February 15, 2014 (Vol. 34, No. 4)

From our February 15 issue: Trends and tips to improve processes are featured in this GEN roundtable with bioprocessing experts.

GEN: In addition to the adoption of single-use technologies, how has bioprocess filtration changed over the past decade or so?

Mr. Bromm:
Filter manufacturers particularly have improved the performance of sterilizing-grade and virus retentive filters. Users’ willingness to collaborate and share the composition of solutions to be filtered has helped vendors better understand blocking mechanisms and design new high-performance filters.

Highly asymmetric polyethersulfone (PES) membranes, which retain contaminants in the entire depth of the thin membrane structure as well as novel surface modification chemistries, enabled a significant increase in filter performance with regard to flow rate, total throughput, and low protein binding.

Novel pleating technologies allow the effective incorporation of more filtration area into filter devices. This further increases the total throughput performance. It also reduces the cost and the footprint of the filtration systems significantly—a prerequisite for single-use processing.


Holger Bromm, Director, Filtration Technologies, Sartorius Stedim Biotech

Mr. MacDonald:
In the past decade or so, bioprocess customers have demanded higher performance from their unit operations. Often this means having to do more with less. Applying this to membrane filtration, customers often want to combine steps to save time, floor space, and therefore money. Membrane filtration suppliers have responded by making membranes that are more selective (allowing membrane steps to do processes that were once the domain of size-exclusion chromatography), faster, or more chemically or physically robust—or a combination of all three—while keeping the cost down.


Tony MacDonald, President, Spectrum Labs

Mr. Martin:
Significant innovations in bioprocess filtration have taken place. These include high-capacity asymmetric membrane filters for bioburden control, advanced cartridge pleat geometries enabling up to 2 m2 filtration area per 10-inch module, more efficient/greater capacity 0.1 µm-rated filters for higher assurance of mycoplasma retention from larger batches of cell culture media, and hybrid layer asymmetric PES/PVDF membrane sterilizing-grade filters.

Additional innovations include high-capacity multilayer cellulosic depth filters to replace centrifuges for cell harvest removal, improved cleanable designs for UF/DF cassettes, new single-pass TFF cassettes for simplification of concentration steps, and automated TFF and DFF process systems.


Jerold Martin, SVP, Global Scientific Affairs, Pall BioPharmaceuticals

Dr. Morgan:
The strategies for achieving filter design and filtration processes that meet industry demands for greater process efficacy and consistent safety results across processes have changed. Design space studies are commonly conducted to assess process robustness in terms of safety, efficacy, profitability, and applicability of process platforms. Quality is achieved through a quality-by-design approach involving the design of the filter, PAT-controlled skids, and vendor-provided technical support.

Newer filter designs maintain the robustness standards achieved in previous decades, but now they do so with greater process efficiency. For virus filtration, increased capacity means greater cost-effectiveness in larger-scale production.


Michael Morgan, Ph.D., VP, Business Development, Asahi Kasei Bioprocess

Mr. Royce:
Bioprocess filtration has become not only more standardized but also more specialized. On the one hand, operations like sterile filtration have become easier due to the smaller volumes coming from bioreactors as process titers increase. This has resulted in more standardized SOPs for these operations and created opportunities for manufacturing teams to design-in sourcing redundancy more easily than in the past.

On the other hand, filters which are optimized for specific unit operations (such as viral filtration and clarification of flocculated cell broth) have been developed as part of more holistic unit operations or processes. These filters are designed to overcome specific challenges which cannot be addressed otherwise.


Jonathan Royce, Senior Product Manager, BioProcess Marketing, GE Healthcare Life Science

Dr. Tkacik:
Several filtration operations have been impacted. Let’s look at them one by one.

Clarification—Depth filters moved from lenticular modules and stainless housings to encapsulated modules, vastly improving pre- and post-use handling.

Sterilizing filtration—Anisotropic PES membranes and the most advanced version, namely, composite membranes, became predominant. Caustic resistance is a standard. Presterilized, encapsulated filters are growing faster than filters in stainless housings requiring SIP.

Virus filters—These moved from a range of pore sizes to standard parvovirus filters. Normal flow dominates, and TFF is disappearing. High-capacity, high-LRV filters are available, some approaching complete parvovirus removal. Prefilters are used increasingly to improve the cost of this step.

