#5. Scaling of COVID vaccine manufacturing: What manufacturing activities are involved and why are they so difficult?

by Öner Tulum, William Lazonick, and Ken Jacobson                            

In March and April 2021, Americans received as many as four million doses a day of COVID-19 vaccines, far surpassing the one-million-dose-a-day target that the Biden administration had set in late January. Notwithstanding the recent pause in Johnson & Johnson (J&J) vaccinations prompted by six cases of rare blood clots that may be associated with the vaccine, we look back in wonder at how, after the genetic sequence of SARS-CoV-2 became known in January 2020, by December 2020 the U.S. Food and Drug Administration (FDA) had authorized the mRNA Moderna and BioNTech/Pfizer vaccines for emergency use, with approval of J&J’s recombinant vector vaccine following in February 2021.

Now the challenge is the mass production of the approved vaccines on a scale that can provide the world’s population with immunity as quickly as possible. Indeed, the very rapidity with which safe and effective vaccines have been developed and approved for emergency use has magnified the problems of learning how to scale the production of vaccine doses to combat the pandemic. The time frame in which such learning must occur has been and remains extremely compressed. When vaccine candidates began clinical trials over a year ago, the vaccine developers as well as government and civil-society agencies concerned with the COVID crisis had to make plans for the mass production of vaccine even though there was no certainty that any of the candidates would ultimately be approved for use.

The mass production of the vaccines has involved three distinct activities:  a) securing access to manufacturing facilities, b) procuring raw materials to carry out the manufacturing process, and c) scaling up production to high levels of efficiency. In previous posts, we have provided an overview of how vaccine developers tackled the capacity issue in preparation for the possible approval of vaccines for use. As soon as a vaccine candidate entered the first phase of clinical trials, the developer began working with one or more manufacturing partners to scale the capacity to mass produce at the highest attainable rate.

Complicating the challenge of COVID-vaccine mass production is the fact that the vaccines currently authorized for emergency use in various countries were developed using novel technologies. Among other advantages, the development of mRNA and recombinant-vector vaccines have enabled a remarkably rapid turnaround in the process of identifying strong vaccine candidates and bringing them to clinical trials. Given the novelty of the technology platforms that have been used to develop the COVID vaccines, the manufacturers possess little prior learning concerning the scaling of the process.

The COVID vaccines that have been developed to date are delivered by injection.  Manufacturing technologies have yet to be developed that would make it possible to deliver these complex biological products in the form of easily manufactured pills that can be taken orally without medical assistance or need for refrigeration. The need to mass produce injectables poses its own particular challenges for scaling COVID vaccines.

The COVID-vaccine manufacturing process entails three major stages, as illustrated in the graphic below: a) pre-manufacturing process design and facility setup; b) production of drug substance (DS), consisting of the active pharmaceutical ingredients (API) in a vaccine which create neutralizing antibodies that prevent viral pathogens from infecting human cells; and c) the manufacture of actual drug product (DP), which entails putting bulk DS into vials or pre-filled syringes. Throughout DS and DP, there are several dozen checks for quality control.

Stages of the vaccine-manufacturing process

[Click image to enlarge]
Note: Formulation is an important step, particularly in the production of mRNA vaccines.

Depending on the vaccine technology used, the two manufacturing stages—DS and DP–entail greater or lesser degrees of difficulty. The vector vaccines developed by Oxford University and J&J have faced their most significant scaling issues in the DS process, while for the mRNA vaccines developed by BioNTech and Moderna, scaling problems during the DP process have proved more difficult. Manufacturing problems are only discovered “on the job”—that is, when a particular stage of production is implemented—and the pressing urgency for the delivery of doses leaves scant time for trial and error in the learning process. Indeed, as we will recount in future posts, any error that occurs in the manufacturing process can immediately become headline news.