Radiation sterilization utilizes the lethal effect of various forms of radiation as a means of microbial destruction. Ionizing radiation (gamma, x-ray, or beam) sterilization is used extensively for the sterilization of medical devices and for a variety of other materials and products. Nonionizing sterilization methods such as microwave, infrared, x-ray, and ultraviolet light may be useful but have more restricted application, and are outside the scope of this chapter. This chapter provides an overview of sterilization using ionizing radiation and its validation, including dose setting, material compatibility, and dose verification.

The effects of radiation on materials can be substantial and are a major consideration when manufacturers select radiation as a processing method. The advantages of sterilization by irradiation include simplicity, absence of mechanical complexity, reproducibility, and overall efficiency. In fact, radiation sterilization is unique because the basis of control essentially is the absorbed radiation dose, which can be precisely measured. Methods used to establish appropriate radiation doses to achieve the desired sterility assurance level are defined in ISO 11137-1 Sterilization of Health Care Products; ISO 11137-2 Sterilization of Health Care Products—Radiation—Part 2: Establishing the Sterilization Dose; and ISO TS 13004: 2013 Sterilization of Health Care Products—Radiation—Substantiation of Selected Sterilization Dose: Method VDmaxSD. These methods include Method 1, Method 2A, Method 2B, and Method VDmax, which differ in the specific testing scheme and the number of articles that are needed for testing and are based on certain assumptions about bioburden. The use of a biological indicator is inappropriate during radiation sterilization validation because (a) there are accurate correlations between dose measurement and microbial destruction for a wide range of microorganisms and (b) the established dose setting methods are based on the material's bioburden in its natural state. These correlations have been developed by the medical device industry and provide a direct methodology for process control. Dosimetry plays a central role in radiation sterilization and serves as a direct means for affirming process lethality. The radiation dose measured in kGy (formerly MRads) is directly related to the lethal effects of the radiation on microorganisms. The measured dose has the same utility as F0 in steam sterilization. Routine process control for radiation sterilization is provided by one or more reference dosimeters on the exterior of the packages (after dosimeters have been correlated during validation with dose measurement inside the package). The robustness and reliability of the absorbed dose of the article to be sterilized can support parametric release, as described in Terminally Sterilized Pharmaceutical Products—Parametric Release 1222, for many items.

Gamma sterilization entails the use of a specifically designed facility where items to be sterilized are exposed to a Co60 radiation source in a manner that ensures uniform dosing. Highly penetrating photons (gamma rays) are emitted from Co60 as it decays to Ni60. The half-life for this isotope is 5.27 years, which means that over the course of each year the source loses about 12% of its radioactivity. This steady reduction in radioactivity requires that radiation process operators adjust their process controls (typically exposure time) to maintain the established dose required. Periodically, additional Co60 is required to maintain practical throughput.

X-ray sterilizers generate highly penetrative photons similar to the gamma photons from Co60 irradiators. X-ray photons are generated when accelerated electrons impact a target such as tantalum. These systems rely on scanning of materials with x-ray photons in order to sterilize them. Properly maintained, these systems are able to deliver a constant dose over time. No local radioactive source is required for x-ray sterilization systems.

Electron beam systems rely on scanning of objects with focused electrons to sterilize the items within a defined radiation field. Properly maintained and controlled, these systems deliver a constant dose, so there is no change in dose with respect to time. The principal advantages of electron beam sterilization are a much higher dose rate and the absence of a localized radioactive source. These systems can be installed and operated by the end user. Electron beam penetration is substantially less than that obtained with photons, and therefore dose mapping is critical to ensure that items of varying density and complexity are properly sterilized. Because of the high dose rates used with electron beam sterilization, some materials can experience significantly higher temperatures than the same materials would experience in Co60 irradiation.

Cycle development for radiation requires the identification of an appropriate radiation dose for the objects and confirmation that the dose does not adversely affect the material's essential quality attributes. In other words, analysts should identify the minimum sterilization dose as well as the maximum dose the material can withstand without negative effects. With this information analysts can set the dose for a specific radiation sterilization application.

Dose setting or dose establishment typically is achieved by following one of the ISO methods. These are Method 1, Method 2A, Method 2B, and Method VDmax. The choice of the most appropriate method depends chiefly on production batch size, knowledge of the normal bioburden, and the material's sensitivity to radiation. Dose mapping plays an important role through the cycle development and dose-setting exercise.