What’s Old is New

Nicotine was first synthesized nearly 120 years ago and is now being considered a new tobacco product.

By Timothy S. Donahue

Synthetic nicotine has been under fire recently. News reports surrounding the product have been negative, and technically, all synthetic nicotine products are illegal in the U.S. Companies had until May 14 to submit a premarket tobacco product application (PMTA) to the U.S. Food and Drug Administration to keep their products on the market. Those that did not gain the FDA’s authorization for their synthetic nicotine products would have had to pull those products from the market by July 13. However, the FDA does seem to be using some discretion in its enforcement of synthetic nicotine products.

During a panel presentation on synthetic nicotine at the Next Generation Nicotine Delivery USA 2022 (NGN) conference in Miami, Florida, in June, Todd Cecil, the acting co-director for the FDA’s Center for Tobacco Products’ Office of Science, commenting from the audience, said that he could not confirm enforcement discretion for synthetic products. He said “everything” on the market after July 13 is illegal. However, he insisted that the agency would evaluate synthetic products based on the science.

“I can say that without doubt … the Office of Science will evaluate synthetic nicotine as you would any product, and [it] isn’t looked at with bias either for or against. It is up to the application to demonstrate that their product is APPH [appropriate for the protection of public health],” said Cecil. “And, like the rest of the FDA, no end verdict is evaluated in the absence of the dosage form in which it is administered.

“So, you may well find a lot of synthetic nicotine products coming off of the marketplace because they didn’t hit the requirements of submission, didn’t hit the requirements of data that’s in the rule, or that they have not demonstrated that it’s APPH, all of which is part of this analysis process. It’s not simply a ‘Well, it’s synthetic. That means it’s OK.’ It has to be evaluated as part of [the PMTA].”

George Cassels-Smith, CEO of Tobacco Technologies Inc., parent to eLiquiTech, the global distributor of SyNic products, said during the NGN panel that public misconceptions present a considerable challenge in the discussion about synthetic nicotine, adding that the FDA may be partly to blame because of the agency’s lack of clarity on the product’s safety and efficacy.

“Our role now is to work with the FDA and to educate people that [synthetic nicotine] is a viable alternative and that it’s got a good spot in the future of tobacco products and pharmaceutical products, that it ticks all the boxes,” explained Cassels-Smith. “But unless we can educate the consumer, we’ll continue working with a 90 percent misconception of what this product actually is.”

Tony Abboud, also speaking on the NGN panel, said that anti-vaping zealots, because of a few bad actors in the vaping industry, wrongly believe that synthetic nicotine was created only to evade the regulatory scope of the FDA. Companies like U.K.-based Zanoprima Lifesciences (the parent to SyNic) “have been manufacturing synthetic nicotine and perfecting the scientific process associated with it for years before the deeming regulation took effect, before the deeming regulation was fully implemented and long before the PMTA process kicked off,” said Abboud. “So that fact suggests that circumvention, again, is no longer an argument that is relevant.”

Synthetic explained

Synthetic nicotine is not new. Nicotine was first synthesized by Swiss chemist Ame Pictet in 1904. Since extracting nicotine from natural tobacco is efficient and inexpensive and synthesis from precursor compounds is relatively complex and expensive, for more than a century, synthetic nicotine had no commercial role, according to researchers at Stanford University in the U.S.

Molecules such as nicotine may exist in mirror image forms with identical chemical makeup but sometimes differing biological activity. The nicotine molecule possesses chirality, meaning it exists in two mirror image versions called enantiomers or stereoisomers. Nicotine comes in left (S) and right (R) forms. The (S) isomer of nicotine greatly predominates in tobacco leaf, which contains only small amounts of the (R) variant (0.1 percent to 1.2 percent).

Most synthetic nicotine has equal parts of both the (S) and (R) isomers. SyNic only has the (S) isomer—the one that holds all the psychotropic effects that nicotine consumers want, according to David Johnson, eLiquiTech’s president and chief scientific officer. SyNic USP/EP, SyNic nicotine bitartrate and SyNic polacrilex resin are manufactured in FDA-registered facilities using current good manufacturing practices. These products have confirmed purity levels of more than 99.9 percent, (S) levels of more than 99.7 percent and are free of tobacco-specific nitrosamines (TSNAs) and carcinogens, according to Johnson.

