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-

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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 edit- ing 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 vac- cines 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-

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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 cyber- infrastructure, 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 common and customizable tools, reagents, from the traditional “process is the product” concept and vectors for the modular, programmable platforms and toward a reliance on product critical quality attri- used in vaccines and CGT biomanufacturing (see Figure butes (CQAs) (i.e., the range of specifi c product proper- 1). Eff orts like Platform Vector Gene Therapy [6], Co- ties within which the product performs in a predictive alition for Epidemic Preparedness Innovations’ (CEPI) manner in a certain disease and patient). This shift, platform technologies for Disease X, and proprietary combined with “intelligent automation” where sensors platforms at Moderna [8] provide some examples, and and in-process or at-line measurements of quality at- further integration of technology, best-practices, and tributes allow one to control process parameters and

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keep CGT or vaccine products within a defi ned qual- the Marcus Center for Therapeutic Cell Characteriza- ity, will allow for reproducible and predictive outcome tion and Manufacturing (MC3M). For example, big data in patients and reduce cost and need for large-scale analytics and AI tools are being used to understand production. Also, the logistics of supply chain robust- and identify CQAs and the corresponding critical pro- ness and storage, shipping, and delivery of raw ma- cess parameters that control those CQAs during man- terials and fi nished products are crucial since delays ufacturing. Similarly, AI tools are being used to fi nd in any part of this supply chain can propagate [9] and correlative biomarkers that are predictive of patient eventually lead to problematic consequences in delay- outcomes for a certain product and disease, which can ing vaccinations or treatment. Modeling an integrative then be controlled and monitored during manufactur- biomanufacturing system from needle to needle while ing to yield consistent, high-quality products [13]. Such optimizing quality, scale, cost, resources, and supply approaches, combined with supply chain and logistics could reduce the frequency of batch failures, anticipate modeling (i.e., an end-to-end data-driven manufactur- and eliminate bottlenecks and weak points, and deliver ing infrastructure) could be transformative to both the products more effi ciently, as recently demonstrated in CGT and vaccine fi elds. CGT manufacturing [10]. Rapid vaccine response ef- forts at CEPI and Gingko Bioworks are examples of Data Sharing and Partnering Across the Public-Pri- fl exible manufacturing approaches that support the vate Continuum production of many diff erent types of products from Biomanufactured products can be quintessential common source materials. public goods (e.g., vaccines) or the ultimate bespoke therapy tailored for an ultrarare patient (e.g., “n of 1” Data Science, AI, and Cyberinfrastructure therapies [14]). Incentives that enable fl exibility and A fragmented digital and cyberinfrastructure is a poor interconnection to easily navigate these markets and way to track health outcomes for an increasingly mo- business models would lead to a public-private infra- bile population. For CGT, long-term monitoring for ad- structure that responds rapidly to variable demands verse events is already required by regulatory authori- for both types of products. CEPI and Catapult in the ties—in some cases, up to 15 years—since adverse United Kingdom, with the Centre for Commercializa- events like cancer from genetic modifi cations could tion of Regenerative Medicine, the National Institute take years to develop after treatment [11]. Regulato- for Innovation in Manufacturing Biopharmaceuticals, ry agencies also recommend extended monitoring of the Advanced Regenerative Manufacturing Institute, vaccinated individuals over months to years. With an CMaT, and MC3M in North America, have all gained sig- integrated data infrastructure across biomanufactur- nifi cant momentum. These eff orts could take further ing and clinical outcomes, data science and AI concepts advantage of a sharing and collaborative spirit shown could provide new insights into how to improve pro- in the scientifi c community in 2020, as demonstrated in cesses, as formulation diff erences and dosing could the surge in the circulation of preprints and sequences be correlated to patient outcomes in electronic health [15]. records and long-term follow up studies [18]. Intense New public-private partnerships are also needed to pressures on biomanufacturing during emergencies keep the world prepared and stocked, especially to can cause inadvertent changes in formulations, as seen develop the next generation of data-driven biomanu- in the Oxford/AstraZeneca COVID-19 vaccine trials [12]. facturing infrastructure that combines fundamental re- Data from these studies and participants should not search with technology development in fl exible manu- be entirely discarded but should be used within a digi- facturing, data science, supply chain optimization, and tal infrastructure to inform future studies. The UK Bio- feedback-driven biomanufacturing, as discussed ear- bank and UC Health system are examples of integrated lier. The US Strategic National Stockpile of therapeutics clinical data infrastructures for extended, longitudinal [16] in the event of a nuclear or chemical attack is an monitoring. These and many similar eff orts currently example of partnering across this public-private divide. lack a strong integration of manufacturing information Similar preparedness and urgency could address less on the products administered to patients, although punctuated but nonetheless urgent demands for CGTs this challenge is being tackled in budding eff orts in the and vaccines. Preordering products and stockpiling is United States like the NSF Engineering Research Cen- part of a broader strategy to provide increased access ter for Cell Manufacturing Technologies (CMaT) and to capital, knowledge, and intellectual property by state

