Guidance

Guidance for licensing electronic cigarettes and other inhaled nicotine-containing products as medicines

Guidance on how to license electronic cigarettes and other inhaled nicotine-containing products (NCPs) as medicines in the UK.

• From: Medicines and Healthcare products Regulatory Agency
• Published: 14 December 2017
• Last updated: 3 November 2022 — See all updates

Introduction

The MHRA is responsible for regulating nicotine-containing products (NCPs) as medicinal products in the UK. These are intended to relieve or prevent craving and nicotine withdrawal symptoms when tobacco smokers wish to quit or reduce smoking. The MHRA seeks to encourage the licensing of electronic cigarettes (e-cigarettes) and other inhaled NCPs as medicines and aims to support companies to submit marketing authorisation applications for these products. In addition to the medicines authorisation, where the E-cigarette is refillable and re-useable it will need to meet the UK Medical Device Regulations 2002 (as amended). Potential applicants who are not familiar with medicines legislation are strongly advised to contact the MHRA for regulatory and scientific advice. The MHRA commits to provide the assistance needed to ensure that potential applicants understand the process and feel able to make applications in a timely manner which are fit for purpose. For applicants with products undergoing the US FDA premarket tobacco product application (PMTA) process, the MHRA can discuss what data may be relevant for a UK marketing authorisation application.

The MHRA is also the Competent Authority for the notification scheme for e-cigarettes and refill containers in Great Britain and Northern Ireland, and is responsible for implementing the majority of provisions under Part 6 of the Tobacco and related Products Regulations (TRPR) and the Tobacco Products and Nicotine Inhaling Products (Amendment) (EU Exit) Regulations 2020. Information on the requirements for consumer e-cigarettes can be found on our consumer products guidance page. These products are not medicines and are not permitted to make medicinal claims.

To license e-cigarettes and other inhaled NCPs as medicines, the proposed products should meet standards of quality, safety and efficacy as defined under medicines regulations. The proposed medicinal products should also meet the usual quality and safety standards for consumer e-cigarettes that have been developed by national and international standards organisations, where relevant. Proposed products may also need to comply with the UK medical device regulations, depending on the design of the product.

E-cigarettes regulated as medicines may be made available in strengths and volumes greater than those permitted under the TRPR (i.e. containing more than 20 mg/ml nicotine, more than 2 ml for single use cartridge/disposable products or more than 10 ml for refill containers).

This document provides more specific guidance on the procedure for licensing e-cigarettes and other inhaled NCPs as medicines.

Applying for a marketing authorisation

The recommended starting point for information on the medicines licensing procedure is the MHRA marketing authorisations, variations and licensing guidance.

Further information can be found here:

• Applying for a licence to market a medicine in the UK
• Types of application (legal basis)
• Fees for licence applications (Note that nicotine is not a new chemical entity so it is expected that application fees would fall within the abridged complex or standard classifications)

As nicotine is not a new chemical entity, a so-called abridged application may be submitted as a generic application under Regulation 51 (previously Article 10.1 of Directive 2001/83/EC) or a hybrid application under Regulation 52 (previously Article 10.3 of Directive 2001/83/EC), of Human Medicines Regulation, as amended. These legal bases allow for submission of a dossier which is abbreviated in relation to safety and efficacy, relying on a pharmacokinetic (PK) study to compare the new product to an appropriate reference medicinal product.

Given the intended route of administration, an already-approved inhaled nicotine product such as the Nicorette 15 mg Inhalator would be a suitable reference and comparator medicinal product.

For a submission under Regulation 51, the proposed product should be bioequivalent to the reference product. This is likely to be the most appropriate approach when developing an inhalator product with reference to an established inhalator reference product, for example. For a submission under Regulation 52, the proposed product need not be bioequivalent to the reference product, but the proposed product’s nicotine PK profile should be justified in relation to where it ‘sits’ compared to the reference product and combustible cigarettes. This is likely to be the most appropriate approach when developing an e-cigarette product with reference to an established inhalator reference product, for example. PK data should be complemented by a discussion of the proposed product’s safety and efficacy with reference to the literature. Please see the ‘clinical requirements’ section for further information.

All marketing authorisation applications (MAAs) must be supported by a risk management plan. This must cover identified and potential risks of the product and the measures to be implemented to minimise these risks. Further information can be found in our Good Pharmacovigilance guidance (GpVP).

