Parametric Release Programs vs. Ethylene Oxide (ETO) Residual Testing
What are sterilization and sterility?
Sterilization is any process that removes, kills, or deactivates all forms of life. Sterilization is related to the term sterile, which means a complete absence of viable microorganisms or microbes that have the potential to reproduce. Thus, sterile products that undergo sterilization are often chemically or heat sterilized after being placed in their final packaging. The chemical or heat sterilization kills any microorganisms inside the products (obtained during manufacturing and packaging). This chemical or heat sterilization process after final product packaging is known as terminal sterilization.
What is ethylene oxide?
Ethylene oxide (ETO) is a gas commonly used to sterilize medical devices and products chemically. The ETO chemical sterilization process is used on materials that cannot withstand traditional heat and steam sterilization methods.
What is a parametric release program?
Parametric release programs use robust manufacturing process controls to allow a finished product to be immediately released instead of going through end-product testing to establish a product batch’s sterility. For parametric release to be an option for your product, in-process manufacturing conditions must show that regulatory and process control acceptance criteria are attained and maintained throughout the manufacturing process. If the in-process controls can prove a certain level of sterility, no end-product sterility testing is necessary. Parametric release programs that are well-designed, validated, and controlled have a very low probability of microbial contamination. Indeed, the likelihood of a nonsterile unit (PNSU) is less than one in a million.
How do parametric release programs and ethylene oxide residual testing relate?
Parametric release programs use process controls to ensure that sterility acceptance criteria are attained and maintained throughout the manufacturing process. These process controls eliminate the need for post-manufacturing sterility testing of product batches. Sterilization methods that have been successfully used in parametric release processes to sterilize drug products, medical products, and medical devices in their primary package are moist heat, dry heat, gas (such as ethylene oxide), and radiation. While parametric release programs can offer time and cost savings (by eliminating the need for end-product sterility testing), they also require real-time data monitoring and acquisition systems in addition to in-process controls to ensure product sterility during processing. These in-process control and monitoring can be expensive to develop. Further, if any process in the parametric release program does not meet the acceptance criteria or data systems are unable to collect the data necessary to prove that in-process controls are being met, the processed product will need to be discarded. Traditional batch sterility testing cannot be performed on parametric release products that did not meet their in-process control criteria. However, well-designed parametric release programs have a probability of less than one nonsterile unit in a million, which exceeds the requirements needed for traditional batch-to-batch sterility testing.
Since ethylene oxide is a common sterilization method successfully used in parametric release programs, ethylene oxide residual testing is an imperative test to validate chemical sterilization processes for parametric release programs. ETO sterilized devices or products incapable of meeting ETO and ECH residual limits after sterilization will not be accepted by the Food & Drug Administration (and other governing bodies) for use. Thus, it is critical to confirm the consistent sterility of the product and confirm ETO residual levels for the product are within ISO standards for parametric release programs that use ethylene oxide sterilization methods.
ETO residual testing is specific to quantifying ETO and ECH residuals from ETO sterilized medical devices or products. Two different methods for ETO residual analysis are used to quantify the amount and type of ETO residuals in your medical device. These two methods for ETO residual evaluation are simulated-use extraction and exhaustive extraction. ISO 10993-7 standards for ETO residual testing are met if a device is evaluated via either simulated-use or exhaustive extraction. Evaluation of a medical device via both simulated-use and exhaustive extraction is not necessary.
Why are ethylene oxide (ETO) residual testing and parametric release programs important?
Viable microorganisms are of concern for the sterility of medical products since live microbes have the potential to reproduce in the human body, on the medical product surface, or within the medical product itself to cause sickness or disease. Sterility testing and sterility validation protocols ensure viable microorganisms do not exist or grow in medical products and keep patients safe throughout product use. Parametric release programs fulfill all USP 71 sterility requirements.
Further, parametric release process controls often exceed USP 71 sterility requirements since all manufactured products are passing the parametric release testing requirements, compared to a sampling of products being tested for sterility testing as a representative of the entire product batch. Due to the advantages of parametric release programs, parametric release programs are commonly used for medical product release and should be used instead of sterility testing when feasible. Note that the application of parametric release requires prior regulatory approval. Parametric release programs must demonstrate a PNSU of equal to or less than one in a million.
Regarding ETO residual testing, ETO sterilized materials vary in their ability to absorb, retain and release ethylene oxide (ETO). If your device isn’t in contact with the patient, there is no need to perform ETO residual testing. However, if your device is in contact with the patient, ETO sterilized devices are placed into one or more of three exposure categories based on the duration of contact a medical device has with a patient. These categories are designed to protect patients against ETO-related cellular toxicity that can cause varying degrees of illness and tissue damage. The classes of EO exposure are limited exposure (less than 24 hours), prolonged exposure (1 day to 30 days), and perpetual exposure (lifetime limit). Each category has specific limits (in milligrams) that must be met. You can find the specific ETO and ECH residual limits for each exposure category here.
Summary
Overall, both parametric release programs and ethylene oxide residual testing support the safety of medical devices or products after manufacture. These tests ensure that medical devices, medical products, therapeutics, and packaging are free from viable microbial contaminants or harmful ETO residuals. Ensure you choose a contract manufacturing organization that can provide appropriate testing options for your unique medical device or product needs.
MycoScience is a contract manufacturing organization that specializes in filling sterile syringes and vials for parenteral products. MycoScience also offers Sterilization Validations, Bacterial Endotoxin Testing, Preservative Efficacy Testing, Bioburden Testing, Cleaning Validations, Microbial Aerosol Challenge Testing, Accelerated Aging, Microbiology Testing, Cytotoxicity Testing, EO Residual Testing, Package Integrity Testing & Environmental Monitoring services for medical device companies, and allied industries. MycoScience is an ISO 13485 certified facility.
References
International Organization for Standardization. Biological evaluation of medical devices — Part 7: Ethylene oxide sterilization residuals. Geneva (Switzerland): ISO; 2008. (ISO 10993-7:2008).
Michael J. Akers. Sterile Drug Products Formulation, Packaging, Manufacture, and Quality. Drugs and the Pharmaceutical Sciences. Informa Healthcare. 2010.
United States Pharmacopeial Convention. <1211> Sterility Assurance. Rockville, MD, USA. 2021. (USPC <1211>).
United States Pharmacopeial Convention. <1222> Terminally Sterilized Pharmaceutical Products- Parametric Release. Rockville, MD, USA. 2021. (USPC <1222>).
