24 August 2020
Rapid scale-up to billions of doses requires collaborative, all-out efforts by innovators, their manufacturing partners, and the entire supply chain.
The biopharmaceutical industry is working at unprecedented speed to develop and manufacture vaccines for the COVID-19 pandemic. Among the challenges of a pandemic is the need to scale up to billions of doses, at a larger scale than typically needed for vaccines, from raw materials all the way through to the materials for the containers for fill/finish.
Collaborative efforts to make a safe and effective vaccine against the novel coronavirus, SARS-CoV-2, are underway around the world. The timeline to develop, produce, and distribute an approved vaccine is being dramatically compressed, and companies are scaling up manufacturing “at risk,” making the vaccines before they have been approved. While pharmaceutical companies are bearing some of the risk, these efforts are being extensively funded by governments as well as non-profit organizations, such as the Coalition for Epidemic Preparedness Innovations (CEPI) foundation and Gavi, the Vaccine Alliance (GAVI). In the United States, the federal government’s Operation Warp Speed program—a partnership among the US Department of Health and Human Services (HHS), the Department of Defense (DoD), and others—is investing in vaccine development and manufacturing, fill/finish capacity, and in capacity for supply of vials, needles, and prefilled syringes. As of August 5, 2020, more than $6.5 billion had been designated to flow through HHS’s Biomedical Advanced Research and Development Authority (BARDA) for countermeasures and $3 billion for National Institute of Health (NIH) research (1).
Scaling up capacity
Production of the billions of doses needed will require manufacturing at multiple sites, and innovators and contract development and manufacturing organizations (CDMOs) are partnering to come up with all the capacity that will be needed globally. Manufacturers know that it is not only the equipment, facilities, and raw materials—although these are necessary and require planning ahead—but also the knowledge and the expertise to run the process. Technology transfer is, thus, a crucial piece.
Consultants at McKinsey note that tech transfer time for vaccines normally can take 18 to more than 30 months, with transfers to external sites taking even longer. They predict, however, that by employing best practices, the time can be shortened to 8–11 months, or even six months with regulatory flexibility (2). Indeed, the tech transfer process is already well underway at CDMOs.
Everyone is working at “pandemic speed,” says Andre Goerke, head of the planning and value chain management business unit at Lonza; Goerke also is the global project lead for Lonza’s efforts to make the active ingredient for Moderna’s mRNA vaccine. The overarching challenge is to do what needs to be done in this accelerated timeline, but the team is unified in making it happen, he explains. “So far, the most significant asset has been the excellent integration of the Lonza and Moderna teams into a single group working for a common target,” says Goerke.
Having adequate raw materials, building and staffing the facilities, and tech transfer are all keys to success. Flexible, modular facility designs allow manufacturers to adapt and move quickly. Goerke says Lonza’s Ibex facilities “have been set up with exactly this challenge in mind, to allow adaptation to manufacture different kinds of products. Adaptability allows us to cut construction time considerably compared to standard builds and gives the flexibility to install a broad range of manufacturing technology. In addition, we can plug into existing infrastructure, including services (gas, water waste, etc.) as well as analytics and quality labs.”
Emergent BioSolutions says that its flexible CDMO capacity deployment model can respond quickly to demand fluctuations. The company’s Bayview multi-suite facility in Baltimore, MD is designated by the US HHS as a Center for Innovation in Advanced Development and Manufacturing (CIADM) and is designed to leverage single-use technologies to manufacture product in large quantities during public health emergencies. The CIADM can accommodate various types of vaccine platforms that can be manufactured in parallel. Four independent suites allow products or customers to move in and out quickly, explains Dino Muzzin, senior vice-president of manufacturing operations at Emergent BioSolutions. Platform-based equipment at the facility allows flexibility and facilitates tech transfer, noted Richard W. Welch, vice-president of development services at Emergent BioSolutions, in a presentation at BIO (3). Additionally, the company is adding new capacity at its Rockville, MD, and Canton, MA sites and expediting an expansion of its Camden facility in Baltimore, MD.
