Jennifer Markarian is a contributing editor for 

Jennifer Markarian

The COVID-19 pandemic has accelerated demand for quickly expanding capacity for manufacturing vaccines, including the facilities for viral vector production and for fill/finish. This capacity crunch is exacerbated because the industry was already capacity constrained before the pandemic began.

Running additional production campaigns in existing plants and adapting existing, suitable buildings for additional current good manufacturing practice (CGMP) lines are two avenues being taken for expanding fill/finish and existing virus- and vector-based vaccine processes, says Stefan Kappeler, technology manager of the global business unit, Biopharma & Life Sciences, at Exyte. For new vaccine platforms, such as mRNA vaccines, however, he says, “The short-term CGMP-compliant production is more difficult, as a completely new production and release process has to be designed and validated for the commercial scale, and then checked and approved by the national authorities.”

These new types of vaccines require new technologies and processes that have to be built from the ground up, and accomplished rapidly without interruption, adds Maik Jornitz, president and CEO of G-CON Manufacturing.

“Manufacturing capacity is the biggest hurdle for producing COVID-19 therapies right now. Companies with frontline options are scrambling to design and order equipment while in parallel designing and building the facility production space,” says Peter Walters, director of advanced therapy medicinal products (ATMP) at CRB. “Many of these therapies are based on pivoting process platforms, so development is being performed in parallel with design and construction of the facility, which makes flexible adaptable spaces so critical right now.”

Modular and prefabricated cleanrooms for manufacturing, which have been promoted for several years for the benefits of fast delivery and flexible capacity, stand ready to meet these needs. Modular process equipment is also finding use.

An established benefit of modular facilities is that they are constructed off-site and then delivered to the site where they will be put into use. Off-site construction has been shown to be particularly valuable under the limits imposed by the pandemic, says Jornitz.

“In an on-site construction, there may be a multitude of delays due to the limited headcount being allowed on-site, if at all. Off-site construction is not affected, because it is considered an essential business and has not stopped or slowed down since the start of the pandemic. As soon as the states opened travel, G-CON shipped four projects [of its prefabricated cleanroom PODs],” Jornitz reports. “The off-site prequalification also helps, as we can shorten the time and resources needed on-site, again to create the lowest headcount density needed and therefore lowest risk.”

The drive to produce COVID-19 vaccines and treatments has led to much faster building of cleanroom infrastructures and entire facilities than in the past, says Jornitz. “Delivery times of three to six months instead of years became the new normal, and this new normal will stay,” he predicts. He believes these short timelines are not unrealistic. “Any application could be predesigned to abbreviate the design timelines and can be prefabricated to stock to be much faster in the construction of the cleanroom infrastructure,” says Jornitz. G-CON introduced six standard cleanroom PODs that enabled them to shorten the delivery timeline further; these structures can be mass produced and then delivered from stock. Jornitz notes that, in addition to fast delivery, the industry requires reliable delivery timelines and robust cost budgets. “Too often we see a time and cost overrun, which puts any planning in jeopardy and cause a tremendous stress on project management. With off-site prefabrication, we avoid these overruns,” he notes. 

Walters agrees that a key benefit of modular facilities is faster time to production compared to other construction models. “Use of fully modular cleanrooms allows a large bulk of the critical technical facility to be constructed in parallel with the remaining facility, creating a more compressed overall facility timeline,” he explains.

CRB’s SlateXpace was introduced in September 2020 as a “suite-based” modular facility design for cell and gene therapy. “SlateXpace is a templated production cleanroom platform to address the growing need for flexible multi-modal capability,” says Walters. “The platform has a pre-engineered design to accommodate changes in processing technology and processing platforms, while also providing consistent and easily scalable design. One big benefit of templated design is that it can provide greater cost predictability and certainty up front, with a more predictable and consistent construction schedule, both of which greatly help in early facility planning.”

Standardization of modular facilities allows replication, which is a faster route to operational availability either at the same manufacturing site or a different location, adds Kappeler. An additional benefit of facility replication is production consistency across a site or different locations. He notes that, in addition, Exyte’s ExyCell prefabricated cleanrooms have been designed to be flexible and configurable, so that the modular units can follow the optimized process flow.

Flexible capacity to address market needs

Flexibility is another benefit of modular designs that allows companies to quickly add capacity to meet demand.

