Integrating U.S. Biomanufacturing Infrastructure.Indd

COMMENTARY Integrating United States Biomanufacturing Across Vaccines and Therapeutics Krishanu Saha, PhD, University of Wisconsin-Madison; and Krishnendu Roy, PhD, Georgia Institute of Technology April 19, 2021 In 2021, as the majority of the world’s population ea- access is critically needed. In addition to supply chain gerly waits to receive safe and eff ective COVID-19 vac- and logistics, advances in the science, technology, and cines, factories worldwide are producing bits of the infrastructure for biomanufacturing (a scientifi c fi eld fo- vaccine components—mRNA, lipids, proteins, key re- cused on making various biological products effi cient- agents, and attenuated viruses—and then assembling ly, in high-quality, and at scale [1,2,3,4]), is necessary them into complete, ready-to-inject vaccines. This pro- to improve the supply, consistency, quality, cost, and cess has now gained signifi cant attention, not just for access of products to meet the current and future de- the speed at which the scientifi c community innovated mand worldwide. and developed multiple and hugely eff ective vaccines In light of these similarities, preparation for the for COVID-19, but also because of the massive short- world’s post-pandemic future should consider the falls in vaccine production, supply, and equitable dis- growth of the vaccine and advanced therapies fi elds tribution across the world. Also under scrutiny is the together. Recent scale-up and modernization of vac- level of government intervention that has been neces- cine biomanufacturing will have spillover eff ects for sary to accelerate vaccine production and distribution. CGTs, while much-needed future innovations and in- What is less recognized is that such inadequacies in vestments in CGT and ETO manufacturing will provide biomanufacturing and supply chain robustness are not surge and advanced manufacturing capacity for vac- just limited to vaccines. The problems are systemic, cines. While some CGTs are in development for infec- plaguing all emerging biologics-based therapies—from tious diseases like COVID-19, the primary targets of cell and gene therapies (CGTs), engineered tissues and CGTs are cancer, blood disorders, liver diseases, and organoids (ETOs), to next-generation vaccines. Similar numerous rare disorders [5]. Compared to communi- to the COVID-19 vaccines, thousands of patients are cable diseases, the conditions addressed by CGT are waiting for cell therapies to treat their cancer, many less cyclical or episodic, resulting in a more linear, pla- more are waiting for gene therapies to address their teauing, and predictable demand for CGT. As the need inherited disease, and only a privileged few can access for worldwide, immediate supply of a particular vac- these therapies. The lack of appropriate advanced cine wanes, a common, integrated biomanufacturing biomanufacturing and supply-chain infrastructure is infrastructure and framework could be used for both a key barrier for widespread and equitable access of advanced therapies and emerging vaccines. these emerging therapies and requires a fundamental Even before the COVID-19 pandemic, high demand change in national and global science policy. and short supply were common features of next-gen- Just as factories produce components of the CO- eration CGTs and vaccines. For example, there were VID-19 vaccines, factories also make the constituent year-long queues at biomanufacturing facilities to DNA, RNA, proteins, viruses, cells, and tissues for ad- make clinical-grade viral vectors from 2017 onwards vanced therapies. Short supply and delays in key re- [6]. The active ingredients in many CGTs also contain agents, especially during a pandemic and as demand RNAs, proteins, and viral vectors, as in vaccines (see increases rapidly, can stifl e the CGT, ETO, and emerg- Figure 1). Vectors (e.g., adenovirus) and lipids (e.g., ing vaccine fi elds. Similarly, distribution logistics of 1,2-distearoyl-sn-glycero-3-phosphocholine [DSPC]) these complex and temperature-sensitive therapeutics could carry therapeutic genes for gene therapy or en- deserve serious attention, and appropriate infrastruc- code antigens for vaccines. Plus, many of the plasmids, ture to ensure scalable, smooth, timely, and effi cient producer cell lines, cell-free systems, in vitro tran- Perspectives | Expert Voices in Health & Health Care COMMENTARY FIGURE 1 | Programmable Vector Platforms for Biomanufacturing Engineered CGTs and Vaccines SOURCE: Developed by authors. NOTE: Nucleic acid sequences encoding antigens from infectious diseases, therapeutic genes, or genome editing machinery could be synthesized by design and on demand to address various ailments. These components could be packaged with nanoparticle or viral delivery vectors as products