Feature Article

By: B.J. Lambert, Abbott Vascular, Temecula, California, USA

Exciting and cost-effective therapeutic opportunities continue to expand for combination medical devices. The United States Food and Drug Administration’s definition of a combination device includes, “A product comprised of two or more regulated components, that is, drug/device, biologic/device …”¹ This formal definition identifies two of four material compatibility challenges concerning sterilisation: devices and active agents (drugs or biologics). Devices without active agents, bioabsorbable polymers or active electronics typically do not represent an overwhelming challenge for current, routinely available terminal sterilisation technologies. Active agents, however, can be exceedingly challenging, as evidenced by the volume of products that are aseptically processed. Aseptic processing is more expensive and less effective in providing patient safety than terminal sterilisation.² Despite this, regulatory agencies and manufacturers are driven to select this option, which highlights the gravity of the problem for active agent sterilisation material compatibility.

 

There are two additional possible components of combination devices that represent significant sterilisation challenges: low glass transition bioabsorbable polymers and active electronics. Bioabsorbable polymers³ often control active agent release rate profiles, typically a critical performance characteristic of combination devices. This is a challenge for terminal sterilisation because, for example, physical properties of bioabsorable materials are negatively influenced by even the relatively low processing temperatures found in standard ethylene oxide (EtO) sterilisation cycles. In addition, embedded active electronics that facilitate cost-effective health monitoring and care management can represent a significant material challenge, especially with radiation sterilisation.⁴ Figure 1 illustrates the sterilisation challenges for this group of products.

To provide terminal sterilisation that will be compatible with all these material challenges, a range of sterilisation methods is available. Figure 2 provides an approximation of the market for the sterilisation of single-use disposable medical devices (sterilisation methods employed in hospital settings are not within the scope of this article). EtO and radiation (gamma, electron beam and X-ray) sterilisation dominate the market because of their robust microbial kill, minimal material effects, high throughput and low cost. They have close to equal share of the market.⁵ Accommodating material compatibility challenges and, in particular, avoiding elevated temperature has been the motivation behind the development of alternative technologies that often get close to having room temperature capability. These alternatives, however, lack the benefits offered by radiation and EtO sterilisation. Yet, if materials are not compatible with the two primary sterilisation methods, manufacturers have no option but to pursue alternatives, either alternative steriliation technologies or other options. The search for steriliation solutions for combination medical devices has proceeded down the four paths discussed below.

 

The development of new sterilisation technologies is one approach to the problem. Information related to the compatibility of novel sterilisation technologies with materials is available, for example, for hydrogen peroxide,⁶ ozone,⁷ nitrogen dioxide⁸ and supercritical carbon dioxide.⁹

 

Developing and/or implementing sterilisation validation methodologies that are more cost-effective and gentler on materials are a second approach. The radiation sterilisation community has been aggressive in this respect with the introduction of new validation methodologies that use fewer samples to qualify lower sterilisation doses.¹⁰ The use of biological indicator/bioburden validation approaches with EtO sterilisation may also be utilised to reduce the effect of EtO parameters on materials.¹¹

Beyond these relatively predictable responses are two initiatives that give an indication of the urgency to have access to a compatible sterilisation method. The International Organisation for Standardisation, Technical Committee 198, is developing a standard for the aseptic processing of solid medical devices.¹² The development of this standard illustrates the need to process challenging materials using aseptic techniques that have greater cost and patient risk than terminal sterilisation.

Perhaps the most telling indication of the need for appropriate sterilisation methods comes from industry’s initiative to challenge the well-established definition of sterility assurance level (SAL) for blood contacting devices: one viable organism (or one non-sterile device) in a million devices. The SAL of 10^-6 historically began in the food and space industries.¹³ This longstanding sterility specification has been reviewed and found wanting in that there is no correlation between the specification and patient safety. The International Irradiation Association (www.iiaglobal.org) has sponsored forums to raise this issue for discussion and to explore the basis of the specification and the potential need to change it. An argument supporting a change in the specification for combination devices relates to an evaluation of negative patient effects, or lack thereof, from products processed to less stringent sterility specifications, either aseptically processed products or products processed at a SAL of 10^-3, that is, one viable organism (or one non-sterile device) in one thousand.

 

Another argument for changing the specification is an attempt to evaluate the mathematical rationale for a SAL as low as 10^-6. The current hypothesis is that the bio-load from hospital application of devices is much higher than the poststerilisation contamination levels on packaged sterile devices. The critical factor to test this hypothesis is the level of contamination deposited on a product between the time the package is opened in a hospital setting and when it is introduced to the patient. Best practice when opening products while performing tests of sterility in laminar hoods at microbiology test houses achieves a level of contamination of approximately one contaminant per 1000 devices. This is lower than the contamination levels found in hospitals. To illustrate a potential outcome, suppose hospital environments could achieve a contamination rate of one contaminant per 100 devices. This is a contamination rate of 0.01 contaminants per device. This level is significantly greater than the contamination coming from a device with a SAL of 10^-6. For example, if one adds the contamination coming from this hypothetical hospital contamination rate (0.01) with that from a device with a SAL of 10^-6 (0.000001), the resulting contamination rate is clearly dominated by the hospital contamination: 0.010001, which rounds to 0.01. Using the same hypothetical hospital scenario with a device with a SAL of 10^-3, the resulting contamination rate is still dominated by the hospital contamination: 0.011, which again rounds to 0.01.