Ultrafiltration—Low-binding, 30 kDa cassettes became a standard for monoclonal antibodies.


Gabriel Tkacik, Ph.D., Director, Filtration R&D, EMD Millipore

GEN: How do bioprocessors achieve efficient, economic large-scale filtration?

Mr. Bromm:
Today, bioprocessors can choose from a large variety of filter material combinations for their specific applications. The trick to achieve efficient large-scale filtration is to identify the optimal filter system in filterability trials that can be carried out with the support of vendors that have automated screening systems in place.

The use of small-scale, flat-filter discs minimizes the amount of highly valuable products needed for testing purposes. Particular attention during filter screening should be paid to selection of an optimal prefilter in front of a final filter, especially for fluid streams with a high concentration of contaminants. Prefilters protect more expensive final filters highly effectively and can prolong the lifetime by a factor of three to five, which results in a significant reduction of filtration costs for highly effective large-scale filtration.

Mr. MacDonald:
Bioprocessors can achieve efficient large-scale filtration by looking to other industries to see how they have been doing it. For example, hollow fiber filtration has been the standard in such large-scale unit operations as water purification at the municipal level and food and beverage applications, such as juice, wine, and beer clarification.

Membrane suppliers now offer scale-up assistance and technology, allowing bioprocessors to perform research and development on the bench (at the microliter and milliliter level) and then to scale that work up, to pilot and process development and then manufacturing (thousands of liters), all using the same membrane.

Mr. Martin:
Asymmetric or hybrid layer membrane filters, along with advanced high-area pleat geometries enable downsizing of direct flow filtration assemblies or reduced operating costs for large-scale filtration processes. Higher efficiency 0.1 µm-rated mycoplasma filters with improved capacities for cell culture media reduce the risk of costly contamination while controlling media filtration costs.

Reusable TFF cassettes with improved cleanability reduce turnaround time and bioburden contamination risks. Single-pass TFF cassettes cut costs by eliminating recirculation loops and allowing in-line processing. And automated filtration systems enable greater process control while reducing operator error.

Dr. Morgan:
The major factors in achieving efficient, economical filtration at production scale are understanding and minimizing process variation. Efficiency is defined in terms of cost per unit of product. Thus, the first step is to conduct a vigorous evaluation process at development scale to select technology that is consistent and economical. Next, it is important for the selected filter to show consistent filtration performance, without variation in throughput or flux, at commercial-scale production.

Minimizing variations in filter performance characteristics in scale-up decreases or obviates the need for expensive and time-consuming process exceptions, putting the resources of the facility toward production rather than problem-solving. Technical support throughout this process is indispensable.

Mr. Royce:
As with any unit operation, the key is to perform enough optimization so that waste is minimized without creating a situation where every molecule in the pipeline needs to be completely redesigned from scratch.

Standardization of methods and SOPs goes a long way toward achieving economic large-scale filtration. Early PD efforts to create unit operations (where filters from multiple vendors can be used interchangeably) can lead to better long-term efficiency in manufacturing. Such efforts can also reduce the risk of downtime.

Dr. Tkacik:
By careful selection of the highest capacity filters, without sacrificing the ease of implementation and use, it is possible to achieve robust performance in the process while minimizing the risk of impact on cleanliness and quality of the product. This needs to be assessed holistically from “cradle to grave,” starting from efficient process development tools, through easy scaling, good documentation for process validation to ease of inventory handling, integrity testing, and disposal.


The key to achieving efficient large-scale filtration is to identify the optimal filter system in filterability trials that can be carried out with the support of vendors that have automated screening systems in place. [Sartorius Stedim Biotech]

Our Expert Panel
Holger Bromm, Director, Filtration Technologies, Sartorius Stedim Biotech
Tony MacDonald, President, Spectrum Labs
Jerold Martin, SVP, Global Scientific Affairs, Pall BioPharmaceuticals
Michael Morgan, Ph.D., VP, Business Development, Asahi Kasei Bioprocess
Jonathan Royce, Senior Project Manager, BioProcess Marketing, GE Healthcare Life Sciences
Gabriel Tkaciak, Ph.D., Director, Filtration R&D, EMD Millipore