themselves (e.g., ready-to-inject vaccines or gene therapies) or be utilized in biomanufacturing processes to generate customizable products (e.g., cell therapies or engineered tissues and organoids). scription enzymes, and recombinant proteins used in gency use authorizations in 2020 in the U.S. of vaccines biomanufacturing are common, as are the analytical from Moderna and Pfi zer-BioNTech (and perhaps No- instruments measuring these components [1,2,3,4]. vavax later in 2021), as well as the role that government Both CGTs and vaccines leverage advances in program- policies have played in ramping up vaccine production, mable biology by modifying the nucleic acids within the purchase, distribution, and administration, illustrate manufacturing process or product. Today’s processes this technology’s promise and capabilities. Many CGTs build on decades of steady innovation in gene synthe- currently in development can be customized to treat sis, genomic sequencing, genetic engineering, editing hundreds of rare diseases and cancers. However, de- genomes, and synthetic biology [7]. Overall, biomanu- spite multibillion-dollar markets with recent double- facturing processes for CGTs and vaccines use com- digit annual growth for both vaccines and CGTs, bio- mon knowledge, technologies, and workforce that are manufacturing eff orts remain siloed and balkanized, potentially applicable to both sectors. In addition, cur- mainly in the private sector within companies focused rent and future data science, artifi cial intelligence (AI), on either fi eld. Stronger connections across these two supply chain, and cyberinfrastructure innovations in fi elds—and with adjacent scientifi c, technological, clini- biomanufacturing can impact CGTs and vaccines alike. cal, infrastructure, and policy fi elds—would increase Customizable and modular platforms now provide resiliency and preparedness to meet the increasing unprecedented fl exibility to develop new vaccines for demand for these products. Specifi cally, additional evolving viruses and tailored therapeutics to treat dis- work in the following fi ve directions (see Figure 2) could parate disease targets across diverse populations. For build a more integrative approach to biomanufactur- example, BioNTech initially targeted cancer with its ing across vaccines and CGTs. technology platform and was able to pivot to COVID-19 vaccines in 2020. The rapid development and emer- Page 2 Published April 19, 2021 Integrating United States Biomanufacturing Infrastructure Across Vaccines and Therapeutics FIGURE 2 | Building an Integrative Approach to Biomanufacturing Across Vaccines and CGTs SOURCE: Developed by authors. NOTE: Concerted support to advance customizable vectors, fl exible manufacturing, data science, AI and cyberinfrastructure, data sharing and partnering across the public-private continuum, and workforce training would build a stronger biomanufacturing base. Priorities for Building an Integrative Approach standardization eff orts across both CGT and vaccine to Biomanufacturing product development is possible. Flexible Manufacturing Customizable Platforms At any point in time, disease burden can be highly The complexity of biological products relative to tradi- heterogeneous and local. Even within a population in tional small molecule drugs present multifaceted chal- a specifi c locale, disparities across race, ethnicity, and lenges for regulatory science, and therefore stringent socioeconomic status can lead to variable demands for regulatory oversight (or good manufacturing prac- diff erent vaccines and CGTs. Further, viral variants can tice) is required for biomanufactured products. For cluster in a region and sweep heterogeneously across example, a simple switch of vendors moving from a populations and geographies. A fl exible manufacturing bovine to a pig serum can change the sugars on the approach could help facilities quickly pivot from cen- surface of proteins and modify the immune response tralized manufacturing of a single product to regional to the product, thereby prompting additional regula- or point-of-care production of diff erent products. In tory scrutiny. Hence, drug master fi les on qualifi ed the United States, if the East and West Coasts surge tools, reagents, and vectors provide essential data in COVID-19 cases and lockdowns, facilities in the Mid- for sponsors to cross-reference in their applications west could ramp up production—and vice versa. Re- for emergency authorizations. Such an approach ulti- silience within this interconnected infrastructure could mately streamlines review by regulatory authorities of also be enhanced with fl exible biomanufacturing. A applications by sponsors, and there is a greater need key aspect of this emerging concept is a shift away for more

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