Tag: Broughton

  • Puffs with Proof

    Puffs with Proof

    Image: The Little Hut

    Why new age verification technology could help solve youth appeal

    By Chris Allen

    The use of e-cigarettes has become more prominent as a smoking cessation tool and has gained popularity among young people. This has caused governments to act, with administrations across the U.K. introducing bans on disposable vaping devices to curb their popularity. One solution is for manufacturers to ensure proper age-gating technology is in place. In this article, Chris Allen, CEO of nicotine testing and regulatory consultancy Broughton, outlines the age-gating options that are available to manufacturers and how it can help bring products to market quicker.

    As governments ban disposables, there is an increasing focus on what manufacturers and retailers can do to replace them but without treading a similar path with subsequent vaping products. The challenge of switching adult smokers presents a paradoxical situation in that any reduced-risk nicotine product must deliver sufficient nicotine to relieve cravings. However, such a delivery mechanism introduces a risk of abuse liability, i.e., the potential to addict naive nicotine users. Disposable products are an exceptional tool to replace the convenience of a pack of cigarettes and a box of matches, due to convenience. Yet, this convenience also increases the risk of abuse liability to youth.

    A shift toward reusable, pod-based systems is likely, given that, prior to disposables’ rise, these were the main consumer products to emerge as the main alternative to smoking.

    Therefore, any leading product that emerges following a disposables ban must not follow the same route as disposables when it comes to youth appeal.

    While many suggest different flavors are part of the youth appeal, there is evidence from studies, including one from the University of Bristol, published in the Journal of Harm Reduction, that a variety of flavors is one of the factors helping smokers quit, with some participants in the study suggesting that a ban on flavors could lead to those who had quit using vapes to return to combustible cigarettes. However, manufacturers may need to take steps to ensure new products do not end up in the hands of young people.

    Indeed, in the U.S., the Food and Drug Administration has placed stringent marketing restrictions to prevent youth access and exposure, including the enforcement of existing laws, prohibiting vending machines from selling the products and its youth tobacco prevention plan, which features education programs for both teenagers and for retailers. With flavored products, there is a higher burden of proof on the manufacturer that the benefit to adults who use combustible cigarettes outweighs the increased risk of youth use.

    Age-Gating

    To ensure that vapes don’t end up in the hands of young people, age verification technology has been suggested as one solution to combat this issue. There are several passive youth access prevention measures in place, such was those that prohibit the sale of vapes to minors and the prevention of marketing targeting these age groups, but the evidence suggests that this is insufficient. Within the U.S., the FDA has clearly stated that marketing and sales restrictions alone are not sufficient to mitigate the risk to youth when assessing applications for a nontobacco-flavored product.

    There is a clear need to develop active measures that ensure vaping products do not end up in young peoples’ hands. Therefore, there has been a market trend toward biometric restrictions for age verification. Retailers, for example, have been experimenting with digital identification tools, but there is scope for manufacturers to include age-gating technology in their product design.

    There is a chance that regulators, such as the FDA, will look favorably on age-gating technology being included as part of the product. Rather than waiting several years for a marketing order like with existing smoking cessation products, manufacturers who include age-gating technology may find a quicker route to market.

    Should manufacturers decide to include age-gating technology to prevent youth access, it is essential that the robustness and security of the technology is demonstrated during any regulatory submission. Additionally, it’s important not to create barriers for adult smokers, as complex procedures of device locks may see nicotine users reaching for the most accessible source of nicotine, combustible cigarettes.

    There are several ways in which a manufacturer may approach the age-gating issue. For example, one solution may be through a mobile app and user database, but manufacturers need to pay a lot of consideration to the technology infrastructure—in how any software works with the device and any third-party age verification tool.

    By working with an expert partner from the outset on product design, analytical testing, stability studies and regulatory standards, this can help bring manufacturers’ next-generation product to market quicker.

    Chris Allen is the CEO of Broughton.
  • Beyond Hot Air

    Beyond Hot Air

    Photo: Valerii Honcharuk

    Designing effective heated-tobacco products

    By Malcom Saxton

    Heated-tobacco products (HTPs) heat tobacco to a high temperature without combusting it. Intended as a tobacco harm reduction tool, good product design is a key aspect in encouraging HTP adoption among adult smokers looking to quit combustible cigarettes. Here, Malcolm Saxton, senior consultant for chemistry at Broughton, which operates a dedicated HTP testing and compliance facility, shares advice on designing an appealing HTP.

    Although a small number of brands currently dominate the HTP market, more businesses are working to bring competitive HTPs to adult smokers by investing in research, development and marketing. For example, in 2023, Japan Tobacco announced that it would invest ¥300 billion ($2.05 billion) in HTPs, with ¥200 billion allocated for marketing internationally.

    Manufacturers can create effective and competitive products by investing heavily in device design—carefully scrutinizing the product’s design requirements, its capabilities and understanding how it will achieve the desired results for target users. 

    Concept and Engineering

    One of the first steps in designing an HTP is creating a target product profile (TPP), which outlines the desired characteristics or “profile” of the product. According to the World Health Organization, TPPs “state intended use, target populations and other desired attributes of productions, including safety and efficacy-related characteristics.” Usually, manufacturers will have a vision of what they want their HTP to look like. While some may try to emulate market-leading products, others will opt for very different flavors, form factors and aesthetics.

    A growing trend in device design is personalization, with some brands launching limited edition products and providing colored panels to personalize their HTPs. Also, Bluetooth connectivity is now standard on many products, such as the latest Glo Hyper Pro, which also has an LED display and can provide real-time feedback. Another notable improvement has been reduced consumable warm-up time, which promises a more effective user experience by making the device faster to use.

