An Elemental Impurities Excipient Database: A Viable Tool for ICH Q3D Drug Product Risk Assessment

Abstract

To support the practical implementation of the International Council for Harmonisation (ICH) Q3D guideline, which describes a risk-based approach to the control of elemental impurities in drug products, a consortium of pharmaceutical companies has established a database to collate the results of analytical studies of the levels of elemental impurities within pharmaceutical excipients. This database currently includes the results of 26,723 elemental determinations for 201 excipients and represents the largest known, and still rapidly expanding, collection of data of this type. Analysis of the database indicates good coverage of excipients relevant to real-world drug product formulations and tested element profiles consistent with ICH Q3D recommendations. The database includes the results from multiple analytical studies for an excipient and thus incorporates within it an indication of both excipient supplier and batch-to-batch variability as well as any variability associated with the different testing organizations and methods employed. The data confirm the findings of earlier smaller studies that elemental impurity concentrations in excipients are generally low and when used in typical proportions in formulated drug products are unlikely to pose a significant patient safety risk. The database is now in active use as one line of evidence in ICH Q3D risk assessments.

Elemental impurities analysis in name-brand and generic omeprazole drug samples

“…Elemental impurities include catalysts and environmental contaminants that may be present in active pharmaceutical ingredients (APIs), excipients and final medications at different stages of their formulation and production, which may occur naturally, be added intentionally, or be introduced inadvertently (e.g. through the interaction with equipment, containers and surfaces during processing or by contamination of the constituent components of the drug, such as raw materials, reagents and excipients (stabilizers, fillers, binders, flavorings, colorants, and coatings) which can generate unwanted and unknown pharmacological-toxicological effects [9,13,14,15,16].…”

ICH Q3D Drug Product Elemental Risk Assessment: The Use of An Elemental Impurities Excipients Database

“…Leftcensored value refers to the specific case where a measurement is reported as being below the LOQ/LOD. 3…”

“…The database only has information for one supplier for both L-Histidine hydrochloride monohydrate and Polysorbate 20, and from two suppliers for L-Histidine. The number of analytical tests is 3). For this formulation, even if the data for some of the excipients may be considered limited, the fact that the excipients under consideration are mainly organic molecules means the risk of introducing elemental impurities is low when compared to small inorganic excipients obtained through mining processes.…”

“…In a previous publication, it was described how a consortium of pharmaceutical companies has established a database to collate the results of analytical studies of the levels of elemental impurities in common pharmaceutical excipients. 3 Since its creation, the elemental impurities excipient database has been expanding and currently houses the results of 2633 analytical studies for 295 excipients and represents the largest known collection of data of this type. 1 Each analytical study employed methods demonstrated to be suitable for their intended use.…”

“…Information on the criteria used to define the validation approach for both quantitative and limit test procedures can be found in the Supplementary material of the previous publication. 3 The database is one viable avenue for assessing the risk of elemental impurities in drug products, covering a wide range of excipients, from a varied supplier base representing materials commonly sourced by Pharmaceutical manufacturers.…”