X-Rays for sterilization

Sterilization is a key process in medical device manufacturing and the pharmaceutical industry. Approximately 40-50% of single-use medical devices are sterilized with ionizing radiation, and probably more than 80% of industrial irradiation capacity is dedicated to sterilizing medical devices.

In the world of pharmaceutical production, the demand for pre-sterilized disposable materials (SUS, Single use systems) is growing rapidly but there are several factors that affect their availability.

Irradiation technologies

There are currently three main industrial irradiation technologies:

• gamma rays: based on Cobalt-60 (60Co) radioactive sources, this technology accounts for approximately 80% of the radiation capacity installed throughout the world;
• electron beam (e-beam): represents approximately 20% of the total capacity of radiation installed;
• X-rays: its application is increasing in the irradiation market.

Virtually all third-party sterilized SUS on the rapidly growing biotech market are now sterilized by Ƴ-rays from a cobalt-60 (60 Co) source. This process, however, is associated with a number of unique risks in the supply chain, ranging from the complex production of the radioactive isotope (The production process of Cobalt-60 occurs by exposing the stable isotope of cobalt, Cobalt-59 ( ^59Co), to a flow of neutrons within a nuclear reactor) to the restrictions and regulatory approvals for the handling and distribution of 60 Co, to the overall increasing demand for ionizing radiation to the need for fundamental requirements for accurate planning to long term. In this sense, the supply of 60 Co and the irradiation, although highly consolidated, are considered high risk. In order to ensure business continuity and mitigate risks, various Life Science experts have deemed it vital to explore alternative sterilization methodologies to support sustainable business continuity plans. SUS suppliers, for example, have said they need to implement alternative irradiation processes by Q4 2023 to continue to meet the current needs of the pharmaceutical industry. The alternative considered most valid today is represented by X-rays.

The potential of X-rays

A prospective analysis of the Ƴ-ray methodology used for the sterilization of Single-Use Systems (hereinafter referred to as SUS) for bioprocessing highlights increasing capacity limitations that could affect the supply chain and production continuity for a rapidly growing market by 2028. X-ray sterilization, now considered a mature technology, offers itself as a similar alternative to Ƴ-rays causing sterilization service providers to replan much of their future sterilization capacity. Qualifying alternative sterilization methodologies, in addition to addressing industry capacity constraints, offers greater flexibility to accommodate disruptions or peaks in demand.

Regulatory tools

For X-ray sterilization to truly offer a reliable and flexible solution for SUS sterilization, the industry needs to adopt a collaborative approach to the qualification and adoption of this emerging technology. In particular, a discussion and a common approach are needed for the evaluation of the impact of irradiation on polymers mainly used for the construction of SUS. In this regard, several discussions have taken place over the years between specialists and players in the pharmaceutical regulatory sector. From a regulatory point of view, in fact, the situation is still being defined. At the moment:

• Annex 12 of the EU GMP “Use of ionising radiation in the manufacture of medicinal products” does not mention X-rays as a technology to reduce bioburden or to sterilize materials, citing only gamma rays and e-beams. However, X-rays could be used in manufacturing processes in the pharmaceutical world as they have a similar principle of action (Compton effect with gamma rays).
• ISO 11137 part 1-3 “Sterilization of health care products – Radiation”, a standard frequently used in the pharmaceutical industry, contemplates the use of both X-rays and transitions from gamma rays to usable to support the implementation of X-rays as long as it does not contradict current regulatory guidelines.
• The European Pharmacopoeia, in Chapter 5.1.1 “Methods of preparation of sterile products”, mentions sterilization with ionizing radiation, referring to the absorption dose as >= 25 kGy but admitting the possibility of using other doses as long as the choice is justified and validated ensuring a SAL (Sterility assurance level) <= 10^-6.

The ISO 11137 tool

In this context, one of the key topics concerns the use of ISO 11137 as a basis for the evaluation of X-ray sterilization, the risk assessment for final product releases, the classification of impacts for the change of methodology. ISO 11137 is a relevant and agreed upon standard for the use of ionizing radiation to minimize the microbiological burden of medical devices. In addition to -Ƴ and e-beam, it covers requirements for the use of X-rays by providing detailed guidance on how to perform and validate the irradiation process with this technology. The standard also recommends close collaboration between the end user and the supplier of the materials in direct contact with the sterile solution of the product.

Following the requirements reported in ISO11137, SUS system suppliers have generated systems for assessing the risk associated with changing sterilization methodologies. Based on the requirements reported, there are three aspects that a SUS system supplier must evaluate to understand the extent of the impact of this change.

1. Source of Irradiation. Irradiation levels must be specified and the potential for inducing radioactivity in the product assessed (using literature and/or any additional tests considered critical).
2. Sterilization effectiveness. Evidence is required indicating that any differences in the operating conditions of the two irradiation sources have no effect on sterilization effectiveness. A test for effective dosage verification (irradiation power).
3. Physical impact. An evaluation is required to demonstrate that X-ray photons do not impact the physical properties of the materials and a comparison of the results with the same dose of photons generated by Ƴ-rays is required.

The evaluation of these aspects has resulted in a Testing strategy which requires SUS system suppliers to:

1. Test for potential physicochemical impacts on polymeric components
2. Test to establish the chemical-physical-microbiological impact following irradiation with a minimum dose (25 kGy)
3. Test to establish the chemical-physical-microbiological impact following irradiation with a minimum dose (40 kGy)

The list of tests defined by the main players and stakeholders (suppliers and users) of the Life Science market has been published and is applied based on an assessment of the criticality of the components used.

The main objective of the risk assessment – and therefore of the criticality of the components – is to demonstrate that the existing qualification data for Ƴ-ray irradiation can be directly applicable to X-rays as a worsening case. The HIGH (mandatory test), MEDIUM (only recommended test) and LOW (not required test) risk assessment and the test results are shared in a Validation package always available to users of SUS systems.

It is important to emphasize that if irradiation is performed external to the manufacturing site, the pharmaceutical manufacturer has overall responsibility for ensuring sterility and quality of the product.

The validation activities to switch from g-rays to x-rays must be defined through a risk assessment contemplating the use:

• Prior knowledge and supporting literature;
• Evaluation of radioactivity induction on irradiated material;
• Impact of the irradiation process on leachables and extractables (comparison with gamma).

Validation of the sterilization process must take into consideration:

• the definition of the process sterilization dose,
• the determination of the minimum and maximum acceptable dose,
• the evaluation of the influence of density,
• defining the monitoring strategy
• the evaluation of the production of impurities and the impact on the characteristics of the materials (e.g. brittleness), even some time after the irradiation process.

EMA’s position

EMA, through its Quality interest group, has also underlined strong attention on the use of X-rays as a sterilization methodology. In April 2023, for example, organized a meeting with representatives of the pharmaceutical industry and other stakeholders, in which various points were discussed including the EU GMP Annex 12, ISO 11137, Extractables & Leachables assessment and the need to make changes to the dossiers to implement this sterilization technique.

In November 2023, Quality interest published a document regarding Questions and answers on the use of X-ray sterilization processes applied to SUS that are used in manufacturing processes in the pharmaceutical world.