    Due to the complexity, cost and time associated with designing HTPs, many manufacturers choose to work with third-party specialists. These expert partners can frame what an ideal finished product will look like and help manufacturers build a TPP that meets both user and market needs. Then, once the manufacturer and partner have agreed upon the TPP, these specialists help turn this vision into actionable targets and design parameters.

    When working toward the TPP, design considerations include the HTP’s thermal design and heating profile. During the heating process, the water in aerosol is distilled off, but unless the hot water is managed effectively, the first puff will be steam—a situation called “hot puff,” which can be dangerous for users. Consequently, manufacturers can design the device airflow to minimize the risk of hot puff by adding a preheating function to drive off the water before the user takes a puff. Another option is adding ventilation capabilities to the stick, which cools the water by drawing in air.

    Iterative Testing

    In these early stages of product realization, it’s important to capture as much data about the HTP’s design and its performance as possible. Regular, iterative tests are essential and so are short development cycles so that manufacturers can quickly capture the data, identify areas for design optimization and make the necessary changes.

    While it’s important to test multiple parameters, manufacturers must be selective with these to avoid costly delays. Some of the key parameters include total particulate matter, the amount of nicotine that the HTP delivers and the presence of a visible cloud upon inhale and exhale. This iterative stage is also a good opportunity to assess toxicological touchpoints, such as combustion markers, and whether the product meets regulatory requirements. Consequently, iterative testing allows manufacturers to understand their product’s suitability from a consumer and regulatory standpoint.

    Toxicological Considerations

    Although HTPs aim to offer smokers a less harmful alternative to combustible cigarettes, these products still carry a toxicological risk, which manufacturers must manage during the design process.

    Data from the Philip Morris International Scientific Update reports that, on average, there were 90 percent to 95 percent lower levels of harmful and potentially harmful constituents (HPHCs) in the aerosol of IQOS compared with combustible 3R4F cigarettes. However, manufacturers should treat toxicology with caution, with a WHO report noting that “some HTPs may emit unique harmful chemicals because of their distinctive characteristics and how they are used.”

    The choice of tobacco and blend is an important toxicological influence. Tobacco-specific nitrosamine—a carcinogen found on tobacco leaves—can form during the curing phase and, depending on the nitrate levels, when the device stick is heated. Therefore, it’s important to control the blend as early as possible in the development cycle, and working with an analytical testing partner can help manufacturers understand the toxicological impact of different blends.

    For a detailed understanding of toxicological risk, manufacturers can evaluate aerosol chemistry. Priority toxicant lists for cigarettes have been developed by a number of organizations, including the U.S. Food and Drug Administration, Health Canada and the WHO Study Group on Tobacco Product Regulation (TobReg). The most widely accepted list of HPHCs to test in the aerosol of HTPs, both for regulatory submission and for producing evidence of potential harm reduction, is the PMI58, a list developed specifically by Philip Morris International to focus on analytes most relevant to IQOS and, more generally, HTPs.

    Preparing for Market

    Building a strong picture of the target market can help manufacturers understand the regulatory requirements and ensure that these are built into their HTPs. Aerosol testing requirements will vary according to the regulatory framework being followed. At the most basic, the European Union and U.K. require a minimum of tar (nicotine-free dry particulate matter), nicotine and carbon monoxide to be measured. While with the far more rigorous requirements of a premarket tobacco product application, required for launch into the U.S., where a full understanding of aerosol chemistry and, more generally, the understanding of the product’s appropriateness for the protection of public health is required.

    Whichever regulatory pathway the manufacturer follows, experts, including analytical chemists, toxicologists and clinical scientists, must design testing protocols that include all the relevant parameters for regulatory approval.

    As investment in HTPs grows, manufacturers will continue to innovate and develop new designs to meet user needs. This means developing products that are both effective and comfortable to use so that smokers adopt them as smoking cessation tools. Working with an experienced partner can make the design process easier by creating an achievable TPP and helping them get the product to market.

    Malcolm Saxton is senior consultant at Broughton.
  • The Takeaways

    The Takeaways

    Image: Parin April

    What can we learn from the first FDA marketing order for menthol ENDS?

    By Chris Allen

    In good news for the next-generation nicotine industry, the U.S. Food and Drug Administration recently granted marketing orders (MOs) for four menthol-flavored e-cigarette products. This marks the first time that the FDA has granted MOs for nontobacco-flavored products via the premarket tobacco product application (PMTA) pathway. In this article, Chris Allen, CEO of PMTA specialist Broughton, summarizes the documentation and shares some pertinent learning points from the decision summaries of the applications from the technical project lead (TPL) review.

    The new products that were granted MOs are Altria’s Njoy Ace Pod Menthol 2.4 percent, Njoy Ace Pod Menthol 5 percent, Njoy Daily Menthol 4.5 percent and Njoy Daily Extra Menthol 6 percent. The Ace products are sealed pod-based systems whereas the Daily products are disposable e-cigarettes with a prefilled, nonrefillable e-liquid reservoir. At the time of writing, Njoy Ace is the only pod-based e-cigarette product with an MO.

    A Big Step for Tobacco Harm Reduction

    Granting an MO for a menthol e-cigarette is a huge step in the right direction for the FDA, opening up a new avenue for tobacco harm reduction to millions of adult smokers across the U.S.

    It is crucial that we have a diverse portfolio of convenient, satisfying and appealing smoke-free products to meet adult smokers’ preferences and needs as they transition away from combustible cigarettes (CC). We hope the fact that the FDA has granted MOs for menthol products will encourage adult smokers to opt for regulated alternatives to smoking rather than illicit products. However, we must bear in mind that these products are now eight years old, so it’s imperative that the FDA streamlines the PMTA process to reduce the time to market for products that are aligned with changing consumer behaviors.

