Manufacturing COVID-19 vaccines

How is vaccine manufacture being supported in the UK?

In April 2020, the UK Government announced a Vaccine Taskforce to ensure that the UK has rapid access to safe and effective vaccines, while supporting access internationally. This includes developing the UK’s domestic manufacturing capabilities.

Public investments in vaccine manufacture made since the outbreak of COVID-19 include:

• £100 m for the Cell and Gene Therapy Catapult Manufacturing Innovation Centre, to accelerate the mass production of a COVID-19 vaccine. This will involve upgrading an existing facility located in Braintree, Essex, to create a fully-licensed manufacturing centre with the capacity to produce millions of doses per month of a range of different vaccine types. The Centre is due to open in December 2021.
• £93 m to expand and accelerate construction of the Vaccines Manufacturing and Innovation Centre for the mass production of vaccines. Under construction in Oxfordshire, this centre is due to open in the Summer of 2021, one year earlier than originally planned. It will have facilities to produce and package a range of different vaccine types.
• £38 m to establish an interim rapid deployment manufacturing facility in Oxford Biomedica’s labs, which was approved for vaccine production in October 2020.
• A joint investment with the biotech company Valneva to upgrade and expand an existing facility in West Lothian. The facility is due to produce up to 200 m doses of inactivated whole virus vaccines (see ‘Inactivated vaccines’ below) in 2021.
• Securing capacity with Thermo Fisher in Swindon and Wockhardt in Wrexham, to carry out ‘fill and finish’, which involves dispensing the vaccine into vials ready for distribution.
• £4.7 m to develop ‘Centres for Advanced Therapies Training and Skills’: facilities and online training to provide industry-standard skills, including in vaccine manufacture.
• £8.6 m to the Centre of Process Innovation in Darlington to develop facilities for producing vaccines using new RNA-based technology (see ‘RNA-based vaccines’ below) that comply with good manufacturing practice.
• Up to £548 m for the COVAX Advanced Market Commitment, which aims to give lower and middle-income countries equitable access to vaccines. COVAX was set up by the World Health Organization, the Coalition for Epidemic Preparedness Innovations (CEPI), and Gavi the Vaccine Alliance, to produce and fairly distribute 2 billion doses of COVID-19 vaccines globally in 2021. It pools financial resources to develop vaccines, purchase them at scale, and invest in manufacturing so that they can be distributed as soon as they are licensed.

Two Future Vaccine Manufacturing Research Hubs had already been established prior to the pandemic, one by Imperial College London, and one jointly by University College London and the University of Oxford. These are addressing the challenges of developing and manufacturing vaccines, particularly for low- and middle-income countries. For more information about access to COVID-19 vaccines for low- and middle-income countries, see House of Lords Library briefing Covid-19 Vaccine: Access for low and middle income countries.

How are vaccines made?

Vaccines work by priming a person’s immune system so that it will respond more rapidly if they are exposed to a specific pathogen, such as a virus. Some vaccines contain dead virus or bits of protein from the virus to trigger an immune response (inactivated and protein-based vaccines), others contain genetic material from the virus that is then used within the body to produce virus proteins after injection, leading to an immune response (adenovirus- and RNA-based vaccines).

Vaccines commonly contain:

• active components that stimulate the immune system (dead virus, virus protein or genetic material from a virus)
• adjuvants that enhance the immune system response
• stabilisers that extend shelf life
• antibiotics that prevent bacterial contamination during manufacture
• preservatives that prevent contamination during distribution (such as when a multi-dose vial is opened).

Each vaccine has a unique manufacturing process, however, certain stages are common. For example:

• propagation of active components by growing them in animal, plant, fungal or bacterial cells (‘cell culture’) or by making them via chemical reactions
• purification to extract the active components
• formulation to mix vaccine components in a way that has been optimised to ensure the vaccine produces an effective immune response, can be taken up by the body, can be produced at scale and remains stable
• fill and finish, when vaccine is filled into syringes, vials or other containers, then labelled and packaged ready for shipment (see ‘Fill and finish’ below)
• sampling and testing, of the vaccine throughout the manufacturing and filling process for consistency and microbiological integrity.

 The Government’s UK COVID-19 vaccines delivery plan, published on 11 January, reported that the UK has secured access to 367 million vaccine doses from seven different developers, at an expected cost of £2.9bn. Three of these vaccines (developed by AstraZeneca/the University of Oxford, Valneva and Novavax) are being manufactured in the UK, in some cases with additional manufacturing in other countries.

