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.”
What can the next-generation nicotine industry expect in 2024?
By Paul Hardman
The U.K. government’s proposal for a “smoke-free” generation and changing consumer opinions toward nicotine products are causing a shift in consumer habits. The year 2023 shone a spotlight on e-cigarette compliance, with a potential ban on disposable vapes on the horizon. So, how will this year’s events impact the manufacturing of nicotine products, and what trends and regulations are we likely to see going into 2024?
Nicotine Pouches
Nicotine pouches represent an extraordinary opportunity to support tobacco harm reduction in adult smokers. Sweden, the world’s most advanced nicotine pouch market, is on the brink of being smoke-free, with less than 5 percent of its population smoking.
However, in the U.K., there is a regulatory gap that allows those under 18 to purchase nicotine pouches legally. In addition, there are concerns that nicotine pouch manufacturers could fall into the same traps as some disposable e-cigarette companies, by creating products that appeal to youth.
If youth use becomes an issue, the easiest move for regulators is to categorize nicotine pouches in the same way as oral tobacco products like snus—rendering them illegal. An alternative response might be to categorize these products as nicotine-replacement therapies and place them under medical product regulations, which would restrict their access.
To keep these products available to adult smokers who wish to quit, manufacturers can act as if regulation is already in place: generate data, devise safety frameworks and ensure the quality of products entering the market. Importantly, manufacturers should present and market their products in responsible ways, including avoiding bright colors, not imitating other consumer goods (e.g., soft drinks) and refraining from using any type of cartoon/video game characters.
Non-Heated Technologies
We have yet to witness a vape product approved via the U.K. Marketing Authorization Application (MAA) pathway, which enables nicotine products to be marketed as smoking cessation nicotine-replacement tools and prescribed by healthcare professionals. However, non-heated vape technology might facilitate MAA approval by addressing the core problem of delivered dose uniformity (DDU).
One example of a non-heated vape technology involves ultrasound sonication, which enables the atomization of e-liquids to create an aerosol, similar to technology used in medical nebulizers. The droplet size and dosage can be predefined according to the dimensions of the mesh, ensuring uniformity in the vapor, thus improving DDU. As we go into 2024, we will likely see more manufacturers exploring this approach. In parallel, e-liquids will be developed specifically for this technology.
Product Development
Nicotine product manufacturers have been moving toward a quality-by-design (QbD) development process, and we will see this continue in 2024. There are no specific guidelines or requirements for the stability testing of nicotine products other than the scientific justification for shelf life. Employing a QbD approach demonstrates a higher level of due diligence, which could produce safer, higher quality nicotine-delivery systems.
In addition, manufacturers are starting to implement extractables and leachables studies during the development process in anticipation of the new guidelines being set out by the European Committee for Standardization. Once these guidelines are published, we can expect to see a more standardized approach throughout the industry.
Paul Hardman is a managing consultant at Broughton, an independent life sciences contract research organization offering analytical testing services integrated with scientific consultancy and global regulatory support.
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 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.
More than a year after the U.K.’s MHRA updated guidance, there are still no medicinal vapes on the market.
By Pete Lomas
The U.K.’s Medicines and Healthcare products Regulatory Agency (MHRA) updated its guidance for licensing electronic nicotine-delivery systems (ENDS) as medicinal products on Oct. 29, 2021. The new guidance marked a shift in approach from the MHRA as it began actively encouraging applications and sought to support companies through the process. Over a year on, however, we have to wonder why the industry doesn’t have any medicinal vapes on the market.
The change in direction by the MHRA was likely spurred by the U.K. government’s desire to meet its “Smoke-Free by 2030”1 target, which stipulates that less than 5 percent of the population should be smokers by the end of the decade. Using ENDS can be a good way to reduce the harmful effects of smoking, and the hope is that this new approach will change the perception of ENDS, bringing them more in line with other nicotine-replacement therapies, including gums, sprays and patches.
Pete Lomas
The pathway via which e-cigarette products can be certified as medicinal products is known as a marketing authorization application (MAA). Since nicotine is not a new chemical entity, the MAA can be abbreviated with respect to safety and efficacy information. Instead, the application will rely primarily on a pharmacokinetic study to compare the new product with an appropriate reference medicinal product. Given the intended route of administration, an already approved inhaled nicotine product such as the Nicorette 15 mg Inhalator has been suggested by the MHRA as a suitable comparator.
