By Alexei Voloshin, Global Head of Bioprocess Science, 3M Biopharmaceutical Purification
Article Synopsis: Modern biotechnology has brought a revolution in improving the human condition around the world both in terms of quantity and quality. The rapid pace of innovation in biopharmaceutical treatments has enabled the treatment of life-threatening and life-changing conditions such as cancer, inflammation, and infectious disease. With this fast-moving, rapidly expanding biopharmaceutical treatment space, comes increasingly complicated and advanced molecules and multi-molecular assemblies. Designing and building systems that can manufacture various modalities rapidly and efficiently is a challenge forcing the industry to re-examine the past and current strategies, technologies, and execution. Bioprocess engineers are thus challenged to consider all technologies together rather than individually, specifically within a holistic platform evaluation.
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Together with this fast-moving, rapidly expanding biopharmaceutical treatment space, comes increasingly complicated and advanced molecules and multi-molecular assemblies, often call “modalities”, that make up a biopharmaceutical drug. Designing and building systems that can manufacture various modalities rapidly and efficiently at the quantity and quality required at every stage of biotherapeutic development is a challenge forcing the industry to re-examine the past and current strategies, technologies, and execution.
Over the past 30 years, the industry has focused on the development of several generations of manufacturing platforms for, almost exclusively, recombinant proteins as therapeutic treatments. Constructing such platforms successfully required understanding the candidate pipeline and patient population size, as well as holistic analysis of manufacturing technologies and the human talent pool charged with the platform’s construction and operation. Holistic improvement of manufacturing platforms requires recognizing the interdependencies between each of the above elements to enable ever more advanced optimization of all parts of the process.
Cell culture and expression of a biopharmaceutical involves an upstream part of the process, where the product is synthesized by the cells. Developing an upstream process that produces more product per volume of the cell culture minimizes system footprint, water, energy, and nutrient resources, but also results in high contaminant levels that must be removed during the purification, or downstream, process that follows.
Some of these contaminants, such as genomic DNA of cells, do not degrade as the cells change generations in the bioreactor and, thus, accumulate. While these impurities did not present a significant problem in the early generation of processes, the current intensified cell-culture processes produce a significant amount of them.
Since the regulatory compliance standards have increased over the years, the levels of permissible impurities in a final drug product have decreased as well. So, the higher starting level of contaminants and higher purity requirements has necessitated and pushed advancement in downstream process strategy and technology.
As a result, several advancements in downstream processing technologies have been developed including novel chemistries for separations, novel formats, such as single-use encapsulated solutions, and novel materials that offer favorable physical properties during purifications. Another aspect that is being scrutinized is the interdependencies of unit operations that make up the manufacturing process. Bioprocess engineers are challenged to consider all technologies together rather than individually, specifically within a holistic platform evaluation.
Why is Holistic Platform Evaluation Difficult?
Holistic platform evaluation in biopharmaceutical manufacturing involves a comprehensive assessment of all aspects of a manufacturing platform, including equipment, processes, facilities, and personnel, to optimize the production of high-quality biopharmaceuticals. Company culture and organizational structure are, perhaps, the two most important elements that enable such evaluations on a regular and structured basis. While the development and optimization of each element of the process require a skilled multi-disciplinary team, an effective global superstructure is necessary to allow and encourage effective communication between teams, setting overall goals for the platform, and breaking down silos when necessary.
If one considers our previous discussion regarding intensification of upstream and downstream processes for biopharmaceutical manufacturing, one can observe that searching for higher titers to accommodate for the intensification of the upstream process may produce a contaminant background incompatible with downstream platforms in terms of performance or facility fit. The downstream process must then accommodate and overcome such issues. Without seamless collaboration and a holistic approach to platform development, the downstream team loses its ability to be efficient, avoid mistakes, and advance processes and molecules quickly from discovery to clinic.
Fortunately, more organizations are recognizing this link and are creating integrated approaches to platform evaluation both in terms of technology and in terms of organizational structure. The result is significantly more interaction between teams where people ask, “If we change a critical parameter in our part of the process, how will it affect your part of the process?” This evolution from local problem-solving to critical thinking at the holistic level leads to the development of upstream technology designed to alleviate bottlenecks downstream.
