Most Australians will receive the Oxford-AstraZeneca vaccine in an effort to prevent the worst effects of COVID-19 and also, health officials hope, reduce how fast the coronavirus spreads.
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The Therapeutic Goods Administration has not approved the vaccine, which is produced within Australia in CSL labs, but the company is working around the clock to produce 50 million doses. The first doses are on track for release in March.
Prime Minister Scott Morrison, during a visit to one of CSL's labs on Friday, said Australians could have great confidence because everything checked out again and again.
The vaccine takes 12 weeks to produce, before heading to TGA labs in Canberra for batch testing, and finally to your local vaccination centre.
Each of those 12 weeks are critical in ensuring the safety and reliability of the vaccine.
Dr Anthony Stowers from CSL, and Chris Larkins from Seqirus, explained to The Canberra Times how their teams take the tiniest starter materials and turn them into the doses that can be injected in people around Australia.
Drug substance manufacture phase
An army of people are involved in checking that everything on site at Broadmeadows is prepared for the arrival of the two key ingredients - a vial of cells and a vial of adenovirus provided to CSL from AstraZeneca.
The cells take the next few weeks to gradually increase in volume and are moved to increasingly larger reactors to help that growth.
"It's quite a slow process, because cells aren't happy when they're in by themselves or when they're in small volumes," Dr Stowers said.
"They're mammalian cells so they take quite a long time to grow. They're not like bacteria cells which replicate in minutes."
The cells have to do all the growing, because the other part of the vaccine, the adenovirus, can't. It's been genetically engineered so it can't replicate itself, so it's a safe vaccine.
They add the adenovirus to the bioreactor and wait for six days so the cells can help the adenovirus replicate to the quantities the government needs to provide doses to everyone in Australia.
The vaccine is then harvested. This is a process of separating the cells and filtering anything that isn't needed in the vaccine, including those original cells.
The bulk, concentrated vaccine is then frozen and stored in cryo-vaults.
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Samples are taken and undergo extensive testing, but it's still just a drug substance - not yet a product ready for use.
"It has to have the right potency - it has to do what it needs to do as a vaccine. Only then do we release the product for the manufacturing process," Dr Stowers said.
The cryo-vaults are transferred across Melbourne to the Seqirus Parkville site - where Mr Morrison toured - and are thawed out ready for formulation.
Each batch so far is started only a few days apart, or they would never reach the quantities needed.
The manufacturing process starts at the six-week point. Six batches have reached this stage so far.
Drug product manufacture phase
Each delivery received at Seqirus contains enough material for millions of doses.
Before they can even open them up they have to go through further quality checks. Those tests take at least another week.
Many people will have seen footage of the orbital shaking machines, which thaws out the vaccine into liquid again at room temperature.
"Once we complete that step on a single batch, the clock is ticking," Mr Larkins said. "From here on in, every step of the process is tracked down to the minute for how long the product spends out of refrigeration."
So far, two batches have reached this critical stage.
For every 20 litres of the drug substance, they transfer it to a 200-litre, single-use sterile mixing bag and fill with a pre-formulated buffer material.
That buffer contains ingredients that will stabilise the vaccine and moderate the pH levels so it can be used as an injectable product.
Before it can go forward, there's another round of tests to check the concentration levels and determine if they need to add more of the buffer.
The next stage is the dispensing and packaging facility in Parkville. At no point prior to this stage has the vaccine been exposed to air or any environment.
The vaccine goes through one more stage of filtering before going on to the filling machine that measures out exactly 6.5 ml in every dose. That ensures every vial can deliver 10 doses.
Above the filling station is "grade A" air and the operators can only access the station through gloves. The stopper and caps go on and everything at that point is still sterilised.
A 12-hour shift at the filling station can produce 300,000 doses from a single batch.
Once sealed, the vials can be removed from the "grade A" environment and put back into refrigeration.
"It's a regulatory requirement for sterile products that every single unit needs to be inspected visually," Mr Larkins said.
"We can't just take a sample." Anything as simple as a scratch on the glass puts the doses at risk.
Final tests and dealing with deviations
An equal amount of samples is sent for testing at CSL and AstraZeneca, as well as the TGA lab in Canberra. The TGA has to give its approval on every batch before it can be sent out.
Mr Larkins said repeat testing by manufacturers and regulatory bodies was standard in all vaccines, but they weren't exactly the same tests.
The final step comes from AstraZeneca as the market authorisation holder in Australia, who review all the data and perform the official release to government.
Deviations in test results are documented and shared with the TGA. In many instances, the root cause of the deviation can be explained and the batch is unaffected.
"In some cases you do get results back or something has gone wrong, in that case we will decide not to release that particular batch," Mr Larkins said.
"But that's all done in conjunction with the TGA on a batch-by-batch basis."
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