Bacterial endotoxin and substances for pharmaceutical use

The European Pharmacopeia will be changing its approach to bacterial endotoxin test limits. The proposed text for the chapter on “Substances for pharmaceutical use (2034)” reads:

“New monographs on substances for pharmaceutical use will no longer include the test for bacterial endotoxins (with possible exceptions); this aspect will now be covered by this general monograph. In other words, it is the manufacturer’s responsibility to decide whether or not the requirements for bacterial endotoxins have to be applied and, if so, to calculate the corresponding limits.”

The specific wording relating to endotoxin testing states:

“Bacterial endotoxins (2.6.14). If offered as a bacterial endotoxin-free grade or if intended for use in the manufacture of parenteral preparations or preparations for irrigation without a further appropriate procedure for the removal of bacterial endotoxins, the substance for pharmaceutical use complies with the test for bacterial endotoxins. The limit, when not indicated in the individual monograph, is determined in accordance with the recommendations of general chapter 5.1.10. Guidelines for using the test for bacterial endotoxins.”

The text also makes reference to finished products:

“Moreover, as specified in the monographs on Parenteral preparations (0520) and Preparations for irrigation (1116), these requirements apply to the finished product. To ensure that a preparation complies with requirements, the manufacturer may therefore use substances that comply with the test for bacterial endotoxins and/or demonstrate that the process includes an appropriate procedure for the removal of bacterial endotoxins. This decision is part of an overall control strategy that the manufacturer establishes for a preparation, as is the decision on whether or not to perform the test for bacterial endotoxins at the level of the substance, in accordance with the General Notices - Demonstration of compliance

with the Pharmacopoeia.”

This General Notice reads:

 “An article is not of Pharmacopoeia quality unless it complies with all the requirements stated in the monograph. This does not imply that performance of all the tests in a monograph is necessarily a prerequisite for a manufacturer in assessing compliance with the Pharmacopoeia before release of a product. The manufacturer may obtain assurance that a product is of Pharmacopoeia quality on the basis of its design, together with its control strategy and data derived, for example, from validation studies of the manufacturing process.”

Posted by Tim Sandle