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Sterile medical devices represent a challenge for their manufacturers. The requirements set strict boundary conditions, must be constantly monitored and complied by all means. seleon advises through various sterilisation processes and their associated procedures.


All sterile or what?

Sterile products represent a significant part of the medical device market. Many consumables are supplied in sterile condition. Often also as accessories for reusable medical devices. These can be purchased and marketed with the own medical device as a system or approved under the own label. In this way, an active medical device manufacturer can quickly become a manufacturer with sterile medical devices. What does it take to manufacture, sterilize and approve a sterile product? And what needs to be considered when controlling the outsourced processes? If you have been in the sterile products business for a while, you will already know the most important basics and principles. But if you are still at the beginning of your "sterile career" or only have an outdated level of knowledge incl. outdated files that drive you to despair, then we would like to take you on a journey through the complex world of sterilisation.

We will look at the approach to validation for various sterilisation processes, but also deal with the topic of "bioburden". The often underestimated topic of "sterile barrier systems" and the associated packaging validation will also receive the necessary attention. Because each of these sub-areas has its own particular challenge, but they all cannot do without each other.

First of all, let's take a look at the terminology and first deal with sterilisation using ethylene oxide (EtO).

What does sterile mean?

Sterility refers to the condition of a medical device that is free of viable microorganisms. In practice, this condition cannot be proven unconditionally. Therefore, the sterility assurance level (SAL) is used. It indicates the probability of the presence of a single viable microorganism on a product after sterilisation. In general, the aim is to achieve an SAL of 10-6, although the level to be achieved should always depend on the end product and its intended use.

The term "sterilisation" is defined as a validated process for freeing a product from viable micro-organisms.

This sterilisation process is validated with the aid of a process challenging device (PCD). It represents a system that has been constructed to represent a defined difficulty in relation to a sterilisation process. Depending on the method, there can be different approaches to validation. It can be a real product or a simulated product. For sterilisation by means of EtO and the associated validation, it should, for example, have a worse gas accessibility than the actual product to be sterilized in order to be used as a worst case and thus be able to transfer the results to the product to be sterilized.

The sterile barrier system represents the primary packaging of sterile medical devices that must maintain sterility after the sterilisation process. It prevents the entry of microorganisms and enables the aseptic provision of the product at the point of use. Probably the best-known material for sterile barrier systems is TYVEK®, which is combined with other materials to form primary packaging.

Sterilisation methods

The three most widely used sterilisation methods in medical technology are sterilisation by ethylene oxide, by radiation and by moist heat. We would like to devote our series of articles to these sterilisation methods. In addition, there are the less common options of sterilisation with dry heat and with low-temperature steam formaldehyde (NTDF) as well as water peroxide plasma sterilisation.

What is there to know in detail about ethylene oxide sterilisation?

Ethylene oxide is a mutagenic, toxic and highly flammable gas which, when fumigated, kills microorganisms by rendering cellular components inactive. Water serves as a catalyst in these reactions, making relative humidity an important parameter in the reaction. The use of EtO for sterilisation of medical devices is widespread, especially for products that are sensitive to heat and radiation. The sterilisation process using EtO is relatively complex and subject to strong control by process parameters. Among the most important, but by far not all, are:

  •     Gas concentration
  •     Temperature
  •     Overpressure
  •     Exposure time

In EtO facilities, the products are usually pre-conditioned on pallets (quantity depending on the size of the sterilisation chamber) first to the temperature and humidity required for the process and then gassed with EtO, whereby the actual exposure time only begins from the time when the chamber is completely filled with EtO. This phase usually lasts several hours and represents the actual sterilisation of the products, which are penetrated by the ethylene oxide during this phase.

Desorption then begins, i.e. the gas is drawn off again from the chamber. In most cases, the products are then transferred to a separate chamber, where the degassing phase follows. During this phase, residual gas escapes from the products, which is a desired and necessary process step due to the critical properties of EtO. The determination of this outgassing phase can be a complex endeavour under certain circumstances, always depending on the design and the intended use of the product. The regulatory requirements for this can be found in EN ISO 10993-7 as well as in the respective national legislation and guidelines, which sometimes contain stricter requirements than the standard.