Several types of vaccines are being developed and tested in the hopes that at least one, but possibly multiple vaccines and of different types, will be approved. The industry is counting on the advantages of “platform” technologies, with development and manufacturing processes that can use the same or similar systems and equipment, tailored for different vaccines. Such platforms allow more rapid development and scale up and, even prior to the current pandemic, were predicted to be useful for responding to an outbreak caused by a new pathogen.
Nucleic acid-based vaccines—based on messenger ribonucleic acid (mRNA) or on deoxyribonucleic acid (DNA)—are examples of platform technologies. Moderna, Pfizer/BioNTech, CureVac, CanSinoBio, and others are making progress using mRNA platforms, with mRNA formulated in a lipid nanoparticle delivery vehicle. Inovio and others are working on DNA-based vaccines. Although nucleic acid vaccines have been tested in clinical trials, for Zika and Middle East respiratory syndrome (MERS), for example, none have yet been approved for use.
Moderna’s vaccine candidate, mRNA-1273, is encapsulated in lipid nanoparticles, and it has progressed to Phase III clinical trials. Moderna is building up manufacturing capacity, partly through its CDMO partner, Lonza, which is adding manufacturing lines in New Hampshire and in Visp, Switzerland. In an interview in late July, Goerke reported that tech transfer for the first step of the process has started as planned, and that preparation was well underway at the Portsmouth, NH facilities, with batches for the first of three process steps (the mRNA step) to be produced in July 2020. “Fit-out of our Visp facility is ongoing. We envisage the start of operations in Visp by the end of 2020,” said Goerke.
“Lonza aims to replicate the facility, equipment, and data management principles developed by Moderna,” adds David Callaert, head of global strategic growth investments and engineering at Lonza. “We plan to further strengthen and pragmatically ensure reliable supply through intense collaboration with the technical teams of Moderna. The aim is to achieve short processing times with high throughput. Going digital and maximizing the use of disposable equipment are some of the key components necessary to achieve these goals.”
Another CDMO partner of Moderna, CordenPharma, will manufacture large-scale volumes of Moderna’s proprietary lipids needed to make the lipid nanoparticle excipients. A challenge is the need to quickly scale-up by a factor of several hundred times the initial scale, says Matthieu Giraud, director, global peptides, lipids and carbohydrates platform at CordenPharma International. “We have to optimize the process for large-scale manufacturing and, at the same time, transfer to our larger assets. In addition, the scales are so incredibly large that we have to leverage our entire CordenPharma network to ensure a sustainable supply chain,” he explains.
The company’s facilities in France, Switzerland, and the US are working on the project; at CordenPharma Colorado, unique high-pressure chromatography systems usually used for manufacturing peptides have been reallocated for purifying lipids. Although making Moderna’s proprietary lipid at large scale is new, Giraud notes that CordenPharma has a long history of large-scale production of standard lipids using its platform technology. CordenPharma’s sister company, Weylchem Innotec, has been able to provide key raw materials for lipid production, Giraud adds.
Quality of the lipids is crucial because of the high proportion of lipids in relation to the mRNA. “The quality of the lipids is known to affect the encapsulation efficiency, liposome internalization by cells, and efflux rate of encapsulated therapeutic agents, all of which have implications for drug delivery and formulation shelf life. It is essential to create a very well-controlled process when manufacturing lipids,” says Giraud.
CordenPharma is on track to meet Moderna’s aggressive timeline, and manufacturing has started at three sites, says Giraud. He points to close collaboration between the company’s facilities, and he says that a rigorous risk management process identified gaps early on, so that risks could be mitigated.
Pfizer and BioNTech are also making progress on their lipid nanoparticle mRNA-based vaccine candidate, BNT162; initial results from Phase I/II studies are positive, and the companies are planning a global Phase IIb/III trial (4). Acuitas Therapeutics is providing lipid nanoparticles for the vaccine. If the trials go well, Pfizer and BioNTech plan to seek regulatory approval or authorization as soon as October. Pfizer says it expects to manufacture 100 million doses by the end of 2020 and approximately 1.3 billion doses by the end of 2021. The US government placed an order for 100 million doses, and the UK government signed an agreement for 30 million doses, both pending regulatory authorization or approval (5). Pfizer says it is building inventory of existing products now to make room for vaccine production later. Additionally, according to a Reuters report, Pfizer plans to shift some of its existing drug manufacturing to CDMO partners so that it can prepare for manufacturing the vaccine candidate at three facilities in the US and one in Belgium (6).