As well as conforming to the MAA requirements, any ENDS devices will also need to be proven to be electromechanically safe. In the U.K., this will require it to be U.K. Conformity Assessed marked, following assessment by an authorized approved body.
Encourage licensing
In a bid to elucidate the new application process, the MHRA initially ran a webinar titled “Licensing Electronic Cigarettes as Medicines,” which was retroactively made available on YouTube.2 In short, the MHRA is committed to providing as much assistance as is needed to ensure potential applicants understand the process and feel able to make applications in a timely manner.
But the MHRA has gone beyond simply putting on talks and answering questions—it has also widened the goalposts slightly, making applications more likely to succeed. One way this has been done is by adapting how delivered dose uniformity (DDU) is measured. As a medicinal product, vapes are classified in a similar way to conventional pressurized metered dose inhalers (pMDIs), meaning the criteria that must be met before approval is very similar.
E-cigarettes, however, are a fundamentally different technology to pMDIs. Whereas pMDIs use a pressurized canister calibrated to deliver an exact amount of aerosol per puff, an e-cigarette is traditionally based on coil and wick technology. This difference makes the DDU per-puff of an e-cigarette much less consistent, and that is before considering self-titration (the patient taking larger or smaller puffs based on preference and habit) is even considered.
So, if ENDS are subjected to DDU regulations on a per-puff basis, then most will fall short—what to do then? To address this, the MHRA has instead set DDU requirements that are averaged over 10 puffs, rather than one, thus making it easier for vapes to comply.
Achieving DDU
Despite the leeway given by the MHRA, delivering dose uniformity is still very important. For products to reach medicinal standards, they must be designed to be as consistent, puff to puff, as possible. In that respect, any applicant seeking approval will need to focus on three key points: consistent power, consistent delivery of liquid and consistent airflow—achieve all three and a device stands a good chance of complying with the new guidance.
Modern developments in vape technology will help address the issue of DDU further. Non-heated vaping technologies based on ultrasonics, piezo-ceramic mesh and micro-nozzles are now being used to develop these products and offer greater inhalation consistency. Piezo-ceramic technology, in particular, is well suited for medicinal products as it offers the ability to fine-tune the mesh, vibration frequency or other parameters within the device, depending on the liquid formulation.
Another key difference between ENDS and their inhaler cousins is that the performance of electronic products tends to vary at the beginning and end of the product’s lifecycle. That means priming and end-of-life doses may not deliver the same uniformity as is expected for the bulk of the product’s use. Within the new guidance, applicants will now be able to define these different doses and exclude them from the uniformity criteria, so long as appropriate justification is provided and information on these differences is communicated to the end users.
Achieving MAA licensing
To date, only one e-cigarette product has successfully passed through the MAA process, around a decade ago. However, smokers did not find the product sufficiently satisfying to make a permanent switch. It was withdrawn from the market only a couple of years after launch due to low smoker compliance. Technology has evolved much since then, resulting in products that are much more satisfying for smokers, allowing them to transition away from combustible cigarettes altogether.
Typically, performing the necessary studies and data gathering for the application would be expected to take 12 months to 18 months. Once collected, the MHRA offers a 150-day accelerated assessment for “high-quality” MAAs, with an intervening “clock-off period” where further clarification and information can be provided, as required. The clock-off period should last no longer than 60 days.
For applicants with products undergoing a U.S. FDA premarket tobacco product application (PMTA) process, or for the 23 ENDS that have already been approved3 via this route, there is opportunity to reduce the number of new studies that are required for an MAA. The MHRA has said it is happy to discuss what data may be relevant for a U.K. MAA, therefore reducing the need for additional studies in some cases.
Even if the majority of the data from a PMTA cannot be used directly as part of the MAA, data generated for the PMTA can be used to help strengthen the Pharmaceutical Development section within Module 3 of the application. In addition, a successful product on the U.S. market will provide confidence to regulators of consumer acceptance, which can be an important consideration.
