Medical Device Link.

MANUFACTURING

Enduring popularity

During the past ten years, manufacturers have continued to employ three standard sterilisation processes for the majority of medical devices processed worldwide: gamma, electron-beam radiation and ethylene-oxide (EtO) gas diffusion. Of these, gamma and EtO are estimated to be used to sterilise 90–97% of all medical devices processed by industrial-scale manufacturers worldwide. EtO, the oldest of the three technologies, continues to flourish as a robust and flexible 21st-century method of industrial sterilisation of medical devices. Once thought of as an anachronism, EtO sterilisation has been shown to offer the following benefits.

• Unlike irradiation methods, EtO does not significantly affect or change the molecular structure of the plastic materials used for the construction of medical devices.
• The long-term stability testing required with sterilisation can be met by adopting prior specific and appropriate studies to thereby allow manufacturers to reduce or eliminate the extended shelf-life testing needed for regulatory approval.
• The growth of drug-coated implanted devices requires a sterilisation modality that will not diminish the product’s potency and effectiveness. The effect of irradiation on the efficacy of a drug product must be proven over the shelf life of the product, whereas EtO cannot penetrate a properly sealed, nonbreathable container, which allows drugs to retain their efficacy poststerilisation.
• EtO meets the needs when combinations of medical devices, materials and packaging are placed in a complex procedure kit; these kits may not be suited to irradiation sterilisation because of their size and density or the effect irradiation may have on the components.

New regulations

Although the highly reactive nature of the EtO molecule (epoxy ring molecule) offers an excellent method of sterilisation, it also presents a significant number of regulatory challenges. There are currently two International Organisation for Standardisation (ISO)standards that are in the process of being changed. These changes will affect the sterilisation of medical devices using EtO gas in the following ways.

ISO/DIS 10993 Biological Evaluation of Medical Devices, Part 7: Ethylene-Oxide Sterilisation Residuals. This regulates the level of EtO residuals and EtO by-products on medical devices in contact with patients. The proposed changes include a restructuring of requirements, which will affect the acceptance criteria and method for calculating residual levels for short-term exposure. This will necessitate a new strategic focus by each medical device manufacturer to ensure compliance.

ISO/DIS 11135 Sterilisation of Health Care Products — Ethylene Oxide, Part 1: Requirements for Development, Validation and Routine Control of a Sterilisation Process for Medical Devices. This standard is expected to include a revision to the qualification requirements of medical device manufacturers for utilising parametric release; specifically the requirement to perform a method A or B validation is eliminated. These changes will require medical device manufacturers to review their supply chain timeframes to determine what, if any, advantages will become possible to aid the speed-to-market of their products. Parametric release eliminates the need to wait for up to seven days for negative growth on biological indicators to confirm successful sterilisation. However, this reduction in quarantine time must be evaluated against the residual off-gassing time requirements to fully evaluate the potential advantages.

Implications for manufacturers

The question that needs to be asked by each manufacturer of sterile medical devices is: “How prepared are we to address these changes and challenges?” Although these changes have been under discussion for several years, they contain elements that could make it difficult to meet the needs of the product and patient supply. The changes to ISO 11135 requirements will probably allow more medical device manufacturers to access the provisions under the parametric release criteria. They could result in improved products being delivered to hospitals and clinicians because the release of sterilisation loads will be based on conformance to parameters and not to biological indicator postprocess release testing.

There are a number of revisions proposed in ISO 10993-7 and a review by an appropriate sterilisation professional, that is, a chemist, sterilisation engineer, consultant or microbiologist is needed to ascertain the total impact on a medical device manufacturer’s process release. Medical devices used for short-term duration (24 hours) will need to conform to significantly reduced residual criteria prior to release for patient use. Without significant changes to the sterilisation process or ventilation of the packaging, the medical device manufacturer can expect an extension to product quarantine time pending the necessary EtO residual levels being met.

Process changes

These regulatory requirements and their increasing challenges highlight the need for continual innovation and insightful process development, upgrading of equipment and reliable services on a worldwide scale. Process developments could include the following.

Figure 1: (click to enlarge) Residual levels in a traditional EtO cycle.

• Alternative mixtures of 100% EtO gas, steam and inert gases being used, which are patterned for maximum lethality and product safety.
• The introduction of humidified gases concentrated to aid EtO penetration and removal.
• While maintaining lethality requirements based on the ISO 11135, a significant reduction of EtO gas concentrations and dwell time through experimental studies and validations using a fractional negative approach, a combination of biological indicator and bioburden approach or a bioburden approach to sterilisation development. All these are aimed at reducing levels of residuals and
by-products.
• Employing methods to reduce loss of product heat, and thus, energy in the load to prevent slowing of extraction of EtO residuals from product.

Figure 2: (click to enlarge) Residual levels in a revised EtO cycle.

Figure 1 shows the quarantine release period necessary for two medical products based on residual release criteria. Product B meets the current requirements and is releasable after approximately 72 hours of quarantine aeration time. Product A, although close to meeting the requirements, needs additional testing to confirm the time in which the residual levels meet the release criteria. However, neither product is remotely close to the new levels now proposed. Figure 2 shows the same data, but with additional data achieved through the use of an all-in-one process utilising some of the techniques identified above. Figures 3 and 4 show an all-in-one sterilisation process in which all the phases: preconditioning, sterilisation and aeration, are performed in one physical location, the chamber, which provides a significant reduction in time.

Figure 3: (click to enlarge) A three-step process performed in a chamber comprising conditioning, delivery of lethality and removal of EtO residue. The product leaves the chamber ready for immediate shipment.

Although more work must be performed by the client to meet the new requirements, the level of EtO residuals has been significantly reduced, as measured immediately from the chamber (zero hours postprocess).

A focussed response

Options available to medical device manufacturers and sterilisers to respond to the changes include:

Figure 4: (click to enlarge) One parametric process in which total process and inventory hold time is 15 hours.

• A review of ISO 10993-07 to ascertain the exceptions given for some medical devices.
• A gap analysis programme to be performed immediately. This could involve performing scientific evaluations to determine the gap between the current product status and the forthcoming requirements; calculating EtO residue reduction (and reduction rate over time) based on empirical data performed utilising additional time in quarantine; and performing appropriate studies with reduced EtO gas exposure and new degassing techniques to evaluate lethality and residues.
• Calculation of the potential impact on costs and loss of inventory velocity versus the reliability of EtO sterilisation as an accepted method of terminal sterilisation.
• Possible redevelopment and re-validation of the package to aid the increase of ventilation and vapour barrier outgassing of the package. Evaluation of the increased product venting for improved gas and vapour transmission, the reduction in sterilisation load density, and alternatives to improve breathable surfaces involving kit overwraps.
• Redevelopment of the EtO process methodology to include all-in-one technologies available to lower EtO concentrations and EtO gas dwells that result in a reduction of residual levels.
• Use of new EtO direct measurement technologies to evaluate EtO outgassing levels in entire loads
postprocessing.
• Once the product residues are considered and the quarantine time is minimised, then product release methodologies, that is parametric release, reduced incubation time studies, rapid incubation biologic products and new testing methods for rapid detection of biological indicator growth can ensure the minimisation of release time.

Innovation and science have brought exciting opportunities to the health-care industry. As technologies are developed and regulatory changes occur, a new focus on sterilisation is required for the medical device manufacturer to meet these challenges.

William T. Young is Vice President EO Technology at Sterigenics International Inc., 2015 Spring Road, Suite 650, Oak Brook, Illinois 60523, USA, tel. +1 630 928 1700, e-mail: byoung@sterigenics.com, www.sterigenics.com.