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Introduction
Medical devices sterilized by Ethylene Oxide (EO) contain certain amounts of carcinogenic, mutagenic, and/or irritant substances ethylene oxide and ethylene chlorohydrin so that respective limits are defined in the applicable standard ISO 10993-7:2008.
Amendment 1 of the ISO 10993-7:2008 “Applicability of allowable limits for neonates and infants” was published and directly became effective in December 2019. Although the ISO 10993-7:2008/Amd.1:2019 (AMD1) might be seen only as a clarification of already existing requirements, it will force many medical device manufacturers to take action.
What are possible consequences for medical device manufacturers and who is affected?
Your product is most likely significantly affected if the target patient population consists of patients younger than adults or if your product (e.g., a procedure pack) consists of more than 5 medical devices and if with your current process you already measure relatively high EO sterilization residual levels.
Especially for these manufacturers, the fulfilment of AMD1 can lead to significant consequences as new and more complex EO residual studies, changes in the product design, changes in the sterilization cycle with new validations, a significant increase of throughput time, and exclusion of certain patient populations.
What is the time frame for getting compliant with the AMD1?
There is no transition period for the fulfilment of the AMD1. Also, because the content of this amendment can be seen as an already existing requirement, as the ISO 10993-7:2008 has derived to the body mass consideration with the calculation of allowable daily limits of EO/ECH in the informative part of the standard in e.g., Annex G.6.4.
However, due to possibly different interpretations of the requirements (which were the reason for AMD1 to be issued), some medical device manufacturers might have gaps here. These manufacturers should at least have a QM-released plan in place about how and when eventual gaps are planned to be covered.
What are the changes and the potential impact?
Following two changes are the most important topics with regards to AMD1 and thus discussed in more detail. A listing of all changes and their evaluation is given in the Table-1.
(Please download the Table-1 linked below. Open the article from your PC if link to table does not appear.)
1) Adaption of residual limits on body mass of intended patient population
The main change coming with the AMD1 is the clarification that “when the device is intended to be used in special populations, the appropriate patient body mass shall be used for the derivation of the allowable limits. For example, if the device is intended to be used in premature neonates, neonates or children, the allowable limits shall be derived using the TI (Tolerable Intake) value of 0.30 mg/kg/day for EO and 0.64 mg/kg/day for ECH as established in G.6.2 and H.4.1.1, for limited exposure. The appropriate default body mass used for each category of special patient population shall be justified and documented” (see Ch. 4.3.4 last paragraph and further chapters of AMD1).
ISO 10993-17 is closely related to ISO 10993-7:2008 and specifies 3.5 kg for neonates and 10 kg for children as default values (see Ch. 6.2.2). Applying a body mass of 1 kg for premature infants has been discussed e.g., in the ANSM communications, but no clear reference is given in the AMD1. However, 1 kg might be the appropriate body mass if premature infants are specifically applied for the device.
Accordingly, the limits applicable for products that are explicitly intended to be used for neonates would be reduced as follows:
With TE: Tolerable Exposure
For devices where the use at adults is dominant but the use at neonates or children is not explicitly excluded it might under certain circumstances still appropriate to justify based on a risk assessment why adjustment of allowable limits to weights lower than 70 kg is not considered. This should include a Risk-Benefit Analysis (this principle is in practice currently applied by some manufacturers and might be still accepted or even recommended by notified bodies).
For devices that will not be pediatrically used (e.g., due to size of device or exclusion in the IFU), a statement should be added to the EO sterilization documentation and the limits will stay with the default values.
2) Adaption of limits depending on the number of devices used at one time
Another important change that might impact certain manufacturers is the adaption of limits dependent on the number of devices used at one time described in Ch. 4.3.1, 3rd paragraph of the AMD1 saying: “If data are available, consideration should be given for proportioning the limits downward if multiple devices with the residue of concern are used at one time, e.g. multi-device systems, convenience kits, or proportioning the limits upward when device use is only for a part of the exposure period of concern. These concomitant exposure factors (CEF) and proportional exposure factors (PEF) are given in ISO 10993-17. A default value of 0.2 for CEF has been given for 5 medical devices used and contributing to the patient residues daily exposure.”
Accordingly, if a convenience kit would consist of e.g., 10 medical devices, the CEF would be reduced from 0.2 (based on 5 medical devices) to 0.1 and thus the limits for each of the individual devices inside the set would be reduced by 50 %.
