Development of a Robust Manufacturing Process for Nutraceutical Gummies Through Quality by Design-Based Critical Process Parameter Optimisation

**Aim and objectives:** The aim of this study was to develop a robust manufacturing process for gelatin-based nutraceutical gummies using a Quality by Design (QbD) approach. The objectives were to identify the Critical Process Parameters (CPPs) that influence the Critical Quality Attributes (CQAs) of the gummies, to optimism these parameters, and to establish a design space and control strategy for consistent production. **Materials and Methods:** The Quality Target Product Profile and CQAs were defined according to ICH Q8(R2), and process risks were assessed by Ishikawa diagram and Failure Mode and Effects Analysis as per ICH Q9(R1). Cooking end-point temperature, depositing temperature and drying time were selected as CPPs and studied using a 17-run Box-Behnken design, with vitamin D3 as the model active ingredient. Hardness, chewiness, moisture content, water activity, assay and drug release were taken as responses. The assay was determined by a stability-indicating HPLC method. Multi-response optimisation was carried out using desirability functions and the optimised settings were confirmed by three verification batches. Stability was evaluated at 40 °C and 75% relative humidity for three months. **Results:** The quadratic models for all six responses were statistically significant (*p*≤ 0.0002), and the lack-of-fit was not significant. Cooking temperature and drying time had the major effect on hardness, chewiness, moisture content and water activity, whereas pH was governed mainly by the citric acid/sodium citrate buffer. The optimised settings were a cooking temperature of 110.8 °C, a depositing temperature of 66 °C and a drying time of 26 h (composite desirability 0.92). The verification batches showed a prediction error of less than 3% and met all specifications: hardness 24.8 N, moisture content 12.4% w/w, water activity 0.576, pH 3.72, assay 99.4% of label claim and drug release 97.2% at 30 min. The gummies remained within specification for three months under accelerated conditions. **Conclusion:** The QbD approach provided a clear understanding of how the critical process parameters affect the quality of nutraceutical gummies. The resulting design space and control strategy support a robust and reproducible manufacturing process.