What’s so hard about making a few billion vaccine doses

About a month ago Jonas Neubert started an excellent detailed living blog: Exploring the Supply Chain of the Pfizer/BioNTech and Moderna COVID-19 vaccines [1]. Neubert’s first, and subsequent posts, have focused on mRNA vaccines, covering their development, their production, and supply chain issues. His posts are highly detailed and well-referenced, but could benefit from a diagram of the processes, their components, the companies that make those components, categories of companies that could make the components, the kinds of jobs that are involved, and software considerations and concerns.

As a goal of the Biotech-Careers.org website is to communicate the diversity and kinds of technical jobs that are needed in the biotech industry, it has many of the details regarding job descriptions. These are presented along with an extensive company database that is organized by a large number of relevant biotech keywords and other data. Thus it seemed apropos to create a map of mRNA vaccine production and its supply chain using the descriptions shared by Neubert and collaborators and combine that information with links to the relevant content in the Biotech-Careers.org database. The result is presented below.

Click the image to view the full scale interactive map

The Map

The interactive map shows the different stages (large gray boxes) in the manufacturing process and the key components (gray ovals) that go into the key processing steps (purple/lavender ovals). Inputs and outputs to each stage are shown in blue ovals. Computer technology and cyber security come into play in the areas shown in light red (gradient L bar, and ovals), with red-bordered ovals indicating points of cyber security concern. Red ovals represent bottlenecks or risks in the supply chain.

The two green ovals indicate where the process starts, with synthetic DNA, and where it ends, with a vaccinated person. 

In addition to process steps and materials, the names of companies that support vaccine manufacturing production and supply components are shown in blue. Each company is linked to its page on Biotech-Careers.org. These companies also belong to larger groups of companies that share the same core activities or business areas. The collection of Core Activities on the map is shown in the “Biotech-Careers.org Company Core Activities” section. Each box is linked to its page on Biotech-Careers.org.

The map also shows different kinds of biotech careers.  Some genomics, molecular biology, biomanufacturing, manufacturing, and facilities positions are identified in the DNA Manufacturing box. Positions related to quality control and quality assurance are shown in the GAMP/Quality Management System area. These job titles, in blue, are linked to job descriptions in Biotech-Careers.org.

Pfizer/BioNTech and Moderna are shown in the map in large bold text that links to their respective pages on Biotech-Careers.org.

The map also contains and interactive legend that can be used to highlight different parts of the map.

Use the legend to toggle the highlighting of items in the map. The first click turns on highlighting, the second click turns highlighting off.


The Processes

Neubert’s blog provides extensive detail and references to information about mRNA vaccine development and manufacturing. He identifies which parts of the Moderna and Pfizer/BioNTech are shared by both vaccines and explains how they are different. From a process perspective, manufacturing has three stages: DNA Manufacturing, RNA Manufacturing, and the production of Lipid Nanoparticles. Moderna employs a contract manufacturer (magenta bordered box), Pfizer does the work internally, but at three locations (blue bordered boxes) and BioNTech (Pfizer’s partner) does some work with Pfizer and some through a contract manufacturer.

One of the key points is that mRNA vaccines begin with bioinformatics. We need sequence data plus an understanding of the sequence elements that encode the epitope-containing antigens needed to elicit an immune response that will produce protective antibodies, and (or) T-cells in nearly all people. With this information, and new information, mRNA vaccines can be rapidly updated. In this way they are programmable. 

The DNA sequence is then used to produce a DNA molecule (synthetic DNA), which is ordered from a company. The next steps follow standard molecular biology and fermentation processes to produce DNA that will be used to make the mRNA.

The mRNA is manufactured via large-scale in vitro transcription, which represents a new biomanufacturing process, and introduces a first bottleneck in the supply chain. That is, to be functional mRNA must be capped and have a 3’ poly A tail. Currently, only one company exists that makes the capping enzymes needed.

After the mRNA is made, it must be packaged in liposomes (nanoparticles). This is also a new art. First, the lipid mix is made from several different lipid components. Some are used in both vaccines and some are different. Of note, the cationic (positively) charged lipids are critical. Packaging the mRNA in the lipid mix requires specialized microfluidic devices. This is a new process as well with the necessary equipment and “know how” currently in short supply and giving us a second bottleneck.    

Nanoparticles are then dispensed into vials in the Fill and Finish stage. Each vial contains a certain number of doses. Vials are then packaged into trays and either cases (Moderna) or cartons, cases, and pallets (Pfizer/BioNTech). Like manufacturing, the Fill and Finish steps can be carried out by partners (Moderna, BioNTech) or internally (Pfizer).

