Sterilisation updated

Despite a reticence to comply by some manufacturers, regulatory changes surrounding the sterilisation of health care products is leading to improved quality and reduced costs

The publishing of the updated standard, ISO 11137: 2006 (Sterilisation of health care products – Radiation – Part 1: Requirements for development, validation and routine control of a sterilisation process for medical devices) has more clearly defined the validation requirements for manufacturers who label products sterile in accordance with the Medical Device Directive. Isotron has also observed that this change has led to regulatory bodies requiring total conformance to this standard.

Although this requirement to fully comply is seen as negative by some manufacturers (due to the increased costs), both the standard and the industry have developed over the last 15 years to bring cost benefits elsewhere in the manufacturing and sterilisation process. These new methods have also been designed to offer more cost effective solutions and ways to reduce testing costs over the product life cycle.

In order to study the current standard in more detail, we need to look at the first ISO 11137 standard which was published in 1995 as an international standard clearly outlining “the requirements for development, validation and routine control of radiation sterilisation for medical devices.” This progressed significantly further than previous localised standards, as it detailed the methods that could be used to establish the required minimum dose of radiation needed for products to conform to a sterility assurance level (SAL) of 10-6.

Despite this significant development, the standard received negative feedback from manufacturers who focused on the costs. This included the costs to undertake the microbiological testing in conforming to this standard and the cost of product that would need to be tested (and hence destroyed) by implementing the methods described. This meant 130 products for Method 1 and 840 for Method 2.

Another criticism was that the 1995 standard did not specify the frequency at which the test should be undertaken. This was due to the ambiguity of the standard which allowed manufacturers to use historical data to conform without undertaking Method 1 or 2 and would need to be clearer to confirm maintenance of process effectiveness. In such cases historical dose information (use of Minimum 25 kiloGray (kGy) for many years), regular and controlled bioburden and risk assessments meant some manufacturers were able to undertake one initial Method 1 without subsequent audits, or in some cases to do no microbiological dose setting validation at all.

The latest version of ISO 11137 addressed the concerns of industry previously noted but also looked at areas of uncertainty for manufacturers and notified bodies. It was published in 2006 after years of developing the standards within ISO, with a number of key changes being made. These included:

1. The addition of the dose substantiation method VDmax, which allows the manufacturer to use a minimum of 40 products for testing rather than at least 130 which reduces microbiological testing costs and also product costs. Two doses can currently be substantiated – 15kGy or 25kGy with more likely to follow.

2. Dose auditing (ISO 11137-1 clause 12.1) must be carried out to ensure the continued effectiveness of the established sterilisation dose and ISO 11137-1 clause 12.1.3 details the requirements for the frequency of dose audits.

3. As ISO 11137: 2006 is a harmonised standard, compliance with this means you are presumed to comply with the relevant essential requirements of the Medical Device Directive. However, application of the dose establishment methods remains voluntary, which means manufacturers are free to choose any technical solution, but must meet the essential requirements of the Medical Device Directive.

Since the end of the transition period between the 1995 and 2006 standard, Isotron has observed a real shift in the regulatory environment within the UK. This includes a key difference in the requirement from regulatory bodies to see the standard implemented in its entirety by all manufacturers of medical devices. The cost of product, bioburden control and use of 25kGy are now no longer acceptable reasons for avoidance. To accommodate this shift brought about by the standard changes, Isotron has recently completed significant investment in its laboratory capacity to support the increased needs of the industry at this time and going forward.

Despite the potential criticisms from manufacturers, this significant shift by regulatory bodies and the industry should not been seen in a totally negative light. A key benefit to the shift is in patient safety, whilst conformance to the standard will also reduce the risk of mitigation in the event of patient infection or problems in the application of product. Another notable benefit is the approach of the regulatory bodies to the standard, which means there will be uniform adoption going forward compared to the current situation where some manufacturers are conforming, whilst other competitors in the industry may not be doing so.

There will be a greater emphasis on suppliers of raw materials and components to the industry to improve product microbial quality. This is due to the requirement to increase monitoring not only of product bioburden but also efficacy to the irradiation dose. Additionally there will be reduction on quality related issues due to a better understanding of cleanroom conditions and the sources of contamination. Ultimately this will lead to a reduction in the cost of manufacture.

Another major benefit to manufacturers is the clause in the standard outlining the frequency of auditing (ISO 11137-1 clause 12.1.3), as they are now able to maintain a low and consistent bioburden. The clause clearly outlines that auditing can reduce from quarterly in year 1, to six-monthly auditing in year 2 and annually from year 3 onwards provided microbiological contamination is controlled and dose audits are successful. This means that the initial validation charges are not the norm throughout the whole product life cycle.

The standard outlines how product families or master products can be used to reduce the need to test every product line. This means that some manufacturers of very similar products only have to validate two or three product lines, whilst still conforming to the standard.

Also the use of VDmax as the test of choice by manufacturers means costs of microbiological testing and product write-off observed when the standard was first introduced are now significantly reduced. This brings overall validation costs in line with the levels experienced by ethylene oxide users for many years.

The main benefit, however, should be in the reduction of radiation dose. The historical use of 25kGy as a minimum sterilisation dose is still the norm today, even 15 years after ISO 11137 was first introduced. The introduction of Method 1 has shown that ultra clean products can be sterilised with doses as low as 11kGy, with the introduction of VDmax 15 and AAMI TIR33 allowing the substantiation of sterilisation doses to be lower than historical standards. This reduction is a significant decrease in time within the irradiation cell, a high proportion of which can be passed on by sterilisation providers in cost reductions. It should also be noted that the reduction in dose could lead to less product damage which may allow less expensive polymers to be used or product shelf life to be extended.

Isotron have also seen changes in requirements for industry members from medical device manufacturers to contract laboratories. This has resulted in companies like Isotron now being seen as an extension of these organisations rather than a service provider. Examples of the requirements include notifying manufacturers of required testing schedules, early notification of out of specifications, fast track testing for product release and consultancy support.

A consistent approach by the regulatory authorities should be seen as a positive move for the industry, as the standards have now been in place for a reasonable length of time. Both the standards and industry have evolved over the last 15 years to offer solutions that reduce costs associated with sterilisation and manufacturing, therefore compensating for the increase in microbiological testing. This now allows validation costs to be roughly equal to those experienced by users of ethylene oxide. Going forward, the introduction of more VDmax dose levels is another positive move which the industry should embrace.