Download PDF Summer Bridge on Advanced Biomanufacturing for Medicines June 16, 2025 Volume 55 Issue 2 This issue of The Bridge features cutting-edge perspectives on the rapid progress and innovation in advanced biomanufacturing for medicines. Guest Editors' Introduction: Advanced Biomanufacturing for Medicines Monday, June 16, 2025 Author: Barry C. Buckland and Kelvin H. Lee In the fall of 2013, Professors Phillip A. Sharp and Robert Langer guest edited an issue of The Bridge on the theme of the Convergence of Engineering and the Life Sciences. The collection forecast the breadth in manufacturing approaches, capabilities, and innovation that would define the decade that followed. Since that pivotal issue, the advanced biomanufacturing community has developed practical approaches to manufacture a diverse range of medicines across a range of scales while maintaining high quality—marking a period of remarkable advancement in medicine. An emerging reality highlighted in the 2013 issue of The Bridge that remains true today is the beneficial synergy among academic institutions, small and large biopharmaceutical companies, and government agencies. Partnerships across these sectors have improved market access to safe, efficacious, high-quality, robustly manufactured medicines that lead to positive patient outcomes. Another residual theme is the multidisciplinary contributions from engineers working with biologists and biochemists. For a process engineer or manufacturing expert, biological research presents a constant reminder of the urgency for—and remarkable opportunity in—innovation. For manufacturing, this connection is critical for developing analytical methods to fully characterize and define both intermediates and the final product. Currently, we are at an inflection point with a sudden increase in the different modalities used to treat disease. Advances in biomanufacturing are needed to help individuals benefit from these new medicines. Success will rely not only on having a safe and efficacious medicine, but also on having a way to scale up, or scale out, the consistent manufacturing of that medicine while maintaining the quality of the product. Innovative biomanufacturing approaches are being developed all the time across a range of applications, including medicine, but many manufacturing technology innovations come from academia or small companies. De-risking those technologies so that they can be adopted to make medicines can be a complicated process, requiring a broad range of stakeholder input and expertise from academia, industry, and government. The Manufacturing USA program was established in 2014 to address this need. Convening diverse stakeholders for precompetitive work and advancing manufacturing technologies, manufacturing USA aims to increase US advanced manufacturing competitiveness in today’s global environment. The 18 Manufacturing USA institutes each have a primary agency sponsor: the Department of Defense, the Department of Energy, or the Department of Commerce. Three have a biotechnology focus: Bioindustrial Manufacturing and Design Ecosystem (BioMADE), National Institute for Innovation in Manufacturing of Biopharmaceuticals (NIIMBL), and BioFabUSA. Several focus on adjacent technology spaces relevant to the biomanufacturing industry, Manufacturing x Digital, Collaborative Ecosystems for Smart Manufacturing Innovation Institute, and Advanced Robotics for Manufacturing Institute, among others. We serve in leadership roles at one of these institutes, NIIMBL. We are fortunate to see firsthand, and in real time, the benefits of precompetitive collaboration towards advancing biomanufacturing capabilities for certain kinds of medicines and medical countermeasures. Incredible advances in biology have led to a much better understanding of many diseases. Our community has been challenged to develop, understand, and adopt new manufacturing approaches to convert these advances into new medicines, heralding an era where medicines are invented but also manufactured in the United States, thereby reducing our reliance on competitor nations for access to medicines and increasing our resilience and economic security. Both are important goals recently outlined in the final report issued by the National Security Commission on Emerging Biotechnology.1 Both were also articulated in a 2020 Consensus Study on Safeguarding the Bioeconomy released by the National Academies of Sciences, Engineering, and Medicine.2 Whereas in 2013, when the issue of The Bridge guest edited by Sharp and Langer was published, biotechnology was used primarily to manufacture antibiotics, vaccines, and recombinant proteins, today it is used to make everything from materials for the manufacturing process to products including multispecific proteins, gene therapies, antibody drug conjugates, and cell therapies. This issue of The Bridge is a timely follow-up to the 2013 issue, this time focusing on the topic of Advanced Biomanufacturing for Medicines, which integrates the theme of biologists working with engineers and echoes that earlier issue through the theme of collaboration across sectors. In celebration of the fact that a remarkably successful community has been built, we chose contributors to this 2025 edition that represent industry, government, and academia. Chris Love summarizes some of the unique manufacturing challenges of biopharmaceuticals in comparison with other industries. Because biopharmaceuticals generally have smaller production volumes (low metric tons or smaller) and are high-value products, different drivers exist in the industry compared to chemical manufacturing, which is characterized by high-volume production (millions of metric tons per year) for generally lower-value products. Love outlines a range of innovations, emphasizing in many cases the opportunity in using different host organisms. Further development and partnership across academia, start-ups with innovative new technologies, industry, and regulatory agencies can begin to realize a new paradigm to provide broad access to these medicines and the ability to make them. Love emphasizes urgency and cautions that failure to invest with haste in ground-breaking new biomanufacturing technologies so as to establish a distributed, resilient base could bring sobering consequences for the country. Paul Collins sees hope in the proliferation of approaches for breakthrough new medicines such as peptides, oligonucleotides, and other gene delivery approaches. Carrier molecules such as lipid nanoparticles have been designed for the purpose of delivering these new molecules to their intended target. Concurrent with the proliferation of these new treatment modalities and delivery vehicles is a new creativity in how these might be combined for patient benefit. Future conjugate structures could include various targeting structures with any number of linked payloads. Can the entire array of creative new potential molecular entities