Using the monocyte activation test as a stand-alone release test for medical devices

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Jeffrey Brown
Amy J. Clippinger
Claire Fritz Briglia
Warren Casey
Kelly Coleman
Anja Fritsch
Thomas Hartung
Djik Maouyo
Thierry Muller
Johannes Reich
Laure Robert
Ruth Roeder
Guillermo Sanchez
Anita Y. Sawyer
Shabnam Solati
Radhakrishna Tirumalai
Walter Zwisler
David Allen


Monocyte activation tests (MAT) are widely available but rarely used in place of animal-based pyrogen tests for safety assessment of medical devices. To address this issue, the National Toxicology Program Interagency Center for the Eval­uation of Alternative Toxicological Methods and the PETA International Science Consortium Ltd. convened a workshop at the National Institutes of Health on September 18-19, 2018. Participants included representatives from MAT testing laboratories, medical device manufacturers, the U.S. Food and Drug Administration’s Center for Devices and Radio­logic Health (CDRH), the U.S. Pharmacopeia, the International Organization for Standardization, and experts in the development of MAT protocols. Discussions covered industry experiences with the MAT, remaining challenges, and how CDRH’s Medical Device Development Tools (MDDT) Program, which qualifies tools for use in evaluating medical devices to streamline device development and regulatory evaluation, could be a pathway to qualify the use of MAT in place of the rabbit pyrogen test and the limulus amebocyte lysate test for medical device testing. Workshop outcomes and fol­low-up activities are discussed.

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How to Cite
Brown, J., Clippinger, A. J., Fritz Briglia, C. ., Casey, W., Coleman, K., Fritsch, A., Hartung, T., Maouyo, D., Muller, T., Reich, J., Robert, L., Roeder, R., Sanchez, G., Sawyer, A. Y., Solati, S., Tirumalai, R., Zwisler, W. and Allen, D. (2021) “Using the monocyte activation test as a stand-alone release test for medical devices”, ALTEX - Alternatives to animal experimentation, 38(1), pp. 151-156. doi: 10.14573/altex.2012021.
Meeting Reports

Anderson, R. L., Watson, W. H. and Chabot, C. C. (2013). Sublethal behavioral and physiological effects of the biomedical bleeding process on the american horseshoe crab, Limulus polyphemus. Biol Bull 225, 137–151.

BMEL (2017). Data on the use of laboratory animals in 2017. Available at: [Accessed November 25, 2020].

Borton, L. K. and Coleman, K. P. (2018). Material-mediated pyrogens in medical devices: Applicability of the in vitro Monocyte Activation Test. ALTEX 35, 453–463.

Cooper, J. F., Levin, J. and Wagner, H. N. (1971). Quantitative comparison of in vitro and in vivo methods for the detection of endotoxin. Transl Res 78, 138–148.

Correa, W., Brandenburg, K., Zähringer, U. et al. (2017). Biophysical analysis of lipopolysaccharide formulations for an understanding of the low endotoxin recovery (LER) phenomenon. Int J Mol Sci 18, 2737.

Davila, M. L., Riviere, I., Wang, X. et al. (2014). Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med 6, 224ra25-224ra25.

Duff, G. W. and Atkins, E. (1982). The detection of endotoxin by in vitro production of endogenous pyrogen: Comparison with limulus amebocyte lysate gelation. J Immunol Methods 52, 323–331.

EDQM (2010). General Chapter 2.6.30. Monocyte-activation test. European Pharmacopoeia.

Fennrich, S., Hennig, U., Toliashvili, L. et al. (2016). More than 70 years of pyrogen detection: Current state and future perspectives. Altern to Lab Anim 44, 239–253.

Hartung, T. (2015). The human whole blood pyrogen test - Lessons learned in twenty years. ALTEX 32, 79–100.

Hartung, T., Aaberge, I., Berthold, S. et al. (2001). Novel pyrogen tests based on the human fever reaction. Altern to Lab Anim 29, 99–123.

Hartung, T. and Wendel, A. (1995). Die erfassung von pyrogenen in einem humanen vollblutmodell (Detection of pyrogens using human whole blood). ALTEX, 70–75

Hasiwa, M., Kullmann, K., Von Aulock, S. et al. (2007). An in vitro pyrogen safety test for immune-stimulating components on surfaces. Biomaterials 28, 1367–1375.

Hasiwa, N., Daneshian, M., Bruegger, P. et al. (2013). Evidence for the detection of non-endotoxin pyrogens by the whole blood monocyte activation test. ALTEX 31, 226.

Hoffmann, S., Peterbauer, A., Schindler, S. et al. (2005). International validation of novel pyrogen tests based on human monocytoid cells. J Immunol Methods 298, 161–173.

ISO (2018). ISO 10993-1:2018 Biological evaluation of medical devices -- Part 1: Evaluation and testing within a risk management process. Geneva: International Organization for Standardization.

ISO (2017). ISO 10993-11:2017 Biological evaluation of medical devices — Part 11: Tests for systemic toxicity. Geneva: International Organization for Standardization.

Lee, D. W., Gardner, R., Porter, D. L. et al. (2014). Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124, 188–195.

Levin, J. and Bang, F. B. (1968). Clottable protein in Limulus; its localization and kinetics of its coagulation by endotoxin. Thromb Diath Haemorrh 19, 186–97. Available at:

Levin, J. and Bang, F. B. (1964). The role of endotoxin in the extracellular coagulation of limulus blood. Bull Johns Hopkins Hosp 115, 265–274

Mazzotti, F., Beuttler, J., Zeller, R. et al. (2007). In vitro pyrogen test - A new test method for solid medical devices. J Biomed Mater Res - Part A 80, 276–282.

Schindler, S., Spreitzer, I., Löschner, B. et al. (2006). International validation of pyrogen tests based on cryopreserved human primary blood cells. J Immunol Methods 316, 42–51.

Schwarz, H., Gornicec, J., Neuper, T. et al. (2017). Biological activity of masked endotoxin. Sci Rep 7, 1–11.

UK Home Office (2018). Annual Statistics of Scientific Procedures on Living Animals Great Britain 2017. Available at: [Accessed November 25, 2020].

United States Pharmacopeia (2017). General Chapter 151 “Pyrogens.” Available at: [Accessed April 20, 2020].

US FDA (2012). Guidance for industry pyrogen and endotoxins testing: Questions and answers. Available at: [Accessed April 20, 2020].

US FDA (2017). MDDT program final guidance, aualification of medical device development tools – Guidance for industry, tool developers, and Food and Drug Administration staff. Available at: [Accessed April 20, 2020].

US FDA (2009). Response from Dr. Norris Alderson, Associate Commissioner for Science. Available at: [Accessed April 20, 2020].

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