Integrated Application of Quality-by-Design Principles to Drug Product Development: A Case Study of Brivanib Alaninate Film–Coated Tablets

• Published in: Journal of pharmaceutical sciences Vol. 105; no. 1; pp. 168 - 181
• Main Authors: Badawy, Sherif I.F., Narang, Ajit S., LaMarche, Keirnan R., Subramanian, Ganeshkumar A., Varia, Sailesh A., Lin, Judy, Stevens, Tim, Shah, Pankaj A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2016
• Subjects: Adhesiveness; Alanine - analogs & derivatives; Alanine - chemistry; Alanine - standards; brivanib alaninate; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; control strategy; critical material attributes; critical process parameters; critical quality attributes; design space; dissolution; Drug Compounding; Drug Liberation; Drug Packaging; Drug Stability; Particle Size; porosity; quality by design; Quality Control; Solubility; Spectroscopy, Near-Infrared; tablets; Tablets, Enteric-Coated; Technology, Pharmaceutical - methods; Technology, Pharmaceutical - standards; Triazines - chemistry; Triazines - standards; brivanib alaninate; control strategy; critical quality attributes; porosity; dissolution; quality by design; critical process parameters; critical material attributes; tablets; design space
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1016/j.xphs.2015.11.023

Modern drug product development is expected to follow quality-by-design (QbD) paradigm. At the same time, although there are several issue-specific examples in the literature that demonstrate the application of QbD principles, a holistic demonstration of the application of QbD principles to drug product development and control strategy, is lacking. This article provides an integrated case study on the systematic application of QbD to product development and demonstrates the implementation of QbD concepts in the different aspects of product and process design for brivanib alaninate film–coated tablets. Using a risk-based approach, the strategy for development entailed identification of product critical quality attributes (CQAs), assessment of risks to the CQAs, and performing experiments to understand and mitigate identified risks. Quality risk assessments and design of experiments were performed to understand the quality of the input raw materials required for a robust formulation and the impact of manufacturing process parameters on CQAs. In addition to the material property and process parameter controls, the proposed control strategy includes use of process analytical technology and conventional analytical tests to control in-process material attributes and ensure quality of the final product.