“One lesson from the current pandemic is the greater emphasis on security of supply and national independence. Modular systems enable the manufacturer to produce regionally on the required scale and thus to react flexibly to the current situation and local requirements,” says Kappeler. When vaccine manufacturing capacity is not in high demand, the facilities can be used instead for viral vectors for the ATMP sector, to combat neglected communicable diseases, or for animal vaccines. “At Exyte, we strive for a high degree of layout flexibility, process adaptability, and design standardization in plant design in order to convert and expand existing manufacturing capacities for new purposes,” he concludes.

“Designing in flexibility is paramount for the current manufacturing industry,” agrees Walters. “The ability to accommodate new processing technologies or swap to different processing platforms without a dramatic schedule-breaking renovation is where the industry needs to be headed to adapt to and accommodate the ever-changing and evolving product pipeline demands.”

Whether capacity constructed for COVID vaccines will be needed for short or longer term is unknown, says Jornitz, but the facilities can be used for other production if it is designed with containment, segregation and repurpose in mind. “Podular infrastructures have the benefit of being mobile, autonomous, and built for segregation. These units can either be used for other applications, moved to a different location where capacity is needed, or broken down to smaller segments for totally different needs. Repurposing cleanroom infrastructures is part of the total cost ownership value,” explains Jornitz.

The industry is moving toward the use of turnkey, predesigned facility platforms, says Jornitz. “Today, most of these facilities are piecemeal and at the end everybody hopes it will work, but it really all depends on the experience and capabilities of the project management,” he says. Moving to turnkey facilities reduces the dependence on project management and allows more predictability. G-CON and IPS partnered to offer the 

CON turnkey modular facility platform solution for biomanufacturing, and Jornitz says it can be used for vaccine production. “It is a complete package, tying together the facility, utilities, cleanroom infrastructure, equipment, and automation,” explains Jornitz. G-CON also partnered with Pall to offer a viral vector manufacturing platform with process equipment from Pall inside a G-CON POD cleanroom. The platform is offered in four scales, from process development through CGMP clinical and commercial manufacturing.

In May 2020, Exyte and Univercells Technologies announced a partnership to deploy modular, standardized facilities for manufacturing vaccines (1). Univercells’ NevoLine vaccine manufacturing platform is an intensified process that uses continuous/semi-continuous process equipment with automation, and the small manufacturing footprint can be housed inside the ExyCell cleanroom. The facilities can be commissioned quickly, regardless of location, says Kappeler.

“Univercells’ process … allows an unprecedented reduction in the necessary scale and the required floor space. We see these developments as fundamental for future vaccine facilities, as they enable a significant downsizing of the plant design and a reduction in complexity regarding the provision of utilities or the biosafety level requirements for building and installations,” explains Kappeler.

The COVID-19 pandemic has put a spotlight on the need to be able to respond quickly and be better prepared for the next time. In the future, although some of the more traditional, large-scale processes for vaccine manufacturing may not see dramatic change, cell-based vaccines will have smaller, more flexible footprints with more single-use process technologies, suggests Jornitz. “We see a strong pull for in-country/for country manufacturing sites [that] are ultimately smaller and still meeting the capacity needs. COVID showed that dependency on supplies from other countries could jeopardize the fulfillment of healthcare needs in one’s own country. These types of facilities will see a higher utilization even with seasonal vaccine needs and could potentially be used for multi-product purposes,” he predicts.

“Companies need to have a way to pivot spaces between different production platforms without having to gut them and renovate every time,” says Walters. “Leveraging the flexibility of single-use technologies, equipment can be rearranged within flexible production spaces to allow for shifting to production of different products. Companies having more facility spaces with this level of flexibility in mind may just help set the stage for a more rapid industry response to the next global shortage.”

Exyte, “Exyte and Univercells Technologies Combine Forces for Rapid Deployment of Vaccine Production Plants in the Wake of the COVID-19 Pandemic,” Press Release, May 14, 2020.

Articles

Modular building and process designs allow faster time to market for COVID-19 vaccines and treatments.

Flexible Facilities Speed Production

The bio/pharmaceutical industry has been talking about Industry 4.0 and digitalization for many years, and commercial use of automation and data analysis tools has been making progress. The sudden pandemic-related travel and business restrictions, however, have driven more rapid adoption of technologies such as 

 modeling, digital twins, remote acceptance testing, virtual and augmented reality tools, and other digital solutions.

