One of the reasons for the implementation delay of the new USP/NF Chapters on Elemental Impurities, which were originally introduced in 2013, but were ultimately not scheduled for implementation until January 2018, was the desire to harmonize the chapters with the International Standard, ICH Q3D, which has also been years in development. The FDA has produced a Guidance document stipulating their current view of how ICH Q3D and USP 232, 233 and 2232 should be interpreted and implemented. According to the Guidance, for both the USP and ICH guidelines, it is generally recommended to perform an elemental impurities risk assessment by, "first identifying known and potential sources of elemental impurities. Manufacturers should consider all potential sources of elemental impurities, such as elements intentionally added, elements potentially present in the materials used to prepare the drug product, and elements potentially introduced from manufacturing equipment or container closure systems. Manufacturers should then evaluate each elemental impurity likely to be present in the drug product by determining the observed or predicted level of the impurity and comparing it with the established Permitted Daily Exposure (PDE). If the risk assessment fails to show that an elemental impurity level is consistently less than the control threshold (defined as being 30 percent of the established PDE in the drug product), additional controls should be established to ensure that the elemental impurity level does not exceed the PDE in the drug product. These additional controls could be included as in-process controls or in the specifications of the drug product or components."
The new USP chapter requirements should be applied to all new NDAs and ANDAs for drug products with an official USP monograph as well as marketed compendial drug products not approved under an NDA or ANDA (e.g., nonprescription over-the-counter (OTC) drug products marketed under an FDA OTC monograph) subject to the provisions of the FD&C Act. Applicants submitting new NDAs and ANDAs for drug products without an official USP monograph should follow the recommendations for the control of elemental impurities as described in ICH Q3D.
The Chapter 233 methods are quantitative and allow for very low limits of detection. The FDA guidance states, "ICH Q3D does not describe specific analytical procedures for routine testing of materials or for performing a risk assessment. FDA recommends that manufacturers use the analytical procedures described in General Chapter 233 or, if those analytical procedures cannot be used for a specific item, analytical procedures that meet the validation requirements described in General Chapter 233. Any analytical procedure used to test for elemental impurities should be properly described, and if used for routine testing, its suitability must be verified under actual conditions of use.
Analytical procedures for both risk assessments and routine testing should be validated. Analytical procedures used during risk assessments must possess characteristics (e.g., accuracy, precision, specificity) such that the manufacturers can be reasonably certain (e.g., at the 95% confidence level) that the measurements can be relied upon to decide whether to include routine testing of materials in the control strategy. This decision depends on whether the amounts of the elemental impurities in the materials are consistently below control thresholds. The analytical procedures should be validated with this goal in mind."