Introduction to Heavy Metals:
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 guidelines, the United States Pharmacopoeia (USP) has published general chapters <232> “Elemental Impurities — Limits” and <233> “Elemental Impurities — Procedures” (you can read more about USP 232 and USP 233 here).
While these chapters are ostensibly for drug products themselves, the FDA continues to expand their regulation of container closure systems and packaging associated with pharmaceuticals. With more and more frequency, the FDA is requiring that extractables and leachables studies, including elemental impurities analysis, be performed on systems such as prefilled syringes. Elemental impurities analysis can also identify the root cause of issues such as syringe discoloration. EKG Labs has recently evaluated a pre-packaged drug product in a syringe that was leaching dangerously high levels of lead.
Syringe Discoloration Case Study:
EKG Labs was approached to analyze an injectable drug product packaged in a glass syringe with brass fittings. The product was being used in clinical applications, and the client was receiving complaints about fluid discoloration, particularly near the syringe tip. The drug product consisted of a drug substance suspended in a strong organic matrix. Given the nature of the organic solvent and experience with some similar studies, EKG hypothesized that the strong organic solvent may have been leaching copper ions from brass (a copper/zinc alloy) fittings, causing the syringe discoloration.
For comparison, EKG tested both drug product from a syringe with a plated brass tip (a “control” syringe) and drug product from a syringe with an un-plated brass tip (the suspect discolored syringe). EKG also conducted a brief accelerated extraction study by exposing the drug substance, organic matrix, and total drug product directly to un-plated brass fittings over 72 hours in a heated environment. A final sample of drug product was spiked with known quantities of a variety of metals to assess recovery within the sample matrix.
These samples were digested in concentrated nitric acid with gentle heat for 24 hours. After dilution, samples were analyzed by ICP-MS for a full elemental scan (~60 elements, including all elements in USP 232/233) with a focus on copper and zinc.
High levels of copper, zinc, and lead (lead is often present in quantities around 2% in brass) were observed in the drug product and organic matrix accelerated extraction samples. These high levels (between 0.1 and 0.5 mg per mL of injection for each element) were also observed in both the plated and un-plated syringe samples at similar levels, suggesting the plating did not prevent heavy metal extraction.
The brass fittings were distinctly shown to be the source of syringe discoloration and a concerning source of heavy metal impurities. EKG Labs was able to expedite this testing to get client the answers they needed to resolve the issue as quickly as possible.
A key way to mitigate risk is to perform an exhaustive extractable/leachable (E&L) study prior to drug product use. Often an extractables (the chemical that can be forced out of a device or product) investigation is done in conjunction with, or prior to, a leachables (the chemicals that migrate from one material matrix into another under normal storage conditions) study in order to get a full profile of the potential hazards of a pharmaceutical product, container closure system, or medical device. This typically incorporates an analysis of storage stability under a variety of controlled conditions. If any leachables of concern are noted, such as in this case, it may also be necessary to develop and validate methods to monitor these elements/chemicals over time and across lots.
About EKG Labs
EKG Labs is an analytical service provider for the medical device and pharmaceutical industries. Our analytical services support regulatory filings, product development, and analytical chemistry investigations. Specialty analytical services include: extractables, leachables, biocompatibility, characterization, impurity identification, method development, method validation, deformulation, and other investigational activities. EKG Labs operates out of Innovative Technology Enterprises (ITE) at the University of Missouri, St. Louis (UMSL).
If you are experiencing a challenge with impurities or need analytical services to support your product development, please contact us at 810-354-5229.