Proposed chapter

The proposed new <232> specifies permissible daily exposure (PDE) limits for elemental impurities in drug products. Elemental impurities include catalysts and environmental contaminants that may be present in drug substances, excipients, or drug products. These impurities may occur naturally, be added intentionally, or be introduced inadvertently (e.g., by interactions with processing equipment). When elemental impurities are present, have been added, or have the potential to be introduced, assurance of compliance to the specified levels is required. Compliance with these limits is necessary for all drug products. To determine conformity, a risk-based control strategy may be appropriate (2).

The performance requirements of the techniques used to measure elemental impurities in pharmaceuticals are described in <233> (2). The chapter describes two analytical procedures (i.e., procedures 1 and 2) to evaluate the levels of the elemental impurities described in <232>. Procedure 1 can be used for elemental impurities generally amenable to detection by ICP–OES. Procedure 2 can be used for elemental impurities generally amenable to detection by ICP–MS.

ICP–OES and ICP–MS for metals analysis

As described above, the proposed chapters specify ICP–OES and ICP–MS as the analytical procedures of choice, thus enabling scientists to accurately and easily determine levels of trace elemental impurities in pharmaceutical products. These powerful techniques identify and quantify each metallic impurity with higher sensitivity and selectivity than conventional precipitation-based detection methods. ICP–OES and ICP–MS can analyze small sample volumes and masses and offer much lower detection limits. They are thus suitable for testing synthetic peptides and proteins as well as drug products in development.

ICP–OES and ICP–MS are fast, multielement techniques that can analyze as many as 60 elements in a 2-min run after sample digestion. This characteristic is a key benefit over wet-chemistry-based methods, which often require as much as 24 h for sample preparation alone. The techniques can also provide precise quantitative determination of the metal content of samples using only small sample quantities.

Application example

An ICP–OES analyzer (Thermo Scientific iCAP 6500 ICP–OES) and an ICP–MS system (Thermo Scientific XSERIES 2 ICP–MS) were used for the analysis of pharmaceutical products. The full suite of procedures outlined in <233> was performed using the ICP–OES instrument to analyze an over-the-counter cold and flu remedy. The medicine was prepared in triplicate by dissolving the product in a 1% (v/v) nitric acid solution, adding analyte spikes when necessary, sonicating for 10 min, and making a final weight of 50 g with 1% (v/v) nitric acid.

Accuracy and repeatability samples were prepared for analysis according to the validation requirements described in <233>. Accuracy samples comprising blank solutions were spiked with 0.5 j, 1 j, and 1.5 j of the limit, respectively (j is the indicated limit). Samples of the material under test were also spiked accordingly. In addition, six independent repeatability samples of the material under test were spiked with the elements of interest.

A quantitative screening of more pharmaceutical samples was performed using the ICP–MS analyzer configured using an Elemental Scientific Instruments (ESI) PC3 FAST sample-introduction system. Nineteen medicines were prepared by microwave digestion of single tablets or recommended doses. Following digestion, the samples were made in quantities as large as 50 mL with ultrapure water and analyzed without further dilution. One medicine was prepared in triplicate with and without a spike of 0.5 μg/g of each element (i.e., the level of the lowest component limit) and 0.01 μg/g of mercury.