title: Evidence for the detection of non-endotoxin pyrogens by the whole blood monocyte activation test.
abstract: Threats of pyrogenicity were discovered more than a century ago. Measures to determine the safety of parenterals and, more recently, medical devices and cell therapies for human use have been in place for 70 years. Currently, there are three testing possibilities available: the Rabbit Pyrogen Test, the Limulus Amebocyte Lysate test (Bacterial Endotoxin Test), and test systems using human whole blood or human monocytes, called Monocyte Activation Test (MAT). The MAT is based on the human fever reaction and thus most closely reflects the human situation. Unfortunately, regulations and testing guidelines are not fully harmonized, despite formal international validation. Furthermore, data showing that the MAT is capable of covering the totality of possible pyrogens relevant to humans were not included in the MAT validations of the last decade. For this review we collate evidence from published literature, unpublished data of our own, and results from the international validation study to show that there is overwhelming scientific evidence to conclude that the whole blood MAT reliably detects non-endotoxin pyrogens. Therefore, further validation exercises do not seem warranted.
authors.affiliation: CAAT-Europe, University of Konstanz, Konstanz, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Hasiwa
authors.forename: Mardas
authors.initials: M
authors.lastname: Daneshian
authors.forename: Peter
authors.initials: P
authors.lastname: Bruegger
authors.forename: Stefan
authors.initials: S
authors.lastname: Fennrich
authors.forename: Astrid
authors.initials: A
authors.lastname: Hochadel
authors.forename: Sebastian
authors.initials: S
authors.lastname: Hoffmann
authors.forename: Felix E
authors.initials: FE
authors.lastname: Rivera-Mariani
authors.forename: Christoph
authors.initials: C
authors.lastname: Rockel
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schindler
authors.forename: Ingo
authors.initials: I
authors.lastname: Spreitzer
authors.forename: Sandra
authors.initials: S
authors.lastname: Stoppelkamp
authors.forename: Kranthi
authors.initials: K
authors.lastname: Vysyaraju
authors.forename: Thomas
authors.initials: T
authors.lastname: Hartung
mesh_terms: D000818:Animals; D004340:Drug Contamination / Q000517:prevention & control; D006801:Humans; D009000:Monocytes / Q000187:drug effects*; D004364:Pharmaceutical Preparations / Q000592:standards; D011749:Pyrogens / Q000737:chemistry* / Q000633:toxicity*; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D004364:Pharmaceutical Preparations; D011749:Pyrogens