Bacterial endotoxins are contaminants from gram-negative bacteria and are the most common cause of pyrogenicity in pharmaceutical products. “Any preparation administered parenterally should be sterile and comply with the test for bacterial endotoxins (BET) as described in the Ph. Eur.,” the EDQM says.
Endotoxin contamination issues most recently put a wrench in GlaxoSmithKline’s Canadian flu plant, which was hit with a warning letter last summer for the problems.
In 2012, the US FDA set out its own perspective on endotoxin and pyrogen testing, noting that the testing should be conducted in accordance with quality by design concepts.
The new policy means that it’s up to the user to determine whether they come into compliance with the set limits.
“It is up to the user of the Ph. Eur. to determine whether compliance to BET is needed or not for a given substance. Where a test is included in the monograph with no specific limit, it is up to the user to set the limit for the substance, based on the following considerations: use of the substance (route of administration, patient population); calculation according to the formula given in general chapter 5.1.10; process capability; or any other considerations raised by the competent authority.”
These new consequences for users come as a test for bacterial endotoxins is not included in new monographs for substances for pharmaceutical use. However, the requirements of the general monograph Substances for pharmaceutical use (2034) apply.
“A test is included only where a specific method has to be described, for example if a specific sample preparation has to be used or if a specific method has to be applied,” the EDQM says. “If a test is included in the monograph, no limit is given for the test.”
Other changes include:
- General chapter 5.1.10 is expanded with further considerations regarding the setting up of limits; and
- General monograph Substances for pharmaceutical use (2034) is also “slightly reworded in order to take the above policy into consideration.”
EDQM said it ran into issues during the elaboration of a monograph, as it is not always known at the level of the manufacturing of the substance whether the substance is to be used for the production of a parenteral preparation and therefore it is not known whether compliance with the BET is needed or not.
“According to the general monograph Parenteral preparations (0520), pharmaceutical preparations to be used parenterally have to comply with the test for bacterial endotoxins or, where justified and authorised, the test for pyrogens,” according to the new policy.