By Joan Sylvain Baughan and Cynthia Lieberman
The U.S. FDA evaluates the safety and suitability of drug packaging as part of the premarket approval process for new drugs. The manner in which packaging suppliers have relayed information confidentially to FDA for consideration as part of the agency’s review of a drug application—namely, through the Type III Drug Master File (DMF)—currently is undergoing a significant transition. FDA has issued binding guidance that will require electronic filing of all DMFs and DMF-related submissions as of May 5, 2017. Unless FDA offers some relief for Type III DMFs, after this date, any new DMF submissions, amendments to existing DMFs, as well as any other DMF filings (for example, Letters of Authorization or Annual Reports) will need to be provided to FDA using electronic Common Technical Document (eCTD) specifications. FDA has stated that it is not requiring that DMFs already on file with FDA be converted into eCTD format. As a practical matter, however, it is difficult to envision how to align an amendment in eCTD format with a DMF that currently is on file with the agency in a very different format. DMF holders may well wish to modify existing DMFs so that future filings prepared according to the mandatory eCTD format will be compatible with the overall DMF structure.
FDA’s most recent webinar on the electronic submission of DMFs, held on August 4, 2016, was widely attended and sparked so much interest from the audience that questions had to be cut off after extending the webinar 30 minutes beyond its scheduled end time. (FDA had previously hosted two webinars earlier this year in which agency officials discussed the new eCTD requirements and how to comply with them.) Some questions during the most recent webinar appeared to stem from confusion surrounding seemingly inconsistent statements made during the webinar. For example, at one point, the agency stated that it will want any paper DMFs that are not in CTD format to be restructured into CTD format before the May 5, 2017, deadline, but not necessarily re-filed in electronic format. Under that scenario, DMF holders would have the option to convert existing paper DMFs to CTD format and re-file the DMFs either in paper copy or in electronic, eCTD format at any time before the May 5, 2017, deadline. Separately, however, the agency indicated that it will not require any reformatting of existing DMFs (either in paper form or electronic form), and that only new information filed on existing DMFs, such as amendments to existing DMFs, would need to be submitted in the new format. Further, FDA indicated that if a DMF holder voluntarily chooses to reformat an existing DMF, this reformatting may be done at any time (even after the May 5, 2017 deadline).
Despite the lack of clarity on some of the details for meeting the new eCTD requirements, FDA announced during its August 4 webinar that it will be holding DMF submitters to a tight standard when reviewing filings prepared according to the eCTD specifications. In addition, the agency representatives stated that FDA would not be considering any waivers or exemption to the eCTD requirements for DMFs. Nevertheless, during an October 18, 2016, meeting with some industry representatives, FDA officials did listen to specific concerns identified by companies that maintain Type III DMFs and agreed to give them further consideration. Given the uncertainty regarding FDA’s ultimate decisions as to whether to allow an alternative to eCTD filing for Type III DMFs, however, and in light of the fast-approaching “deadline” for compliance, packaging suppliers would be well-advised to familiarize themselves now with FDA’s electronic filing requirements and investigate options for making their DMF submissions electronically.
Overview of FDA’s Drug Packaging Regulations
To place the new eCTD filing requirements for Type III packaging DMFs into context, it is helpful to have some general understanding of the manner in which FDA regulates drug packaging materials. FDA does not provide premarket authorization for drug packaging and drug packaging components on an individual basis. Rather, FDA reviews packaging materials for new drugs within the context of the agency’s evaluation of a new drug submission. Packaging suppliers may provide information on their packaging materials directly to the drug manufacturer, which in turn can submit the information to FDA as part of the new drug application. This process can raise concerns, however, because the types of packaging information that are relevant to the FDA drug reviewers, such as manufacturing process and formulation information, are proprietary to the suppliers. Consequently, companies often prefer to avoid having to disclose these details to their customers. The DMF system offers an alternative means for the packaging supplier (as well as upstream suppliers to packaging manufacturers) to provide FDA with the necessary information on a drug’s packaging to support the agency’s review of the drug application as a whole.
