The new elemental impurities regulations stress the importance of controlling all sources of elemental impurities in drug products. The regulations also impact all upcoming and current commercial drug products for human use. To comply with these regulations, it is critical to have an efficient, cost-effective, and agency-accepted approach.
Elemental impurities can contaminate or leach into a drug product from multiple sources (i.e. drug substance, excipients, water, equipment, and container closure systems), therefore, it is no longer acceptable to monitor the inlet raw materials only. A conservative risk-based approach to drug product contamination is recommended, which should address all potential sources of elemental impurities. If it can be demonstrated that the elemental impurities present in the drug product are under control (less than the control threshold for three lots), then analysis at release is not needed.
The US Food and Drug Administration (FDA), US Pharmacopeia (USP), European Pharmacopoeia (Ph. Eur.), and Medicines & Healthcare products Regulatory Agency (MHRA) are consistent with the International Harmonisation (ICH) Q3D for the new regulations, which affect All New Drug Applications (NDAs), Abbreviated New Drug Applications (ANDAs), and commercially approved drug products for humans. A drug product’s risk assessment should utilize data from methods that are accurate, precise, linear, specific, and sensitive.
Risk assessment reports can include data and information from the following sources:
- Testing data
- Vendor data
- Scientific rationale
- GMP controls
In order to reduce the cost and time to complete this analysis, a validation at the time of analysis has been employed to generate phase appropriate results for materials to be included in the risk assessment. Method development is not necessary beyond the dissolution/digestion of the sample matrix. Keep in mind, instrument parameters and dilution factors are based on the required sensitivity, elements of interest, and scientific expertise (knowledge of interferences and stability of elements in various solutions).