The key ingredient that could hold back vaccine manufacturing

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Pharma companies like Moderna and Pfizer need specialty lipids to help protect the mRNA in their Covid-19 vaccines. | Joe Raedle/Getty Images

Lipid nanoparticles are essential to the Moderna and Pfizer/BioNTech vaccines — and we’re staring down a shortage.

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As vaccines are distributed around the world, an effective end to the Covid-19 pandemic seems to be on the horizon. There’s a new vaccine from Johnson & Johnson now being delivered, with supplies soon to be boosted by a deal with the pharmaceuticals giant Merck. President Biden now says the United States will have enough doses for every American by the end of May. But still, many still want to know why there aren’t more shots to go around right now.

Here’s part of the answer: We’re still racing to make a special type of lipid, a relatively unknown but critical component of the vaccines being manufactured by Moderna and Pfizer/BioNTech. These vaccines use messenger RNA, the genetic component commonly known as mRNA that instructs cells to make proteins, which in turn teach the human body how to fight the virus that causes Covid-19.

However, because mRNA molecules are very fragile, they need to be protected. That’s where lipid nanoparticles, which are made of ingredients like cholesterol and harder-to-make specialty compounds like the ionizable cationic lipid, come in. Like a fatty, biological shield, lipid nanoparticles in the vaccine encase mRNA molecules and act as a delivery system, as they travel from the syringe and through a person’s body.

Though they’ve been studied and used in a clinical setting for decades, the use of lipid nanoparticles as a drug delivery mechanism was first approved by the Food and Drug Administration (FDA) just three years ago as part of a treatment for a disease that only affects about 50,000 people worldwide. This meant the supply chain for lipid nanoparticles was unprepared for the demands of a new type of vaccine that was created in record time. Instead of requiring lipid nanoparticles for thousands of drug doses, the world now needs them for billions of vaccines.

Now, vaccine manufacturers and the US government are racing to catch up, not only to make sure we can inoculate ourselves against Covid-19, but also to ensure we’ll have enough of these critical chemicals to fight the next epidemic, whenever it hits.

What are lipid nanoparticles, and how are they made?

Two of the three vaccines currently authorized for use in the United States — one made by Moderna and the other by Pfizer/BioNTech — rely on mRNA, or messenger RNA, a technology that can deliver sets of genetic instructions to cells. The basic idea behind these vaccines is that they use mRNA to teach your body to make the same so-called spike proteins that the SARS-CoV-2 virus uses to attach to human cells. The mRNA molecules in the vaccines cause healthy cells to produce harmless versions of these spike proteins, and once the immune system notices these proteins, it starts gearing up and producing antibodies to fight potential infection.

But mRNA can’t just be injected into the body by itself. It’s too fragile and would be destroyed. That’s why vaccine researchers use lipid nanoparticles to protect the mRNA molecules as they travel through the human body.

Making lipid nanoparticles on a scale that could contend with the demand for Covid-19 vaccines is not so easy, especially while the pandemic is still raging. One challenge vaccine manufacturers face is having to find specialty ingredients for lipid nanoparticles.

In particular, Covid-19 vaccine manufacturers are racing to find a special kind of charged lipid called ionizable cationic lipids, which essentially facilitate the entrance of the mRNA into the cell. These ionizable cationic lipids are made synthetically in what can be an incredibly complex process, and can require between 14 and 20 steps, according to Padma Kodukula, the chief business officer at the genetics medicine company Precision Nanosystems that works on mRNA and lipid nanoparticle technology.

“You start with some raw materials, you combine them in a reaction, and then you get an intermediate, you add some more components, you get a second intermediate — and then that could go on up to 12 times,” Kodukula told Recode. “Then, in the last step, you have purification and extraction and purification. So it is a pretty intense process, the making of this lipid in the purity that you need to put it in a human.”

There are a limited number of facilities outfitted to produce ionizable cationic lipids, and retrofitting an existing facility to produce them could be a monthslong process, experts told Recode. Even when all the basic ingredients are procured, there’s also the task of combining these lipids into larger nanoparticles and with the mRNA itself, which requires specialized facilities and machinery that combine all of these materials.

The equipment has a big role. “You basically are squeezing them through tiny little orifices to form these nanodroplets,” explained Andrey Zarur, the co-founder of Greenlight Biosciences, a company working on RNA-based vaccines. At the same time, the facility where this happens also has to be pristine. “[There are] people walking around in bunny suits having gone through a sterile door, and suiting up in that sterile door, having covered everything [and] breathing through respirators,” he explains.

Another element is that these facilities must meet Good Manufacturing Practices regulations, which are enforced by health authorities like the FDA, that govern pharmaceutical equipment. Manufacturing pharmaceutical ingredients safely also involves an arduous amount of tracing, including the source of the material, the people who analyzed it, and the temperature at which it was stored, explains Zarur. This process is designed to avoid the potentially catastrophic scenario of something going wrong with a vaccine batch and, if that does happen, to trace what went wrong.

Again, not every Covid-19 vaccine or vaccine candidate is built like those from Moderna and Pfizer/BioNTech. The Johnson & Johnson vaccine candidate as well as the Oxford/AstraZeneca vaccine don’t rely on mRNA or lipid nanoparticles. Instead, they use modified, non-harmful versions of an adenovirus, a type of virus that’s responsible for the common cold, in order to deliver RNA to cells. This RNA then instructs the cells to make spike proteins and trigger an immune response.

