The messenger RNA (mRNA) COVID-19 vaccines from Pfizer/BioNTech and Moderna are the first such vaccines to receive any form of regulatory approval, in this case, emergency use authorizations. The key challenge for development has been stabilization and effective delivery of large and fragile mRNA strands into target cells. A number of strategies have been evaluated to overcome these issues, including polymer-based carriers, cationic nanoemulsions, and lipid nanoparticles (LNPs).
The solution for the mRNA COVID-19 vaccines is encapsulation inside LNPs. “LNPs protect the mRNA from degradation and ensure that it is taken up into human cells where it is translated into the proteins that it encodes,” explains Paul Spencer, vice president of drug delivery and medical device solutions at Evonik Health Care.
Distinct LNPs
While the Pfizer/BioNTech and Moderna vaccines are both based on mRNA, the two products are distinctly different from one another. They have different required dose levels, likely due to differences in the specific genetic sequences employed, and use different, proprietary LNPs for delivery. Moderna developed its own LNP technology, while Pfizer/BioNTech licensed an LNP technology developed by Acuitas Therapeutics.
The LNP particles are less than 0.1 micron in size. Their lipid composition dictates their physicochemical properties, from size and shape to lipophilicity to long-term stability. Acuitas Therapeutics, for instance, has synthesized more than 500 novel cationic lipids and investigated their performance in LNPs for the delivery of a variety of therapeutic payloads, including small interfering RNA, mRNA, and DNA.
Biophysical and structural data have been correlated by Acuitas to enable the rational design of LNP compositions with improved potency and therapeutic index, according to the company’s president and CEO Thomas Madden. Notably, the Acuitas technology has been clinically validated as well; it is used by Alnylam Pharmaceuticals for its RNAi drug Onpattro, a treatment for an otherwise fatal genetic disease called transthyretin amyloidosis.
Four key lipids
In addition to typical excipients including salts (e.g., potassium and sodium chlorides, monobasic and dibasic potassium phosphates, tromethamine hydrochloride, sodium acetate), weak acids (e.g., acetic acid) and bases (e.g., tromethamine), and sucrose, the Pfizer/BioNTech and Moderna mRNA vaccines also contain crucial lipid excipients—some common and some highly specialized—comprising their unique LNPs.
Lipids are defined chemical building blocks, with common examples including cholesterol and many different phospholipids. The LNPs used to protect the currently authorized mRNA vaccines for COVID-19 each consist of a total of four lipids that build a protective shell around the mRNA active ingredient, according to Spencer.
One of the lipids, says Madden, is an ionisable cationic, ionizable lipid with two functions: it allows loading of the mRNA inside the LNP and then release of the mRNA once the LNP is inside a cell. A polyethylene glycol (PEG) lipid and cholesterol are both used to stabilize the LNP during manufacture and storage, he adds. The phospholipid 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) helps to form the LNP bilayer structure and facilitates formulation, notes Spencer.
Specialized GMP manufacturing is required
DSPC and phosphocholine are common, nonproprietary lipids, while the PEG and cationic, ionizable lipids are proprietary lipids. Both types, according to Madden, require specialized manufacturing expertise, equipment, and facilities to produce under good manufacturing practice (GMP) conditions at the high level of quality required for use in vaccines. Some of the lipids, adds Spencer, are produced using multiple reaction steps, which contributes added complexity.
“It has been challenging to rapidly upscale the production of the various lipids, according to GMP standards, to ensure they are suitable for pharmaceutical applications,” Spencer states. “There are a limited number of places in the world where these types of lipids at this grade can be made, and never before have we had to manufacture the quantities needed to support vaccines to combat a global pandemic.”
Supply-chain impacts
Excipients used with other vaccine technologies
Excipients used in other types of vaccines (live weakened/attenuated virus, killed virus, viral vector, and protein-based) include preservatives such as thimerosal to prevent contamination; adjuvants, which most commonly are aluminum salts, to boost the immune response; and stabilizers including sugars and gelatin. Trace amounts of cell-culture materials, inactivating ingredients used to kill viruses or inactivate toxins, and antibiotics may also be present. A list of the substances in US-approved vaccines other than the active ingredients can be found on the Centers for Disease Control and Prevention website (1).