All of the vaccines ordered by the UK fall into one of the following four categories: inactivated, protein-based, adenovirus-based and RNA-based. The manufacturing process for each type is discussed in more detail below. For further information from POST and the House of Commons Library about how vaccines work and are developed, visit our Vaccination and Covid-19 webpages.

1. Inactivated vaccines

These include the Valneva vaccine (in clinical trials). They are a well-established type of vaccine, which contains virus that has been killed and therefore cannot multiply in the human body. Examples include the inactivated influenza vaccine, which is offered annually in the UK.

They are produced by isolating a strain of the virus that is then grown either in cells (such as mammalian cells) or within eggs, where the virus replicates. During this replication process, the infected cells divide, producing even more cells containing the virus. The virus is extracted using purification techniques such as filtration. It is then deactivated by exposure to a chemical or physical process, such as radiation, that stops it being infectious.

This approach involves producing large quantities of live virus and therefore requires high-level biosafety containment, such as the use of filtered ventilation and access to decontamination equipment. These requirements contribute to the high costs of this vaccine type. Scaling up the cell culture process can also be technically challenging.

2. Protein-based vaccines

These include the Novavax vaccine (in clinical trials) and the GlaxoSmithKline/Sanofi Pasteur vaccine (in clinical trials). They contain part of the virus (usually the Spike protein found on the surface of SARS-CoV-2) to trigger an immune response. The virus protein is produced in large quantities by growing it in a cell culture system. Once grown, the virus protein is extracted through an extensive purification process.

This approach is well established. It does not use the whole virus and is therefore safer to work with and does not require high-level biosafety containment.

3. Adenovirus-based vaccines

These include the AstraZeneca/University of Oxford vaccine (approved and in use in the UK) and the Janssen vaccine (in clinical trials). They contain a harmless weakened adenovirus that has been modified to include the genetic information of the SARS-CoV-2 surface Spike protein.

Following vaccination, the body ‘reads’ this genetic information, produces the Spike protein and develops an immune response against it. During manufacture, the modified adenovirus is grown in mammalian cells and then purified.

Adenovirus-based vaccine technology has not been widely used to date. As the virus is not harmful, high-level biosafety containment is not required. This makes it easier to produce the vaccine in larger quantities. It is also quicker and easier to construct new manufacturing facilities or to repurpose existing ones. As these vaccines contain a live virus, they typically need to be refrigerated or frozen. The AstraZeneca/University of Oxford vaccine can be stored in a standard fridge.

4. RNA-based vaccines

These include the Pfizer/BioNTech vaccine (in use in the UK, the first ever RNA-based vaccine to be approved for use in humans) and the Moderna vaccine (approved for use in the UK). They contain the genetic information needed to build the SARS-CoV-2 Spike protein. Once injected, the human body ‘reads’ these instructions and produces the protein, then develops an immune response against it.

RNA-based vaccines can be produced using chemical processes that don’t require a cell culture system or high-level biosafety containment, making manufacture faster and easier than for other types of vaccine. A manufacturing facility created to produce one RNA-based vaccine should be able to rapidly manufacture other RNA-based vaccines, with minimal changes to processes and vaccine formulation.

Production may be slowed down, however, if there are challenges with obtaining the large quantities of reagents (such as enzymes) needed to produce RNA-based vaccines on a global scale. Other difficulties include optimising vaccine formulation to ensure that the RNA doesn’t degrade and is taken up by the body effectively. Formulation of the Pfizer/BioNTech vaccine involves coating tiny quantities of vaccine with lipid (fat-like molecules) to protect the RNA and help it to enter the body’s cells, where it is read.

RNA-based vaccines typically degrade at room temperature. The Pfizer/BioNTech vaccine needs to be frozen at particularly low temperatures of -70⁰C for transportation. Before the current pandemic, RNA-based vaccines had never been manufactured at scale, and so there is limited large scale manufacturing capacity and experience for this type of vaccine.

What are the challenges to manufacturing at scale?

There are an estimated 15 million people in the four highest priority groups for vaccination under the UK’s COVID-19 immunisation programme. These include adult care home residents and their carers, frontline health and social care workers, people aged 70 and over, and people who are clinically extremely vulnerable.

Under the dosing schedules for the three vaccines currently approved for use in the UK (the Pfizer/BioNTech, AstraZeneca/University of Oxford and Moderna vaccines), each person will require two doses. The Government has said that it aims to offer a first vaccine dose to everyone in the four highest priority groups by 15 February. 530,000 doses of the AstraZeneca/University of Oxford vaccine were reportedly available for use in the UK from 4 January.

