The availability of Covid 19 vaccines and potential delays has made this topic of interest to the public.
The usual form for modern vaccines is a liquid (normally sterile water) containing a number of identical fragments of the organism, protein or RNA strand which the body’s immune system will use to train itself to identify the real organism and build antibodies to fight the infection. This liquid and a few chemical additives to help keep things stable are altogether called the vaccine. The process to make a vaccine is like making a cake and we follow a very specific recipe detailing each ingredient and each step of the manufacture. It is much more complicated than baking a cake but the analogy is useful. The vaccine is normally made in large quantities (thousands or millions of doses in a batch). This is generically known as the vaccine Drug Substance and it is stored ready for dividing into individual containers such as vials. So again, the analogy would be the cake mixture (being the Drug Substance batch) and each cupcake being the individual doses of vaccine which is generically known as Drug Product.
The Drug Substance batch manufacture has to be tightly controlled and is fully documented against an approved and proven process which can be repeated over and over to make large quantities of Drug Substance. This is referred to as a validated process. Various analytical tests are carried out on samples of this batch as part of Quality Control. There are lots of documents that trace every part of the process, such as where we get the ingredients for each part of the manufacture, how we manufacture, how long we take to do each step in the manufacture, what temperatures and other conditions are used to make the batch, what tests we do on the finished batch, etc. All of these documents form the batch records.
The Drug Substance batch records and Quality Control records showing that the batch has been made correctly and to specification are then independently reviewed by an independent group called Quality Assurance whose role is to do just that, assure Quality.
Once all of these Drug Substance stages of the process are completed satisfactorily, the Drug Substance may be formulated further and filtered to get the vaccine to the final formulation. It will then be filled into much more useful containers, (elastomer stoppered vials) or devices (pre-filled syringes) to be used in the clinic for delivery to patients. In the pandemic, this is likely to be in vials (a small bottle) containing approximately 5-10 doses currently. (Each vaccine specifies how many doses are in each vial.) The process to fill the Drug Product into smaller containers is again a tightly controlled process, completed in clean rooms, often in further contained spaces to avoid any contamination. This is generically called Fill and Finish. At this point, the contained product is now called a Drug Product. From here on, it gets labeled and packaged for transport.
The filled containers are labeled for full traceability and then these are put into labeled boxes with product information leaflets for use at the clinic. The individual boxes are then put into larger storage boxes. Again, the process is completed to very detailed procedures and these are all documented. Most of the pictures on the News are of this Fill and Finish part of manufacturing.
Once the Drug Product is packaged in its individual cartons and then placed into larger containers, it is stored awaiting another review of the Fill and Finish batch records. Quality Control will test a number of vials or syringes from across the batch to ensure that they meet the pre-agreed specification for each tested container. Failures can result in whole batches being rejected. Manufacturing and Quality Assurance approve the batch records and recommend approval.
A designated person, recognised by the MHRA (Medicines and Healthcare Regulatory Authority) called a Qualified Person (QP) reviews all of the documentation from the entire process to check that the vaccine has been made in a compliant manner, that it meets is pre-determined specification and that any details specified in the licence from the MHRA have been met. In short, the QP confirms the product is fit for use and is safe for the patient. If all this is acceptable, the QP releases each batch onto the market.
In order to best supply the Drug Product as quickly as possible, the Drug Substance can be made “at risk” before regulatory approval and kept in anticipation of approval of the vaccine by the MHRA, which may be granted with a range of conditions. As these conditions are not known until regulatory approval, the Fill and Finish part of the process is not usually done in advance of regulatory approval.
Until the Drug Product has approval for use, it will usually be stored on the Manufacturer’s premises because the release of, in this case, vaccine has to be assured. The Drug Substance can be approved for release at this stage and this saves time in the release of the Drug Product by the QP who can refer back to the approval of the Drug Substance manufacturing processes.
In the case of the three approved Covid 19 vaccines, the MHRA must also approve the batches for release as an additional step because this is being done under an Emergency Use Authorisation. Full marketing approval will almost certainly be given at some point when the MHRA deems this to be the correct decision.
The manufacture of pharmaceuticals requires well trained personnel, a comprehensive record, and an enormous amount of checking and Quality Assurance. The aim is to ensure that the scaled-up manufacturing process used to make your vaccine is as close as possible to the vaccine given to people on the clinical trials, whose data has convinced the regulators of the safety, quality and efficacy of the vaccine. This means that pharmaceutical manufacturing might seem slow and difficult compared to other industries and certainly compared to baking cakes but the processes are essential when dealing with people’s lives directly.
For more information please contact the ISPE UK Covide 19 response team: firstname.lastname@example.org
ISPE UK Covid 19 Response team.