USP General Chapters <232> and <233> have been introduced to replace the historic method of measuring heavy metals by USP <231>.
USP <231> Heavy Metals
The conventional means of testing pharmaceutical substances for heavy metal content is USP <231> Heavy Metals. This test proceeds by precipitating heavy metals as the metallic sulfide. The final result is made by visual comparison of the unknown to a lead standard. This test has been the industry accepted standard method for over 100 years.
The test has a number of shortcomings:
- Not specific for individual elements. If the test fails, further investigation is required to identify which element(s) is causing the sample to fail.
- Does not give results for chromium or other metals. The test only works for elements that readily precipitate as sulfides.
- Sample preparation may result in the loss of mercury. USP <231> Method II is conducted by ashing the sample in a furnace (ca. 600ºC). Mercury evaporates under these conditions, making the method unsuitable for mercury analysis.
As a result of these issues, USP introduced two new general chapters for the analysis of heavy metals: USP <232> Elemental Impurities – Limits and USP <233> Elemental Impurities – Procedures.
USP <232> Elemental Impurities – Limits
This general chapter lists the elements within the scope of USP Elemental Impurity testing along with their corresponding limits. Each analysis using general chapters <232> and <233> must include the elements cadmium, lead, arsenic and mercury. Other elements include: iridium, osmium, palladium, platinum, rhodium, ruthenium, chromium, molybdenum, nickel, vanadium and copper.
When deciding what elements to include, USP advises the use of a risk assessment (risk-based control strategy) to determine what elemental impurities may be present in the drug substance, excipient or product. If an elemental impurity may occur naturally, be added intentionally or be introduced inadvertently, then the element needs to be monitored to assure compliance with the limits of USP <232>.
USP <232> includes two tables that contain limits. Table 1 is for drug products and Table 2 is for drug substances and excipients. Both tables have information presented based on the route of administration: oral, parenteral, inhalation and large-volume parenterals (for drug products). Please contact us to request more information or assistance on applying the limits in USP <232> to your product.
Click here for comments on performing a risk-based analysis on products that are exposed to stainless steel equipment.
USP <233> Elemental Impurities – Procedures
USP <233> relies on Inductively Coupled Plasma Atomic Emission Spectroscopy (ICP-AES) or Inductively Coupled Plasma Mass Spectrometry (ICP-MS) for the determination of elemental impurities. The general chapter is segmented into two procedures: Procedure 1 is for ICP-AES, Procedure 2 is ICP-MS.
This general chapter also contains instructions for procedure validation.
(Note: USP <233> uses the terms “procedure validation” and “procedure verification.” For clarity, we refer to these activities as “validation.”)
Before the initial use of USP <233>, the procedure must be validated for the instrument and sample according to the instructions in USP <233>. The general chapter gives validation instructions for limit and quantitative tests:
|Type of Procedure||Detectability||Accuracy||Repeatability||Ruggedness||Specificity|
Click here for more information on how we validate USP <233>.
Quantitative or Limit Validation?
The client should consider the intended use of the product to determine what type of validation is required. In general, drug products should be tested against a limit test validation. Drug substances and excipients should be tested against a quantitative validation to allow the summation option of calculating a products elemental impurity content.
Once the procedure has been validated, GLI can perform routine testing on the drug product, excipient or drug substance according to USP <233>. This testing can be provided to meet GMP requirements at any level of service: regular turnaround (approximately 10 days), 3-5 day rush and 1-2 day rush.