In assembling the dossier for an application for marketing authorisation, the guidelines relating to the quality, safety and efficacy of medicinal products need to be considered. The dossier will need to follow the format published by the European Commission in EudraLex Volume 2 - Pharmaceutical Legislation Notice to applicants and regulatory guidelines medicinal products for human use. In particular, Volume 2B – Presentation and content of the dossier provides a useful overview of the data which make up a marketing authorisation and gives specific reference to many of the guidelines which should be referred to when compiling the data to support a marketing authorisation. These guidance documents can also be found on the MHRA website.

Further information on applying for a marketing authorisation can also be found in our licensing guidance. This gives relevant information in such areas as which procedure route to follow, fees, naming of the medicine and ways to make the submission. Applications should be submitted using the electronic Common Technical Document (eCTD).

There are several routes to obtain a marketing authorisation in the United Kingdom (UK), Great Britain (England, Scotland and Wales) or Northern Ireland. The national 150-Day Procedure is an accelerated procedure available for high-quality applications to market a medicine in the United Kingdom, Great Britain or Northern Ireland. Applicants are encouraged to contact the MHRA if alternate routes of submission are being considered.

Quality requirements (Module 3 of the dossier)

The quality data (Module 3) requirements are clearly defined and apply to all MAAs. Two main sets of information are needed, the first dealing with the active substance (Module 3.2.S) and the second with the finished medicinal product (Module 3.2.P).

All relevant information should be provided on the product development, the manufacturing process, characterisation and properties of the product, the quality control operations and test specification, the stability as well as a description of the composition and presentation of the finished medicinal product.

Module 3 should also include:

• information on the nicotine active substance including its synthesis and control
• details of other ingredients in the formulation of the finished medicinal product and of the container components (e.g. cartridges).
• the procedures and methods used for manufacturing and controlling the finished medicinal product. These need to be described in sufficient detail to enable them to be repeated in control tests, carried out at the request of the competent authority.
• all test procedures shall correspond to current scientific standards and need to have been validated. Results of the validation studies should be provided. In the case of test procedures included in the European or British Pharmacopoeia, the description may be replaced by the appropriate detailed reference to the monograph(s) and general chapter(s).

Both the active substance and the finished product should be manufactured at sites which operate in compliance with the principles of Good Manufacturing Practice (GMP). For the finished product manufacturer, the site must hold a valid manufacturing authorisation and GMP certificate before a marketing authorisation for the product can be granted.

Further information on the additional licenses required in support of an MAA is provided below under ‘Manufactured in UK, EU/EEA or third country for sale in UK’.

Active substance (drug substance)

Nicotine is the subject of a monograph of the European Pharmacopoeia. The drug substance specification must be in line with that monograph and with the general monograph on substances for pharmaceutical use.

There are a number of ways in which the applicant can submit the information on the drug substance and a specific guideline has been developed which explains these in detail.

Other ingredients (excipients)

Other ingredients should meet European Pharmacopoeia monograph requirements where they exist; if flavouring components do not have monographs, then they should meet EU food safety legislation requirements. Excipients should be approved for inhalation use or have appropriate toxicological data to support use by that route of administration.

For glycerol and propylene glycol, an issue may be potential contamination with diethylene glycol. Note the European Medicines Agency (EMA) Good Manufacturing Practice (GMP) Q+A, which although it refers to glycerol should also be taken into account for propylene glycol.

Container closure components (packaging)

Container closure components which come into contact with the finished product (primary packaging) should meet European Pharmacopoeia monographs where they exist. If the materials are not covered by such monographs, then they should comply with the applicable EU food safety legislation requirements.

The products or their packaging should comply with child resistance standards (BS EN ISO 8317 for reclosable containers and BS EN 14375 for non-reclosable containers) and be tamper evident.

Further guidance on plastic components can be found in the CHMP Guideline on Plastic Immediate Packaging Materials (CPMP/QWP/4359/03). For metal components, there is no particular guidance. The specification should state the grade of stainless steel.

Finished product (drug product)

A description of the product, together with details of the composition of the formulation should be provided in the dossier with details of the development and manufacture of the product. Where applicable, evidence of CE / UKCA marking which is required by the applicable UK legislation on medical devices should be provided. For example, this would be required for e-cigarettes where the ‘cigarette’ device either contains cartridges of nicotine which can be replaced or if the device can be refilled with nicotine solution.

