MANUFACTURING
Isotron Ltd, Swindon, UK
Inspiring the future
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The main objective of the 2008 International Meeting on Radiation Processing (IMRP2008), jointly hosted by Isotron and REVISS, was to present a technical programme that would inspire delegates to pursue novel research projects, new applications and exciting business developments. The event attracted more than 400 delegates from 40 countries. In the context of health care, urgent topics include the increasing longevity of populations in the western world, the development of ever more sophisticated drug delivery systems and the challenges of cost, quality and availability faced by health care providers. All these things have the potential to influence radiation processing applications in the medium to long term. Demand for irradiation technologies is expected to increase in the developing economies and new approaches to sterilisation processes and dosimetry are required to accommodate the new generation of drug–device combination products.
Convergent products
David Liu, Johnson & Johnson (www.jnj.com), developed the theme of convergent products, which he described as two or more products or disciplines that are combined to provide a new, more effective response to disease. These include products such as drug enhanced devices, and regenerative, genetic and cellular therapies. Products such as drug eluting stents are being delivered now. Next generation products that enable organ regeneration and cell therapy are under development. Device miniaturisation and the application of nanotechnology principles offer further potential for drug or cell delivery to target sites. Achieving these goals will require novel research and development approaches and significant additional resources from the health care industry. It is likely that radiation will become the sterilisation method of choice for these products. This is because of material compatibility requirements, and the fact that radiation provides a robust, relatively low cost methodology with established regulatory approvals that is amenable to rigorous validation. However, there will be challenges. These new products are likely to require that the technology is applied in unfamiliar ways. Cryogenic temperatures, oxygen free environments, low and narrow dose ranges, and precision “per product” dosimetry are probable requirements that the industry is currently not well equipped to deliver.
Regulatory hurdles
Anastasia Lolas, United States (US) Food and Drug Administration (FDA), addressed some of the regulatory challenges being raised by development of these new convergent products. She outlined the characteristics of small batch size, probable low bioburden, and the susceptibility of the materials the product is made from and the drug that it contains to degradation under high energy sterilisation conditions. She noted the likely need to use combinations of existing technologies such as ultraclean manufacture and low dose terminal sterilisation treatment, and the importance of process validation and control in the manufacture of these products. FDA appears keen to encourage new processes and innovation and will consider each on a case by case basis.
New drug formulations
The complexity of pharmaceutical formulation development and the fact that product formulation becomes fixed early on in the product development process was noted by Neera Jain (Synta Pharmaceuticals, www.syntapharma.com). Consequently, there is a requirement to have a clear view of the sterilisation process and the ability to validate that process at an early stage in the product development programme.
Biological tissue sterilisation
The application of radiation for the sterilisation of biological tissue was discussed by Martell Winters (Nelson Laboratories, www.nelsonlabs.com). Sterilisation of tissue, including bone and collagen/elastin, for implantation is becoming increasingly common, but has a confused background. Some clinicians use irradiated material, others do not, and some seek high doses (50 kGy) to kill potential viral load and there have been inconsistent reports of damage from the process. In addition, there is an absence of standards or guidance on how to irradiate and test these materials. The potential value of alternative options to validate the sterilisation process were addressed such as modifications to Method 2 stated in ISO 11137-2:2006, Sterilisation of Health Care Products, Radiation, Establishing Sterilisation Dose. The use of alternative microbial populations to population “C” that underlies the methodology in ISO 11137-2 and consideration of sterility assurance levels other than 10-6 were recognised. A sterilisation dose as low as 5 kGy was suggested as potentially achievable. The benefits of lower sterilisation doses are reflected in minimising the loss of tensile strength and flexibility in implanted collagen/elastin matrices. This is also particularly important with bone, which is usually employed for its mechanical strength; any reduction in strength as a result of irradiation is of concern.
Impact of process variations
Extending the discussion of sterilisation of combination products, Alan Tallentire (Air Dispersions, www.airdispersions.com) considered the impact of variations in the principal processes and in product composition on the achievement of a defined sterility assurance level. In particular, he considered gaseous environment, water content, temperature and the presence of additives as potential factors that could alter the inactivation rate constant of indicator microorganisms. He illustrated the increased sensitivity of cells to radiation in the presence of oxygen and demonstrated that oxygen needed to be present at the instant of irradiation of wet cells to be effective in this respect. It was apparent that some gases such as nitric oxide are able to protect against some of the oxygen dependant cell damage. Similarly, both simple and complex additives will affect susceptibility to radiation sterilisation and these effects are more marked at high water vapour pressures. In summary, it is clear that the response of microbial populations to radiation is affected by processing conditions and product composition and that changes in these conditions can cause appreciable changes in microbial response. Consequently, it becomes critical that experimentation to determine and verify sterilisation dose is conducted under conditions that reflect those specified for the sterilisation process.