In many cases, the reduction of residuals only based on the number of medical devices might lead to an unnecessary restriction as e.g., if a set (with limited exposure) consists of 9 small swabs with relatively low levels as e.g., 0.1 mg EO per device and one surgical gown with relatively high levels of e.g., 3.0 mg per device. The limits would have to be reduced for the surgical gown, although the overall EO levels of the set would be relatively low. In such cases, it might be appropriate to justify in a risk assessment why adjustment on a number of devices is not considered, e.g., supported by a limitation of the total amount of EO sterilization residuals in the set.
In practice, it might be again appropriate to cover this requirement by a risk assessment similar described above instead of reducing the limits (e.g., if a portfolio consists mainly of sets containing one device with high EO residual levels and e.g., 15 pads with very low levels).
Please find a detailed listing of all changes and the potential impact of the AMD-1 in Table-1. ( link is shared above).
Approaches for affected medical device manufacturers
Following approaches can be applied in parallel or individually for reduction of EO sterilization residual results. Some of the approaches require great efforts as e.g., a change of the product design, and would usually be only implemented if other, less complex approaches as e.g., optimization of laboratory methods would not sufficiently reduce the residuals.
1. Optimization of laboratory methods
Optimization of the laboratory methods will of course not reduce the level of residuals inside the devices but can be a very efficient approach to significantly reduce the measured values.
Following optimizations are often very effective and at least some of them can often be applied by legal manufacturers:
a) Perform simulated use extraction with shorter extraction time: For simulated use extraction is frequently applied a 24 h extraction time by default, although the device is only applied for much shorter times (e.g., a syringe filled with a medium which is then injected into the patient’s blood). We experienced reductions of EO sterilization residuals of up to 90 % by reduction extraction time for simulated use extraction from 24 h to the max. expected use time of the device of e.g., 10 min.
b) Test only the surfaces with direct patient contact instead of the whole product:
Often products are completely immersed in water for simulated use extraction, although only a part of the device is getting in contact with the patient (also indirectly contact by liquids entering his/her bloodstream) as e.g., a syringe or tubing.
Only the part with direct patient contact must be measured, e.g., by filling the device with water. Following the example of the syringe, a reduction of more than 50 % can be expected as the plunger rod and outer part of the syringe barrel will not be extracted.
c) Reduce simulated use extraction temperature from 37 °C to 25 °C:
Simulated use extraction temperature for products that have no direct patient contact and get in contact with liquids at room temperature might be able to be reduced from 37 °C to 25 °C.
d) Priming/rinsing before extraction:
If rinsing or priming of the devices is demanded in the IFU before, this can also be applied before extraction of the devices and will lead to a reduction of the EO sterilization residuals, especially in the case of short simulated use extraction times of e.g., 10 min.
e) Change from exhaustive to simulated use extraction:
A change from exhaustive to simulated use extraction would reduce EO sterilization residuals by up to 90%.
2. Validate single instead of double sterilization
A sterilization cycle fails to question the sterility assurance level of the devices so that it is important for the manufacturers to have the option of a re-sterilization for such cases. Many manufacturers, therefore, perform EO sterilization residual studies only with double sterilization, so that a re-sterilization can be performed in routine without additional tasks as e.g., EO sterilization residual tests of certain devices and assessments. This might lead to unnecessary long degassing times for 99 % of their cycles.
A usually more recommendable approach would be to perform at least the main part of EO sterilization residual studies with single sterilization. If re-sterilization is necessary in routine, then products can still be special-released with an assessment supported by longer degassing times and specific EO sterilization residual tests (lot release according to ISO 10993-7 Ch. 5.2). Under certain circumstances, it might be useful to complete EO sterilization residual studies with some data for double sterilization.
Please note that other studies for product integrity or biocompatibility must be usually performed with double sterilization allowing re-sterilization in routine.
3. Optimization of sterilization cycle and system
The EO sterilization residual levels can be significantly reduced by optimizing the sterilization parameters. There should be an optimization between the parameters of microbiological, physical, and product safety requirements.
Some of the possible approaches for optimization of the sterilization cycle are summarized below:
a) Adding gas wash pulses like steam, air, or dilution gas (non-reactive gases like nitrogen, carbon dioxide, etc.) after gas dwell time to dilute the EO gas. This dilution will help to reduce the EO concentration inside of the product during the sterilization cycle.
The EO gas molecules can easily hold on to the water molecules.
b) Deeper vacuum, optimization of vacuum levels, and optimized holding times are also an option if it is applicable regarding the product and packaging safety. The deep vacuum and vacuum holding times will help to aerate the product.
c) Increase of temperature in active and passive degassing phases will help to accelerate the removal of the EO from the products. It is demonstrated with many tests that the aeration time is reduced to half with every 10° C temperature increase.
