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.

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.

i) OINDPs are dosed directly to diseased tissue

ii) OINDPs are usually associated with chronic conditions, such as asthma, and so are taken by patients during their entire lives

​

Looking at these two factors, it is clear that the extremely conservative figure of 0.15 µg per day is unlikely to be relevant for other drug products, which either have different routes of delivery, or which are not used for chronic conditions. Examples could include parenterals, pre-filled syringes, autoinjectors, ophthalmics, topicals, etc.

​

The ICH M7 guidance ‘Assessment and Control of DNA Reactive (mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk’, provides a similar threshold based approach for assessing genotoxic impurities in drug substances and drug products. ICH M7 defines a Threshold of Toxilogical Concern (TTC) of 1.5 µg per day, for exposure to a genotoxic impurity for > 10 years to lifetime.

In addition, ICH M7 also provides thresholds for ‘less than lifetime’ (LTL) exposures, which are potentially more relevant for drug products used for acute conditions.

​

Drug product taken for ≤ 1 month; Acceptable daily intake = 120 µg per day

Drug product taken for > 1 – 12 months; Acceptable daily intake = 20 µg per day

Drug product taken for > 1 – 10 years; Acceptable daily intake = 10 µg per day

Drug product taken for > 10 years to lifetime; Acceptable daily intake = 1.5 µg per day

Using this approach, the ICH M7 guidance has been successfully applied to the assessment of extractables and leachables in non-OINDPs. Both the 1.5 µg per day lifetime exposure figure, and the LTL exposures have been used, and have been accepted by regulatory agencies around the world.

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…..

AETs for different products will vary 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 smoking 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

Analytical techniques affect AET values due to a variety of factors, with arguably the most important being the variation in response of individual leachables and/or extractables analysed by any given analytical technique/method.

Methods can be 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, and careful consideration must be given to how the AET is employed.

​

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

​

Exhaustive extractables 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.