The finished product should be controlled by appropriate specifications. Controls would include:

• ensuring the levels of nicotine meet recognised pharmaceutical standards (for example, 95.0 to 105.0 % of the declared content) throughout the product shelf-life
• limits on impurities to ensure they are controlled at safe levels throughout the product shelf-life
• evidence that the product consistently delivers the correct dose of nicotine during use and over the shelf life of the product. This should be kept in mind when selecting the battery for a battery-operated device
• compliance with the requirements of the European Pharmacopoeia monograph for Preparations for Inhalation
• compliance with the requirements of the British Pharmacopoeia monograph for Nicotine Inhalation Cartridges

Relaxation of any test limits requires robust justification and such requests would be reviewed on a case-by-case basis during the assessment. As mentioned above, the finished product must be able to consistently deliver the correct dose during use and throughout the shelf-life of the product. This may be demonstrated using the test equipment and conditions described in BS ISO 20768:2018 ‘Vapour products — Routine analytical vaping machine — Definitions and standard conditions’.

If changes are made, these should be fully explained and justified. When using such test equipment and conditions, the MHRA permits 10 puffs/inhalations to be considered as one dose. For doses which are outside the European or British Pharmacopoeia limits it may be helpful to determine whether these could be considered to be priming doses (at beginning of product/cartridge use) or tailing doses (at end of product/cartridge use). If this were to be the case, and if appropriately justified, it may be possible to address this non-consistent dose delivery by appropriate wording in the product information.

General guidance on pharmaceutical development studies is given in ICH guideline Q8 (R2) on pharmaceutical development (EMA/CHMP/167068/2004) and CHMP note for guidance on development pharmaceutics (CPMP/QWP/155/96).

The CHMP guideline on the pharmaceutical quality of inhalation and nasal products (EMEA/CHMP/QWP/49313/2005 Corr) discusses the pharmaceutical development studies which are required for inhalation products, which would include e-cigarettes. Further information on the requirements of the finished product (‘specification’) is also included in the guideline. The development studies listed in Table 4.2.1 for pressurised metered dose inhalers would normally be expected for this type of product, except for item (f) ‘fine particle mass with spacer use’, which would not be required.

• Studies into extractables and leachables should consider the metal contaminants from the manufacturing process or use of the product, for example the heating element, as well as those from the plastic and rubber components.
• Robustness studies should also investigate resistance to biting/chewing and fire resistance.
• The vaporisation products of the e-cigarette should be studied. Potential changes of the formulation on thermal decomposition, and the potential for the heating element and associated components (including adhesives and solder) to shed metallic and other particles on heating, should be investigated.
• Foreign particulate matter in the delivered dose should be investigated.
• Characterisation of individual inhalations (puffs) is expected, although it is appreciated that individual inhalations may vary depending on the individual user.
• The length of time (continuous, ‘normal/average’ and occasional use) a charged product can be used for and the length of time to re-charge the device (full and, if applicable, partial charge) should be determined.
• The interchangeability of a battery-operated device with different re-charging equipment should also be considered and potential risks identified and discussed, together with proposing appropriate measures to mitigate these risks.
• Device functionality testing should also be performed. For example, testing whether the e-cigarette shuts off when the reservoir is empty (i.e. it does not continue to heat), whether any visual indicator on the e-cigarette functions as intended (e.g. on, off, reservoir empty) and whether the e-cigarette overheats during use.

As the design and use of the product may vary, it is not possible to itemise all the individual studies required.

Non-clinical (safety) requirements

With respect to safety, the toxicological consequences of heating and vaporising the formulation of nicotine and excipients (including flavourings) during the normal use of the product need to be considered. For example, particular concern has been raised in studies about the presence of acrolein and other carbonyls, such as formaldehyde and acetaldehyde, that can be produced as a consequence of the thermal decomposition of glycerol and propylene glycol. Analytical chemistry data should be used to confirm the compounds present in the vapour produced by an e-cigarette device under its normal operating conditions. Information on the potential toxicity of any degradation products at relevant exposure levels and all routes of exposure should be provided.

The applicant should also provide a detailed safety review of all the components in the formulation, such as flavourings and excipients, from available published research. Discussion of repeat-dose toxicity studies using the oral route of administration could provide information on any systemic toxicity and support the long-term use of an excipient. Information on local toxicity following inhalational administration may be difficult to source, the following are methods that applicants may find helpful to provide missing information:

• Read-across to predict end points. This is done by using a structurally similar substance to describe the likely toxicity profile of the target substance and could be utilised to bridge the gap between existing data where data from a target excipient are lacking.
• PK modelling could be used to predict local and systemic exposure. However, data would need to be provided to justify the safety of an excipient at relevant exposure levels in any proposed formulation. These data need to consider any effects from an inhalational route, the potential for long-term use and the reversibility of any pathology observed.
• Adverse Outcome Pathways, a model for identifying the sequence of molecular and cellular events required to produce a toxic effect, could be used to identify intermediate markers of toxicity.
• Where post-marketing surveillance data is available from a commercial product, this could be used to support long-term use and/or potential toxicity from an inhalational route of exposure where there is a lack of existing non-clinical data.

