6 Filtration Challenges in Downstream Biopharmaceutical Production

Membranes and membrane processes are efficient filtration tools in the manufacturing of biopharmaceutical products. These tools continue to evolve in response to new therapies and processing methods. The membranes used in separation and purification are beginning to play an even more important role as market demand for monoclonal antibodies (mAbs) and other gene and cell culture therapies have expanded in recent years. The global mAb therapeutics market is projected to grow from almost US$ 95.6 billion in 2017 to US$ 174.2 billion by 2026.

Although the market outlook for mAbs and related therapies is healthy, manufacturers face a number of challenges related to filtration during downstream processing for those products. These challenges, if not resolved, will limit their availability. While some innovations in membrane technology have been developed to meet some of these challenges, more new tools and methods are needed in future years.

The Evolving Functions of Membranes in Filtration for mAbs Manufacturing

For the past two decades, manufacturers of mAbs have adhered to a standard method of production, using membranes for separation, purification, and viral clearance. The development of more intensified processes, however, has created a need to increase the efficiency of membranes as well as the processes in which they are used. These processes range from standard batch processing to end-to-end continuous processing, with manufacturers gradually progressing towards the latter.

The trend towards developing drugs with higher concentrations for subcutaneous delivery is also affecting the requirements of the filtration process. The progression toward continuous processing, new applications, and new therapies means that membranes are not only expected to perform more efficiently, but their functions are expected to expand and diversify also. The new requirements for membrane function, capacity, and processes are related to:

• Biosafety. Membranes that are viral retentive are needed, as are membranes that decrease bioburden further for "low bioburden" processing steps that are not at high risk for exposure to bacteria.
• New Processes. The use of bind-elute chromatography, which is often used in closed processes, requires disposable membranes. Another new process, tangential flow filtration (TFF) or crossflow filtration, rapidly separates larger biomolecules from the feed stream. Both of the processes are favored in the production of highly concentrated mAbs.
• New Membrane Characteristics. The demands of continuous processing necessitate increased capacity for membranes. Sterilizing-grade filters that handle higher drug concentrations and that can also maintain stable flow rates are necessary. Other characteristics required with the advent of new methods are more specialized membranes as well as more flexible single-use ones.

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The Challenges that Manufacturers Face

The new paradigm shift that is unfolding in filtration processes has created a crop of challenges for mAbs manufacturers. Controlling costs while maintaining efficiency is a delicate balancing act as manufacturers transition to new processes. Speed of processing and preventing bottlenecks are part of the efficiency challenge since some of the current downstream operations, such as nanofiltration, are not compatible with continuous processing.

Drugs produced in higher concentrations can create two problems in downstream manufacturing. First, decreasing the number of impurities from fluid streams becomes more difficult in the separation stage. The other problem is that loss of process fluid in bind-elute chromatography and TFF methods negatively affects processing. The shortage of single-use membranes for chromatography is a pain point for manufacturers because they are forced to regenerate and sanitize conventional resin technology after it is exhausted after a few service cycles. This interruption slows production. 

Closed processing presents another concern for manufacturers. Despite the advantages of increased flexibility, decreased changeover cleaning requirements, and lowered risk of product contamination, it is more difficult for manufacturers to maintain material integrity through the connected operations in this mode of processing.

Continuous processing presents its own set of biosafety challenges for manufacturers. The longer processing time creates more of a risk of exposure to bacteria for processing equipment, which means that tighter bioburden control needs to be put in place.

Another challenge is implementing sample collection without jeopardizing the sterility of the manufacturing environment. Maintaining a sterile environment in this manufacturing process also indicates a need for stronger sterilization methods for devices, such as gamma radiation. Lastly, sterile filter validation is required to ensure that filters are virus-retentive.

The Future of Filtration Technology

In the wake of the evolution of mAbs development, the drug industry has stepped up its interest in other antibody-drug conjugates. As the demand for more therapies increases, drug manufacturers will explore more diverse processes that use more complex molecules. These processes require efficient separation and purification capabilities across a variety of methods and steps: both batch and continuous processing, for fluid streams of both high and low concentrations, and for quick setup and changeover.

Conclusion

There is much promise for the development of "intelligent" membranes that collect data, new and updated technology for novel therapies, and more rigorous scaling tools for separation and purification membranes. Breakthroughs in single-use bioprocessing will continue to be developed as well. The potential for newer and better antibody drug therapies is far-reaching as long as drug manufacturers seek improvements and innovations in membrane technology.