Сòòò½APP

Сòòò½APP understands that submitting a premarket tobacco product application (PMTA) to the US Food and Drug Administration (FDA) can be a challenging and rigorous process. With so much previously uncharted territory and a constantly evolving regulatory landscape, it is difficult for e-liquid manufacturers, developers and distributors to determine where to find accurate and non-biased information about the PMTA regulatory pathway.

Сòòò½APP recently spoke with Marc Sanchez, an attorney specializing in FDA and United Sates Department of Agriculture (USDA) regulations, to better understand the PMTA submission and filing process. To ensure that both the legal and scientific aspects of the PMTA process were adequately represented, we also talked with Сòòò½APP’s subject matter expert on the PMTA, Dr. Derek Beauchamp. By exploring both the legal and scientific perspectives, we aim to shed more light on the PMTA submission process within this article.

Key components of the Premarket Tobacco Product Application (PMTA)

According to Sanchez, the most important components of a PMTA submission are analytical testing (Figure 1), a literature review in lieu of clinical data, an environmental assessment, and, finally, detailed information in various modules describing the device or e-liquid. It is also critical to provide the FDA with any necessary details or specifications regarding the manufacturing process. The data generated with analytical testing supports multiple sections of the PMTA application, including the toxicology review, and can potentially also inform the environmental assessment portion of the application. The analytical testing component of a premarket tobacco product application must include:

Harmful and Potentially Harmful Constituents (HPHC) testing

All PMTA submissions must include the reporting of Harmful and Potentially Harmful Constituents (HPHCs) in tobacco and nicotine products and tobacco smoke under section 904(a)(3) of the FD&C Act. HPHCs are chemicals and chemical compounds found in tobacco products, including electronic cigarettes or tobacco smoke, that cause or may cause harm to smokers or nonsmokers. Every unique product must be tested for these components, ingredients, additives, and properties. There are up to 20 key analytes for HPHC testing from the full list of 93 HPHCs that manufacturers of new tobacco and e-liquid products must report on for each unique product.

Stability testing

Stability data must be included in each PMTA submission, which includes testing of HPHCs over the relevant shelf life of the finished product. This ensures the sameness and safety of the product over the entire lifecycle of the product. To meet the stability requirements of the PMTA, e-cigarette companies must complete both an accelerated and real-time stability study.

Extractables and leachables (E&L) testing

Extractables and leachables (E&L) studies are a requirement for any PTMA submission to the FDA. The components of the packaging, device, container, and container closure must be analyzed to ensure that harmful chemicals do not leach into the finished product during storage and use.

Figure 1. Analytical testing components of PMTA submissions

The manufacturer’s role in PMTA submissions

Manufacturers play a key and vital role in the PTMA submissions process, as they interact with not only the e-liquid company, but also the laboratory ENDS companies choose to partner with for analytical testing and regulatory support.

“Working with manufacturers has definitely been a learning curve. There are good manufacturers who communicate extremely well and provide necessary information quick and efficiently,” says Sanchez. However, he goes on to say, “Some manufacturers are a lot slower and need more handholding which can slow down your submission.”

Beauchamp adds, “Making sure the manufacturer is good at communicating is more important than some may think. If the manufacturer is poor at communicating with you, imagine how tough it is for the lab to work with them to get the necessary information to complete your testing.”

One of the FDA’s most sought-after pieces of information, specifically how manufacturers control quality, is provided directly from the manufacturer. PMTA applicants must also rely on their manufacturers to furnish several additional critical details, including specifications or schematics related to the e-liquid product or ENDS device, as well as thoroughly documented manufacturing processes explaining how the product is prepared from beginning to end in precise detail.

Open versus closed device filing

Sanchez mentions the FDA’s skepticism of closed, disposable devices, “because they’re newer and the overall marketing towards youth is a big deal. It’s the main difference in an open versus closed device filing.”

One of the primary requirements for a closed device filing is youth prevention, as the FDA believes closed devices are both more attractive and more accessible to youth, whereas the demographics associated with those who prefer open devices are aligned with those seeking showmanship or are considered vape connoisseurs. Nevertheless, open systems also present their own unique set of challenges, and the seemingly unlimited possibilities for customization, specifically with various modifications or accessories, is a variable that has given the FDA reason for concern.

E-liquids versus device PMTA filings

Filing a PMTA for a stand-alone e-liquid is entirely different than filing an application for a vaping device and/or closed device which contains e-liquid. Sanchez explains, “in an e-liquid application, you will have more information and data relating to the formulation, whether it is to be used in an open or closed device, and the differences in manufacturing.”

Sanchez also notes that many vape shops are struggling to submit a PMTA application for custom or proprietary e-liquid blends created within their shop. Each of these custom or “create-your-own” e-liquid blends require a unique PMTA to be filed with the FDA. Although the process to do so is both challenging and costly, Sanchez has seen some retailers pursue this option.