2.9 million people in the UK had received at least one dose of vaccine by 13 January 2021.

Manufacturing vaccines rapidly and at scale can involve several challenges, relating to cost and timescales, access to manufacturing facilities, access to expertise and specialist knowledge, supply chains, the fill and finish stage when the vaccine is put into containers for distribution, and quality control.

Cost and timescales

Establishing a vaccine manufacturing facility can cost roughly £40-500 m ($50-700 m) and can typically take three or more years. Other costs include those of the raw materials and other consumables, utilities, personnel, and quality assurance and compliance. The additional resources being made available to develop COVID-19 vaccine manufacturing capacity are shortening these timescales.

A survey of manufacturers conducted by CEPI in April to June 2020 estimated that there is capacity to produce 2–4 billion doses of COVID-19 vaccine globally by the end of 2021, without disrupting existing vaccine supplies. Other estimates suggest this might be higher, and that AstraZeneca, Pfizer and Moderna alone could produce a combined total of 5.3 billion COVID-19 vaccine doses in 2021. However, models predict that it may be 2023 or later before sufficient vaccine is produced to cover the global population.

Access to manufacturing facilities

Much of global vaccine manufacturing capacity is located in India, China, Europe and North America. The UK has limited facilities for vaccine manufacture, although it does have capacity to make vaccines for influenza and some childhood diseases. The UK Government is investing in developing new manufacturing capacity for COVID-19 vaccines (see above).

Two approaches to producing larger quantities of vaccine are: scaling up by increasing the size of vaccine batches, and scaling out by creating multiple production streams. It is likely that a combination of these approaches will be needed to achieve the volumes of COVID-19 vaccine required globally.

Conventionally, vaccine manufacturing has been scaled up in large, centralised, bespoke facilities. These can make quality control and regulation easier, and help to lower costs. However, these are more difficult to change or repurpose for new vaccines, and can have long supply chains for obtaining materials and distributing the vaccine. In addition, newer types of vaccine (such as RNA-based vaccines) have not been produced in large quantities before and there may be limits on how far production processes can be scaled up without spending significant time and money on process development.

Scaling-out typically involves setting up a larger number of small scale manufacturing facilities at different locations. This has the advantage of avoiding some of the challenges associated with manufacturing at very large scale, and reduces the risk of losing production capacity or experiencing supply chain disruption – if one site stops production, others in the network can continue.

It may also make it easier to access local knowledge of regulatory issues and make distribution easier if facilities are closer to the population where the vaccine is to be administered. However, this decentralised approach can create challenges for ensuring that manufacturing processes are robust enough to be replicated, that the facilities required are available, that any intellectual property associated with the production process is shared, and that production is consistent across different facilities.

Some parts of the manufacturing process, such as fill and finish, can be more easily adapted to new vaccines. Single-use technologies (such as using large plastic bags for cell culture instead of stainless steel bioreactor tanks) can also help to rapidly repurpose existing manufacturing facilities at lower capital costs.

Access to expertise and specialist knowledge

Vaccine manufacture requires personnel with technical competence and knowledge of the latest technologies and global regulatory requirements. Globally, there is a shortage of people with these skills, and hiring and training staff can be a challenge for even experienced manufacturers.

The UK Government has recently announced funding for skills training in vaccine manufacturing (see above).

Accessing the proprietary knowledge needed for vaccine production can also be challenging for manufacturers. This can include technical information about the type of cells used to grow virus proteins in, or the production software used.

Knowledge of a vaccine’s manufacturing process can offer competitive advantage, and many vaccine patents protect the manufacturing process itself rather than the product produced. Historically, manufacturers have reverse-engineered the manufacturing processes used by their competitors in order to produce their own version of a vaccine, however this can be time consuming and costly.

To improve access to information, the World Health Organization is establishing a COVID-19 technology access pool to facilitate the sharing of knowledge, data and intellectual property globally. In another initiative, a group of six pharmaceutical companies researching antibody treatments for COVID-19 obtained permission to share technical information about their manufacturing processes and platforms, under anti-trust law in the US.

Such information exchanges may help to speed up the development of treatments for COVID and could improve standardisation and reduce secrecy over manufacturing information in the longer term. However, knowledge may still be difficult to share if it is context-specific or based on experience, and therefore harder to capture and communicate.

