Managing API raw material variability in a continuous manufacturing line - Prediction of process robustness

Area of Science:

• Pharmaceutical Manufacturing
• Chemical Engineering
• Process Analytical Technology (PAT)

Background:

• Continuous manufacturing (CM) studies often isolate the granulator, neglecting upstream/downstream impacts on product quality.
• Product critical quality attributes (CQAs) are influenced by multiple unit operations, not just granulation.
• Managing active pharmaceutical ingredient (API) batch-to-batch variability is crucial for consistent tablet production in CM.

Purpose of the Study:

• To investigate managing API batch-to-batch variability in a high-drug-loaded formulation within a continuous line.
• To achieve consistent tablet CQAs and ensure long-term process stability for 24/7 continuous manufacturing.
• To understand the influence of API critical material attributes (CMAs) and critical process parameters (CPPs) on CQAs and process stability.

Main Methods:

• A screening design of experiments (DoE) was employed, varying API CMAs and granulation, drying, and milling CPPs.
• Process deviations recorded by sensors were utilized to evaluate factors affecting process stability with reduced material usage.
• The fully integrated continuous manufacturing line was studied to identify interactions between unit operations and API CMAs.

Main Results:

• Product CQAs were solely dependent on process CPPs, while process stability was significantly impacted by API CMAs.
• API batch-to-batch variability's effect on process stability could be mitigated through optimized granulation conditions.
• Appropriate CPP ranges were defined to ensure both consistent product CQAs and robust process stability.

Conclusions:

• A robust continuous manufacturing process was designed by studying the integrated line and understanding interactions.
• Optimizing granulation conditions is key to managing API variability and ensuring process stability.
• This approach enables consistent tablet CQAs and reliable long-term operation in continuous pharmaceutical manufacturing.