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and federal governments. These actions are all neces- fi elds to meet today’s needs, and in due course, the sary, and given suffi cient political will, they could have post-pandemic world. further energy if organized under a large eff ort like the Manhattan Project or moonshot solution for biomanu- References facturing. In the United States, the Cancer Moonshot 1. Roh, K.-H., R. M. Nerem, and K. Roy. 2016. Bioman- Initiative is an antecedent of future accelerated eff orts, ufacturing of Therapeutic Cells: State of the Art, potentially within a recently-proposed Advanced Re- Current Challenges, and Future Perspectives. An- search Projects Agency-Health (ARPA-H) [17]. nual Review of Chemical and Biomolecular Engineer- ing 7:455-478. https://doi.org/10.1146/annurev- Workforce Training chembioeng-080615-033559. Finally, in addition to traditional capital investment, 2. Aijaz, A., M. Li, D. Smith, D. Khong, C. LeBlon, O. the biomanufacturing fi eld needs investment in hu- S. Fenton, R. M. Olabisi, S. Libutti, J. Tischfi eld, M. man capital. Besides keeping up with the latest biol- V. Maus, R. Deans, R. N. Barcia, D. G. Anderson, J. ogy and engineering, the technicians and leadership Ritz, R. Preti, and B. Parekkadan. 2018. Biomanu- in biomanufacturing need to understand and use facturing for clinically advanced cell therapies. Na- new advances in automation and data science [1]. The ture Biomedical Engineering 2:362-376. https://doi. biomanufacturing workforce has now been pressure org/10.1038/s41551-018-0246-6. tested, as they have kept operations up and running 3. Bundy, B. C., J. P. Hunt, M. C. Jewett, J. R. Swartz, despite lockdowns and social distancing requirements D. W. Wood, D. D. Frey, and G. Rao. 2018. Cell-free during the COVID-19 pandemic. For example, many biomanufacturing. Current Opinion in Chemical En- biomanufacturing organizations now have an updated gineering 22:177-183. https://doi.org/10.1016/j.co- list of essential people who have established routines che.2018.10.003. and protocols to keep biomanufacturing facilities op- 4. Kis, K., R. Shattock, N. Shah, and C. Kontorav- erating in the event of another pandemic-related lock- di. 2019. Emerging Technologies for Low-Cost, down. The professional development of these people Rapid Vaccine Manufacture. Biotechnology Jour- should be nurtured, so that the wisdom of working nal 14(1):e1800376. https://doi.org/10.1002/ through a pandemic is preserved within the workforce. biot.201800376. In addition to a national stockpile of biomanufac- 5. Haddock, R., S. Lin-Gibson, N. Lumelsky, R. Mc- tured vaccines or therapeutics, a “national guard” for Farland, K. Roy, K. Saha, J. Zhang, and C. Zylber- biomanufacturing could be just as important. Such a berg. 2017. Manufacturing Cell Therapies: The workforce needs to come not just from four-year col- Paradigm Shift in Health Care of This Century. NAM leges and universities and post-graduate trainees, but Perspectives. Discussion Paper. National Acad- also, importantly, from the nation’s two-year technical emy of Medicine, Washington, DC. https://doi. and community colleges, which are the primary sup- org/10.31478/201706c. plier of manufacturing technicians across all indus- 6. Brooks, P. J., E. A. Ottinger, D. Portero, R. M. Lo- tries. In April 2020, students in the life sciences quickly mash, A. Alimardanov, P. Terse, X. Xu, R. J. Chandler, organized to establish a COVID-19 National Scientist J. Geist Hauserman, E. Esposito, C. G. Bönnemann, Volunteer Database to fi ll in during shortages at facili- C. P. Venditti, C. P. Austin, A. Pariser, and D. C. Lo. ties, and such eff orts building on a public service ethos 2020. The Platform Vector Gene Therapies Proj- could be given more support to increase our prepared- ect: Increasing the Effi ciency of Adeno-Associated ness. Virus Gene Therapy Clinical Trial Startup. Human Conclusion Gene Therapy 31(19-20):1034-1042. https://doi. org/10.1089/hum.2020.259. In summary, the COVID-19 pandemic is a portal into 7. Tan, X., J. H. Letendre, J. J. Collins, and W. W. the current state of our biomanufacturing infrastruc- Wong. 2021. Synthetic biology in the clinic: engi- ture—illuminating opportunities to strategically invest neering vaccines, diagnostics, and therapeutics. for greater preparedness. As the demand for vaccines Cell 184(4):881-898. https://doi.org/10.1016/j. and therapeutics increases, a concomitant strengthen- cell.2021.01.017. ing of biomanufacturing infrastructure requires new 8. Widge, A. T., N. G. Rouphael, L. A. Jackson, E. J. An- cross-cutting integration across the vaccines and CGT derson, P. C. Roberts, M. Makhene, J. D. Chappell,

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This material is partially based upon work supported by the National Science Foundation under Grant No. EEC-1648035. The views expressed in this paper are those of the authors and not necessarily of the Nation- al Science Foundation.

Confl ict-of-Interest Disclosures Dr. Saha reports sponsored research support from Spotlight Therapeutics. Dr. Roy reports receiving grants from the National Science Foundation; personal fees from Terumo BCT, Alpha Sights, Merck, Clearview Healthcare Partners, and LEK Consulting; and holding two pending patent applications.

Coorespondence Questions or comments about this manuscript should be directed to Krishanu Saha at [email protected] and Krishnendu Roy at [email protected].

Disclaimer The views expressed in this paper are those of the au- thor and not necessarily of the author’s organizations, the National Academy of Medicine (NAM), or the Na- tional Academies of Sciences, Engineering, and Medi- cine (the National Academies). The paper is intended to help inform and stimulate discussion. It is not a report of the NAM or the National Academies. Copyright by the National Academy of Sciences. All rights reserved.

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