In line with the Ph. Eur. implementation strategy for the ICH Q3D guideline for elemental impurities, the test for heavy metals (2.4.8) has been deleted and a new section is included: “If purified water in bulk does not meet the requirement for conductivity prescribed for Water for injections (0169) in bulk (1.3 µS/cm), a risk assessment according to general chapter 5.20 Elemental impurities is carried out. The risk assessment should consider the role of water in the manufacturing process, in particular when water is used in a process but is no longer present in the final product.”
This new section states that if the purified water presents a conductivity level lower than 1.3 µS/cm at 25ºC, the risk is consistently controlled and elemental impurities content is sufficiently reduced to avoid the risk assessment analysis. Therefore, when the conductivities are between 1.3 µS/cm (water for injection limit) and 5.1 µS/cm (purified water limit) at 25ºC, the risk assessment should be conducted to have a better knowledge of the elemental impurities present in the water and their potential sources. In such cases, a screening of all 24 elemental impurities is the best way to obtain adequate conclusions.
Nowadays, the ICP-MS is the technology of election to reach the low level of quantification required for certain impurities and the possibility to have results for all impurities using a general validated method in one single injection.
A general method should be validated including at least 3 representative samples of purified water, covering all the potential variability. The selection criteria should include parameters such as different days, different point of use, and any other circumstance that may be relevant. The demonstrable LOQ in our labs can reach concentrations equivalent to 30% of PDE calculated taking into account an oral administration route and 4L of maximum diary dose.
Specifically, the analytical method at most should capable to demonstrate that the elemental impurities are lower than the following concentrations, fulfilling the requeriments of the ICH Q3D Guideline.
Elemental Impurities Limits: