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An increasingly complex development pipeline and industry considerations, such as sustainability, are leading to a greater need for more efficient separation and purification in downstream processing.
As the biopharmaceutical industry grows year on year, it is becoming more pressing to improve yields and process efficiencies. A common bottleneck in downstream processing (DSP) is found in the purification and separation of the biopharmaceutical products. To learn more about purification and separation in DSP, BioPharm International spoke with Alexei Voloshin, global application development manager at 3M Separation and Purification Sciences Division.
BioPharm: What are the main techniques and technologies employed for DSP separation and purification of biopharmaceutical products?
Voloshin (3M): Ultimately with this downstream process, unit operations are needed to separate the biopharmaceutical product from a complex mixture of expression organism, byproducts of the organism’s metabolism and other cell waste, and then purify that product to the highest stage of purity, especially for injectables that must be safe and efficacious.
There are four main techniques for separation and purification: separation by size, typically referred to as filtration; separation by chemical property, also known as chromatography; separation by affinity, another type of chromatography, which utilizes a protein’s biological structure or function for purification (this process can be likened to a lock and key: there is set of interactions or features that must be in an exact order for a product to filter through or bind to it); separation by density, which utilizes centrifugation to separate the large, denser particles from less denser ones.
Each of these techniques is implemented by a technology solution to help the downstream process scale to a level that allows for mass production of biopharmaceuticals. These technologies include filters or chromatography devices (e.g., columns of packed, porous beads, membranes, or fibers functionalized with a special property).
These separation techniques and technologies are typically arranged in a sequence with a precise strategy as dictated by engineers or lab technicians and are chosen based on what the problem requires. Some or all separation techniques and corresponding technologies may be used in a downstream sequence.
BioPharm: Could you run through the key challenges of downstream separation and purification in biopharmaceutical development?
Voloshin (3M): At a high-level, the industry is challenged by the need to produce exponentially more as new therapies are brought to market. Biopharmaceutical companies want to expand into new markets, which they can only do through decreasing the cost of drugs and treatments. However, this expansion is limited due to production inefficiencies.
To battle these inefficiencies, we need a qualitatively simpler downstream process with fewer steps, as well as more efficient methods to scale up and scale out of the processes. Some processes require many steps, which not only requires many different types of equipment, but also highly trained staff to operate it. The industry is working hard to improve technology and to update outdated processes that have long caused bottlenecks in DSP separation and purification.
BioPharm: How can companies overcome the bottleneck issues commonly associated with DSP separation and purification?
Voloshin (3M): The bottlenecks in DSP separation and purification come back to inefficiencies; there are too many steps, and each individual step can be seen as a bottleneck itself. Some steps are high-performance, but some are not—they fall victim to outdated technology and processes.
To combat this, the industry collectively needs to be able to execute high-performance separation, or high-fidelity separation, at all stages of the process. For example, if you can only separate one type of impurity per one part of the process, that’s a lot of steps. But, what if we design and implement technology that helps reduce a wide range of impurities in one unit operation by cleverly managing the chemistry and physics of the separation? This approach greatly reduces the number of unit operations and makes the process more efficient and robust at the same time.
The industry is transitioning to convective technologies—such as fibrous separation media and membrane separation media—to achieve better separation at all stages of the process. The physics of these technologies is compatible with being able to separate qualitatively better, therefore eliminating or combining process steps.
BioPharm: Is the increasing complexity of biomolecules in the development pipeline impacting DSP purification and separation?
Voloshin (3M): The increasing complexity and variety of biopharmaceutical modalities present both exciting opportunities for patients, but also challenges in building new purification platforms. For example, when insulin was being produced, it was one specific product, and the process could be improved over time. More recently, monoclonal antibodies came around, and they have minor variations across the scaffold, so scientists developed a purification platform that was improved and simplified over time. Scientists can then use this knowledge to build out platforms of emerging modalities such as viral Frankenstein molecules, nano-particle particles, viral vectors, and cells. Each platform must be able to deal with unique chemical and physical characteristics of the expression platform and the product itself.
For example, with the emergence of gene therapy, scientists have discovered we cannot use the same technologies that have been used for years for recombinant proteins. The physics backed into the purification technologies for proteins simply does not work very well on large particles used in gene therapy. With the increasing complexity of biomolecules, there is a new awareness of the fact that we need to look even closer at the physics and chemistry of these molecules to ensure the separation and purification technologies are compatible.
BioPharm: As sustainability and being environmentally friendly are increasingly important considerations for industry, what are the key aspects of DSP purification and separation that can be improved, in your opinion, to ensure greater sustainability or less of an environmental impact?
Voloshin (3M): Efficiency is key—the more efficient we are, and with less materials used, the more we can make with less, therefore having a smaller environmental footprint. We achieve better efficiency through better technology, specifically technology that cuts down steps and makes each step smaller. For example, one of the biggest footprints in bioprocessing is the use of ultra-pure water as it takes a lot of energy to create it. If we can combine steps that perhaps cut down on the need for as much ultra-pure water, we could improve the environmental impact of the separation and purification process. These are principles of process simplification and intensification.
It also may seem counter-intuitive, but the use of single-use systems can help plants be more sustainable. It takes a lot of water and chemicals to use multi-use systems, given the incredibly thorough cleaning they must undergo between uses. Some plants use steam-cleaning for their sterilization process which also takes a lot of energy. By making small, high-performance single-use devices for the separation and purification process, the waste and energy input is much smaller compared to what it would be otherwise.
BioPharm: Are there any particular trends for the future, say in the next 5–10 years, that you believe will be impactful for purification and separation in DSP?
Voloshin (3M): The acceleration of process technology innovation is key to enable the next generation of manufacturing processes for the biopharmaceutical industry; specifically, technology that reduces steps in the process and is more automated.
We will also see a transition to convectionally driven separation technologies, given they have been proven to be much faster than legacy technology.
Finally, we will see more portable integrated processes, which is specified as a scalable system together with the product. When you want to scale up or to scale out, you either clone the process or use defined rules to build a bigger version of itself. This is another paradigm where single-use technologies are key as the unit operations exist as scalable units of discrete building blocks that you can readily implement anywhere. If there is a sudden need to make a mass amount of that therapeutic, like in the instance of a pandemic, you can ship the process anywhere in the world with a suitable basic facility and implement it very quickly.
Felicity Thomas is senior editor of BioPharm International.