Material mediated pyrogenicity testing: MAT the road forward

Testing the material mediated pyrogenicity of medical devices is mandated by the ISO. With RPT now being transitioned away, and LAL unable to detect NEPs, the only feasible detector of material mediated pyrogenicity is the MAT test.

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What is material mediated pyrogenicity?

Academic research has not formally defined material mediated pyrogenicity. That being said, both academically and in the field, material mediated pyrogenicity is considered to occur as a result of contamination by a group of pyrogens outside of those comprising endotoxins, but within those constituting non-endotoxin pyrogens. More specifically, material mediated pyrogenicity is thought to derive from surfaces or materials of medical devices as well as contaminations that may have arisen during production or packaging. Material mediated pyrogenicity is understood to stem from contaminants of mold releases, processing aids, cutting fluids or cleaning agents  — among others.

Must material mediated pyrogenicity be tested for?

According to The International Organization for Standardization (ISO), all medical devices must be tested for material mediated pyrogenicity. ISO released the globally-harmonized ISO10993 standards for the assessment of medical device biocompatibility. In accordance with ISO 10993-11:2006 Biological evaluation of medical devices – Part 11: Tests for systemic toxicity, regulation standards worldwide require manufacturers to ensure their released medical devices have been tested for material mediated pyrogenicity.

When testing for material mediated pyrogenicity, you could consider—

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Using LAL for material mediated pyrogenicity tests

The LAL’s mechanistic pathway is based on an enzymatic reaction, unlike those akin to the human immune system febrile response. As a result, while LAL can effectively detect endotoxins, it fails to detect non-endotoxin pyrogens associated with material mediated pyrogenicity. There are in-vitro alternatives to this ex-vivo assay like the rFC, however they too fail in detecting material mediated pyrogenicity. As a result, BET assays in general cannot be employed for detecting material mediated pyrogenicity.

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Employing RPT for material mediated pyrogenicity tests

The RPT has been the gold standard of assays in assessing pyrogenic contamination in medical devices. The RPT’s mechanistic pathway is based on a biological reaction. Resultantly, both endotoxin and non-endotoxin pyrogens – including those of material mediated pyrogenicity – can be detected using this assay. While RPT is effective in testing material mediated pyrogenicity, international pharmacopoeia like the European Pharmacopoeia are mandating the transition away from in-vivo assays towards in-vitro alternatives. As a result, employing RPT as an assay to test material-mediated pyrogenicity may prove short-sighted.

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Making use of MAT for material mediated pyrogenicity tests

Using the blood of healthy human donors, MAT mechanistic pathway specifically simulated the biological, human immune system febrile response. MAT successfully detects both endotoxins and material mediated pyrogens which in part comprise non-endotoxin pyrogens. Learn more about our market leading MAT technology, here.

Comparing RPT vs. MAT for testing material mediated pyrogenicity.

Assay analysis

Rabbit 
Pyrogen Test
(RPT)

Monocyte Activation Test (MAT)

In-vitro test

Accepted by
ISO

Delivered

results

Human-specificity

Qualitative only

Quantitative & Qualitative

/ 

Testing for material mediated pyrogenicity across different medical devices

Aneurism clips

Mazzotti et al. (2007) successfully tested for material mediated pyrogenicity on aneurism clips using monocyte activation testing;
 

Gelatin materials

Gelatin materials intended for manufacturing of capsules were effectively tested for material mediated pyrogenicity using MAT by Mohanan et al. (2011)

Intraocular lenses

In 2009, a paper was published on the successful detection of material mediated pyrogenicity found on intraocular lenses using MAT by Werner et al.

Testing for material mediated pyrogenicity on large, abnormally shaped or multi-material medical devices

Until recently, a challenge for medical device manufacturers was how to detect material mediated pyrogenicity on large, abnormally shaped or multi-material medical devices using MAT. Two examples of recent research underline some of the ways MAT BioTech has helped its partners successfully tested for material mediated pyrogenicity on such more challenging devices:
 

  1. Hasiwa et al. (2006) evidence how large, abnormally shaped or multi-material medical devices can be tested for material mediated pyrogenicity using a 15-well, stainless steel incubation chamber. At the bottom of the chamber, a flat sheet of test material is held with wells that provide access to the material for the humans MAT cells for interaction. With very simple chamber modifications, samples of the device  could be kept in different wells to screen for material mediated pyrogenicity with high-throughput.
     

  2. Presenting an alternative methodology of testing for material mediated pyrogenicity, Stang et al.’s 2014 paper highlights the method of dynamic incubation which allows for large medical devices such as blood transfusion sets which would have been impossible using RPT. Specifically, by using dynamic rotation of the device during incubation with the blood cells, the entire surface of the device is at at least one point in direct contact with the cells and that any material-mediated pyrogenicity can be detected.
     

Want to test for material 

mediated pyrogenicity?

Simply reach out to us and we’ll schedule an online consultation with our chief scientist. Together we’ll devise a plan to successfully test your medical device – whatever it may be – for material mediated pyrogens

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