This month marks the two-year anniversary of FDA’s release of its process analytical technology (PAT) guidance for industry. Since that time, life sciences companies have undertaken a multitude of PAT projects, from sensor development and data analysis on specific process units to corporate regulatory strategies and standardized process analytical technology platforms.This breadth of projects reflects the large and sometimes ambiguous scope of PAT. To achieve common ground in defining and discussing PAT, it is useful to refer back to the FDA’s four principles that form the pillars of a PAT strategy:
• Process understanding
• Risk-based approach
• Regulatory strategy to accommodate innovation
• Real-time release Companies applying these four principles to their manufacturing and development operations to achieve science-based manufacturing are taking the first steps transitioning from quality-by-inspection to real-time quality-by-design. The economic and time-to-market benefits can be enormous, but the undertaking is not trivial. Over a series of four articles, we will explore the concepts, tools and value each principle provides life sciences manufacturers within a comprehensive PAT program.
The First Principle - Process Understanding
With the goal of PAT to understand and control the manufacturing process – achieving quality-by-design – it is not surprising that process understanding projects in many forms dominate the PAT spend. The FDA defines process understanding as:
• All critical sources of variability are identified and explained
• Variability is managed by the process
• Product quality attributes can be accurately and reliably predicted and controlled to be within specifications
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Process Understanding Recaptures Money Lost by Variability
A great example of the path to process understanding and the resulting benefits involves a solid dosage process at a major pharmaceutical manufacturer. Sudden, unacceptable dissolution rate variability exposed a glaring need to identify the true critical process parameters affecting the dissolution rate in order to apply controls to help maintain the process within specifications. The challenge was identifying the critical process parameters across the solid dosage line with well over a hundred process variables, further complicated by the fact that data was available from only a little over two hundred lots.
Process Understanding Across the Formulation-to-Commercialization Continuum
In the previous case, process measurements were already established, and the results showed that variability could be reduced without adding additional sensors to glean more insight into the process state. In some situations, the process state simply cannot be ascertained with the current measurements and models. This type of challenge is typical in development organizations where scientists and engineers must define critical process parameters and measurements for new processes. Silo approaches to process development are entering a paradigm shift. Many companies are increasing collaboration between development and commercial manufacturing early in the path to commercialization, integrating process understanding activities along the formulation-to-commercialization continuum.
Process Understanding Translates to Rapid Scale-up
An example of this has been in place for some time at a major manufacturer of oral and parenteral dosage forms and drug delivery systems. Several years ago, the company’s development department was dealing with typical problems encountered by functional silos. Disparate systems for storing data, limited knowledge transfer mechanisms, and standalone instrumentation meant that much of the process understanding
uncovered along the development path was not readily available or used across different scales.