In Vivo: 医療用医薬品・医療機器産業の経営層向けニュース
By Deanna Kamienski 06 May 2021
During Q1, biopharma merger and acquisition value reached $34.8bn and drew in $35bn in potential deal value (PDV) from alliances...
“Never was so much owed by so many to so few,” the infamous quote attributed to wartime leader Winston Churchill, referring to the pilots that engaged in the Battle of Britain, has never been more applicable to a modern situation than the one we are facing globally today. Indeed, the world is at war again. This time, the enemy is a mutating virus that has brought industry and education to a standstill. This time, “the few” we must thank for standing up to the enemy, and giving the world back its normalcy, are the chemists, scientists and manufacturers behind the COVID-19 vaccines that have been approved and are still in development.
Never has the biopharmaceutical industry been asked to move so fast to counter a global health crisis. According to Bloomberg data at the end of February 2021, more than 231 million vaccine doses had been administered across 88 countries. The latest rate was roughly 6.35 million doses a day. As of the end of February, , the UK had vaccinated 25% of its population, with a target to offer a vaccine to all UK adults by 31 July, 2021 . In the US, for the last week of February, an average of 1.45 million doses per day were administered.
Behind these remarkable figures is a tireless manufacturing wheel that keeps on turning. While the pharmaceutical industry remains entrenched in the quagmire of the pandemic, it may be too early to take stock of the lessons learnt. However, there are ways in which manufacturers of the vaccines have operated that deserve to be applauded.
Clive Glover, director of strategy at Pall Corporation and the lead on manufacturing strategy for Oxford University and AstraZeneca PLC’s AZD-1222 vaccine project, told In Vivo that while the speed of the manufacturing process has been remarkable, it has “not been easy.”
The COVID-19 vaccine was co-invented by the University of Oxford and its spin-out company, Vaccitech. It uses a replication-deficient chimpanzee viral vector based on a weakened version of a common cold virus (adenovirus) that causes infections in chimpanzees and contains the genetic material of the SARS-CoV-2 virus spike protein. After vaccination, the surface spike protein is produced, priming the immune system to attack the SARS-CoV-2 virus if it later infects the body.
The speed at which the AZD-1222 vaccine has been manufactured is significant. Within eight weeks, Pall Biotech designed the manufacturing process to deliver millions of doses per batch, then delivered and installed the equipment the contract manufacturing partner would need to make the vaccine.
The first manufacturing run began less than two months after Pall received the starting material from Oxford University. To put this into context, Pall’s previous record for this process was nine months. Glover said this action required a combination of ground-breaking innovation, huge amounts of funding, relentless effort from some of the greatest scientific minds on the planet and, crucially, a consortium-wide commitment to the principles of lean process development and production.
As the scale of pandemic became apparent, Oxford University put out an open call for process development capabilities to scale up the manufacturing process to make millions of doses. “Pall responded to this call as we have our Integrated Solutions team located in Portsmouth, UK,” explained Glover. The Integrated Solutions team routinely develops these kinds of processes for clients. In the last three years, Pall Biotech has developed more than 30 processes for clients and most of its expertise is around developing large scale viral vector manufacturing capabilities. This fit very well with Oxford University, as its vaccine is based on an adenovirus.
Oxford University only had a small-scale manufacturing process worked out. It provided the initial starting materials and guidance to the Pall team who then took this and developed the large-scale manufacturing process. At the same time, Pall was in constant contact with the contract manufacturing organizations to ensure that the process Pall had developed would fit into their facilities, and to coordinate Pall’s supply chain with their availability. Pall tech-transferred the process to three CMOs; UK companies Cobra Biologics and Oxford Biomedica, and Halix based in the Netherlands. The Vaccine Manufacturing and Innovation Centre also provided invaluable logistical coordination and advice to the whole team, added Glover.
In total, at Pall there were about 20 people that worked on the project full time for eight weeks, but they were supported by many others, and several of them continue to support the manufacturing process today. The Integrated Solutions team consists of the Process Development Services lab and the Engineering team. These two teams work together very closely. Together they suggested technologies that could be used to manufacture the vaccine at scale. The Process Development Services team then tests these technologies on a small scale initially and then at full manufacturing scale to ensure that the process works as planned.
