depyrogenation. For example, one ethylene oxide depyrogenation method requires 12% ethylene oxide, 50% humidity, and 6.5 hours of holding time at that EtO concentration and humidity level. Ethylene oxide sterilization and depyrogenation processes are similar as EtO gas exposure occurs under vacuum and humidity. Also, both processes involve a lengthy degassing process to reduce EtO residuals on processed products.
Summary
Medical devices, products, and therapies must be sterile and pyrogen-free. Sterilization is any process that removes, kills, or deactivates microbes, whereas depyrogenation is a process that removes pyrogens. The most prevalent and problematic pyrogens are the bacterial endotoxins found in the outer cell walls of gram-negative bacteria. Ethylene oxide sterilization uses a combination of vacuum, humidity, temperature, and gas to sterilize materials at lower temperatures than dry heat or steam sterilization methods. Most medical devices can be sterilized with ethylene oxide. However, medical devices with embedded batteries may not handle the vacuum of ethylene oxide sterilization cycles. Ethylene oxide depyrogenation destroys endotoxins through lengthy exposure to an ethylene oxide gas combination under 50% humidity and low pressure. Alternative sterilization methods such as radiation or filtration may be needed if ethylene oxide methods are too extreme for product materials. While effective, ethylene oxide can result in toxic residuals. Thus, any ethylene oxide sterilized medical devices or products must undergo ethylene oxide residual testing to meet FDA requirements. Overall, ensure you choose a contract testing organization that can provide appropriate sterility, bacterial endotoxin, and ethylene oxide residual testing for your unique medical device or product needs.
Ethide Labs is a contract testing organization specializing in EO Residual Testing. Ethide Labs also offers Microbiology Testing, Bioburden Testing, Sterility Testing, Bacterial Endotoxin Testing, Cytotoxicity Testing, Environmental Monitoring & Package Integrity Testing services for medical device companies and allied industries. Ethide is an ISO 13485 certified facility.
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