Information on the genotoxic potential of any excipient should be provided (EMA/CHMP/ICH/83812/2013). Given that excipients will most likely be in line with European Pharmacopoeia monograph requirements and/or EU food safety legislation requirements, it is anticipated that there would be no need for reproductive toxicity or carcinogenicity studies. Information that justifies that exposure at the proposed excipient levels is safe with regard to genotoxic, carcinogenic potential and reproductive toxicity, should also be provided. Read-across could be useful where there are gaps in available data. Consideration as to how data is relevant to a paediatric population should be included if a product is to be marketed to those under 18 years of age (EMEA/CHMP/SWP/169215/2005).

If no or limited non-clinical or clinical data exist in the public domain, the applicant should consider conducting appropriate studies in line with the ICH guideline M3(R2) on non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for pharmaceuticals (EMA/CPMP/ICH/286/1995) and the CHMP guideline on non-clinical local tolerance testing of medicinal products (EMA/CHMP/SWP/2145/2000 Rev. 1, Corr. 1*).

A toxicological evaluation of any potential extractables and leachables originating from all components of the e-cigarette should also be provided (CHMP guideline on plastic immediate packaging materials CPMP/QWP/4359/03 and EMEA/CVMP/205/04).

The Committee on Toxicity’s work on flavourings is a helpful introduction to the information required.

Clinical (efficacy and safety) requirements

The efficacy and safety of an NCP intended for treating tobacco dependence depends in part on the plasma nicotine levels produced by the product. Therefore, as a general principle, an applicant would be required to demonstrate that the plasma nicotine concentration which their product will achieve when used as intended is both effective and safe. To ensure efficacy, plasma nicotine concentrations of the applicant’s product should not be substantially less than for established nicotine replacement therapy (NRT) products. To ensure safety, plasma nicotine concentrations of the applicant’s product should not be more than for a tobacco cigarette.

Assuming that submissions will be made as generic or hybrid applications (see Section 2: applying for a Marketing Authorisation), an applicant should compare plasma nicotine concentration achieved with the ‘test product’ (the applicant’s product) to that achieved with an authorised ‘reference product’ (an NRT already licensed on the basis of a full dossier). The reference product should ideally be chosen to have comparable characteristics to the test product, e.g. an inhaled e-cigarette test product should ideally be compared to an inhaled reference product such as the Nicorette 15 mg Inhalator.

The MHRA can advise on other appropriate reference products or comparator products for submission of the application and can advise on conduct of the comparative bioavailability study.

To compare plasma nicotine concentrations between the test and reference products, the recommended approach is to conduct a comparative bioavailability study with a randomised crossover design. Here, an appropriate number of healthy volunteer smokers will be randomly assigned to receive the test product or reference product in the first treatment period. Following 14 hours of abstinence from nicotine (usually overnight and confirmed with an exhaled carbon monoxide test) and a baseline blood sample, each subject will use their assigned product in a standardised manner (e.g. five inhalation sessions each separated by 1-hour intervals; an inhalation session defined as 10 inhalations, each inhalation completed within 3 seconds with a new inhalation every 30 seconds) and their blood sampled periodically. This multiple-session design is recommended since it allows data to be collected on accumulation, on ‘priming doses’ for the device, and safety data after repeated dose. Subjects should then be allowed to restabilise their usual smoking/vaping regimen, before the second treatment period where each subject receives the product they did not receive in the first treatment period.

The study design should follow, whenever appropriate, the Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/Corr**). Biopharmaceutical and bioanalytical data should be presented as described in the guideline. The study can be conducted in the fed state, however meals, drinks and/or water should be avoided 15 minutes before and after each inhalation session.

Blood samples should be analysed for nicotine content to allow the comparative PK (maximum concentration, total exposure) to be determined. Blood sampling should be of sufficient frequency and duration to capture the exposure (Cmax and area under the curve (AUC)) of nicotine following both the first and last inhalation session. Pre-dose samples prior to each inhalation session should also be taken and analysed for nicotine.

The following PK parameters should be determined and summarised with descriptive statistics: AUC0-t, AUC0-∞, residual area, Cmax and tmax. The following PK parameters should be determined and analysed to compare between study products: Cmax,0-tau, partialAUC0-tau, Cmax,lastdose-t, and partialAUClastdose-t. The PK parameters for 0-tau should be determined following the first, but just before the second inhalation session.

