Extractable and Leachable Study of Pharmaceutical Packaging Material used to Store Penicillin-V Using ICPMS-2050

Extractables and Leachables Study of Penicillin‑V Packaging Using ICPMS‑2050 — Executive Summary

Significance of the topic

The identification and quantification of extractables and leachables (E&L) from pharmaceutical packaging are essential to ensure drug safety and efficacy across shelf life. Regulatory expectations (ICH Q3D, PQRI, USP) require demonstrating that elemental and organic impurities that can migrate into drug products remain below toxicologically based thresholds. Robust elemental screening and targeted quantification by ICP‑MS support risk assessment, method development for leachable monitoring, and regulatory submissions.

Objectives and overview of the study

This application study evaluated elemental extractables from a container closure pack (CCP) intended for Penicillin‑V storage and assessed leachables in the drug product. Primary aims were to:

• Perform non‑targeted elemental screening to build a comprehensive extractable profile.
• Quantify targeted elements (ICH Q3D classes and additional non‑targeted elements) relative to analytically derived Analytical Evaluation Thresholds (AETs).
• Demonstrate suitability of the Shimadzu ICPMS‑2050 (with Mini‑Torch and LabSolutions ICPMS software) for regulatory‑grade E&L work.

Methodology

Experimental design

• Extractable experiments: Two accelerated extraction protocols (Experiment‑A and Experiment‑B) using empty CCPs incubated inverted with 100 mL of 5% (v/v) HNO3 (Experiment‑A) or 5% (v/v) HCl (Experiment‑B) at 85°C for 72 h with intermittent agitation and a 10‑min ultrasonication step for homogenization.
• Qualitative screening: Direct infusion of extracts using the instrument’s QualAll (full scan) mode to detect non‑targeted elements; elements with signal ≥10× blank proceeded to QuanAll quantification.
• Leachable analysis: Lyophilized Penicillin‑V powder diluted with Type‑I water (85 mL). A 1.0 mL aliquot was microwave digested with 5 mL conc. HNO3 and 1 mL conc. HCl (ramp to 130°C, hold 5 min; ramp to 220°C, hold 30 min), then diluted to 50 mL prior to ICP‑MS analysis.
• AET calculation: AET values derived from oral Permitted Daily Exposures (PDEs) per ICH Q3D and the maximum daily dose (used 10 g/day for demonstration) to set analytical reporting limits.

Instrumentation used

• ICP instrument: Shimadzu ICPMS‑2050 equipped with AS‑20s autosampler.
• Torch: Proprietary Mini‑Torch (enables reduced argon consumption ~11 L/min while maintaining sensitivity and plasma stability).
• Acquisition modes: QualAll (non‑targeted full qualitative scan) and QuanAll (quantitative acquisition for multiple isotopes/elements).
• Typical operating conditions: RF power 1.2 kW; sampling depth 5 mm; plasma gas 9.0 L/min; auxiliary gas 1.1 L/min; carrier gas 0.85 L/min; chamber temperature 5°C; He collision gas; pump speed 20 rpm; total cell flow 6 mL/min; aqueous sample introduction kit.
• Internal standards: Continuous online addition of Sc, Ge, Y, In, Ce, Bi at 10 ng/mL (sample:IS ~9:1). Internal standard recoveries remained within 80–120% across sequences.
• Calibration and QA: Seven calibration levels covering 0.05–1.5× working concentration (J), two QC solutions at 0.5J, blank and Continuous Calibration Verification (CCV). Acceptance: correlation coefficients R ≥0.995, LOQ precision %RSD <10%, CCV recovery targets 90–110% (extractables) and matrix recovery 70–130% (leachables).

Main results and discussion

Qualitative screening (QualAll)

• Non‑targeted screening identified a subset of elements with responses above the diluent/blank: Al, B, Ca, Fe, K, Mg, Na and Si. These were advanced to quantitative analysis along with the 24 ICH Q3D classified elements.