Crucial process data is also captured at the time to help with future regulatory filings. Once the Process Development Services team have demonstrated that the proposed technologies work at scale, the Engineering team takes the process, puts together a full equipment list and designs all the required single-use manifolds that are essential to tie the process together. It also ensures that the equipment will fit in the clients’ facility. Once the process has been tested and the facility designed, the client gets final approval. In parallel to this, Pall’s supply chain team becomes involved to ensure that it can deliver both the equipment and the single-use components on time.
“The key to the rapid development of this process is that we did not design it from scratch,” said Glover. While every product has its own unique requirements, the backbone of the process remains consistent for each viral vector. “We use the 80/20 rule here: 80% of the process is common but it does require the final 20% customization both because of the individual product and also because of the specific facility that the process needs to be fitted into,” he explained. Two years previously, Pall had developed a standardized viral vector manufacturing process. “We had already worked out this process in a high degree of detail and it was to this was that we turned when required to develop this process,” he recalled.
This was a complicated project with many different stakeholders including Oxford University, the three CMOs as well as the UK government. AstraZeneca became involved in the process in early May 2020 to take the vaccine global. “This was all taking place just as we were all getting used to working from home so that really complicated matters. Adding to that, social distancing in a process development lab can be difficult particularly when two people may be required in some parts of the process,” recalled Glover. “Furthermore, our supply chain had to be operating at full capacity in order to get equipment and consumables together in a timely manner. However, there was a very singular and urgent focus to the team, and through taking the correct safety precautions, the team in the lab were able to collaborate which enabled us to work through issues that arose quickly and efficiently.”
Glover describes the supply chain efficiency offered by Pall Biotech as a “normally well-oiled machine.” However, the Oxford-AstraZeneca vaccine was of course not the only vaccine in development. In fact, at that time there were more than 200 different vaccines and therapeutics in development and many of them were also requesting urgent supplies from Pall Biotech to support those efforts.
One of the crucial things Pall did was to rely on the standardized viral vector manufacturing process. “The standardized process allowed us to harmonize single-use consumables across multiple manufacturing sites. This, in turn, gave our supply chain fewer part numbers and designs to have to work on and increased the volume on particular designs allowing us to manufacture these in bulk,” he explained. “This has the advantage that it considerably reduces the supply chain risk with any single part, which is very important.”
This became even more critical for the project as the vaccine went global. AstraZeneca is now working with more than 20 different manufacturing partners globally and needs to be able to produce more than three billion doses. “Minimizing risk in the supply chain at this scale is essential,” affirmed Glover.
“The challenges we have faced setting up production lines are mainly linked to the extremely compressed timelines,” explained André Goerke, business unit head, mRNA, at Lonza, a service provider manufacturing active pharmaceutical ingredients and innovative dosage forms for the global industry.
The timeframe meant sourcing equipment and raw materials as well as hiring and training new staff in record time, Goerke told In Vivo. “There are more than 400 raw materials that we need to bring together and we are working closely with Moderna, Inc. and suppliers. A very frequent governance with all suppliers has been key. We are monitoring certain key compounds, their availability and projections on a daily level. All of our suppliers are aware of the importance of our needs and we try to jointly anticipate potential bottlenecks, to enable timely ramp up of production.”
In May 2020, one of the vaccine front runners, Moderna, announced a 10-year strategic collaboration with Lonza as its drug substance manufacturing partner for Moderna’s vaccine messenger RNA (mRNA-1273) vaccine. This was the first collaboration of its kind between Moderna and Lonza and allowed Moderna to accelerate its manufacturing capacity 10-fold.
The goal of the collaboration is to enable the manufacturing of up to one billion doses per year. The manufacturing process was developed by Moderna and the tech transfer began a month later, in June 2020, with the first batches of mRNA-1273 manufactured at Lonza’s Portsmouth, New Hampshire, plant in July 2020.
“The manufacturing of Moderna’s COVID-19 vaccine in Visp, Switzerland, takes advantage of the Lonza Ibex Solutions facilities,” explained Goerke. “Two years ago, Lonza made a considerable investment into flexible and technology agnostic manufacturing shells,” he said. These pre-built shells are already linked up to central infrastructure and services (including analytics and quality control labs) and allows Lonza to drop in the manufacturing technology that is needed for a particular drug or vaccine. “This is important,” he said “given that vaccines and drugs are becoming more diverse and a facility for one drug or vaccine cannot be easily used for another type of molecule. By using prebuilt shells, we have been able to set up dedicated facilities for mRNA production in less than eight months, compared to the two or more years it would take to set up a new facility from scratch.”
