Sterile products represent a not insignificant part of the medical device market. Many consumables are supplied in sterile condition. Often also as accessories for reusable medical devices. Within the framework of our series on sterilization, we will focus on the various methods, but also on other processes related to validation. In the first part, we explained some key terms and took a look at sterilization using ethylene oxide.
In this second part, we will now focus on sterilization using radiation.
What is there to know about sterilization by radiation?
Sterilization using radiation can be performed using different types of radiation
- Beta radiation
- Gamma radiation
Beta radiation is produced during beta decay, during which a neutron in a radioactive element is converted into a proton by emiting an electron. Most often, the source of radiation is caesium-137, which converts to barium-137.
Gamma radiation, on the other hand, represents electromagnetic radiation that can occur during both alpha and beta decay. The alpha and beta radiation produced by these processes consists of charged particles, while gamma radiation consists of uncharged photons or quanta. For example, after beta decay of a caesium-137, an excited (metastable) barium-137 is produced, which emits the excess energy in the form of a gamma quantum (photon), thus producing gamma radiation. This radiation can be compared to X-rays, even though the cause of the radiation is different.
In both cases (beta and gamma), the radiation during sterilization energy input into the product takes place, which has or can have an effect on the product, the packaging and the microorganisms on it. Don’t worry, your product will not become radioactive as a result of the radiation!
The mechanism of action of sterilization with radiation is based on the indexing of strand breaks in the DNA. During this process, the microorganisms present on the product are being killed, but remain attached to the product as such. Since the radiation must penetrate the entire medical device on the one hand, but on the other hand must not negatively affect the functionality, performance and safety of the product, this sterilization method is particularly popular for simple disposables.
A central aspect for the development phase of a medical device and its sterile barrier system is the choice of material. Not every material is suitable for sterilization by radiation, because radiation not only causes chain molecules such as DNA to break down, but can also lead to degradative reactions in chain molecules such as those present in plastics, which means a deterioration in the material properties and thus in safety and performance over the entire product life cycle. However, there is also the reverse effect: in certain plastics, radiation sterilization can even lead to cross-linking reactions, which means an improvement in material properties. There are also plastics that behave neutrally in the applied radiation range and are thus neither positively nor negatively affected by the sterilization process. All this must be checked during the development phase and included in the material selection.
How does sterilization by means of radiation work?
Sterilization by means of radiation has a number of advantages over sterilization with ethylene oxide, which are found in particular in the sequence of the actual sterilization process and make it considerably shorter:
- Pre-conditioning of the products is not necessary.
- A downstream outgassing phase is not necessary.
- No limit values have to be taken into account with regard to the sterilization process.
- The products can be transported or placed on the market immediately after sterilization.
The process differs depending on the type of radiation in the area of the sterilization chamber or the packing method of the products: during gamma radiation sterilization, the products travel on pallets on an automated belt around a radiation source until the appropriate amount of kilogray (kGy), the radiation dose, has been reached. In contrast, with beta radiation, products are irradiated whilst packed in cardboard boxes, but not on entire pallets. The cardboard boxes are placed on a conveyor belt passing under the electron source and are then irradiated with the corresponding dose.
EN ISO 11137-1 & -2 – normative requirements for sterilization by radiation
For sterilization by radiation, there is EN ISO 11137-1:2015 + A2:2019 “Sterilization of healthcare products – Radiation – Part 1: Requirements for the development, validation and control of the use of a sterilization process for medical devices”. This standard and the related EN ISO 11137-2:2015 “Sterilization of healthcare products – Radiation – Part 2: Establishment of the sterilization dose” have also already been harmonized by the EU Commission for both regulations, MDR 2017/745 and IVDR 2017/746. The only thing that should not be confused is the edition statuses of EN ISO 11137-1, it is best to fall back on the DIN-EN-ISO version of 2020.