CureVac in Germany is also working on an mRNA vaccine, CVnCoV, and Phase I clinical trials began in June 2020 in Germany and Belgium. The company has a proprietary RNAoptimizer platform, which includes an end-to-end, good manufacturing practice (GMP) manufacturing process designed for mRNA-based drugs. The company is expanding its GMP facility and completing construction of its fourth production site in Tübingen, Germany. The company said the facility has the capacity to potentially supply several hundred million doses per year, depending on the human dose defined in the clinical trials (7).
In addition to its large-scale production facilities, CureVac is developing a small-scale, portable manufacturing “facility” it calls The RNA Printer, which it envisions could be transported to outbreak regions or placed in hospitals. In early 2019, CEPI and CureVac announced a partnership to advance the automated equipment that can produce several grams of lipid nanoparticle-formulated mRNA, which could potentially be more than 100,000 doses, in a few weeks (8).
A challenge for distribution of mRNA-based vaccines is the need to keep them frozen. Inovio’s DNA-plasmid vaccine candidate, INO-4800, however, is stable at room temperature for more than a year and does not require being frozen in transport or storage, the company reports (9). Inovio announced positive interim Phase I results at the end of June and had hopes to begin Phase II/III over the summer. The company has a proprietary delivery device, the Cellectra 3PSP, that delivers the DNA-plasmid vaccine directly into the skin. The US DoD provided funding for large-scale manufacturing of the device, and Inovio says it has produced initial quantities at its San Diego, CA, facility and demonstrated that the manufacturing process could be transferred to contract manufacturers (10). An earlier version of the Cellectra has been used in clinical trials of Inovio’s DNA medicines.
Viral vector vaccines
Viral vector vaccines are another platform, which uses a live, attenuated virus as a vector or delivery vehicle for an antigen’s genetic code. A benefit of this type of platform is that the viral vectors are made with a standardized manufacturing process independent of the active part of the vaccine, noted CDMO Cobra Biologics (11).
Vaccines made with this type of platform from Merck, Johnson & Johnson, and CanSino Biologics have approvals for Ebola, and these companies are using their respective platforms for vaccine candidates against the novel coronavirus. China’s CanSinoBio’s viral vector vaccine for Ebola has been approved by China’s regulatory agency; the company’s vaccine candidate for the novel coronavirus uses adenovirus 5 (Ad5) and, as of August 9, 2020, was preparing to begin Phase III trials. Merck’s Ebola vaccine, approved by FDA in December 2019, uses an engineered vesicular stomatitis virus (VSV) as the viral vector; Merck currently is working on a VSV-based COVID-19 vaccine. In addition, Themis, which was acquired by Merck in June, has a platform technology that uses a measles vaccine vector.
The Janssen Pharmaceutical Companies of Johnson & Johnson (J&J) received European marketing authorization for their two-dose viral vector vaccine for Ebola on July 1, 2020 (12). The first dose of this approved vaccine uses Janssen’s AdVac viral vector platform, based on adenoviruses that are genetically modified, so they are non-replicating in humans. The AdVac platform is being used for the company’s investigational SARS-CoV-2 vaccine, Ad26.COV2-S, recombinant, which moved into Phase I/IIa first-in-human clinical trials in late July. J&J’s goal is to manufacture more than one billion doses, and it is scaling up manufacturing capacity globally. On August 5, 2020, the company announced that the US government, through BARDA, is committing more than $1 billion for large-scale US manufacturing and delivery of the vaccine following FDA approval or authorization (13). The company said its partnership with CDMO Emergent BioSolutions for drug substance, announced in April 2020, was “the first in a series of prospective global collaboration agreements designed to accelerate manufacturing” (14).
