A biopharmaceutical manufacturer's objective is to maximize process efficiency while maintaining product safety, purity and efficacy. Product contamination can derive from a variety of sources: endogenous to the cell, additive to the process or byproducts derived during processing – all of which must be minimized.

Typically in a heat liable biological production process a series of filtration steps including prefiltration, clarification, chromatography, membrane adsorbers, viral clearance and sterilizing-grade filters, are used to remove product/process contaminants.

Among the filtration steps, prefiltration is an effective method to lowering production costs by extending the throughput of downstream filters. Prefilters remove contaminants that would negatively impact downstream product quality and would otherwise plug a downstream membrane filter, reducing its effectiveness and service life.

Prefilters have a long history of successfully reducing or eliminating microorganisms and particulates without degrading the process stream. A variety of filter media types at a range of nominal pore sizes are used to efficiently reduce bioburden; among them, mixed cellulose esters, borosilicate glass, and microporous membranes. The decision of which filtration technology to use for a given step depends on process efficiency requirements, process stream properties, required processing conditions (batch size, time, yield, etc.) and product quality requirements.

Selection of a prefilter is based upon the retention efficiency required for the filtration process step. Choosing the proper nominal pore size prefilter ensures optimum dirt-holding capacity and retention for improved process economy. Other considerations for prefilter selection may include: compatibility with the fluid being filtered and with cleaning and sanitizing agents, filter extractables and leachables, product hold up, formulation binding, robustness and ease of sterilization and handling.
Recent development work has focused on creating microporous membrane prefilters that improve process efficiency and meeting user needs to minimize extractables, leachables and product losses. Improving prefilter robustness has also been a key development objective. Many of the new microporous membrane prefilters can handle high temperature which enables sterilization of the prefilter together with other unit operations for improved handling and process efficiency.

Availability in self-contained gamma irradiable disposable capsule is another enabling feature for many of the new microporous membrane prefilters. Gamma irradiable capsules available in nominal pore sizes >0.2 micron enables flexible, efficient operations for a variety of streams and rapid change-overs for fast, efficient processing, reduced labor costs, and time savings through simplified set up, installation and operations.

New microporous prefilter

Millipore Express® HPF is a new, highly retentive microporous polyethersulfone (PES) membrane prefilter; comprised of a 0.5 µm membrane prefilter layer and a tighter 0.3 µm downstream layer. This highly retentive membrane prefilter maximizes efficiency of downstream sterilizing-grade applications though a combination dirt-holding capacity on the prefilter itself and through very high particle-retention for protection of more costly downstream operations.
A recent research study[1], compared Millipore Express HPF 0.5/0.3 µm prefilters, in combination with Millipore Express SHR 0.1 µm sterilizing-grade filters with other prefilter-final filter combinations in various serum-free media. Prefilters tested included other PES-based membrane prefilters and Polysep™ II prefilters. Results are presented as device requirements for a typical batch volume and process time for large-scale media filtration.
Figure 1 compares device requirements with EMD soy media of Millipore Express HPF 0.5/0.3µm with Millipore Express SHR 0.1 µm sterilizing-grade filter to another prefilter and 0.1 µm filtration train.

Figure 1

With this media challenge the Millipore Express HPF 0.5/0.3 um and Supplier A 0.8/0.45 um PES prefilters required a similar number of total filters. However with the lowest sterilizing-grade filter devices required, Millipore Express HPF filters in combination with Millipore Express SHR 0.1 um provided the most economical media filtration train.

Figure 2 displays device requirements for customer specific media with various prefilter-final filter combinations.

Figure 2

Millipore Express HPF and Polysep CGW1 and CGW3 prefilters yielded similar device requirements. However, Millipore Express HPF and Polysep CGW1 prefilters demonstrated the greatest protection of the final filter resulting in the smallest final filter device requirement. Supplier B PES 0.2/0.2µm prefilter required at least 20% more total devices and 70% more final filters than Millipore Express HPF filtration series.

Device requirements for filtration of a second customer specific serum-free media is presented in Figure 3. Polysep CGW3 and Millipore Express HPF prefilters were evaluated as prefilters in this trial. Millipore Express SHR 0.1µm and Durapore 0.1µm filters were evaluated as the final filter in this trial.

Figure 3

While prefilter device requirements are similar for Polysep CGW3 and Millipore Express HPF prefilters, final filter protection/particle retention differs significantly as measured by the downstream 0.1µm sterilizing-grade filter device requirements.

Figure 4 presents various prefilters and final filters with a third customer specific media.

Figure 4

Other membrane prefilters required 20% more prefilter devices and 2X more final filter devices versus Millipore Express HPF prefilters. In addition to higher throughput, Millipore Express HPF filters provided better protection for the downstream Millipore Express SHR 0.1µm sterilizing-grade filter. The open structure of the Millipore Express HPF 0.5µm membrane prefilter layer provides greater capacity to capture particles in media preventing blockage of the membrane.

Figure 5 presents comparison of Millipore Express HPF and Polysep CGW1 prefilters with a fourth customer specified media.

Figure 5

In this customer-supplied soy-based media, both Millipore Express HPF and Polysep CGW1 prefilters, in combination with Millipore Express SHR 0.1µm as the downstream sterilizing-grade filter, provide similar total device requirements. Millipore Express HPF in combination with Millipore Express SHR, provided greater throughput than Polysep CGW1 in combination with Supplier A final filter. Versus the combination of Polysep CGW1 with Supplier A PES 0.2/0.1µm final filter, Millipore Express HPF in combination with Millipore Express SHR 0.1µm sterilizing-grade filter requires 25% fewer devices to filter a 10,000 L batch within the specified 2 hour time frame.

In summary, the study results showed that the Millipore Express HPF prefilter performed well for throughput for all five serum-free media evaluated. Of the 0.1 µm media filtration trains assessed, Millipore Express HPF prefilter in combination with Millipore Express SHR filter performed the best and required fewer devices overall than other 0.1 µm filtration trains. Millipore Express HPF prefilter demonstrated the greatest protection of the downstream 0.1 µm filter for lower total device requirements across the majority of the media tested.

Microporous membrane prefilters in the future

New microporous membrane prefilters, such as Millipore Express HPF prefilters, have been shown to improve process efficiency and economy by significantly reducing particulate load on more critical downstream operations. Advancements made with many of the new microporous prefilters to reduce filter extractables and leachables, expand chemical and thermal stability and improve handling and robustness are enabling biopharmaceutical manufacturers to improve product quality and process efficiency.


[1] Millipore Corporation, Application Note: Throughput Performance of Millipore Express® HPF vs. Other Polyethersulfone Membrane-based Prefilters in Combination with 0.1 µm Sterilizing-grade Filters for Serum-free Media Filtration Applications, 11/07.