The US Pharmacopeial Convention (USP) recently announced new required methodologies to replace its General Chapter for Heavy Metals (USP <231>). USP has proposed two new General Chapters (<232> on limits of elementary impurities, and <233> on procedures), as well as a Supplemental General Chapter on contaminants in dietary supplements (USP <2232). The implementation date for the new chapters is January 2018.
The new chapters will apply to all pharmaceutical, biotechnology, excipient, medical device and nutraceutical manufacturers. The updated methodologies utilize modern technologies to provide better precision and yield higher recoveries. To comply with these changes, drug products will be required to fall within the proposed limits.
The chapters will replace the historic method of measuring heavy metals by USP <231>. This test, which was the industry standard for more than a century, works by precipitating heavy metals as metallic sulfide. The final result is made by visual comparison of the unknown to a lead standard.
The test has a number of shortcomings:
- It is not specific for individual elements. If the test fails, further investigation is required to identify which element(s) caused the sample to fail.
- It 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. 600º C). Mercury evaporates under these conditions, making the method unsuitable for mercury analysis.
USP <232> – Limits
This 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 a risk assessment (risk-based control strategy) to determine what elemental impurities may be present in the drug substance, excipient or product.
USP <233> -- Procedures
This chapter 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.
While the USP has established January 1, 2018, as the new date of applicability of the Elemental Impurities Limits General Chapters, the FDA has set December 2018, as the expected date of compliance for existing products. Under GMP drug quality and regulatory requirements elemental impurities will have to be monitored for all existing drug products, APIs, and excipients at that time, not just for the 15 elemental impurities of USP<232>, but for the full 24 elemental impurities of Q3D.
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 method of calculating a products elemental impurity content.
Once the procedure has been validated, Synergy Bioscience 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 (10 days), 3-5-day rush and next day rush (24/48-hour rush).
Synergy Bioscience offers analytical services specifically designed to comply with USP <232> Elemental Impurities-Limits and <233> Elemental Impurities-Procedures by employing a step-wise approach to assessing the presence of elemental impurities in excipients, drug substances and products.
Step 1 – Qualitative Screening Methods
We have developed and validated two internal methods for detecting and quantifying elemental impurities in water-soluble materials and products:
1. “Analysis of USP Class 1 Elemental Impurities by ICP-MS” (Cd, Pb, As and Hg), and
2. “Analysis of USP Class 2 Elemental Impurities by ICP-MS” (Ir, Os, Pd, Pt, Rh, Ru, Cr, Mo, Ni, V and Cu)
Clients may choose to run one or both of the in-house screening methods or they may request that Synergy Bioscience run an individual screening method; depending on the level of supply chain control and their specific knowledge of the test article.
The screening method will qualitatively determine the presence of any elements of concern in a specific matrix and to provide a gross estimate of element concentration, consistent with USP default concentration limits.
Step 2 – Element-specific and/or Test-Article-specific Method Development
If the qualitative screening method identified elemental impurities, the desired specification limits are below the USP limits, or the test article is not water-soluble, we will develop a method specific to the test article.
Step 3 – Element-Specific Method Validation
Many clients may choose to validate the material-, product- or element-specific Method. The method attributes of accuracy/range, system/method precision, intermediate precision, linearity, specificity, LOD/LOQ, robustness and solution stability are generally recommended for validation quantitative assay methods. For limit-test methods, the attributes of specificity, Limit of Detection (LOD), and accuracy (at the established limit) are generally recommended.
Please contact a member of our technical staff to receive more information or request a free quotation.