Under this system, the packaging supplier establishes a Type III DMF with FDA and authorizes certain companies (typically their drug company customers, but also, in some cases, downstream packaging manufacturers who have their own DMFs) to make reference to the DMF in their drug-related submissions. The Letter of Authorization from the packaging supplier to its customer can be broad, providing the authorized party with permission to reference the entire contents of the DMF. Alternatively, a Letter of Authorization may permit the authorized party to reference only certain sections of the DMF. Authorized parties include a copy of the Letter of Authorization in their drug-related submissions (e.g., New Drug Applications, DMFs, etc.) to FDA. The packaging companies likewise add duplicate copies of their Letters of Authorization to their own DMFs. Through this system, information maintained in the DMFs remains entirely confidential—only FDA reviews the information in the Type III DMF and only when authorized to do so in connection with its review of a new drug application.
When FDA evaluates drug packaging, the agency focuses on the safety of the packaging components for use with the dosage form and route of administration, the compatibility of the package with the dosage form, the ability of the packaging system to adequately protect the dosage form, and the function of any special performance features. The pharmaceutical companies take the lead in determining that a particular package is acceptable for enclosing the type of drug in question. This determination is premised on the understanding that the drug, as packaged, complies with FDA’s Current Good Manufacturing Practice (cGMP) regulations for finished pharmaceuticals. FDA’s cGMP regulations state that the packaging must adequately protect a drug against external factors. Furthermore, drug product containers and closures must not be reactive, additive, or absorbtive so as to alter the safety, identity, strength, quality, or purity of the drug. In other words, the packaging cannot compromise the safety, effectiveness, or stability of the drug.
Type III Packaging DMFs and Organization in CTD Format
DMFs are vehicles for providing all manner of confidential information to FDA to support the agency’s review of a new drug application, and drug packaging materials are covered by one particular type of Master File (Type III). Because DMFs, including Type III DMFs for packaging materials, are voluntary submissions, traditionally there have been few hard and fast rules as to what information must be included (though FDA has developed a growing number of administrative and informational “requirements” in recent years). At a minimum, Type III DMFs must contain some confidential information about the packaging material described therein, as well as: (1) administrative information (the name and address of the DMF holder, addresses of the manufacturing facilities and, if applicable, the name and address of a U.S. agent); (2) statements of commitment that the DMF is current and that the holder will continue to manufacture the products as described in the DMF and will operate its facilities in accordance with applicable environmental laws; and (3) an up-to-date list of each entity that has been authorized to incorporate by reference information in the DMF.
As for the confidential product information provided in the DMF, FDA affords companies the flexibility to determine how much detail to include. The only requirement is that the DMF contain some confidential information prompting the need to submit a DMF in the first instance (rather than including the information as part of the drug submission, itself). Because Type III packaging DMFs have long been provided to FDA in paper format, the agency has generally left it to a company’s discretion how to assemble the product-specific information within the DMF, and DMFs were structured so as to provide information to FDA on the drug packaging in a logical and organized manner. The CTD format to which FDA is transitioning for DMFs is much more rigid by contrast and does not take into account the differences in the types of information provided in the various categories of master files.
The CTD structure contains five modules. Module 1 covers administrative information, Module 3 covers the technical information on the product or products described in the DMF, and Modules 4 and 5 cover nonclinical and clinical study reports, respectively. Module 2 is intended to include summaries of the technical information and study data that are provided in full in Modules 3, 4, and 5. FDA has issued several guidance documents relating to preparing submissions in CTD format. The agency makes clear in the guidance that it is not necessary to submit all Modules and, specifically for Type III packaging DMFs, Modules 4 and 5 covering clinical and nonclinical study data are irrelevant.
Importantly, the CTD format was developed for the purpose of harmonizing the information to be provided to regulatory bodies responsible for the review and authorization of new pharmaceutical products. Therefore, the technical information to be included in Module 3 is broken down by Drug Substance (3.2.S) and by Drug Product (3.2.P). Type III DMFs often cover several different formulations or multi-component products within a single file. FDA’s guidance on conversion to CTD format recommends that, for Type III DMFs, single packaging components or materials of construction (e.g., film formulations) should be considered as “Drug Substances” such that the relevant supporting information on these components should be contained in the DMF in section 3.2.S of Module 3. Likewise, FDA suggests that container-closure systems and multi-material packaging products (e.g., PVC/foil blister packs) should be classified as “Drug Products” with the relevant information being provided in the DMF in section 3.2.P of Module 3. Organizing the type of information typically included in a Type III DMF into this structure can be quite challenging.
