MANUFACTURING
Meissner Consulting GmbH, Munich, Germany
How X-ray works
X-rays are generated using high powered beams from electron accelerators. Electron accelerators function in a similar way to large cathode ray tubes in old fashioned TVs. They accelerate electrons from a plasma around a filament using electric fields to the desired energy (or speed). Hence their radiation can be turned on and off. To generate X-rays, the electron accelerator needs to be equipped with an X-ray converter. The X-ray converter is designed to stop the accelerated electrons and is typically a water cooled tungsten or tantalum plate in an appropriate mechanical assembly. A lot of heat is generated and the primary engineering concern for X-ray converters is to maximise the X-ray production and minimise the thermal challenge.
Available systems
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Figure 1: Schematic view of the processing area.
(click image to enlarge) |
The most efficient X-ray systems are designed specifically around a product handling system. An optimised design will bring the cost of X-ray sterilisation into the gamma sterilisation range. Neither of the two existing industrial systems in Germany and the United States (US) is currently sterilising medical devices. Figure 1 shows a view of the processing area.
Much more common are electron beam (e-beam) facilities that have an X-ray converter as an add-on. Although these facilities could offer excellent dose uniformity properties, they are not designed for efficiency. Most of these facilities use the X-ray converter only occasionally and use direct e-beam for generating cash flow. Facilities of this type can be found in the US, Germany, Japan, Russia and Iran.
Industrial use
X-rays have similar properties to gamma rays. In addition, X-rays are created by a machine source that can be turned on and off. Dose uniformity with X-rays is excellent and clearly sufficient for complete pallet sterilisation. All the product handling methods that are used for gamma sterilisation could easily be adapted for X-ray sterilisation. Hence, X-rays avoid the challenges posed by e-beam irradiation such as complex dose validation, packaging considerations and missing pallet integrity.
The flexibility of X-rays is the most compelling reason to use this sterilisation method. In gamma sterilisation, source loadings are prepared by detailed calculations on where to place the source pencils. Then the configuration of active and not-so active pencil locations (and hence the radiation field) is fixed until the next source loading, which may be one year later. X-ray beam configurations, however, can be changed literally by a mouse click. The e-beam intensity distribution on the X-ray converter is changed according to prevalidated settings and within an instant the desired radiation field intensity in the treatment room is uploaded.
The radiation field of an X-ray system is smaller and the dose rate is higher than with gamma. The X-ray converter is typically between one and two metres long and irradiates the product from the side in efficient industrial facilities or from the top. The product is exposed to the radiation field for less time than during gamma sterilisation and negative material effects are reduced. The smaller radiation field also allows better temperature control during the irradiation.
The capital expenditure of X-ray systems is still high compared with gamma irradiators. The direct operating expenses, however, may be lower for the same production capacity. If designed for high volume sterilisation of low cost medical products, X-ray sterilisation is only competitive for large systems.
X-ray sterilisation of drug–device combination products is a promising application. Here, the value of the product is high. Because the pharmaceutical product typically has a low tolerance for radiation and temperature deviation, dose uniformity and fast processing is of utmost importance. E-beam facilities with add-on X-ray converters typically provide excellent dose uniformity ratios (Dmax/Dmin = 1.01). Typically, a small batch of X-ray products can easily be integrated into the normal production. This precision sterilisation is seldom available in gamma irradiators. The much improved dose uniformity control is a strategic advantage and justifies in many cases the slightly higher sterilisation cost.
Regulation of X-ray sterilisation
ISO 11137: 2006, Sterilisation of Health Care Products, and also the previous version, ISO 11137: 1995, stated specific requirements for X-ray, but there is no mention of it in EN 552:1994, Sterilisation of Medical Devices, Validation and Routine Control of Sterilisation by Irradiation. There was a need to harmonise ISO 11137 and EN 552. The updated and harmonised ISO 11137: 2006, Part 1, is now effective and states specific requirements and guidance for using X-rays as the sterilisation agent.