As the variety of biopharmaceutical modalities continues to grow rapidly, the current manufacturing technology has not caught up with the complexities of molecular design.
Consider the basic problems of drug discovery and manufacturing: during candidate discovery, high throughput screening of product candidates is the key goal, allowing researchers to screen an enormous number of molecules quickly. That process has to fit into a scientific laboratory workflow that has different needs and requirements from scale-up to clinical manufacturing.
As a drug candidate proceeds along its development path, the manufacturing process evolves with it, as does the manufacturing platform established by the organization. Specifically, at each stage of candidate development, purity, scalability, safety, and portability must satisfy both internal and external requirements, such as those set by regulatory agencies. For example, what is acceptable for early toxicology studies may not be acceptable for Phase I clinical study or for investigational new drug (IND) FDA filing.
Building a Holistic Bio-Process Platform Evaluation for Efficiency
Establishing a common vision is a necessity for breakthrough innovation in a complex regulated bio-process environment. If you want to implement a novel bio-processing solution, you must ensure from the start that all stakeholders share a vision and that no obvious show-stopping roadblocks are present. Then, when the product launches, everybody evaluates the solution implemented and what value the new approach brings to the end-user, as well as ensuring all necessary performance, regulatory, and commercial requirements are met.
The second tenet to building out a holistic approach is technology innovation and commercialization. When a novel technology paradigm is created, it’s not immediately capable of doing everything you want to. As one begins to understand the technology and how it brings value to your customers, you are now able to bring that value commercially in the form of a product and a solution. The first commercial implementation of a new technology is primarily a compromise of what one can do and maximization of the value for the end user. As you and your customers learn the technology’s capabilities and how to control it better in the commercial sphere, you create follow-on solutions that solve even more complex challenges.
Deployment of innovative and disruptive solutions into a bio-processing platform is only the start of the journey. A truly innovative technology changes the performance metrics of the entire process rather than merely solving a problem unique to a certain unit operation. Recognizing these global process changes and learning how to take full advantage of them requires close collaboration between the biopharma manufacturer and the technology solution provider.
One good example of such technology and such a journey is the development and deployment of fiber chromatography (sometimes call non-woven chromatography) systems in bio-processes in recent years. Unlike filtration or traditional porous bead-based chromatography, fiber systems are capable of separating both soluble and insoluble contaminants over the entire range of sizes relevant in the biopharma world. In effect, the fiber-based separation paradigm does away with the divide between the filtration of insoluble particles and chromatography of soluble particles, to create a concept of “chromatography of everything.” This change in process has a profound impact on how a purification platform can be structured – allowing fewer purification steps that are more precise increases the productivity of the process by increasing the final yield of the purified product in each manufacturing batch.
In addition to making the process more efficient, fiber chromatographic technology can make the process more scalable. Because chromatography scales predictably, using a chromatographic solution at clarification at one scale, predicts its performance at any other scale with a level of accuracy that one expects from a high-fidelity separation technology. For example, an engineer designing a 2000-liter clinical manufacturing process expects the same scaling and quality of clarification as a discovery scientist from a 15-milliliter robotized high-throughput reactor farm. This is a very different outcome compared to a legacy approach where discovery, preclinical, clinical, and commercial manufacturing utilize different approaches to clarification that, very often, do not scale between each other. Not having to reinvent a big part of the process at each major part of the drug candidate’s journey gets a therapeutic to the clinic and the patients faster.
Final Thoughts
Modern biotechnology is a rapidly changing field driven by innovation. Innovation necessitates change and changing the mindset and expectations of the process development organization with respect to new possibilities is an exciting journey, but also one that requires careful experimentation, curiosity, championship, and cross-functional communication.
About The Author
Alexei Voloshin is the Global Head of Bioprocess Science at 3M Separation and Purification Sciences Division. He is responsible for product application strategy and manages technology projects, collaborations, and alliances around the globe. Alexei brings more than 15 years of experience in commercial bioprocess development, as well as technical, operational, and business knowledge in the biotechnology space. Alexei earned his Ph.D. in chemical engineering from Stanford University and Bachelor of Chemical Engineering and B.S. in computer science from the University of Minnesota Twin Cities.
