Pyrogen testing was borne out of the need to screen medical devices and pharmaceuticals for molecules (pyrogens) that could initiate an intense reaction mimicking septic shock. These pyrogens can survive steam sterilisation. They are endotoxins from bacteria that survive beyond the sterilisation from the microorganisms themselves. The most potent of these pyrogens is the lipopolysacaride (LPS) molecules of gram negative bacterial. In vivio pyrogen testing was replaced by an endotoxin-specific test using a protein cascade found in the hemolymph of the horseshoe crab Limulus polyphemus. The Bacterial Endotoxin Test has become synonymous with QC testing for pharmaceutical products. Since the acceptance of the gel clot technique as a compendial test in 1980, endotoxin testing has become a crucial anchor for the expansion and development of safe pharmaceuticals and medical devices. Although much has changed in the 40+ years, the invaluable benefit of endotoxin testing has only grown. With the recent development, and compendial acceptance anticipated?, sustainable testing reagents have only ensured the permanency of the Bacterial Endotoxin Test for the next generation of pharmaceutical and medical advancements. In this editorial, I will provide an overview of the areas that are experiencing growth in their need of endotoxin testing.
Pharmaceutical Injectables
The Bacterial Endotoxin Test is primarily focused on testing pharmaceutical injectables for product release. The guidelines provide guidance on calculating endotoxin limits allowing for concrete endotoxin limits to be determined. Since the 1980s, the BET has been well established as a requirement for injectables (USP), and so most manufacturers of pharmaceuticals will be well established in endotoxin testing. The primary focus for these clients will be to transition to improved reagents due to its sensitivity or endotoxin specificity. FUJIFILM Wako provides reagents that are formulated to be endotoxin-free using large amounts of b-1, 3-glucan to saturate the protein (Factor G) found in the reagent that reacts to these molecules. This renders the LAL reagent to be endotoxin specific.
However, in recent years, with the withdrawal of the FDA’s definite guidelines on sampling requirements, as well as the increase in customised drug products that are manufactured in small batches, new and expanded requirements have been created for the monitoring and control of the endotoxin manufacturing process and raw materials. Emphasis is placed on more continuous monitoring; allowing for sampling numbers to be lowered for end-product testing. Among contract drug manufacturers, often one form of endotoxin testing will be the standard practice, but they may be looking to expand their testing to different methods to better suit the needs of their customers.
As a result, rapid, affordable, quantitative data at the point of test has gained in popularity among pharmaceutical manufacturers. The primary focus is on the compliant, end-process testing that the reagents allow. However, a new market opening will be for the monitoring that rapid, economical testing provides.
For raw materials, excipient manufacturers generally have set endotoxin limits set by pharmacopeial monographs. However, API manufacturers, especially if they are new technologies such as cell and gene therapies, will often not have endotoxin limits. These areas are becoming more familiar with the endotoxin level needs of their clients and are a good market for adopting endotoxin testing.
The products in the pharmaceutical industry that are well established or expanding in their need of endotoxin testing are active pharmaceutical ingredients (API) manufacturing, excipient production, production and monitoring of sterile water for injection, expanded need for in-process product monitoring, contracted drug manufacturing, raw materials, injectable veterinary pharmaceuticals, PET tracers, and custom medical devices.