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  • A New Direction for ENDS

    A New Direction for ENDS

    ~ What FDA approvals mean for ENDS flavoured tobacco products ~

    The FDA’s decision to authorise flavoured Electronic Nicotine Delivery System (ENDS) products marks one of the most significant regulatory developments the sector has seen in recent years. While tobacco and menthol authorisations had already signalled a gradual shift in regulatory thinking, the approval of mango and blueberry flavoured products suggests the agency is increasingly willing to assess reduced-risk nicotine products through a broader public health lens. Here, Chris Allen, CEO of nicotine testing and regulatory consultancy Broughton, explains the significance of this decision and why it reflects a growing emphasis on evidence-based harm reduction, behavioural science and product safeguards.

    Central to the FDA’s assessment process is its “Appropriate for the Protection of Public Health” (APPH) standard, which requires regulators to weigh the potential benefits for adult smokers against the possible risks associated with youth uptake. Emerging evidence suggests that flavoured alternatives may help some adult smokers move away from combustible cigarettes, particularly those who do not successfully transition using tobacco-flavoured products alone.

    One longitudinal study published via the National Library of Medicine found that adult users of sweet or fruit-flavoured nicotine vaping products were more likely to transition away from cigarette smoking than those using tobacco-flavoured alternatives.

    In draft guidance published in early 2026, the FDA acknowledged that non-tobacco flavoured ENDS products may, “in certain circumstances”, support adult smokers in switching away from combustible cigarettes or increasing quit attempts. However, ENDS products continue to face heightened scrutiny due to historic concerns surrounding youth access, abuse liability and the toxicological considerations associated with inhaled products.

    Importantly, the latest authorisations should not be interpreted as a relaxation of regulatory expectations. If anything, they reinforce the extent to which manufacturers are now expected to integrate public health and compliance considerations into product development at an early stage. For ENDS products in particular, this means fully characterising products from a toxicological perspective, understanding behavioural risk factors and demonstrating that appropriate controls are built into the product itself.

    The FDA’s continued scrutiny of inhaled nicotine products – particularly flavoured variants – means manufacturers must increasingly show not only that products can support adult smokers in moving away from combustible cigarettes, but also that meaningful steps have been taken to restrict youth access and minimise unintended use. This will likely place greater emphasis on access-control technologies and submission-ready behavioural data as regulators continue to refine their expectations around next-generation nicotine products. For developers, regulatory strategy can no longer be treated as a final-stage compliance exercise; they must be incorporated into product design from the outset.

    The latest authorisations may also have implications beyond the US market. While regulatory approaches continue to vary globally, the FDA’s decision reflects a broader shift towards more nuanced, evidence-led discussions around harm reduction and the role alternative nicotine products may play in supporting smoke-free ambitions. Increasingly, the debate is moving away from whether reduced-risk products should exist at all, and towards how they can be appropriately regulated to maximise public health benefits while minimising unintended consequences.

    Ultimately, the significance of these authorisations extends far beyond the approval of two flavoured products. They signal that regulators are willing to consider the full public health picture – including adult switching potential, behavioural evidence and technological safeguards – when assessing alternative nicotine products. For manufacturers that raises the bar for scientific substantiation, product stewardship and regulatory preparedness. However, it also demonstrates that innovation supported by robust evidence and responsible product design can still find a pathway through even the most rigorous regulatory environments.

    As the regulatory environment for nicotine products continues to evolve, manufacturers face growing pressure to navigate increasingly complex submission requirements across multiple international markets. Broughton supports businesses through the product lifecycle, combining scientific expertise with regulatory insight across ENDS, nicotine pouches and other alternative nicotine products. To find out how Broughton can help support your submission, visit its website.

  • How LIMS supports GMP compliance

    How LIMS supports GMP compliance

    ~ The impact of LIMS in modern labs, from data integrity and traceability to materials management and quality control ~

    Good Manufacturing Practice (GMP) compliance is fundamental for laboratories operating in regulated industries such as pharmaceuticals, medical devices, medicinal cannabis, and reduced-risk nicotine products. Ensuring data integrity, maintaining traceability, and enforcing controlled processes are all essential components of GMP. Here, Chris Allen, CEO of contract research organisation Broughton, explains the critical role of laboratory information management systems (LIMS) in supporting these requirements.

    Regulators are no longer just inspecting facilities; they are interrogating data. From the US Food and Drug Administration (FDA) to the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) and Health Canada, there is a clear and consistent expectation that companies must demonstrate complete data integrity, traceability and control across the product lifecycle.

    Paper-based systems or fragmented digital tools can make this difficult to achieve consistently. Against this backdrop, LIMS are rapidly evolving from operational tools into critical infrastructure for GMP compliance.

    Ensuring data integrity and traceability

    A well-designed LIMS embeds these controls directly into laboratory workflows, helping ensure processes are followed correctly and records remain secure, complete, and auditable.

    Key capabilities of LIMS that support GMP data integrity include full audit-trail systems that record user actions and changes, version control for methods, products, and specifications, electronic signatures for reviews and approvals, and permission-based access controls to manage user roles and system permissions.

