In May 2016, the US Food and Drug Administration (FDA) initiated planned requirements for e-liquid and tobacco chemicals testing. Premarket tobacco product applications (PMTAs) for electronic nicotine delivery systems (ENDS) are required to be submitted for every flavor at every nicotine strength, with supporting pre-clinical and clinical safety data. In June 2019, the FDA released an updated guidance for the submission of PMTA authorizations.
Many similarities exist between the guidance issued in May 2016 to that of the newly announced guidance in June 2019, but there are also some notable differences. The major similarities and differences in the PMTA are outlined below.
What’s NOT Different in the 2016 and 2019 New FDA PMTA Regulations?
Analytical methods must be validated
The analytical methods developed and used for the analysis of the e-liquids and their aerosolized form must be validated. The method validation for HPLC, GC, and ICP-MS must verify accuracy, linearity, precision, specificity, robustness, limit of detection, and limit of quantitation per ICH guidelines. Method validation is a requirement of FDA submissions, and is a standard practice and requirement for regulatory applications.
Formulation details must be included
An understanding of all of the components of the formulation is required. This may require a deformulation (reverse engineering) of the e-liquid or a complete batch record that details which components are used in the manufacturing of the product.
The number of batches and replicates has not changed
The analysis of a minimum of 3 batches of material with a minimum of 7 replicates per vape flavor is still required. This means that for every e-liquid flavor, a minimum of 21 replicates will be required for analysis.
A stability study is required
A stability study needs to be undertaken to ensure changes in the e-liquid formulation or degradation of the vape formulation do not occur during normal storage of the product. While an accelerated stability study can be submitted to obtain conditional shelf-life approval from the FDA, data from a real-time study must also be submitted upon completion of the real-time study. In summary, while an accelerated stability study can support a shelf life of 1 year in just 90 days, in order to achieve full approval, the product must also remain in a real-time stability study for 1 year under real-time storage conditions.
What are the DIFFERENCES of the 2016 and the 2019 PMTA FDA Regulations on Vaping Products & E-Cigarettes?
PMTA compliance deadlines
The FDA defined compliance deadlines, and it is unlikely that the FDA will enforce regulations during the extended period to become compliant. At the time the June 2019 PMTA for ENDS guidance was released, the original timeline to initiate a PMTA strategy to ensure compliance and stay on the market was tight, and compliance deadlines were:
• August 8, 2021 for newly regulated combustible tobacco products
• August 8, 2022 for newly regulated noncombustible products
However, with a recent July 2019 court ruling, deadlines have gotten even tighter for submission, and the ENDS industry must now meet a fast-approaching May 2020 filing deadline. This May 2020 date may be challenged by the FDA, but as of July 2019, the FDA has not commented on whether they will appeal or not.
What needs to be tested is further defined
In the guidance, FDA states that components that are used in finished products do not need to be tested, but rather the finished ENDS device is required to be tested. Also, all e-liquids in final packaging need to be tested. These include:
• All products made and distributed by manufacturers
• All products sold in retail stores
• Custom one-off bottles/products made in retail stores or vape shops
An extractables and leachables study is required
An extractables & leachables (E&L) study must be performed on the packaging (container and container closure) system. E&L studies ensure the packaging will not leach harmful chemicals into the product during typical storage and use. The onus of responsibility for this study falls on all of the e-liquid, ENDS, or e-cigarette manufacturer and the container manufacturer.
An analytical bridging study is defined
A bridging study been defined and clarified by the FDA in the new June 2019 PMTA guidance. The FDA states that the following strengths of nicotine in the finished e-liquid should be tested for each flavor:
• Lowest strength
• Middle strength
• Highest strength
The approach had been thought of as an acceptable approach to test vapor juice flavors, and is now clarified in the new guidance.
If respiratory irritants are identified upon review, the product must be re-tested for those irritants
As before, the product must be tested for a defined list of constituents and chemicals. However, after a review of the flavor, if known respiratory irritants are present in the blend, these will need to be tested for as well. SVBS
Dr. Derek Beauchamp is the Senior Technical Director of Analytical Sciences at Avomeen Analytical Services. He is an expert with a wide breadth of regulatory expertise, nicotine and e-liquid research, characterization techniques and the respective instrumentation and software such as p-XRD, single crystal XRD, thermal analysis (DSC and TGA), Crystal 16, Crystalline, NMR, FT-IR, TOF-MS, DART-MS, UV-VIS, gas sorption, HPLC, LC-MS, particle size analysis, GC, SEM, and Raman Spectroscopy. Dr. Beauchamp also has years of experience with pre-formulation development of small molecules and their physical properties and has designed and demonstrated large scale crystallization processes. He has also led the development of crystallization processes for a number of late discovery pre-clinical candidates.