The current standards for radiation sterilisation of medical devices are EN 552 and ISO 11137. EN 552 is harmonised as a European Standard and gives a presumption of conformity to the European Medical Devices Directives; ISO 11137 has been adopted as an American Standard and is recognised by the FDA. The standards are technically equivalent and entirely compatible, but they are editorially different, adding complexity for manufacturers and radiation processors who need to comply with both the European and US requirements in order to market medical devices in both jurisdictions.
Work started on preparing these standards in 1989. The European standard was published in 1994 and the International Standards Organization (ISO) standard in 1995. Under the normal practice of the respective standards organisations, standards are reviewed after five years and it was agreed in 1999 that a joint revision should be prepared under the leadership of the ISO.
This process is now drawing to a close and a revised standard, EN ISO 11137, is ready for its final ballot prior to approval.
STRUCTURE OF THE REVISED STANDARD
The review and revision of the radiation sterilisation standard was undertaken in parallel with the standards for the other major sterilisation methods of ethylene oxide and moist heat. It was decided at the beginning of the revision process that the structures of the standards for the three methods of sterilisation should be the same, based on the structure of ISO 14937, ‘General requirements for characterising a sterilising agent and the development, validation and routine control of a sterilisation process’. In addition, it was agreed that the same definitions should apply in the three process standards.
At the initial review of the radiation standard to develop the strategy for the revision, it was decided to divide the standard into three parts:
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- EN ISO 11137-1 – Requirements and guidance
- EN ISO 11137-2 – Establishing the sterilisation dose
- EN ISO 11137-3 – Guidance on dosimetric aspects
Based on these early decisions, the title of the document giving requirements and guidance was agreed as ‘Sterilisation of health care products – Radiation – Part 1: Requirements for the development, validation and routine control of a sterilisation process for medical devices’.
ELECTRON BEAM ENERGY LEVELS AND INCLUSION OF X-RAYS FOR STERILISATION
There was a need to harmonise the differences between the scopes of the existing European and international standards; the European standard had not covered the use of x-rays for sterilisation and it set a maximum energy level for electron beam. Conversely, the international standard included x-rays but set no maximum energy level for electron beams.
The decision to include the use of x-rays within the scope was straightforward, but there was much discussion on the limitation of energy levels. The conclusion of this discussion and review was that, if the energy level of electrons for sterilisation exceeds 10MeV or the energy level for electrons used for the generation of x-rays exceeded 5MeV, the manufacturer would be required to assess the potential for induced radioactivity in product.
TRANSFERRING A STERILISATION DOSE
Transferring a sterilisation dose from one gamma irradiator to another has always been relatively straightforward because, with gamma rays, changing the dose rate generally has little or no effect on microbicidal action.
Dose rates from electron accelerators of different designs can vary widely. With electron beams, dose rate can affect microbial inactivation, particularly in the presence of water in its liquid state. Consequently, the standard stipulates restrictions on transfer of sterilisation or verification doses between different electron beam or x-ray irradiators. A manufacturer has to demonstrate that differences in operating conditions of the two irradiators do not alter microbicidal effectiveness unless the transfer is between:
- Two electron sources with identical operating conditions or for doses applied to dry products.
- Two x-ray radiation sources with identical operating conditions or for doses applied to dry products.
Restrictions also apply to transfer of sterilisation doses determined with gamma radiation to either electron beam or x-ray irradiation.
The two methods of dose-setting described in Annex B of ISO 11137:1995 have been revised editorially to clarify the required procedure and ensure consistency, but there have been no technical changes in the methods themselves.
Users of Method 1 will note that the table listing the verification dose and sterilisation dose for a range of levels of average bioburden has been amended so that the table is organised in regular progression of value of average bioburden. Additionally, the lower limit for Method 1 has been set at an average bioburden of 0.1 and the method is not to be applied to average bioburden below this value.
SUBSTANTIATING A STERILISTION DOSE OF 25GY (VDMAX25)
The decision to include Method VDmax25 for the substantiation of a sterilisation dose of 25kGy, the basis of which was developed by Kowalski and Tallentire 1, 2 and published in AAMI TIR 27, alongside the methods of dose setting described in Annex B of ISO 11137:1995 was made early in the revision process.
DOSE-SETTING FOR PRODUCTS WITH LOW BIOBURDEN
There was considerable discussion on the appropriateness of the methods of dose setting to determine the sterilisation dose for product with a low bioburden. Particularly, it has been demonstrated that dose setting Method 1 becomes less sensitive as the average bioburden decreases below 1.0. This meant that manufacturers of product with an average bioburden equal to or less than 1.0 were choosing to dose-set for such products using Method 2.
It has always been somewhat paradoxical that manufacturers of products with such low bioburden appear to be penalised by the need to perform extensive microbiological investigation. As a consequence, it was decided to include a variation on Method VDmax25, to be designated Method VDmax15, permitting manufacturers with an average bioburden less than 1.5 to select and substantiate a sterilisation dose of 15kGy.
Moreover, it was agreed that a lower limit for average bioburden on 0.1 should be set for applying Method 1, but that there should be no lower limit for the application of Method VDmax25 or Method VDmax15. Examination of the tables indicating the verification doses for the two substantiation methods shows that the verification dose at the lowest value in the table is 0.0kGy; therefore a verification experiment is conducted on unirradiated product.
MAINTAINING PROCESS EFFECTIVENESS
ISO 11137:1995 contained a requirement for sterilisation dose audits to be conducted at three-month intervals. This requirement had been subject to much discussion and debate. EN 552 did not stipulate the frequency at which sterilisation dose audits were required; EN 552 required that this frequency be rationalised and defined by the manufacturer.
The revised standard recognises two strategies for determining the frequency of sterilisation dose audits: a stipulated time interval of three months or a time interval based on a documented rationale. This rationale is required to consider: the available data on bioburden and its variation over time; the controls in place on the manufacturing environment, materials and processes; and the manner in which the sterilisation dose has been established. The standard balances the frequency of sterilisation dose audits with that for bioburden determinations; as the sterilisation dose audit frequency is reduced, the requirement for routine determinations of bioburden increases.
An out-of-specification bioburden result could trigger a sterilisation dose audit. The standard permits the frequency of sterilisation dose audits to be reduced as experience is gained and successful audit results obtained with a product over time.
The usual practice on revision of an international standard is for the previous version to be withdrawn after six months. This is potentially problematic for a standard used to demonstrate regulatory compliance, as is the case with ISO 11137 and EN 552. Therefore, it was decided that there should be a three-year transition period to allow manufacturers adequate time to prepare and revise their supporting processes and documentation.
With the expected publication of EN ISOI 11137-1, -2 and -3 in late 2005, this transition period will run until late 2008.
A RAISED STANDARD
EN ISO 11137, which will replace ISO 11137:1995 and EN 552 as the standard for validation and routine control of radiation sterilisation, should be published at the end of 2005. This revision to the standard will provide manufacturers with opportunities by confirming the international acceptance of Method VDmax25, defining a more flexible approach for maintaining the effectiveness of the sterilisation dose and introducing Method VDmax15 for the substantiation of 15 kGy for the sterilisation of product with average bioburden below 1.5.