Critical versus non-critical process parameters

How to use the previous data to establish if the load and load conductivity are critical process parameter?  The outcome of that decision is going to have profound affects down range as the commercial organization takes on the responsibility of commercial production.  A good place to start is with the regulatory guidances (see the links to the right).  Starting from Q8, the critical process parameters are those

"whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality." 

The previous post related the changes of the aggregate percentages and CHO HCP levels, along with the recovery.  Of these, only the former two would be considered as quality attributes (recovery being a business factor).  

Protein aggregation is hard to argue against as a critical quality attribute and that means the load and load conductivity would be critical process parameters.  The next step is to scientifically justify the greatest acceptable operating range for the process and JMP provides some exceptionally useful tools to assist in this effort.

We could begin with a graphical representation of the space we want to claim as our acceptable operating space

How much do our product quality attributes vary within this region?  The prediction profiler within JMP allows the two prediction curves to be shown simultaneously.  Translating the limits from the previous figure establishes the initial lower and upper operating limits (LOL, UOL).  These are shown as dashed, red vertical lines in the figure.  The cross-hairs are set approximately at the center point of this region.

From a quality perspective, the design space is really one sided all product quality attributes meet our design criteria below the lower operating limit.  The yield may take a hit, but that's a business problem - not quality.  Examining the lower and upper edges of the design space offer predictions as to how the product quality attributes vary with the process

Product Quality at Lower Operating Limit

Product Quality at Upper Operating Limit

Increasing the model's power, in terms of communication, simulations offer additional insight into the process.  The load is set to a the lower operating limit, under the assumption that this number can be readily set within the batch record, and then the load conductivity is allowed to vary by 2 mS/cm.  Another feature is the ability to include the standard deviation from the experiment into the responses and then allow the simulation to proceed for an N=5000.

The result is a graphical representation of the expected process variation and it's impact upon the product quality attributes.  These can then be used in supporting the overall process control strategy.  When the process is at its upper limits, there is a significant portion of the samples that would not meet the upper limit of 0.8 % aggregate.  The operating limits may have to be adjusted lower, at the expense of recovery, to ensure the maintenance of the product quality.

Thus, an iterative process of defining and modeling enables a scientific justification for the acceptable operating range of the critical process parameters.