Advances in medical treatment in recent years has led to a marked increase in the use of biologics—complex macromolecular therapeutics produced by living sources.
These powerful therapies, such as Avastin, Humira, Remicade and Enbrel, can be life-changing for the treatment of cancer, arthritis, Crohn’s disease, and other major diseases. But like any drug, biologics come with big pluses and some drawbacks.
Making biologics is significantly more complex than making small molecule drugs. Aspirin, for example, is made up of just 21 atoms in contrast to large biologic drugs, which can be composed of more than 1,300 amino acids and can be as heavy as 150,000 g/mol. The complexity of biologic manufacturing raises serious barriers for innovation in the biopharmaceutical industry. And while there is no magic pill for overcoming the hurdles involved, it is clear that gaining a deeper physical and chemical understanding of how basic molecules work and interact will undoubtedly help move the industry forward.
A two-fold challenge
Today’s biotherapeutics have evolved far beyond simple peptides and now include a wide array of complex molecules, such as globular proteins, antibodies, antibody-drug conjugates, and other modalities. Moreover, these molecules need to be formulated in a variety of different situations, ranging from low to high concentration liquid formulations to lyophilized formulations to various manufacturing unit operations.
As a result, one of the major hurdles we encounter is the inherent instability of large molecules due to degradation processes, such as aggregation, oxidation, hydrolysis, and deamidation. Even the slightest change in the manufacturing process can impact the quality, safety or efficacy of the final product. Addressing these issues requires understanding not only the complexity of the biotherapeutics themselves, but also the mechanisms of instability and any potential methods to maintain molecular structure. Ultimately, this foundational knowledge can be used to create molecules that will interact with other molecules in ways that are desired, consistent, and predictable. This in turn will make the drugs more stable, so that they can be used in pharmaceuticals in ways that are much more convenient and helpful for patients.
Beyond trial and error
Right now, the biopharmaceutical industry relies primarily on rules of thumb when it comes to drug formulation. We rely on experiments to discover how molecules interact, and testing to make sure the molecules interact with what we want them to and don’t interact with what we don’t want them to react to. There’s a lot of experimenting that takes place to see what how drugs and the mechanisms for manufacturing take shape.
Our goal is to move the industry toward a more rational design approach. But again, systems are only becoming more complex. What’s more, drug companies that used to only manufacture either small molecule drugs or biologics have now started to pursue both. The result is more people have less background in large molecule drugs. These trends combined only increase the need for additional education on basic principles. Making the formulization of biologics more mechanistic as early as possible in the design process to eliminate experimental protocols is critical to ongoing future progress.
Machine learning and artificial intelligence will also be helpful to move the needle. But the challenge is to employ these methods with limited data. Even when more data becomes available, the successful application of these methods will necessitate detailed molecular-level understanding of these complex systems based on understanding their chemistry and biology.
A three-pronged approach
What can biopharmaceutical scientists, engineers and other professionals in the field do to drive innovation and progress? First, they can think mechanistically about the molecules and systems that their working with. Remember, at its most fundamental level, the field of biopharmaceuticals will always be about complex systems that incorporate not only molecules, but the larger structures for which the molecules form parts. Given all the ways that the field of biopharmaceuticals has changed, it’s important to keep in mind “the fundamentals,” incorporating what is known about the physical, chemical, and biological properties of systems as experimental protocols to design, formulate, and stabilize a product are developed.
Next, think about the systems holistically. Understand that whenever a change is made to address one problem—which, with regard to molecular instability, could be a problem with deamidation, aggregation, viscosity, or something else entirely—it is invariably going to cause changes in other factors. That is why systems thinking is absolutely critical; we need to take a systems approach to the formulation and its components.
Lastly, zoom out even farther and consider the entire process of biopharmaceuticals from discovery to development to manufacturing. Remember that formulation and stabilization are part of a much larger process; they are not separate, standalone considerations. Start to think about formulation and stabilization during the discovery phase. That way possible issues can be identified, such as routes of instability, early on and rational and mechanistic approaches to resolve them can be determined. Designing molecules with the right formulation properties can significantly streamline development and manufacturing. In addition, often considerable resources are expended in the development phase to stabilize molecules that could have been stabilized earlier at less cost.
Going forward, gaining a better understanding of the fundamentals of stabilization of biotherapeutics or biologics will have an ever-widening impact on the industry in terms of finding solutions to various problems that exist and will continue to emerge as these drugs become more sophisticated. Acquiring this fundamental knowledge will enable biopharmaceutical scientists and engineers to develop new cutting-edge approaches and techniques for manufacturing a variety of modalities from antibodies to globular proteins, from peptides to vaccines and antibody-drug conjugates, not to mention cell and gene therapies. This in turn will help unleash the potential of biologics and enable broader access and use to further advance the treatment of illnesses and other conditions worldwide.
About Bernhardt L. Trout
Bernhardt L. Trout is a Professor of Chemical Engineering at MIT and instructor of the MIT Professional Education course, Formulation and Stabilization of Biotherapeutics. He is currently Director of the Novartis-MIT Center for Continuous Manufacturing Co-Chair of the Singapore-MIT Alliance Program on Chemical and Pharmaceutical Engineering. Professor Trout’s research focuses on molecular engineering, specifically the development and application of both computational and experimental molecular-based methods to engineering pharmaceutical formulations and processes with unprecedented specificity. He has published over 150 papers and currently has 21 patent applications.