For a generic submission under Regulation 51, the proposed product should be bioequivalent to the reference product. In this case, no comparison against combustible cigarettes is necessary.

For a hybrid submission under Regulation 52, the proposed product need not be bioequivalent to the reference product, but it should be justified where the proposed product’s nicotine PK profile ‘sits’ in relation to the reference product and combustible cigarettes:

• To justify efficacy, for Cmax and AUC values the lower bound of the 90% confidence interval for the ratio of the test NCP and reference NRT products should be greater than 80.00% (i.e. plasma nicotine concentrations of the applicant’s product should not be substantially less than those of the reference NRT). It is not a requirement that the upper bound of the 90% confidence interval for the ratio of the test NCP and reference NRT products should be less than 125.00% for submissions under Regulation 52.
• To justify safety, an optimal comparative bioavailability study for a new medicinal NCP would also include tobacco cigarettes as an additional comparator, with each participant receiving all three products over three periods. Here, the upper bound of the 90% confidence interval for the ratio of the test NCP and tobacco cigarettes should not be more than 100.00% (i.e. plasma nicotine concentrations of the applicant’s product should not be more than for a tobacco cigarette). The analysis for each comparison should be conducted excluding the data from the product that is not relevant for the comparison in question.
• Alternatively, instead of including tobacco cigarettes in the study, it may be possible to cite bibliographic data comparing blood nicotine concentrations in the reference NRT product to those following tobacco smoking. It should be justified that these data are an adequate substitute for including tobacco cigarettes in the study. The bibliographic data should be used to justify acceptance limits for the upper bound of the 90% confidence intervals for the ratio of the test NCP and reference NRT products for each analysed parameter in the absence of a tobacco cigarette period in the study. For example, if the bibliographic data showed that for AUC0-t the 90% confidence interval for the ratio of the reference NRT product and tobacco cigarettes had an upper bound of 60.00%, an acceptable choice for the acceptance limit for the upper bound of the 90% confidence interval for the ratio of the test NCP and reference NRT products for AUC0-t could be 166.66% (derived from 100/60.00). The acceptance limits and justifications should be included in the study protocol and not derived retrospectively.

It is encouraged that clinical bioavailability studies also include a pharmacodynamic assessment such as a visual analogue scale (VAS) of craving for nicotine, to supplement the PK data.

For products with multiple strengths, it may be preferable to investigate all strengths in the clinical bioavailability study, however a strategy to control multiplicity will need to be pre-specified in the protocol and the analysis for each comparison should be conducted excluding the data from the products that are not relevant for the comparison in question. Alternatively, it may be sufficient to investigate only one strength (usually the highest) in the clinical bioavailability study, and obtain a waiver for the other strengths if supported by adequate in vitro data.

If the applicant develops additional flavouring of an NCP, it will usually be adequate to provide nicotine bioavailability data for a single flavour only. The applicant should justify that the additional flavourings do not contain differences in composition or interact differently with other components of the product and/or alter the formulation pH in a way which may affect nicotine bioavailability.

Other approaches may be acceptable and should be discussed with the MHRA. In general, applicants are encouraged to contact the MHRA when planning their study.

The Clinical Overview and Clinical Summary should include justification of the safety and efficacy of the proposed product for each claimed indication with reference to the published literature. It should be justified to what extent the cited literature is relevant to the safety and efficacy of the proposed product given the PK data generated in the bioavailability study. The addictive properties of the product should also be justified with reference to literature on tobacco cigarettes, e-cigarettes, and licensed NRTs.

The licensed indications for e-cigarettes and other NRTs should always include the ‘quit’ indication, i.e. ‘to aid smokers wishing to quit or reduce prior to quitting’. It is preferred to include the full indication in line with the reference product, e.g.: ‘[Product name] relieves and/or prevents craving and nicotine withdrawal symptoms associated with tobacco dependence. It is indicated to aid smokers wishing to quit or reduce prior to quitting, to assist smokers who are unwilling or unable to smoke, and as a safer alternative to smoking for smokers and those around them.’

Impact of medical device regulations

Products intended to administer a medicinal product may be regulated as either medical devices or as medicinal products, depending on the presentation and use of the individual product.

A good starting point for medical device regulation can be found here in our guidance.

Medicinal Product and Medical Device co-packaged or provided separately

Where the e-cigarette device and the nicotine-containing medicinal product are separate entities and the device may be re-used or re-filled, for example an e-cigarette that has separate cartridges, then the device will need to be CE / UKCA (as applicable) marked as a medical device under the appropriate legislation.