Today, the vaccine is made from one manufacturing line in Portsmouth and three lines in Visp. Globally, several hundred people work on the manufacture of the vaccine. “Compared to traditional biotech, this manufacturing platform is extremely efficient; many doses can be produced with a relatively small manufacturing footprint and number of staff,” said Goerke.
Approximately 60 million doses globally, including approximately 55 million doses to the US government, have been shipped to date and the first four million doses shipped from Modern’s ex-US supply chain.
An additional 33 million doses have been produced in the US, have been filled in vials and are in the final stages of production and testing before release. Moderna expects to complete delivery of the first 100 million doses to the US Government by the end of the first quarter 2021, the second 100 million doses by the end of May 2021 and the third 100 million doses by the end of July 2021.
Production planning during a pandemic is uncharted waters. New variants of coronavirus mean that a one-size-fits-all approach is not the end of the story. At the end of February, Moderna announced new capital investments to increase capacity at its owned and partnered manufacturing facilities, which it expects will increase global 2022 capacity to approximately 1.4 billion doses of its COVID-19 vaccine, assuming a 100 μg dose. The investments will enable additional production of the current vaccine and provide flexibility in addressing production of potential vaccine boosters that may be needed to address emerging variants of SARS-CoV-2.
While the 2022 capacity of up to 1.4 billion doses reflects an assumption of a 100 μg dose, the 2022 output will depend on the dose of the booster. Moderna plans to study a dose range of 50 μg and lower for variant-based boosters and an additional booster of mRNA-1273. If the effective dose for a booster is 50 μg, then the 2022 supply could be significantly higher than 1.4 billion doses.
The company said it is “continually learning and working closely with its partners and the federal government to identify ways to address bottlenecks and accelerate production.” For example, one of the recently identified constraints on production has been the capacity of the fill-and-finish process. Moderna has now studied the possibility of adding more doses to each vial of vaccine to allow complete manufacturing to run more quickly and reduce the need for consumable materials that are in high demand. The FDA has provided positive feedback on this proposal, and Moderna said it is pursuing a plan that may allow up to 15 doses to be drawn from each vial. This will allow the production and delivery of additional doses more quickly.
Increasing production is also on the mind of other vaccine producers. AstraZeneca and the German contract development and manufacturing organization (CDMO) IDT Biologika have announced they intend to “explore options” to accelerate output of finished vaccines in the second quarter of 2021. The companies are making an undisclosed joint investment to build large additional drug substance capacity at IDT Biologika’s production site in Dessau, Germany. They will build up to five 2,000-litre bioreactors capable of making tens of millions of doses per month of AstraZeneca/Oxford’s COVID-19 vaccine, estimated to be operational by the end of 2022.
The investment could also allow for the manufacture of other vaccines sharing a similar manufacturing process, greatly expanding Europe’s domestic vaccine production capability, said the companies in a joint statement. “IDT Biologika will have among the largest vaccine manufacturing capacities of its kind in Europe and play an important part in ensuring Europe’s future vaccine supply independence.”
Of course, not all vaccine manufacturing and delivery has gone smoothly. At the end of January, a diplomatic tussle broke out in Europe over a shortfall in projected vaccine doses from AstraZeneca’s Belgian plant. Local health authorities inspecting the factory in Senneffe after a “glitch” with the manufacturing process brought the promised 80 million doses down to 31 million. AstraZeneca CEO Pascal Soriot said that the Novasep plant had experienced low yields, which was to be expected as worldwide production was scaled up so rapidly in such a short space of time.
Commenting at the time, Novasep said that manufacturing the COVID-19 vaccine is a “pioneering process in terms of scale, complexity and quantity.”
Because the UK’s supply of the vaccine was undisturbed the European Commission demanded doses of the vaccine be sent from British manufacturing plants to make up for the shortfall. The UK government resisted the pressure and insisted that its orders must remain in Britain.
However hard manufacturing during a crisis is, planning during one is equally difficult.
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