Bikash Chatterjee, CEO of Pharmatech Associates, points out that the pandemic situation is driving the pharma industry to adopt the tools it has been talking about for more than a decade. Pamela Docherty, Life Sciences industry manager at Siemens, adds that her company saw an immediate uptake of digital tools when R&D personnel were restricted from accessing their laboratories, and that 

 modeling tools allowed them to continue their experiments virtually. 

When travel shut down, equipment suppliers introduced remote factory acceptance testing (FAT). IMA, for example, instituted virtual FATs in which customers could witness by video as the IMA engineers performed tests (1). Companies supplying virtual and augmented reality tools were able to step in to provide solutions. Apprentice.io, for example, deployed its smart glasses and Tandem technology platform to pharma manufacturers and their suppliers; the tools facilitated tech transfer, facility tours, and acceptance testing (2). API manufacturer Cambrex noted that digital tools allowed employees to operate remotely and internal and external audits to continue for both client and regulatory audits (3).

Digital tools will continue to benefit pharma manufacturing operations after the pandemic restrictions are in the past. On Nov. 11, 2020, 

 will host a panel discussion on digitalization that looks at using real-time monitoring and artificial intelligence to optimize manufacturing operations. Chatterjee and Docherty will be part of the panel, along with Amos Dor, general manager of the Pharma Team in the Automation Products Group at Applied Materials, and Bob Lenich, global life sciences director at Emerson. To listen to the discussion, 

www.pharmtech.com/view/ima-introduces-digital-platform-remote-fat

www.pharmtech.com/view/augmented-reality-kits-deployed-wake-travel-bans

Automation and tools for remote monitoring are finding increased use as pharmaceutical manufacturing adapts to pandemic restrictions. 

Pandemic Drives Digitalization in Bio/Pharma Manufacturing

As the industry gears up for the expectation of high demand for COVID-19 vaccine containers, suppliers of traditional glass vials are increasing capacity, and suppliers of alternative primary packaging materials are offering potential solutions as well. Honeywell recently introduced its Aclar Edge polymer bottles and vials for pharmaceutical packaging that are made from polychlorotrifluoroethylene (PCTFE). The compay says the containers can eliminate the risk of breakage found with glass containers; the containers are also 75% lighter than their glass counterparts, which reduces transportation costs (1). The containers meet the requirements of the compendia pharmacopeia for extractables, elemental impurities, and biological reactivity and are classified as Medical Grade Class VI, says Kori Anderson, general manager for Honeywell Healthcare Packaging

 spoke with Anderson about designing containers for vaccines.

 What are the key requirements for vaccine containers?

 Vaccine packaging must ensure suitability, safety, protection, compatibility, and performance. The primary package must be tested and validated to ensure container closure integrity, sterility, drug stability, and manufacturing feasibility. Materials of construction need to demonstrate low to no levels of detectable extractables, leachables, particulates, bacterial endotoxins, impurities, degradation products, volatile and involatile organics, and free ions to avoid adverse interaction that may react with the drug product and render the product unstable or ineffective. Materials of construction must not create changes in pH of the drug product and must meet stringent biocompatibility safety standards through appropriate compendia testing.

Vaccine vials must establish and maintain appropriate moisture and oxygen barrier levels to ensure against drug product degradation or loss of potency or efficacy. Since many vials are stored and transported in cold-chain environments, the vials must be tested in accordance with the recommended storage and transportation environmental conditions to ensure container closure integrity, stability, and functional performance are maintained throughout the distribution lifecycle of the product. Distribution testing should be mapped to include temperature excursions to demonstrate the robustness of the packaging system to maintain drug stability and container closure integrity. Vials must not exhibit any surface characteristics that may cause the proteins or other active ingredients to bind to the walls of the container. They need to exhibit a high level of clarity in order to permit inspection the product for visible particulates and cross-contamination.

www.pharmtech.com/view/industry-builds-fillfinish-capacity-pandemic-response

www.pharmtech.com/view/expanding-options-for-vaccine-packaging

 What do you see as the key challenges for distributing vaccines on a global scale?

 There are many variables that need to be addressed, including general shipping and freight issues with temperature control to ensure the stability and efficacy of vaccines. The sheer numbers for the COVID-19 vaccine could stress the supply chain to the max. It’s important for pharmaceutical companies to develop a back-up plan. We see Aclar Edge as a solution to alleviate those constraints.