The above-mentioned process parameters are monitored via various sensors throughout the entire process and form the basis for the release of the sterilisation batch. Requirements for this or for their determination are contained in EN ISO 11135.

The selection of the cycle parameters and the duration of the gassing, exposure and degassing time are strongly dependent on the gas accessibility of the sterile barrier system and the geometry of the medical device. Multilayer packaging or folded layers, narrow tubes, cavities on or in the medical device, as well as the loading structure have a strong influence on the gas accessibility, which must be taken into account accordingly.

EtO thus represents a highly complex sterilisation method. Disadvantages are the relatively long cycle durations, the costs and the use of a toxic reagent. Nevertheless, this method is widely used, as other methods put significantly more stress on the materials and thus the safety and performance of medical devices is no longer given.

EN ISO 11135:2019 - Requirements for sterilisation with ethylene oxide

EN ISO 11135 establishes requirements for the development, validation and control of the application of the ethylene oxide sterilisation process for medical devices. Many requirements are usually fulfilled by the operators of the EtO plant, e.g. structural regulations, sensor technology in the gassing chamber or the Installation Qualification ("IQ") and Operational Qualification ("OQ") of the site. Nevertheless, some product-specific activities related to sterilisation remain for the manufacturer. Depending on whether or not there is an existing Process Qualification of the operator, the following items may become necessary:

  •     Evaluation of the gas accessibility of the medical device and its sterile barrier system
  •     Selection of a suitable cycle procedure
  •     Determination of the permissible bioburden before sterilisation
  •     Proof of product compatibility (assessment of the safety and performance of the product by the sterilisation method)
  •     Proof of suitability of the PCD (Process Challenging Device)
  •     Subordination of own product to an already established PCD
  •     Proof of suitability of the bioindicator (process definition)
  •     Proof of reaching the Sterility Assurance Level
  •     Determination of possible gas residues and definition of the outgassing phase
  •     Contractual agreement with the contract sterilizer according to the requirements of EN ISO 11135

So which aspects should all be covered in a validation report, you ask? In addition to EN ISO 11135, the somewhat outdated ZLG paper3.9 B 26, which lists the minimum contents of validation reports for EtO, can help here. This also includes information on the characterization of the equipment, the IQ and the OQ, i.e. activities of the contract sterilizer, over which most manufacturers have no influence. Under the MPG, the relevant documents were often referenced here and an on-site inspection by the contract sterilizer was made possible. How handling these extensive reports under the MDR remains to be seen, since it is generally a documentation according to point 3b from Annex II, which are to be "fully included in the technical documentation".

Often, inexperienced manufacturers in these areas rely on their contract sterilizer or a supplier to perform sterilisation on the manufacturer's behalf. This can lead to unclear documentation and responsibility problems. However, the manufacturer of the medical device is responsible for the validation of all process steps with regard to product conformity in the sense of a new approach conformity assessment procedure, as it is represented by the MDR and also already applied under the MDD. If he outsources relevant activities, a control of these activities as well as the conclusion of quality agreements and the review of processes and validation documents are a must for a compliant manufacturer. Many steps of sterilisation also affect the actual product design and are therefore to be kept as evidence in Chapter 6.2, Annex II of the MDR. A well-functioning cooperation between the process owner (usually the contract steriliser) and the product owner (the manufacturer) is therefore essential and not easy to carry out if there is insufficient process and product knowledge. It is therefore also of particular importance for manufacturers to build up know-how within their own company and, if in doubt, to seek support from an external expert. Especially in view of the increased requirements and the harmonization of EN ISO 11135:2014/A1:2019 under the MDR as well as the IVDR, manufacturers should, in case it has not already happened, contact their contract sterilizers and check the documentation for compliance with this version of the standard.

Have you already set your sights on EN ISO 11135? But is the fog of requirements still blocking your view? Or do you want to market a sterile product under the MDR for the first time? Contact us, we will be happy to assist you, also in the communication with your supplier.

Please note that all details and listings do not claim to be complete, are without guarantee and are for information purposes only.

Every product is unique – the mandatory tasks and measures for entering the market need to be specified individually. seleon advises you on your individual questions without any obligation.


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