    The PMTA Process

    Compiling a PMTA is a rigorous and lengthy task, with manufacturers required to provide data and evidence to demonstrate that the product is “appropriate for the protection of public health” (APPH) as required under the Tobacco Control Act. Manufacturers must consider the risks and benefits of the product, both to users and nonusers. To date, 27 products and devices have been granted marketing orders, and a full list is kept here.

    The FDA’s approval of menthol products demonstrates that it is possible to achieve the requirements of PMTA approval with a high-quality menthol product and compelling data. Shannon Leistra, president and CEO of Njoy, said, “We believe these marketing orders are a testament to the quality of the Njoy products and the strength of evidence supporting the authorizations of the Njoy menthol e-vapor products.”

    It will be interesting to see the FDA’s next move regarding flavored electronic nicotine-delivery systems (ENDS) and whether granting MOs for menthol opens up the door to other flavors. Njoy has resubmitted PMTAs for blueberry-flavored and watermelon-flavored pod products that work exclusively with the new Njoy Ace 2.0 age-gated device and is awaiting the outcomes.

    What Can We Learn from These Products?

    PMTAs are reviewed on a case-by-case basis, and the MO is specific to these products only. Understandably, many in the industry are looking to learn from this industry first to apply it to their own products and PMTAs.

    The most interesting outcome, naturally, is that the FDA determined there was robust and reliable evidence of an added benefit from the menthol flavor relative to that of tobacco-flavored products in facilitating adult smokers switching from CCs. This was deemed to outweigh the increased risk of youth use.

    About the approval, Brian King, director of the FDA’s Center for Tobacco Products, said, “It is the responsibility of the applicant to provide the necessary evidence to obtain marketing authorization, and the FDA has made clear what’s needed to successfully achieve that outcome. This action is further reinforcement that authorization of an e-cigarette product is possible when sufficient scientific evidence has been submitted to the agency to justify it.”

    Reducing the Risk of Youth Use

    A shared concern of the general public, manufacturers and regulators is the youth appeal of nontobacco-flavored products. The FDA has placed stringent marketing restrictions to prevent youth access and exposure, and for flavored products, there is a higher burden of proof on the manufacturer that the benefit to adults who use CCs outweighs the increased risk of youth use.

    While the application did include studies of youth use with low prevalence estimates for the new products, the FDA deemed the sample size insufficient. It noted the recent National Youth Tobacco Survey on popular flavors and devices, referencing the increased risk of youth appeal of menthol-flavored ENDS compared with tobacco-flavored ones, but adding the risk is lower than some other flavors (e.g., fruit).

    The TPL noted, “FDA’s experience shows that advertising and promotion restrictions and sales access restrictions cannot mitigate the substantial risk to youth from flavored ENDS sufficiently to reduce the magnitude of adult benefit required to demonstrate APPH. Rather, for flavored ENDS, only the most stringent mitigation measures have such potential; to date, the only such measures identified with the potential for that kind of impact have been device access restrictions.”

    The FDA’s ruling highlights that “stringent mitigation measures” such as device access restrictions have the mitigation potential to demonstrate APPH. However, the Njoy menthol-flavored PMTAs did not propose such mitigation restrictions and therefore required reliable and robust evidence of a potential benefit to adults who smoke, i.e., cessation of combustibles with continued ENDS use or cessation of combustibles leading to cessation of ENDS use.

    The application also proposed limiting youth exposure by not engaging in social media promotions, limiting human portrayals to those over 45 and prohibiting these products from being sold on third-party websites.

    Comparisons from Adult Smokers

    In this case, the FDA found “acceptably strong evidence” from submitted data from an online, observational longitudinal cohort study comparing its menthol Njoy Daily product with its tobacco-flavored Njoy Daily device. The study suggested a 21 percent to 31 percent rate of switching over a period of six months (three months primary outcome cohort), higher than the rate of ENDS in the literature.

    The comparison analyses showed the menthol Daily products were associated with statistically significant and higher rates (32 percent to 43 percent) of complete switching than the rate of tobacco-flavored Njoy Daily ENDS (21 percent to 37 percent) at three months or six months.

    Additionally, the comparison analyses demonstrated a 24 percent to 45 percent substantial added benefit from the menthol-flavored Njoy Daily ENDS in switching away from CCs among smoking adults compared with their tobacco-flavored equivalent. The submitted clinical studies demonstrated a similar abuse liability to CCs, suggesting they are a suitable substitute.

    For Njoy Ace menthol products, the longitudinal cohort study found behavioral benefits compared with tobacco-flavored Njoy Ace products in robust and reliable rates of switching from CCs, though the exact figures were redacted.

    Overall, the studies showed that the products have the potential to promote CC cessation, or significantly reduced use, compared with tobacco-flavored comparator products. The review concluded that there was a benefit to public health in the significantly higher smoking cessation rates achieved as compared with equivalent tobacco-flavored products.

    Biomarker data showed fewer and lower levels of harmful and potentially harmful constituent exposure compared with CCs, and toxicological evaluation of the aerosol suggested a lower excess lifetime cancer risk using Njoy Daily than using CCs. Ultimately, the FDA ruled that this data “demonstrated the potential for these new products to benefit adults who smoke combustible cigarettes as compared to adults who continue to use combustible cigarettes exclusively.”

