1 of 4
Quality control lab at Nicobrand Ltd. Credit: Nicobrand Ltd.
2 of 4
Scaled-up synthetic nicotine production at Nicobrand Ltd. Credit: Nicobrand Ltd.
3 of 4
Fig. 1: The molecular structure of synthetic S-nicotine and tobacco-derived nicotine is identical.
4 of 4
George Cassels-Smith, global distributor of the SyNic synthetic nicotine brand. Credit: TTI Inc.
Though initially causing some anxiety, synthetic nicotine now being regulated in the US should make for calmer future waters.
Previously being largely unregulated, the United States’ Food and Drug Administration (FDA) as of mid-April 2022 assumed full regulatory jurisdiction over tobacco products containing synthetic nicotine (or “non-tobacco nicotine products” as they’re termed officially). Quintessentially, they are now subject to pretty much the same regulations as products containing tobacco-derived “natural” nicotine. In other words, all companies that plan future synthetic nicotine product launches in the US market must file premarket tobacco product applications (PMTAs) with the FDA which are then vetted and – if war-ranted – approved.
Initial scrambling eventually settles into routine
All seems well, but of course, there ensued quite some anxious scrambling at first. Numerous companies already had a market presence prior to the law coming into effect. They largely fell into two distinct categories: those that never filed a PMTA in the first place because they didn’t need to and those who were previously denied PMTA approval for their natural nicotine tobacco products and simply switched to synthetic nicotine to outsmart the system. They suddenly found themselves in a tight spot when US president Joe Biden on April 14 handed regulatory authority to FDA. If these companies wanted to continue selling in the US, they had no choice but to rush their PMTAs by an almost impossible May 14 submission deadline.
“There probably will be a tightening in the market… [as] the PMTA [deadline] is not realistic for people unless they’ve already been doing a lot of the data generation earlier,” well-respected industry veteran George Cassels-Smith predicted in a Tobacco Asia podcast interview* in late April. As c.e.o. of Tobacco Technology Inc. (TTI, tobaccotech.com), Cassels-Smith is the global distributor of Zanoprima Life Sciences’ SyNic branded synthetic nicotine. Yet the writing certainly was on the wall long before the April 14 date. With a little due diligence, affected companies could have prepared their PMTA documentations in a timely fashion.
“The use of synthetic nicotine in lieu of tobacco-derived [i.e. natural] nicotine in tobacco products has been the subject of much debate over the past few years, as products containing synthetic nicotine have been entering the US market,” confirmed Mark McQuillan, director of Nicobrand Ltd. (nicobrand.com), another leading synthetic nicotine supplier. McQuillan also pointed out that “FDA has been quite clear that products which previously received a denial order when submitted with natural nicotine would not be considered acceptable when simply substituting with synthetic nicotine.”
But things will settle now that the hurried initial submission deadline is over and done with. Future PMTAs will become routine and resemble quite closely the process for other tobacco products. To assist with the extensive documentations that must accompany new applications, Nicobrand and TTI/Zanoprima provide their clients with tobacco product master files (TPMFs) for their respective brands. Both suppliers not only carry a range of synthetic S-nicotine powder and solution formulations for e-liquids, white pouches, and HNB sticks, but also synthetic polacrilex resin, an ingredient in lozenges and gums used for nicotine replacement therapy (NRT).
Regulation was the right step
Cassels-Smith and McQuillan welcomed regulating synthetic nicotine as the right step. Not only will regulation help establish quality standards but also protect consumers from products containing so-called R-S-nicotine. The substance is not to be confused with the S-nicotine isomer form of synthetic nicotine, which is chemically identical to natural nicotine (cf. fig 1).
“We have been aware of the influx of less pure forms of synthetic nicotine infiltrating the marketplace in recent years, namely racemic mixtures of nicotine known as R-S-nicotine,” explained McQuillan. “This is not the same material as tobacco-derived nicotine and contains some 50% of the R-nicotine isomer. In fact, R-S-nicotine has a completely different CAS registry number [while S-nicotine shares the same CAS number with natural nicotine]. I am quite sure the FDA will be cognizant of this during their [PMTA] re-views and will not wish for consumers to be ex-posed to R-nicotine,” he added.
