Keys to design an mRNA vaccine manufacturing facility

As we mentioned in one of our previous publications, the mRNA vaccines used against SARS-CoV-2 are neither a coincidence nor a one-off event. This field of biotechnology has been in development for years, and the pandemic was just the trigger to polish this technology. The Pfizer and Moderna vaccines were the first to use mRNA, but we are sure that they are the first of many because of the innumerable advantages they offer over other types of vaccines.

This revolution in the biopharmaceutical sector has huge implications. This type of drug was not produced until a few months ago because the technology was not 100% developed. Now an immense amount of doses are needed and in the near future, vaccines with very similar characteristics will start to be used. Therefore, a new type of production plant is required to be able to cover all this demand. And what features must fulfil a plant where these types of vaccines are produced? Klinea, as an engineering company specialised in (bio)processes and GMP plant design, will put some light on the topic.

Before we start, let’s take a brief look at how mRNA vaccines work and how they act in our body. The mRNA vaccines to prevent Covid-19 introduce mRNA fragments protected by a lipid envelope into our body. These fragments will reach specific cells, which will be able to interpret the mRNA information. The information contained in this mRNA allows our cells to produce a protein found in the SARS-CoV-2 envelope, called protein S. Protein S itself does not cause any damage, but is able to act as an antigen (a substance that generates immunity in our body). In other words, the cells of our immune system will be able to recognise protein S and generate specific antibodies against it. So if the virus were to enter our body, we would already have specific antibodies that would recognise the S protein present in the virus envelope. And the antibodies would neutralise and kill the virus before it could cause serious illness.

The following considerations will be taken into account in the production of the vaccine:

• The mRNA fragments. These are made up of a chain of nucleotides. Several strategies can be used to produce the mRNA. In this particular design we will use the following one. A DNA strand, called a plasmid, will act as a “template”. The mRNA will be produced by adding nucleotides, which will be arranged in the order established by this “template”.
• The plasmids acting as a ‘template’. These plasmids will be produced using cells that will be grown in a fermenter. After the necessary time has elapsed, the plasmids can be purified using the following operations: centrifugation, cell lysis, clarification, chromatography, enzymatic digestion, ultrafiltration/diafiltration and finally sterilisation by filtration.

When designing the plant, it is essential to take into account the regulations governing the type of medicinal product to be produced. Contrary to what may initially appear, mRNA vaccines are not considered ATMPs (Advanced Therapy Medicinal Products). In the American framework, they are regulated by 21 CFR 600 – 680. As for the design of the plant itself, the FDA has published the following document: FDA’s Development and Licensure of Vaccines to Prevent COVID-19 Guidance for Industry (FDA-2020-D-1137). In terms of European regulation, the conditions of Annex II would apply, as it is considered a biological medicinal product for human use, as well as Annex I, as it is a sterile medicinal product. In addition, the regulation of gene therapies is also applied (Annex IV).

In an mRNA vaccine production plant, we will find the following operations:

1. Plasmid production. This involves the cultivation of cells (probably bacterial) in fermenters and the subsequent purification of the plasmid mentioned above.
2. Production of mRNA. Using the plasmid and other components, such as nucleotides and certain enzymes, the mRNA fragments that will go into the vaccine will be produced. Again, purification will be necessary to separate the mRNA from the other remaining elements involved in the reaction.
3. Lipid envelope production and mRNA binding. From lipids, envelopes will be produced that will protect the mRNA until it reaches the cell. Once produced, the mRNA fragments will be encapsulated within these lipid envelopes.

These are each dedicated area that are “out of the ordinary” in the design of a biopharmaceutical production plant. Apart from these, there will be other more common ones among which we find: the area for the formulation of the final drug, the warehouse for the finished product (with freezers, if required), the filling area, primary and secondary packaging, and auxiliary areas, such as technical areas, buffer preparation room, weighing room, etc.

We are currently in a time of change, with the design and construction of new mRNA vaccine production plants. And although there is currently a lot of uncertainty about certain regulatory aspects of this type of environment, the needs of the market demand that we are able to provide solutions to meet the growing demand. In addition, these new plants give the possibility to include very high levels of automation at the process control and data acquisition level. This represents an excellent opportunity for the biopharmaceutical sector to continue on the path to Industry 4.0.

If you are interested in learning more about GMP plant design and how we can help you, please contact us: klinea@klinea.es