X-ray sterilization: Understanding the science and the process of changing methods

Gamma sterilization has been used for more than 60 years in the terminal sterilization of materials, most notably medical devices and more recently the array of single-use sterile disposable plastic items used across different pharmaceutical processes.

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Radiation methods, like gamma, are straightforward processes to monitor, generally they have good process reliability, and process stability.

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In recent years, the use of gamma sterilization processes has become more challenging, based around the supply of cobalt-60 and regulatory requirements for transport and disposal of cobalt-60 (1).

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This has led to an increased focus on E-beam and X-ray sterilization (so-termed accelerator-based technologies). In this article, the focus is with X-rays. ?

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Ionizing radiation methods

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Radiation refers to the transmission of energy through space. This extends to microwaves, ultraviolet, electron beam (E-beam), gamma, and X-rays. Specific forms of radiation that strip away electrons - ionizing radiation - (modalities: gamma rays, X-rays, E-beam) – is the form used to terminally sterilize a product (2). The electron cascade is generally achieved by Compton scattering effects.

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Ionizing radiations interact with biological material causing an irreversible DNA degradation (it damages nucleic acids) (3). For this reason, they are generally suitable for inactivating microorganisms on and within materials.

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X-rays and gamma rays are types of radiation that incorporate or comprise the same elementary particle: the photon (4), albeit produced in different ways. Crudely, X-rays are emitted by electrons, while gamma rays are emitted by the atomic nucleus (5):

• Gamma rays arise from the nucleus of unstable atoms (radioactive isotopes) where energy is ejected in the form of electromagnetic radiation.
• X-rays originate from outside the atomic nucleus near the electron shells (bremsstrahlung radiation), where an external electron passes by an atom and undergoes a slight deceleration as it deflects, leading to the release of electromagnetic radiation.

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With photons, their energy is inversely proportional to their wavelength. As photons interact with a material this process creates free radicals (unpaired electrons) that undergo thousands of ionization events. The ionizing electrons are responsible for the radiation effects on an item (structural change and inactivation of biological material, causing sterilization).

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Producing X-rays

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X-rays for sterilization are produced using the bremsstrahlung process. This generates X-rays by directing 7.5-MeV electrons onto a dense, high-Z material such as tantalum. As the electrons are scattered by the target material atoms, a broad spectrum of X-rays is produced (6).

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Dose rate

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Dose rate is a key differential parameter between gamma, electron beam and X-ray. This affects processing time and the temperature profile.

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Dose rate is the quantity of radiation absorbed per unit of time (7).

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The quantity of radiation (the dose) is conventionally measured as kGy. The minimum dose provides and assessment of sterilization; the maximum dose requires a consideration of material computability.

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[The gray (Gy) is a unit of ionizing radiation dose, defined as the absorption of one joule of radiation energy per kilogram of matter. It measures the energy deposited by ionizing radiation in a unit mass of absorbing material and is used for measuring the delivered dose in radiation sterilization].

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The dose rate is assessed by dosimeters. The selection and use of these should be in such a way that they provide a quantitative measurement of the dose received by the item itself.

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X-rays, generated on absorption of high energy electrons (5–7 MeV) in an appropriate target, are used commercially for sterilization purposes (8). This is generally higher than with gamma radiation.

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Standards

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Gamma ray, electron beam, and X-ray sterilization methods are considered closely related and the applicable standards (11137-1 to -4) apply (9-12):

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Advantages of X-rays

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There may be some technical advantages for X-ray compared with gamma and e-beam in terms of better dose uniformity and less oxidative stress for certain polymers.? In addition, X-ray processing is suitable for irradiating items on pallets (whereas gamma requires items to be placed onto totes).

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Selecting X-ray sterilization

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When selecting X-ray (or another irradiation method) there are two central objectives:

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·???????? Microbicidal effectiveness.

·???????? Material compatibility.

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Microbial assessments are typically in the form of natural product bioburden followed by a sterility test. However, biological indicators can be used, such as Bacillus pumilus endospores (10^6 population). Microbial kill follows log-linear inactivation kinetics (13).

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Most studies infer that wherever a specified minimum radiation dose is delivered, the sterilization dose can be transferred between irradiation technologies in industrial sterilization of items without any impact on product sterility. What requires greater assessment is often material compatibility across the material shelf-life.

Change process

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Increasingly, pharmaceutical manufacturers are being notified of intentions to change sterilization methods away from gamma. Given that, in principle, any sterilization change could affect the final product safety and performance any proposal for change must be supported by scientific data and go through an approved change process.

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To assess a change:

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a)????? Undertake a supplier qualification.

b)????? Review the facility’s X-ray accelerator and installation and operational qualification documentation.

c)????? Review of the method of dose establishment, such as VDmax25 or VDmax20, based on item groupings and selected load configurations.

d)????? Ensure a qualification process is performed that can demonstrate that a given pallet configuration of a given density range can be successfully irradiated with X-rays, achieving the required dose range (typically a minimum of 25 kGy) and dose uniformity ratio.

e)????? Assessment of any potential induced radioactivity (a product safety consideration). The likelihood of this occurring relates to the materials being irradiated and the energy of the incoming photons.

f)?????? Assess the maximum dose. This needs to be set with consideration of the items subjected to sterilization and their specified functional requirements throughout the defined lifetime of the items. This requires an assessment of the dose rate and product temperature during irradiation.