Meanwhile, Cassels-Smith also extolled synthetic nicotine’s exceptional purity of at least 99.95%, as well as the circumstance that it can be traced and tracked throughout the supply chain. He said that unlike natural nicotine, synthetic nicotine “is completely free of heavy metals and tobacco-specific nitrosamines (TSNAs), because it’s made in the lab. So, any product – especially oral ones - that were to make a switch from natural nicotine to synthetic nicotine would have a qualified and quantified toxicity profile that is cleaner than what can be had from natural nicotine.
Furthermore, it has track-and-trace ability. Natural nicotine starts with a biomass that’s not tracked and traced to a seed. Therefore, [synthetic nicotine’s] track and traceability is another huge factor that would bring a responsible manufacturer into closely considering the substitution of synthetic nicotine for natural nicotine.”
However, McQuillan did not uniformly concur with Cassels-Smith’s observations regarding tobacco-derived nicotine. As a manufacturer of nicotine for over 30 years servicing most of the western nicotine replacement market, Nicobrand (and its parent company Contraf-Nicotex-Tobacco, or CNT) have complete oversight of their supply chain, he claimed. This is bolstered by the two firms’ pioneering “Sustainable Nicotine Project” (SNP) which ensures traceability right from the tobacco seeds going into the ground to distillation of the finished product. Where it must be pointed out that the distillation procedures actually prevent heavy metals from finding their way into the end product, it also should be considered that synthetic nicotine is quite a recent phenomenon, and one which inevitably requires the use and inclusion of a multitude of chemicals in a complex manufacturing process. But such processes have as yet not been scrutinized by any regulatory agencies, according to McQuillan
“This is not to say that we should avoid synthetic nicotine. Rather, we should proceed with caution and take note of the exemplary safety record of tobacco-derived nicotine,” he said.
US is current main market, but other opportunities may present For Nicobrand, the US is for the time being the primary market, also under the aspect that the recent ruling now provides a regulated pathway for products containing synthetic nicotine.
“There are some other geographies where synthetic nicotine could be a possibility for certain legal or regulatory reasons, for example Japan or even South Korea,” said McQuillan. “But as of today, these markets are not really featuring at any significant demand level for synthetic nicotine.” But he doesn’t entirely rule out becoming active in other regions once the time is right. “As global demand for nicotine [in general] grows in the future, we do foresee the potential of synthetic nicotine as one option to ensure continuity of supply on a long-term basis.”
Cassels-Smith, whose customer base for SyNic likewise is concentrated in the US, even sees a future opportunity for penetrating China**, where demand for natural nicotine has been soaring lately, leading to an enormous price increase. “My understanding is that there was not enough natural nicotine to go around in China, which is a huge exporter of finished e-juices from the Shenzhen area. So the per-kilo price of natural nicotine went up to US$800,” he said. And that, Cassels-Smith opined, was only one example that threw the persistent notion out of the window that synthetic nicotine was simply too costly com-pared to its tobacco-derived counterpart, as he anticipated similar price hikes elsewhere (if perhaps not as steeply as in China).
“Natural nicotine is getting more expensive every day and will continue in this process because there is no free tobacco in this world and there’s a huge demand and low supply,” said Cassels-Smith. “My synthetic nicotine I can now get at US$450 a kilo. That’s exactly in the ballpark of natural nicotine and so I think the argument is off the table that I can’t compete with natural nicotine on price.”
Nicobrand and TTI will both attend this year’s InterSupply show in Dortmund, Germany (September 15-17). As usual, Nicobrand will share a booth with its parent company CNT, while TTI will bunk up with Universal Leaf.
__
*Listen to the full podcast interview (Tobacco Asia Podcast #9) with George Cassels-Smith
**It is imperative to point out that for the time being this perceived opportunity may not exist. In April 2022, the China Tobacco Monopoly promulgated its final version of the “Standard on E-cigarettes”, which states that only (and exclusively!) nicotine extracted from tobacco is allowed for use in locally manufactured vaping products. While this may well refer only to products for the domestic market, it is not entirely clear whether this restriction also applies to OEM/ODM products exported to markets outside China. At press time, Tobacco Asia has not been able to obtain a concrete clarification regarding this issue.