be accommodated by existing platforms? What is the value of new versus retrofit? To what extent should new platform development be encouraged in a pre-competitive collaboration? The central role that analytics and the establishment of standards play in biopharmaceuticals is described by Katharina Yandrofski, Megan Cleveland, Zvi Kelman, Mike Tarlov, and John Marino from the National Institute of Standards and Technology (NIST). In this piece, the NIST team focuses on the manufacture and release of antibodies, currently the largest and most successful biologic platform. By extensively characterizing a reference material and at the same time providing a sample, the NIST team made it possible for many groups to participate in the development of improved analytical methods and better understand the clinical impacts. The resulting program, based on a reference material known as NISTmAb along with a cell line to express the antibody known as cNISTmAb, has had a significant impact on progress in antibody manufacturing and provides a widely available, commonly understood approach to analytical measurements that helps ensure high-quality products are consistently made. The contribution by Chris Williams, Eric Hacherl, Tim Charlebois, Erik Barton, Stephen Kaminsky, Brenna Kelley-Clarke, Angie Snell Bennett, Marco Thomann, and Anastasia Yemelyanova makes the case for an innovative approach to treating rare diseases. The significant number of rare diseases that affect small patient populations could, in theory, be treated by a single dose of a gene therapy. For small companies and universities, the cost of developing a manufacturing process to make clinical-grade treatments is high, yet for large companies the market for any resulting product is small. This article describes a promising approach to solving this issue in the design of a platform to support a decentralized user base, potentially accommodating hundreds or even thousands of user applications. Platform services will prioritize growth and maturity in digital resources, data aggregation, and critical starting-material availability. The platform is intended to be compatible with existing industrial infrastructure and thus will remain agnostic to competing product lines of non-critical equipment and materials. This approach fosters sustainable and scalable development, reducing the financial and logistical burdens of large capital projects and extensive administrative overhead. The contribution by Melanie Tomczak and Penny Norquist from the BioMADE Manufacturing USA institute describes three example approaches that rely on bioindustrial manufacturing to make critical products. The BioMADE institute advocates for the use of American-grown crops (e.g., corn, soybeans, and sugar beets) to produce everyday items as well as more specialized products. In this piece, Tomczak and Norquist describe approaches to manufacture SARS-CoV-2 antigens using different cell hosts and to manufacture vaccine adjuvants such as squalene and saponins that can be difficult to source and are now manufactured microbially in large quantities. The piece by Misti Ushio and Barry Buckland is a retrospective study of one of the most important medicines ever developed: penicillin. The original development of penicillin in the 1940s is an excellent example of a successful government, academic, and industry consortium. This gave birth to the widespread and transformative use of antibiotics. Until the late 1970s, leadership and capacity of this manufacturing infrastructure operated in the United States, but since then, this capability has been outsourced or migrated offshore. As a result, little microbial fermentation capacity remains available for manufacturing antibiotics in the United States or Western Europe. At the same time, antibiotics continue to be incredibly effective against many infectious diseases. Over 200 million prescriptions were written in the United States in 2023 alone. This chapter illustrates the need for a national policy for the supply of critical medicines such as antibiotics and, in the promising future, for antibodies. It also illustrates the benefit and urgency for investing in improved methods for manufacture using tools such as synthetic biology and continuous culture. Synthetic biology has played a central role in the discovery of the current portfolio of biologically made medicines. Mruthula Rammohan, Akash Vaidya, Spencer Grissom, Rachel Silvestri, Christopher Pirner, Kevin Solomon, and Mark Blenner describe the impact of continued progress in synthetic biology as a way to address biopharmaceutical manufacturing challenges. For example, these approaches can help with the manufacture of bispecific antibodies at high purity, messenger ribonucleic acid manufacturing, and with the targeting of recombinant adeno-associated viral vectors toward specific tissue types. The authors describe the use of continuous cultivation to better understand both drivers of phenotypic variation and the synthetic circuits that control culture stability. They suggest the benefits of genome reduction to remove sources of instability. Synthetic biology is no longer restricted to the natural protein building blocks. Recent decades have seen tremendous strides in genetic code expansion, enabling the incorporation of non-canonical amino acids into full-length proteins. This has created new manufacturing challenges as described in the chapter by Collins. Collectively, these pieces demonstrate the significant impact of advanced biomanufacturing developments and innovations on today’s world and our country’s health and economy. If the United States is to maintain its competitiveness and resiliency, then creating and nurturing rapid development and adoption of advanced biomanufacturing innovations for life-altering and life-saving medicines is vital. The proof is in the pudding. During the past 30 years, our nation has experienced the remarkable growth of the biotechnology industry, resulting in better health and the creation of significant value through improved medicines for devastating diseases, including cancer, infectious disease, and autoimmune disorders. Given the multitude of developments in progress, we are excited for the future. Acknowledgments This work was funded in part by support from the US Department of Commerce, National Institute of Standards and Technology (70NANB21H086). 1 NSCEB [National Security Commission on Emerging Biotechnology]. 2025. Charting the Future of Biotechnology: An Action Plan for American Security and Prosperity. Online at https://www.biotech.senate.gov/final-report/chapters/. 2NASEM [National Academies of Sciences, Engineering, and Medicine]. 2020. Safeguarding the Bioeconomy. Washington, DC: The National Academies Press. About the Author:Barry C. Buckland is executive director at NIIMBL. Kelvin H. Lee is institute director at NIIMBL and Gore Professor of Chemical & Biomolecular Engineering at the University of Delaware.