by Öner Tulum, William Lazonick, and Ken Jacobson
This is the second installment of a three-part series on the scalability of mRNA vaccine production. The current article focuses on the process of lipid procurement and the subsequent formulation of mRNA within LNPs.
The availability of an abundant supply of lipids is fundamental to the mass manufacture of mRNA vaccines. For decades, scientists have recognized lipids as effective for nucleic acid delivery to cells, but their pharmaceutical applications have remained rather limited. Only five major producers worldwide serve the niche markets that make use of lipids, and these lipid suppliers face their own scaling challenges.
Of the four types of lipids used in mRNA vaccines, the two functional lipids, ionizable cationic lipids (ICLs) and PEGylated phospholipids (PPLs), are in particularly short supply. With the mass manufacture of mRNA COVID vaccines, the demand for functional lipids has grown at an unprecedented rate. Functional lipids are making their vaccine debuts as excipients in mRNA and viral-vector COVID vaccines. But the therapeutic use of PEGylated lipids goes back to 1995, with the first nano-drug approved by the U.S. Food and Drug Administration (FDA).
Although PEGylated lipids have also been widely used in such consumer products as toothpastes and shampoos, their safety in vaccines had not been well established prior to the pandemic. Because PEG is a chemical compound derived from petroleum, questions have been raised about whether it may be responsible for rarely occurring, severe allergy-like reactions among recipients of COVID vaccines. PEGylated lipids were in the COVID vaccines that underwent clinical trials and have continued to be used in the mass production of the approved vaccines, as scientists have yet to gather any clinical evidence linking PEG to those allergic reactions. If evidence were to emerge that PEGylated lipids are unsafe, the COVID vaccines that contain them would have to undergo new clinical trials with an alternative functional lipid in order to be reapproved for use.
Potential applications of ICLs as nanocarriers of molecular cargoes were initially discovered in the 1980s, but it was not until 2018 that the FDA approved the first mRNA-based drug, thus validating LNP containing ICLs as safe and effective non-viral carriers of nucleic acids. The actual use of ICLs in vaccines is, therefore, very new, and, in general, the previous LNP-based drug products have been for niche markets. In COVID vaccines, ICLs account for over one-half of the total lipid mix in the LNP formulation and hence present vaccine manufacturers with a more pressing supply issue than do any of the other three lipids needed. In the delivery of mRNA COVID vaccines, scaling the manufacture of LNP systems remains a major bioprocessing problem.
The manufacturing of synthetic ICLs is a highly complex process that entails about two dozen steps from various purification stages to the manufacture of high-quality lipids. There is only a small number of suppliers available worldwide for carrying out such a complex manufacturing process. Even after the vaccine manufacturers arrange for the retooling of additional facilities to expand capacity, lipid suppliers cannot keep up with the pandemic-driven global lipid demand. A major problem of lipid manufacturers has been recruiting and training highly specialized scientific personnel capable of ramping up production while maintaining the quality of the lipids.
Having signed supply contracts with almost every major lipid producer, the CEOs of Pfizer and BioNTech, as we noted in post #8, made a special trip to the lipid supplier Polymun in September 2020 to ask that company to transfer its lipid formulation knowhow to Pfizer facilities. In March 2021, Pfizer was able to launch the production of lipids at its global R&D headquarters in Groton, CT. By taking direct control of lipid production, Pfizer has been able to increase its estimate for global COVID-vaccine production for 2021.
Even when they solve the lipid-supply problem, the mRNA-vaccine producers have had to learn how to formulate the encapsulated vaccines, which entails the high-speed and large-scale mixing of mRNA with lipids. The key piece of equipment for this process is the impingement jet mixer (IJM), which prepares drug products which can, in the fill-and-finish process, be packaged in vials or syringes for shipment to procurers.
The encapsulation of mRNA with LNPs is the most critical stage in the vaccine-manufacturing process. It took BioNTech/Pfizer up to six months to receive and install the new equipment in multiple facilities at various production sites. The IJMs used in the formulation of LNPs that carry mRNA molecules in the vaccines manufactured by Pfizer and Moderna are run by custom-order high-pressure pumps that enable the formulation of mRNA within LNPs. This process must be carried out at a high level of precision.
Had more time been available, IJMs could have been designed to enable the production of significantly greater numbers of doses using fewer resources. But the pandemic emergency necessitated the use of IJM models that were ready to hand. Since the encapsulation of mRNA within LNPs is the most critical stage in the vaccine-manufacturing process, the microfluidics mixing solutions now available need improvements to attain a more scalable manufacture of LNP systems to meet the growing demand for mRNA vaccines. Further complicating this issue is the fact that, currently, there are only two major suppliers of IJMs worldwide that are capable of upgrading the technology for microfluid and nanofluid mixers.
The upcoming post in the series will explain the process of selecting vaccine candidates based on dosing, stability, and optimization studies carried out during the clinical development of mRNA vaccines.