Setting new standards for medical devices

The standards for sterilisation of medical devices have been revised in the past few years. Henry Sibun, manager of Medical & Health Services for TÜV Product Service gives an overview of what a Notified Body auditor looks for in a company’s sterilisation validation.

In 600 BC Homer wrote in The Odyssey that on Odysseus’s return he fumigated his home, saying: “Bring me sulphur, which cleanses all pollution, and fetch fire also that I may burn it, and purify the cloisters” (burning sulphur produces sulphur dioxide).

The writings provide a good indication that the need to protect ourselves from unseen micro-organisms and the diseases they cause has been known for millennia. However, it was not until 1875 that Louis Pasteur developed pasteurisation and our understanding of the causative agents progressed significantly.

There are many methods to produce sterile products, including physical methods such as radiation or heat (dry/moist) and chemical methods such as ethylene oxide, glutaraldehyde, formaldehyde, hydrogen peroxide, ozone and peracetic acid .

Ensuring medical products are sterile is a complex process and the standards for the three main commercially used processes were all revised in 2006 and 2007. These include the standards for ethylene oxide (EtO), radiation and moist heat (see Table 1). These new versions replaced and combined the old standards at European and International level into single standards. They are much more detailed and longer than those they have replaced (see Table 2).

Recent changes

All standards are reviewed on a regular basis – usually every five years. The old standards (see Table 2) were mostly published in 1994 or 1995 and it was decided in 1999 to revise jointly the European and International versions and issue a combined standard. Although the old EN and ISO standards were technically the same, there were editorial differences and manufacturers selling into both the US and Europe had to work with and show compliance with both versions. The wording in some parts of the guidance annexes was also open to different interpretations.

The most obvious change is that all three requirement standards (the part-one standards) have a common structure and format and use the same terminology. This is based on the ISO 14937 standard,1 which defines the content and structure for all future standards covering sterilisation and gives a much more consistent basis from which to work for those companies that apply more than one method of sterilisation. The requirements for the different sterilisation methods are now all specified to the same level of detail.

The clauses of the three part-one requirement standards are now the same and are shown in Table 3. All three printed standards now take up many more pages, being 30-60% longer. In the case of both EtO and Moist Heat a “part 2” of the standards will be published in the form of a “Technical Specification” rather than a standard itself. These will give comprehensive guidance on application of the requirements in the Part 1 standards as well as general information in support of the sterilisation method.

Validation

The new standards give a much more detailed and clearer explanation of validation. They also use the international terminology of Installation Qualification (IQ), Operational Qualification (OQ) and Performance Qualification (PQ).

Detailed protocols for performing validations are essential to ensure that the process is adequately validated. Much time can be saved by putting the majority of the effort of the validation into developing and writing the protocol rather than the report.

The protocol:

• helps to define the process and make sure that all important parameters are identified for monitoring;
• makes the review at the end of the validation simple and objective (pre-defined acceptance criteria);
• reduces the need to repeat parts (or all) of the validation because important aspects are missed out.

Although the standards give details of the activities within the validation they are not prescriptive about the contents of the protocol. Detailed information on validation protocols is provided by the Global Harmonization Task Force (GHTF Study Group 3).2

Validation protocols are recommended to include the following:

• Identification of the process to be validated;
• Identification of device(s) to be sterilised using this process;
• Objective and measurable criteria for a successful validation;
• Length and duration of the validation;
• Shifts, operators, equipment to be used in the process;
• Identification of utilities for the process equipment and quality of the utilities;
• Identification of operators and required operator qualification;
• Complete description of the process;
• Relevant specifications that relate to the product, components, manufacturing materials etc;
• Any special controls or conditions to be placed on preceding processes during the validation;
• Process parameters to be monitored, and methods for controlling and monitoring;
• Product characteristics to be monitored and method for monitoring;
• Any subjective criteria used to evaluate the product;
• Definition of what constitutes non-conformance for both measurable and subjective criteria;
• Statistical methods for data collection and analysis;
• Consideration of maintenance and repairs of manufacturing equipment;
• Criteria for revalidation.

