AQbD-based headspace GC-MS/MS method development under ICH Q14 guidelines for simultaneous analysis of residual...

Area of Science:

• Pharmaceutical Analysis
• Analytical Chemistry
• Quality by Design (QbD)

Background:

• Residual solvent impurities (RSIs) are critical quality attributes in pharmaceutical drug substances.
• Current analytical methods may require optimization for comprehensive and efficient RSI detection.

Purpose of the Study:

• To develop and validate a headspace GC-MS/MS method for simultaneous quantification of 11 RSIs.
• To apply a risk assessment-driven Analytical Quality by Design (AQbD) approach for method development and optimization.

Main Methods:

• Utilized Taguchi screening and Pareto analysis to identify critical method variables (CMVs).
• Employed central composite design (CCD) to optimize method responses and define the Method Operable Design Region (MODR).
• Validated the method for specificity, resolution, tailing factor, theoretical plates, and linearity.

Main Results:

• Established Proven Acceptable Ranges (PARs) for split ratio, agitator temperature, and ion source temperature.
• Achieved high resolution (≥2), theoretical plates (>14,000), and linearity (R² > 0.98).
• Demonstrated accurate and precise quantification of RSIs in multiple drug substances.

Conclusions:

• The developed headspace GC-MS/MS method is robust, validated, and suitable for routine quality control.
• The AQbD approach ensures a reliable and efficient analytical method for RSI determination.
• The method supports regulatory compliance for pharmaceutical drug substances.