Are you capable of answering the Notified Body questions on EO sterilization validation?

Notified Bodies raise expectations regarding sterilization processes and controls

In the past, a sterilization validation could be easily arranged. The manufacturer would send a sufficient number of products to a sterilization company and would receive a validation report in return to use in the technical file. Currently, Notified Bodies are no longer satisfied by showing the validation report, but expect the manufacturer to be able to answer detailed questions on the validation process itself. This is not an easy task, especially for ethylene oxide sterilization (EO.)

As EO sterilization is the most widely used sterilization process, as well as the most difficult to understand, I will provide insight into this validation process, and which options are available to you.  This basic knowledge will assist you in providing a detailed explanation of the process to your Notified Body Auditor.   

The standard on the EO sterilization validation process  is the ISO 11135. The 2014 version of this standard combines two previous standards: the ISO 11135-1:2007 and the ISO 11135-2:2008. The first one contained the normative requirements for validation and routine control, and the latter one the guidance for EO sterilization. Although the EN ISO 11135-1:2007 is still harmonized in the European Community, I recommend following the 2014 version of the standard, as it covers the requirements of both previous standards and most importantly, the 2014 version is recognized (prescribed) in the USA. Thus, one validation then suffices for both your EU and your USA file.

Three main qualification processes are part of a sterilization validation:  the Installation Qualification (IQ), the Operational Qualification (OQ), and the Performance Qualification (PQ). The IQ and OQ are basic qualifications on the sterilization equipment and EO sterilization process, and thus should be arranged and documented by the EO sterilization company. The focus of this blog will be on the PQ, as the validation of the performance is what will be reported to the medical device manufacturer.  

The PQ should prove that the EO sterilization process is specifically capable of sterilizing your products in the configuration they are usually sterilized (i.e. in boxes, on a pallet, etc.). Usually ‘a worst-case load’ is used during testing, especially when the you have different products sterilized, or when there is variation in the loading density.

For sterilization, two different methods can be used:  the “biological indicator / bioburden approach” or the “overkill” approach. By far, most manufacturers apply the overkill approach, meaning the sterilization level is higher than the required Sterility Assurance Level (SAL) of 10-6 (which means a remaining chance of one non-sterile product per million sterilized products).

In the overkill method, the Performance Qualification (PQ) consists of two parts: during the microbiological PQ (MPQ), it is determined whether the products are sterile after the sterilization process, while in the physical PQ (PPQ), the focus is on the influence of the sterilization process on the performance of the product. The MPQ uses a half sterilization cycle, (half of the normal time in the sterilization chamber), and aims to show this is already sufficient to reach the required SAL of 10-6. The MPQ includes at least three tests (half-cycles), and during all three tests it is a requirement that all products are sterile. The full sterilization cycle is thus, an “overkill”. The PPQ testing method uses a normal EO sterilization cycle to show that after the product has been sterilized, it still performs as intended.

You can also choose to add a second cycle for the PPQ to confirm it is possible to sterilize the product a second time, without influencing the performance. The advantage of this double cycle is that in case the event something goes wrong during the first sterilization cycle, you can perform a second one, without the need for additional validations, because it is already proven that such a re-sterilization does not negatively affect product performance.

The set-up of the MPQ is the difficult part in the EO sterilization validation. During the MPQ, so called “Process Challenge Devices” (PCD’s) are placed inside and outside the load. These PCD’s contain so called “Biological Indicator’s” (BI’s), simulating contamination of the load. The BI is usually a strip with a million bacteria, of a species which is relatively resistant against EO gas. The terms PCD and BI are often mixed, which can lead to further confusion. The PCD inside the load are the Internal PCD’s (IPCD) and those outside are called External PCD (EPCD). The Internal PCD is representing the product, while the External PCD is a standard item used by the sterilization company as a control during the routine sterilization process. The challenge is to demonstrate that the BI’s in the Internal PCD are killed more easily than the BI’s in the External PCD.  This is checked during a separate “sub-lethal” cycle in which the sterilization cycle is too short to kill all of the million bacteria of the BI’s. When the percentage of kill is larger for the Internal PCD’s than for the External PCD’s, the monitoring of routine production cycles can be performed with External PCD’s only.

Apart from the sterilization validation itself, the subject of residual testing will appear, the residuals being the remains of the EO gas used during the sterilization process. Although residual testing is not directly part of the ISO 11135 standard, the standard does mention that the EO sterilization residuals should be below the levels mentioned in the ISO 10993-7 standard. For this reason, it is common practice to determine the EO (& ECH) residual levels as part of the validation process.

Finally, the receipt of the sterilization validation report is not the end of the process. The Notified Body requires proof that the results of the validation are actually used to determine the routine release process of products after sterilization. After routine sterilization, the manufacturer should compare the cycle parameters with the specifications of the validated cycle, and seek confirmation from the sterilization company that all BI’s in the External PCD’s were killed. It should be kept in mind that the PCD’s are process indicators, not sterilization indicators, and that a sterilization company will never guarantee that the products are sterile.

Many more details can be written about EO sterilization validation, for example, parametric release, the effect of design changes, or the adoption of new products under an existing validation, but this falls outside the scope of this blog. I hope this information will help guide you through some of the basic questions that might be raised by your auditor.

Should you require further support on this subject, do not hesitate to contact Qserve and ask for me!


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Jan-Paul van Loon
Post date: April 01, 2017
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