Preparation and use of endotoxin indicators for depyrogenation process studies. LAL Users Group.

Biological Indicators (B.I.'s) have traditionally been employed in the validation and routine monitoring of sterilization processes used for the manufacture and control of pharmaceuticals and medical devices. In this paper, the phrase "Endotoxin Indicator" has been coined to describe a tool analogous to the BI which can be used in the validation and routine control of endotoxin reduction processes. Like the BI, the Endotoxin Indicator provides the user with an in vitro biological test to complement physical measurement used to control the manufacturing process. It must be remembered that the total pyroburden in an aseptically processed drug is the sum of the pyroburden of each factor contributing to the manufacture of that product. This includes raw materials, packaging components, the environment and the manufacturing process itself. Therefore, all aspects of the process must be considered for a complete validation. This pyroburden may also change during processing of a drug. Fluctuations in pH, solvent content, and temperature may decrease pyroburden while introduction of some raw materials, especially water, may increase endotoxin content. Regularly scheduled monitoring of all aseptic processes should identify and address each step of the process considered to have potential for the possible introduction or removal of endotoxin in the final product. Most of these situations can be thoroughly studied using Endotoxin Indicators to challenge routine production conditions, thereby providing insight to the assurance of endotoxin-free final products.