The Fill and Finish stage represents two, non-obvious supply chain issues. First, the vials are made of borosilicate glass, which contains boron, and is only mined in two places in the world (Turkey and California). Borosilicate glass is able to withstand a wide temperature range, from  negative 80°C to room temperature, without cracking. While glass manufacturers continue to experiment with other forms of glass, we, for now depend on it. Second, the production of dry ice, needed to keep the Pfizer/BioNTech vaccine cold, is tied to petroleum production. It turns out that CO2 is a byproduct of petroleum refining and accordingly, is manufactured by oil refineries. Since the pandemic has reduced oil consumption it has also impacted decreased the production of C02.  

The last step, kitting, involves packaging the vials of vaccine together with the syringes and other materials needed by qualified health care professionals need in order to inject people and complete the process. This last step has another bottleneck when it comes to the number of qualified professionals.

The Jobs

Obviously, a process as complicated and extensive as this requires a significant number of skilled workers at many levels, in particular technicians. Some of the technical jobs are highlighted on the map. It is worth noting that some of these roles are important throughout the process. For example Genomics and Molecular Biology Technicians can also work on DNA and RNA manufacturing. The positions shown in the GAMP (Good Automated Manufacturing Practices) / Quality Management Systems are found in all stages as well.

While many job types (10) are indicated on the map, the jobs related to supply chain and logistics are missing. We’ll leave that as an assignment for future Biotech-Careers updates.

The Companies

20 different companies are shown on the map. These were named in Neubert’s blog along with companies that make the glass vials, and thermal packaging systems, and others that are involved in the supply chain, but are not directly related to biotechnology. As noted, these 20 companies can be segmented by core business activities. Together, these core activities have over 1300 peers in Biotech-Careers.org 

Cyberbio and Cybersecurity

This work is funded in part by a grant (Biomedical Emerging Technology Applications: BETA Skills) from the National Science Foundation (DUE 1800909). In our view, mRNA vaccines couldn’t be more BETA. Manufacturing mRNA at scale, and packing it into nanoparticles for effective drug delivery, requires new manufacturing processes, new manufacturing standards, and new methods for QC/QA (quality control and quality assurance).

Recently, the BETA skills project has been seeking to understand cyberbio-impacted processes with an eye toward cybersecurity and workforce implications. Scaling manufacturing processes requires significant automation and computer tracking. Automation systems are controlled through software, and steps and data are recorded in batch records that are stored in LIMS (Laboratory Information Management Systems). The LIMS ultimately link the lot numbers that follow the process stage outputs. All of this information then needs to be linked to each vial of vaccine that ships. The key tracking device on a vial is a QR (Quick Response) code. QR codes are 2D (dimensional) barcodes that store information.

As to cybersecurity, it is an issue throughout the entire process, hence both legend buttons “Computers and systems,” and “Cyber Security,” highlight the same sections for the map. LIMS systems are commonly controlled by using passwords to restrict operations to the individuals who are qualified to execute certain steps. Many LIMS also use electronic signatures that require federal registrations. The FDA provides guidance on software requirements under 21 CFR part 11: Electronic Records.

In the map, the items “Labels,” “Cold cases,” and “Vaccine Cards,” are specifically called out as targets for cybersecurity. The QR code also protects against phony vaccines. According to Neubert, in the United States QR code information is defined by the Drug Supply Chain and Security Act (DSCSA), and at a minimum must encode a product identifier, serial number, batch number, and the expiration date. 

To track the “Cold” cases, temperature trackers are embedded in each package of vaccines. Modern trackers are IoT (Internet of Things) devices that record GPS (Global Positioning System) data along with temperatures. Although the ability to transmit information is useful, it also makes them vulnerable to hackers.

Last, the Vaccine Card. It’s a piece of paper that is used to record who was vaccinated, when, and which dose was received (first or second). Vaccine cards are a simple solution to tracking 1000’s of people getting vaccinated in parking lot vaccination stations, so what could go wrong? Plenty. People like to proudly share that they’ve been vaccinated on social media with their card next to their smiling masked face. Unfortunately, that card has identifiable information. When you share your picture, with your card, you are sharing it with identity thieves.

So, do get vaccinated, do tell the world, and keep your card to yourself.


1) https://blog.jonasneubert.com/2021/01/10/exploring-the-supply-chain-of-t...

2) https://www.logisticsmgmt.com/article/dry_ice_is_a_critical_supply_chain...

4) https://www.aarp.org/money/scams-fraud/info-2021/covid-19-vaccination-ca...

Submitted by Todd Smith on Mon February 15, 2021.