But even with the approval of the Johnson & Johnson vaccine, the Moderna and Pfizer/BioNTech vaccines will still be critical for reaching herd immunity not just in the United States, but globally. Even beyond these mRNA-based vaccines, the demand for lipids, and lipid nanoparticles, will only grow. These vaccines have shown that mRNA drugs can be developed relatively quickly, and health care experts expect we’ll need more lipids for all sorts of applications of this new biotechnology.

Why we don’t have enough of these lipids

The supply chain issues affecting lipid nanoparticle production aren’t quite so dire that we face the risk of running out of them completely. Rather, experts told Recode the challenges in scaling up production of these necessary chemicals could be holding back vaccine production in general.

“What we’ve got now is probably fairly close to the maximum that you could get with only 10 months of lead time to round up the supply chain,” said Derek Lowe, a drug discovery chemist and industry blogger.

Right now, relatively few companies in the world actually have the equipment and facilities to make lipids nanoparticles, or the special ionizable cationic lipids. Only a few others have machinery and facilities that can be retrofitted to make more, and of those that do, not nearly enough of them are ready to make the kind of lipid nanoparticles we’d need to distribute billions of mRNA vaccine doses quickly.

“Relatively small amounts of mRNA are enough to immunize a lot of people,” explained Pieter Cullis, a biochemistry professor who has been described as the “grandfather” of the lipid nanoparticle technology, and is the co-founder of the company Acuitas Therapeutics, whose tech has been licensed for the Pfizer/BioNTech vaccine. “The holdup seems to be more on the manufacturing of the other components like the ionizable cationic liquid and cholesterol, which are two of the larger components of the lipid nanoparticle.”

An additional wrinkle in the situation has to do with patents. Since lipid nanoparticles are a new biotechnology, scaling up their manufacture has led to some intellectual property fights, though it’s unclear how consequential those issues may be for the vaccine rollout. Moderna had been embroiled in a dispute with the biotechnology company Arbutus over patents related to lipid nanoparticles, but it’s not likely to affect the company’s vaccine production.

“I don’t see any universe right now where Pfizer/BioNTech’s or Moderna’s vaccine is being slowed down because of these patent threats,” Zachary Silbersher, a patent attorney, told Recode. He added that the amount of investment in and benefit of distributing the Covid-19 vaccine is so high right now, it’s unlikely that fear of patent issues would hold back other companies from making these kinds of vaccines, even if a dispute might come up.

What the government and pharma companies are doing about the shortage

Right now, the best way for vaccine manufacturers to address these supply chain issues is to work with other companies that can retrofit their facilities and add capacity to produce lipid nanoparticles.

In addition to pledging to expand its own lipid production capabilities, for instance, Pfizer is also buying lipids from a British chemical company called Croda and its Alabama-based subsidiary, Avanti Polar Lipids. The Pfizer/BioNTech vaccine also has contracts with the Germany-based companies Evonik and Merck KGaA — which is a different company than US-based Merck & Co. that’s helping Johnson & Johnson with vaccine production — to make more lipid nanoparticles.

Moderna, for its part, has expanded its partnership with CordenPharma, which makes lipids in both Europe and Colorado, to boost its supply of lipids. An executive at the company told a trade chemical outlet earlier this year that, since it started working with Moderna, its production of lipids for that company has grown by more than 50 times.

There’s also the Defense Production Act, a Korean War-era law that lets the president order private companies to boost production of materials in an emergency. Both Trump and Biden have reportedly invoked the law to keep lipids funneling toward vaccine companies. In the near term, this will likely have limited effect, since manufacturing capabilities are so constrained, but the Biden administration is focused on the long-term. Its national Covid-19 Strategy Plan says that the expansion of lipid nanoparticles would be key to not just stopping Covid-19, but empowering the “expected central role of mRNA vaccines in responding to future epidemics.”

All that said, there are other potential shortages that concern vaccine manufacturers. As vaccine candidates went through their trials, the US government and manufacturers took extra care to beef up supply of ancillary vaccine equipment, like syringes, needles, and glass vials. Despite that effort, we’re running low on special syringes that can squeeze an extra dose out of the vials that carry the Pfizer/BioNTech vaccine.

The list goes on. Some companies have looked for help with fill-finish manufacturing, the part of the process that actually gets the vaccine into little bottles and requires very sterile conditions. The limited number of facilities that can do this is causing vaccine makers to turn to other drug companies for help. Meanwhile, drug executives told the Washington Post they’re also worried about the supply of ingredients that provide the basis for the actual mRNA as well as synthetic capping agents, chemicals in the vaccine that tell the body when to start reading the mRNA. There is currently only one company producing these.

But even as we continue to discover and resolve new hurdles in the Covid-19 vaccine roll-out, more challenges will surely lie ahead.

“I don’t want to give you the impression that once we solve the lipid nanoparticle issue, then the 16 billion doses for humanity are solved,” said Zarur, of Greenlight Biosciences. “Because the reality is, we solve that bottleneck, and then we’ll find another bottleneck.”

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