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Extractable and leachable testing (E&L) is now a requirement of the US Food and Drug Administration’s (FDA’s) Premarket Tobacco Product Application (PMTA) regulatory pathway, per the finalized June 2019 guidance.

E&L studies are not new to the FDA, as these studies are a mainstay requirement in biopharmaceutical products and submissions. Moreover, E&L studies are used by a variety of industries including pharmaceuticals, medical devices, cosmeceuticals, dangerous goods, foods and beverages, and now the e-cigarette, e-liquid and vaping industry. To provide additional context, for the pharmaceutical industry, E&L studies provide critical data regarding product packaging and ensure harmful chemicals will not leach into the drug product from packaging during storage and use.

Although extractable and leachable studies are now required for products subject to the PMTA regulatory pathway, little guidance is available as to exactly how to approach these studies, particularly for electronic nicotine delivery systems (ENDS). When developing a protocol for E&L testing of ENDS devices, all materials of construction must be determined and evaluated. As there can be some overlap in several the materials used in the construction of an ENDS device, these may be considered a single component for the purposes of E&L study design, but a determination must be made on a case-by-case basis.

The importance of extractable & leachable testing

E&L studies detect and identify the organic and inorganic compounds that may be inadvertently released into the finished product. These analytes include low molecular weight oligomers, additives, catalysts, mold release agents, dyes and colorants, plasticizers, antioxidants, and stabilizers. Certain extractable and leachable compounds can interact with drug, food, and beverage products, thus compromising the safety and efficacy of those products. Likewise, these compounds likely interact with vape flavors, e-liquids, and e-juices.

This type of extractable and leachable testing is critical for the pharmaceutical and medical device industries where packaging safety and toxicology studies are required for product registration. Let our scientists guide you through the process to access and profile your products’ extractables and leachables while meeting FDA regulations.

PMTA guidance recommendations for E&L testing of e-Liquids, e-cigarettes and vape flavors

The June 2019 PMTA guidance specifically addresses the product’s container closure system, stating that PMTA applications should include information regarding how the product is preserved and protected by the container-closure system, such as damage from transport, environmental contamination, and leaching and migration of the container-closure system into finished products. The FDA expects this portion of the study to be carried out by the container-closure manufacturer or the applicant, using the final container-closure system for their products.

An overview of extractables and leachables studies for ENDS products

Extractables studies of ENDS

Prior to embarking on an extractables screening, analytical evaluation thresholds (AETs) must be calculated for device components. Based on toxicologist recommendations, the maximum daily dose for an e-liquid can be determined, and the safety threshold concern can be determined. Once the maximum daily dose and safety concern thresholds (SCT) are determined, the AET can be calculated, and further converted to inform experimental design, based on the number of device components utilized for the extractable study. After determining the materials of construction and calculating the AET, extractables studies can be performed on the components under exaggerated, “worst-case” conditions using a range of analytical instrumentation. This may include gravimetric analysis to determine non-volatile residues (NVR), ICP-MS to identify elemental extractables, GC for semi-volatile and volatile extractables, and LC to characterize non-volatile extractables. An example of a general workflow for an extractables study of an ENDS device is illustrated in Figure 1.

Figure 1. General workflow for the preparation of extractables of ENDS

Leachables studies of e-liquids

To ensure sensitive and selective methods for leachables analysis, a general approach can be taken when developing leachables methods. As before, the AET for leachables must be calculated to determine how to prepare the e-liquid samples for analysis. When developing the leachables methods, a virgin sample of e-liquid that has not been into contact with the vape device can be utilized. In instances where there are multiple flavors to be evaluated, the flavor with the lowest background should be selected for method validation. However, scientists should also review and consider data generated from the analysis of other flavors, as that data is useful for sample testing, ruling out excipients from the e-liquid flavors. To simulate the worst-case leachables, extracts from the extractables study can be spiked into the e-liquid samples to determine if the extractable peaks are well-resolved.

Generally, two methods are developed and validated for monitoring leachables throughout routine stability testing. Both methods should be MS compatible, in the event that a leachant needs to be identified in the future. Following method development, leachables methods are then validated following ICH Q2 guidelines to demonstrate suitability for the monitoring of leachables in e-liquids at the calculated AET. The following parameters are assessed during method validation: linearity, accuracy, method precision, intermediate precision, limit of detection (LOD), limit of quantitation (LOQ), robustness, and specificity. An example of a general workflow of a leachables study of e-liquid is outlined in Figure 2.

Figure 2. General approach to leachables method development for e-liquids

How Element can support FDA PMTA submissions

Element is an FDA-registered lab with years of experience working on successful FDA regulatory submissions, and as an independent e-liquid and e-cigarette testing lab we proudly serve entrepreneurs, manufacturers, distributors, lawyers, other laboratories, and companies of all sizes. Our team of regulatory and industry experts are experienced with the testing standards pertaining to the e-liquids/e-cigarettes and the FDA’s Premarket Tobacco Product Application (PMTA) requirements. Our regulatory consultants can support your team in their efforts to gain FDA approval, both during and after a project is completed.