Process Parameters Review
The inclusion of process parameters in the PHA serves primarily as a communication tool to ensure that the receiving site
knows the important parameters to control and monitor. This list includes not only any CPPs, if defined, but also any other
parameters that are likely to affect product quality, yield, or consistency, such as pH, temperature, conductivity, product
concentration, and intermediate step purity and yield. The receiving site will be able to assess whether its equipment set
is capable of achieving the required process control. This also is an opportunity for the receiving site to ask questions
about process parameters it has observed to be important in other processing experiences. Table 1 shows an example of a process
parameter table for an ion-exchange process step. Bold text is used to denote CPPs or other quality parameters that must be
Table 1. An example of a process parameter comparison for an ion-exchange process step. Bold text denotes critical process
parameters or other quality parameters.
Table 1 shows that there are differences between the sending site's process parameters and the receiving site's parameters.
As with all sections of the PHA, it is important to have a summary to discuss areas of concern that may need more development.
The process parameters also include important scale-up parameters. These parameters may not be directly controllable parameters,
but may be significant in attempting to reach comparability. Table 2 shows a list of some of the process parameters that are
critical for scale changes.
Table 2. A sample of process parameters that are critical for scale changes.
The equipment capability section of the PHA compares the mechanical and instrumentation capability of the pieces of equipment
used for the execution of each process step. Equipment capability is a critical assessment, whether the scale of the process
changes or not. When transferring a process, there will be many differences between the equipment used to execute the same
process step at two different locations. It is important to determine where the differences are in critical design features.
Critical design features may affect the ability of the equipment to control or achieve the important process parameters listed
in the previous section. Differences in process scale, and what scaling factors were used in the design, should also be included.
Table 3 shows an example of an equipment parameter table comparing a piece of equipment used for the same process step at
two different manufacturing sites.
Table 3. Comparison of equipment parameters from two different manufacturing sites
Two of the most critical equipment capabilities are buffer capacity and process mixing. When calculating comparable scales
between the sending site and the receiving site, buffer and process volume comparisons must be performed. The amount of additional
buffer needed is dependent on process transfer line size, flush volumes, and lower height equivalent to a theoretical plate
(HETP) values for larger chromatography columns. Larger columns may need more buffer column volumes to equilibrate because
of natural inefficiencies with larger columns. Directly scaling buffer volumes from the sending site must be done carefully
to account for the differences in the receiving site's tank capacities. In many cases, buffer makeup and storage capacity
may be the limiting constraint on process scale-up. Companies can easily purchase larger portable columns, but installing
capacity in buffer hold areas can be extremely expensive and result in long lead times. If a process involves any critical
reactions or rapid pH changes, it is critical to assess the mixing characteristic between the sending and the receiving site.
It is much easier to obtain well mixed environments at smaller scales. Blend time calculation is an easy way to perform an
initial comparison, but other comparisons may be required for crystallizations, viscous fluids, or other complex scenarios.
In one instance, what was thought to be slow mixing at a pilot-scale was actually faster than what could be obtained at production-scale.
Many software packages are available for these analyses.