Robustness of a continuous direct compression line against disturbances in feeding

Area of Science:

• Pharmaceutical Technology
• Process Engineering
• Drug Manufacturing

Background:

• Ensuring consistent drug product quality during manufacturing is critical.
• Continuous manufacturing offers potential advantages in pharmaceutical production.
• Understanding process robustness against feeding variations is essential for reliable continuous direct compression (CDC).

Purpose of the Study:

• To evaluate the robustness of an integrated CDC line against feeding disturbances.
• To assess the impact of formulation properties (API particle size) and production rates on process performance.
• To characterize disturbance smoothening capabilities and identify key process stages.

Main Methods:

• Simulated feeding disturbances (API impulses, step changes) were introduced to an integrated CDC line.
• Two formulations were tested: standard API particle size and large API particle size.
• Production rates of 5 kg/h and 10 kg/h were investigated.
• Residence time distribution (RTD) analysis was performed to understand material flow and mixing.
• Uniformity of Dosage Units (UDU) was assessed against USP pharmacopoeia limits.

Main Results:

• The CDC line successfully smoothened disturbances, meeting USP UDU limits for individual tablets across all tested conditions.
• The primary formulation (standard API particle size) consistently met pharmacopoeia UDU requirements for the entire run.
• The modified formulation (large API particle size) failed pharmacopoeia UDU requirements for the entire run due to high inter-tablet variability.
• Higher production rates (10 kg/h) resulted in poorer smoothening due to shorter RTD.
• Significant back-mixing was observed after the blender, indicating the tablet press plays a crucial role in disturbance smoothening.

Conclusions:

• The robustness of a CDC line is highly dependent on formulation characteristics, particularly API particle size.
• While CDC lines can mitigate short-term disturbances, formulation choice is critical for long-term process consistency and pharmacopoeia compliance.
• The tablet press contributes significantly to disturbance attenuation, especially for events longer than the blender's mean residence time.