MAT as a Developmental Pyrogen Test Tool

Parenteral drugs, including products produced by biotechnology, are required to have a pyrogen test by the health authorities in most markets. As described in the prior chapter, the rabbit pyrogen test (RPT) was the earliest test codified by law or compendia, and was used exclusively in the past. For at least two decades, however, the bacterial endotoxin test (BET) has served as an alternative test on the premise and overwhelming evidence that most pyrogens are lipopolysaccharides (LPS). It remains the obligation of the drug manufacturer to demonstrate that the BET is suitable as the sole pyrogen test, typically by confirming that at least three commercial scale batches are non-pyrogenic in the RPT and validating the BET. More recently, the FDA division reviewing biologics has begun requesting additional studies to determine if the BET for a given product is prone to the phenomenon described as low endotoxin recovery (LER) (Chen and Vinther, Presentation at PDA annual meeting, 2013, Orlando). If LER is observed, often with high dose products with formulations containing a surfactant and a chelator, FDA often require manufacturers demonstrate the absence of pyrogenicity by a variety of means until the LER is resolved (Hughes et al., BioPharma Asia, 2015, 4(2):14–24; Chen et al., Lowe Endotoxin Recovery, PDA Technical Report No.82, 2019, pp. 1–128). This may require spiking products to ascertain sensitivity in the RPT. Consequently, the demand has increased for additional RPT studies for LER products, even if they are nonpyrogenic (unspiked).