    All of these points contributed to the FDA’s decision to designate the products as APPH. This monumental ruling has excited many in the next-generation nicotine industry, as it helps us achieve our shared goal of tobacco harm reduction for millions of adult smokers across the U.S. We are likely to see manufacturers working closely with regulatory consultants like Broughton to ensure their PMTAs contain robust and rigorous data and that their regulatory dossier is presented to support the best chance of success.

    Chris Allen is the CEO of Broughton.
  • Good Reads

    Good Reads

    Photo: Broughton

    The importance of literature reviews in support of tobacco harm reduction.

    By Dean Hatt

    Toxicology plays an important role in bringing next-generation products (NGPs) to market, ensuring they meet global regulatory requirements and contribute to the global body of evidence supporting tobacco harm reduction. Alongside analytical testing of the product’s aerosol, literature reviews are an important step in the toxicology human health assessment to build an understanding of the product’s performance, improve safety and ensure regulatory compliance. Here, Dean Hatt, senior toxicology consultant at scientific testing and consultancy specialist Broughton, shares insight into literature reviews for next-generation nicotine product toxicology.

    Toxicological tests help build an informed, scientifically justified understanding of the risk that NGPs present to health. This involves considering the nature of any hazards presented by an ingredient, exposure levels during normal usage, and the physical dose response, to build a risk characterization for the overall product.

    Toxicology assessments must be developed using a tailored approach to study design, data gathering, and risk assessment based on the product requirements and the proposed regulatory pathway.

    Importance of Literature Reviews

    Literature reviews are useful in two key areas of NGP development. Firstly, for hazard assessment, to gather data on specific toxicology endpoints for any chemical in the product and/or its aerosol. Hazard assessment is usually conducted relatively early in the product development process. By doing so, scientists can provide input into the sensitivity of analytical studies to establish if the identified components may be a health risk at the quantities identified.

    Literature reviews are also required as part of certain submissions, later in the product development process when completing the regulatory dossier. A thorough literature review is essential for manufacturers seeking approval via the marketing authorization application pathway to get their product approved as a nicotine-replacement therapy in the U.K. It is also necessary for those targeting premarket tobacco product application approval for consumer products in the U.S.

    Conducting a Literature Review

    A literature search for an NGP is a large body of work that can take several hundred hours to complete, depending on how wide the scope is. It encompasses assessing specific chemicals using authoritative sources or pre-agreed search terms and libraries.

    The literature search will typically involve hazard assessments for product-specific chemicals, where the scientist will look up various endpoints, e.g., carcinogenicity, genotoxicity, reproductive and developmental toxicity, irritation and sensitization from a number of sources to identify whether there is evidence that the chemical has toxicity associated with those endpoints.

    A CAS Registry Number is used as a unique identifier for a chemical, as some chemicals are referred to by different names or have different isomers. Menthol, for example, can take many forms: D menthol, L menthol, levomenthol and more.

    The researcher may also look for health-based guidance values, which demonstrate the level at which a chemical is deemed not to be of any concern. This is compared against the exposure concentration, which is derived from analytical data and estimated product consumption to quantify the risk.

    Wider Research

    When conducting wider research via a literature search as part of the regulatory application, the process will typically begin by agreeing on the search terms, such as “nicotine,” “toxicity” and “inhalation.” The researcher can then search agreed platforms, such as PubMed, PubChem and The British Library, to create a list, which often exceeds 2,000 references. The researcher will then prioritize these according to quality, recency and relevance to narrow the list down to the papers with the most appropriate information.

    If, during the literature search, a chemical is flagged for a specific toxicity, the researcher may recommend a more comprehensive assessment of that chemical, particularly if they have identified something the research team was not aware of.

    Further research may be required if there is a gap in the literature. It may be that the chemical has not been studied before or that it has not been included in any previous products due to its likely toxicity. There is also modeling (in silico) software available, such as Derek Nexus and Leadscope Model Applier, which can help predict the likelihood of a chemical structure being carcinogenic or genotoxic by comparing it against a library of other structures. This is utilized where experimental data of the chemical in question is unavailable.

    The toxicologist can also build a toxicity profile in support of product safety. This is tailored to the relevant regulatory pathway based on the existing hazard data, published scientific studies and expert body reviews. Toxicologists can also produce a quantitative risk assessment and create a comprehensive regulatory report evaluating the potential health risks associated with both individual ingredients and the whole product. These reports would be the output from the literature review and subsequent toxicology assessments.

    Due to the scale and complexity of the task, many NGP manufacturers choose to outsource their literature searches to a trusted analytical testing and integrated consulting partner. This partner can then provide swift expert toxicological advice to ensure the product is safe and compliant with relevant regulatory requirements while saving the manufacturer time and ensuring quality.

    Dean Hatt is senior toxicology consultant at Broughton.
  • Mastering the Maze

    Mastering the Maze

    Photo: Istock

    Toxicological considerations to be considered when bringing HTPs to market

    By Malcolm Saxton

    Heated-tobacco products (HTPs) are a type of reduced-risk nicotine device that offers a similar experience to combustible cigarettes but can help reduce exposure to potentially harmful toxicants. With the pressure on manufacturers to develop safer, smoke-free alternatives, Malcolm Saxton, senior consultant for chemistry at Broughton, which operates a dedicated facility to help manufacturers bring HTP products to market, shares insight into the testing and toxicology associated with HTPs.

    In combustible cigarettes, temperatures can reach up to 950 degrees Celsius. As well as liberating the nicotine, this process breaks the tobacco down to produce over 8,000 known chemicals. However, in HTPs, tobacco is not burnt—the maximum temperature is 350 degrees Celsius, providing enough heat to liberate nicotine and aroma without being high enough to result in combustion. Instead, a pyrolytic process known as torrefaction takes place, which is the same process that occurs when roasting coffee beans to release flavor.

