5/6 October 2022
Within the framework of risk analysis i.e. qualification and preparation of sampling plans for new purified water (PW) systems, the question arises as to whether PW should be tested for endotoxins.
According to the pharmacopoeia (e.g. USP or Ph.Eur.), Purified Water does not have to be tested for endotoxins. The endotoxin level is not a test point according to the applicable pharmacopoeia monographs (e.g. Ph.Eur., USP) for Purified Water.
However, if PW is used as feed water for distillation and pure steam generators for the production of WFI or pure steam, it may be useful to test for endotoxins as part of the qualification process.
This is due to the fact that distillation and pure steam generation - depending on the technology or manufacturer - only achieve 3 to 6 log levels of reduction of endotoxins.
For the validation of the water system, the efficiency of the purification process must be demonstrated.
This applies to all quality parameters (in this example the endotoxin level in WFI) and is only possible if the initial concentration of an impurity is known.
Many plants with PW and WFI do not measure endotoxins in PW during routine sampling. They measure those endotoxins in the WFI and usually have low detection limits (<0.06IU/ml).
However, some companies consider these sample measurements in the WFI to be insufficient. If endotoxin values are found occasionally above the detection limit (0.06IU/ml) but below the WFI pharmacopoeia limit (0.25IU/ml), it is necessary to analyse the cause within the framework of trend evaluation. By those means, the measurement of endotoxins (informative) has been included in the sampling SOPs for PW at some sites.
PW systems with membrane technology generally show endotoxin levels below the WFI pharmacopoeia limit (0.25IU/ml).
PW systems without membrane technology, especially older fully deionised systems with poor flow-through (with anion and cation exchangers) can, however, show values significantly above the WFI pharmacopoeia limit value.
There are also applications of Purified Water in the biotech sector in which endotoxins can play a role, e.g. in the fermentation process or in purification. Here too, PW should be tested for endotoxins.
A general recommendation is the preparation of a small risk analysis and clarification of the questions:
Accordingly, tests can then be carried out with alarm and limit values to set interval specifications.