Determination of Leachables in Orally Inhaled and Nasal Drug Products (OINDP) by GCMS/MS

Importance of the Topic

This study addresses the migration of trace contaminants (leachables) from inhaler components into orally inhaled and nasal drug products (OINDPs). Such leachables, including nitrosamines, phthalates and polycyclic aromatic hydrocarbons (PAHs), pose potential toxicity and carcinogenic risks when delivered directly to the respiratory tract. Regulatory guidance and stability studies require robust analytical methods to detect these impurities at low parts-per-billion (ppb) levels over product shelf life.

Objectives and Study Overview

The primary aim was to develop and validate a highly sensitive, selective and reproducible GC-MS/MS method for simultaneous quantitation of 40 leachable compounds in OINDPs. The study demonstrates sample preparation by solid phase extraction (SPE), method optimization using Smart MRM tools, and performance evaluation through linearity, precision and detection limits.

Methodology and Instrumentation

Sample preparation employed C18 SPE cartridges to extract leachables from the aerosol content of a salbutamol metered-dose inhaler using dichloromethane elution and sodium sulfate drying. Calibration standards (1–100 ppb) were prepared for nitrosamines, phthalates and PAHs.

Applied Instrumentation

The analysis was performed on a Shimadzu GCMS-TQ8040 triple quadrupole system equipped with:

• Rxi-5Sil MS capillary column (30 m × 0.25 mm × 0.25 µm)
• Programmed Temperature Vaporization (PTV) injector in splitless mode
• Helium carrier gas, linear velocity 36.1 cm/s
• Electron Ionization (EI) source at 230 °C and interface at 280 °C
• Smart MRM optimization and UFsweeper® for fast, interference-free scans

Main Results and Discussion

Using Smart MRM and collision energy optimization, a segmented MRM method for 40 leachables was developed. Calibration curves showed excellent linearity (r2 0.995–0.9999). Limits of quantitation ranged from 0.4 ppb to 10 ppb and limits of detection from 0.1 ppb to 3 ppb. Intra-day precision (%RSD, n=6) was below 10% for all analytes. Analysis of five commercial salbutamol inhalers revealed no leachable compounds above detection limits.

Benefits and Practical Applications

This validated GC-MS/MS method provides pharmaceutical laboratories with a sensitive screening tool for OINDP extractables and leachables. The rapid SPE extraction paired with Smart MRM accelerates method development, ensures compliance with industry guidelines and supports product safety monitoring.

Future Trends and Opportunities

Ongoing advances may include:

• Integration of high-throughput autosamplers and automated SPE for increased sample capacity
• Expansion of compound libraries to cover emerging leachable classes
• Application of ambient ionization techniques and real-time monitoring
• Use of machine-learning algorithms for data interpretation and predictive leachability assessments
• Alignment with evolving regulatory thresholds and inhalation safety standards

Conclusion

The presented GC-MS/MS approach on Shimadzu GCMS-TQ8040 delivers a robust, reproducible and high-sensitivity solution for quantifying nitrosamines, phthalates and PAHs in OINDPs. It meets stringent performance criteria and can be adopted for routine quality control and regulatory compliance.

Reference

1. Ball D, Blanchard J et al. Toxicological Sciences. 2007;97(2):226–236.
2. Product Quality Research Institute (PQRI). Safety threshold and best practices for extractables and leachables in orally inhaled and nasal drug products. 2006.