The University of Oxford and AstraZeneca’s novel coronavirus vaccine candidate (AZD1222) uses a recombinant adenovirus viral vector platform that has been used in experimental vaccines for Ebola and MERS. Phase II/III trials have started in the United Kingdom, Brazil, and South Africa, and are planned for the US, with more than $1 billion from BARDA for development, production, and delivery planned for fall 2020 (15). AstraZeneca has committed, so far, to more than two billion doses, in supply agreements with the UK, the US, Europe’s Inclusive Vaccines Alliance, the Coalition for Epidemic Preparedness, Gavi the Vaccine Alliance, and the Serum Institute of India (16).
Preparations for large-scale viral vector manufacturing capacity were picking up speed late in 2019 as the biopharmaceutical industry was beginning to address shortages due to the rapidly growing demand for viral vectors from the pipeline for cell and gene therapies and viral vaccines. Modular facilities and single-use systems are seen as one way to build capacity more quickly (17).
While vaccines based on mRNA, DNA, or viral vectors are still new, recombinant DNA vaccines made in cell-based bioprocesses are another technology that offers the potential for rapid scaleup and have been in use on the market for several years. For example, the Flublok Quadrivalent influenza vaccine, initially approved by FDA in 2013 and acquired by Sanofi Pasteur in 2018, uses a recombinant DNA technology that combines the target DNA sequence in a plasmid with a baculovirus (BV) DNA, which produces antigens in a host cell; the antigens are then collected and purified to be formulated in the vaccine. These cell-based processes are more easily controlled and scaled than the traditional egg-based influenza vaccine production method, thus the recombinant DNA technology had been recognized for its potential as a response to a pandemic.
In December 2019, Sanofi entered an agreement with BARDA to increase its domestic pandemic influenza vaccine production capabilities in Swiftwater, PA. And now Sanofi’s platform is being put to use for the COVID-19 pandemic; Sanofi and GlaxoSmithKline (GSK) are partnering to produce a vaccine candidate using Sanofi’s S-protein COVID-19 antigen and GSK’s adjuvant technology.
Novavax’ recombinant nanoparticle vaccine platform uses recombinant BV to infect Sf9 insect cells, which express the antigens that are then purified as multimeric nanoparticles. Although the company does not yet have an approved drug, the platform is used to make the company’s seasonal influenza vaccine candidate, NanoFlu, which received FDA fast track designation in January 2020. The platform is being used to make the company’s NVX-CoV2373 COVID-19 vaccine candidate, which is a stable, prefusion protein with Novavax’ proprietary Matrix M adjuvant.
Novavax received more than $1.6 billion from BARDA to manufacture NVX-CoV2373 and to stockpile raw materials needed for the Matrix M adjuvant (18). The company is working with Emergent Bio to manufacture both its NanoFlu seasonal influenza candidate and its COVID-19 candidate at Emergent’s Bayview, MD, facility.
Novavax also announced a manufacturing partnership with CDMO Fujifilm Diosynth Biotechnologies (FDB) to make the bulk drug substance for NVX-CoV2373, and FDB’s site in Morrisville, NC, began production in July (19). AGC Biologics was contracted to manufacture the Matrix M adjuvant to expand Novavax’ capacity.
China’s Sinovac is using an even more traditional technology of an inactivated vaccine for its novel coronavirus candidate, CoronaVac. The company is conducting Phase II trials in China and has been approved for Phase III clinical trials, which will be conducted in Brazil and Bangladesh. The company is building a commercial vaccine production plant that is expected to manufacture up to 100 million doses annually (20).
The finish line
The importance of fill/finish for vaccines is well known, and the supply chain is ramping up capacity for materials (including injection needles and the glass for vials) and for filling. CDMO capacity will be crucial in this stage, as well. Companies expanding capacity for fill/finish include Thermo Fisher Scientific; Emergent Bio, which received fundingfrom BARDA and is working with four vaccine innovator companies; and Catalent, which is ramping up to support Janssen, Moderna, AstraZeneca, and others (21).
While the world waits for the results of the clinical trials for vaccines to prevent COVID-19 and, hopefully, regulatory approval or authorization of one or more successful candidates, pharmaceutical manufacturers are moving ahead with manufacturing at commercial scale, while also preparing to adapt to changes that arise, as development is also still being completed. The vaccine fill/finish line will, if all goes well, be the beginning of the end of the global pandemic.
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