An Introduction to Elemental Impurities
Elemental impurities analysis encompasses trace metal/heavy metal testing to evaluate pharmaceutical products for elevated concentrations of elements that are of significant toxicological concern. Based on ICH Q3D guidelines, the USP has published general chapters <232> “Elemental Impurities — Limits” and <233> “Elemental Impurities — Procedures”. The chapters apply to almost all drug products, generally divided into three classes: oral, parenteral, and inhalational.
EKG has written more extensively about ICH Q3D, USP 232, and USP 233 here.
IV Product Case Study:
Because of the large daily dosages delivered by IV bags, IV solutions can be challenging to assess to the low limits of USP 232. This challenge is compounded by the high salt matrices of these solutions. Inductively Coupled Plasma Mass Spectrometry (ICP-MS), the primary method for assessing elemental impurities, is very sensitive to matrix effects. In particular, high concentrations of dissolved solids can deposit on instrument cones and internal optics. High concentrations specifically of easily ionized salts suppress ionization of analyte material. These issues lead to reduced signals over time and increased response variability.
EKG Labs was recently approached with the challenge to evaluate elemental impurities in IV bags containing uniquely high densities of salt and a 2 L/day dosage limit. We began our feasibility study by preparing 1 ppb (1 ng/mL) mixed elemental standards in dilute nitric acid and by spiking at 1 ppb directly into the sample IV formulation to assess recovery within the sample matrix. The samples were analyzed by ICP-MS for all elements in USP 232/233.
An ICP-MS at EKG Labs
In the “clean” matrix of dilute nitric acid, the limits of detection for each USP 232 element were well below the USP limits, as expected. However, in the sample matrix, a couple elements had USP limits near the instrumental LOD.
Given that our ICP recommends infusion of samples with no more than ~0.25% total dissolved solids, significantly below the known salt concentration in this IV solution, we knew dilution was necessary. However, given the already high dosing, it was preferable to avoid benchtop dilutions for risk of raising detection limits and not meeting USP limits. Due to this, we turned to our unique on-instrument dilution with argon (Ar) gas. The ICP-MS is capable of diluting up to 1:100 sample infusion to Ar gas ratio. Since detection limits naturally increase with increasing Ar gas dilution, we discovered that for this project a 1:8 sample infusion to Ar gas ratio provided sufficient detection limits while still diluting the sample to a final, instrument acceptable, 0.1% concentration of salts.
Using this on-instrument dilution, we generated a spiked in-sample calibration curve containing all the USP elements of interest that. The curve was linear beyond the necessary USP limits for even the most challenging elements.
Where could elemental impurities in IV products come from?
Elemental impurity sources in pharmaceuticals can be categorized in four main ways:
- Residual catalysts or inorganic reagents added intentionally in synthesis
- Impurities unintentionally added through the use of impure drug substance, excipients, or reagents in the preparation of the drug product
- Contamination or leaching from manufacturing and processing equipment
- Leaching from container closure systems
A key way to mitigate risk from the latter two categories is to perform an extractable/leachable (E&L) study. Extractable and leachable testing of container closure systems is performed under USP <661.2>. Procedures for testing manufacturing and processing equipment are detailed in USP <665>.
Elemental Impurities Testing at EKG Labs
EKG Labs provides elemental impurity testing services to the pharmaceutical and medical device industries. Using our state-of-the-art ICP-MS, EKG Labs is capable of detecting elemental impurities down to an analytical parts-per-trillion level. EKG Labs can perform USP compendial and ICH testing for any or all of the elements listed in USP 232 and/or ICH Q3D. We have experience demonstrating precise recovery even in most challenging matrices and can extract or digest your unique sample as necessary. EKG Labs can also develop and validate a risk-based, product-specific method in order to monitor one or more targeted elements.
While medical devices and other products may not require direct compliance with USP 232/USP 233 or ICH Q3D testing, EKG Labs prides itself on developing comprehensive extractable and leachable studies, many of which include ICP-MS trace metal analysis. An EKG Labs elemental survey scan can analyze over 60 elements! At EKG Labs we work with you to provide a customized solution to your impurity identification and analysis needs.
About EKG Labs
EKG Labs is an analytical service provider for the pharmaceutical and medical device industries. Our wide variety of analytical services supports product development, regulatory filings, and analytical chemistry investigations.