Process Harmonization Assessments for Technology Transfer - A process harmonization assessment can aid in smooth technology transfer by comparing data across equipment and sites. - BioPharm

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Process Harmonization Assessments for Technology Transfer
A process harmonization assessment can aid in smooth technology transfer by comparing data across equipment and sites.


BioPharm International Supplements


Process Parameters Review


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.
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 maintained.

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.


Table 2. A sample of process parameters that are critical for scale changes.
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.

Equipment Capability


Table 3. Comparison of equipment parameters from two different manufacturing sites
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.

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.


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