title: International validation of novel pyrogen tests based on human monocytoid cells.
abstract: It is a requirement that parenteral medicines be tested for pyrogens (fever causing agents) using one of two animal-based tests: the rabbit pyrogen test and the bacterial endotoxin test. Understanding the human fever reaction has led to novel non-animal alternative tests based on in vitro activation of human monocytoid cells in response to pyrogens. Using 13 prototypic drugs, clean or contaminated with pyrogens, we have validated blindly six novel pyrogen tests in ten laboratories. Compared with the rabbit test, the new tests have a lower limit of detection and are more accurate as well as cost and time efficient. In contrast to the bacterial endotoxin test, all tests are able to detect Gram-positive pyrogens. The validation process showed that at least four of the tests meet quality criteria for pyrogen detection. These validated in vitro pyrogen tests overcome several shortcomings of animal-based pyrogen tests. Our data suggest that animal testing could be completely replaced by these evidence-based pyrogen tests and highlight their potential to further improve drug safety.
authors.affiliation: Institute of Biochemical Pharmacology and Steinbeis Center InPuT, University of Konstanz, Universitätsstrasse 10, D-78457 Konstanz, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Hoffmann
authors.forename: Anja
authors.initials: A
authors.lastname: Peterbauer
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schindler
authors.forename: Stefan
authors.initials: S
authors.lastname: Fennrich
authors.forename: Stephen
authors.initials: S
authors.lastname: Poole
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Mistry
authors.forename: Thomas
authors.initials: T
authors.lastname: Montag-Lessing
authors.forename: Ingo
authors.initials: I
authors.lastname: Spreitzer
authors.forename: Bettina
authors.initials: B
authors.lastname: Löschner
authors.forename: Mirjam
authors.initials: M
authors.lastname: van Aalderen
authors.forename: Rogier
authors.initials: R
authors.lastname: Bos
authors.forename: Martin
authors.initials: M
authors.lastname: Gommer
authors.forename: Ria
authors.initials: R
authors.lastname: Nibbeling
authors.forename: Gabriele
authors.initials: G
authors.lastname: Werner-Felmayer
authors.forename: Petra
authors.initials: P
authors.lastname: Loitzl
authors.forename: Thomas
authors.initials: T
authors.lastname: Jungi
authors.forename: Marija
authors.initials: M
authors.lastname: Brcic
authors.forename: Peter
authors.initials: P
authors.lastname: Brügger
authors.forename: Esther
authors.initials: E
authors.lastname: Frey
authors.forename: Gerard
authors.initials: G
authors.lastname: Bowe
authors.forename: Juan
authors.initials: J
authors.lastname: Casado
authors.forename: Sandra
authors.initials: S
authors.lastname: Coecke
authors.forename: Jan
authors.initials: J
authors.lastname: de Lange
authors.forename: Bente
authors.initials: B
authors.lastname: Mogster
authors.forename: Lisbeth M
authors.initials: LM
authors.lastname: Naess
authors.forename: Ingeborg S
authors.initials: IS
authors.lastname: Aaberge
authors.forename: Albrecht
authors.initials: A
authors.lastname: Wendel
authors.forename: Thomas
authors.initials: T
authors.lastname: Hartung
mesh_terms: D000818:Animals; D001681:Biological Assay / Q000191:economics / Q000379:methods; D006801:Humans; D009000:Monocytes / Q000378:metabolism*; D011749:Pyrogens / Q000032:analysis*; D011817:Rabbits; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013997:Time Factors
chemical_list: D011749:Pyrogens