Complying with USP <232> and USP <233> Elemental Impurities Standards

In alignment with the International Conference on Harmonization (ICH) limits in the Guideline for Elemental Impurities Q3D, the United States Pharmacopeia (USP) has finalized its revisions to the elemental impurities standards in General Chapter <232> (Elemental Impurities—Limits) and General Chapter USP <233> (Elemental Impurities—Procedures). These standards were implemented on January 1, 2018.

USP <232>: Elemental Impurities—Limits

Prior to 2016, USP <232> specified 15 elements for consideration as impurities in drug products, whereas ICH Q3D specified the same 15 elements and also included nine additional elements. As of 2017, USP <232> and ICH Q2D have been fully aligned with respect to elements, element concentrations, and toxicity classification.

These elements have been placed into three classes, based on their toxicity and likelihood of occurrence in the drug product (see Table 1).

Table 1 — Permitted daily exposures (PDEs) for elemental purities in drug products

USP <232> does not apply for radiopharmaceuticals, articles intended only for veterinary use, vaccines, cell metabolites, DNA products, allergenic extracts, cells, whole blood, cellular blood components, or blood derivatives, including plasma and plasma derivatives, products based on gene therapy, cell therapy and tissue engineering, dialysate solutions not intended for systemic circulation, total parenteral nutrition, and elements that are intentionally included in the drug product for therapeutic benefit and dietary supplements and their ingredients.

USP <233>: Elemental Impurities—Procedures

USP <233> describes sample preparation steps and two analytical procedures (Procedures 1 and 2) for evaluation of the levels of elemental impurities in drug products. USP <233> also allows for an alternate procedure validation if the procedures do not meet the needs of a specific application.

Sample preparation

Selection of the appropriate sample preparation depends on the material under test. As stated in USP <233>, sample preparation includes the following:

• Neat: used for liquids or alternative procedures that allow the examination of unsolvated samples
• Direct aqueous solution: used when the sample is soluble in an aqueous solvent
• Direct organic solution: used where the sample is soluble in an organic solvent
• Indirect solution: used when a material is not directly soluble in aqueous or organic solvents. The sample is digested in a concentrated acid using closed-vessel digestion to minimize the loss of volatile impurities.

Procedure 1: ICP-AES/OES

Procedure 1 can be used for elemental impurities that can be detected by inductively coupled plasma-atomic emission spectroscopy (ICP-OES) or inductively coupled plasma-optical emission spectroscopy (ICP–OES). Below are the requirements for this procedure:

• Two calibration standards are required: a high standard at 1.5× the target elements in a matched matrix, and a low standard at 0.5× the target elements in a matched matrix
• Matching the matrix between the standard and samples: the dissolution method should be the same for calibration standards and samples
• Dilute the sample stock solution with an appropriate solution to obtain a final concentration of the target element at 1.5× the target elements in a matched matrix
• Run the analysis according to the manufacturer’s recommendations for program and wavelength, making sure to correct for any spectral overlaps.

Procedure 2: ICP-MS

Procedure 2 can be used for elemental impurities that can be detected by inductively coupled plasma-mass spectroscopy (ICP-MS). Below are the requirements for this procedure:

• Two calibration standards are required: a high standard at 1.5× the target elements in a matched matrix, and a low standard at 0.5× the target elements in a matched matrix
• Matching the matrix between the standard and samples: the dissolution method should be the same for calibration standards and samples
• Dilute the sample stock solution with an appropriate solution to obtain a final concentration of the target element at 1.5× the target elements in a matched matrix
• Run the analysis according to the manufacturer’s recommendations for instrumental conditions and analyte masses, making sure to correct for matrix-induced polyatomic interferences.

Alternate procedure validation

If a specified procedure does not meet the needs of a specific application, an alternative procedure may be used, provided it meets the validation requirements of detectability, accuracy, precision, repeatability, and specificity, and must be shown to be acceptable with the validation criteria of USP <233>.

Resources for users

The 24 elements in USP <232> can be prepared in either a nitric acid (HNO₃) matrix or a hydrochloric acid (HCl) matrix for ICP measurements, taking into account certain safety and stability issues that must be considered for certain elements.

Nitric acid matrix

The most common nitric acid matrix is 1–10% by volume of nitric acid, and all 24 elements listed in USP <232> are compatible with this matrix.

In selecting a nitric acid matrix, the following must be considered:

• The element osmium may be oxidized in a HNO₃ matrix to OsO₄, with the volatility of OsO₄ having the potential to increase nebulization efficiency during sample introduction. The volatile OsO₄ is also toxic and should be avoided for health and safety reasons. At dilute concentrations of HNO₃, OsO₄ formation may be limited.
• With elements such as Sn and Sb, the addition of a complexing ligand such as fluoride may be required to ensure their stability in HNO₃. Tartrate may also be added to in this capacity to stabilize Sb. If both elements Sb and Hg are to be analyzed, and tartrate is added to stabilize Sb, Hg may not be stable in the solution. Therefore, if all three elements (Sn, Sb, and Hg) are to be analyzed, an HNO₃-HF matrix will be the better choice for the analysis of all three elements.
• The platinum group metals and Au are typically stabilized with HCl added to HNO₃. However, mixing HCl in the presence of Ag or Tl⁺¹ can create unstable chloride complexes of these elements.
• Mercury can be unstable with plastic labware, particularly at concentrations lower than ~10 ppm. This instability may be remediated by using clean low-density polyethylene (LDPE) containers for preparation and storage in dilute HNO₃ spiked with 1 ppm AuCl₃, provided Au is not an element of interest.

Hydrochloric acid matrix

The 24 elements listed in USP <232> are also compatible with a hydrochloric acid matrix.

In selecting a hydrochloric acid matrix, the following must be considered:

• Silver has limited solubility in a hydrochloric acid matrix, and long-term stability of silver in a hydrochloric acid matrix is limited by the photoreduction of silver chloride to silver. Therefore, exposure to light should be limited.
• Thallium must be present in solution as Tl⁺³ to avoid precipitation as Tl-chloride.

Selecting an acid matrix

Below are the general considerations for selecting the acid matrix:

• If a hydrochloric acid matrix is acceptable, all 24 elements of USP <232> are expected to be stable at 1–10 ppm in 10–20% (v/v) HCl when stored and prepared in LDPE containers, although Ag will be photosensitive, and exposure to light should be minimized.
• If a nitric acid matrix is required, trace amounts of HCl and HF may be necessary. A 10-ppm solution of all 24 elements in 2–5% (v/v) HNO₃ with trace HCl-HF and prepared and stored in LDPE would require monitoring for osmium oxidation to OsO₄ and Ag, Au, and Hg instability.

Conclusion

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. For more information, please visit www.inorganicventures.com.

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.