Application of Quality by Design (QbD) in Pharmaceutical Development of Fixed-Dose Combination Containing Herbal Extract and Synthetic Active Ingredient

The development of fixed combinations (FCs) containing plant extracts and synthetic active pharmaceutical ingredients (APIs) is a promising area of modern pharmacy. However, the inherent variability of phytochemical composition creates challenges for quality assurance and regulatory compliance. The Quality by Design (QbD) paradigm provides a systematic framework for establishing a robust pharmaceutical development through the identification of critical quality attributes (CQAs), critical process parameters (CPPs), and the design space.

This study presents a QbD-oriented strategy for the pharmaceutical development of an FC containing a standardised extract of Pelargonium sidoides roots. The research approach includes comprehensive analytical characterisation of the extract using UHPLC-Q-TOF-MS/MS to identify key phytochemical markers. The marker profile serves as a basis for defining the CQAs of the plant-derived component. Additionally, the extract is subjected to in vitro biological activity screening to establish antimicrobial and antifungal activity for further justification of the selection of functional markers for efficacy control. Computer modelling is used to identify potential molecular targets of the identified markers, providing a rationale for the selection of pharmacodynamic markers.

The ultimate goal is to establish a multi-tier standardisation system: authenticity markers for raw material identification and functional markers for controlling pharmacological activity relevant to the target FC. This system enables the development of a robust analytical control strategy, supports stability studies, and facilitates the establishment of the design space for the FC composition. The proposed approach aligns with ICH Q8-Q11 guidelines and provides a science-based foundation for the QbD development of plant-synthetic FCs with predefined quality, safety, and efficacy profiles.