Extractables quantitative findings

• Experiment‑A (HNO3) and Experiment‑B (HCl) produced measurable concentrations for several major elements. Representative concentrations (µg/L) included high sodium and silicon responses in extracts (e.g., Na ≈1.8×10^3 µg/L in extracts; Si several hundred µg/L; Ca and Mg present at high hundreds to low hundreds µg/L depending on extractant).
• Trace toxic metals (As, Cd, Hg, Pb and other ICH class 1/2 elements) were at or below LOQ in extractants. Method performance: calibration linearity R >0.995, LOQ precision and CCV within acceptance criteria.

Leachable analysis (drug product after microwave digestion)

• Following microwave digestion of the Penicillin‑V formulation, quantifiable detections were limited primarily to common inorganic excipients or packaging‑derived majors: Na ≈ 601.5 µg/L, Si ≈ 272.5 µg/L, Mg ≈ 0.57 µg/L. Calcium, and most transition and toxic elements (As, Cd, Hg, Pb) were below LOQ in the drug matrix.
• All toxicologically relevant elements monitored (Class 1 and 2A) were below derived AETs in the leachable assay; no exceedances of analytically derived thresholds were observed.

Interpretation

• The observed major element signals (Na, Si, Ca, Mg) likely reflect formulation excipients and/or packaging contributions; qualitative screening aided in selecting which elements to quantitatively monitor in the drug matrix.
• Absence of Class 1 toxic metals above LOQ and AET supports a low elemental leaching risk from the evaluated CCP under accelerated extraction conditions. The data justify limiting routine leachable surveillance to priority classes when supported by extractable profiling.

Benefits and practical applications of the method

• QualAll scanning enables broad, non‑targeted elemental profiling to detect unexpected or non‑classified elements prior to targeted analysis, improving risk‑based element selection for leachable studies.
• QuanAll multi‑element quantitation provides capacity to quantify up to and beyond ICH Q3D panels with robust calibration and QA/QC workflows (CCV, LOQ precision, internal standardization).
• Mini‑Torch reduces argon consumption (~11 L/min total) lowering operating costs without compromising sensitivity or plasma stability — attractive for routine lab operations.
• LabSolutions ICPMS software streamlines data handling, CCV/bracketing, and regulatory compliance documentation for submissions and audits.

Future trends and potential applications

• Regulatory convergence toward more formalized E&L guidance (e.g., ICH Q3E) will increase demand for standardized non‑targeted screening workflows and harmonized AET approaches.
• Integration of high‑resolution ICP‑MS or time‑of‑flight detectors could enhance speciation and isotopic discrimination for complex matrices and low‑level contaminants.
• Hybrid workflows combining chromatographic separation (for organics) with elemental screening will support comprehensive E&L assessments spanning inorganic and organic migrants.
• Automation of extraction, digestion and data pipelines, together with curated spectral libraries and AI‑assisted screening, will speed non‑targeted identification and reduce manual review burden.
• Continued focus on resource efficiency (lower gas consumption torches, lower sample volumes) and greener workflows will be important for high‑throughput QC laboratories.

Conclusion

The Shimadzu ICPMS‑2050 (with Mini‑Torch and LabSolutions ICPMS) proved capable of sensitive, regulatory‑oriented extractable and leachable testing for a Penicillin‑V container closure system. Non‑targeted QualAll screening identified a small set of major inorganic species (Al, B, Ca, Fe, K, Mg, Na, Si) which were then quantified; toxicologically relevant elements were below LOQ/AET in the drug matrix after microwave digestion. The study highlights the value of combined qualitative and quantitative ICP‑MS workflows for E&L risk assessment while demonstrating operational benefits from reduced argon consumption and robust QA/QC practices.

References

• Product Quality Research Institute. Safety Thresholds and Best Demonstrated Practices for Extractables and Leachables in Parenteral Drug Products (Intravenous, Subcutaneous, and Intramuscular). PQRI Recommendation 2022.
• ICH. Final Concept Paper, ICH Q3E: Guideline for Extractables and Leachables (E&L). ICH Database, 2020.
• United States Pharmacopeia. USP <1663> Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems.