Ethylene oxide (EO) is a colourless, flammable gas that for many years has been used as one of the primary sterilants for medical devices. The EO sterilisation process requires state-of-the-art equipment and trained personnel as it is a highly toxic and flammable gas: chronic exposure has been associated with the occurrence of cancer, reproductive effects and mutagenic changes.
Use of EO as a sterilant and, more specifically, the amount of allowable residue left behind on a device after sterilisation, has therefore been closely regulated since 1995 and is referenced in international standards, such as ISO 11135:1995 (EO process validation and routine control) and ISO 10993-7:1995 (EO residuals).
These ISO standards have both recently been reviewed and republished. The new EO residuals standard will set new challenges for device manufactures, particularly manufacturers of limited-exposure devices, or devices such as syringes that will be used on a patient for under 24 hours (such as syringes, catheters, infusion sets).
The key change under the new ISO 10993-7:2008 is that the amount of residual EO or its by-products allowed to be left on such limited exposure devices will be significantly reduced, explains Hans Aeschlimann, vice-president of regulatory affairs at contract sterilisation company Sterigenics.
"The fivefold reduction in allowable limit for this category of devices has tightened things up and that is part of the challenge, so what manufacturers need to be doing is looking to redesign existing EO sterilisation processes by developing new approaches to meet the new limits," he says.
Of the two ISOs, ISO 10993-7:2008 defines the allowable limits of EO and ISO 11135-1:2007 is a recent revision of an ISO standard originally published in 1994 and outlines requirements and guidance on how to validate the EO sterilisation process for a device, containing the sort of methodology that should be used and how to design optimal sterilisation processes.
Manufacturers under pressure
As with the introduction of any new ISO, there is a transition period between publication and implementation – in this case three years. However, that does not mean medical device manufacturers have time to sit on their hands, in fact far from it, argues Aeschlimann.
"Companies need to have the transition period – which gives firms until October 2011 to become compliant – because the standard provides for a fivefold reduction in one category of medical device products, which may not be that easy to achieve in a short timeframe," he says. "It may be challenging for some devices, particularly if you have a product that was only just compliant according to the old standard and you have to now achieve a fivefold improvement."
Against the backdrop of the tougher economic climate, with device manufacturers already under pressure to bring products to market as quickly as possible as well as to use quicker sterilisation techniques, such as parametric release, these are standards that device manufacturers cannot ignore, agrees Peter Strain, vice-president of technology at Sterigenics.
"There may be this transition period of three years but the reality is that any new device coming on to the market needs to comply with the new standard," he says. "The simplest solution is to leave a product to aerate and allow the residue to dissipate, but that can add days or weeks to the process. Processes such as parametric release are also becoming more widespread and increasingly used. It allows you to eliminate the use of biological indicators, meaning you can reduce the sterilisation time from usual ten days to three or four.
"Manufacturers need to be looking at whether they can make their sterilisation processes more optimal. Too many processes are designed with massive overkills (EO overexposure) leaving high EO product residuals. But it is possible to have a process that has more targeted lethality and can avoid the build-up of excessive residue. There are, for example, high-tech degassing techniques that have now become quite efficient at removing residues."
Device manufacturers, Strain recommends, need to be looking at four key areas:
- redesigning their processes to ensure less EO is put into the device
- considering better degassing methods
- looking at more optimal methods of extraction during residue analysis
- addressing the absorption rate of their plastic used for their device, how it is packaged to allow better aeration of the product and how this whole issue can be included as early as possible within the design process.
"Everyone who makes a medical device that is sterilised by EO needs to be looking at their device, whether it is a device that is for limited, prolonged or permanent use on a patient," he stresses.
However, as it is going to be limited exposure devices that are most affected – as these are the devices where residues will need to be reduced fivefold – it is important to assess, first, how your device, particularly if it is one being newly developed, will be used on the patient, points out Aeschlimann.
"You also need to focus on the extraction methods and how the product is going to be used in the patient," he explains. "It may be that the device is only going to be used for a short period of time."
There are a number of key ideas that manufacturers should pay attention to:
- Review or revalidate your device to see how it will be affected by the new standards, is your device categorised as limited-prolonged exposure or permanent contact?
- Recognise that, if you are required to make the fivefold reduction under the new ISO rules, it may be a challenging and time-consuming process, so don't leave it until the last minute.
- Closely assess your existing sterilisation processes, do you for example need to be putting so much EO into the whole device by using excessive in-cycle EO concentrations?
- Look at more optimal methods of removal of EO residues, such as more efficient degassing techniques.
- Consider switching to a less EO-absorptive or easy to degass plastic for your device.
- Look at whether you can redesign or adjust your packaging to help with EO removal.
- Ensure EO residue removal and the minimisation of in-process EO concentration are incorporated as early as possible into the design cycle of the device.
- Recognise that any revalidation projects or assessment of EO levels for new or existing products should be performed in accordance with the 2008 version of the standard rather than the 1995, despite the transitionary period.
What devices are affected?
For prolonged exposure devices, where the device is being used for only up to 30 days (such as a urine drainage bag) and for permanent contact devices, such as an implant or a repeat dialysis, the residue levels will not be changing under these new ISOs.
What's more, EO-sterilised devices that have no patient contact (such as, for example, in vitro diagnostic devices) are not covered by ISO 10993-7:2008.
"The EO reductions that you need to achieve are different for each category – and it is only for limited exposure that you need to achieve the fivefold reduction – so you will need to check which category your device falls into," agrees Strain.
Any revalidation projects or assessment of ethylene oxide levels for new or existing products should be performed in accordance with the 2008 version of the standard rather than the 1995 version, he adds. It is also, of course, worth stressing that for some device manufacturers, the reality is that their processes and procedures will not need to change under this new ISO regime.
"Some people's devices may be absolutely fine without any changes – they may be easily aerated and may not need to do anything," Strain says. "Nevertheless, it is important that device companies begin to understand what they are doing and what the new standards will mean, so that they have time to find a solution.
"For example, if you to redesign your sterilisation process it can be six months' work. So you need to understand the limits and ensure that you have taken adequate steps, where necessary, to redesign your processes and packaging. There may be a three-year transition period, but you do not want to leave it to the last minute."