Phase 1 - Column and Solvent System Screening
Fusion Method Development^TM brings a new methodology to automated HPLC columns and solvent system selection rooted solidly in QbD principles. The methodology, adapted to multiple instruments and instrument data system, overcomes the limitations inherent in both the sequential and classical Design of Experiments (DOE) approaches to place the column screening activity on a rigorous and quantitative footing.

Phase 2 - Robust Method Development and Optimization
Fusion Method Development brings a new QbD-based methodology to formal HPLC method development. Regulatory guidances state that the best-practices approach should address robustness during formal method development. Therefore, a critical element of the new methodology is the integration of automatically computed robustness metrics into method development experiments. The new methodology thus automates a best-practices approach in which HPLC methods can be rapidly developed and simultaneously optimized for mean chromatographic performance and method robustness.
Note - in the image below candidate Methods A and B have the same mean performance, but Method B is by far the more robust method.

To benchmark time savings using Fusion Method Validation^TM versus current practice, a senior analytical chemist at an international pharmaceutical customer facility used Fusion Method Validation to carry out all Early Phase and Final Phase method validation experiments (except Robustness, which was done subsequently at a different lab). The entire method validation exercise took less than 12 hours using Fusion AE.

Work records showed that on average - from SOP planning and experiment design construction to final reporting - using “current practice” the same work would have required more than two weeks of analyst time.

PhRMA’s Analytical Technical Group recommends a phased approach to analytical method validation in which early phase validation efforts are done upstream on a reduced set of validation elements appropriate to the stage of development.

Early phase experiments are structured for internal consumption to support and guide method development.

Fusion Method Validation - Early Phase Method Validation (Characterization):

• Analytical Capability and System Suitability
• Specificity
• Filter Validation
• Accuracy
• Linearity and Range
• LOQ, LOD
• Repeatability* (intra-assay precision)
• Sample Solution Stability (stability for a given time period under prescribed conditions)

Final phase experiments are structured with the rigor and regulatory compliance overlay required of results that may be exported outside the lab.

Fusion Method Validation - Final Phase Method Validation (FDA and ICH Submittal Quality):

• Analytical Capability and System Suitability
• Specificity
• Accuracy/Linearity and Range/Repeatability – Combined Design
  (ICH-Q2A states that Accuracy, Linearity, and Repeatability can be done together as a single combined experiment).
• LOQ, LOD
• Intermediate Precision and Reproducibility (USP Ruggedness)
• Robustness