Although EN 552 may still be used for existing sterilisation centres during a transition period, all new sterilisation processes should be validated according to ISO 11137: 2006, which harmonised EN 552 and ISO 11137: 1995. This is, of course, true not only for X-ray sterilisation, but also for gamma and e-beam sterilisation. Hence, the standards that apply for X-ray sterilisation are
- EN ISO 11137-1, Requirements and Guidance
- EN ISO 11137-2, Establishing the Sterilisation Dose
- EN ISO 11137-3, Guidance on Dosimetric Aspects.
It is not within the scope of this article to detail the changes in the harmonised standard; good overviews are available1,2 and more related literature references can be found on the author’s website. However, some of the essential requirements on X-ray sterilisation are mentioned below.
Beam energy. It is commonly accepted by regulators and expert committees that no radioactivity is induced when
- sterilising with e-beams with an e-beam energy up to 10 MeV, or when
- sterilising with X-rays, where the e-beam employed to generate the X-rays has a beam energy of up to 5 MeV.
ISO 11137: 2006 reflects this agreement of experts. It states that sterilisation with beam energies above these levels require an evaluation of potentially induced radioactivity. Several publications3,4 provide evaluations for X-rays with higher energy levels. The US Food and Drug Administration (FDA) has gone one step further. Upon petition by Ion Beam Applications (Louvain-la-Neuve, Belgium, www.iba.be), the FDA has approved food irradiation with X-ray energies up to 7.5 MeV. This step is in conformance with recommendations by the International Atomic Energy Agency and the World Health Organisation; both recommend that there should not be a limitation at 5 MeV.
In the world of medical products all the approvals around food irradiation do little to convince medical device manufacturers. Medical products have been studied, but the results are held confidential by the respective companies. Essentially, one extra standard operating procedure may be required to have a product evaluated once for potential radio activation during X-ray sterilisation. This testing can be performed by many laboratories equipped with the appropriate high resolution low activity measurement systems. If implemented correctly, the cost of a product’s radiological evaluation is minimal and results can typically be delivered in less than a few days. For X-ray energy levels of less than 7.5 MeV no problems are expected.
Transferring sterilisation dose. Transferring a sterilisation dose from one gamma irradiator to another has always been relatively straightforward because with gamma rays changing the dose rate generally has little or no effect on microbicidal action. Dose rate, temperature and the presence of water in its liquid state may affect the antibiotic properties of radiation. Before transferring a sterilisation dose these effects must be evaluated. Dose rates from electron accelerators or X-ray sterilisers of different designs can vary widely. With e-beams and X-rays, dose rate can affect microbial inactivation, particularly in the presence of water in its liquid state. Consequently, the standard stipulates restrictions on transfer of sterilisation or verification doses between different e-beam or X-ray irradiators.
A manufacturer must demonstrate that differences in operating conditions of the two irradiators do not alter microbicidal effectiveness unless the transfer is between
- two electron sources with identical operating conditions or for doses applied to dry products
- two X-ray radiation sources with identical operating conditions or for doses applied to dry products.
Restrictions also apply to the transfer of maximum acceptable sterilisation dose determined with gamma radiation to e-beam or X-ray irradiation.
Reference
1. J. Meissner, “Regulatory Issues For Radiation Sterilisation Centres,” IAEA TECDOC (2005).
2. E. Hoxey, “Standard Deviation,” Medical Device Developments (2005).
3. O.Grégoire, M.R. Cleland, J. Mittendorfer et al., “Radiological Safety of Medical Devices Sterilised With X-rays at 7.5 MeV,” Radiation Physics and Chemistry, 67, 149–167 (2003).
4. O. Grégoire, M.R. Cleland,J. Mittendorfer et al., “Radiological Safety of Food Irradiation With High Energy X-rays: Theoretical Expectations and Experimental Evidence,” Radiation Physics and Chemistry, 67, 169–183 (2003).
Dr Jörn Meissner is Managing Director of Meissner Consulting GmbH, Petuelring 92, D-80807 Munich, Germany, tel. +49 8930 765 220, e-mail: info@meissner-consulting.com, www.meissner-consulting.com.
