AGILENT SOLUTIONS FOR QUALITY-BY-DESIGN IMPLEMENTATION IN PHARMACEUTICAL DEVELOPMENT

Significance of the Topic

Quality by Design (QbD) is a science- and risk-based framework that improves robustness and reliability of analytical methods, reducing late-stage failures and safeguarding product consistency.
By moving quality control upstream, QbD fosters deeper process understanding, early identification of variability sources, and enhanced control over critical quality attributes (CQAs).
The approach aligns with ICH guidelines (Q8–Q11) and is increasingly mandated by regulatory bodies such as FDA and EMA.

Objectives and Study Overview

The document reviews Agilent’s suite of solutions supporting QbD implementation in pharmaceutical analytical development, focusing on:

• Development of robust chromatographic methods through automated, multivariate screening.
• Seamless method transfer across diverse LC platforms using intelligent emulation and dynamic mixing.
• Evaluation and control of CQAs via dissolution testing and advanced impurity profiling.

It intends to illustrate workflows, case studies, and instrumentation that enable science-based design spaces and continuous improvement.

Methodology and Instrumentation

A QbD workflow spans defining the analytical target profile (ATP), performing risk assessments, designing experiments (DoE), modeling design spaces, validating robustness, and establishing control strategies.
Key instrumentation and software include:

• Agilent 1200 and 1290 Infinity Series LCs with Method Development Solutions and Method Scouting Wizard.
• QbD software platforms: ChromSword, ACD labs/AutoChrom, S-Matrix/FusionAE.
• Intelligent System Emulation Technology (ISET) for LC method transfer without hardware changes.
• 1290 Quaternary and Binary Pumps for dynamic online mixing.
• 708-DS and 709-DS dissolution systems for automated, biorelevant testing.
• 1200 Infinity HDR-DAD and 1290 Infinity 2D-LC for enhanced impurity detection.
• 7900 ICP-MS and 700 Series ICP-OES for elemental impurity profiling per ICH Q3D/USP<232>/<233>.
• Compliance software: OpenLAB CDS ChemStation, OpenLAB ECM, Automated Compliance Engine.

Main Results and Discussion

Case studies demonstrate that automated, multivariate screening accelerates stability-indicating method development (e.g., linagliptin), defining robust operating ranges and design spaces.
Method emulation with ISET achieved identical retention times and peak shapes across legacy and modern LC systems, simplifying transfers.
Dynamic mixing via the 1290 Quaternary Pump improved retention time precision compared to premixed solvents.
Dissolution platforms enabled development of discriminating, in vitro biorelevant methods, linking API properties to CQAs.
HDR-DAD provided up to tenfold lower detection limits for trace impurities in combination drugs.
Heart-cutting 2D-LC resolved co-eluting impurities unachievable in 1D separations.
Advanced ICP-MS/OES platforms met stringent detection requirements for 16 ICH-regulated elemental impurities.

Benefits and Practical Applications

• Reduced development timelines and failure rates through automation and systematic design.
• Simplified method transfer and harmonization across labs and instruments.
• Enhanced impurity detection and quantification accuracy, supporting safety risk assessments.
• QbD-driven dissolution and impurity protocols that align with regulatory expectations.
• Continuous improvement enabled by defined design spaces and real-time control strategies.

Future Trends and Potential Uses

Expect further integration of QbD principles into routine laboratories, driving adoption of electronic qualification, real-time analytics, and AI-assisted method optimization.
Emerging platforms may offer deeper multivariate insights, holistic data integrity, and predictive modeling for analytical performance.
Broader industry harmonization on QbD-based system suitability criteria and flexible regulatory frameworks is anticipated.

Conclusion

Agilent’s comprehensive portfolio—spanning automated method development, intelligent transfer, advanced dissolution, impurity analysis, and compliance tools—provides a robust foundation for implementing QbD in pharmaceutical analytics.
These solutions advance scientific understanding, optimize process control, and ensure consistent product quality across the development lifecycle.

Used Instrumentation

• Agilent 1200 and 1290 Infinity Series LC systems
• Agilent 1290 Infinity Quaternary and Binary Pumps
• Method Scouting Wizard, ChromSword, AutoChrom, S-Matrix/FusionAE
• ISET emulation technology
• 708-DS and 709-DS dissolution apparatus
• 1200 Infinity HDR-DAD, 1290 Infinity 2D-LC
• Agilent 7900 ICP-MS, 700 Series ICP-OES
• OpenLAB CDS ChemStation, OpenLAB ECM, Automated Compliance Engine

References

1. ICH Q8(R2), Q9, Q10, Q11 Guidelines (2006–2011)
2. EMA-FDA QbD Pilot Program and Q&A Documents (2013)
3. Nethercote et al., Pharmaceutical Manufacturing, 2010
4. Borman et al., J Chromatogr Sci, 2011
5. Agilent 5991-3834EN, 5990-9715EN, 5991-0098EN, 5991-0115EN, 5991-0834EN, 5990-9365EN
6. USP General Chapters <1058>, <621>, <232>, <233>
7. ICH Q3D Elemental Impurities Guideline (Step 2B, 2013)