Efficient Method Development on Pharmaceutical Impurities based on Analytical Quality by Design

Importance of the topic

Pharmaceutical impurities must be tightly controlled to guarantee drug safety, efficacy, and adherence to regulatory guidelines. Analytical Quality by Design (AQbD) enhances method development by systematically optimizing parameters and ensuring robust performance across varying conditions.

Objectives and Study Overview

The study showcases the application of LabSolutions MD for AQbD-driven method development targeting ketoprofen and its impurities. Key goals include:

• Establishing an efficient workflow for screening, optimization, and robustness evaluation
• Visualizing resolution across mobile phase composition, column temperature, and flow rate
• Confirming method robustness across multiple column lots

Methodology

An isocratic LC method was developed by varying:

• Acetonitrile ratio (40–60% in 5% increments)
• Column oven temperature (35–45 °C in 5 °C increments)
• Flow rate (0.6–0.8 mL/min in 0.1 mL/min increments)

Design spaces were constructed to map resolution between ketoprofen and impurity pairs, guiding selection of optimal conditions and robustness regions.

Used Instrumentation

• Nexera X3 Method Scouting System
• Shim-pack Velox C18 column (100 mm×3.0 mm I.D., 2.7 µm)
• PDA detector (SPD-M40, 254 nm, UHPLC cell)

Key Results and Discussion

Optimal separation was achieved at 40% acetonitrile, 35 °C, and 0.6 mL/min. Design space plots revealed resolution values above 8.0 for ketoprofen/Imp2 and above 2.0 for Imp2/Imp3 within the chosen region. Robustness evaluation with three different column lots confirmed consistent resolution across slight variations (±1% organic content, ±1 °C), demonstrating method reliability.

Benefits and Practical Applications

• Accelerates identification of optimum conditions by visualizing multi-parameter effects
• Reduces reliance on trial-and-error and expert intuition
• Streamlines robustness testing across column batches
• Supports regulatory requirements through systematic AQbD documentation

Future Trends and Applications

• Integration with artificial intelligence for predictive optimization
• Real-time method adjustments using online monitoring data
• Expansion to gradient methods and complex sample matrices
• Broader adoption of AQbD principles in QC and R&D laboratories

Conclusion

LabSolutions MD enables efficient AQbD-based development of a robust LC method for ketoprofen impurities by visualizing design spaces and validating performance across column lots, ultimately enhancing method reliability and compliance.