“The molecule is the same and the three-dimensional structure’s the same. It’s not different. There’s nothing new. And so all those studies that were done with tobacco-derived nicotine can be bridged to this synthetic product, so it creates some synergies, reduces some effort on the part [of] people who are generating reports and reduces some of the burden on the regulators in terms of assessing the data that’s generated as well,” explains Johnson. “So this seems to be a pretty straightforward case, right? You have a pure product in terms of the active ingredient. You have delivery mechanisms that clearly evolve at the low end of the risk containers, and you have a strong basic science upon which you compare the products and then evaluate them.”

Naturally derived nicotine and synthetic nicotine are identical on a molecular level. The differences are the individual or potential impurities. Nicotine derived from tobacco can contain potentially harmful impurities if it is not purified sufficiently. That can be difficult and costly because the impurities appear structurally similar to the nicotine molecule itself. But synthetic nicotine is virtually free of any impurities from the beginning, and none of its varieties are carcinogenic.

ELiquiTech is committed to Zanoprima to serve as SyNic’s global distributor and the manufacturer of record for synthetic nicotine bitartrate and synthetic nicotine polacrilex resin as well as proprietary SyNic e-liquid formulas. Zanoprima holds the patent, and eLiquiTech maintains the exclusive rights for global distribution to the tobacco and electronic nicotine-delivery system industries. ELiquiTech does not sell flavorings for e-liquids.

Cassels-Smith said the marketplace for synthetic nicotine has been a rollercoaster. He said SyNic does not make any sales to people that do not have an active PMTA. He said that when marketing denial orders for flavored tobacco-derived nicotine products began to come down from the FDA, the demand for synthetic nicotine was strong. However, SyNic only did business with companies that submitted a PMTA. Subsequently, the FDA opened a short window for new products to enter the marketplace.

“We saw a very robust sampling and ordering process for people to [bring new products to market]. Now, we are in a period where companies would be marketing that product. But surprisingly, I’m not seeing the demand that I experienced in the beginning,” said Cassels-Smith. “My guess is that people are waiting to find out how those applications will be reviewed before they come in. I think their concern is that if there’s a market denial order and they must remove the products from the shelves, they would have excessive inventory and a high exposure to potential cash flow issues.”

Globally, the United States has always been the country that “tosses the paddle in the water, and then we quickly see over in Europe the ripple effect,” according to Cassels-Smith. He said that he had recently spent time in Europe and was amazed at the number of vapers and heat-not-burn consumers there.

“The ratio of people that were smoking cigarettes was the smallest that I’ve ever seen in Europe. I was in Poland for the Global Nicotine Forum. Going to the conventions, I was in Birmingham for [the World Vape Show] two weeks prior. Synthetic nicotine was all the rage, and the U.K. is seeing smoking plummet because of its embracing of vapor products. World Vape Show Dubai had many synthetic products too … it’s very strong right now in the Middle East. And most recently, we see that China is licensing companies to produce an estimated 200 metric tons to [a rumored] 500 metric tons of synthetic nicotine. With those kinds of quantities, they must anticipate an extremely strong demand.”

Forward thinking

The vapor industry is always changing. However, nicotine has always been a traditionally quiet segment. When some companies announced that they would use synthetic nicotine to circumvent FDA regulation, the U.S. Congress acted. It changed the definition of tobacco in the Tobacco Control Act to include synthetic nicotine. That change turned the synthetic nicotine market on its head.

Cassels-Smith predicts a bifurcation in the nicotine market. This is due to factors such as making the cost of synthetic production more affordable and the certain security guarantees that synthetic nicotine offers over its natural cousin. Synthetic nicotine can be purchased for nearly the same price as tobacco-derived nicotine and in some instances for even less. This is due to advancements in the commercially scaled bulk production of synthetic nicotine for use in the tobacco, vaping, pharmaceutical and scientific research industries.

However, natural nicotine may not be the best option for nicotine-replacement therapy (NRT) and next-generation nicotine products. This is because nicotine extraction outside the U.S. comes from a supply of dust and recon. India, for example, has used its large stocks of tobacco dust to create a crude nicotine, which is then refined into a purer liquid nicotine extraction.

Several NRT products have been taken off the market by the FDA recently because they were found to contain TSNAs, residuals from the natural nicotine used in the NRT’s production. Synthetic nicotine has no TSNAs, the harmful, cancer-causing chemicals found in combustible tobacco products, because TSNAs are formed when tobacco leaves are grown, cured, aged and processed. The problem with the tobacco used in most naturally derived liquid nicotine is that the leaf used for extraction can’t be traced back to its origins.

