How To Perform Sterilization Validations For Radiation Sterilized Products
How does the United States Food and Drug Administration (FDA) define sterile?
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.
What are sterilization validations, and why are they important?
Since the sterility of a medical device or product is based on acceptance criteria, the process that a product or device undergoes to become sterile must be validated to prove that sterility acceptance criteria are consistently met. Sterility can be assured only using a validated sterilization process under current good manufacturing practices (cGMP). Sterility cannot be demonstrated by reliance on periodic sterility testing of final products alone. Thus, sterilization validations are tests that accumulate data about a sterilization process and statistically prove that the sterilization process can consistently sterilize medical devices or products under “worst-case scenario” conditions.
What is radiation sterilization (sterilization by radiation)?
Sterilization by radiation is a non-thermal sterilization method that functions by destroying microorganisms in a product with gamma radiation, beta particles (electron beam), x-ray, or ultraviolet light. Other than sterile filtration, sterilization by radiation is the only other sterilization method that doesn’t rely on elevated temperature to sterilize. Sterilization by radiation is an excellent alternative for products that cannot be sterilized with heat or chemicals.
What items can be sterilized by radiation?
Items sterilized with radiation are the same as items that gaseous methods can sterilize. Standard devices and materials sterilized with radiation are plastics, heat-labile materials (e.g., electronics), and powders. Radiation damages the nucleoproteins of microorganisms and thus is not recommended for biologics.
How are radiation sterilization validations performed?
Radiation sterilization is accomplished by exposing products to a certain dosage of radiation. This dose of radiation is dependent upon the abundance and types of microbes on the product (product bioburden). As you may expect, a higher bioburden population results in higher microbial resistance to radiation sterilization, whereas a lower bioburden population has lower resistance to radiation sterilization. Thus, a higher bioburden will require a greater radiation dose to sterilize a medical device or product. Sterilization validations for radiation use a bioburden approach versus the traditional overkill approach used with most heat-based sterilization methods. Thus, the control and monitoring of product bioburden are vital for items that will be sterilized via radiation. Interestingly, biological indicators are not used for radiation sterilization validations because product bioburden and dosimetric measurements are more reliable. The activities performed and assessed for radiation sterilization validations are detailed below.
Validations for radiation sterilization processes assess the following activities:
#1: Dose Verification
Analysts use pre-sterilization bioburden controls and regular evaluations of manufacturing process effects on bioburden levels to keep up sterilization cycle efficacy. Increases in bioburden or bacterial spore populations could increase the radiation dose necessary to provide sterility. Indeed, the bioburden’s natural radiation resistance levels and concentrations allow analysts to extrapolate a radiation dose that produces only a single nonsterile unit in a million sterilized products. During dosage verification, the radiation dosage must match the actual bioburden of the products being sterilized.
#2: Product Material Compatibility
Once the minimum dose for sterility is determined, analysts often establish the maximum radiation dose by determining the highest likely dose that a product could experience during the radiation sterilization process. Radiation has initial and long-term effects on materials. Thus, some materials may appear unchanged immediately following radiation exposure and then deteriorate over time. Material compatibility studies should evaluate all materials exposed to the radiation for their functionality over the product’s intended use period. For pharmaceutical products, the material compatibility of the drug product and its primary container is of greatest concern post-radiation.
#3: Equipment Qualification
Gamma sterilization systems (and other radiation sterilization systems) require the initial and regular evaluation of software and equipment controls. Examples of radiation sterilization system controls include scan speed, source intensity, and system timers. Most radiation chambers have a conveyor belt system that moves products through the radiation sterilization cycle. Thus, equipment qualifications for machines that transport products are also required.
#4: Empty Chamber Dose Mapping
Empty chamber dose mapping is not always required to validate radiation sterilization processes. Open chamber dose mapping provides a useful performance baseline for the radiation sterilization system.
#5: Full Chamber (Load) Dose Mapping
Load dose mapping aims to determine the distribution of a radiation dose throughout the processed items (load items). When sterilized, products are arranged in containers, carriers, or pallets. Load dose mapping determines an item loading configuration that minimizes radiation dose variation across the product’s materials. Sterilized items are mapped using dosimeters positioned within the load undergoing sterilization (internally) and at strategic intervals within the radiation system (externally). With load dose mapping, the location of minimum dose exposure and maximum dose exposure within the group of sterilized items and within the radiation system can be identified. This dose mapping data support later routine monitoring of the sterilization process.
#6: Dosimetry Verification
Radiation sterilization relies on dosimetry for both initial development and ongoing sterilization process verification. Dosimeters give a local reading of the radiation level in a particular area of the radiation sterilization system. Dosimeters must be calibrated regularly to ISO standards to maintain their accuracy. Dosimeter calibrations should be documented both for initial sterilization validation and during routine sterilization process control and monitoring.
#7: Radiation Sterilization Process Confirmation
The primary aim of sterilization validation is to confirm the lethality of the radiation dose received by the products processed through the radiation-sterilizing equipment. Sterilization cycle efficacy is accomplished by replicating studies that prove the dosimetry results correspond to the required minimum radiation value for sterility assurance. Further, these studies must demonstrate that the maximum radiation dosage is not exceeded during the sterilization process.
How are routine monitoring and control of validated radiation sterilization processes performed?
Radiation sterilization process controls must be monitored and kept up to maintain validated status. The following practices must be maintained to keep radiation sterilization processes operating effectively:
- Personnel training
- Dosimeter and equipment calibration
- Physical measurements and data documentation
- Bioburden monitoring
- Change control system management
- Periodic radiation dose audits
- Equipment qualification and preventative maintenance
- Regular load dose mapping
Summary
All in all, medical product and device sterility can be assured only by using a validated sterilization process under current good manufacturing practices (cGMP). Sterilization validations prove that set sterility acceptance criteria (of one unsterile product in a million or less) are consistently met. Radiation sterilization is a non-thermal method of sterilization that functions through destroying microorganisms in a product with gamma radiation, beta particles (electron beam), x-ray, or ultraviolet light. Radiation sterilization is used for medical devices and products that cannot withstand chemical or heat sterilization methods. Radiation sterilization validations require assessment of the following activities: dose verification, product material compatibility, dosimetry verification, and overall statistical confirmation of the sterilization process. Overall, ensure you choose a contract testing organization that can provide appropriate sterilization validations for your unique medical device or product needs.
Ethide Labs is a contract testing organization specializing in Sterilization Validations & Microbiology Testing. Ethide Labs also offers Bioburden Testing, Bacterial Endotoxin Testing, EO Residual Testing, Sterility Testing, Cytotoxicity Testing, Environmental Monitoring & Package Integrity Testing services for medical device companies and allied industries. Ethide is an ISO 13485 certified facility.
References
United States Pharmacopeial Convention. <1229> Sterilization of Compendial Articles. Rockville, MD, USA. 2021. (USPC <1229>).
United States Pharmacopeial Convention. <1229.10> Radiation Sterilization. Rockville, MD, USA. 2021. (USPC <1229.10>).
