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Ensuring regulatory compliance by quality by design (QbD) approach to optimize the manufacturing process of API: ferric ammonium citrate as an example

Forum Jalundhwala, Vaishali Londhe, and Bharat Shah

Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM’s NMIMS, Mumbai, India



Received: 21 May 2022  Accepted: 28 October 2022


It is challenging for a small-scale pharmaceutical manufacturer to comply with evolving regulatory standards. Quality by design (QbD) is a simple solution. The purpose of this study is to demonstrate the use of QbD in optimizing the synthesis of Ferric Ammonium Citrate which will help manufacturers ensure higher regulatory compliance. Three key starting materials (KSM) were reviewed for their synthetic pathways. QbD approach was used to develop the process. The central composite design was used to design experiments of two variables at three levels. Percentage yield, description, and iron content were recorded. Optimized values of variable factors were obtained by contour plots, 3D response surface graphs, and prediction profiler. Repeatability and scale-up were performed with the optimized values. The process was developed using iron powder as KSM and a combination of 50% v/v nitric acid and air bubbling as an oxidizing agent. Risk assessment tools led to selection of variable factors like the quantity of nitric acid and time for air bubbling for optimization. Percentage yield increased with an increase in air bubbling time, whereas the description did not comply with an increase in nitric acid content. All the experiments resulted in iron content within the range. Contour plots and prediction profiler confirmed the optimized values of content of nitric acid as 125 g and air bubbling time of 19 h for a batch size of 400 g. An optimized process leads to fewer variations and better quality assurance. This leads to ensuring higher regulatory compliance.

Keywords: Quality by design; Central composite design; Ferric ammonium citrate; Regulatory compliance; Process optimization

Full paper is available at

DOI: 10.1007/s11696-022-02569-3


Chemical Papers 77 (3) 1469–1477 (2023)

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