Towards a full integration of optimization and validation phases: An analytical-quality-by-design approach

Abstract

20When using an analytical method, defining an Analytical Target Profile (ATP) focused on 21 quantitative performance represents a key input, and this will drive the method development 22 process. In this context, two case studies were selected in order to demonstrate the potential of 23 a Quality-by-Design (QbD) strategy when applied to two specific phases of the method 24 lifecycle: the pre-validation study and the validation step. The first case study focused on the 25 improvement of a Liquid Chromatography (LC) coupled to Mass Spectrometry (MS) 26 stability-indicating method by the means of the QbD concept. The Design of Experiments 27 (DoE) conducted during the optimization step (i.e. determination of the qualitative Design 28 Space (DS)) was performed a posteriori. Additional experiments were performed in order to 29 simultaneously conduct the pre-validation study to assist in defining the DoE to be conducted 30 during the formal validation step. This predicted protocol was compared to the one used 31 during the formal validation. A second case study based on the LC/MS-MS determination of 32 glucosamine and galactosamine in human plasma was considered in order to illustrate an 33 innovative strategy allowing the QbD methodology to be incorporated during the validation 34phase. An operational space, defined by the qualitative DS, was considered during the 35 validation process rather than a specific set of working conditions as conventionally 36 performed. Results of all the validation parameters conventionally studied were compared to 37 those obtained with this innovative approach for glucosamine and galactosamine. Using this 38 strategy, qualitative and quantitative information were obtained. Consequently, an analyst 39 using this approach would be able to select with great confidence several working conditions 40 within the operational space rather than a given condition for the routine use of the method. 41This innovative strategy combines both a learning process and a thorough assessment of the 42 risk involved. 43 3

Quality by design‐assisted development of a capillary electrophoresis method for the chiral purity determination of dexmedetomidine

“…Subsequently, the CPPs are identified in initial experiments followed by the establishment of the design space of the method. The latter refers to experimental conditions where the ATP is fulfilled . In the process, DoE methodology is employed.…”

“…In the process, quality by design (QbD) principles were implemented. QbD has been increasingly applied in analytical chemistry in recent years . This approach employs multivariate design of experiments (DoE) and risk‐assessment tools for the identification of the critical process parameters (CPPs), which are the experimental factors that influence the critical quality attributes (CQAs) of the method.…”

Uncovering interaction by QbD in Optimization of Stability-indicating HPLC Method for Simultaneous Estimation of Low Dose Aspirin and Lansoprazole

“…6b. Battu and Pottabathini reported a new impurity, 7-(3-methyl-4-(2,2,2-trifluoroethoxy) pyridin-2-yl)-7H-benzo [4,5]imidazo [2,1b]benzo [4,5] imidazo [2,1-d]- [1,3,5]thiadiazine formed in harsh basic conditions [28] . DP-3(L), DP-4(A), DP-6(L) and DP-8(L), were formed in basic hydrolysis.…”

“…Even though International Conference on Harmonization (ICH Q8 R2) guidelines do not discuss analytical method development in correlation with design space, it is implicit that the concept can be utilized to analytical design space and continuous improvement in method understanding [1] . A number of excellent articles appeared in the literature [2][3][4][5][6][7][8] that described strategies for the application of QbD principles to chromatographic method development. The work presented in this article addressed key steps of AQbD with special focus on method optimization.…”

Statistical Model Based HPLC Analytical Method Adjustment Strategy to Adapt to Different Sets of Analytes in Complicated Samples

“…However, in some cases, higher order effects or interaction effects of the analytical parameters should be considered (Tyteca et al , ). In recent years, a statistical model based approach was proposed (Debrus et al , , ; Rozet et al , ; Hubert et al , ; Taraji et al , ). The relationships between analytical parameters and t R were studied with design of experiment (DoE) methodology and then quantitatively represented in the form of empirical models built by multivariate statistical modelling methods.…”