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ShareIn September 2018, PETA Science Consortium International and the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) co-organised a workshop to discuss in vitro approaches for medical device pyrogen testing. A report summarising the workshop can be found here.
Pyrogens are a diverse group of substances and materials that can produce fever when introduced to the body. Medical products for implantation or injection must be shown to be free of pyrogens before they can be marketed. The pyrogen tests commonly used to meet regulatory testing requirements—the rabbit pyrogen test (RPT) and the bacterial endotoxin test (BET)—are performed using rabbits or haemolymph derived from horseshoe crabs, but non-animal replacements are available.
The workshop focused on the use of the monocyte activation test (MAT) as a standalone release test for medical devices that can replace the use of the RPT and the BET when satisfying biocompatibility and sterility testing requirements. Scientists and regulatory authorities from government and industry reviewed the MAT and discussed ongoing challenges. Participants also described industry experiences with the MAT and identified hurdles to its implementation.
A central element of this workshop was exploring the US Food and Drug Administration Center for Devices and Radiological Health (FDA CDRH) Medical Device Development Tools (MDDT) program. This program allows device sponsors to qualify in vitro methods for use within a defined context of use as a replacement for animal-based tests used by the agency to approve medical device products for marketing. Workshop participants explored the process of developing an MDDT proposal to qualify the MAT as a replacement for the RPT and/or BET with input from FDA CDRH attendees.
| Introduction and Overview: Monocyte Activation Tests | Thomas Hartung, Johns Hopkins Center for Alternatives to Animal Testing |
| The FDA MDDT Program and Considerations for MAT Testing of Medical Devices | Molly Ghosh, FDA/CDRH Biocompatibility Standards Task Group |
| Material Mediated Pyrogenicity and ISO/TC 194 Standards | Anita Sawyer, International Organization for Standardization Technical Committee 194 |
| Alternate Pyrogen Tests | Radhakrishna Tirumalai, United States Pharmacopoeia |
| Material-Mediated Pyrogens in Medical Devices | Kelly Coleman, Medtronic |
| Pyrogen Detection on Medical Devices | Anja Fritsch, Confarma |
| Monocyte Activation Test: A Relevant Alternative Tool for Medical Device Development | Djikolngar Maouyo, PyroDex Testing |
| Monocyte-Activation-Test as a Pyrogen Test for Medical Devices | Walter Zwisler, Zwisler Laboratorium GmbH |
Pyrogen testing guidance and standards
- FDA Guidance for Industry: Pyrogen and Endotoxins Testing: Questions and Answers
- FDA Guidance for Industry and Food and Drug Administration Staff: Use of International Standard ISO 10993-1, “Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process”
- Webinar: Final Guidance on “Use of International Standard ISO 10993-1, Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process” – July 21, 2016
- United States Pharmacopeia General Chapter <151> (“Pyrogens”)
- ISO 10993-1:2009, Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk management process
- ISO 10993-11:2017, Biological evaluation of medical devices — Part 11: Tests for systemic toxicity, Annex F (informative), Information on material-mediated pyrogens
FDA CDRH MDDT Program
- Introduction to the Medical Device Development Tool (MDDT) Program, Jennifer Goode, FDA
- MDDT Program final guidance, Qualification of Medical Device Development Tools – Guidance for Industry, Tool Developers, and Food and Drug Administration Staff
- MDDT public webpage
- For additional information on the MDDT program, email [email protected]
Additional publications
- Hasiwa M, Kullmann K, von Aulock S, Klein C, Hartung T. An in vitro pyrogen safety test for immune-stimulating components on surfaces. Biomaterials. 2007;28(7):1367-1375.
- Hartung T. The human whole blood pyrogen test – lessons learned in twenty years. ALTEX. 2015;32(2):79-100. Open Access
- Fennrich S, Hennig U, Toliashvili L, Schlensak C, Wendel HP, Stoppelkamp S. More than 70 years of pyrogen detection: Current state and future perspectives. Altern Lab Anim. 2016;44(3):239-253.
- Borton LK, Coleman KP. Material-mediated pyrogens in medical devices: Applicability of the in vitro Monocyte Activation Test. ALTEX. 2018;[Epub ahead of print]. Open Access
- Kerecman Myers D, Goldberg AM, Poth A, Wolf MF, Carraway J, McKim J, Coleman KP, Hutchinson R, Brown R, Krug HF, Bahinski A, Hartung T. From in vivo to in vitro: The medical device testing paradigm shift. ALTEX. 2017;34(4):479-500. Open Access
- Hasiwa N, Daneshian M, Bruegger P, Fennrich S, Hochadel A, Hoffman S, Rivera-Mariani FE, Rockel C, Schindler S, Spreitzer I, Stoppelkamp S, Vysyaraju K, Hartung T. Evidence for the detection of non-endotoxin pyrogens by the whole blood monocyte activation test. ALTEX. 2013;30(2):169-208.
- Stoppelkamp S, Würschum N, Stang K, Löder J, Avci-Adali M, Toliashvili L, Schlensak C, Wendel HP, Fennrich S. Speeding up pyrogenicity testing: Identification of suitable cell components and readout parameters for an accelerated monocyte activation test (MAT). Drug Test Anal. 2017;9(2):260-273.