All told, any applicant beginning data collection for an MAA should anticipate the entire process, from product finalization to market approval, taking in the region of two years. This explains why we are yet to see a product reach approval since the guidance was only updated in October 2021. As we approach the two-year mark at the back end of 2023, it seems plausible that the first medicinally licensed ENDS could come on sale in the U.K.
Credit: Minerva Studio
Where to find medicinal vapes
If the license granted permits the product to be sold and supplied as a General Sales List (GSL) medicine, then the retailer does not need to be a pharmacy. Examples of common GSL medicines include ibuprofen and paracetamol, which can be purchased from retail outlets such as convenience stores and supermarkets, where they are available for self-selection, albeit with appropriate sale restrictions on purchaser age and quantity of the product.
Most existing nicotine-replacement therapies—products like patches, gum and sprays—are listed as GSL items, and so the assumption is that ENDS would be made available in the same way. That said, approval onto the GSL doesn’t automatically exclude a product from being prescribed to patients by a healthcare professional. Applicants may still wish to secure contracts with healthcare providers to distribute their product through alternative channels, which can include being exclusively sold as a prescription treatment.
Making a difference
It is fair to say that the perception of vaping, both in the eyes of the public and healthcare professionals, has declined in recent years. A 2021 survey by Action on Smoking and Health4 (ASH), for example, found that nearly a third (32 percent) of smokers incorrectly believe that vaping is more or equally as harmful as smoking. Whatever the reasons are behind this—I suspect there are several—it needs to change if we are to reach the smoke-free target by 2030.
The hope is that by licensing ENDS as medicinal products, it will provide credibility that these products are not just safe but have genuine harm reduction potential. MHRA approval will provide customers with confidence that they are making a healthy choice when switching from smoking to vaping.
A barrier to the success of this reclassification of vapes as medicinal products may be smokers’ perceptions of themselves. Many don’t want to be seen as “patients” per se, and so they might resist being bundled into such a group. Medicines, however, are as much about the prevention of disease as for its treatment, and given that these products will hopefully be available as GSL medicines, resistance to their purchase should be minimal. Most people don’t feel like a “patient” when purchasing ibuprofen after all.
The impacts of the change in guidance will only become apparent once we start seeing products approved via this route. For now, there are still over 6 million people5 in the U.K. who smoke cigarettes; e-cigarettes, which have been through the rigorous medicinal licensing process, could be a safe, effective and trusted part of the solution moving forward.
Broughton is establishing a U.S. subsidiary to enhance its presence in the region. Leading the U.S. team will be Tony Jones, who joins Broughton as managing consultant. Jones has extensive experience in toxicology and risk assessment.
“I am delighted to be spearheading this exciting next stage of the development of Broughton in the U.S. market,” said Jones. “I’m looking forward to introducing the full lifecycle development services offered by the Broughton team to U.S. clients across pharmaceuticals, nicotine and cannabinoids to help the company support their clients to accelerate innovation to market and improve health outcomes.”
Along with the appointment of Jones, Broughton has strengthened its consultancy team with several new members.
Libby Clarke and Carol Beevers have joined the company’s toxicology team. Clarke is a European registered toxicologist and has substantial experience devising toxicology testing strategies and compiling submissions to regulatory bodies, such as the U.S. Food and Drug Administration and Health Canada. Beevers is a genetic toxicology specialist and has contributed to more than 20 papers in peer-reviewed journals. She is a member of the U.K. Committee on Mutagenicity and several international working groups on genotoxicity testing.
In recognition of the growing importance of behavioral science in regulatory submissions, Broughton has also strengthened its in-house team with the appointment of Oliver Knight-West. Knight-West has conducted multiple behavioral and clinical studies into next-generation nicotine products and pharmaceuticals for dossier submission to the FDA, the U.K. Medicines and Healthcare products Regulatory Agency, and the European Medicines Agency.
He has published many scientific papers in several highly cited publications.
To complement the appointment of Paul Hardman in 2021, Malcolm Saxton has joined the chemistry consultancy team. Saxton will help ensure that Broughton remains at the forefront of the industry in terms of novel method development aligned with evolving market and regulatory needs.
‘’Since 2006, our focus has always been to help our clients succeed,” said Broughton CEO Chris Allen. “With a passion for enhancing societal health and wellbeing, the establishment of a North American subsidiary is a natural next step to enable us to better partner with our customers in the region.”
