After the withdrawal of FDA’s 1987 guideline on the LAL test, there were gaps in the regulatory documents regarding certain aspects of endotoxin testing like RSE/CSE standardization. On 01 December 2019, USP therefore published General Chapter <1085> Guidelines on the Endotoxins Test.
This new chapter aims to “provide additional background information and guidance for the performance and proper application of the compendial bacterial endotoxins tests”. It covers a broad range of topics ranging from preliminary testing (e.g. RSE/CSE assay, training, qualification of equipment and consumables) over method suitability (calculation of endotoxin limits for different cases including APIs and excipients, interference testing) to routine testing (sampling, pooling, handling of Out-of-Specification results).
For example, for analyst training, Chapter <1085> recommends a mixture of practical training to demonstrate proficiency, but also theoretical training to make sure analysts understand the test. This need to understand is emphasized again in the section discussing standard curve control.
Of particular interest might be the part regarding Out-of-Specification (OOS) results and how to handle them. In accordance with current thinking, Chapter <1085> recommends a two-phased approach: First an investigation if a lab error might be responsible, and if that is not the case, expanding the investigation to include manufacturing. Investigational testing is allowed, but has to be regulated by an SOP to ensure it is sufficiently distinguished from a re-test. This mirrors the principles outlined in FDA’s guidance on investigating OOS test results, with chapter <1085> closing the gap that previously existed as biological tests were specifically excluded from the FDA document.
Written by Saskia
Scientific Support Specialist