 

A device manufacturer can explore new sterilisation technologies and evaluate sterilisation validation methodologies to reduce the required “dose” of sterilant (radiation dose or dose of gas sterilant/related parameters) to achieve a given SAL. However, before exploring expensive options related to aseptic processing of solid medical devices, the manufacturer should follow available sterilisation material compatibility guidance such as AAMI TIR17:2008. This will optimise the chance of qualifying materials and products with terminal sterilisation.

 

The first point made in the guidance is to select materials with the highest possibility of compatibility with the sterilisation modality of choice. AAMI TIR17 provides qualitative comparison of more than 60 families of materials, largely polymers, with six sterilisation methods. This provides general insights into compatibility.

 

A second point states that the materials of interest should be characterised together with the fundamentals of the interaction of those materials with the chosen sterilisation method. It is exceedingly valuable to know thermal boundaries; the importance of interactions with moisture; and the mechanisms of radiation chemistry, alkylation chemistry and/or oxidation chemistry as appropriate for the chosen sterilisation method. Table I provides a summary of the parameters that need to be considered when evaluating the effects of each sterilisation method on materials.¹⁴

 

Examples of experiments to facilitate an understanding of these are given in Figures 3 to 5.¹⁴ Figure 3 illustrates the response of an oxidant to EtO sterilisation. The oxidant is designed to protect a drug over time in a combination device. Either the heat or the alkylation chemistry of the EtO cycles is reducing the concentration of the oxidant. If the oxidant truly plays an important role in preserving the drug over time, this will be an important consideration when defining sterilisation compatibility and number of repeat sterilisation cycles. Designed experiments can challenge the range of sterilisation parameters of interest (Table 1) and are also valuable for determining parameters that effect critical device performance characteristics. Figure 4 shows the loss of drug with dose in a radiation-sterilised product. Determining the dose response of critical performance characteristics of a product gives the device manufacturer robust information to design sterilisation compatible products. Figure 5 demonstrates the effect of varying the environment of the drug, in this case varying the polymer environment from which the drug elutes. This type of experiment can provide further insights into the mechanism of drug loss.

 

Further points of guidance follow and focus on the foundation of optimal material selection and thorough understanding of the interaction of product materials with the sterilisation modality selected. It is critically important to avoid material processing techniques that introduce stresses into materials. These stresses can lead to deleterious material effects significantly greater than the effect of sterilisation on materials. In addition, keeping a sharp focus on clinically relevant testing avoids patient risk from missing performance features required for patient safety, as well as avoiding unnecessary costs in designing for product characteristics that are not relevant to patient safety. It is important to focus on the critical quality features of the product, not merely standard tests that are available. Examples of relevant testing for drug eluting stents are micro- and nano-characterisation tools such as imaging Fourier transform infrared spectroscopy for drug distribution and coating uniformity; atomic force microscopy (AFM) for surface swelling; AFM and local conformal raman spectroscopy for microstructure and phase dispersion; and thermal transitions using micro-thermal analysis.

 

The final point of guidance in AAMI TIR17 relates to challenging the material compatibility of sterilisation over the expected shelf life of the device. For combination devices, there is a need to differentiate device accelerated ageing from drug-accelerated stability.¹⁵ For device components, the guidance provides a conservative accelerated ageing method, the “Fixed Ageing Factor Method,” and a more aggressive “Iterative Ageing Factor Method.” Both require confirmation with real-time ageing. The former can be broadly applied because it has a firm theoretical and empirical foundation for utilisation.¹⁶ The latter requires additional resources to correlate real-time and accelerated-ageing data, but offers the promise of reduced development time in accelerated-ageing chambers and/or extended shelf life with a given accelerated ageing time.

Meeting the terminal sterilisation needs of the blossoming combination device market¹⁷ will require the development and utilisation of new sterilisation technologies and new sterilisation validation methodologies. Device manufacturers will need to take advantage of these options as well as explore expensive aseptic processing paths, particularly if the industry is not successful in challenging sterilisation specifications not linked to patient safety. In all scenarios, it is prudent to follow available guidance to optimise opportunities for material compatibility in relation to sterilisation. 1

 

is Senior Associate Fellow, Sterilisation
Science, at Abbott Vascular, 26531 Ynez Road Temecula, California 92591, USA
tel. +1 951 914 2156 
e-mail: byron.lambert@av.abbott.com 
www.abbott.com