Whether we are discussing pharmaceutical products, ENDS or e-liquids, the topic of extractables and leachables is considered an important regulatory topic.

​During the manufacture and subsequent shelf life of a pharmaceutical, ENDS or e-liquid product, it may come into contact with materials associated with processing equipment, packaging and/or delivery device components. During these product contact periods, there is a potential for ingredients or impurities from these materials to leach into the product, and so

a. Be delivered to patients/consumers

b. Affect the efficient operation of the delivery device

​As such, global regulatory agencies have a very real expectation that the development process for the product will include a full assessment of the potential for leachables to be present in the final product, and that a summary of this assessment will form part of the final regulatory submission. Consequently, the extractables and leachables strategy, including the regulatory approach, is an increasingly important part of the overall development process for pharmaceutical, ENDS or e-liquid products.

To further highlight the increasing importance that regulatory agencies place on the subject, there are now a number of regulatory and industry guidance documents specifically dedicated to or which refer to extractables and leachables, including:

• FDA Guidance for industry (May 1999) – Container Closure Systems for Packaging Human Drugs and Biologics
• EMEA Guideline (EMEA/CVMP/205/04) – Guideline on Plastic Immediate Packaging Materials
• FDA Guidance for industry (April 2018) – Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Products – Quality Considerations
• FDA Guidance for industry (June 2019) – Premarket Tobacco Product Applications for Electronic Nicotine Delivery Systems
• USP <661.1> – Plastic Materials of Construction
• USP <661.2> – Plastic Packaging Systems for Pharmaceutical Use
• USP <1663> – Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems
• USP <1664> – Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging Delivery Systems
• USP <381> – Elastomeric Closures for Injections
• PQRI – Safety Thresholds and Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Products
• ICH Q6A – Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products

Subjecting all of the materials used in a

• Pharmaceutical container closure system
• Pharmaceutical manufacturing process
• ENDS
• e-liquid

​​to a full extractables study, and then using the subsequent data to develop and validate leachables methods capable of monitoring ALL potential leachables, at or below the AET, is a huge task, and takes large amounts of time, resource and budget to carry out.

It can be argued, with good scientific justification, that not all materials used are high risk with respect to generating leachables. At the very least, it can be argued again with good scientific justification, that they are not all high risk with respect to generating leachables that are harmful to patients/consumers.

As such, a process to filter out the lower risk materials, which have little or no potential for generating leachables, from the higher risk materials, which are very likely to generate leachables, and so should have the majority of time and effort spent on them, has the potential to save significant amounts of time, resource and budget, whilst providing much more relevant information on the identities and levels of leachables a patient/consumer is likely to be exposed to.

​An extractables and leachables risk assessment is a tool that when performed in a robust manner, will act as this filtering process.

The outputs from the risk assessment will inform which materials are of high risk of generating leachables, and so need close attention and a greater level of time and resource spent on assessing them. Mitigation activities can then be carried out on these higher risk materials. This may involve some form of testing (extractables and/or leachables studies) or other forms of mitigation activity, in order to reduce the risk of patients/consumers being exposed to leachables.

​The outputs from the risk assessment just as importantly provide a scientific justification for NOT testing materials that are of low risk of generating leachables. This means that resources are directed at the materials most at risk of generating leachables.

Whilst using an ENDS device and/or an e-liquid product, materials associated with processing equipment, packaging and/or delivery device components can be leached and delivered to consumers of the product.

As such, FDA has a very real expectation that the development process for the product will include a full assessment of the potential for leachables to be present in the final product, and that a summary of this assessment will form part of the final PMTA regulatory submission. Indeed, several references are made to E&Ls within the recent FDA PMTA guidance document.

Consequently, the extractables and leachables strategy, including the regulatory approach, is an essential part of the overall development process for ENDS and e-liquid products.

Failure mode and effect analysis (FMEA) is a commonly used industrial tool used for performing risk assessments, whereby the probability of an event occurring is evaluated against the severity of it occurring.

In an extractables and leachables FMEA, each product contact material is scrutinized. Through discussions with subject matter experts (SMEs) on the product, potential failure modes with respect to leaching, and their causes and effects, are identified.