 What are the requirements for filling equipment and automated inspection equipment using this container type?

 Vials must be evaluated for manufacturing feasibility and demonstrate resilient performance with high-speed packaging lines. Vials must demonstrate robust mechanical and physical strength to avoid jamming and impact damage during unpacking, collating, conveying, filling, capping, labeling, shipping, and distribution. PCTFE vials exhibit excellent physical properties, which prevent breakage during filling and capping as well as during transportation testing.

Automated inspecting equipment differs based on several factors, but any equipment that is compatible with plastic containers should also be compatible with Aclar Edge. Since the exterior is PET [polyethylene terephthalate], any labels used on PET bottles should work well with Aclar Edge bottles and vials. We have not performed testing specifically for automated inspecting equipment for Aclar Edge, but the containers have been run by one of our lead customers working on glass alternatives, with no major issues on their commercial lines.

Polymeric containers offer an alternative to glass.

Considering Materials for Vaccine Containers

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).

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 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 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

HHS, “Fact Sheet: Explaining Operation Warp Speed,” 

C. O’Sullivan, P. Rutten, and C. Schatz, “Why Tech Transfer may be Critical to Beating COVID-19,” 

R. Welch, “Solutions for Rapid Development and Manufacturing Responses to COVID-19 and Other Public Health Threats,” Presentation at BIO (June 2020).

Pfizer, “Pfizer and BioNTech Announce an Agreement with US Government for up to 600 Million Doses of MRNA-based Vaccine Candidate Against SARS-CoV-2,” Press Release, July 22, 2020.

Pfizer, “Pfizer and BioNTech Announce Agreement with the United Kingdom of MRNA-based for 30 Million Doses Vaccine Candidate Against SARS-CoV-2,” Press Release, July 20, 2020.

Reuters, “Pfizer to Outsource Some Drug Production, Focus on Coronavirus Vaccine,” May 8, 2020.

CureVac, “Germany: EIB and European Commission Provide CureVac with a €75 million Financing for Vaccine Development and Expansion of Manufacturing,” Press Release, July 6, 2020.

CureVac, “CEPI Awards US$34M Contract to CureVac to Advance The RNA Printer—a Disruptive, Transportable Mrna Vaccine Manufacturing Platform That Can Rapidly Combat Multiple Diseases,” Press Release, Feb. 27, 2019.

Inovio, “INOVIO Announces Positive Interim Phase 1 Data For INO-4800 Vaccine for COVID-19,” Press Release, June 30, 2020.

Inovio, “INOVIO Receives $71 Million Contract from US Department of Defense to Scale Up Manufacture of CELLECTRA 3PSP Smart Device and Procurement of CELLECTRA 2000 for COVID-19 DNA Vaccine,” Press Release, June 23, 2020.

Cobra Biologics, “Blog: COVID-19 Vaccine Hopes and Hurdles,” 

Johnson & Johnson, “Johnson & Johnson Announces European Commission Approval for Janssen’s Preventive Ebola Vaccine,” Press Release, July 1, 2020.

Johnson & Johnson, “Johnson & Johnson Announces Agreement with U.S. Government for 100 Million Doses of Investigational COVID-19 Vaccine,” Press Release, Aug. 5, 2020.

Johnson & Johnson “Johnson & Johnson Announces Collaboration to Expand Manufacturing Capabilities For its COVID-19 Vaccine Candidate in Support of the Company’s Goal to Supply More Than One Billion Vaccine Doses Globally,” Press Release, April 23, 2020.

AstraZeneca, “AstraZeneca Advances Response to Global COVID-19 Challenge as It Receives First Commitments for Oxford’s Potential New Vaccine,” Press Release, May 21, 2020.

AstraZeneca, “COVID-19 Vaccine AZD1222 Showed Robust Immune Responses in All Participants in Phase I/II Trial,” Press Release, July 20, 2020.

Novavax, “Novavax and FUJIFILM Diosynth Biotechnologies Initiate Large Scale Manufacturing of COVID-19 Vaccine Candidate,” Press Release, July 23, 2020.

Sinovac, “Sinovac Secures $15 Million in Funding to Accelerate COVID-19 Vaccine Development,” Press Release, May 22, 2020.

