New drug delivery systems or ‘combo’ devices are becoming more prevalent in the market. Mark Botting, UK commercial manager, Isotron, reviews some current challenges and potential future changes in sterilising drug device combination products
With recent developments in advanced drug delivery systems manufacturers and contract sterilisation providers are now required to work more closely together than ever before to find a satisfactory sterilisation option for these devices. This new generation of combination devices presents a unique challenge to all parties as the regulatory environment requires that they conform to both pharmaceutical and medical device standards for sterility assurance.
The contract sterilisation industry has been able, in most cases, to adapt its processes to handle current requirements through the use of microbiological control and new sterilisation techniques, such as Electron Beam. However, going forward, regulatory changes are being considered to make the process more adaptive.
the combo challenge
Medical device manufacturers do not face the same challenges as their pharmaceutical counterparts because the devices are normally manufactured using plastics, metals or materials that are easily adapted to terminal sterilisation. Sterility assurance is obviously still critical for this market and standards have been developed and unified over the past 30 years that clearly outline how conformance to medical device sterilisation standards can be undertaken.
The latest version of ISO 11137: 2006 ‘Sterilisation of health care products – Radiation – Part 1: Requirements for development, validation and routine control of a sterilization process for medical devices’ defines the requirement to conform to a sterility assurance level (SAL) of 10-6 using irradiation as well as the microbiological tests required to achieve this.
The development of the drug combination devices for complex diseases offers challenges to manufacturers about how to conform to both approaches. While pharmaceutical producers can follow either path, the risk of infection from the device plus the clearly defined requirement for terminal sterilisation of devices has meant that regulatory bodies and manufacturers are increasingly looking for ways to terminally sterilise their combination devices.
A number of approaches have been developed over the past 10 years by manufacturers and their sterilisation providers to find ways of sterilising the devices while not adversely affecting efficacy. These include:
- Electron Beam processing
- Reduced irradiation dose (exposure) due to clean manufacturing
- Temperature control and inert atmospheres
sterilisation options
The pharmaceutical approach to under-standing microbiological risk through Quality Risk Management (QRM), using ultra-clean and consistent processes, has stood the test of time while avoiding the need for terminal sterilisation. This approach has developed largely due to the issues associated with using the main industrial sterilisation techniques of Gamma irradiation and Ethylene Oxide gas. These high energy processes involve free radical production which has always caused problems with the efficacy of the drug.
In the case of Ethlyene Oxide, the addition of heat and steam and residual safety concerns has made this technique non-viable. However, terminal sterilisation using Gamma has remained an option for pharmaceutical manufacturers and is used in some cases.
electron beam processing
Over the past 20 years, the development of 10 MeV sterilisation beams (which are commercially viable and used by a large proportion of the medical device industry) has created new options for pharmaceutical manufacturers. Time is the main advantage of this technique, as the sterilisation dose can be applied in a matter of minutes, as opposed to the hours needed for Gamma. This reduction in exposure time directly correlates to a reduction in free radical generation and the negative effects that this causes to drugs and medical plastics.
The use of Electron Beam for drug eluting stents has been common for many years. In addition the use of shielding, thin product target areas (pizza box shapes) and orientation of products to the beam have allowed maximum doses to be controlled to relatively low levels of around 40kGy.
Historically, contract irradiation plants have processed medical devices at dose ranges in the region of 25–40 kGy in line with medical device requirements set out by the industry and the Association for the Advancement of Medical Instrumentation (AAMI) in the 1970s. The development of the ISO 11137 over the past 15 years (which outlines the requirement to undertake microbiological testing) has, however, opened the door for a reduction in processing doses.
This standard allows devices with low bioburden to be sterilised by minimum processing doses of 15kGy, or even lower in some cases, and through regular auditing of bioburden. As such, the efficacy of the sterilisation dose can be maintained while conforming to the standard.
Even the slight increases in temperature seen during Gamma and Electron Beam of around 5–10% can, in some cases, cause degradation, so this needs to be checked during validation of the process. However, it has been proven that keeping the product at a reduced temperature through the use of dry ice prior to and during irradiation (Gamma only), helps to protect the drugs from the effects of free radicals and dampens the chemical reactions these cause in the drugs.
A major negative effect of the Gamma and Electron Beam sterilisation technique is the production of the highly reactive compound ozone, which occurs through the ionisation of air. The use of sealed packaging filled with inert gases, such as nitrogen, stops or severely reduces the production of ozone in the proximity of the drug and reduces the potential damage to efficacy even at doses of 25kGy using Gamma.
A consideration with either of these techniques will be control of packaging and shipping, cost of manufacturing and the ability of the sterilisation provider to handle either low temperature products or the risk of handling pressurised containers.
The uses of the methods outlined above have allowed combination devices to be produced and sterilised routinely for many years. However, the expected large increase of these products over the next two decades along with the complexity of drugs and devices, have meant that manufacturers and contract sterilisers are looking for a new regulatory route to make terminal sterilisation easier to achieve.
reduced SALs
One major discussion was based on the fact that SAL levels of 10-3 or 10-4 are common-place for vaccines and other pharmaceuticals produced by aseptic processing. This has, therefore, opened up an opportunity for the industry to select scientifically the appropriate SAL for a healthcare product rather than taking the arbitrary 10-6 currently used by the medical device industry. This SAL of 10-6 is seen as overkill in some cases rather than a level required for safe use.
The subject of drug device combination products continues to be an area of interest for all related industries. The International Irradiation Association (iiA) sponsored three workshops on drug combination devices held in San Diego, US, in December 2006, Washington DC, US, in June 2007 and London, UK, in 2008. These workshops brought together experts in the field of medical device manufacturing, sterilisation, drug development and regulatory approval to review the technical and process challenges associated with drug-device combination products, many of which have been outlined earlier in this article.
future changes
The workshops managed to gain both industry and US FDA support, and allowed iiA to request the setting up of an AAMI working group (WG90) in June 2008 to look at the current regulatory standards for SAL, taking into account infection rates and patient outcomes. The working group is expected to report back its initial finding by the end of 2010.
In conclusion, the development of drug combination devices that require terminal sterilisation has meant that the contract sterilisation industry has looked to develop ways of processing drugs through tight control of dose, bioburden, Electron Beam and controlled packaging, while not aversely affecting the efficacy of the drug. These techniques allow manufacturers to routinely sterilise drug combination devices but could also facilitate terminal sterilisation of drugs if required.
It is important that the manufacturer gets input from the contract steriliser at an early stage in the development to ensure that the drug can be sterilised using an irradiation technique.
The contract sterilisation industry, however, is aware that these techniques are not the only solution and are now working with manufacturers, notified bodies and AAMI to look at ways to reduce the sterilisation dose further through adapting the regulatory requirement for SAL to patient need, rather than using the arbitrary levels currently in place.
