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Production and supply – A logistics challenge

The manufacturing, packaging and transportation of COVID-19 vaccines requires a smooth, effective and safe supply chain. Time is of the essence, and the pharma industry supply chain is facing big logistics challenges.

In record time the global life science industry has been able to discover and develop one vaccine approved for full use, six vaccines approved for early or limited use, and 14 vaccines that are currently in large-scale efficacy tests (Phase 3), according to statistics from the New York Times released on December 9th 2020. There are also around 17 vaccines in Phase 2 and around 40 vaccines in Phase 1.

We are experiencing a mobilization we have never seen before, but the mission also imposes great challenges and pressure on the entire pharma supply chain – the task of producing and distributing vaccines, should they receive final regulatory approval, to a global population of around seven billion people.

Ramping up production

Our vaccine makers and manufacturers believe they will be able to deliver vaccine doses to a third of the world’s population by the end of 2021. Many countries, however, primarily the development countries, will probably not have a vaccine until 2024, according to calculations by the Duke Global Health Innovation Centre in the US. The three big pharmas spearheading the vaccine race, Pfizer, Moderna and AstraZeneca, estimate that they will be able to produce 5.3 billion doses during 2021, which corresponds to approximately almost three billion individuals. Other vaccine producers, for example in China and Russia, have also started to mass-produce vaccines.

One critical hurdle to overcome in order to bring a COVID-19 vaccine to the market and the patients is the ability to supply the capacity needed to meet the demand. This means having a good manufacturing practice (GMP)-compliant manufacturing that is fast, reliable and cost-effective.

One critical hurdle to overcome in order to bring a COVID-19 vaccine to the market and the patients is the ability to supply the capacity needed to meet the demand. This means having a good manufacturing practice (GMP)-compliant manufacturing that is fast, reliable and cost-effective. The technology infrastructure must be in place to ramp up production and there must also be capacities to meet temperature-sensitive needs.

Pfizer, the company that has come the furthest so far with its mRNA vaccine candidate BNT162b2 together with BioNTech, took pre-emptive steps to scale up its manufacturing operations in May 2020. These steps included exchanging technology for rapid facility, equipment, and process design planning, ordering materials, establishing two parallel supply chains for redundancy, modifying facilities and re-prioritizing capacity for COVID-19 vaccine manufacture, recruiting and training staff for operations support and flexibility, and investing at risk for quick production of many doses when vaccine is available.

 

BioNTech

Photo: BioNTech

 

AstraZeneca has stated that it will have a capacity of up to 3 billion doses of the vaccine in 2021 on a rolling basis, pending regulatory approval, and large-scale manufacturing has already begun.

“Accelerating production at this kind of scale requires partners around the world with capabilities to manufacture using our standard process to ensure consistency and quality of the vaccine. We are working tirelessly to establish mass supply globally, so if our vaccine is approved by regulators, it will be ready for distribution,” states Per Alfredsson, Senior Vice President, Global Biologics Operations, AstraZeneca.

Another vaccine in the final sprint is Moderna’s, which was recently announced to be more than 94% effective. The company has partnered with the Swiss drugmaker Lonza, who will produce ingredients within Moderna’s vaccine, formally called mRNA-1273, in facilities in the U.S. and Switzerland.

“Then, linked to the speed (issue), you have to have access to the equipment, install the equipment, and then test your manufacturing facility, so (these are) big challenges, resolved, or almost resolved, in less than one year.”

“There are a few issues; the first is speed. We only started 10, 11 months ago and now we are producing the first commercial batches of the drug substance in North America, and we are planning the first batch of commercial volume in one or two weeks in Switzerland, so the speed has been a challenge. The second challenge is to find the people. For each manufacturing line you need 60-70 educated persons. We’ve installed four manufacturing lines so you have to identify and train these people,” explained Albert Baehny, Chairman of Lonza to CNBC. “Then, linked to the speed (issue), you have to have access to the equipment, install the equipment, and then test your manufacturing facility, so (these are) big challenges, resolved, or almost resolved, in less than one year.”

