Industry feedback on the bacterial endotoxin test (BET)

A USP comparability study of recombinant reagents (recombinant Factor C and recombinant cascade) to lysate reagents

The absence of bacterial endotoxins in parenteral products is a key attribute to ensure patient safety. The compendial test described in this USP uses the lysate from the blood cells of horseshoe crabs. An alternative known as the Recombinant Factor C (rFC) method that uses only synthetic reagents, as opposed to animal-sourced ones, was developed, and patented in 1997, and has been successfully implemented since 2018.  

The rFC method is now a compendial method in the European and Chinese Pharmacopoeias. The USP has been considering publication of a general method for the rFC method for several years; however, it is looking for additional assurance that the new method is as reliable as the current compendial method. It therefore designed a study to collect data comparing the rFC and the lysate reagents method described in <USP85> Bacterial Endotoxins Test. It aims to compare levels of endotoxin activity arising from autochthonous gram-negative bacteria present in pharmaceutical (deionized) water samples, which are analyzed by both the current monographed methodology and recombinant reagents. The USP has published details of the proposed study in Bacterial Endotoxin Test (BET): A USP Comparability Study of Recombinant Reagents (Recombinant Factor C and Recombinant Cascade) to Lysate Reagents (LAL) and has asked for industry comments. 

 BioPhorum has published Industry feedback on Bacterial Endotoxin Test (BET). It contains feedback on the USP document grouped into these areas: 

  • Protocol review 
  • Reagents 
  • Samples for study 
  • Number of samples and statistical methods. 

The paper comments on issues such as the feasibility of testing the recommended matrix using four different recombinant reagents and four different lysate reagents, and that water post-deionization (low-purity) but before distillation/ultra-filtration (high-purity) is not representative of samples typically tested for bacterial endotoxins. It also questions whether industry will be able to provide known contaminated samples as these would be difficult to obtain and then compare. 



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Industry feedback on the Bacterial Endotoxin test (BET) January 2022.pdf
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