title: Comparison of temperature rise interpretations in the rabbit pyrogen test among Chinese, Japanese, European, and United States pharmacopeias and 2-2-2 theoretical models proposed by S. Hoffmann.
abstract: Although the rabbit pyrogen test is one of the crucial methods included in each pharmacopeia to evaluate the safety of parenteral medicine, the experimental procedures and pyrogen result judgment algorithms (PRJAs) are still greatly different from one another. In the first stage of testing, original data of 879 batches from a total of 2637 rabbits in our laboratory were judged by PRJAs in the Chinese Pharmacopoeia 2005 III, the Japanese Pharmacopoeia XIV, the Japanese Pharmacopoeia XV, the European Pharmacopeia 6.0, the United States Pharmacopoeia 32 NF27 and two theoretical models proposed by S. Hoffmann, respectively. The results were analyzed to evaluate the effects of various PRJAs. It was shown that: (i) the significant differences in the results judged by various pharmacopeias and Hoffmann's theoretical models were mainly due to the PRJAs and the great differences in PRJAs should be harmonized throughout the world based on balance of reducing animal use and guaranteeing the safety of medicines; (ii) it is better to use PRJAs that depend on the threshold of the sum of temperature rise of all tested rabbits than those that depend on the number of rabbits that are over the threshold of temperature rise of individual rabbit according to clinical proof and the experimental data; and (iii) the PRJA of the Japanese Pharmacopoeia XV has obvious advantages when the total suspicious rate of samples was less than 10%. Additionally, a new PRJA designed for reducing the additional experiment stages and animal consumption is promoted for evaluation.
authors.affiliation: National Institute for the Control of Pharmaceutical and Biological Products, Beijing, People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Du
authors.forename: Xiu-Ji
authors.initials: XJ
authors.lastname: Li
authors.forename: De-Jiang
authors.initials: DJ
authors.lastname: Tan
mesh_terms: D000465:Algorithms; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002681:China; D003661:Decision Support Techniques; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000592:standards; D064420:Drug-Related Side Effects and Adverse Reactions; D005060:Europe; D005334:Fever / Q000139:chemically induced* / Q000453:epidemiology* / Q000517:prevention & control; D006801:Humans; D007263:Infusions, Parenteral; D007564:Japan; D004364:Pharmaceutical Preparations / Q000008:administration & dosage; D010602:Pharmacopoeias as Topic; D011749:Pyrogens / Q000008:administration & dosage / Q000009:adverse effects*; D011817:Rabbits; D012015:Reference Standards; D014481:United States
chemical_list: D004364:Pharmaceutical Preparations; D011749:Pyrogens