PharmTech Outsourcing Resources Supplement

Jennifer Markarian is manufacturing editor, 


Vol. 44, No. 9
September 2020
Pages: 16–20

When referring to this article, please cite it as J. Markarian, “Preparing Pandemic Vaccine Capacity,” 

Rapid scale-up to billions of doses requires collaborative, all-out efforts by innovators, their manufacturing partners, and the entire supply chain. 

Preparing Pandemic Vaccine Capacity

Designing and then manufacturing a drug–device combination product is a complex process that must take into consideration variables in manufacturing the drug delivery device, such as an inhaler or an autoinjector, as well as interactions between the drug and the device. Phillips-Medisize, a Molex company, has both clinical and commercial manufacturing facilities for drug–device combination products, and the company is expanding its Global Innovation and Development site in Struer, Denmark by adding a dedicated unit for manufacturing development. 

 spoke with the company’s experts: Justin Westendorf, product development manager; Bryan Moris, director of Global Pre-Production Quality; and Chris Conger, director of Connected Health Device Technology, about some of the best practices in manufacturing drug–device combination products.

 What are some of the best practices in moving from clinical manufacturing to commercial manufacturing of a drug–device combination product?

 During the design development process, there must be a good partnership and engagement between the device development team, formulation development team, clinical team, and the regulatory team. When scaling from building 500 units to 10,000 units to 10 million units, the device design can often undergo significant evolutionary changes. All stakeholders need to be aligned on which areas are allowed to change (such as assembly features) and which areas have to be locked down early (such as drug contacting features), as well as when features must be locked down to protect the integrity of the data being generated throughout the device development lifecycle.

It’s important to point out that there are perspective differences between a commercial manufacturing team and a product development team. When building products in commercial manufacturing, devices are built with the expectation that if the components and assemblies are produced to specification, then the performance requirements of the device will be met for the intended use population. In product development, however, the need for product may come before the design or manufacturing processes are well established or controlled. There are more nuances associated with ensuring the design and the drug formulation will successfully work together in these early builds.

For instance, there may not be time or value in performing process validation for early builds when the design is still evolving. This situation requires a flexible but compliant quality management system to work with stakeholders on a risk-based approach to controlling early device builds. In addition, how users will use the product must be assessed. This means getting device samples into users’ hands to study how they interact with them in the context of specific environments. If it’s determined that there are points of confusion that could lead to use errors and harm, regardless of drug performance, the design team will need to make adjustments to the design. By the time a product gets to commercial manufacturing, all of these types of questions have been answered by a robust design development process.

 What are some of the concerns for choosing materials for the device in a drug–device product? Do you need to evaluate potential interactions between the device and the user or between the drug and device?

 Physical interaction with a user is one concern. It’s important to understand the intended use and use environment and make sure you’ve identified how the user will interact with the product. You should consider which product components may interact with the user’s hands, skin, mouth, nasal passages and other areas of the body. Materials need to be assessed for the potential risks they may pose to the user.

Drug interaction also must be considered—especially for inhalers, where you have very small, often organic, charged molecules that are flowing through a pathway that’s typically plastic and may also be charged. These types of interactions can have an impact on how—and how much—of the drug exits the device. It’s also important to understand the chemical interactions to make sure nothing from the components could leach into the drug or change its chemistry.

Manufacturing is also a consideration. Every component will be manufactured via some means (e.g., machining, injection molding) and likely be assembled using some technology (e.g., adhesive, laser welding). A key variable in material selection is the compatibility between the material, the desired manufacturing method, and assembly to other components in the device.

Early in the design development process, you identify candidate materials. But then you must use tools and evaluation techniques to gain confidence in those candidate materials. It’s here you may realize you need to make a material change, perhaps because structural performance is lacking or clinical performance is falling short, or it could be you’re simply having a hard time making a device component with that material.

‘Material selection’ isn’t an event that happens, but rather a maturing of the design and better understanding of the materials and how they interact with the drug and the patient and how suitable they are for the intended manufacturing processes. This understanding improves as you progress through later stages of the development and verification testing process to reach a point where you’ve demonstrated the component materials meet performance and manufacturing requirements.

 What are some best practices for quality assurance (QA)/quality control (QC) of drug-delivery device manufacturing? What are some of the factors that need to be tested that are unique to a drug delivery device?

