As Moderna and the partnership of Pfizer and BioNTech struggle to respond to huge demand for their messenger RNA (mRNA) COVID-19 vaccines, suppliers of the specialty lipids needed to deliver the vaccines are scrambling to keep up, and one new firm is entering the business.
Lipids are an unsung component in the two mRNA-based shots, the only vaccines to be approved so far in the US. Naked mRNA quickly degrades in the body, and can trigger an unwanted immune reaction. To get the genetic material to its target cells, vaccine developers combine it with a mixture of several sophisticated lipids to form lipid nanoparticles, or LNPs.
Very few companies in the world supply these custom lipids in significant quantities and to the standards needed for vaccine production. On Feb. 5, one of them, the German firm Merck KGaA, announced that it will “significantly accelerate the supply of urgently needed lipids” for BioNTech to use in producing the Pfizer-BioNTech vaccine.
Merck said it has been “working hard” in recent weeks to expand its lipid capacity by further improving production technologies and implementing new process steps. It expects to increase lipid shipments toward the end of 2021. Although Pfizer is so far the main producer of the partners’ vaccine, BioNTech is starting to make it in a facility in Marburg, Germany, that it recently acquired from Novartis.
And on Feb. 11, Evonik Industries said it will begin lipid production at two sites in Germany, also as part of a partnership with BioNTech. The chemical company, a newcomer to large-scale specialty lipid manufacturing, expects to be making commercial quantities as early as the second half of 2021.
Other companies are likewise rapidly scaling up. Croda, a British specialty chemical firm, is increasing production in Alabama at its subsidiary Avanti Polar Lipids to supply Pfizer. And the German pharmaceutical services firm CordenPharma has been investing in Switzerland, France, and Colorado, to supply lipids for Moderna’s vaccine under an agreement announced in May.
mRNA vaccine producers use a package of 4 lipids to formulate their LNPs: An ionizable cationic lipid that encapsulates the negatively charged mRNA; a PEGylated lipid that helps control particle life and size; distearoylphosphatidylcholine (DSPC), a phospholipid that helps form the structure of the LNP; and cholesterol, which also contributes to structure.
The cationic lipid is the most important of the four, and the most complex to produce. Matthieu Giraud, global director of CordenPharma’s peptides, lipids, and carbohydrates business, says the synthesis requires about 10 steps and several product isolations. A complete manufacturing campaign is measured in months.
To meet soaring demand for this and the other lipids, CordenPharma executives realized they needed to supplement their primary lipids site in Switzerland and start production at a facility in Chenôve, France. The firm also transferred lipid purification to its facility in Boulder, Colorado, which is home to its largest purification column, and is usually used for peptides. And it embarked on process-optimization projects at each site, Giraud says.
In addition, the company firmed up its raw material supply chain, ensuring it has dual sourcing for all key raw materials. And it enlisted the help of a sister company, WeylChem, to produce some raw materials internally. In all, CordenPharma went through multiple waves of hiring, investment, and expansion as Moderna’s lipid requirements increased since last May, Giraud says.
These projects are just now beginning to bear fruit. “We started this month to kick off the next level that’s expected by Moderna,” Giraud says. Overall, CordenPharma has increased its lipid production for Moderna more than 50-fold, he adds, and more increases are possible depending on the vaccine firm’s future needs.
Although Evonik is new to lipid production, it has been formulating LNPs since 2016 when it acquired the Canadian firm Transferra Nanosciences. It can produce encapsulated mRNA there for the early phases of clinical testing and make commercial quantities at its site in Birmingham, Alabama. Last year the company entered the cholesterol business with the purchase of Wilshire Technologies.
Now, says Stefan Randl, vice president of R&D for Evonik’s health-care business, Evonik will add production at plants in Hanau and Dossenheim, Germany, for the two most important lipids needed to make LNPs: cationic and PEGylated lipids. The fourth lipid, DSPC, is less critical, Randl says, and can be purchased from other firms.
Both Giraud and Randl say the efforts by their companies to meet the lipid needs of their vaccine customers have been unprecedented.
Giraud says CordenPharma brought together a team of more than 50 employees across multiple locations. “We really have now a good concept to meet demand from Moderna,” he says. And CordenPharma is prepared to supply other COVID-19 vaccine developers that require lipid-based delivery systems.
Similarly, Randl sees his firm’s investment extending beyond vaccines to serve developers of next-generation mRNA-based medicines such as cancer immunotherapies, gene-editing therapeutics, and protein-replacement therapy. “We really believe this mRNA trend is there to last,” he says.