Frequently Asked Questions
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What are the expectations from regulatory agencies regarding extractables and leachables?
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
How does a risk assessment assist when evaluating extractables and leachables?
Subjecting all of the materials used in a
- Pharmaceutical container closure system
- Pharmaceutical manufacturing process
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.
How do E&Ls impact a PMTA submission to FDA?
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.
Does an E&L assessment need to be provided for an EU TPD2 submission?
Whilst there are no references to E&Ls in TPD2, an assessment of the E&L risks associated with an ENDS or e-liquid product should form part of the due diligence conducted prior to commercial launch. Ensuring the materials used in the product are of a sufficiently high standard will make the use of the product safer for consumers.
Additionally, TPD2 is currently undergoing revision. TPD3 when it arrives is likely to contain similar provisions for assessing E&Ls to the recent FDA PMTA guidance. Conducting an E&L assessment during development will not only assure the safety of a product for consumers (as discussed above), it will ensure compliance against potential future regulatory requirements minimising risks of product withdrawal.
What is failure mode and effect analysis?
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.
What is the difference between an extractables and leachables risk assessment and an extractables and leachables safety assessment?
An E&L risk assessment looks at the various unit operations associated with the manufacture of a pharmaceutical, ENDS or e-liquid product, and identifies failure modes associated with leaching of components from the materials involved in each of these unit operations. Using failure mode and effect analysis (FMEA), probability & severity factors are assessed for each failure mode. As a result of the FMEA assessment, each failure mode is defined as being either high, medium or low risk.
As such, the outputs from the risk assessment process drive mitigation activities towards the high and medium risk failure modes (i.e. time, resource and budget is directed at those areas of the manufacturing process most at risk of generating leachables), whilst providing a scientifically robust justification for discharging any risk associated with the low risk failure modes.
An E&L safety assessment is performed on any extractable or leachable that is observed at levels above a predefined threshold from a corresponding extractables or leachables study. The levels observed are reported to a toxicologist, who will then carry out a paper based exercise to determine whether the reported level is likely to present a risk to the health of patients/consumers.
The toxicologist uses a variety of methods to determine whether the reported level of the extractable/leachable observed is acceptable or not, including:
- A literature search for published data on the extractable/leachable in question
- In silico modelling to predict toxicity based on the structure of the extractable/leachable in question (e.g. Toxtree; QSAR; Leadscope; DEREK, etc)
Based on the results of their investigations, the toxicologist is able to provide a scientific justification for whether the extractable or leachable in question is safe at the level reported.
How does the ICH M7 guidance on genotoxic impurities assist in the evaluation of extractables and 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.
What is the safety concern threshold (SCT)?
The SCT is an absolute exposure, expressed in terms of total daily intake (total exposure per day). It must be converted into a relative amount, expressed in terms such as the amount of an individual leachable in a particular product (e.g. µg per vial in a parenteral product or µg per bottle in a e-liquid product), to be useful to an analytical chemist conducting extractables and leachables studies. This conversion is performed by using information on the product configuration such as
- The number of doses per vial
- Number of vials per day
- Number of mLs per dose
- Number of mLs per day
The converted SCT, which should be used by the analytical chemist in method development activities, is called the Analytical Evaluation Threshold or AET.
The SCT can be applied to the majority of potential extractables and/or leachables, however there are a number of classes of compounds that have lower SCT values e.g. N-nitrosamines, PAHs, PNAs. Compounds such as these require special consideration due to their associated toxicities, and need to be evaluated by more specific and sensitive analytical techniques.
What is the analytical evaluation threshold (AET)?
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
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
(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.
Why is materials selection important in relation to extractables and leachables?
In addition, where possible, information on what testing has been conducted on the material should be sought from the supplier, especially any extractables testing. Where this information is available, at worst it provides an insight into some of the potential leachables that may be in the final product. If the suppliers extractables data is of a high enough standard, it may help to reduce the time and resources required to completely ‘derisk’ a material from an extractables and leachables perspective.
What is an extractables study?
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.
What is a leachables study?
A leachables study is generally performed on a final drug/ENDS/e-liquid product, but may also be performed on API/BDS under certain circumstances (e.g. where disposable single use assemblies have been used in the manufacture, or where leachables data on the API/BDS container closure system is required). A leachables study is used to identify and quantify the actual levels of compounds that a patient/consumer may potentially be exposed to.
A leachables study is performed by storing representative samples of the final drug/ENDS/e-liquid product (or API/BDS as appropriate) up to the proposed shelf life, under standard chemical stability conditions (as per ICH Q1A). In fact, leachables studies can be carried out in parallel to a normal chemical stability program.
During the study, samples are pulled at regular intervals and tested for leachables using methods utilising a variety of analytical techniques. Depending on the requirements of the study, they may be developed as quantitative procedures or as limit tests. Either way, they should be validated in accordance with the guidance provided in ICH Q2(R1).
In-use leachable studies may also be employed to determine potential levels of leachables delivered to patients/consumers whilst using a final drug product or ENDS device. For example, the mouthpiece of an asthma inhaler or an ENDS device can be studied in an attempt to determine what levels of leachables, if any, are delivered to a patient/consumer when their lips come into contact with the mouthpiece of that device. This type of in-use study is normally carried out as a one-off piece of work, as exposure is unlikely to change between uses.
What is an extractable?
An extractable is a compound that can be extracted from
- The device components or surfaces of a ENDS/e-liquid product container.
- The single-use disposable components or surfaces of an API/BDS or drug product manufacturing process.
They are individual chemical entities that can be extracted from components (e.g. plastic and/or elastomeric stoppers, tubing, gaskets, bottles, bags, connectors, vials, etc) in the presence of an appropriate solvent under relatively vigorous laboratory conditions. As such, extractables can be considered as potential leachables in the final product.
What is a leachable?
- The device components or surfaces of a drug/ENDS/e-liquid product.
- The disposable single-use components or surfaces of an API/BDS or drug product manufacturing process.
Leaching can be promoted by the formulation, or components of the formulation, for example, the organic propellants used in metered-dose inhalers. Leachables are often a subset of or are derived directly or indirectly from extractables. However, not all leachables will necessarily be found during the extractable study. For example, formulation components or buffers may interact with a polymer or its additives, to form a new ‘leachable’ contaminant, not present during the original extractable study.
As leaching is essentially a time-dependent, diffusion-driven process, leachables are generated over the shelf-life of a product. The extent to which this occurs is determined during appropriate leachable and/or accelerated leachable studies.
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