​Each failure mode and the resulting effect (i.e. leaching) is recorded in a product specific FMEA worksheet. As well as these failure modes, as much information as possible is pooled on each material (e.g. supplier test data, compliance statements, previous in-house experience with the material, etc), and again recorded on the FMEA worksheet.

​A second discussion with the SMEs is then undertaken, where the specific failure modes are considered, and the probability and severity factors each given a score. The product of these scores yields a risk priority number (RPN), which is a numerical representation of the risk of a patient/consumer being exposed to leachables from each of the identified failure modes. All possible RPN scores are categorized based on their values, into low, medium and high risk.

All failure modes that generate a medium or high risk RPN are considered for mitigation activities, which may involve extractables and/or leachables studies, or other forms of mitigation activity, in order to reduce the risk of patients/consumers being exposed to leachables.

The AET, which is calculated from the SCT, has been defined by the PQRI guidance document ‘Safety Thresholds and Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Products (OINDPs)’, as the threshold at or above which a chemist should begin to identify a particular leachable and/or extractable and report it for potential toxicological assessment.

For non OINDPs, the AET can be calculated from the TTC or the LTL exposures defined by ICH M7 (see Q5). Additionally for elemental extractables and leachables, AETs for individual elements can be calculated from the PDEs defined in ICH Q3D ‘Guideline for Elemental Impurities’.

To be useful, the AET should be expressed in terms of the amount of an individual leachable in a particular product, e.g.,

• µg per vial
• µg per canister
• µg per bottle of e-liquid
• µg per mL
• µg per dose
• etc…..

The units used to express the AET will vary for different products depending on:

(i) the particular dosing regimen for a drug, e.g.

• number of doses per vial
• number of vials per day
• number of mLs per dose
• number of mLs per day
• etc…..

​(ii) the way an ENDS or e-liquid is used, e.g.

• ​number of times the ENDS is used per vaping episode
• number of times the ENDS is used per day
• volume inhaled

​(iii) the technique(s) used to detect and quantify individual leachables and/or extractables

In practise, the calculated AET is adjusted by an “uncertainty factor” to account for the variability in response of individual leachables and/or extractables analysed by any given analytical technique/method, to give the final or working AET.

For E&L studies, methods are developed and validated to monitor for specific leachables and/or extractables or can be employed as general screening methods. In the latter case, the variation in response of individual compounds to a given analytical technique becomes extremely important. Careful consideration must be given to the uncertainty factor applied to the calculated AET, to ensure the final AET is appropriate for its intended purpose.

An extractable study (also known as a controlled extractable or extraction study) is an assessment performed on a material, which attempts to identify the substances from that material, which may potentially leach into the final product.

​There are various types of extractable study, but by far, the two most common are

• ​Exhaustive extractable studies
• Targeted extractables studies (aka Simulated leachables studies)

​An exhaustive extractables study involves placing the material of interest (a plastic; an elastomer; etc) into a range of strong organic solvent systems, and subjecting these systems to vigorous laboratory extraction conditions, in order to maximize the levels of extractables derived from that material.

​A targeted extractables study is an option used, where strong solvents systems may not be the most appropriate for predicting likely product leachables (e.g. aqueous drug products, aqueous manufacturing product streams, etc.). The material of interest is once again placed in a range of solvent systems, which in this case, much more closely resemble either the solvent system of the product stream (in the case of single use manufacturing systems) or the solvent system of the product. Again, vigorous laboratory extraction conditions are used to try and maximize the levels of extractables derived from that material, this time however under the targeted solvent conditions.

​The resulting solutions from either type of study are then interrogated via a series of analytical techniques, in order to identify and quantify individual extractables.

Overall, a well designed and executed extractables study can provide ‘worst-case’ leachable levels for an individual material, and provide valuable information for the development of appropriate analytical methods for leachables studies. Conversely, a poorly designed and poorly executed extractables study, almost always involves wasting large amounts of resource, time and budget, and can create significant problems during any subsequent leachables studies.