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As part of the Jenner Institute, the Clinical BioManufacturing Facility has been at the forefront of manufacturing vaccines for known and emerging pathogens. Some diseases are well known, such as malaria, HIV and tuberculosis. Others are less well-known, such as Rift Valley fever and Lassa fever. Regardless, the aim of the Jenner Institute and the CBF has been to accelerate the development and manufacture of vaccines for diseases with pandemic potential.

 

Incremental progress over many years has been made in the research laboratory settings of the Jenner Institute, and importantly also in the optimisation of manufacturing practices at the CBF.  Research brings the new ideas, and manufacturing makes the new ideas viable as medicines for human diseases in the form of doses ready to be delivered to the clinic. Over the years, different viral backbones were employed, and different manufacturing processes were developed. The now well-known ChAdOx1 vector was developed by the researchers at the Jenner Institute in 2012.

 

In December 2019, a pneumonia-like disease was spreading through Wuhan, China. The sequence of the SARS-CoV-2 virus was made freely available by Chinese researchers, in the first of many international acts of collaboration seen throughout the pandemic. In January 2020, researchers at the Jenner Institute designed a string of DNA containing the sequence of the Spike protein of this new virus. How did they know to use the Spike protein as their target? From work performed a few years back on another coronavirus, MERS. The CBF was involved in the manufacture of the MERS vaccine, along with other ChAdOx1 vectors.

 

Thanks to the previous knowledge of how to design an effective vaccine to a coronavirus AND the experience of manufacturing a vaccine to the highest standards, the unique position of the Jenner Institute researchers and the qualified team at the Clinical BioManufacturing Facility allowed the teams to move at an extremely rapid pace.

 

The Starting Material team received the SARS-CoV-2 Spike protein DNA from the researchers on 18th February 2020 and we began by inserting this into the ChAdOx1 backbone, in a process known as ‘cloning’. The name given to the vaccine was ChAdOx1 nCoV-19. At this time, COVID-19 was not yet known to spreading far beyond the boundaries of China. The team continued working hard on obtaining and characterising a single clone of the virus that was suitable for rapid transfer into GMP, and the Quality Control Team diligently performed the in process checks to ensure the highest levels of quality were being achieved.

 

Meanwhile, the Production Team were in the manufacturing cleanroom suites working on another vaccine at the time, but it quickly became evident in February that COVID-19 was becoming a concern worldwide and a decision was made in agreement with the Principal Investigator and the CBF Senior Management Committee to postpone the final part of the campaign and to move swiftly onto the ChAdOx1 nCoV-19 project. While on paper this seemed straight-forward, many simultaneous processes had to take place in order to make this happen, all in rapid time. In addition to the practical work being performed 7 days a week by the Starting Material, Quality Control, and Production Teams, many other aspects needed to be addressed in regards to risk assessments, documentation, and supply of materials, for which the Quality Assurance Team, Qualified Persons and IMP team also worked long evenings and weekends to ensure all processes were being completed as required by regulations. During this time, the Facilities Team were also making sure the building, labs, equipment and cleanrooms were all maintained to the highest standard. Storage space quickly became an issue but this was sorted thanks to the Operations Manager and Operations Assistant.

 

On the 6th of March 2020, the Production Team started the GMP manufacture of the ChAdOx1 nCoV-19 vaccine in the cleanrooms. Timelines were evaluated and re-visited seemingly hour-by-hour (day and night) to ensure that all the many targets we needed to hit were still on-time and achievable. We had many years of experience growing the type of cells required for this project, and so we knew exactly on which date we would have enough cells to start the next phase of manufacturing. This next phase was when we took the material, generated by the Starting Material Team and tested by the Quality Control Team, and added the virus to the cells to make more virus. The process of making more virus, under the conditions we had extensively evaluated and optimised over many years, took about 48 hours. A process then known as ‘harvesting’ took place, where we took all the cells we had grown (all 10 billion), filled with many copies of ChAdOx1 nCoV-19. We performed some ‘purification’ steps to clean away the virus from the cellular material that we didn’t need. At this point, our highly qualified fill and finish operators manually filled hundreds of vials, ready for inspection by the Quality Teams, labelling by the IMP team, testing by the Quality Control team and also sent same-day delivery to external Contract Research Organisations (CROs) for testing.  The date of the ‘Fill/Finish’ was 2nd of April 2020.

 

During these long days in the laboratories and cleanrooms, the CBF office-based team was also on a 7-day a week schedule. All items ordered needed to be inspected and released for use according to our specifications; many pages of documentation were being generated, and this needed to be checked for compliance and reviewed. Many phone calls were made to our critical suppliers to ensure we had all the supplies required for manufacture, and of course, we all needed hand gel! Our Facilities Team kept our building standing throughout this time, all while dealing with unexpected critical equipment breakdowns.

 

The testing results came quick and fast, both from our Quality Control Team and our external CROs. These results needed to be checked, investigated, approved and summarised. All batch documentation also had to go through this process. The Quality Assurance Teams and the QPs had the job of making sure all the processes had been followed according to our Standard Operating Procedures, Product Specifications, Manufacturing Instructions, and the regulator’s requirements.

 

Our batch of ChAdOx1 nCoV-19 was released by our Qualified Person on 22nd April 2020, and the first volunteers were injected on 23rd April 2020, about 20 meters away at the Oxford Vaccine Group by Dr. Andy Pollard and his group.

 

The unique set-up at Oxford University of the expert Jenner Institute academics, the trained staff at the Clinical BioManufacturing Facility, and the experienced clinicians at the Oxford Vaccine Group enabled the first clinical trial of a COVID-19 vaccine to be initiated within 4 months of the discovery of the disease. All the previous years of trial and error, collaboration, practice and scale-up from these groups culminated in a rapid response to a pandemic situation not seen before.

 

Of course, the story does not end here, as billions of doses are now required, and still many hours of input are still being made by the Jenner Institute and the Clinical BioManufacturing Facility into the large-scale manufacturing efforts led by AstraZeneca. Each vaccine has their story, and this one has been different from many others. This won’t be the last pandemic we live through, but this experience will hopefully help us target the next one even more quickly.