    Together, these features help laboratories maintain confidence in their data while ensuring they are inspection-ready. This both reduces the chances of failing inspections and makes audits less disruptive.

    Traceability of materials and proper equipment management are also essential elements of GMP compliance. Laboratories must maintain visibility over the reagents and materials used during testing, while ensuring that instruments remain calibrated and fit for purpose.

    A LIMS can support this through integrated management of lab resources, including stock batch traceability, stock expiry monitoring, stock status controls, and equipment maintenance and calibration scheduling.

    By centralising this information, laboratories can reduce compliance risks while improving operational efficiency.

    Importantly, the impact of LIMS goes beyond compliance alone. Leading organizations use these systems to gain greater operational control and insight as real-time visibility of laboratory data allows quality teams to identify trends, investigate anomalies and make informed decisions more quickly. This can support faster batch release timelines, improved product consistency and more proactive risk management. In this sense, LIMS is not just a compliance tool, but a platform for continuous improvement.

    Supporting quality control

    Quality management processes, such as identifying and investigating out-of-specification results, are essential components of GMP laboratory operations. Managing these processes manually can introduce delays or increase the risk of errors.

    Within a LIMS environment, testing results can be automatically assessed against predefined specifications, allowing the system to immediately flag potential issues. Investigation workflows can then be initiated and tracked in the system, ensuring corrective actions are documented and managed consistently.

    Embedding these quality processes in the LIMS helps laboratories maintain structured, auditable procedures that align with regulatory expectations.

    Future-proofing labs with LIMS

    As regulatory expectations continue to evolve, the importance of robust digital infrastructure will only increase. Laboratories must manage growing data volumes, support increasingly complex supply chains, and respond to more stringent oversight.

    In this environment, LIMS is no longer a ‘nice to have’, but a foundational component of modern GMP compliance that enables organizations to meet today’s requirements while preparing for those of the future.

    For companies operating in highly regulated sectors, the question is no longer whether to adopt LIMS, but how effectively it can be implemented to support both compliance and long-term operational excellence.

    Broughton has developed its own LIMS platform, LabHQ, to address the real-world challenges laboratories face when operating in highly regulated environments. Drawing on its experience delivering GMP testing services, LabHQ was designed to support the workflows, traceability and data integrity requirements that laboratories need to meet regulatory expectations. To find out more, visit the Lab HQ website.

  • Toxicology beyond the laboratory

    Toxicology beyond the laboratory

    ~ Separating scientific risk assessment from consumer perception ~

    Ingredient scanning apps, social media commentary and retail marketing claims have brought chemical safety under more scrutiny than ever, with everyday consumers now encountering toxicological language when choosing products. As simplified narratives circulate quickly, confusion has emerged between the identification of hazardous properties and the assessment of real-world risk. Here, Dean Hatt, Senior Toxicology Consultant and Toxicology Manager at Broughton, a contract research organisation specialising in analytical testing, toxicology and regulatory consultancy examines several misconceptions shaping public debate around product safety.

    Consumer-facing ingredient-scanning apps that interpret toxicity and hazard data now reach large, and often young, audiences, with Yuka alone having 55 million active users and toxicology content attracting hundreds of millions of views on platforms such as TikTok. These tools present results in formats that resemble regulatory judgement, using simple scores or colour codes that suggest definitive safety conclusions.

    However, the simplicity of these tools can be misleading. Safety is not determined by looking at individual ingredients in isolation – or even their concentration – but by understanding how a finished product behaves as a whole. In reality, risk assessment is a structured scientific process that considers multiple factors together: how ingredients interact within a formulation, how the product is used, how often it is used, and how the body is exposed to it. Two products containing the same ingredient at similar levels can present very different risk profiles depending on these variables.

    In regulated markets such as the UK and EU, safety is therefore assessed based on the complete product and its intended use, not a simplified view of individual components. This process draws on a weight of evidence, including study design, data quality and real-world exposure scenarios, to reach a balanced and scientifically robust conclusion.

    Hazard does not equal risk

    In toxicology, hazard identification represents an early step in a broader scientific process. A substance may possess hazardous properties under certain conditions yet pose minimal or no risk from the route of exposure or at realistic exposure levels. It isn’t as simple as providing a universal list of things that can and cannot go into products, so working with a partner who understands the nuances is key in product development.

    Expert toxicological assessments determine how much exposure occurs, how often it occurs, the route of exposure and how the body responds under those conditions, resulting in a subjective assessment of risk.

    Therefore we must be wary of the oversimplification of toxicology on ingredient-scanning tools and simplified scoring systems that compress analysis from reaction-based voting. A toxicological review can be initiated as a RAG (red, amber, green) system to aid in product development but must be followed by a comprehensive review that incorporates dose, context and margin of safety. This principle underpins international regulatory frameworks such as the EU’s REACH Regulation (EC) No 1907/2006, which requires chemicals to be assessed in relation to their intended uses and exposure scenarios.

    Removal is not always safer

    Public pressure to remove ingredients perceived as undesirable has increased. Research shows the UK free-from foods sector continuing to outpace the wider market as manufacturers innovate to meet growing demand for products free of allergens and certain additives.

