Innovating Production and Manufacture to meet the Challenge of COVID-19
At AstraZeneca, we have committed to support the truly global effort to fight the COVID-19 pandemic across multiple fronts. The need for an urgent response to the virus has challenged scientists around the world to accelerate the large-scale global clinical investigation and development of potential medicines and vaccines to potentially prevent or treat COVID-19.
We are collaborating with scientists, governments and multilateral organisations, sharing our scientific knowledge and expertise as we follow the science, put patients first and do the right thing for society.
Normally, the manufacturing of our medicines increases in line with their progression through clinical development and when they are ready for launch commercially, a central supply chain is already in place to support supply.
But the urgent need for the rapid manufacture of effective treatments and vaccines has required a different approach during the pandemic. Led by a global team, we are changing how we produce and manufacture a vaccine at scale and pace.
This robust pandemic response has seen our manufacturing and supply chain experts, engineers, technical scientists and Quality professionals work in parallel with clinical development to rapidly apply innovative thinking to commercial vaccine production. We have already started manufacturing the vaccine so that, should clinical trials prove successful and the vaccine be approved by regulators, it will be available to support broad and equitable access.
To produce billions of doses of a potential vaccine for markets around the world, we have built more than a dozen regional supply chains to provide rapid access to as many countries as possible, as quickly as possible following regulatory approval, while reducing transportation and any potential export or importation constraints. This network was designed with our broad understanding of global supplier capabilities, combined with a focus on local manufacturing where possible and a drive to balance speed of supply with affordable costs.
To accelerate vaccine production and supply involves collaboration with more than 20 supply partners in more than 15 countries, supported by more than 20 analytical testing sites.
Our supply chain includes multiple manufacturing facilities across each stage of production - drug substance, drug product, and finished packaging. These partners will collaborate with us throughout the entire manufacturing process, receiving support and technical guidance.
Central to our mass supply capability is defining the chemistry, manufacturing and controls (CMC) of the production process. During CMC, we are developing an optimised, repeatable manufacturing process that delivers maximum yields and ensures high-quality product across our supply chain.
This manufacturing process is then transferred to our partners to establish supply at their respective facilities. Because quality testing is required throughout the manufacturing process, as well as to support product release in market, we have also built an extensive analytical network and are rapidly transferring our analytical methods to these laboratories.
Our procurement team is also working to secure and accelerate a global supply chain of critical raw materials, reagents and consumables in collaboration with our suppliers to enable rapid manufacturing and quality testing.
It is very important to us at AstraZeneca that we can produce as much vaccine as possible to ensure broad, equal access as soon as possible after a potential approval. 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.
Making a vaccine at a glance
These are the crucial manufacturing processes needed to create a vaccine on an unprecedented scale:
- CMC – A commercial manufacturing process has been developed from an initial small-scale process before rapidly scaling to increase productivity yields, all the time ensuring purity of the final product. This consistent process is employed by each manufacturing facility we are collaborating with.
- 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 infected by the virus seed 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.
Ensuring the vaccine produced is of consistent, high quality, the production process utilises living ‘producer cells’ derived from a human cell line, created more than 50 years ago. The cells are altered to act as ‘mini factories’ to produce the vaccine rapidly.
Growth of the producer cells takes place in single use bioreactors, which reduces the risk of cross contamination and enhances biologic and process safety. Conditions including pH and temperature are very tightly controlled to ensure growth occurs at an optimal rate.
As a biopharmaceutical company, we are highly-experienced with the process and protocols required for biomanufacturing. However, manufacturing a live vaccine at this scale has required us to rethink how we can rapidly optimise to accelerate into large-scale production. This has required a clear focus on the underpinning science of the vaccine and available technical process data, coupled with real-time learning from the clinical supply programme. It has been a true collaboration between Oxford, our supply partners and our internal team at AstraZeneca
Once the producer cells reach a phase of growth that contains the required viral particle concentration, the vector vaccine is harvested. The cells are burst open using a lysing chemical to release the vaccine. The culture then undergoes a series of filtration steps to remove cell debris, followed by a series of filtration processes to improve yield and clarity of the vaccine product. Normal flow filtration (NFF) is used, passing the culture through a series of membranes containing varying pore sizes that filter out different sized cell debris and waste products. At this stage, some of the sample can also be removed to create another batch of vector vaccine working stock.
Membrane chromatography is then carried out to further purify the product. This ‘giant’ chromatography step can be carried out at large scale and works by the vaccine selectively binding to its surface, which is then released as the purified product. Finally, ultrafiltration re-buffers the viral vector vaccine into its final formulation.
The final drug substance is transported for ‘fill and finish’ into multi-dose vials and packaged into cartons. The finished drug product is anticipated to be stored and transported at 2-8oC, pending ongoing stability studies. Final determination of temperature and shelf life will only be made once sufficient data has been collected for the vaccine over time and approval by regulators.
Safety and quality standards of vaccine manufacturing are of paramount importance and quality testing is required throughout the process, as well as to support product release authorisation in the markets and regions. Numerous tests are carried out at each step of the drug substance and drug product manufacturing processes and quality control measures are employed throughout to ensure consistency and quality of the vaccine. In total, more than 60 tests per batch are conducted to ensure safety, purity and efficacy.
We use various technology platforms such as polymerase chain reaction (PCR) to rapidly identify the vaccine and sequencing technology to verify the adenoviral vector carries the spike protein genetic code, high pressure liquid chromatography (HPLC) to assess purity and anion exchange chromatography (AEX) to measure viral titer. In addition, researchers from Bristol University have recently confirmed the vector vaccine accurately follows the programmed genetic instructions to form the spike protein within a cell, through advanced sequencing and protein analysis technology.1
The impact of factors such as heat, light, radiation, environmental changes, as well as interaction with container materials are also determined for the vaccine through testing. Storage and handling conditions are defined at each stage of the production process to optimise product stability, shelf life and ensure safety, quality and efficacy is maintained. Given the need to progress at pace, stability testing is being carried out in parallel with drug product manufacture and data collected over time to determine the optimal temperature range for vaccine transport and storage.
All manufacturing partners are subject to Current Good Manufacturing Practice (CGMP) and appropriate Quality Systems leading to licensure in their specific supply region. The manufacturing process is used by our partners at their respective facilities and we are rapidly transferring our analytical methods to ensure a repeatable manufacturing process that ensures high-quality product across our supply chain.
AstraZeneca has committed to the global development and production of a potential vaccine for COVID-19 to ensure supply for as many countries as possible, at no profit during the pandemic period. We have built a global supply network adhering to the highest quality and safety standards with a capacity so far towards three billion doses. We have done this so that if clinical trials show the vaccine is safe and effective and approvals for use are received from regulators, the governments and multilateral organisations that we have formed agreements with can then work to ensure fair allocation and distribution of the vaccine within their countries and regions.
The safety and high quality of a medicine or vaccine is absolutely paramount. That is why safety and quality control are embedded throughout the production process. More than 60 tests are carried out during the making of every batch of vaccine. We are employing the same rigour we apply to every product we make, carrying out tests and checks quickly and in parallel to ensure we can deliver the vaccine at pace and in the vast quantities needed.
1. SARS-CoV-2 candidate vaccine ChAdOx1 CoV-19 infection of human cell lines a normal low range of viral backbone gene expression alongside very high levels of SARS-CoV-2 S glycoprotein expression. Available at: https://www.researchsquare.com/article/rs-94837/v1
Veeva ID: Z4-28549
Date of preparation: November 2020