A kinetic model was established for the inactivation of endotoxins in water at temperatures ranging from 210°C to 270°C and a pressure of 6.2 ؋ 10 6 Pa. Data were generated using a bench scale continuous-flow reactor system to process feed water spiked with endotoxin standard (Escherichia coli O113:H10). Product water samples were collected and quantified by the Limulus amebocyte lysate assay. At 250°C, 5-log endotoxin inactivation was achieved in about 1 s of exposure, followed by a lower inactivation rate. This non-log-linear pattern is similar to reported trends in microbial survival curves. Predictions and parameters of several non-log-linear models are presented. In the fast-reaction zone (3-to 5-log reduction), the Arrhenius rate constant fits well at temperatures ranging from 120°C to 250°C on the basis of data from this work and the literature. Both biphasic and modified Weibull models are comparable to account for both the high and low rates of inactivation in terms of prediction accuracy and the number of parameters used. A unified representation of thermal resistance curves for a 3-log reduction and a 3 D value associated with endotoxin inactivation and microbial survival, respectively, is presented.The connection between pyrogens and fevers in patients who receive unsanitized intravenous fluids was first reported by Florence Seibert in the 1920s (32). One subset of pyrogens is bacterial endotoxins which cause the pyrogenic reactions. Endotoxins come from the outer membrane of the cell wall of Gram-negative bacteria. Endotoxins are polymeric materials represented by lipopolysaccharides (LPS) having a number average molecular weight on the order of 10,000. The active sites in endotoxins are known as lipid A (29).Pyrogen-free water is an essential material for the medical and pharmaceutical industries. Commonly known as water for injection (WFI) and sterile WFI (SWFI), the specifications require the removal of dissolved and suspended solids, sterilization, and depyrogenation (38). Distillation is the oldest method of producing pyrogen-free water (33). Distillation requires heat to separate pure water from its high boiling point impurities: inorganic solids, microorganisms, pyrogens, and all organics with boiling points higher than the operating temperature. The process also achieves sterilization of the product water. Because of energy intensity, heat recuperation by vapor compression or multiple-effect distillation is required to make the process economical.Reverse osmosis (RO) is used industrially to produce WFI in Japan (22). The RO process relies on semipermeable membranes to remove impurities from water. Due to the possibilities of membrane defects, two-stage RO is required. Since there is no heat involved in the RO process, the product water is considered WFI, unless the water is posttreated by proven methods to ensure its sterility.The thermal sterilization and depyrogenation techniques can be achieved by either wet heat or dry heat. In a wet heat application such as the commonly practiced autocl...