Keeping Up To Date With X-Rays

Gamma irradiation (using cobalt-60) is considered the standard method when it comes to sterilizing single use systems, but the high demand has caused supply issues. However, X ray sterilization can be used as an alternative. To help companies understand more, the Bio-Process Systems Alliance (BPSA) released a guide in 2021 titled: X-Ray Sterilization of Single-Use BioProcess Equipment, Part 1: Industry Need, Requirements & Risk Evaluation.

Now, the BPSA has released Part 2, which focuses on Representative Qualification Data. Readers can expect risk assessments, and data comparing X-ray and gamma irradiated components, generated by multiple component manufacturers for different types of single-use components and materials.

We spoke with Christopher Clark (Executive Director at the BPSA), James Hathcock (Director Regulatory and Validation Strategy at Cytiva), and Samuel Dorey (Principal Scientist Materials & Irradiations Product Development at Sartorius) to learn more. 

What are the problems with gamma irradiation?
 

It takes years to produce colbalt-60 radioisotopes needed for gamma irradiation, not to mention the associated high costs. Gamma irradiation also requires replacing 12.3 percent of the globally installed base per year to account for radioactive decay, whilst navigating the challenges of regulatory approval.

Supply chain management and forecasting needed to meet industry demand has been impressive to date. However, rapid spikes in demand – such as those seen during the COVID-19 pandemic – have made it clear the industry needs alternative technologies that can supplement the growing need and strengthen the overall security of supply for irradiation sterilization.  

The continued success and rapid growth of single-use technologies in bioprocessing relies on a robust irradiation-sterilization supply chain. Within our own companies, our sourcing partners suggested the only way to secure the irradiation capacity needed over the next 2-3 years was to embrace alternative (and now mature) technologies such as X-ray. An informed industry approach to qualifying alternative modes of irradiation sterilization may strengthen business continuity in the single-use industry, with the end goal of ensuring innovative patient therapies can be rapidly developed and delivered. 

This is not to say that gamma irradiation will go away. Instead, it will continue to be a part of the holistic irradiation capacity solution moving forward, which can be strengthened and complemented by X-ray.

What are the most important points covered in the BPSA guide?
 

To support the risk assessments needed for implementation, multiple BPSA member companies have been working to generate and share supporting data aligned to the science-based protocol outlined in part one. Data not only help verify the understanding that X-ray and gamma are equivalent, but also show how different labs, components, and suppliers can be summarized and interpreted. 

BPSA is not a standards organization; we do not set specific acceptance criteria for the testing results. However, we believe that sharing representative data and interpretations from different parties openly – as opposed to under confidentiality agreements – can help accelerate industry understanding and acceptance. The data include ISO 11137 standard requirements around the irradiation process, such as radioactivity (aka ‘activation’) and temperature effects, and the industry aligned test methodology to assess the suitability for use of single-use components.

What was covered in part 1? 
 

A holistic approach to the assessment and qualification of X-ray sterilization entails a fundamental understanding of the impact of X-ray on single-use materials and components — as well as an overall assessment of the final packaged assembly. 

In addition to establishing a cross-industry view on the types of testing that will best assess any potential risk, the working team identified specific tests (i.e., physical, functional, biological, and chemical) to be performed on representative components.

It is expected this risk and data-based assessment of materials and components used in the biotech single-use industry will support the strongly-touted arguments that X-ray is equivalent, or better, than gamma, thereby enabling much of the qualification data already in place for gamma to be leveraged as fully applicable to X-ray. For example, instead of performing animal-based USP <88> testing for biological compatibility, largely considered a requirement from which the industry is looking to move away, the BPSA team recommended non-animal-based cell culture testing associated with USP <87>. 

Similarly for extractables and leachables evaluation, an extremely costly exercise that has been a major alignment challenge for the industry over the past decade, the team agreed to recommend a rigorous, but rationalized risk based approach using USP <665> moderate level testing, to verify the impact of the irradiation technologies are equivalent.

Do you expect X-ray technology to be used increasingly in the future?
 

The simple answer? Yes.

Investments from different service providers in all major geographies show this as a major trend to complement existing sterilization technologies – this includes new X-ray sites in Europe, the Americas, and Asia. Furthermore, with the recent challenges in ethylene oxide emissions, public perceptions, and pending new restrictions, there is a concern that this market, equal in size to gamma irradiation, could add pressure on other forms of contract sterilization. Overall there continues to be strong and increasing global demand for sterilization spanning from food irradiation, medical devices and consumables, single-use, and so forth.

What were the biggest challenges in developing the guide?
 

The challenges, especially around timelines and sense of urgency were daunting!

Testing single-use components can be very costly, and, in some cases, can require up to a year or more. Suppliers felt they could more readily justify the business case to generate data for their newest products on the market, which – in reality – represented fairly low irradiation volumes than products already on the market. In addition, the testing needed to include a direct comparison of X-ray and gamma-irradiated materials could nearly double the cost of already expensive testing measures. And since the relationships between X-ray and gamma- irradiating test materials at a specific dose were not yet established, this was especially challenging.

Many biomanufacturers wanted to see noteworthy data as soon as possible, whereas the rate at which testing was completed and available was incremental. We also found that having only one or two datasets to scrutinize can easily lead to overinterpretation of small statistically meaningless variations in the data. 

I feel that we have addressed both of these with the most recent BPSA paper.

Additional concerns from biomanufacturers include regulatory acceptance requirements – with the subject of prior approval becoming increasingly concerning as the timeline progressed. In our case, we were very fortunate to be closely connected with BARDA. By working together with a small group of end users, suppliers, and industry subject matter experts, we were able to socialize the outputs of the first BPSA paper, representative supporting data, and end user risk assessment concepts with regulators, including the FDA Emerging Technologies Team, EMA Quality Innovation Group, and Japan PMDA. The feedback was largely supportive and has been shared with BPSA (1).

What else are you focusing on at BPSA?
 

Our focus is currently on how to best track and share X-ray qualification datasets from a large number of suppliers – and for an even larger number of single-use components. There is strong interest in monitoring successful implementations, as well as receiving additional regulatory feedback. 

There will also be papers coming out from BioPhorum, which share an elegant risk evaluation strategy based on the types of data expected from the first BPSA X-ray white paper, and how the components are used in actual biopharmaceutical manufacturing processes. This should be a complementary paper illustrating how the outputs of BPSA dovetail and feed well into the other. 

Certainly there are many other high-impact BPSA initiatives too, including responses to the REACH proposal to ban all PFAS materials – many of which are critical to the vast majority of medicines on the market (2). Other key initiatives include key guidance papers on integrity assurance for single-use systems, updates to the BPSA Quality Test Matrix, and efforts to ensure and improve sustainability in the biopharma sector.