Analytical Quality by Design (AQbD) & LC Method Development Vocabulary

Key vocabulary terms underpinning the Analytical Quality by Design framework and its application to liquid chromatography method development and optimization.

Analytical Quality by Design (AQbD)

A systematic, science- and risk-based approach to developing, optimizing and controlling analytical methods across their life-cycle.

Quality by Design (QbD)

FDA/ICH framework (2004-2005) for designing pharmaceutical products and processes to assure predefined quality.

Analytical Target Profile (ATP)

Statement that defines what the analytical procedure must measure and the performance criteria it must meet (e.g., accuracy, precision, range).

Critical Method Attribute (CMA)

Measured response (e.g., resolution, tailing) that indicates whether the method meets the ATP; analogous to a drug’s CQA.

Critical Method Parameter (CMP)

Method variable (e.g., pH, gradient time) whose variation can impact a CMA and therefore method performance.

Design of Experiments (DoE)

Structured, statistical technique in which multiple factors are varied simultaneously to understand and model their effects on responses.

Screening Design

Initial DoE (e.g., Plackett-Burman, fractional factorial) used to identify the few significant factors among many potential CMPs.

Response-Surface Design

Higher-order DoE (e.g., central composite, Box-Behnken) used to model curvature, interactions and find optimal CMP settings.

Full Factorial Design

DoE that studies all possible combinations of factor levels, allowing estimation of main effects and interactions.

Fractional Factorial Design

Reduced version of a full factorial that examines only a carefully chosen subset of experiments to screen factors efficiently.

Plackett-Burman Design

Two-level screening design especially efficient for examining a large number of factors with a minimal run count.

Central Composite Design (CCD)

Response-surface design combining factorial points, axial (star) points and center points to fit quadratic models.

Box-Behnken Design

Three-level response-surface design that avoids extreme factor combinations while allowing quadratic modeling.

Method Operable Design Region (MODR)

Multivariate region within which all CMA criteria are simultaneously satisfied with predefined probability; the method’s design space.

Design Space

ICH Q8 term for the multidimensional combination of input variable ranges that assures quality; movement inside is not a regulatory change.

Knowledge Space

Combined scientific understanding gained during development before the formal design space is finalized.

Monte Carlo Simulation

Computer sampling of model uncertainty used to estimate the probability that CMAs meet targets across the design space.

Risk Assessment

Process of identifying, analyzing and prioritizing method variables that could cause failure; often visualized by an Ishikawa diagram.

Ishikawa (Fishbone) Diagram

Cause-and-effect tool that categorizes potential sources of variability (materials, equipment, methods, etc.).

Failure Mode and Effects Analysis (FMEA)

Quantitative risk-ranking tool that scores severity, occurrence and detectability of potential failures to prioritize CMPs.

Robustness (ICH Q2)

Ability of an analytical procedure to remain unaffected by small, deliberate variations in parameters.

System Suitability Test (SST)

Set of checks (e.g., resolution, tailing, plate count) performed before analysis to verify the method is operating within the MODR.

Stability-Indicating Method

Analytical procedure that accurately measures active ingredients, impurities and degradation products without interference.

Forced Degradation Study

Deliberate exposure of drug substance/product to stress (heat, light, oxidation, hydrolysis) to generate degradation products for method development.

Hydrophilic Interaction Liquid Chromatography (HILIC)

LC mode that retains polar analytes on a polar stationary phase using predominantly organic mobile phases.

Ultra Performance Liquid Chromatography (UPLC)

High-pressure LC technique (<2 µm particles, up to ~15,000 psi) enabling faster, higher-resolution separations.

Response Modeling

Fitting mathematical equations (usually polynomial via multiple linear regression) to DoE data to predict CMAs.

Resolution (Rs)

Measure of chromatographic separation between two peaks; common CMA target ≥ 1.5 or 2.0.

Tailing Factor (T)

Peak shape metric; values near 1 indicate symmetric peaks; excessive tailing can impair quantitation.

Theoretical Plates (N)

Column efficiency metric calculated from peak width; higher N means sharper peaks.

Selectivity Factor (α)

Ratio of retention factors (k) for two analytes; indicates relative separation capability.

Gradient Time (tG)

Duration over which mobile-phase composition changes during gradient elution; a critical CMP in LC.

DryLab®

Commercial software that builds retention models (e.g., tG-T-pH cube) from a small set of LC experiments to predict separations.

MODDE®

Umetrics software package for experimental design, multivariate analysis and design-space establishment.

Design-Expert®

Stat-Ease DoE software used for creating designs, modeling responses and visualizing design spaces.

Analytical Procedure Lifecycle

Total life of a method: design & development, performance qualification (validation/transfer) and continued verification.

Control Strategy

Planned set of controls (SSTs, parameter limits, monitoring) to ensure method performance remains within the MODR.

Chaotropic Salts

Additives (e.g., perchlorate) used to disrupt water structure and modify retention/selectivity of basic analytes in LC.

Automated Sample Preparation

Robotic or workstation-based handling that reduces human error and integrates with AQbD for controlled, reproducible extraction steps.

Critical Resolution Space (CRS)

DryLab term for the 3D region (tG–T–eluent) where the critical resolution criterion is satisfied.