Strategic advice regarding the health risk assessment/risk management of elemental impurities in two injectable drug products


A pharmaceutical company requested an assessment of elemental impurities in each of two injectable drug formulations, in line with the ICH Q3 Guideline on Elemental Impurities (EMA, 2016; ICH, 2014).


A pharmaceutical company.

Project goals

Bibra was asked to evaluate, if possible, the toxicological risks posed to patients by the presence of metal impurities, at the estimated ‘worst-case’ maximum doses, by comparison with the Permitted Daily Exposures (PDEs) recommended in the ICH Q3 Guideline.


The client provided a description of each of the two drug products, giving their full composition (drug substance, excipients) and the product contact materials in their packaging and manufacturing trains. A standard requirement for the ICH Q3 assessment is typically either an analytical report on each source material, giving a measured level or a Limit of Detection (LoD) figure for each of the ten metals deemed relevant for an injection exposure by the Guideline, or a statement of absence from the component manufacturer.

Upon inspection, a number of the reports the client had obtained from their suppliers lacked sufficient detail for a calculation of the potential maximum exposure of the patient to each metal from each source material (e.g. not all metals were analysed). It was therefore not possible, in the first instance, to estimate the total exposure to each metal from either of the drug products for comparison with the relevant injection PDEs. The client was advised to contact the various suppliers to seek more comprehensive assessments of each source material, possibly necessitating further analytical testing of some of the components.

Project outcome

Due to short deadlines, the client decided to commission analytical tests on the final drug products themselves, rather than on the constituents and contact materials. This approach is robust in that it provides a clear picture of elemental concentrations. One potential problem with such an approach is that, if any of the metal impurities are present at concentrations in the final product that would lead to an exposure exceeding the relevant PDE, it would not be obvious which of the components is(are) responsible. The focus of any risk management measures would then be unclear (e.g. refining an analytical test for a particular source material, or changing a process or a supplier) and subsequent analytical testing of individual components may still be necessary.

Bibra project team

Anne Edwards
Pete Watts


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