Pre- and post-2016 market status

Companies who created e-liquid and vape products after the 2016 Maryland ruling are operating in a gray area. According to Sanchez, “the FDA will not put you on the safe list (pre-2016), but they have not formally pushed to remove companies in non-compliance from the market.” However, pre-2016 companies are allowed to stay on the market for at least one year while they wait for the review of their PMTA submissions. Sanchez does believe that, as it is still early on in the process at the time this article was written (December 2020), the FDA may pursue more strict enforcement and compliance measures in the future in regard to PMTA submissions.

“Regardless of when your company was founded, your PMTA submission will be the same and treated equally,” states Sanchez. The PMTA regulatory pathway is firmly in place, and each company will receive the same treatment throughout the review of their regulatory submission.

Preparing PMTA submissions for the Center for Tobacco Products (CTP) portal

Although paper or thumb drive submissions are offered as options by the FDA for PMTA applications, the FDA prefers applicants make use of the CTP portal that has been developed by the Center for Tobacco Products (CTP) when submitting PMTA applications. First and foremost, applicants must ensure they request access to the CTP portal. To gain access, applicants must agree to follow stated and published rules of behavior, as well as sign a document stating they have the legal right to sign on behalf of the company the PMTA is being submitted for.

Once access is granted, there are several steps that must be followed, and the format of the file containing a complete PMTA application must be an e-submitter validated .zip file. The e-submitter program is set up to walk applicants through which files are needed, as well as acceptable file formats. The CTP portal will then validate submitted files to be uploaded to the portal. Sanchez does warn against the use of special characters in file names, including exclamation points or scientific symbols, cautioning “it won’t validate if you use any of those, so be careful.”

When applicants are ready to submit their PMTA, once logged into their CTP account, information can be uploaded to the designated area. For applicants filing without the support or help of an attorney, consultant, or lab, Sanchez advises a slow, thoughtful approach, without rushing through the process. He jokingly states, “The programs are a bit clunky, a bit dated, and can be tricky at times. Even getting access to the portal itself may take weeks, so plan accordingly.”

Beauchamp mentions that although an attorney or consultant may be largely responsible for submitting applications through the CTP portal, testing labs are responsible for the tobacco product master file, also referred to as the TPMF. “The TPMF contains our analytical methods, validations, validation reports, and any other confidential information that is proprietary to the lab completing the testing.” Beauchamp goes on to explain, “this information is used by the FDA to understand and interpret the data resulting from testing.”

What to expect after a PMTA is submitted to the FDA

PMTA applicants will first receive confirmation through the CTP or other means of communication that the application has been received by the FDA. There are then two phases of review which the application must pass prior to the review phase, the stage during which the decision will be made as to whether the product will receive marketing authorization. These first two review phases include the acceptance review and the filing review phase, described in greater detail below.

After an application passes the first two review phases, a submission will likely remain with a reviewer for at least six months, and possibly longer, for a substantive review. The FDA will follow up directly with applicants to address any possible questions or requests for additional information or data needed. Whether applicants receive an acceptance or refuse to accept, the FDA will reach out either via phone or overnight carrier. If applicants find themselves in receipt of a refuse to accept, the FDA will most likely contact them to address deficiencies in hopes of obtaining an eventual approval.

Acceptance review

The FDA’s acceptance review phase is very high-level. The acceptance review ensures the product cited in the PMTA meets the criteria required of products that are subject to the PMTA regulatory pathway.

Filing review

During a filing review, PMTA submissions are double-checked to make sure the application is complete, and contains required information and components, including the environmental assessment and literature review, etc. Sanchez suggests including a cover letter with a summary and table of contents to aid the FDA in quickly confirming all required sections of the submission have been included and addressed in the application.

Finding the right partner for your PMTA submission

Beauchamp has a few tips and considerations for finding the right laboratory partner to support PMTA submissions. “Working with a lab, such as Сòòò½APP, that has strong expertise as well as relevant and necessary experience is crucially important. Having the experience in the analytical product testing space, as well as a history of successful interactions with the FDA, helps to expedite the testing process and aid in remedying any potential deficiencies or answering questions the Agency might have.”

Labs that have experience working with the FDA on regulatory submissions, as well as labs who have a proven track record success supporting and submitting PMTAs should be your top priority when considering a scientific laboratory to work with to support a regulatory filing. Additionally, Beauchamp believes the first question you should ask of a potential partner is regarding the experience the laboratory has with specific product types and testing. Applicants should be comfortable requesting to see examples of the laboratory’s work, inquiring about the relationship of the lab with the FDA, and ensuring the laboratory has a clear and solid understanding of the data requirements for the PMTA.

Beauchamp also says it is important that the team of scientists working on validating these methods have the correct experience for your project and product. Furthermore, the lab should be in it for the long haul, rather than solely completing the testing and providing data. Beauchamp notes, “a thorough lab will be there for questions, to perform additional work, and most of all, be there to support your PMTA application through the very end.”