A Comprehensive review of Analytical Quality by Design, ICH Q14, and design of experiments in pharmaceutical Analysis: A Synergistic Paradigm for enhanced quality and regulatory efficiency

Abstract

In the modern pharmaceutical landscape, the demand for robust, reliable, and efficient analytical methods is paramount. This manuscript provides a comprehensive review of three interconnected paradigms that are fundamentally reshaping pharmaceutical analysis: Analytical Quality by Design (AQbD), the ICH Q14 guideline on Analytical Procedure Development, and the application of Design of Experiments (DoE). Historically, analytical method development followed a trial-and-error approach, often leading to methods that were fragile, poorly understood, and difficult to transfer. This reactive paradigm is being superseded by a proactive, science- and risk-based approach. AQbD establishes a structured framework for building quality into an analytical procedure from the outset, moving beyond simple compliance to a state of enhanced method understanding and robust performance. ICH Q14 formalizes this approach within a global regulatory context, providing a clear pathway for a structured development process, a well-defined Analytical Target Profile (ATP), and a lifecycle management strategy for analytical procedures.

Simultaneously, DoE serves as a critical statistical tool, enabling the systematic exploration of method parameters and their interactions, thereby facilitating the identification of a robust operating design space. This review explores the foundational principles of each paradigm, detailing their core components and objectives. It then delves into their synergistic integration, demonstrating how DoE is the key enabler for implementing an AQbD strategy as outlined by ICH Q14. Practical applications and case studies from various analytical techniques, such as chromatography and spectroscopy, are presented to illustrate the tangible benefits, including improved method ruggedness, reduced method transfer failures, and streamlined post-approval changes. Finally, this review discusses the challenges in implementing this synergistic approach, proposes solutions, and offers a glimpse into future perspectives, highlighting the potential for automation, advanced data analytics, and continuous improvement in analytical procedures. This integrated paradigm represents a crucial evolution in analytical science, promising to enhance product quality, accelerate drug development, and foster greater regulatory efficiency.