Sterilisation equipment
IBA (www.iba.be) has been actively developing its X-ray irradiation equipment in recent years and the company presented a performance summary of its eXelis product range, which has a sterilisation capacity ranging from 11000 to 124000 m3 per year. This is based on the Rhodotron electron accelerator delivering electrons to a target that emits X-rays with an energy of 7 MeV. Palletised product is moved through the X-ray field employing an incremental dose system and multisided irradiation. The reported performance data were derived from a medical device sterilisation facility installed in conjunction with Leoni Studer Hard (www.studerhard.ch). Throughput, dose uniformity, flexibility and cost of processing were all claimed to be competitive with an equivalent cobalt-60 based gamma irradiation plant.
MDS Nordion (www.mds.nordion.com) considered some of the unique processing requirements for the sterilisation of next generation health care products. It examined solutions such as special loop processing systems and the addition of inserts to totes or carriers derived from the modification of existing radiation sterilisation plant. The company’s preferred solution, however, was described in concept as a small self-contained batch processing unit offering variable dose rate and the ability to control the temp-erature of the process chamber. The concept was presented as a solution for small-scale sterilisation capability to handle the requirements of product development and small-scale production processing.
Linac Technologies (www.linactechnologies.com) presented a summary of the recent developments of its Ster-Star and Ster-Box range of inline electron beam (e-beam) sterilisation units. The low energy Ster-Star units, which employ three radially oriented low energy accelerators, have been coupled with isolator units to provide a seamless system for feeding sterilised components into aseptic filling environments.
Practical experience of inline e-beam sterilisation as part of an aseptic filling process was presented by Janssen Cilag (www.janssen-cilag.co.uk) and illustrated by its manufacturing facilities in Belgium and Switzerland. Both sites employ an e-beam tunnel to sterilise syringe components on their way to a filling station housed within inline isolator protected aseptic filling lines. Active ingredients are aseptically compounded or sterile filtered for delivery into the filling lines. In both cases, the e-beam sterilisation stage is performed by low energy (180–200 keV) beams delivered by three radially oriented accelerators. Because the energy is low, shielding requirements are kept to a minimum. The e-beam approach was chosen after evaluating a number of alternative component sterilisation options. The validation philosophy and subsequent efficacy trials and lethality studies were reviewed together with dosimetric qualification programmes.
Dosimetry and modelling
Historically, confidence in measurements of the delivered dose of radiation at temperatures below –76 °C has been problematic. Peter Sharpe (National Physical Laboratory, www.npl.co.uk) reported investigations into the performance of alanine dosimeters at these low temperatures. Conclusions were complex, but data are now available that allow interpretation of dose measurements made at temperatures from 100K (equivalent to –173 °C) upwards. A contribution from the National Institute of Standards and Technology (www.nist.gov) reported a hitherto unrecognised element of dose rate dependence in alanine dosimeters and identified some of the underlying chemistry. The finding has some significance for standards laboratories and also for e-beam applications where calibrations are often based on gamma calibrated systems.
A contribution from Risø NRL (http:\\hdrl.risoe.dk) addressed the issue of dosimeter thickness and impact on dose measurement for low energy beams (typical of those used in inline aseptic fill situations). In introducing the Dµ concept, which is an approach that seeks to determine the absorbed dose at the surface of the dosimeter, methods for calculating correction factors to enable the dose absorbed in the first micron of the dosimeter were illustrated. These correction factors must be calculated for each facility, beam energy and dosimeter type and are essentially tasks for calibration laboratories.
Contributions reporting practical experiences with modelling in the United Kingdom (UK) and US demonstrated the capability of modelling processes and the potential benefits that can be achieved. However, they also recognised that the barriers to establishing modelling capabilities in terms of the time and skills required were limiting uptake by radiation processors.
Other aspects of radiation processing
Although this report concentrates on the elements of the Conference content relevant to medical device sterilisation, it should be noted that there were two other subject strands, Advanced Materials and Global Trade, that were considered in equal depth. A number of contributions in these strands touched on activities of relevance to medical device manufacture. In particular, presentations addressed recent advances in material qualification, developments in processing ultra high molecular weight polyethylene for orthopaedic implants and processing hydrogels. Although they were not directly linked to sterilisation, all considered the role of radiation in processes, which in some cases achieved sterilisation as well as inducing beneficial changes in the materials under discussion.
A call to action
The Conference was brought to a close by John Masefield, Chairman of the International Irradiation Association, iiA. He delivered a Call to Action for the radiation processing industry to actively pursue novel applications relevant to the changing demands of the 21st century in health care, as well as environmental conservation and fuel and water economy. He urged communication and collaboration across academic, industrial and political boundaries to promote upstream integration of radiation processing and achieve earlier, faster and more cost-effective product development.
Proceedings
Publication of the Conference proceedings will be undertaken by Radiation Physics and Chemistry Abstracts of the presentations and posters can be found on the iiA website: www.iiaglobal.org. The oral presentations and ultimately the scientific and technical contributions will be available in full on the iiA website.
Dr John Woolston, Isotron Ltd, Ground Floor Stella, Windmill Hill Business Park, Whitehill Way, Swindon SN5 6NX, UK, tel +44 1793 891 891, e-mail: john.woolston@isotron.comwww.isotron.com
This is an abridged version of Dr Woolston’s full Conference report. For more IMRP2008 Conference highlights, including those from the plenary presentations, go to www.devicelink.com/mdt/sterilisation