There are a number of changes to how medical devices are placed on the UK market from 1 January 2021, including a new conformity assessment route for the purposes of the UKCA mark. However, CE marked medical devices will be accepted on the Great Britain market until 30 June 2023 and on the Northern Ireland market indefinitely. Any medical devices placed on the UK market will need to be registered with the MHRA and non-UK based manufacturers will need to appoint a UK Responsible Person. Information on UK medical device requirements from 1 January 2021 is available here. Please also refer to the Guidance on Medical devices: conformity assessment and the CE mark. As an e-cigarette contains components such as a battery and heating element, standards relating to electrical components are also relevant.

Two- or three-piece e-cigarettes or refillable one-piece e-cigarettes

The MHRA considers that the part of the e-cigarette containing the battery together with any associated charging accessories would be a Class IIa active therapeutic medical device, unless the administration is in a potentially hazardous manner in which case they would be Class IIb.

This means that a separate application needs to be submitted to a duly designated Notified Body / UK Approved Body to have the device elements of the e-cigarette assessed and then CE / UKCA (as applicable) marked. Further information about Notified Bodies / Approved Bodies can be found on our website.

Although it often contains the heating element, the cartridge containing the nicotine solution is considered to be part of the medicinal product. Note that the heating element section is still required to comply with the relevant essential requirements in Annex I of the Medical Devices Directive (93/42/EEC) for Great Britain or, from 26 May 2021, Annex I of the Medical Device Regulation (2017/745) for Northern Ireland or UK wide applications, and evidence of this will be required. It is assumed that the safety and performance of the cartridge will also be examined by a Notified Body / UK Approved Body at the same time as the battery, since the two are intrinsically linked. The company needs to consider the interaction between the ‘device’ and the heating element within the cartridge.

Integral combination of medicinal product and medical device - one-piece disposable e-cigarettes

Where the device and the medicinal product form a single integrated product designed to be used exclusively in the given combination and which is not refillable the whole product will be regulated as a medicinal product and require a marketing authorisation. However the ‘device’ elements will need to meet the relevant Essential Requirements of Annex I of the Medical Device Directive 93/42/EEC transposed through the UK Medical Devices Regulations 2002 (SI 2002 No 618) as amended (in the form that they exist on 1 January 2021). This transposes the three EU Directives, including the Medical Devices Directive (93/42/EEC) into UK law.

From 26 May 2021 the EU Medical Devices Regulation (2017/745) fully applies in Northern Ireland and the EU. The ‘device’ elements must meet the General Safety and Performance Requirements as set out in Annex I of these regulations for purposes of the Northern Ireland market and apply to applications for UK wide marketing authorisations. In that case it is not necessary to separately comply with the Essential Requirements of the Medical Devices Directive.

Those regulations also require the device components to have undergone an assessment by an EU Notified Body to demonstrate compliance with the General Safety and Performance Requirements of the regulation and that the assessment of the EU-designated Notified Body will need to be submitted with the MAA. In effect, the Notified Body / Approved Body will evaluate the device component as though it required a CE mark / CE UK(NI) mark.

For further information on the CE UK(NI) mark please see our guidance for medical devices.

Non-nicotine containing e-cigarettes

If the e-cigarette does not administer or contain nicotine or any other active substance, then it is not considered a medicinal product under the definitions of Human Medicines Regulation 2012, as amended. Consequently, a marketing authorisation is not required.

If data can be provided to show that the non-nicotine containing product can be used to treat specifically nicotine addiction, then the product can be considered to be a medical device under the Medical Device Regulations and consequently, it must be authorised as a medical device. The medical claim would be limited to the treatment of nicotine addiction.

e-liquid or nicotine liquid only

If a medical claim is made, it would be possible to apply for a marketing authorisation for the nicotine liquid only. However, it would be necessary to demonstrate that the liquid is safe and effective in specified e-cigarettes or other vaporising devices. Furthermore, such e-cigarettes or vaporising devices would need to be registered as medical devices and carry a CE / UKCA (as applicable) marking. As the respective vapouriser manufacturer may alter their product over time, there would need to be an agreement with the manufacturer that all relevant changes to their e-cigarette or vaporising device are notified to the nicotine liquid manufacturer/supplier, as well as the Notified Body / UK Approved Body. The applicant for a nicotine liquid MAA would need to consider the potential for misuse (including overdose) of the liquid.

