Requirements at or tighter than the DS specification limits
The criteria for DS uniformity may be established to be the same as the DS specification limits. While this is a relatively
simple way of setting the uniformity process validation acceptance criteria (PVAC), it does carry the undesirable risk of
failure for DP specification and uniformity limits if the sample measurements are at the DS specification limits, especially
if there are stability concerns during storage. One way to reduce this risk is to set the validation acceptance criteria within
the DS specification limits, thereby providing a safety margin. One should also ensure that the documented analytical method
precision is able to achieve results of the reduced range. The advantage of this approach is its simplicity in applying a
safety margin relative to the specification limits, which ensures robustness in meeting the process needs. The downside is
that the safety margin allowance may be subjective and may not align with the method precision.
Table I: Typical processing steps in drug substance filtration operation. (FIGURE IS COURTESY OF THE AUTHOR)
Inclusion of analytical method variance (to account for potential measurement error)
This strategy takes into consideration all potential errors that could contribute variability to the uniformity results, such
as analytical method variability and volume measurement for the product and additives, in order to ensure acceptable DS uniformity.
The root mean squares of the potential errors are calculated to derive the acceptance criteria. The acceptance criteria may
be established based on the analytical method variability or precision when the analytical method variance is significantly
greater (more than one order of magnitude) than the process variance. It should be emphasized that the prospective method
validation acceptance criteria should be used in the calculation, rather than the results from the analytical method validation
exercise. One must also ensure that sound technical justification exists for how the method validation acceptance criteria
are developed. The latter is typically based on a fairly small data set and could result in overly tight acceptance criteria,
resulting in a failure of the uniformity study. The acceptance criteria is set so that the percentage relative standard deviation
(RSD) of the sample points is less than or equal to the analytical method precision. An assessment on process impact in using
this method is recommended to ensure that validation acceptance criteria are not set too wide.
Percentage of the feed stream concentration
Another simple way to establish uniformity study validation acceptance criteria is to evaluate individual samples against
a percentage of the feed material concentration. Selection of the actual percentage value could use a similar approach to
that described the two previous methods. This method is based on the assumption that typically, there may be a small amount
of product adsorption onto the bulk filter or dilution from flush water/buffer retained in the filter apparatus. As such,
this source of variability is expected during the initial phase of the bulk filtration step. This method is applicable where
the principal uniformity failure mode is based on dilution. It is fairly simple to implement, but can be problematic if the
method variability is high.
Figure 2: Concentration curves for surrogate (0.1 M NaCl) and product filtrations. (FIGURE IS COURTESY OF THE AUTHOR)