The validation of the sterilization method is relatively straightforward thanks to EN ISO 11137-1. First, EN ISO 11137-1 requires aspects of quality management, e.g. product realization and others, but these are generally covered by EN ISO 13485 and should not be particularly challenging. Aspects of characterization of the sterilizing agent or the process and equipment, as well as the acceptance assessment (IQ) and the functional assessment (OQ) are usually the responsibility of the contract sterilizer, as radiation sterilization is classically an outsourced process. Nevertheless, manufacturers should not blindly rely on their contract sterilizer in the area of IQ and OQ, but should find out its status. As with almost all sterilization validations, an important task of the manufacturer is the determination of the bioburden before sterilization, including warning and action limits. Compared to sterilization with ethylene oxide, the use of bioindicators is no longer necessary and is replaced by the use of dosimeters.
In the context of the performance assessment (PQ) that the manufacturer together with the sterilization service provider must provide for its products, the dose distribution using the product with a specified loading pattern in the irradiation container is necessary. When irradiating pallets or cartons, it is necessary to ensure that all products within these units receive the minimum dose to achieve sterility. And, of course, that the product is not exposed to more radiation than necessary so as not to adversely affect the safety and performance of the product. To ensure this, “dose mapping” is performed with a large number of measurement points. In the subsequent standard run, the data collected during the performance assessment can then be used to convert from the standard measurement points to the minimum and maximum dose to determine the actual radiation dose, and thus release the batch in question.
The EN ISO 11137-1 and EN ISO 11137-2 know several procedures for the validation of radiation sterilization:
- Procedure 1
- Procedure 2A and Procedure 2B
- VDmax Method VD max25
- VDmax Method VD max15
In methods 1 and 2, a product-specific radiation dose is first determined, which must then be validated. This means a high effort for demonstrating conformity. The VDmax methods are based directly on the application of a radiation dose of 25 or 15 kGy and are therefore much simpler in terms of validation effort; however, it applies, for example, that for VDmax 25 in the batch medium the bacterial load must not exceed 1000 CFU. For VDmax15 the value is 1.5 CFU germ load in the batch mean. In the following, we will only explain the VDmax method.
First of all, the bioburden is determined according to EN ISO 11137-1 on ten product units of three independent product batches each. The average load per product unit is determined. This bioburden must be determined with the aid of the correction factor. We will provide you with more detailed information on this in a subsequent article on the subject of bioburden as part of our series of topics.
The radiation dose to be applied in the dose verification test shall be taken either directly from Tables 9 or 10 of EN ISO 11137-2 or calculated using the formula SIP VDmax25 = (SIP equal to 1,0 VDmax25) + (SIP dose reduction factor × log SIP).
If this calculated verification dose is exceeded, the test must be repeated.
In connection with maintaining the effectiveness of a sterilization process, EN ISO 11137-1 specifies clear limit values and minimum requirements. In most cases, the bioburden is to be monitored at least every three months, in special cases even every month. A check during a renewed dose verification test as to whether the sterilization dose is sufficient is also carried out every three months, unless the extension of the time intervals is duly justified and special requirements are met.
Important parameters of radiation sterilization are:
- Radiation dose delivered in kGy
- Speed of the conveyor belt
- Loading pattern
- Density and material of the product and packaging
In summary, radiation sterilization has advantages in processing time and residue-free sterilization. Disadvantages can be that the materials or the device itself can be damaged and that sterilization plants generally cannot be connected directly to the own production and thus the products have to be delivered to the plant and transported back afterwards.
The following topics are new in the latest edition of EN ISO 11137-1:
Under 6.25 there is a new supplemented requirement for technical documentation. Point m) states that devices for adjusting the irradiation shall be documented which would take effect in case of malfunctions of the target cooling systems.
A definition for the product family has been added: Here, products can be grouped if their properties allow sterilization under the same defined process conditions and include the same type and number of microorganisms.
A sterilization dose for a product family can only be defined if the requirements for the definition of a product family according to EN ISO 11137-2 are met.
In chapter “8.2 Determination of the sterilization dose” reference is made to DIN EN ISO 11137-2.
You are now beaming with enthusiasm for this method? Well, as already stated, the method is becoming increasingly popular. We will be happy to assist you in providing all the necessary documentation and planning your processes together with your sterilization service provider.
You missed the first part? Then take a look here https://www.regulatory-affairs.org/entwicklungsprozesse/artikelseite-entwicklungsprozesse/der-dreck-muss-weg-auch-der-unsichtbare/
Please note that all details and listings do not claim to be complete, are without guarantee and are for information purposes only.