    The absence of combustion substantially reduces the number of chemicals released, with harmful and potentially harmful constituents (HPHCs) in HTP aerosols shown to be significantly reduced from cigarette smoke. Data from the Philip Morris International Scientific Update showed a 90 percent to 95 percent reduction in the average levels of HPHCs in the aerosol of IQOS,1 the leading HTP brand, compared with combustible 3R4F reference cigarettes. In addition, there is thought to be little youth appeal.

    Due to their reduced-risk profile and similarity in experience to smoking combustible cigarettes, interest in HTPs is growing, and IQOS now has around 20 million users worldwide.

    Bringing an HTP to market

    Most countries do not have specific regulations for HTPs but regulate them in the same way as either combustible cigarettes or alternative tobacco products. In the EU and U.K., HTPs are regulated by the Tobacco Products Directive and the Tobacco and Related Products Regulations, respectively, which carry stringent requirements for testing, packaging and more.

    In the U.S., HTPs are regulated using the premarket tobacco product application (PMTA) or the modified-risk tobacco product (MRTP) process, with the PMTA being the established route to market. There are very few products that have been submitted and granted a PMTA or an MRTP from the U.S. Food and Drug Administration, which is required to make reduced-risk claims.

    To have the best chance of approval, it can be beneficial to work with a partner that offers a fully integrated service that covers product development, extractables and leachables, testing and characterization, toxicology, stability studies and regulatory consultancy. In addition to freeing up internal capacity, outsourcing testing and toxicological assessments can help streamline the product design and regulatory application process, benefiting from the partner’s previous experience.

    Toxicological Considerations

    HTPs are intended to be a smoking cessation tool, so they must be tested to ensure a reduced toxicological risk compared with conventional combustible products. In addition, the individual toxicological risk profile should be understood to establish that new hazards are not introduced or that current ones have not increased. The first three stages of evaluating an HTP typically include evaluating product design, testing aerosol chemistry and performing a toxicological assessment.

    The product design will vary based on the type of HTP, which can be electrically heated, carbon heated or aerosol heated. Heating mechanisms can comprise a resistive heat-blade system or may use induction heating. Product design is important in achieving an appropriate yield and aerosol cloud without increasing risk, and iterative testing can help ensure optimal design. Working with a partner who understands the intricacies of product design and how it impacts toxicological risk and regulatory approval can ensure manufacturers get it right the first time.

    The composition of the HTP aerosol will depend on the product design, including the materials in the hardware, as well as the ingredients, such as flavors. Desk-based toxicology, including a literature search, can help assess whether listed ingredients and materials are associated with anything that is of high concern.

    Aerosol testing requirements vary according to the purpose of testing and the regulatory framework being followed. At the most basic, the European Union and U.K. require a minimum of tar (nicotine-free dry particulate matter), nicotine and carbon monoxide. Other priority toxicant lists for cigarettes have been developed by a number of organizations, including the FDA, Health Canada and the World Health Organization Study Group on Tobacco Product Regulation. The most widely accepted list of HPHCs to test in the aerosol of HTPs, both for regulatory submission and for producing evidence of potential harm reduction, is the PMI-58, a list developed specifically by PMI to focus on analytes most relevant to IQOS and, more generally, HTPs.

    Analytical chemists will design a testing protocol that includes all relevant parameters for regulatory approval. For example, PMTAs typically require more data than other markets, and the testing package may need to be more rigorous as a result.

    The aerosol HPHC profile forms the basis of risk reduction characterization for various human diseases, such as cancer and respiratory disease, and can be contextualized against a combustible cigarette to establish the level of harm reduction. Exposure assessments can be generated from product-specific data, by looking at how the product is used in the market, or by using data from the literature.

    Compiling the relevant analytical testing and toxicological information for an HTP can be a challenging task. Working with an expert partner can make the process easier, reducing strain on your resources and complementing the skills of your in-house team.

    Malcolm Saxton is senior consultant at Broughton.

    Citation

    1Afolalu EF, Langer P, Fischer K, Roulet S, Magnani P. Prevalence and patterns of tobacco and/or nicotine product use in Japan (2017) after the launch of a heated-tobacco product (IQOS): a cross-sectional study. F1000Res. 2021 Jun 25;10:504. doi: 10.12688/f1000research.52407.2. PMID: 35528952; PMCID: PMC9069173.

  • Broughton to Open HTP Testing Facility

    Broughton to Open HTP Testing Facility

    Photo: Broughton

    Broughton will open a dedicated facility for heated-tobacco products (HTPs) at its Oak Tree House site in Lancashire, U.K. The space will allow the scientific consultancy and testing specialist to assist manufacturers with a fully integrated HTP service, from the testing and characterization of products through to toxicology and regulatory submission support. 

    Broughton’s HTP facility will house new testing equipment, such as conditioning cabinets, smoke engines and analytical equipment.

    Broughton can test an HTP for a specific suite of harmful and potentially harmful constituents based on the PMI-58 and regulatory required analytes to ensure there are no major toxicological concerns. Its team will also conduct paper-based toxicology assessments to confirm the absence of any other ingredients or materials of high concern.

    “Heated tobacco is an area of growing interest in the next-generation nicotine market, as it’s widely accepted that most of the toxicants associated with combustible cigarettes are caused by the burning of tobacco,” said Chris Allen, CEO of Broughton.

    “Developing and commercializing heated-tobacco products can offer smokers a reduced-risk alternative—the device heats sufficiently to release nicotine but not high enough for combustion.”

    “Understanding the potentially harmful chemicals and the toxicological impact of a nicotine product is essential for marketing authorization,” said Malcolm Saxton, senior consultant at Broughton. “Our new facility will aid our provision of accredited, accurate and flexible testing for all stages of HTP product development.”