Swedish CDMO Recipharm has signed agreements to manufacture COVID-19 vaccines. Most recently the company entered into an agreement to formulate, fill and finish Moderna’s COVID-19 vaccine candidate, mRNA-1273. The activity will be performed in Recipharm’s drug product manufacturing facility located in Monts, France. In addition, the company has also signed an agreement with Arcturus Therapeutics to support the manufacture of vaccine candidate LUNAR-COV19 (ARCT-021), which is in an ongoing phase 1/2 clinical trial.

“One of the key challenges is compressing timelines as much as possible, but also sourcing the right equipment, components and starting materials quickly, and this has to be done as a priority.”

“We are currently utilizing two sterile facilities in our network in Germany and France to support the manufacture of vaccines. Preparations are well underway with recruitments, investments, tech transfers and all the associated activities,” states Mark Quick, Executive Vice President of Corporate Development at Recipharm.

 

Mark Quick

Mark Quick, Executive Vice President of Corporate Development at Recipharm.

 

For large scale production of COVID-19 vaccines he sees a number of challenges.

“One of the key challenges is compressing timelines as much as possible, but also sourcing the right equipment, components and starting materials quickly, and this has to be done as a priority.”

Boosting Sweden’s resilience against future pandemics

Valneva Sweden, currently manufacturing the cholera vaccine DUKORAL, is preparing to perform part of the production of the company’s COVID-19 vaccine, VLA2001, currently the only inactivated COVID-19 vaccine in clinical development in Europe.

“Inactivated virus vaccines are historically one of the safest and most effective vaccine development strategies, with billions of patients having been vaccinated with this technology over the past 100 years. This means inactivated vaccines can be used in people with weakened immune systems, who are at the greatest risk of COVID-19,” explains Janet Hoogstraate, Site Manager, Valneva Sweden.

 

Janet Hoogstraate

Janet Hoogstraate. Photo: Jan Landefeldt

 

Valneva’s manufacturing site in Solna, Sweden, already has an aseptic filling line in place and is now working on building another to increase capacity.

“The site has been hosting vaccine manufacturing operations for more than 30 years and has an established international distribution network. Valneva has already reallocated some of its existing filling, packaging and final product distribution capacity in Solna to VLA2001. Additional fill and finish capacity is also being established in Solna and should be operational in the second half of 2021. Valneva is the only commercial vaccine manufacturer in Sweden involved in COVID-19 fill and finish operations,” states Hoogstraate.

“Additional fill and finish capacity is also being established in Solna and should be operational in the second half of 2021. Valneva is the only commercial vaccine manufacturer in Sweden involved in COVID-19 fill and finish operations.”

The company is in ongoing discussions with regional and national authorities to garner support for the development and production of VLA2001, as well as Valneva’s role in boosting Sweden’s resilience against future pandemics. Hoogstraate adds that this expansion, which is part of a broader plan to increase capacity in Sweden and at Valneva’s production site in Livingston, UK, will also help drive jobs in the local community.

The manufacturing of the vaccine itself is done at Valneva’s facility in Scotland. This drug substance, formulated bulk, will then be shipped to Sweden to be filled into vials, then packaged and distributed.

“The vaccine will likely require standard cold chain transport and storage, 2 to 8°C, meaning there is no need for specialized distribution channels, in addition to reduced deployment complexity and cost. Additionally, clinics are able to use existing facilities for storage and administration,” says Hoogstraate.

Critical temperatures

Temperature, and keeping the vaccines cold enough during transportation, is indeed a big challenge. In particular, Pfizer’s mRNA vaccine requires a storage temperature of -70°C. Together with BioNTech, the company has developed specially designed, temperature-controlled shippers that can maintain recommended storage conditions (-70°C ±10°C) for extended periods of time without any additional equipment other than dry ice. The shipper can maintain temperature for 10 days unopened, which allows for transportation to markets globally, state the companies. Once opened, a vaccination center may use the specially designed shippers as a temporary storage solution to maintain the recommended storage conditions for up to 30 days, with re-icing every five days in accordance with the handling instructions. Each shipper contains a GPS-enabled thermal sensor to track the location and temperature of each vaccine shipment 24 hours a day, seven days a week. Once thawed, the vaccine vial can be stored for up to five days at refrigerated conditions. Regardless of this solution, freight forwarders will be facing logistics challenges in maintaining the transportation conditions.