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This process involves (14-16):

• Identifying specific polymers/elastomers used in products that present the greatest impact if transitioned to X-ray.
• Measure of any physical effects that these materials exhibit when they are given sterilization-level radiation doses from X-ray. One of the key risks is with extractables, which is the characterization of chemical compounds which have the potential to migrate from the irradiated materials into the drug manufacturing process.
• Determine whether these effects would preclude the use X-ray.
• Maximum dose can also affect the level of ozone generated during sterilization. This has the potential to carry adverse effects on product and packaging.

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Overall, risks tend to be greater at doses above 50 kGy.

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g)????? Assessment of the suitability of the routine monitoring of the dose audit processes.

h)????? Assess deleterious effects on the item across its shelf-life e.g. material stability, embrittlement (a consequence of oxidative effects, chain cleavage, or cross-linking), and color change.

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Important points to consider are:

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a)????? Grouping of similar materials to establish a product matrix. The rationale for this should be assessed.

b)????? Sterility validation of the items within each group.

c)????? A dose audit for each group.

d)????? Whether re-sterilization is likely (is the item likely to remain stable when resterilized?).

e)????? Factors that limit exposure: time, distance and shielding.

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A sufficient number of studies should be conducted in order to assess the reliability and robustness of the process.

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Summary

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This article has looked at X-ray sterilization, which is becoming more common within pharmaceuticals and healthcare in relation to single-use technologies. Many of these items will have been previously qualified with gamma radiation and hence a change assessment and approval process is required. Some of the points raised here will assist in developing this form of change control.

Dr. Tim Sandle is a pharmaceutical microbiologist and the creator of Pharmaceutical Microbiology Resources.

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References

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1.????? van den Brink S, Kleijn R, Sprecher B, Tukker A. Identifying supply risks by mapping the cobalt supply chain. Resources, Conservation & Recycling. 2020; 156: 104743

2.????? Ryan, Julie (2012) Ionizing Radiation: The Good, the Bad, and the Ugly. The Journal of Investigative Dermatology. 132 (3 0 2): 985–993

3.????? McEvoy B, Michel H, Howell D, Roxby P. X-ray: an effective photon. Biomed Instrum Technol. 2020; 54( suppl. 1): 23– 30

4.????? Sato, Y., Takahashi, T., Saito, T. et al. (1993) Sterilization of health care products by 5 MeV bremsstrahlung (X ray), Radiation Physics and Chemistry, 42 (4-6):

5.????? Volume 42, Issues 4–6: 621-624

6.????? Denny PP, Heaton B (1999). Physics for Diagnostic Radiology. US: CRC Press. p. 12

7.????? National Academies of Sciences, Engineering, and Medicine; Division on Earth and Life Studies. Radioactive Sources: Applications and Alternative Technologies, National Academies Press (US); 2021.

8.????? Hansen J, Fidopiastis N, and Bryans T, et al. Radiation sterilization: dose is dose. Biomed Instrum Technol. 2020; 54( suppl 1): 45– 52

9.????? Grégoire O, Cleland MR, and Mittendorfer J, et al. Radiological safety of medical devices sterilized with X-rays at 7.5 MeV. Radiation Physics and Chemistry. 2003; 67( 2): 149– 67.

10.? ISO 11137-1:2006 (R2015)/A2:2019. Sterilization of health care products—Radiation—Part 1: Requirements for development, validation, and routine control of a sterilization process for medical devices

11.? ISO 11137-2:2013/(R)2019. Sterilization of health care products—Radiation—Part 2: Establishing the sterilization dose. Arlington, VA: Association for the Advancement of Medical Instrumentation

12.? ISO 11137-3:2017. Sterilization of health care products—Radiation—Part 3: Guidance on dosimetric aspects of development, validation and routine control. Arlington, VA: Association for the Advancement of Medical Instrumentation

13.? ISO TIR13004:2013/(R)2016. Sterilization of health care products—Radiation—Substantiation of a selected sterilization dose: Method VDmaxSD. Arlington, VA: Association for the Advancement of Medical Instrumentation

14.? McEvoy, B., Maksimovic, A., Howell, D. (2023) Studies on the comparative effectiveness of X-rays, gamma rays and electron beams to inactivate microorganisms at different dose rates in industrial sterilization of medical devices, Radiation Physics and Chemistry, 208: 110915

15.? Fintzou AT, Kontominas MG, Badeka AV, Stahl MR, Riganakos KA. Effect of electron-beam and gamma-irradiation on physicochemical and mechanical properties of polypropylene syringes as a function of irradiation dose: study under vacuum. Radiat Phys Chem. 2007; 76(7): 1147-1155

16.? Croonenborghs B, Smith M, Strain P. X-ray versus gamma irradiation effects on polymers. Radiat Phys Chem. 2007; 76(11–12):1676-1678

17.? Kroc T. Monte Carlo simulations demonstrating physics of equivalency of gamma, electronbeam, and X-ray for radiation sterilization. Radiat Phys Chem. 2023; 204:110702