  • Unpacking the Pouch

    Unpacking the Pouch

    Photo courtesy of Broughton

    How we can better understand the toxicological risk of nicotine in modern oral and other nicotine products

    By Libby Clarke

    Nicotine may be acutely toxic via all routes of exposure if the dose is high enough, but determining the true extent of its toxicity is challenging because of the variation in data. In 2014, Bernd Mayer highlighted the discrepancy between the generally accepted lethal dose of nicotine and documented cases of nicotine intoxication. Examining these accidental oral ingestion case studies gives us another data point for consideration when determining nicotine toxicity.

    In this article, Libby Clarke, managing consultant for toxicology at contract research organization (CRO) and scientific consultancy Broughton, explains how manufacturers can understand the true impact of oral pouches and other nicotine-based products.

    The U.S. Centers for Disease Control and Prevention and the National Institute for Occupational Safety and Health, along with other sources, report an estimated lethal dose of around 60 mg when nicotine is ingested orally. While broadly accepted by the Food and Drug Administration and other regulatory bodies, this value is derived from a series of self-experiments conducted by two individuals in the 19th century, where non-fatal adverse effects were reported.

    Mayer estimated that a dose of 60 mg of nicotine would give rise to a plasma concentration of approximately 0.18 mg per liter based on 20 percent oral bioavailability and assuming linear kinetics. Cases of fatal nicotine intoxication cited by Mayer suggest a much higher lethal nicotine blood concentration of approximately 2 mg per liter, corresponding to 4 mg per liter in plasma. Many existing case studies include data on accidental ingestion in children and infants, where the lethal dose is likely lower, as with nicotine naive adults.

    There is a significant disparity in the levels of nicotine that individuals can tolerate and a broad range in the upper level of nicotine that nonsmokers can consume without experiencing adverse effects. Research indicates that tolerance increases with repeated use of nicotine products, but the speed at which tolerance grows depends on the frequency of nicotine use, the amount absorbed systemically and individual genetics.

    Research Challenges

    Understanding nicotine toxicity is essential for determining the likelihood of adverse effects associated with certain products and concentrations, but research is limited. It is unethical to test nicotine toxicity in nonsmokers, and light or nondaily nicotine users are likely to have a lower tolerance, putting them at a higher risk of experiencing adverse effects such as dizziness, nausea and vomiting. On the other hand, established smokers have upregulated receptors in the brain, meaning many more nicotine receptors are available to bind nicotine than in nonsmokers. Therefore, the higher levels of nicotine that produce adverse reactions in nonsmokers are often required to satisfy the cravings of regular smokers.

    The wide range in tolerance among adult nicotine users makes it challenging for manufacturers to define a threshold for nicotine toxicity in their products. Meanwhile, attempting to extrapolate findings from children to adults is not recommended due to differences in metabolic capacity, which increases as people grow. There is also a vast difference in metabolic efficiency, even among adults, which limits extrapolation.

    Understanding the Effects of Nicotine

    One option is for manufacturers to review case studies, conduct postmarket surveillance (PMS) on the incidence of reported adverse effects and use surveys to understand consumer use and the subjective effectiveness of nicotine delivery. For example, Massen et al. (2020) evaluated case studies reporting the clinical symptoms and outcomes associated with accidental or intentional ingestion of nicotine-containing e-liquids, which are limited to 20 mg per milliliter in the EU. Gerdinique C. Maessen et al. reported that the highest nicotine plasma concentration in the surviving group was 0.8 mg per liter. In comparison, the lowest plasma concentration in the patients who did not survive was 1.6 mg per liter.

    Another approach is working with a CRO that can conduct dissolution, aerosol characterization for inhaled products and pharmacokinetic studies to inform on the nicotine levels being delivered to users. CROs can also conduct behavioral studies under controlled conditions to understand the use patterns for certain products and what products and strengths are used across population samples.

    When developing oral pouches, manufacturers must adhere to the regulatory guidelines that are starting to be brought in by some markets. The rate at which nicotine transfers from the pouch across the buccal membrane is one of the main factors associated with users experiencing adverse effects, so manufacturers should consider a range of nicotine strengths. Dissolution studies and clinical studies may provide useful data to inform nicotine exposure from pouches, and case studies and PMS may also provide valuable insights. Working with a CRO that can conduct such studies is an effective way of understanding a product’s safety profile and form part of a manufacturer’s product stewardship and duty of care responsibilities.

    Libby Clarke is managing consultant for toxicology at Broughton, a global scientific consultancy-based CRO across industries in pharmaceuticals, next-generation nicotine-delivery products and cannabinoids.
  • Broughton Adds Extractables and Leachables

    Broughton Adds Extractables and Leachables

    Photo courtesy of Broughton

    Broughton has launched a new extractables and leachables (E&L) testing service for the reduced-risk nicotine industry. The new service will offer tailored E&L studies for products aimed at the premarket tobacco product application (PMTA) and the marketing authorization application (MAA) pathways. 

    According to Broughton, regulatory bodies increasingly focus on the interactions between manufacturing components, nicotine delivery devices and container-closure systems, and the final product formulation. Producers must identify and assess any toxicological risks that could arise via such interactions via E&L studies.

    Aimed at supporting reduced-risk nicotine product categories such as electronic nicotine delivery systems, Modern Oral nicotine pouches and nicotine replacement therapy, the service is available across all stages of the product development lifecycle.

    The new testing service includes study design, extractables studies, extractables toxicology assessments, leachables method development and validation, leachables shelf-life studies and leachable toxicology evaluation.