Air circulation through the load is an important criterion during the active and passive degassing phases. If it is applicable, the aeration of the products can be supported with a fresh air injection applied to the load. The injected fresh air temperature should be considered to avoid a temperature decrease. There needs to be a distance between the loads and pallets to provide air circulation. If it is applicable, the EO can be exhausted with a ventilation system in the passive aeration room.
d) Vacuum degassing cell system will accelerate the evacuation of the EO sterilization residuals out of the packaging and products during aeration with heated fresh air. Dependent on the product and process, time reductions of up to 65 % and more can be expected when performing the aeration in a vacuum system instead of a usual heated aeration.
4. Change from overkill to bioburden approach
Using the bioburden approach instead of the overkill method for the validation can also reduce the EO sterilization residuals significantly.
The injected EO amount can be reduced (keeping the same EO-dwell time), by using the bioburden approach (ISO 11135 annex A). As a rule of thumb: a 50% reduction of the EO concentration results in a 50% reduction of EO sterilization residual levels on the products.
5. Optimization of product design
The EO sterilization residual levels are strongly related to the design of the product. Complex product designs and certain material types are very critical criteria for residual levels of products.
The following optimizations regarding product design can be an option to reduce EO sterilization residual levels.
a) Optimization of product design as e.g., increasing number of openings, decreasing the amount of material, especially the parts of significant patient contact, and change of materials.
b) Optimization of sterile packaging design for EO removal by increasing the permeable area of the packaging.
c) Sterilization in baskets instead of cardboards, as the latter absorb EO gas during the sterilization cycle and reduce aeration of the product.
d) Optimization of pallet configuration by decreasing the pallet density or stacking with a chimney in the middle of the pallets.
6. Split of products in different target patient populations
In case products are intended explicitly to be used for neonates as well as for adults and the limits of neonates would have to apply, it might make sense to split such products into a neonate and an adult version so that at least for the adult version the higher limits and accordingly lower degassing times might apply.
7. Change of sterilization method
A change from EO sterilization to another method as radiation or steam sterilization can be a reasonable approach. A change e.g., from EO- to Gamma-sterilization can be relatively simple and implemented by only a respective sterilization validation and several (eventually reduced) additional studies as e.g., for biocompatibility and product and packaging integrity. In certain cases, a change can be extremely complex and require several years of development but might still be reasonable as e.g., the change is put into practice by many manufacturers of single-use dialyzers from EO to steam sterilization.
How can SteriComp support you?
SteriComp GmbH is a German consulting company specialized in the sterilization of medical devices and has many practical experiences in performing EO sterilization residual studies in accordance with AMD1, meeting expectations of notified bodies and authorities, and considering your business needs.
A typical AMD1 project with SteriComp would contain the following steps:
First non-binding meeting to discuss your needs and possible support from SteriComp,
Preparation of basic investigation report, containing a GAP analysis for the AMD1, a discussion of promising approaches considering your gaps and your business needs, and estimation of project costs and timelines.
Performance of feasibility study containing a detailed assessment of the effectiveness of individual approaches (covered usually by explorative EO sterilization residual studies) and evaluation of their impact on your organization.
Performance of EO residual studies, considering the chosen approaches as e.g., a new product grouping and its QM-documentation or new laboratory methods.
Implementation of possible changes in your routine process.
We look forward to hearing from you to agree to a first meeting!
Please contact us via phone on +49 7326 27399 80 or email as to info@SteriComp.com
BIBLIOGRAPHY
[1] ISO 10993-7:2008 Biological evaluation of medical devices — Part 7: Ethylene Oxide sterilization Residuals.
[2] ISO 10993-7:2008/Amd.1:2019 Biological evaluation of medical devices — Part 7: Ethylene Oxide sterilization Residuals. — AMENDMENT 1: Applicability of
allowable limits for neonates and infants
[3] ISO 10993-17 Biological evaluation of medical devices — Part 17:Establishment of allowable limits for leachable substances.
[4] ANSM Information update: Ethylene oxide-sterilized medical devices in neonatology and paediatrics: Implementation of standard NF EN ISO 10993-7.
DISCLAIMER
The article is provided by SteriComp on an “as is” basis from the related amendment 1 of the ISO 10993-7. This article makes no representation or warranties of any kind, express or implied, as to the operation of your services, or the information, content or materials included therein.
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