Validation reports

The validation report allows a simple review of the results of the actual activities undertaken against what had been planned. This report should be factual and brief with the minimal information necessary to record how the protocol was met. All deviations from the protocol requirements must be listed, discussed and justified.

The test results should be summarised against the acceptance criteria (preferably in a table) so that the reviewers can easily see if these have been met. Statements on whether they have been met or not should be made and any non-conforming results discussed, leading to a suitable justification of accep-tance or corrective action. A conclusion must be made that clearly states whether the validation requirements have been met.

Appendices with all raw data should be attached. The final report should be reviewed and approved by the validation team and appropriate management.

Regular review

The validation process has not been completed until the re-qualification requirements have been defined and documented. Requalification requirements include a regular review of the sterilisation process at defined intervals according to documented procedures. The statement “the sterilisation load has not changed” is not a sufficient justification for not conducting any requalification activities!

The procedure should summarise and discuss all changes including:

• product changes during the year (e.g. new products, physical changes to existing products, new raw material suppliers, etc.);
• product bioburden levels;
• environmental monitoring results;
• changes to the manufacturing facility;
• changes to personnel in the product realisation process;
• changes to the steriliser (including maintenance, repair, etc.)

Depending on the outcome of this review, a decision can be made on what level of re-validation is necessary.

There are a number of non-conformities found during audits of companies manufacturing sterile medical devices that are very common, including:

• No summary description of the steriliser (e.g. load volume, usable chamber volume, total chamber volume, etc.);
• Sterilisation cycle development conducted simultaneously to the validation activities – the specification including tolerances for all parameters should have been determined prior to starting PQ;
• Validation protocol has insufficient detail to allow the validation results to be judged against it;
• Validation report indicates that protocol was not followed but there is no explanation of this (e.g. protocol required 21 temperature probes, the report stated 15 were needed, location map showed 11 probes & the data traces for 13!);
• Deviations from the requirements of the protocol are not identified or discussed in the report;
• The validation report (ethylene oxide) does not summarise all of the points listed in section 9.5.4 of ISO 11135-1 and tolerances are not given for all of them;
• Compliance with the Standard is claimed but not all requirements met or followed;
• No traceability from results to steriliser number or cycle number;
• Steriliser timer is not calibrated or checked

Unexpected results or errors during the validation are common – as long as they are acknowledged and discussed, this is not a problem.

Summary

The standards for ethylene oxide, moist heat and radiation sterilisation have been substantially revised and re-issued with a common structure. The international and European standards have been combined into one.

The Validation Protocol should be a detailed “meaty” document defining all of the expected outcomes (including tolerances) and what to do if they are not met. The Validation Report should summarise the parameters observed (and their ranges) and compare them with those expected in the protocol.

Regular review

All deviations to the Protocol, however small, must be documented and justified in the report. The sterilisation process should undergo a regular documented review according to a defined procedure. The procedure should define the inputs to the sterilisation process that could influence its adequacy.

Time and effort invested in getting the protocol right will save time when reporting and trying to make sense of data if it was not as expected. A well-documented (but concise) validation will be simpler to review and approve internally. It will also speed up Notified Body reviews and reduce the risk of non-conformities being raised.

Compliance with the EN55X standards will cease to be a presumption of conformity with the Medical Devices Directive on the following dates: EN552 on 30 April 2009, EN554 on 30 August 2009 and EN550 on 31 May 2010.

A greater expertise in sterilisation is needed; if this is not available in-house, buy in this expertise. Don’t rely on external sterilisation companies to tell you what to do – they are a knowledgeable source of information but you need the ability to independently review the validations. Obtain copies of the new standards (discuss these as part of management review).

Three-year transition periods were given before the previous versions become obsolete but these are now down to ~7 months (irradiation), ~12 months (moist heat) and ~21 months (EtO). Start working now to ensure all processes are updated and revised in accordance with the new standards – conduct a gap analysis on your procedures and prepare an action plan with timescales for compliance with the revised standards.

Make sure staff in R&D are aware of the new standards so that they are taken into account in the development process.