    “Extractable and leachable studies are essential to the PMTA and MAA regulatory pathways for reduced-risk nicotine products to ensure their safety and demonstrate evidence of mitigating risk. Even in emerging categories, where regulations may not exist, such as nicotine pouches, they should be adopted as a best practice approach to product understanding and stewardship,” said Chris Allen, CEO of Broughton.

    “Our scientific experts and toxicologists have years of combined experience conducting E&L studies across a range of reduced-risk nicotine product and device categories. By offering a one-stop solution for E&L studies, we can ensure a fully integrated approach across study design, extractables study delivery, leachables method development and toxicology assessment with our specialized consultants available to troubleshoot, problem-solve and develop analytical solutions to issues that may arise.”

  • Broughton Joins UKVIA

    Broughton Joins UKVIA

    Photo: Courtesy of the Broughton Group

    Broughton has joined the U.K. Vaping Industry Association (UKVIA) as the 2023 vaping awareness month, VApril, kicks off. Nveed Chaudhary, chief scientific and regulatory officer at Broughton, attended a meeting of industry experts at the Houses of Parliament to encourage more regulatory rigor in applying U.K. vape regulation to protect consumers, according to a press release. The event provided a platform for key stakeholders to discuss the current state of the vaping industry and explore ways to improve public health outcomes.

    “Recent compliance issues with some manufacturers could impact consumer trust in vapes in the U.K.,” said John Dunne, UKVIA director. “Quality control and analytical testing experts Broughton joining UKVIA at this time illustrates the importance of product quality and safety to ensuring the continued transition of smokers away from cigarettes.

    “At UKVIA, we believe vapes have a key role to play in helping reduce death and disease caused by smoking. Ensuring vape safety is of the utmost importance to us and our members, and as a group, we’re advocating for stronger action against noncompliant vapes. This should include faster removal of noncompliant products, complete testing of products and greater penalties for manufacturers and retailers who break the rules.”

    Broughton has also introduced a new U.K. and European Union Vape Compliance Package to help address concerns about vape regulatory compliance. The service will focus on labeling, packaging, nicotine strength, fill volume and banned ingredients.

    Manufacturers, distributors and retailers who use the compliance package will receive a Certificate of Analysis that verifies their products’ compliance with current U.K. or EU regulations.

  • A Taste of Things to Come?

    A Taste of Things to Come?

    Nveed Chaudhary | Photo Courtesy of the Broughton Group

    What the recent marketing denial order for Logic’s menthol vapes implies for flavored e-cigarettes

    By Stefanie Rossel

    On Oct. 26, the U.S. Food and Drug Administration wrote a new chapter in the story of electronic nicotine-delivery systems (ENDS) regulation. That day, the agency for the first time rejected a premarket tobacco product application (PMTA) for a menthol e-cigarette. Logic Technology Development received marketing denial orders (MDOs) for its Logic Power Menthol E-Liquid Package and its Logic Pro Menthol E-Liquid Package.

    In a press release accompanying its decision, the FDA said the rejection was based on a full scientific review. The applications, the FDA argued, “lacked sufficient evidence to demonstrate that permitting the marketing of the products would be appropriate for the protection of the public health.” The evidence provided within the application, it said, did not demonstrate that these menthol-flavored e-cigarettes were more effective in promoting complete switching or significant cigarette use reduction relative to tobacco-flavored e-cigarettes among adult smokers.

    In its statement, the agency also referred to the 2022 National Youth Tobacco Survey (NYTS), which had been released shortly before the Logic MDO. “For nontobacco-flavored e-cigarettes, including menthol-flavored e-cigarettes, existing evidence demonstrates a known and substantial risk with regard to youth appeal, uptake and use,” the FDA wrote.

    Tobacco harm reduction advocates were dismayed. The MDO shattered their hopes that mentholated vapor products would be allowed to remain on the market as a less risky alternative to mentholated cigarettes, which the FDA wants to prohibit. They were also surprised given that the FDA in late 2021 authorized 22nd Century Group to market its reduced-nicotine VLN Menthol King brand as a modified-risk tobacco product.

    According to data by the Centers for Disease Control and Prevention, menthol-flavored products accounted for 37 percent of all cigarette sales in the U.S. in 2019 and 2020.

    Misplaced Priorities

    Critics also lambasted the agency’s focus on the risk of youth uptake at the expense of the opportunity to move adult smokers to lower risk products. Christopher Russell, director at Russell Burnett Research and Consultancy, made up a quick calculation based on recent NYTS data. Of the 2.55 million U.S. students who had used an e-cigarette in the past 30 days according to the survey, 84.9 percent had used flavored vapes. Of the current flavor vapers, 26.6 percent consumed menthol ENDS, which corresponded to 2.12 percent of U.S. youth having vaped menthol in the past 30 days. “MDOs for menthol e-cigarettes,” he concluded, “equals banning menthol to 100 percent of adults in order to protect under 3 percent of youth.”

    Neil McKeganey, co-director of the Centre for Substance Use Research, went a step further, quoting a Scottish study carried out by his institution that looked at ENDS use among representative samples of U.S. youth and adults in 2021 and 2022. Out of the 1,215 youth aged 13 to 17 surveyed in 2022, he said, 0.2 percent had ever used a Logic Power and 0.5 percent had ever used a Logic Pro.

    When the Scottish researchers looked at youth e-cigarette use over the last 30 days, the levels of Logic use shrank to 0.1 percent of youth reporting having used the Logic Power during that period whereas the level of Logic Pro use was so low that it was not even recorded.

