Horseshoe Crab

 

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  • This "phenomenon" has been observed for more than 20 years, but never identified
  • Underlying mechanism of action is still unknown
  • Primarily affects formulations of polysorbate/citrate buffers

 

Low Endotoxin Recovery (LER) is a controversial topic that has been circulating throughout the endotoxin detection community for the last two years.  This phenomenon is hypothetically described as a “masking effect” manifested in the biophysical formation of a complex that blocks the ability of Factor C, the main component in LAL detection, to bind endotoxin (J. Chen, Low Endotoxin Recovery in Common Biologics Products, presented at the 2013 Annual PDA Meeting, Orlando, FL, April 2013).

Two common drug excipients, polysorbate and citrate, have been identified as probable causes of the masking effect more commonly referred to as LER.  These substances are estimated to be used in more than 70% of protein formulations (Maggio, 2012).  There is also some evidence that phosphate-containing formulations may also be affected by LER.  However, the LER effect has only been observed in combination formulations of the aforementioned excipients, and not in individual raw materials.

The issue of LER was brought to regulatory attention by Dr. Joseph Chen (Genentech) who experienced difficulty recovering known amounts of spiked endotoxin from drug products stored prior to final release testing.   As a result of this finding, the U.S. FDA included a stability screen requirement in their 2012 Guidance for Industry Pyrogen and Endotoxins Testing: Questions and Answers.  This guidance recommends that the industry perform hold-time studies to verify the amount of time a sample can be reasonably stored prior to final release testing.  

In response to the increasing industry concern regarding the validity of the LER phenomenon, Lonza has formed an internal task force to review existing data and coordinate an internal investigation on the LER effect.  To date, there are still many more questions than answers available about this topic.  Our LER Task Force is also interested in collaborating with customers who are experiencing this issue with their products, so that we not only look at this issue from an internal point of view, but also include actual customer samples or products into our investigation of this topic. 

 

For more information about LER and collaborating with Lonza to investigate your own products, please contact Lonza Scientific Support .

 

Related Information

Low Endotoxin Recovery (LER) in Drug Products 

Polysorbates, Immunogenicity, and the Totality of Evidence

Endotoxin Test Concerns of Biologics: LER From a Broad Biologics Test Perspective

LER: Microbiology's Hottest Urban Myth