 When it comes to drug delivery devices or combination products, it’s really about control—control of the product and control of the components going into it. A high level of control is required, but that can mean many different things. It could refer to additional levels of training or processes and procedures that are well-vetted to ensure control over the drug itself, whether it needs to be filled into a container or in containers that are already prefilled.

A high degree of control is paramount when going from clinical manufacturing to commercial manufacturing. Designing processes and having conversations up-front based on best practices for controlling the device and the drug, from both a clinical and volume manufacturing standpoint, are important. For example, if you’re working with different dosages, you want to ensure a unique vial labeling or color-coding system exists to help minimize the potential for a mix up.

You also need to ensure a fool-proof shift from labor-intense, detailed, and manual clinical processes to automated commercial processes. The process must be carefully designed from the beginning, so that when it does ramp up and a product goes to many global commercial sites, you’re set up for success. Because, ultimately, you’re designing a product for commercialization.

The fact is, there will be variations in the production of the device—from device development to the manufacturing process to final refinements in commercial manufacturing. That’s why it’s important to uncover, on the front end, where variation can occur and how that variation might impact drug delivery performance. Then it’s crucial to take that a step further by characterizing how the variation that’s expected in commercial manufacturing will impact drug delivery performance. Skipping this characterization step can negatively impact the investment around, and commercial success of, the device.

 What are some of the risks for a drug delivery device that should be considered in manufacturing?

 The biggest risk to commercial manufacturing is the investment and effort—or lack thereof—made in design development and the manufacturing development that should occur in parallel to development. If you spend time focusing on de-risking the technology piece, but not much time finding sources of manufacturing variation and de-risking them during design development, you’re passing residual risk into the commercial environment, where a combination of variations in manufacturing processes is unavoidable.

There can be an investment impact, especially pertaining to schedule and price. When collaborating with customers to construct a design development proposal, it’s therefore important to understand their approach to risk-based decisions and what they consider important. Some are more willing than others to accept a certain amount of residual risk and deal with those potential repercussions in commercial manufacturing, in favor of speedier outcomes. So, it comes down to collaboration and building a strategy together to determine how much time and effort will be spent identifying user, technology, and manufacturing risks. Both parties will need to decide on either a ‘fast’ approach, in which the customer agrees to accept transferring more risk, or a more thorough approach that draws risk down further during design and development, even if that takes more time.

 What are some considerations for designing and manufacturing a drug delivery device that is connected to the Internet?

 For connected drug delivery devices, you introduce design and manufacturing techniques beyond what are needed for a typical mechanical device. Two additional considerations require significant attention in the design process: validation of the software that goes into the device and managing the cybersecurity of the device.

Validation is typically done against the ISO standard, IEC 62304 (1), which encompasses the process of managing software development through the entire lifecycle, from the beginning of development through the end of the market life of the device. Our development and management processes conform to this standard, which tells us how to develop the device, how to document the development, and how to test it and validate the device so that it meets all requirements.

Device cybersecurity requires as much attention as validation. Once a device is connected, the potential for malicious remote device intervention remains a threat. For this reason, FDA has issued detailed guidance on how to approach device security, which includes taking a risk-based approach to both the software and hardware of the device (2). Risk assessments should be conducted to determine what could go wrong or where vulnerabilities exist, and then correlated to how serious the consequence is of each identified risk. If it’s determined to be a serious risk, the mitigation you must enact to prevent the risk becomes significant. On the other hand, if the potential risk is not very high, the effort to mitigate is much less significant.

1. ISO, IEC 62304:2006, Medical device software—Software life cycle processes (May 2006).
2. FDA, “Cybersecurity,” 

www.fda.gov/medical-devices/digital-health/

Jennifer Markarian is manufacturing editor, Pharmaceutical Technology.

Pharmaceutical Technology
Vol. 44, No. 9
September 2020
Pages: 33–35

When referring to this article, please cite it as J. Markarian, “Manufacturing Drug–Device Combination Products,” 

A device manufacturing process must be carefully designed in the early stages of development to ensure success in commercial manufacturing. 

Manufacturing Drug–Device Combination Products 

Continuous manufacturing for oral solid-dosage (OSD) drugs continues to grow in acceptance as early adopters and equipment manufacturers refine their equipment and processes. With six small-molecule OSD drugs approved using continuous manufacturing—including both new products and existing products made in a batch process and now made in a continuous process—the precedent has been set for other companies to follow. By manufacturing in a new way, processors hope to reap benefits, such as faster development, a smaller equipment footprint, greater flexibility in manufacturing scale, tighter process control, and the potential for real-time release. The advanced process control with continuous monitoring used in continuous processes allows more consistent quality, which reduces waste and lowers operating costs.