    “In dispatching the MDOs for these two products,” he stated, “the FDA seems to have set aside a commitment to review the data around individual devices and liquids and to formulate a response in terms of the brand of products being used and justify the denial orders issued by reference to the NYTS data.”

    Jim McDonald of Vaping360 predicted a rise in illicit trade if the FDA blocks the legal path to market for menthol vape products. The FDA, he said, ignored the fact that most youth vapers use unauthorized gray market flavored disposable vapes, many of which are menthol flavored. “They will continue using these products, too, while the FDA pursues its goal of eliminating legal vaping, locked into the belief that its ‘authority’ has some effect on the market,” wrote McDonald.

    In March, the FDA authorized Logic devices with tobacco-flavored refills. To date, the agency has not approved a single vapor product with nontobacco flavors.

    Shortly after receiving its MDO, Logic Technology Development secured a stay of the FDA order in court, allowing retailers and wholesalers to continue selling Logic menthol products for the duration of the stay. Even if the court requires the FDA to reevaluate the evidence, this does not guarantee a more favorable outcome for Logic and the future of menthol vape in the United States.

    Understanding the FDA’s Requirements

    Despite Logic Technology Development’s travails, Nveed Chaudhary, chief scientific and regulatory officer at Broughton Group, is confident the recent MDOs do not mark the beginning of the end for menthol and other nontobacco-flavored e-liquids in the U.S.

    While he agrees with McKeganey that the FDA’s positions are being driven in large part by the data from cross-sectional studies like the NYTS, Chaudhary believes the fundamental issue is how the PMTA studies were designed, how the data has been interpreted and how the arguments have been presented to the FDA. “Based on the original PMTA guidance and then the Final Rule, many, if not all, of the applications for menthol and nontobacco-flavored products were considered to be ‘equal,’” he says. According to Chaudhary, the relative benefits of all the ENDS flavors together were compared with the risks of smoking combustible cigarettes. The youth access measures introduced were the same across all flavors of a given platform.

    “What has become very clear from the FDA’s recent communications, especially through the MDOs, is that they do not consider all flavors of ENDS to have the same risk profile—in this case, the risk of promoting on-ramping amongst youth,” says Chaudhary.

    “Therefore, the expectation from the FDA has evolved. Given the data from studies such as NYTS, the FDA are now saying that the PMTA applications need to demonstrate that there is additional benefit of the menthol over tobacco flavors for current smokers—essentially that the additional benefit outweighs the continued risk of youth finding menthol more attractive. Over time, as the industry presents this data to FDA and FDA begin to approve menthol-flavored products, I can imagine a situation where the same would apply to other nontobacco and nonmenthol flavors—only that, for these flavors, an additional benefit for smokers compared with menthol that outweighs the risk on youth use would be required.”

    Remediating Deficiencies

    Chaudhary believes that “with the addition of a few relatively inexpensive studies and an overhaul of the dossier to build the arguments that FDA want to see,” Logic Technology Development should be able to convince the agency of the additional benefits of nontobacco flavors.

    Attempts at rectification, however, may prove futile. In January 2020, the FDA banned all flavors except tobacco and menthol in cartridge-based e-cigarettes. In September 2020, the agency signaled that it would not authorize flavored products without extraordinary evidence. With Logic Technologies Development being part of Japan Tobacco International, one of the world’s leading players, it may furthermore be assumed that the company submitted a very comprehensive application.

    While acknowledging that many of the applicants are large multinationals with the financial power to conduct large complex studies, Chaudhary says this does not mean that the studies that the FDA is now looking for were in fact conducted. “It all goes back to the industry’s understanding of the PMTA guidance and final rule back in September 2020 and the way in which the FDA have chosen to enforce the rule today,” he says. “The ongoing view of FDA is that that NYTS illustrates a preference for menthol flavors amongst youth. Therefore, since the original studies were designed to compare all flavors of ENDS to combustible cigarettes; they are not geared to demonstrate additional benefit of menthol flavors compared with tobacco flavors. I would say for any new applications, that has to be a central question to which the application must provide answers.”

    Chaudhary deems it likely that much of the data required to build these arguments already exists in the comprehensive PMTA applications—perhaps with some gaps that could be potentially filled with relatively inexpensive studies. He expects the FDA to apply the same logic to flavored disposable products, which are exempt from the agency’s 2020 flavor ban and have recently experienced a surge in sales. “I would imagine that unless any company has constructed their PMTAs to show the additional benefit of flavors compared to menthol and menthol compared with tobacco flavor, they will also receive MDOs,” says Chaudhary.

    “I think we all agree that this is awful news for U.S. smokers who will be denied the wide range of options that they need to stop smoking,” he continues. “It seems that the only way to re-offer smokers these critical choices is to ensure that we as an industry are responsible. We must ensure that we understand the evidence the FDA want to receive and provide this data to them so that menthol and ultimately other flavors can be authorized back into the marketplace, and all smokers can continue their off-ramping journeys.”

    Chaudhary says the industry needs to move forward, put aside grievances that have arisen as a result of how the FDA has enforced the PMTA final rule and provide the agency with the data it wants to see to ensure that smokers can have these products in their hands at the earliest opportunity.

    “Any integrated technology that can minimize or even eliminate underage use of e-cigarettes would lower the risk of youth use and therefore lower the bar for the additional benefit data that the FDA are now asking for,” he says.

    Stefanie Rossel is Tobacco Reporter’s editorial contributor. An experienced trade journalist, she combines sharp reporting skills with in-depth knowledge of the tobacco and vapor industries. Prior to joining Tobacco Reporter, Stefanie was editor-in-chief at Tobacco Journal International, where she worked for a decade. Fluent in English, German and French, Stefanie covers tobacco news around the world. She is based in Germany.