Manufacture, import, export and wholesaling

The MHRA provides guidance on manufacturing and wholesaling. The requirements will vary depending on where the different functions are performed.

Sites which are involved in the manufacture of the medicinal product will need to be approved by the MHRA if located in UK or the national medicines competent authority in its territory. Sites which are involved in the manufacture of a medical device component will be approved by a UK or EU/EEA Notified Body. Good liaison between the different parties is essential. Likewise, clarity of the different operations performed by the different sites is required. If the same site is involved in both medicinal product and medical device manufacture, then ensure that the requirements of EU GMP (Good Manufacturing Practice) and the Medical Device directive (Quality System; ISO 13485) are covered. The company should do a gap analysis to consider areas not covered by GMP but that are relevant to the Quality system of the device.

Sites which are only involved in the manufacture of the medical device will need to be inspected by an EU Notified Body or a UK Approved Body. Further information on UK Approved Bodies can be found in the Medical Devices section of the MHRA website. Information on EU Notified Bodies may be located on the European Commission website.

Manufactured in UK, EU/EEA or third country for sale in UK

If the product is manufactured in the UK, the manufacturer will require a manufacturer’s license that authorises the manufacture/assembly, quality control testing and batch release of this type of product. The manufacturer will require a Production Manager, Quality Control Manager and Qualified Person. The manufacturer must comply with GMP.

From 1 January 2021 there are additional requirements to register medical devices with the MHRA in line with the grace periods set out in the guidance below. The requirements differ depending on whether medical devices are being placed on the Great Britain or Northern Ireland market. All devices placed on the Great Britain market will need to be registered with the MHRA, and non-UK manufacturers are required to appoint a UK Responsible Person. For the Northern Ireland market, certain devices will need to be registered with the MHRA and in certain circumstances a UK Responsible Person is required. Please see the guidance below for further detail on these requirements. In addition, where the manufacturer is based outside Northern Ireland or the EU, the manufacturer must appoint a Northern Ireland or EU-based Authorised Representative if they wish to place devices on the Northern Ireland market. This requirement applies to Great Britain-based manufacturers placing devices on the Northern Ireland market. See the MHRA guidance on regulating medical devices in the UK for more information.

If the product is manufactured in a third country that is not an approved country for import and imported into the UK for use in the UK, the importer will require a manufacturer’s license that authorises the import of this type of product. The importer will need a Qualified Person (to certify the product prior to batch release) and must comply with GMP, which will include the quality control testing of the product within the UK or an approved country for batch testing. The manufacturing site in the third country will also need to be inspected (by the UK inspectorate unless already inspected by an international partner under the scope of a Mutual Recognition Agreement) to ensure compliance with GMP.

If the product is manufactured in an approved country for import (initially, EU/EEA), then the manufacturing site will need to be inspected (by the competent authority of the country concerned) to ensure compliance with GMP. If the site is only used for nicotine containing products, then it may be that the concerned country does not consider the product to be a medicinal product, in which case the applicant is advised to consult with the MHRA. Qualified Person (QP) certified products from the EU/EEA are accepted in Great Britain (England, Wales and Scotland) without re-testing or re-certification by a UK Qualified Person (QP) if imported and checked by a wholesale dealer in Great Britain. Certain checks are required by a Responsible Person for Import. These are explained in guidance on Acting as a Responsible Person for Import.

If the product is subsequently distributed by way of wholesale dealing in the UK, or supplied direct to Northern Ireland from the EU/EEA, the distributor will need a wholesale dealer’s license that authorises the wholesale distribution of such a product. The holder of a wholesale dealer’s license requires a Responsible Person and must comply with Good Distribution Practice (GDP).

The licenses can only be obtained following satisfactory inspection by the UK Inspectorate. They should be consistently reviewed against current GMP/GDP practices and will be re-inspected to ensure ongoing compliance at regular intervals. Further details of inspections and the costs associated.

Labelling and packaging requirements

The Human Medicines Regulation 2012, as amended, includes details of the information which must be included on the labelling of the medicine along with the information required in the patient information leaflet which will need to be included in the pack (unless all the necessary information is on the outer pack). Additional guidance is available on our website.

There is a Best Practice Guideline on the Labelling and Packaging of Medicines which describes in detail how the labelling requirements are applied in practice. Clear differences in product packaging (including product name and visual appearance) between the proposed medicinal product and any of the company’s consumer products would be expected.

Similar guidance exists for the preparation of the patient information which accompanies all medicines. Patient information must be subject to user testing with target patient groups to make sure it is clear and easy for people to use.

