ICH Q3D Risk Assessments – Case Studies for the Elemental Impurities Excipients Database
Figure 1 shows how to access an excipient’s elemental impurities profile from the database. First, an excipient is identified during a risk assessment which has no, or insufficient, data available from the supplier:
- Search the database for this excipient by name. Searches can be restricted by the elements or element classes of interest if desired.
- Review the elemental impurities data available in the Summary data table. This includes summary statistical parameters such as mean, minimum and maximum concentrations (µg/g). Further detailed information on each record, including method, can be accessed if required.
- Export the elemental impurities data from the database as a detailed report; available in a suitable format for incorporation into risk assessment calculation.
Figure 1: shows an example of the Elemental Impurities Excipient Database search page, the summary table data for excipient Lactose monohydrate, and two options for export format (data for other elements not shown).
The first case study reviews a new formulation of existing intravenous (IV) drug submission. Elemental impurity data was evaluated from available sources:
- Data was generated for the active pharmaceutical ingredient (API).
- Data was retrieved from the Elemental Impurities Excipient Database
The risk assessment using ICH Q3D option 2B1 concluded that there was no significant risk and therefore no drug product testing was considered necessary. This was, in part, because as an IV drug it had a simple formulation. The risk assessment was accepted by the regulatory authority.
The second case study reviews the risk assessment for an oral tablet formulation.
Table 1 shows the maximum values for each class 1 and 2A element1 that has been retrieved from the Elemental Impurities Excipients Database (version 2018.1.0). This data was used to calculate the estimated total elemental impurity level in the drug product. All class 1 and 2A elements were estimated to be below 30% of the permitted daily exposure (PDE) given in ICH Q3D.
Test data generated on the finished drug product (9 lots at commercial scale), was used to further validate the assessment of negligible overall risk for this formulation.
|Element||Cmax for Excipient 1 (ppm)||Cmax for Excipient 2 (ppm)||Cmax for Excipient 3 (ppm)||Cmax for Excipient 4 (ppm)||μg/day from Excipient 1||μg/day from Excipient 2||μg/day from Excipient 3||μg/day from Excipient 4||μg/day Film coat*||Sum||% Oral PDE|
Calculation based on: 4 x 25mg tablets (approx. 1g of drug product) and composition of each tablet.
*Supplier data used
Table 1: This shows the class 1 and 2A elements and the maximum results observed from a number of records and suppliers. It then shows the calculations made based on the composition of the oral tablet.
The third case study shows the risk assessment for an oral formulation. The risk assessment process identified that the API and 5 excipients were the only potential sources of elemental impurities.
Data was generated on 6 pilot scale batches of the API. Data for all 5 excipients was sourced from the Elemental Impurities Excipients Database (version 2018.1.0). Table 2 shows how many records and suppliers were associated with this excipient data. The summary table within the database can be used to summarise any variance in the elemental impurities determinations using statistical parameters.
Assessment of all data using ICH Q3D option 2B concluded that there was no significant risk from any component, the greatest potential level of any single element was <3% of the PDE.
|Data from the Elemental Impurities Excipient Database|
|Excipient||Number of records||Number of suppliers|
Table 2: Shows the numbers of records and supplies for 5 excipients in the Elemental Impurities Excipient Database (version 2018.1.0).