USP 233 Elemental Impurities - Procedures

The standard "USP 233 Elemental Impurities - Procedures," published by the United States Pharmacopeia (USP), describes two analytical procedures for assessing the levels of elemental impurities. This standard also provides criteria for acceptable alternative procedures. Analysts confirm through validation studies that the analytical procedures described herein are suitable for use on the specified material.

This standard also specifies criteria for acceptable alternative procedures. Alternative procedures that meet the verification requirements specified herein may be used where necessary.

System standardization and conformity assessment using applicable reference materials should be performed on the day of analysis.

Procedure 1 can be used for elemental impurities that are generally suitable for detection by inductively coupled plasma-atomic (optical) emission spectroscopy (ICP-AES or ICP-OES). Procedure 2 can be used for elemental impurities that are generally suitable for detection by ICP-MS. Before first use, the procedure must be verified as suitable for the instrument and sample used by meeting alternative procedure validation requirements (procedural validation).

Sample preparation formats include:

• Neat
• Direct aqueous solution
• Direct organic solution
• Indirect solution is found

The selection of the appropriate sample preparation depends on the material being tested and is the analyst's responsibility. When sample preparation is not specified in the monograph, the analyst may use any of the appropriate preparation procedures. Standard solutions may contain more than one target element. All liquid samples should be weighed.

USP 233 provides standard test methods for detecting and measuring elemental impurities in pharmaceutical substances, products, and ingredients. It complements USP 232, which defines permissible daily exposures to various toxic elements. Together, these two standards align with the elemental impurities guide and ensure global consistency in safety assessment.

The main purpose of the USP 233 standard is to:

• To provide modern, accurate and reproducible test methods for measuring elemental impurities.
• To replace older classical tests such as the heavy metals limit test (USP 231) which lack specificity and sensitivity.
• Ensuring that pharmaceutical products meet the safety thresholds for elemental impurities established in the USP 232 standard.

This standard outlines validated analytical procedures and acceptance criteria for measuring elemental impurities in drug products, drug substances, and excipients. It covers arsenic, cadmium, lead, mercury, and other metals that pose potential health risks.

This standard applies to:

• Pharmaceutical substances
• Excipients
• Finished pharmaceutical products

These procedures are designed to detect elements that are divided into three classes (Classes 1, 2, and 3) based on their toxicity and probability of occurrence.

The USP 233 standard provides two advanced instrumental methods:

• Inductively coupled plasma-mass spectrometry (ICP-MS): This technique is best used for the detection of trace levels (parts per billion) of elemental impurities. This technique offers high sensitivity, multi-element capability, and a wide dynamic range. It is often used to detect toxic elements such as arsenic, cadmium, mercury, and lead.
• Inductively coupled plasma-optical emission spectroscopy (ICP-OES): This technique is best used to measure elements at moderate to high concentrations. It detects the light emission from atoms to quantify the elements. This technique has good sensitivity and robustness, and is faster for some matrices. It is typically used to detect elements such as copper, zinc, or nickel when they are present at higher levels.

These techniques were chosen for their accuracy, sensitivity and ability to detect multiple elements simultaneously.

The USP 233 standard provides flexibility in sample preparation:

• Closed-vessel microwave digestion: Closed-vessel digestion (typically microwave-assisted acid digestion) is the most common method used to fragment the sample into a form suitable for instrumental analysis.
• Open-vessel digestion
• Direct dissolution

The goal is to efficiently and reproducibly transfer all target elements into solution without contamination or loss. It is important to prepare a homogeneous solution compatible with the detection method while maintaining analyte stability.

Before routine testing, laboratories must validate the method. The USP 233 standard requires the following validation criteria (system suitability):

• Accuracy: Recovery of sharpened sample between 70 percent and 150 percent
• Precision: RSD of at least 20 percent for six repetitions
• Specificity: No interference from the sample matrix
• Detection limit
• Quantification limit: At or below the specification limit

At the same time, a system conformance test should be performed to ensure device readiness.

To ensure reliability of results:

• A system conformance test must be performed to verify device performance.
• Spike recovery experiments are used to demonstrate method accuracy.
• Repeatability: The relative standard deviation (RSD) should not exceed 20 percent.
• Medium precision: The Relative standard deviation (RSD) from multiple analysts or instruments should not exceed 25 percent.

The main advantages of the USP 233 standard are:

• Modernization: Replaces older colorimetric methods with more sensitive and robust instrumental techniques.
• Global compliance: Complies with international standards such as ICH Q3D, facilitating regulatory acceptance.
• Flexibility: Laboratories may use alternative validated methods as long as they meet performance criteria.

USP 233 references USP 232 for the limits for each elemental impurity when defining procedures. Reporting is generally required for elements above the quantitation limit. Final results should be expressed as μg/g, μg/day, or percentage, depending on the product type and daily dose.

USP 233 standard complies with:

• ICH Q3D (International Conference on Harmonization)
• FDA Industry Guidance
• European Pharmacopoeia Chapter 5.20

Compliance with the USP 233 standard is mandatory for all drug products labeled in accordance with USP standards in the United States.

In short, in terms of testing requirements, USP 232 does not prescribe analytical methods; instead, it defines the limits. The actual testing procedures are described in USP 233. That is, USP 232 does not directly describe the test methods to be performed, but rather refers to the complementary USP 233 standard.

The USP 233 standard marks a significant advance in pharmaceutical testing by introducing modern analytical procedures for detecting elemental impurities.

Our organization, which has been supporting businesses across all sectors for years through a wide range of testing, measurement, analysis, and evaluation activities, has a strong team of employees who closely follow global developments in science and technology and are constantly improving themselves. In this context, we also provide testing services in accordance with the "USP 233 Elemental Impurities - Procedures" standard.