Tolerable Exposure Limits For Ethylene Oxide Sterilized Medical Devices
What is ethylene oxide sterilization?
Ethylene oxide (also known as EO or EtO) is a gas commonly used to chemically sterilize medical devices and products. 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. Sterilization by ethylene oxide kills microorganisms through exposure to ethylene oxide gas under vacuum and humidity. EtO is used either as 100% EtO or in combination with carbon dioxide. Please see our article on “Sterilization By Ethylene Oxide” for more information on EtO sterilization.
What are ethylene oxide (EtO) residuals?
The primary issue with using ethylene oxide for sterilization is its absorption into certain materials and its reaction with water or other material components to form toxic residual compounds.
Ethylene oxide residuals are:
- Ethylene oxide (EO or EtO)
- Ethylene chlorohydrin (ECH)
- Ethylene glycol (EG)
These residual compounds are hazardous both to people and to the environment. Ethylene glycol is formed from ethylene oxide and water reaction, while ethylene chlorohydrin is formed from the interaction of ethylene oxide and chloride compounds.
What is ethylene oxide residual testing, and why is it needed?
Ethylene oxide residuals are toxic and carcinogenic to humans at certain levels. Thus, products sterilized with ethylene oxide must meet strict ethylene oxide residual limits to keep patients safe during medical device and product use. Current ISO 10993-7 EtO residual limits can be found here. Limits are given for EtO and ECH. Products within the EtO and ECH limits also fall within EG limits. Devices undergoing ethylene oxide (EO) sterilization can fall into more than one EtO limit exposure category based on the duration of contact a medical device has with a patient.
What products require ethylene oxide residuals testing?
Any items sterilized using ethylene oxide that come in physical contact with a patient require EtO residuals testing. If your device or product isn’t in physical contact with the patient, there is no need to perform EtO residual testing.
If unsure, determine if your product requires ethylene oxide residuals testing HERE. If your device does require ethylene oxide residuals testing, determine which ethylene oxide extraction method is best for your device and find out how to prepare your samples for testing. If you need ways to reduce your ethylene oxide residuals to meet the required limits, please visit our article on key factors influencing EO residuals levels.
What are the key differences between USP 1115, USP 1116, and USP 1211?
USP 1115 covers nonsterile monitoring and manufacturing conditions that do not require the same restrictions and quality as the aseptic manufacturing conditions in USP 1116. USP 1211 covers the third type of sterilization process, terminal sterilization. Most terminally sterilized products do not undergo aseptic processing and instead meet the same sterility criteria as aseptically processed products through a final sterilization process that guarantees a quantifiable safety level. Terminal sterilization is much cheaper than aseptic processing. Thus, most products will meet FDA sterility requirements through nonsterile manufacturing followed by a terminal sterilization processing instead of aseptic processing.
How is ethylene oxide residual testing performed?
When determining the amount and type of EtO residuals in your medical device, two different methods are used for EtO residual analysis. Simulated-use extraction and exhaustive extraction are the EtO residuals testing methods. Evaluation of a device via both testing methods is not necessary. Use of either simulated-use or exhaustive extraction is sufficient to meet the ISO 10993-7 standards for EtO residual testing.
Simulated-Use Extraction For Ethylene Oxide Residuals
ISO 10993-7 states that simulated-use extraction evaluates “residue levels available to the patient or user from devices during the routine use of a device with water extraction to simulate product use.” This extraction method is used when only part, not the entire EtO sterilized device, will contact a patient. Thus, the simulated-use extraction will simulate the exposure of a patient to the fraction of the EtO sterilized device that the patient would interact with during normal product use. For large, surface-contacting devices (such as drapes or gowns), the EtO residual transferred to the patient may be estimated with a transfer reduction factor approach. The transfer reduction factor approach may be based on a weight or a surface-area-proportion basis (Annex E of ISO 10993-7). Additional information on simulated-use extraction for EtO and ECH can be found in our article on simulated-use extraction measuring methods.
Exhaustive Extraction For Ethylene Oxide Residuals
ISO 10993-7 states that exhaustive extraction involves the extraction of EtO “until the amount of EtO or ECH in a subsequent extraction is less than 10 % of that detected in the first extraction, or until there is no analytically significant increase in the cumulative residue levels detected.” This extraction method is best used when the entire device will contact a patient and estimates the majority of EtO residual that a patient would be exposed to during device use. Extractions are typically performed every 24-hours until the criteria for exhaustive extraction and device use (limited, prolonged, and permanent exposure) are met. For large or complex devices, exhaustive extraction may be impractical. In these instances, extracting representative portions of the device may be used to extrapolate the EtO residuals for the entire device. If the yield of the first extraction is tiny (as is the case with devices with little residue or devices that release analyte at a slow rate), continue extraction until the increase in the cumulative yield of the analyte extracted is small relative to the analytical uncertainties. MycoScience’s article on exhaustive extraction for EtO and ECH contains additional information on exhaustive extraction measuring methods.
