Analytical quality by design in biopharmaceutical method development: from current perspectives to practical applications

Biologics have experienced rapid development on a global scale in recent years. Their analytical techniques, encompassing molecular structural characterization, purity and impurities analyses, function and stability assessment, play a crucial role in ensuring biologics' quality. Quality by design (QbD), as a systematic approach, has been widely adopted in the pharmaceutical industry to optimize manufacturing processes and ensure the reliability of final product quality. Derived from QbD, analytical quality by design (AQbD) ensures the quality of analytical methods by providing confidence and assurance in their development. AQbD begins with defining the analytical target profile (ATP) and employs risk assessment to identify and analyze critical method attributes (CMAs) and critical method parameters (CMPs). By design of experiments (DoE), mathematical models are constructed to explore the relationships between CMPs and CMAs, ultimately establishing the method operable design region (MODR) and an analytical control strategy. Compared to traditional analytical method development, AQbD-based methods offer greater robustness within the MODR, reducing the occurrence of out-of-trend (OOT) or out-of-specification (OOS) results due to method-related factors. This, in turn, enhances regulatory flexibility and reduces analytical costs. This review outlines the AQbD workflow, discusses its current applications in biologics analytical method development, and explores the opportunities and challenges associated with its implementation in this field.