One of the biggest challenges for many vaccines, not just mRNA products, is their instability and the need for low-temperature storage. Researchers at the University of Texas at Austin have developed a potential solution—a thin film technology that can preserve live viruses, bacteria, antibodies, and enzymes without refrigeration for months to in some cases a
few years (2).
References
1. CDC, “Vaccine Excipient Summary,” February 2020.
2. I. Barjovicm, et. al., Science Advances, 6 (10) (March 4, 2020).
“Until one year ago, lipids were only needed in gram quantities for very specialized drugs and for development projects,” observes Spencer.
The quantities of lipid excipients required to support the manufacture of more than 2 billion doses of the Pfizer/BioNTech vaccine alone represented a huge increase from previous expectations, according to Madden. An early clinical batch of vaccine might require 100 grams of lipid, while commercial manufacture of more than 2 billion doses would require approximately 2 metric tonnes, he says.
The COVID-19 pandemic marks the breakthrough of this niche technology, Spencer asserts. “The worldwide demand on a tonne scale could not have been foreseen a year ago and requires a short-term expansion of manufacturing capacities,” he says. The increase in demand, in fact, has required a huge scale up by specialized contract manufacturing organizations (CMOs) and the engagement of additional CMOs to meet production needs.
Specialized contract manufacturers play key roles
Only specialized CMOs that are registered to manufacture components for clinical products are used to produce the lipid components in vaccines to ensure their quality and safety.“As with any component that goes into a drug, the lipid excipients in vaccines must be manufactured by an organization that is inspected by, and registered with, regulatory agencies. This ensures that the manufacturer has the expertise, experience, trained personnel, facilities, and documentation systems to produce high-quality and safe products,” Madden says.
Multiple CMOs are supporting the manufacture of the Pfizer/BioNTech and Moderna vaccines in order to meet the global need. Pfizer started with a five-year lipid supply agreement with Croda (through its acquired Avanti Polar Lipids business) and added AMRI, which was already providing development, scale-up, and manufacturing services for the vaccine, in February 2021 (1).
BioNTech also has agreements with Evonik and Merck KGaA. Moderna’s main lipid supplier is CordenPharma.
Expanding lipid production capacity
Many of these contract manufacturers are expanding capacity for lipid production to support the effort to roll out billions of COVID-19 vaccine doses. For instance, Evonik, which produces two of the four lipids for the Pfizer/BioNTech vaccine, is investing in the short-term expansion of its specialty lipids production at its Hanau and Dossenheim sites in Germany. First quantities were delivered to BioNTech in April, months earlier than planned, according to Spencer.
Merck KGaA also announced in February 2021 plans to boost production of the lipids it supplies to BioNTech. The company committed to significantly accelerating the supply of lipids and increasing the quantity of lipids delivered near the end of 2021. This commitment comes after weeks of investment in the further development of production technologies and the implementation of new, highly complex process steps, according to a Merck KGaA press release (2).
Croda is also doubling and quadrupling lipid product capacity in the United States and United Kingdom, respectively (3).
According to CEO Steve Foots, the company has already been able to improve the purity of the lipids while scaling its manufacturing process, which has enabled Pfizer to raise the storage temperature for its mRNA vaccine above ultra-cold conditions.
Meanwhile, CordenPharma, announced in April 2021 that the company expanded its lipid purification capacity at CordenPharma Colorado with the addition of more production lines. The company expected the investment to yield higher lipid shipments as soon as July 2021 (4).
References
1. AMRI, “AMRI Joins Network of Approved Manufacturers of Lipid Excipients for Pfizer-BioNTech COVID-19 Vaccine,” Press Release, Feb. 22, 2021.
2. Merck KGaA, “Merck KGaA, Darmstadt, Germany, and BioNTech Extend Strategic Partnership Through Accelerated Supply of Urgently Needed Lipids,” Press Release, Feb. 5, 2021.
3. M. Muvija and I.S. Jasmine, “UPDATE 2 -Croda Pins Life Science Sales Boost on Pfizer Vaccine Deal,” Reuters, March 2, 2021.
4. CordenPharma, “CordenPharma Expands Lipid Excipients Purification,” Press Release, April 19, 2021.
About the author
Cynthia A. Challener, PhD, is a contributing editor to BioPharm International.
Article Details
BioPharm International
Vol. 34, No. 6
June 2021
Pages: 18–20
Citation
When referring to this article, please cite it as C. Challener, “Meeting the Demand for Lipid Excipients,” BioPharm International 34 (6) 2021.