In addition to the statutory information which must appear on the labelling and in the patient information leaflet, additional information can be included provided it is consistent with the marketing authorisation, is considered useful for the patient/consumer and importantly is not promotional.

The MHRA offers scientific advice meetings to applicants to discuss with applicants how best to display the information on the pack and in the patient information leaflet to ensure regulatory compliance.

Advertising requirements

The promotion of all medicines must comply with Part 14 of the Human Medicines Regulations 2012, as amended.

An advertisement for a medicine must:

• comply with the particulars listed in the Summary of Product Characteristics (SmPC)
• encourage the rational use of the product by presenting it objectively and without exaggerating its qualities
• not be misleading

Advertisements directed at the public should be presented in such a way that it is clear that the message or material is an advertisement and that the product being advertised is a medicine. The advert must include the name of the medicine and the common name where the product contains only one active ingredient. They must also include one or more indications for use of the product and an invitation to read the label. There are also a number of specific requirements including prohibitions on advertising to children under 16, supplying free samples and celebrity or healthcare professional endorsement.

Separate requirements apply to advertising to healthcare professionals and other suppliers of medicines. Medicinal claims may not be made for unlicensed medicines. It is also prohibited to promote a medicine undergoing assessment but yet to receive a marketing authorisation.

Further guidance in all these areas can be found in the MHRA Blue Guide: Advertising and Promotion of Medicines in the UK.

The control of medicines advertising in the UK is based on a long-established system of self-regulation. The statutory powers of the MHRA, acting on behalf of Health Ministers, underpin and support this system. For over the counter medicines you may also find it helpful to consult the guidance provided by the Proprietary Association of Great Britain (PAGB) and the Advertising Standards Authority (ASA) and their Committees of Advertising Practice.

For the purposes of Northern Ireland, from 26 May 2021, Article 7 of the EU Medical Devices Regulation (2017/745) must be met regarding claims made about the device.

Retailer requirements

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. People can buy GSL medicines from retail outlets such as corner shops and supermarkets, as well as pharmacies where they would be available for self-selection.

Costs and processing times

Costs

Licensing fees are reviewed annually, and are updated on our Fees page. As nicotine is a known medicinal substance an e-cigarette containing nicotine would not attract a ‘major fee’. The application would be expected to be submitted under Regulation 52 of the Human Medicines Regulations, as amended, and would therefore be classified as a ‘complex abridged application’.

Once approved, periodic fees would also be due. The fees for any medical device requirements are set by the individual Notified Body and would be in addition to any medicines licensing fees.

E-cigarettes and packs of refill cartridges

Separate marketing authorisations are not needed for an e-cigarette and packs of refill cartridges. If the refill cartridge pack contains the same cartridge(s) provided with the e-cigarette then it would be permissible for the initial pack (e-cigarette, cartridge, charger) and refill cartridge pack to be two presentations on the same marketing authorisation.

Disposable and rechargeable versions of an e-cigarette

Separate marketing authorisations will be needed for disposable and rechargeable versions of an e-cigarette.

Strength and flavour

A separate marketing authorisation is needed for each strength or flavour of e-cigarette.

Processing times

A 150-day assessment timeline is offered for all high-quality MAAs.

From receipt of a valid application, the MHRA aims to assess the application for phase-I within 80 calendar days. There are usually outstanding points which the applicant then needs to resolve. These should be addressed by the applicant within 60 days, within a clock off period. Requests for extension of the clock off period for up to another 60 days may be granted only for exceptions. The application process should conclude within 150 days (excluding the time taken to provide further information or data required) for all high quality MAAs.

Webinars

Licensing Electronic Cigarettes as Medicines

Licensing Electronic Cigarettes as Medicines

Contact

If you have preliminary queries about the licensing of e-cigarettes as medicinal products which are not addressed by the guidance above please contact:

Dr Efua Anno: efua.anno@mhra.gov.uk

For precise, scientific issues or questions then our formal Scientific Advice service is available. It may also be appropriate to seek guidance from a regulatory consultant if the applicant does not have sufficient in-house experience on the licensing requirements for medicinal products and medical devices.

Published 14 December 2017
Last updated 3 November 2022 + show all updates

1. 29 October 2021

   We have updated the Guidance for licensing electronic cigarettes and other inhaled nicotine-containing products as medicines. The key changes made relate to guidance on the quality standards for dose uniformity, non-clinical toxicological data requirements, and the design of the clinical pharmacokinetic studies. The updates also reflect changes to the regulatory environment post-Brexit

2. 14 December 2017

   First published.