Extractable Study of Pharmaceutical Packaging and Delivery System Used for Ophthalmic Drug Product

Significance of the Topic

Extractable and leachable (E&L) studies are critical in pharmaceutical development to ensure patient safety and drug efficacy throughout shelf life. Regulatory bodies such as the FDA and industry consortia like PQRI mandate these assessments as part of filing dossiers for parenteral and ophthalmic products.

Objectives and Study Overview

This study aimed to characterize and quantify organic and inorganic chemical entities released from polymeric container closure components (CCCs) used for a moxifloxacin ophthalmic solution. Both targeted and untargeted extractables were evaluated under simulated worst-case conditions.

Used Instrumentation

• Gas Chromatograph–Triple Quadrupole Mass Spectrometer: Shimadzu GCMS-TQ8040 NX with AOC-20i autosampler.
• Thermal Desorption System: Shimadzu TD-30R coupled to GCMS-TQ8040 NX.

Methodology

Sample preparation combined six complementary extraction approaches:

• Experiment A – Aqueous incubation of CCCs at pH 2.5, 7.0 and 10.5 (65 °C, 72 h).
• Experiment B–E – Reflux extraction with ethanol (75 °C), n-hexane (65 °C), isopropanol (80 °C) and dichloromethane (38 °C) for 2 h.
• Experiment F – Direct thermal desorption of CCC fragments (300 °C, 10 min).

Analytical protocols:

• Method I – Simultaneous SCAN/MRM on GCMS-TQ8040 NX for 17 common extractables (antioxidants, phthalates, siloxanes), LOQ 5–50 ppb.
• Method II – MRM-based quantification of 16 polyaromatic hydrocarbons (PAHs), LOQ 1 ppb.
• Method III – TD-GCMS for volatile/semi-volatile compounds (benzene, toluene, xylenes), LOQ 0.2 ng on tube.

Main Results and Discussion

Aqueous incubations produced no compounds above the Analytical Evaluation Threshold (AET ~3 ppm). Organic reflux extracts revealed:

• Phthalates: diethyl phthalate up to ~236 ppb, di-isobutyl phthalate ~1939 ppb, diamyl phthalate ~9 ppb.
• Antioxidants: BHT ~28 ppb.
• PAHs: phenanthrene ~37 ppb, fluoranthene ~12 ppb; all below regulatory concern.

Thermal desorption identified volatile leachables: benzene (73 ppb), toluene (178 ppb), ethylbenzene (23 ppb), o- and p-xylene (32 ppb, 22 ppb). Untargeted screening detected numerous high-molecular-weight oligomers and siloxanes, particularly in hexane reflux and TD analyses, guiding material characterization. Overlayed chromatograms highlighted solvent-specific extractables not seen in aqueous tests.

Benefits and Practical Applications

• Regulatory compliance via trace-level qualitative and quantitative data.
• Early risk assessment for pharmaceutical packaging selection.
• Efficient screening of multiple extractable classes in one run using simultaneous SCAN/MRM.
• Reduced sample preparation time and VOC loss through direct thermal desorption.

Future Trends and Possibilities

Advancements may include high-throughput GC-MS workflows, enhanced trap materials for ultra-volatile compounds, AI-driven deconvolution of complex extractable profiles, and in-situ monitoring of leachables under real-time storage conditions. Integration with non-targeted HRMS platforms could improve unknown identification.

Conclusion

Combining solvent reflux, aqueous incubation and thermal desorption with GCMS-TQ8040 NX and TD-30R enabled comprehensive E&L profiling of ophthalmic CCCs. All detected compounds remained below safety thresholds for aqueous dosage forms, supporting the suitability of the evaluated packaging. The methodologies demonstrated here offer a robust framework for extractables screening in pharmaceutical quality control.

References

• USP <1663> Assessment of extractables associated with pharmaceutical packaging/delivery systems.
• Product Quality Research Institute (PQRI) safety concern thresholds and Analytical Evaluation Threshold guidance.