White Paper on New FDA Endotoxin Testing Guidance Now Available

Former U.S. Food and Drug Administration (FDA) official Steven G. Richter, Ph.D., has written and released a white paper that helps medical device manufacturers understand recent changes to the agency’s approach to endotoxin testing. Richter now serves as president and chief scientific officer of Microtest Laboratories Inc., an Agawam, Mass-based contract testing laboratory.

The paper, titled “FDA Updates Medical Device Endotoxin Testing Program (New Guidance),” discusses the FDA’s recently published document, “Guidance of Industry Pyrogen and Endotoxin Testing: Questions and Answers.” The FDA document replaces the agency’s 1987 Endotoxin Guidelines, now considered out of date due to changes in the U.S. Pharmacopeial Convention and pharmaceutical dosage forms. It presents the FDA’s current position on pyrogen and bacterial endotoxin testing requirements for pharmaceuticals, biologics, and medical devices. Medical devices that contact circulating blood or cerebrospinal fluid, or are used with intraocular products or in-vitro fertilization procedures are required to be endotoxin-free.

A pyrogen is any chemical that, when introduced into the bloodstream, induces a fever. Endotoxins are toxins that exist within a bacterial cell, and are released only when the cell wall of the bacterium is destroyed.

Since the majority of pyrogens found on medical devices are bacterial in nature, the paper focuses on those contaminates. Some of the most notorious devices for carrying endotoxins that must be tested are:

• Intravenous catheters and tubing
• Cardiac stents and angioplasty balloons
• Certain implants such as pacemakers/defibrillators
• Spinal catheters
• Transfusion catheters
• Intraocular lens implants
• Cranial drills
• Perfusion tubing
• Dialysis tubing and filters
• Vascular grafts
• In-vitro fertilization catheters

In the paper, Richter answers such questions as how to establish a sampling plan for in-process and finished products for the FDA to test, how to store and handle samples, and limits for the presence of endotoxins and pyrogens.

If a medical device company deviates from the new guidance or recognized standards, the FDA now requires 510(k) premarket notification submissions. Significant deviations include sampling fewer than three lots for inhibition enhancement testing, using a lesser sensitivity to endotoxins, and using more than 40 milliliters per device for rinsing without adjusting the dilution factor, which would cause a greater dilution than the guidance document allows.