Transition of DMFs to eCTD Format
The President signed into law on July 9, 2012, the Food and Drug Administration Safety and Innovation Act, which amended the Federal Food, Drug, and Cosmetic Act to add section 745A, “Electronic Format for Submissions.” Section 745A(a) specifies that submissions to new drug applications (NDAs), abbreviated new drug applications (ANDAs), biologics license applications (BLAs), and investigational new drug applications (INDs) must be provided in an electronic format no earlier than 24 months after FDA issues final guidance specifying an electronic submission format. FDA issued final guidance for industry pursuant to Section 745A(a) in December 2014. This guidance noted that FDA determined it would not be feasible to describe and implement electronic formats that would apply to all submissions covered by section745A(a) in one guidance document and, therefore, that FDA would develop additional guidances to specify electronic formats for various types of submissions. FDA has since issued an abundance of guidance documents on which submissions must be submitted electronically and the electronic format to following in making those submissions.
Of most relevance to Type III DMFs, FDA makes clear in its Providing Regulatory Submissions in Electronic Format—Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications May 2015 Guidance, that the agency considers “master files” to be submissions to an NDA, ANDA, BLA, or IND and therefore to fall within the scope of requirements set forth in section 745A(a).  Master files are defined to include “new drug master files” and any amendments to and annual reports on previously submitted DMFs. Unless they have been specifically exempted, submissions that fall within the types covered by the guidance, including DMFs, that are not provided to FDA in the electronic format described in the guidance will not be filed or received by FDA.
According to FDA’s guidance, electronic submissions must be made using the version of the eCTD that is currently supported by FDA, as specified in the Data Standards Catalog. The guidance document provides links to additional specifications documents that spell out what technical support a submitter needs to file with FDA in eCTD format (hint: you will be required to purchase software or work with a third party who has access to the software). The eCTD organization mirrors the CTD structure and maps the CTD hierarchy and headings to Extensible Markup Language (XML) elements, which are presented through an XML viewing tool.
Before making any electronic submissions, FDA requires a pre-assigned application number that can be obtained by contacting the appropriate Center at FDA, either the Center for Drug Evaluation and Research (CDER for NDAs, ANDAs, INDs, and DMFs) or the Center for Biologics Evaluation and Research (CBER for BLAs). More specific instructions on how to acquire an application number are provided on FDA’s eCTD webpage. Finally, FDA requires that submitters use the agency’s Electronic Submissions Gateway (ESG) for all submissions that are 10 gigabytes (GB) or smaller. Essentially any Type III DMF for drug packaging materials will be smaller than 10 GB in file size. Additional information on submissions using the ESG can be found on FDA’s website.
Notably, Section 745A(a) permits FDA to establish waivers and exemptions from the electronic submission requirements. Thus far, FDA has exempted only noncommercial investigational new drug applications from the electronic submission requirements. To date, the agency has not been amenable to the idea of providing an exemption for Type III packaging DMFs, though these types of filings would seem to us to be good candidates for exemption, not only because the types of information included in these filings are so incompatible with eCTD format, but also because suppliers of packaging materials will be significantly burdened by having to transition their DMFs into a structure that can be harmonized with the electronic submission requirements. Thus, the possibility of obtaining a waiver or exemption from the eCTD formatting requirement for Type III DMFs is still being explored and, as mentioned above, some FDA officials have agreed to give the matter further consideration. The window of opportunity in this regard is closing fast, however.
Unless FDA shows some inclination toward granting an exemption to packaging suppliers very soon, affected companies should familiarize themselves with the eCTD requirements if they have not already done so. As the May 5, 2017, deadline for electronic filings is rapidly approaching, the time to begin implementing the measures necessary to ensure a smooth transition to FDA’s mandatory electronic submissions to avoid disruptions with FDA’s review of your customers’ drug applications has arrived.
 See FDA – Manual of Policies and Procedures (MAPP) 5015.5.
 See 21 C.F.R. Part 211.
 See 21 C.F.R. Part 211.94.
 A few of the relevant documents include:
- Draft Guidance for Industry: Submitting Marketing Applications According to the ICH-CTD Format – General Considerations, August 2001
- Guidance for Industry: M4Q: The CTD – Quality, August 2001
- Guidance for Industry: Granularity Document: Annex to M4: Organization of the CTD, October 2005
 This Guidance was 24 months prior to the May 5, 2017 deadline for submitting all DMFs in electronic format.
 See:Guidance for Industry: Providing Regulatory Submission in Electronic Format – Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications, May 2015.