Comparison of Manufacturing Process Robustness: From a Manual to an Automated Method

Context
The annual volumes of hospital-compounded 5 mg melatonin preparations (>20 000 units/year) led us to switch from a manual capsule-filling method (CAP) to an automated tablet compression method (TAB).

Objectif
To compare the robustness of the two manufacturing processes.

Materials and Methods
The study was conducted on 9 batches complying with specifications: 5 batches of CAP and 4 batches of TAB, all manufactured between January 1, 2025, and March 31, 2026. For each batch, individual values obtained from mass uniformity (MU) testing (Eur. Ph. 11th edition, 2.9.5) and content uniformity (CU) testing (Eur. Ph. 11th edition, 2.9.6) were collected. Data were analyzed using Minitab^® software to calculate process capability indexes : Cp, evaluating overall process robustness, and Cpk, evaluating process centering relative to the target value. For each pharmaceutical form, the inter-batch and intra-batch process capabilities for MU and CU were calculated using a specification of ±10% around the target values.

Results
For MU, the inter-batch Cp and Cpk values and the range of intra-batch capability indexes were, respectively, 1.63 [1.10–2.89] and 1.63 [1.00–2.54] for the CAP form, and 3.99 [4.11–7.50] and 3.95 [3.76–7.19] for the TAB form. For CU, the inter-batch Cp and Cpk values and the range of intra-batch capability indexes were, respectively, 0.99 [0.92–1.49] and 0.55 [0.51–0.79] for the CAP form, and 1.07 [0.79–1.50] and 0.92 [0.61–1.50] for the TAB form.

Discussion – Conclusion
Automation has significantly improved process capability for the MU. It also led to an improvement in Cpk, and to a lesser extent Cp, regarding CU. Industrial standards generally consider a process to be robust when both indexes values exceed 1.3. These targets were achieved with both processes for MU. However, for CU, only one TAB batch was compliant, highlighting insufficient control of the mixing step. An analysis of critical factors related to raw materials and the mixing process appears necessary. Although these requirements specifications are stringent for hospital production, the annual volumes manufactured justify the implementation of process performance indicators and support a product quality review approach, as introduced in the 2023 French Good Preparation Practices (Bonnes Pratiques de Préparation).

Keywords: Tablets, Quality Control, Drug Compounding

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