OPERATIONAL PARAMETERS

Prior to entering uniformity validation, it is necessary to have robust control of the preparation operations for the bulk filtration step. If the bulk filter is autoclaved or sterilized in place, this may result in retention of steam condensate on the filter, filter housing, and/or system piping, which in turn could result in dilution of the DS and increased variability in uniformity results. Additionally, the filter may be integrity tested prior to use (either prior to or after sterilization) or preflushed with buffer to remove potential extractables/leachables and equilibrate the filter. The buffer flush is especially important if the formulation buffer contains polysorbate or other agents which are known to bind to the filter. The buffer flush could alternatively be performed post autoclave/SIP of the filter, however, this adds complexity to the operation to ensure that the aseptic state of the equipment is not compromised during the flush. The integrity test procedure requires wetting of the filter with water. Although the majority of water is removed during the integrity test (diffusion or bubble point), there may be sufficient residual water retained in the filter. A good practice is to implement an in-process control point to ensure that the residual liquid from the integrity test flush, buffer flush, or steam condensate is reduced to an acceptable level prior to processing. This approach could be carried out in the form of an air-purge step, a filter-drying step (in an oven),or a simple comparison of the filter weight before and after preparation steps. The allowable residual fluid in the filter can be calculated based on the uniformity requirements. Such control measures provide confidence that the potential sources of dilution are removed or minimized prior to validation.

These controls are especially important to ensure that the DS meets specification limits in the event of reprocessing across the bulk filtration step (e.g., if the post-use integrity test fails). Table I highlights typical steps in preparation for the drug substance filtration operation. It should be noted that not all the steps shown in Table I may be required; some steps may be eliminated depending on the need for operational simplicity, for example, by minimizing manipulations such as the air purge or buffer flush to the filter assembly post autoclave. The final decision on the number and order of steps should ensure that the potential failure modes are adequately addressed while maintaining a robust and consistent process to meet the uniformity requirements.

Another important consideration with respect to the product flush is the size of the filter and filter housing. While it is appropriate to size the filter with a safety margin so that it can process batches in a robust manner and in a reasonable time frame, oversizing the filter could result in challenges from a bulk uniformity perspective. One way to address this issue is to perform a prefiltration step with a larger filter to remove particulates which may foul the 0.2 µm filter. The prefiltration can be performed as part of the preceding unit operation so as to collect a clarified feed stream for the bulk filtration step. A further variation is to perform a batch-wise bulk filtration into a single collection vessel, thereby allowing for a buffer chase to maximize product recovery and also any dilution that may be necessary to achieve the target product concentration. This option could also be adapted into a continuous mode by the use of a surge tank between the filter and collection containers to avoid dilution effects. Following adequate mixing, the product may be dispensed aseptically into appropriate collection vessels. This obviates the need for the product flush, and thus maximizes product recovery during processing.