Practical Considerations for Demonstrating Drug Substance Uniformity - The authors describe considerations and best practices for meeting drug substance uniformity. - BioPharm International


Practical Considerations for Demonstrating Drug Substance Uniformity
The authors describe considerations and best practices for meeting drug substance uniformity.

BioPharm International
Volume 24, Issue 4, pp. 30-37

Other considerations to achieve uniformity at the bulk filtration step are the design and operation of the upstream feed vessel. Mixing studies should be used to establish set point and ranges for agitation speed and time to ensure thorough mixing of the contents to be filtered (e.g., top, middle and bottom of vessel). The design of the vessel is also important to ensure that dead zones and holdup volumes (both line and sample port) are minimized. This is especially important if dip tubes are present, which may be used for product introduction into the vessel and/or subsequent withdrawal for the bulk filtration step. Both examples may impact uniformity if lines are not efficiently flushed, or if hydrostatic pressure within the tube results in concentration changes over the course of the filtration. It is preferable to use separate routes for product introduction and to locate dip tubes such that they do not result in a dead zone within the tank. The vessel location and piping required to transfer the product from the feed vessel through the filter should also be evaluated to minimize holdup volume and ensure proper drainage (to account for condensate drainage following product transfer line steaming) in order to minimize the possibility of dilution.


Characterization studies to confirm that preparation procedures are adequate and robust should be performed prior to performing uniformity studies with product. These can be performed using buffers or salt solutions with pH and/or conductivity as convenient indicators to assess uniformity through filtration. Careful assessment of the buffer used for such studies is necessary to ensure that the buffer selected is a representative model to use, and parameters such as density and viscosity which could impact the kinetics of filtration should be considered. Figure 2 shows the result from one such study where a sodium chloride solution was used to determine whether a product flush would be required. As expected, the initial samples during the filtration step have a slightly lower conductivity but this quickly stabilizes to greater than 97% of the initial concentration. The results from replicate studies are consistent, showing that the operation is reproducible. An alternative strategy would be to utilize a representative protein surrogate, if possible.

It would be prudent to also perform a (non-GMP) engineering run with product prior to the process validation studies. This provides added assurance that the uniformity validation study acceptance criteria will be met. Figure 3 also compares the product profile with the surrogate salt filtration runs, confirming the results and conclusions drawn from the wet testing. If there is a potential for reprocessing at the bulk filtration step (e.g., as a result of failed filter integrity test post use or operational errors which may have compromised the aseptic nature of the batch), it is recommended to test the uniformity of the batch at the reprocessing step during the engineering run.

The standard practice in industry is to perform uniformity validation during the conformance runs (also referred to as process performance qualification, and historically referred to as process validation). Future process changes also require an assessment of the validated state of the step and whether revalidation is necessary to confirm that uniformity is not affected. However, since ongoing uniformity testing is not typically performed, subtle shifts or trends in the process would not be detected. The use of the filter weight checks as inprocess controls along with robust maintenance of operational parameters provide assurance that DS uniformity is maintained. It may be desirable to perform uniformity testing on a periodic basis to provide further confirmation. The approach of using the "percentage of feed stream concentration," described above, provides a simple means to confirm uniformity on an ongoing basis.

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