“CM practitioners will need to have a more advanced level of process understanding to apply advanced quality measurement and control strategies. However, if carried out successfully, the payoff will be a flexible and robust drug supply chain that can be ramped up quickly in time of health crisis,” notes Professor Johannes Khinast, head of the Institute for Process and Particle Engineering in the Research Center Pharmaceutical Engineering (RCPE) at the Graz University of Technology in Austria.

“CM is a tremendous opportunity to advance drugs to the market at a much faster pace than traditional batch manufacturing and [enable] enhanced product quality based on enhanced process understanding and a richer data environment,” agrees Jose Luis Santos, head of Drug Product Continuous Manufacturing at contract development and manufacturing organization (CDMO) Hovione.

A challenge for continuous manufacturing is that the material handling and feeding into the process is critical, and there are two primary concerns: some of the APIs and excipients are poorly flowing powders and feeding very low levels of API can be difficult.

“We need to significantly increase the consideration of process interconnection and materials aspects when designing and operating a continuous processing facility,” says Khinast. “The unpredictability of in-process material behaviour is tough, since small changes in the formulation can have significant effects on the rheology, stickiness, segregation tendency, chargeability and other parameters.”

Accurate and consistent feeding is a challenge, along with low-rate feeding and containment designs for high potency ingredients, agrees Sharon Nowak, business development manager at Coperion K-Tron USA. “High accuracy loss-in-weight feeders are at the heart of most continuous processes. As the pharmaceutical industry implements these systems, more and more robust designs in weighing technologies, loss-in-weight feeder controls, modularity in design, and also overall cleanability are being demanded,” she explains. Nowak points out that the importance of the refill system to the loss-in-weight feeders is crucial, but sometimes overlooked, by process designers. “It is imperative that the feeder technology and refill system chosen are designed to include not only optimal performance, but also integrated to ensure the highest accuracy and consistency levels in feeder mass flow output,” she cautions.

“The primary challenge with poorly flowing powders is inconsistent filling of the screw pitch,” adds Sarang Oka, process development engineer at Hovione. “Vendors have experimented with various agitator and screw geometries to improve screw filling, and these have shown promising results. Some powders, such as certain grades of silica with very low bulk density and substantial electrostatic adhesion tendency, however, continue to pose a challenge. Another trick in the book is coprocessing the poorly flowing powder with a flow aid prior to introducing the powder to a feeder.

Pretreating the API can be a solution if changing the feeder design doesn’t work, says Doug Hausner, senior manager, Continuous Manufacturing Business Development, Pharma Services, Thermo Fisher Scientific. “Silication is the most prevalent and easiest pretreatment, but there are a number of options and companies are coming to market with solutions,” he notes.

Although feeders have been designed to feed low levels of APIs, there is a limit. “There is a physical lower limit below which signal-to-noise ratios even for the most sophisticated load cells becomes too low for effective gravimetric control, and this handicaps our ability to feed below a certain flowrate,” says Oka. “A management strategy has been to preblend (in batch) the ingredient with low weight fraction in the formulation with another ingredient, and then feed the preblend at the combined, higher feedrate.”

Development, tech transfer, and digital twins

In theory, CM processes should not require scale-up; instead of larger equipment, the line can be run for a longer time. CM thus offers the potential for faster development and easier tech transfer, but practitioners are still working on achieving these benefits. 

Because development is conducted in the same equipment and the same scale, there is potential for faster development cycles, agrees Santos. He suggests, however, that development in CM is currently slowed by a steep learning curve at most companies.

Currently, tech transfer is often conducted between units that are similar or identical in size and other characteristics, notes Oka. “One can be very confident that experiments performed, and results obtained on a standalone loss-in-weight feeder will translate well when an identical feeder is used to feed the same material in the integrated process train,” says Oka. “The challenge arises when development is performed on equipment that is different from commercial equipment. We still do not have correlations that help us transfer processes between dissimilar pieces of equipment or process trains. Recommended practice for organizations who wish to build multiple lines is to develop identical lines, if there is desire to transfer products between lines.”