“When you pick up a pack of cigarettes, you can tell that tobacco is grown in this farm, in this soil, with this seed, with this residual pesticide, with this amount of heavy metals … with a nicotine extraction, you have no idea. You can’t track and trace it,” explains Cassels-Smith. “So that’s an advantage to our product. And I think that you’re going to see more and more of tobacco grown from a specific area with a farmer with known residual pesticides and known heavy metal contents of the soil, and that will be extracted. And I call that the pedigree of natural nicotine. I do see an opportunity for a pedigree brand of natural nicotine to have a substantial seat at the table.”

Johnson said that having a manufacturing process that produces a synthetic nicotine offers a controlled process that’s repeatable, reproducible and well defined. Every raw material that goes into the production process can be traced by lot. Ingredients can all be tracked back to the source. “You’ve got batch records. You’ve got lot tracking. It meets that pharmaceutical model for producing a product that’s very well characterized [and] very reproducible,” said Johnson from the NGN panel stage. “The product that you produce is very low in impurities. It has no TSNAs, OK? Because those are not produced in this process.”

David Renteln, co-founder and CEO of Lucy Goods, said that a pure, consistent, traceable form of nicotine is both easier to work with and also better for the consumer. He said that if one were to consider what the future of farming is going to look like, it isn’t going to be the traditional growing on billions and billions of acres of land. And land that needs to be used for food won’t be taken up by tobacco.

“We’re still using farmland to grow tobacco, something that we’ve done for thousands of years [it’s labor intensive and bad for the environment]. The chemical production and synthetic production of key chemicals is something that will definitely not be done [in the future] by just growing plants on essentially two-dimensional plots of land,” said Renteln. “And as a result, the efficiencies are better for the environment, it’s better for human quality of life and labor practices. And when we reach scale, it will probably be less expensive, all the while being better for the manufacturer and the consumer.”

A closing cause

The benefits of synthetic nicotine could extend to other products, such as pharmaceuticals. The 1958 Food Additives Amendment requires the FDA to ban additives that are found to cause or induce cancer in humans or animals as indicated by testing, such as TSNAs.

Cassels-Smith said that this is why his company is preparing its drug master file for SyNic. The lack of track and traceability for natural nicotine has been a problem not only for the tobacco industry but also for the pharmaceutical industry and NRT manufacturers.

“I think a lot of data needs to be presented, but I think [an] argument clearly can be made that this is more helpful to use in a habitual way than a Nicorette gum or something else in the NRT space. So, yes, a rising tide will lift all ships,” he said. “We will eventually see pharmaceutical, as well as tobacco products, with a cleaner active ingredient because what’s good for the goose is good for the gander.”

Renteln said that the agency has the ability to do what it wants. It has a high degree of latitude to make decisions that it believes will help the agency achieve its mission: protecting public health. He said that the intent behind regulating vaping products is to ensure that these products that are APPH remain on the market and that those that aren’t APPH are not allowed to remain on the market.

“We should take an appropriate amount of time and get the burden of evidence that they need to make that decision. I think that there are, just using common sense, products that are more complicated and will require more time to assess, and then there are products where it would be kind of difficult to mess up,” he says. “I think enforcement priorities can make a great deal of sense. We’ve seen that work relatively effectively already, and so I think they’ve got a precedent that’s not perfect but good enough.”

Instead of overzealous regulatory actions, Renteln said he would like to see more action taken against the bad actors of the industry. Nobody seems to care if they get a warning letter. He thinks misinformation is a serious issue, claiming 90 percent of the doctors he has spoken with believe nicotine causes cancer and is extremely poisonous. He also doesn’t want the FDA’s decisions to be political.

“The problem we have is misconceptions and people telling false truths. Nicotine isn’t made in a microcosm; nicotine does have an addictive quality to it, but it’s super clean. It’s not carcinogenic,” said Renteln. “My biggest concern is just that there will be a great deal of pressure [on the FDA] to bow to political influences rather than scientific decision-making … that’s really the agency’s role; that’s their mission. That’s their approach to dealing with everything. I think that the scientists at the agency tend to feel very strongly that they’re going to make a decision based on science.”