 

Photo: iStock

Pfizer is also currently working on developing a freeze dried version of the vaccine, which would be able to be handled at normal temperatures. This would improve the transportation chain and benefit storage of the vaccine in development countries. The Russian vaccine, Sputnik V, will also be freeze dried, the country states. Currently it has to be stored at -18°C to maintain its effect.

Freeze drying has existed for over 100 years. In short, the water is removed so that there is just a powder. When it is time to use the vaccine it is resuspended in liquid and then injected as usual.

Moderna’s vaccine remains stable at 36 to 46 degrees Fahrenheit, the temperature of a standard home or medical refrigerator, for up to 30 days, the company states. It can be stored for up to six months at minus 4 degrees Fahrenheit. AstraZeneca’s vaccine can be stored, transported and handled at normal refrigerated conditions (2-8 degrees Celsius/ 36-46 degrees Fahrenheit) for at least six months and administered within existing healthcare settings.

From departure to destination

Securing transportation of the vaccines all over the world is an enormous logistics challenge Freight forwarders face the work-intensive task of ensuring vaccines move door-to-door while maintaining their temperature, from the airport to the final destination. Particularly vulnerable are development countries, and UNICEF is working with major global airlines and freight providers to step up efforts to deliver COVID-19 vaccines to over 92 countries around the world as soon as vaccines become available.

“The procurement, delivery and distribution of COVID-19 vaccines is anticipated to be the largest and fastest such operation ever undertaken.”

“We need all hands on deck as we get ready to deliver COVID-19 vaccine doses, syringes and more personal protective equipment to protect front line workers around the globe. By protecting these workers, we are ultimately protecting the millions who depend on their critical services,” said Etleva Kadilli, Director of UNICEF’s Supply Division. “The procurement, delivery and distribution of COVID-19 vaccines is anticipated to be the largest and fastest such operation ever undertaken.”

In December Bill & Melinda Gates Foundation made its largest single contribution to fight the pandemic, USD 250 million. Why then? Because now, the world has much of the science it needs to end this pandemic, and as regulators start to put their stamp of approval on it, the field of action is widening beyond the lab, the foundation stated. They also emphasized that the access to vaccines is very different for the majority of human beings that live in low- and middle-income nations.

”Will 2021 actually play out this way, with vaccines, drugs, and tests going mainly to the richest places? Or will the lifesaving science be available to everyone, regardless of location or income? Our foundation has a clear perspective on what the answer should be,” says Mark Suzman, CEO, Bill & Melinda Gates Foundation.

”The Pfizer vaccine, for instance, needs to be kept at sub-zero temperatures, which will be very difficult when transporting it to very rural areas. Our foundation will keep funding innovation.”

The foundation also wants to support further development of new drugs, vaccines and tests, in part because some of these initial ones aren’t ideally suited for low-income nations. ”The Pfizer vaccine, for instance, needs to be kept at sub-zero temperatures, which will be very difficult when transporting it to very rural areas. Our foundation will keep funding innovation.”

It is hard to give a sense of scale of the public health effort needed to end the pandemic. The closest analogue might be India’s campaign to vaccinate 400 million kids with the measles-rubella vaccine, said the foundation. The project took two years, with another of planning. ”For COVID-19, the world must cover almost 18x the population – and do it in hopefully half the time. The ACT-Accelerator estimates that it needs another  USD 28 billion next year. National governments are the only institutions with that kind of budget,” states Suzman.


Making a vaccine
– crucial manufacturing processes

CMC: A commercial manufacturing process is developed from an initial small-scale process before rapidly scaling to increase productivity yields, all the time ensuring purity of the final product.
Virus seed stock & host cell bank: These starting materials are used by manufacturers around the world to initiate vaccine production.
Drug substance: Host cells are grown in a series of bioreactors of increasing scale and seeded (infected) with the virus to produce a final vaccine molecule. A series of filtration and chromatography steps are taken to harvest and purify the vaccine.
Drug product: The drug substance is combined with buffers to achieve a final formulation and then filled into multi-dose vials, which are labelled and packaged.
Testing and quality control: Extensive testing is conducted on every batch throughout the manufacturing process. Quality control measures are employed at all stages of production to ensure consistency and quality.

Source: AstraZeneca