An FDA panel steps in to resolve confusion over a standard screening tool for endotoxins. Stay tuned!

Last year, we celebrated the 50th anniversary of a seminal publication elucidating the vital role horseshoe crabs played play in drug safety. The study showed how a horseshoe crab’s blood cells (amoebocytes) contained a clotting factor released outside cells in response to highly toxic, heat stable lipopolysaccharides (LPSs) known as endotoxins. In essence this was the birth of the Limulus Amebocyte Lysate (LAL) test, which the US Food and Drug Administration (FDA) approved in 1973 for testing drugs, products and devices that come in contact with the as an alternative method to the much slower and more expensive pyrogen test. The LAL has served us remarkably well, but in recent years a phenomenon known as low endotoxin recovery (LER) has raised questions about the utility of the test.

The fundamental issue surrounding LER comes down to a definition of potency vs. activity. Potency is the activity of LPS on a weight basis (EU/ng). Activity is merely that; activity relative to the primary LPS standard (RSE) or a secondary standard (CSE) that has been matched and calibrated with a specific lot of LAL. For any given raw material, in-process, or finished product sample, the pass/fail disposition of that sample is based on activity. The concern expressed by the FDA and some others is that LPS activity that has been lost in LER samples may be restored in vivo. If so, this could mean untoward pyrogenic patient reactions with unknown clinical consequences. But is this even possible?

There are no peer-reviewed papers thus far that have demonstrated the latent expression of LPS and 40 years of LAL experience suggests that this concern in unfounded. To try and resolve this issue, the PDAcreated a task force that includes recognized and accomplished PDA scientists, members from LAL industry, and the FDA. Its mission is to establish clear definitions as to what LER is and what it is not, to identify the underlying mechanisms of LER, to assess the potential patient safety risk, and finally, to develop a standardized protocol for endotoxins hold time studies. Hopefully, the task force will help resolve this lingering confusion surrounding what appears to be an academic question. If not, expect this controversy and confusion to continue.

—John Dubczak, General Manager of Charles River’s Endotoxin and Microbial Detection Division.