Supply chains

Vaccine manufacture may be slowed down by limited access to raw materials and equipment, such as vials, tubing, bioreactors, cell culture medium (required for growing cells) and reagents such as enzymes. For example, the enzymes used to make RNA-based vaccines are not currently produced in quantities approaching those required for global-scale vaccination, and so their manufacture will also need to be significantly increased.

Concerns have been raised about the availability of glass vials needed to store and transport the finished vaccines. Supply chains are at risk of being disrupted by the pandemic itself if borders are closed, transportation and travel limited, or if staffing is reduced because of sickness or COVID-safe working conditions.

Fill and finish

Another key manufacturing bottleneck is the ‘fill and finish’ process, which involves putting the vaccine into vials or other containers for distribution. Large glass vials with capacity for up to 20 doses have been used in the past, but these volumes will not be sufficient to transport the amount of COVID-19 vaccine required for global scale vaccination. Alternative fill and finish technologies are currently under evaluation, including a 200-dose bag to help speed up roll-out.

The UK Government is investing in developing fill and finish capacity at sites including in Swindon and Wrexham. Such investment is based on assumptions about the types of vaccine most likely to be given approval, their storage requirements and how they will be administered. Facilities may need significant modification if they are used for other types of vaccine. Fill and finish does not need to happen at the same location as vaccine manufacture, and more efficient use of existing global fill and finish capacity could help to speed up this stage of the manufacturing process.

Quality control

Before any vaccine can be widely used in people, it needs to obtain a medicines licence (also referred to as a marketing authorisation). These are granted by national regulators after evaluating all the data from preclinical and clinical trials and deciding whether it is effective, safe and has acceptable side effects.

Following the UK’s withdrawal from the EU, the Medicines and Healthcare products Regulatory Agency (MHRA) is responsible for granting medicines licences in the UK. These licences cover the processes by which a vaccine is produced, tested and released for use, in addition to the vaccine itself.

Vaccine manufacture must take place in a registered manufacturing facility and follow Good Manufacturing Practice and Good Distribution Practice.  These guidelines ensure that products are of a consistent high standard, appropriate for use, and meet the requirements of their licence.

The MHRA carries out inspections to check compliance, which can involve site inspections, interviews with personnel, reviewing documents, and taking samples for testing. Changes in the manufacturing process, such as new facilities or equipment or changes in raw materials, may alter the purity, safety, or efficacy of a vaccine. They often require further time-consuming validation, such as additional clinical trials, in order to maintain a product’s licence.

Every batch of COVID-19 vaccine (and any other biological medicine) must be tested for safety and effectiveness before it is released for use in the UK. This is the responsibility of the National Institute for Biological Standards and Control (NIBSC). NIBSC is an independent government laboratory and a centre of the MHRA.

Its tests are in addition to manufacturers’ own testing regimes. It checks the quality of each batch and reviews the manufacturer’s documentation describing their production process and quality control testing. To speed up the process, this independent batch testing is done in parallel with the testing done by the vaccine manufacturer. The UK Bioindustry Association has highlighted the need to ensure that the MHRA and the NIBSC have sufficient resource to meet their significantly expanded responsibilities in light of both Brexit and COVID-19.

Beyond manufacture

Once COVID-19 vaccines are manufactured, there may be significant challenges to ensuring that they are distributed and administered effectively. These include: setting up distribution systems to deliver vaccines to where they are needed, ensuring an adequate supply of needles and syringes, and training sufficient numbers of personnel to give vaccinations safely.

Most vaccines need to be kept chilled or frozen during transport and storage, adding to the logistical challenge, especially in low- and middle-income countries. For global coverage, international collaboration will be needed to ensure vaccines are affordable and available.

As for other infectious diseases, vaccines are widely considered to be the most effective public health intervention against COVID-19. Once the UK’s programme for immunising priority groups has concluded, more data will be available to tell us how effective vaccination is for protecting people from infection and reducing transmission of the disease in the population. One possibility is that COVID-19 may become one of many circulating winter respiratory diseases, for which annual immunisation is required.

Plans for vaccine manufacture to meet national requirements for annual COVID-19 immunisation could be managed in the same way as for other diseases, such as influenza. In the UK, the Government takes advice from the Joint Committee on Vaccination and Immunisation on who should be immunised, then orders enough vaccine to cover these groups.

As the number of approved COVID-19 vaccines increases (each of which are likely to differ in levels of protection), government decisions about which vaccine to offer which groups, operational logistics and cost-effectiveness will also come into play.

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