Considerations For Establishing Endotoxin Limits For New-Age Medical Devices

Published on 15th May 2024

Microbial pyrogens, particularly bacterial endotoxins, are the main cause of fever, meningitis, and low blood pressure when introduced into the bloodstream or tissues. [1] This highlights the importance of pyrogen testing in medical devices to prevent the spread of infections. 

Medical devices vary widely in their intended use, design, and materials. Some devices directly contact blood, while others interact with cerebrospinal fluid or other bodily fluids. Therefore, the endotoxin limit for a specific device depends on its purpose and the type of contact it has with the body.

New Age Medical Devices

Modern medical devices are not plastic based (like catheters, blood sets, etc), but instead have evolved to be Cell based, Enzyme based, Irrigation devices and wound care devices. Examples include heart valves, vascular grafts, cerebral spinal shunt systems, intraocular lenses, skin grafts, bone grafts, solvents like normal saline, dialysis solution and more. 

To prevent misleading results, understanding the process of sample extraction and determination of endotoxin limits for a particular device is crucial.

Endotoxin Limits for Medical Devices

According to FDA guidelines, the acceptable limits for endotoxins on medical devices vary depending on how they will be used and their tissue contact. 

  • Products that come into contact with the cardiovascular system should have limits of 0.5 EU/mL in a recommended extraction volume of 40 mL or 20 EU/device. 
  • Devices in contact with cerebrospinal fluid are defined to have lower levels, with a limit of 0.06 EU/mL (in the same extraction volume) or 2.15 EU/device. [2]

In the past, endotoxin limits were defined for each device. Now, there is a push to define endotoxin limits per unit dosage for modern medical devices. 

Combination products include both devices and drugs (Prefilled drug/ biologic delivery system, Device coated with drug, Co-Package kit), and currently do not have a specific standard to determine endotoxin levels. 

To ensure patient safety, the USP General Chapter <85> Bacterial Endotoxins Test recommends that most drugs should not exceed a maximum endotoxin exposure of 5 EU/kg (within 1 hour), considering an average patient weight of 70 kg. 

The recommended maximum exposure for drug products given intrathecally (or epidurally to avoid accidental intrathecal administration) is 0.2 EU/kg in 1 hour. 

Topical ophthalmic drugs do not need a bacterial endotoxin test until they are declared pyrogen-free.

Calculation Of Endotoxin Level

The calculation of the endotoxin limit in parenteral drugs is usually done using the K/M formula. Here, K represents the Threshold Pyrogenic Dose (TPD) and M represents the drug dosage in units per kilogram per hour. K is a statistical measure of endotoxin activity required to cause rabbit fever.

The TPD for IV or IM administered products is 5 EU/kg/hr. If a product is administered Intrathecally (IT), meaning it is injected into the cerebrospinal fluid space, the K value is decreased to 0.2 EU/kg/hr. For non-intrathecal administration of radiopharmaceuticals, K equals 175 EU, while for intrathecal administration, K is 14 EU.[3]

Special Considerations in Pyrogen Detection Tests

Medical devices coated with anticoagulant, containing heavy metals, or having particulates can create testing challenges or affect their functionality. This is addressed by processes like digestion, dilution, adding buffers, centrifugation, or filtration.[4]

When multiple units of the same device from one manufacturer are used during a surgical procedure or placed in the same surgical site, they should generally adhere to the same limit of endotoxins as a single device that is administered during the procedure.[4]

In conclusion, establishing appropriate endotoxin limits for new-age medical devices requires careful evaluation, adherence to regulatory guidance, and a commitment to patient well-being. Manufacturers must collaborate with regulatory bodies and stay informed about evolving standards.

 

References

  1. Roth, J. and C.M. Blatteis, Mechanisms of fever production and lysis: lessons from experimental LPS fever. Compr Physiol, 2014. 4(4): p. 1563-604.
  2. Kimble, A., J. Hauschild, and G. McDonnell, Affinity and Inactivation of Bacterial Endotoxins for Medical Device Materials. Biomed Instrum Technol, 2023. 57(4): p. 153-162.
  3. McCullough, K.Z., Calculating Endotoxin Limits for Drug Products. Americal Pharmaceutical Review, 2018.
  4. Sandle, T., FDA guidance on pyrogens and endotoxin testing.