Drug Master File – Count Down

Posted by Chris Englerth | Mar 31, 2017 7:21:00 PM

The FDA deadline on NDA, ANDA, BLA and DMF (paper submissions) is less than 4 weeks away. By 5th of May 2017 the FDA requires that all DMFs are to be submitted in the eCTD format via the Electronic Submissions Gateway (ESG). If your DMF is in paper format with FDA, the same submission does not need to be resubmitted in eCTD format. However, as you move forward it is important to make sure your documents are properly prepared (bookmarked, OCR’d, proper orientation) and you can create your baseline DMF submission as eCTD. The DMF in eCTD format mandate applies to amendments, letters of authorization and annual reports.Submitting your DMF in eCTD has many advantages for the FDA as well as for you. eCTD submissions can be easily reviewed and information can be extracted quickly. It doesn´t matter if the data was part of the original submission or added later by the product sponsor. Therefore, the review, approval and management process of your products can be much shorter. Once your data is in an eCTD format you can use this layout for many countries, since this is a widely accepted standard.

But what are the key steps in getting you and your company ready for DMF submissions in eCTD format? We have found there are these 5 key steps:

  1. Identify your requirements and next steps
  2. Understand the eCTD and submission process
  3. Initiate the ESG (Electronic Submission Gateway) application process with the FDA
    1. Once your test access has been setup, you are required to submit a test submission in eCTD format, use PhlexSubmission to prepare it and submit it
    2. Once the test submission has been sent and validated, your account will be updated to a productive account by the FDA
  4. Prepare your DMF submission in eCTD
  5. Manage your eCTD lifecycle

The eCTD has five modules in which your content is organized:

  • Module 1: Administrative information and prescribing information
  • Module 2: Common technical document summaries
  • Module 3: Quality
  • Module 4: Nonclinical study reports
  • Module 5: Clinical study reports

Module 1 is a country specific module, which in this case is specified and provided by the FDA, whereas Modules 2 – 5 are common to all regions and are specified by the International Committee for Harmonization (ICH).

Every eCTD has the same structure of files. For all documents in the eCTD apply the following regulations:

  • PDF Table of Contents
    • and Bookmarks should be the same
    • For documents 5 pages or longer
    • Up to 4 levels deep in hierarchy
  • Orientation
    • Any documents provided in the submission should be in the correct orientation
  • Do not include form 356h when submitting via gateway.
    • DMFs are automatically processed without submitting a form
  • Scanned documents, including cover letters should be made searchable via OCR prior to submitting
  • Leaf titles of documents should be clear and indicative of the document and content
  • Cover letters should include the sequence number and if possible, date of submission (e.g. coverletter-0004Oct-13-2017)
  • Leaf titles for all annual report documents should include the reporting period (e.g. “AR-specifications-Oct-122016-Oct-11-2017). That way, reviewers can differentiate between one year’s report from another.
  • Cover letter should have contact information for agent, if applicable
  • Provide electronic submissions point of contact for technical issues
  • Provide correct telephone, email or fax number for rejection notices

Some Advice:

  • Be sure to apply the correct metadata for 3.2.p and/or 3.2.s eCTD sections for every submission.
    Any minor change will add another 3.2.p. and/or 3.2.s section thus, creating duplicate sections.
  • Always apply the correct eCTD life cycle operator (e.g. replace) when submitting updates to documents. Do not submit updated documents as “new”.
  • When submitting your DMF, the eCTD envelope requires the specification of a -digit application number. Use your DMF number for this, prefix leading zeros (0) to the DMF number to reach 6 digits as needed

Below we provide two examples about how to fill out your submission envelope information. Therefore, we thought of two scenarios: One if your first eCTD is an amendment to a DMF, and the other for the case where your first eCTD is an annual report for your DMF.

Paper DMF to eCTD example:

When transitioning from paper to eCTD, the most common scenarios are below:

  • First eCTD submission is an amendment to the DMF
  • In this case, use a submission type of original application and submission subtype of application. Use eCTD sequence number = 0001 and Submission ID = 0001.
    • Subsequent amendments, including letters of authorization, submitted in eCTD should use a submission type of original application and submission subtype of amendment. Use next available eCTD sequence number and Submission ID = 0001 (Submission ID for the first eCTD submission to the Original application)
  • First eCTD submission is an annual report
  • In this case, use a submission type of annual report and submission subtype of report. Use eCTD sequence number = 0001 and Submission ID = 0001.

In the eCTD process, you do not just produce your submission in electronic format, but send it via the FDA Electronic Submission Gateway (ESG). Thus, there might be additional new pieces of information you need to consider. Information such as different contacts and contact information will need to be provided in the submission in case the FDA needs to reach out to you about possible questions. More information to these document guidelines and the ESG can be found here: http://www.fda.gov/ectd If you still have open questions you can ask our Phlexglobal DMF expert at info@phlexglobal.com or simply write to dmfquestion@cder.fda.gov

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Update on 10.04.2017:

This article got published shortly before the FDA updated their guidance document https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm333969.pdf

The DMF deadline got moved from 2017 to 5th of May 2018.

 

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