Elemental Impurities, USP <232> / <233>

Screening, method development and method validation for elemental impurities in pharmaceutical and medical device products

Pace Analytical Life Sciences (PLS) offers analytical services specifically designed to comply with USP <232> Elemental Impurities-Limits and <233> Elemental Impurities-Procedures by employing a step-wise approach to assessing the presence of elemental impurities in excipients, drug substances and products.

Step 1 – Qualitative Screening Methods

PLS has developed and validated two internal methods for the detection and quantification of elemental impurities, as defined in USP <232>, in water-soluble materials and products:

1. PLS LM 247, “Analysis of USP Class 1 Elemental Impurities by ICP-MS” (Cd, Pb, As and Hg), and
2. PLS LM 249, “Analysis of USP Class 2 Elemental Impurities by ICP-MS” (Ir, Os, Pd, Pt, Rh, Ru, Cr, Mo, Ni, V and Cu)

Clients may choose to run one or both of the in-house screening methods or they may request that PLS run an individual screening method; depending on the level of supply chain control and their specific knowledge of the test article.

The screening method is intended to qualitatively determine the presence of any elements of concern in a specific matrix and to provide a gross estimate of element concentration, consistent with the USP default concentration limits for drug substances and excipients. If client internal specification limits are lower than the USP default concentration limits, use of the PLS screening methods is not appropriate and it is recommended that a client-specific laboratory method (CLM) is developed as described in Step 2 below.  

Step 2 – Element-specific and/or Test-Article-specific Method Development

If the qualitative screening method assessment results in identified elemental impurities of concern, if the desired specification limits are below the USP published limits, or if the test article is not water-soluble, PLS will develop a method specific to the test article.

When developing a method—such as a quantitative assay or a limit test—dependent upon client requirements, initial method development will include an initial assessment of accuracy in the presence of the test article (spiked samples), precision and specificity, as appropriate.

Step 3 – Element-Specific Method Validation

Many clients may choose to validate the material-, product- or element-specific Method, once it has been developed. The method attributes of accuracy/range, system/method precision, intermediate precision, linearity, specificity, LOD/LOQ, robustness and solution stability are generally recommended for validation quantitative assay methods. For limit-test methods, the attributes of specificity, Limit of Detection (LOD), and accuracy (at the established limit) are generally recommended. PLS offers method validation quotes that list the method attributes by line item, such that clients may choose to select or omit certain attributes based on their internal procedures or their intended use of the final method.