Why is there a movement in the pharmaceutical and biotech manufacturing industries to consider continuous manufacturing over traditional batch manufacturing processes? A 2012 U.S. Food & Drug Administration presentation, FDA Perspective on Continuous Manufacturing, captured some of the reasons why. Author Dr. Sharmista Chatterjee listed some advantages:
- Integrated processing with fewer steps
- No manual handling, increased safety
- Shorter processing times
- Increased efficiency
- Smaller equipment and facilities
- More flexible operation
- Reduced inventory
- Lower capital costs, less work-in-progress materials
- Smaller ecological footprint
- On-line monitoring and control for increased product quality assurance in real-time
- Amenable to Real Time Release Testing approaches
- Consistent quality
Together, these open of the possibility to significantly reduce costs and improve quality.In a Pharmaceutical Processing magazine article, Continuous Progress in Continuous Manufacturing, Emerson’s Jonathan Lustri and co-authors Doug Hausner with C-SOPS and Paul Brodbeck with QbD Process Technologies describe process design, measurement, and control for enabling continuous processing.
While the cost benefits are clear, the challenges to implement are as well. These challenges include:
…process design, measurement, material traceability, and control.
To address these challenges:
Manufacturers, suppliers, and research institutions are collaborating to solve these challenges at projects across the globe, including the Engineering Research Center for Structured Organic Particulate Systems (C-SOPS) [hyperlink added], based at Rutgers, the State University of New Jersey.
A large question is how to ensure quality and regulatory compliance when there are no breakpoints as batch production features. The answer:
…is to monitor critical process parameters (CPP) and critical quality attributes (CQA) at a frequency that allows for sufficient monitoring of the process and product quality. In addition, the real-time application of Process Analytical Technology (PAT) for continuous processes is essential to quality control and must be integrated into the process control strategies.
Another question for continuous processes is material traceability, which is critical for regulatory compliance, safety and efficacy. Rather than physically discrete batches, traceability in continuous processes:
…relies on statistical probabilities.
It may only be possible to predict, for example, that there is a 90 percent chance that the material in a particular tablet came from Lot #1, a 9 percent chance that it came for Lot #2, and a 0.9 percent chance it came from Lot #3. The probability distribution depends on a concept called Residence Time Distribution (RTD)—a function that describes the amount of time a particle could spend inside the vessel.
…has developed models for unit operations to predict the RTDs under different process situations.
These models have the advantage of:
…being able to predict RTDs dynamically based on process parameters including flow rate, mixing speeds, and density. If a PAT application using an NIR analyzer to predict a CPP after the blender is out of specification, the RTD models can be used to predict when and which tablets need to be rejected.
By integrating these models into the process control system, traceability is synchronized in real-time.
Read the article for examples of how advanced controls for feedforward and feedback controls have been developed and implemented by C-SOPS in applications such as API concentration and how these RTD models help optimize plant design and production unit operations.
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