Karen Zink McCullough
BET scientists have known for years that product matrices can significantly interfere with the detection of endotoxin in drug products. In fact, FDA and others published quite extensively on this topic in the 1980s and 1990s.
In 2012, FDA released a BET Q&A guidance document. Question 3 speaks to the recovery of endotoxin in product. FDA has indicated that the original intent of this question was to assure that endotoxin would be recovered in naturally contaminated product. However, some researchers who deliberately prepared a CSE spike for undiluted product have reported an unexpectedly low endotoxin recovery, or LER.
The compendial BET requires that prepared product be spiked with RSE or CSE and the spike recovered with 50-200% of the nominal spike value. As one might expect, this new request to spike undiluted or unprepared product has led to more complex interference problems than would normally be seen in the compendial BET suitability test. These complexities have precipitated some important questions:
- Does the LER phenomenon make BET less useful?
- Does the LER phenomenon make products less safe?
- Is BET still the endotoxin test of choice?
- Since endotoxin contamination in products is not purified lipopolysaccharide, is RSE or CSE the best choice for spike/recovery studies? Is a natural endotoxin preferable? Under what circumstances? How does one make and standardize a natural endotoxin?
While there have been no reported concerns over patient safety, many interference questions remain unanswered. The phenomenon has sparked a renewed interest and focus on BET. The Pharmaceutical Microbiology Forum invites you to attend a forum devoted entirely to the issue of BET interference and test recovery. At the Bacterial Endotoxin Summit, you’ll hear from and network with:
- Industry veterans with many years of experience regarding causes of and mitigations for interference.
- Researchers who have observed and studied the LER phenomenon, and who have executed studies to understand if LER is correlated with pyrogenicity in rabbits.
- FDA on their current thinking about interference management.