Digital twins are proving to be a valuable tool for development of continuous processes. These computer models of a process allow process developers to run experiments 

, allowing a greater number of experiments to be run more quickly and a better process understanding to be developed before evaluating process conditions on the actual equipment.

“People are pushing in the direction of digital twins to limit development time, because the software/control is often the rate limiting step in getting a system up and running, not the process development in a chemistry, manufacturing, and controls sense,” says Hausner. Digital twins also allow users to demonstrate the process on different production lines, such as when transferring to a different facility, he notes.

Running experiments off-line is particularly important for CM, because the process of cleaning between products is time-consuming. “Tools that help us minimize the use of the rig are incredibly important to us [because of the time for cleaning.]These tools could be very sophisticated models or simple tools based on engineering correlations that predict the performance of the product in the rig,” says Oka.

Digital twins have been commonly used to run 

 residence time distribution (RTD) experiments, says Oka. “These experiments can be done either at the unit operation level or at the full process train level. Thorough characterization of the RTD enables one to track evolution of disturbance through the rig, a crucial element of today’s control schemes. The underlying models, if well calibrated, also enable the practitioner to ‘dial-in’ and test a desirable RTD.” Other uses of digital twins include understanding the impact of material properties and process parameters on process performance and eventually product quality.

RCPE’s particle-simulation based approach is a digital twin of CM processes, developed in collaboration with pharmaceutical companies and equipment suppliers. “We believe that such digital twins are crucial for the future of continuous manufacturing, as this technology allows us to better process and visualize real-time data to enhance our ability to predict and control the process dynamics,” says Khinast. “Specifically, we can use digital twins to monitor and predict critical quality attributes and key performance indicators throughout the process line, while simultaneously feeding data back to optimize the process output in terms of quality and yield. … Digital twins have the potential to make continuous manufacturing faster, cheaper, and less error-prone.”

Khinast says that RCPE’s digital twin allows development of key processes, such as continuous powder blending, based on material properties that can be measured with small amounts of material. “Because this 

 approach is based on the fundamental physics, it is far more efficient, compared to the traditional trial-and-error approach, when you need to transfer the product and process to a different set of equipment,” he explains.

Simulations and modeling are also commonly used to identify bottlenecks and eliminate inefficiency in processes, explains Dave DiProspero, director of Pharmaceutical Process Technology at CRB. “A continuous manufacturer’s success, survival, and profitability depends heavily on process efficiency. During the times when equipment is being maintained, cleaned, turned over or idle work in progress awaiting upstream processes, efficiency is being reduced and profits are being lost,” says DiProspero. Modeling can be used to find efficiencies in areas such as personnel movement, travel distances from operation to warehouse, process loading and unloading times, and quality control holds. “Wherever and whenever a step in the process can provide for a time reduction, operational improvements are achieved,” he says.

Another aspect of facility design is the need for maximizing flexibility and capability to handle different products on the CM line. “One of the best practices for modern OSD facility design to address flow is to incorporate uniflow operations, with minimal path crossing or back tracking,” says DiProspero. “Ideally, process flow should run in a linear motion from raw materials in, to final drug product out. Placing the weigh/dispense unit operation close to the warehouse, with direct access, and combining unit operations (e.g., granulation/drying and blending/milling) are common today.”

In addition to optimizing the equipment and facilities, manufacturers need to develop the workforce for operating CM processes. Such teams are different from those that typically support batch solid dose manufacturing, says Santos. “Now the skill set should comprise a strong background as well on process modeling, automation, and control. PAT [process analytical technology] is now a mandatory role in the teams. The quality teams should either adjust themselves to embrace a new paradigm, or new focused teams should be put together,” he explains.

Training is becoming more available, compared to in the past when most had to figure things out for themselves, says Hausner. The United States Pharmacopeia, for example, is offering training and is also considering developing standards for CM. The International Society for Pharmaceutical Engineering (ISPE) is also discussing standards as related to standard capabilities and connectivity technology to allow systems integration, reports Hausner.

Jennifer Markarian is manufacturing editor, 

 
Supplement: APIs, Excipients, and Manufacturing 
September 2020
Pages: 29–31

When referring to this article, please cite it as J. Markarian, “Solid-Dose Continuous Manufacturing Presses On,” A

Early adopters and equipment manufacturers refine their equipment and processes, paving the way for broader use. 