Robustness Evaluation of a Semi-Solid Extrusion 3D Printing Process for Oral Dosage Forms: A Case Study with Melatonin

Objective
This study evaluates the robustness of the manufacturing process for personalized 3D-printed oral dosage forms containing melatonin (3 mg), using semi-solid extrusion. The process is assessed through the production of three pharmaceutical compounding batches.

Method
Each batch consists of 600 units printed via semi-solid extrusion from industrially produced drug paste cartridges containing the active pharmaceutical ingredient and excipients. The manufacturing process includes the printing step followed by in situ drying (MED U PROD 1.0 ^® – MB Therapeutics). Quality control tests are conducted in accordance with the current European Pharmacopoeia, including: uniformity of mass (2.9.5), uniformity of dosage units by mass variation (2.9.40), and disintegration (2.9.1). Process robustness is evaluated through statistical capability analyses (descriptive statistics, normality, Cp/Cpk) on the measured weights (30 units per batch).

Results
The process achieves a printing speed of 1 unit every 10 seconds, corresponding to 1 hour and 22 minutes of printing per batch, followed by 10 minutes of in situ drying. Analytical results confirm that all three batches comply with the European Pharmacopoeia requirements.
For mass uniformity (2.9.5), mean weights are 32.94 mg (batch 1), 32.52 mg (batch 2), and 31.62 mg (batch 3), with standard deviations of 0.41 mg, 0.75 mg, and 0.58 mg, respectively. Cp and Cpk indices meet the acceptance criterion of ≥1.3, demonstrating the capability of the process.
Regarding dosage unit uniformity (2.9.40), the mean contents are 102.1%, 100.1%, and 97.96%, respectively. The relative standard deviations (RSD) are ≤2%, and acceptance values (AV) are below 15.0 (2.9; 5.4; 5.1), confirming compliance for all three batches.
Finally, disintegration times at 37 °C range from 88 to 146 seconds on average, qualifying the printed units as orodispersible, in accordance with monograph 2.9.1.

Conclusion and Discussion
This study supports the interest and patient safety benefits of a hospital-based production system for 3D-printed oral forms using semi-solid extrusion. The process is automated, rapid, reproducible, and compliant. The observed statistical capability (≥1.3) confirms the robustness of the process, which is well-suited for personalized treatments, including pediatric use, drugs with a narrow therapeutic index, or small-scale productions with batch sizes ranging from 100 to 1000 units.

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