    Yet reformulation is not automatically synonymous with improved safety. Substitutes are likely to have less extensive and reliable toxicological datasets or unknown impurity profiles. Altering a formulation can change absorption, metabolism or cumulative exposure patterns in ways that are not intuitive. Removing a flagged ingredient without structured evaluation may simply exchange a well-characterised substance for one that is less understood, and therefore potentially more hazardous.

    Toxicology does not end at launch

    Post-marketing toxicology has become increasingly important as public concern evolves. Online discussion and consumer perception often shifts faster than formal review cycles, creating pressure to respond quickly.  Barcode-scanning ingredient apps illustrate the dynamic. As their scores circulate widely on social media, brands have reformulated products to avoid using flagged additives, even where those substances remain permitted by regulators in their real-world use.

    Clearly, when an app’s outputs are treated as final judgements rather than starting points for inquiry, they risk amplifying fear in places where evidence indicates low risk, while weakening trust in regulatory science more broadly. Therefore, clear public guidance is essential to ensuring health decisions remain grounded in scientific evidence.

    For more information on toxicology, risk assessment and how evidence-based toxicology supports product safety and regulatory compliance, visit Broughton’s toxicology services page.

  • The FDA’s evolving approach to youth-risk mitigation

    The FDA’s evolving approach to youth-risk mitigation

    ~ The latest updates on regulating next generation nicotine products in the United States ~

    Since December 2025, the Food and Drug Administration (FDA) has started to develop a more targeted and consequential regulatory landscape to help improve transparency and efficiency in next-generation nicotine and tobacco product review, while reinforcing expectations around enforcement, youth-risk mitigation, and product-specific evidence. Here, Lilian Ortega, founder and chief regulatory compliance strategist of WOW Solutions, a regulatory consultant partner of nicotine testing expert Broughton, explains the latest developments from regulators across pouches and electronic nicotine delivery systems (ENDS) and the latest enforcement of rules in the United States.

    Nicotine pouches

    The FDA’s authorization of six nicotine pouch products under its pilot program suggested a shift to faster product reviews and approvals. However, since the on! PLUS range was approved there have been no additional authorizations, leading to questions about whether it’s a scalable pathway or a one-time demonstration. Simultaneously, Refuse-to-File (RTF) decisions – where an application is deemed insufficient or incomplete – are being challenged in court, highlighting the challenges for the regulator at the filing stage of approval. The FDA has shown it can move quickly, but only for a narrow subset of applications. We’ll be keeping a close eye out for any additional nicotine pouch marketing decisions to see if the pilot expands.

    ENDS

    Following a roundtable on February 10, 2026, where small manufacturers shared their challenges with the PMTA process with the FDA, there is now a greater expectation of greater transparency, particularly with ENDS products. The overarching message was that the FDA is working to clarify what kind of evidence and how much of it is required, in turn helping to increase predictability. This makes the process more nuanced and should not be confused with any lowering of standards.  

    The FDA’s drafted guidance ‘Flavored Electronic Nicotine Delivery Systems (ENDS) Premarket Applications – Considerations Related to Youth Risk’ further reinforced this by emphasizing that youth risk remains the central driver, reiterating concerns around fruit, dessert, and sweet flavors, while introducing a more refined ‘risk-proportionate, product-specific approach.’

    The document acknowledges that flavored ENDS may provide benefits to adults, including switching, cessation, and reduction, but makes clear that they must outweigh youth risks. The guidance also introduces the concept of ‘differential youth appeal’ across flavor categories, signaling that flavor-specific evidence will increasingly be required. Also, the FDA clarifies that Device Access Restrictions (DAR), including age-gaiting, can support an application but cannot replace scientific evidence of adult benefit.

    This was followed by the first FDA authorization of an age-gated ENDS product – the GLAS device – which contains a tobacco-flavored pod, developed by a small US-based manufacturer. However, the lack of detail via a press release and publication of the Technical Project Lead (TPL) leaves some uncertainty about the remaining portfolio covered in the PMTA.

    Like pouches, there is potential for a streamlined pilot review for ENDS to help combat illicit trade.

    Enforcement

    In late 2025, U.S. Congress provided funding direction with the hope of kickstarting the FDA’s enforcement drive. The provision requires $200 million in user fees to be directed toward ENDS enforcement, mandates updated to enforcement priorities, including flavored disposable devices, and introduces semi-annual reporting to Congress.

    However, with 65 warning letters issued so far in 2026 compared to over 200 at the same stage in 2025, along with minimal penalties suggest there hasn’t been a meaningful increase in enforcement. The required update to enforcement priorities guidance may serve as the inflection point, particularly as Congress has signaled a focus on flavored disposable ENDS.

    Further enforcement priorities guidance should be available in the near future, so we’ll be looking for any initial reporting and if any enforcement activity materially increases.

    To ensure your tobacco and nicotine products comply with the latest FDA regulations and guidance, it’s important to work with a trusted regulatory specialist, so your product can navigate the PMTA pathway as smoothly as possible. Visit Broughton’s website to find out more about how working with a partner can bring your product to market.

  • 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.”