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Specifications for Endotoxin levels for Medical Devices

Endotoxin has the potential to trigger a pyrogenic response when introduced into the body. This response is dependent on the amount of endotoxin that is present and where in the body it has been introduced. Points of contact of concern are the blood, cerebrospinal fluid, and the intraocular area. Therefore, devices that are known to have direct or indirect contact with these areas are assigned an endotoxin limit. When a device surpasses its limit during testing it is potentially hazardous to the patient and should not be used. 

Endotoxin limits for drug products are determined by the quantity of drug administered to the patient and are therefore represented as EU/mg or EU/mL. These limits will be discussed in more detail in later posts. However, limits for medical devices are typically in units of EU/device as we must anticipate all endotoxin present in the patient contacting portion will be transferred to the patient during use. These limits may be represented in EU/mL, however this should only be done when the volume used for extraction is established and able to be kept consistent. For example, if 40 mL is used for the extraction of a blood contacting device then a limit of 0.5 EU/mL would be appropriate. If 50 mL were then used for extraction on one occasion the endotoxin present on the device would be slightly more diluted leading to a lower concentration of EU/mL. The 0.5 EU/mL limit would then no longer be appropriate. Further information regarding extraction methods can be found in the separate blog post “Extraction of Medical Devices for Bacterial Endotoxin Testing” included in this series.   

As the three points of contact in the body that are concerns for endotoxin have different sensitivities to endotoxin, pyrogenic responses can be elicited at varying levels. Therefore, the use of the device should be considered when establishing which device endotoxin limit to use. A blood contacting device should have a limit of 20 EU/device, 2.15 EU/device for devices contacting cerebrospinal fluid, and 0.2 EU/device is generally the guidance for ophthalmic devices. These limits do not necessarily represent the amount of endotoxin that is harmful to the different areas of the body. They are values which have been reduced to account for acknowledged inefficiencies in the extraction as well as the pooling of up to 10 samples that may be done during testing. However, they should still be considered the standard by which to determine the safety of a medical device. Implementing limits other than those listed above may be considered based on the device’s intended use. However any divergence from these limits must be thoroughly justified. 

Peter Cornelis, Ir.

Senior Expert Microbiology

Peter Cornelis graduated from the Catholic University of Leuven (Belgium) in 2000 as a Master in Applied Biological Sciences (Major Biotechnology). In 2003 he started working for Toxikon Europe (now Nelson Labs) as a study director Microbiology and in-vitro Toxicology. From 2007 until 2016, he was department supervisor for Microbiology and in-vitro Toxicology. Since 2016, he is responsible for research, validation, and development of new microbiological and in-vitro toxicological methods. Peter is a member of the ISO committee TC 194 WG5, Cytotoxicity and WG 8, Irritation and sensitization. As an expert, he was involved in the adaptation of ISO/TC 194 ISO/DTS 11796:2022(E) Biological evaluation of medical devices — Guidance for interlaboratory studies to demonstrate the applicability of validated in vitro methods to assess the skin sensitization of medical devices.

Nathan Pett

Study Director BET

Nathan Pett graduated from Utah State University in 2018 with a bachelors in Biochemistry. In 2019 he began work for Nelson Labs as a Lab Analyst and in 2021 transitioned to the role of Study Director in the BET department.

Emily Spackman, B.S., RM(NRCM)

BET Consulting Study Director

Emily Spackman has worked for Nelson Laboratories in the Bacterial Endotoxins Lab for over 16 years. She graduated from the University of Utah and holds a bachelors degree in Biology. She is a member of The National Registry of Certified Microbiologists and has experience with both medical devices and pharmaceutical products.