Additional considerations for EtO residual testing parameters are listed at the bottom of our article “Simulated Use vs. Exhaustive Extraction.” This list of EtO residual testing considerations is explained in further detail here. Calculations for EtO residuals can be found here.
Tolerable Exposure Limit Calculations
EtO residuals are calculated in a variety of ways. Tolerable exposure (TE) is the calculated average daily dose tolerated without harmful exposure effects. TE is expressed in milligrams per day (mg/d). TE is the product of tolerable intake (TI), body mass (BW), and utilization factor (UTF).
Tolerable Limit Equation:
TE = TI x BW x UTF
Where:
TI = tolerable intake (mg/kg/d)
BW = body weight (kilograms (kg))
UTF = utilization factor
And:
UTF = CEF x PEF
Where:
CEF = concomitant exposure factor
PEF = proportional exposure factor
When BW is unknown, it is assumed to be 70 kilograms. As indicated above, the UTF is the product of a concomitant exposure factor (accounting for exposure to EtO from several devices) and a proportional exposure factor (accounting for situations where a device is not used for the entire duration of anticipated use). The concomitant exposure factor (CEF) and proportional exposure factor (PEF) are assumed to be 0.2 and 1, respectively.
The units for tolerable intake (TI) are mg/kg/d. TI values are derived from the scientific literature. The TI device limits from the 1995 edition of ISO 10993 have been retained for both the prolonged and permanent exposure categories due to the successful clinical history since adopting the 1995 EtO residual limits. Additional information about TI value derivation can be found in Annex G of ISO 10993.
Current EtO & ECH Tolerable Exposure Limits Are:
- 4 mg/d of EO and 9 mg/d of ECH for limited exposure (first 24 hours of exposure)
- 2.0 mg/d of EO and 2 mg/d of ECH for prologued exposure (1 day- 30 days of exposure)
- 0.1 mg/d of EO and 0.4 mg/d of ECH for prologued exposure (more than 30 days of exposure)
Summary
Overall, ethylene oxide sterilization is alternative to traditional thermal sterilization methods (like steam). However, ethylene oxide residuals (EtO, ECH, and EG) are toxic and carcinogenic to humans at certain levels. Thus, products sterilized with ethylene oxide that come in physical contact with patients must undergo ethylene oxide residual testing and meet strict ethylene oxide residual limits to keep patients safe during product use. When determining the amount and type of EtO residuals in your medical device, either simulated-use or exhaustive extraction is sufficient to meet the ISO 10993-7 standards for EtO residual testing. The simulated-use extraction method is used when only part, not the entire EtO sterilized device, will contact a patient. Thus, the simulated-use extraction will simulate the exposure of a patient to the fraction of the EtO sterilized device that the patient would interact with during normal product use. The exhaustive extraction method is best used when the entire device will contact a patient and estimates the majority of EtO residual that a patient would be exposed to during device use. Tolerable exposure (TE) is the calculated average daily dose (EtO and ECH) tolerated without harmful exposure effects. Current tolerable exposure limits for EtO and ECH are 4 mg/d of EO and 9 mg/d of ECH for limited exposure (first 24 hours of exposure); 2.0 mg/d of EO and 2 mg/d of ECH for prologued exposure (1 day- 30 days of exposure); and 0.1 mg/d of EO and 0.4 mg/d of ECH for prologued exposure (more than 30 days of exposure). All in all, ensure you choose a contract testing organization that can provide appropriate sterilization validations and ethylene oxide residual testing for your unique medical device and product needs.
Ethide Labs is a contract testing organization that specializes in Ethylene Oxide Residual Testing, Sterility Testing and Sterilization Validations. Ethide Labs also offers Bioburden Testing, Microbiology Testing, Bacterial Endotoxin Testing, Environmental Monitoring, Cytotoxicity Testing & Package Integrity Testing services for medical device companies and allied industries. Ethide is an ISO 13485 certified facility.
References
International Organization for Standardization. Sterilization of health care products- Moist heat- Part 1: Requirements for the development, validation, and routine control of a sterilization process for medical devices. Geneva (Switzerland): ISO; 2006. (ISO 17665-1:2006/(R)2016).
Irritation. Merriam-Webster Online Dictionary. 2020.
Michael J. Akers. Sterile Drug Products Formulation, Packaging, Manufacture, and Quality. Drugs and the Pharmaceutical Sciences. Informa Healthcare. 2010.
United States Pharmacopeial Convention. <1115> Bioburden Control of Non-Sterile Drug Substances and Products. Rockville, MD, USA. 2021. (USPC <1115>).
United States Pharmacopeial Convention. <1116> Microbiological Control & Monitoring of Aseptic Processing Environments. Rockville, MD, USA. 2021. (USPC <1116>).
United States Pharmacopeial Convention. <1211> Sterility Assurance. Rockville, MD, USA. 2021. (USPC <1211>).
