The elemental impurities standards in General Chapter <232> (Elemental Impurities—Limits) define the permitted daily exposures (PDEs) for elemental purities in drug products, and General Chapter USP <233> (Elemental Impurities—Procedures) outlines the procedures for testing for these elemental impurities. A discussion of the limits in USP <232> and the procedures in USP <233> can be found here.
Since the implementation of USP <232> and USP <233> on January 1, 2018, several questions have arisen in connection with this implementation and many resources are available to aid in their implementation.
Frequently asked questions:
Q: What materials or products are covered by the scope of USP <232>?
A: There are several materials that are covered by USP <232>. They include drug products, including drug substances such as active pharmaceutical ingredients as well as excipients. The scope also includes biologic drug products such as purified proteins and polypeptides, the derivatives of these compounds, and products of which they are components.
Q: What materials or products are not covered by the scope of USP <232>?
A: There are numerous materials and products that are not covered by USP <232>. They include radiopharmaceuticals, vaccines, cell metabolites, DNA products, allergenic extracts, cells, whole blood, cellular blood components or derivatives, gene therapy products, cell therapy products, tissue engineering products, dialysate solutions not intended for systemic circulation, dietary supplements, veterinary products, and total parenteral nutrition products (TPNs).
Q: When does USP <232> need to be applied?
A: USP <232> needs to be applied when elemental impurities are known to be present, have been added, or have the potential for introduction. The recommended approach is to perform a risk assessment to characterize the likelihood that a particular elemental impurity may be present and base the application of USP <232> on this assessment.
Q: What options exist for determining elemental impurity content?
A: There are three basic options for determining elemental impurity content: the drug product analysis, the summation option, and the individual component option. The drug product analysis option represents the analyses of elemental impurities in the final product form, where the typical dosage unit is scaled to a maximum daily dose. The summation option characterizes elemental impurity concentrations in specific ingredients in their dosage form, and then sums these contributions, which must be less than the PDE. The individual component option is simply a subset of the summation approach and may be useful for suppliers of specific drug product components.
Q: Is compliance with USP <232> and USP <233> limited to using ICP analytical techniques?
A: Compliance with USP <232> and USP <233> is not limited to using ICP analytical techniques. Other analytical techniques, such as atomic absorption (AA, GFAA) or X-ray fluorescence (XRF), are acceptable.
Q: Do the analytical methods need to be validated?
A: The analytical methods should be validated, and USP <233> offers guidance in this regard. Two general approaches may be used: a limit test or a quantitative impurity test. The limit test (not-more-than test) has fewer validation requirements as it applies upon nonquantitative acceptance criteria such as detectability, repeatability, and specificity. The quantitative impurity test includes additional validation parameters such as accuracy and limits of quantitation, range, and linearity.
Q: Does one have to measure all 24 elements that are described in USP <232>?
A: One does not have to measure all 24 elements that are described in USP <232>. Using an appropriate risk assessment can help determine which elements, if any, can be excluded from the analyses. A general recommendation is to follow the approach detailed in Section 5 of ICH Q3D, which is the international guideline for elemental impurities aligned with USP <232>. This approach details the inclusion (or exclusion) of specific elements in risk assessments. It is based upon whether the elements are intentionally added to the drug product and the respective element toxicity class. For example, Class 2B elements (e.g., Os and the precious metals) can generally be excluded from the risk assessment unless they are known to be intentionally added to the drug product.
Q: What information is needed to go from PDE to permitted concentration?
A: As the PDE is provided in units of µg/day, the permitted concentration is simply the PDE divided by the applied dose, which is in units of mass per day (e.g., grams/day). In this case, the permitted concentration will have units of µg/g (assuming the applied dose is grams/day). For example, if the applied dose is 100 grams per day, and the PDE is 2 µg/day for cadmium (Cd), then the permitted concentration would be (2 µg/day) ÷ (100 g/day) = 0.02 µg/g Cd.
Q: What information is needed to go from the permitted concentration to the J concentration?
A: The J concentration is the working concentration of the spiked replicates and working standards. If we use the above example of a 0.02 µg/g Cd permitted concentration, and the preparation is to dissolve 0.1 gram of sample in 50 mL, then the J concentration would be equivalent to (0.02 µg/g) × (0.1 g) ÷ (50 mL) = 0.00004 µg/mL Cd.
Q: When is it appropriate to apply digestion versus dissolution?
A: It is appropriate to apply digestion versus dissolution when the solubility of the sample in a particular solvent is not complete or acceptable. When choosing appropriate solvents or digestion methods, it is important to consider if they will result in a sample matrix that possesses acceptable analytical properties. Common examples of materials that may require digestions include oral dosage form excipients that may contain refractory pigments or final drug products that solubilize poorly due to active pharmaceutical ingredients. All tested materials and analytes need to be completely digested and solubilized without loss due to volatility, and this should be demonstrated experimentally.
Q: How does one analyze biomolecules?
A: Biomolecule formulations can have pronounced matrix effects. It can help to matrix match working standards to the samples as closely as possible using very high-purity salts, etc., to mimic the physical and spectral properties of the sample solution. The use of multiple internal standards by ICP-MS is recommended and this approach can significantly improve method validation parameters such as accuracy, precision, ruggedness, and robustness.
Resources
To aid in the implementation of USP <232> and USP <233>, there are many available stock certified reference material solutions that are tailored to the class and type of elements detailed within USP <232> and ICH Q3D. Common formulations are detailed here. Additional information regarding the chemical compatibility and stability of the 24 elements described in USP <232> is available here. General suggestions for ICP analyses may be found at https://www.inorganicventures.com/icp-operations-guide.
Lina Genovesi, Ph.D., JD, is a technical, regulatory, and business writer based in Princeton, NJ, U.S.A.; e-mail: [email protected]; www.linagenovesi.com.