For Pharmaceuticals and Biotechnology

Navigating the FDA's New Requirements for eCTD Submissions
by Antoinette Azevedo, Founder of e-SubmissionSolutions.com


The United States Food and Drug Administration (FDA) is taking concrete steps to require the submission of all types of regulatory communication in electronic format. Globally, regulatory authorities are all moving to require electronic submission of regulatory communication. The reasons are many but one reason is clear: the public safety responsibilities of the regulators requires significantly faster access to content that can be supported by paper format.

All regulatory authorities who accept electronic submissions have very strict requirements for the format and electronic navigation aids within PDF files.

The cost of preparing the content to be reviewable in electronic format is the bulk of the time and human resources needed to prepare electronic submissions. Failing to prepare the electronic content in compliant format can result in the regulatory authority refusing to conduct the review until the lack of compliance is corrected. This could have a profound impact on a company's viability if a competitor drug is approved while the first sponsor is correcting non-compliant content.

Compliance of electronic documents can be easily and inexpensively achieved through the proper use of Microsoft Word to author documents, combined with the use of templates with electronic submission compliance features built into the template design.

History of Electronic Submission Requirements

  • FDA Centers for Drug Evaluation and Research (CDER) and Biologic Evaluation and Research (CBER) has required submission of electronic case report tabulation (CRTs) and case report forms (CRFs) in electronic format for new drug and new biologic license applications (NDAs and BLAs) since 1999.

  • FDA CDER has required package inserts to be submitted in electronic Structured Product labeling (SPL) format since October 1, 2005.

  • The FDA CDER has required electronic submissions to be presented in the electronic Common Technical Document (eCTD) format since January 1, 2008.

  • FDA is requiring the content of the Drug Establishment and Drug Registration forms to be submitted in electronic format beginning June 1, 2009.

  • FDA has published the proposed rule that retired previous electronic submission formats and set the stage to require all submissions be in electronic format using the eCTD organization structure and electronic navigation aids.
The electronic submission juggernaut is not limited to the US market:
  • The European Medicines Evaluation Agency has announced a timeline which requires all agencies participating in the centralized procedure for marketing authorization applications (MAA) to begin submitting electronic format in January 1, 2009, and in the eCTD format in January 10, 2010.

  • Health Canada has published the timeline to require electronic submissions in eCTD format.

  • The Japanese Ministry of Health Labor and Welfare (MHLW) has begun accepting electronic submission in the eCTD format.

Finally, there is an international effort underway with involvement by regulatory authorities and industry to define the next generation of bi-directional communication of regulatory submissions' content in a messaging format called Regulated Product Submission that is intended to address electronic submission requirements for all products regulated by FDA: drugs, biologics, devices, veterinary medicine, food additives, and cosmetics.

Technical Requirements

Since 1999, the fundamental building block of electronic submissions has been the Adobe Acrobat Portable Document Format (PDF). However, this format is not an ordinary run-of-the-mill PDF created by scanning or printing to Adobe PDF. All regulatory authorities who accept electronic submissions have very strict requirements for the format and electronic navigation aids within PDF files. Regulatory authorities globally have refused to review electronic submissions whose PDF files lacked required navigation aids.

All of these requirements can be met by implementing MS Word templates and configuring PDF conversion to support these requirements. PDF conversion can be done via PDFMaker, a plug-in to the Microsoft Office suite that is automatically implemented with the Microsoft Office applications, which are installed first (Adobe Acrobat Standard or Professional is installed second). These properties can also be assured by correct configuration of Acrobat Distiller. Further, companies with MasterControl electronic document management systems (EDMS) configured for life science applications frequently have a PDF rendition server or generator in the EDMS suite that can be configured to support the requirements that are identified below.

FDA has published a guidance that describes the requirements for PDF files for eCTD submissions, Portable Document Format Specifications, version 2.0, dated 2008-06-04, http://www.fda.gov/cder/regulatory/ersr/PDF_specification_v2.pdf. Other regulatory authorities have published requirements that are virtually identical to the guidances supplied by FDA.

Fundamental PDF Requirements

One of the strongest directives from the regulatory authorities' requirements is that PDF files conform to predefined page sizes, have adequate margins on all sides and have adequate font sizes for legibility. These translate into the following specifications:
  • US Letter page size for the FDA;

  • A4 page size for rest of the world;

  • Margins of at least one inch on all four borders, with larger margins on the binding edge in the event that paper volumes will be required;

  • Times New Roman or Ariel font, with the body text in 12 point and tables no smaller than 10 point.

PDF File Format and Display Requirements

PDF files should be in File Format 1.4 and be set to open to Fast Web View. These properties can be configured in the PDFMaker or PDF rendition process but can be added to PDF files after the fact by using the PDF Optimizer function of Acrobat Standard or Professional.

PDF files should automatically open to the page orientation of legibility. If PDFMaker, Distiller or a rendition engine is used to convert from MS Office to PDF format, this property can be automatically applied to the individual pages. However, if the PDF is created from scanned images, this requires the pages to be individually inspected and the page rotation property adjusted for pages that display incorrectly.

PDF Files Created by Scanning

Scanning is to be avoided unless there is no other choice. Scanned documents of sufficient quality should be made searchable via Optical Character Recognition (OCR), which has been validated for accuracy of the recognition (that is that 1 has not been translated as l or i, or 0 has not been translated as O or o).

If scanning must be done, the FDA guidances provide specifications that include:

  • Recommended resolution for different types of content;
  • Compression algorithms for black and white, grayscale and color;
  • Image color matching to assure fidelity of the depiction of color for screen and print output formats.

Navigation via Hyperlinks and Bookmarks

One of the most critical requirements to facilitate review is that PDF files contain hyperlinks and bookmarks to aid review in navigating within a file and between files. Examples of hyperlinks include:
  • From table of contents, list of figures, list of tables, list of appendices, to the content of the document.

  • To supporting annotations, related sections, references, appendices, tables, or figures not located on the same page as the narrative text.

Bookmarks should match the table of contents hierarchy and depth, so that the document can be navigated via either the table of contents or the bookmarks.

All bookmarks and hyperlinks should have relative file paths; that is, they should not refer to server names, drive letters, or any company-specific network components.

All bookmarks and hyperlinks should have the magnification property of Inherit Zoom, so that the reviewers viewing preferences are preserved when navigating via bookmarks and hyperlinks.

Hyperlinks should be designated via think blue lines or by blue text. If documents are created from an intelligent source - such as the MS Office applications, the blue text property can be applied at the time the documents are authored and the PDF conversion process carries this property to the PDF file. However, if documents are scanned, hyperlinks can be represented only by thin blue lines.

Page Numbering

Individual PDF files in an eCTD should be page numbered beginning at page one, so that the PDF file and the document page number are the same.

Conclusion

All of the PDF file properties described in the FDA guidance document can be assured by:
  • Using MS Word templates designed for eCTD compliance;

  • Styling the document using headers (1 through 9) and captions;

  • Using MS Word properly - building tables of contents, tables of figures and tables, inserting hyperlinks or cross-references when referring to related content;

  • Configuring PDFMaker, Distiller or PDF appropriately to ensure that engines to create compliant output;

  • Be aware of the recommended configurations of resolution and color when scanning documents.

These requirements apply not just to internal authors and regulatory operations staff, but should be made part of the standard deliverables from contract writers, contract research organizations, and other outside suppliers.

Correct preparation of PDF files for eCTD submissions assures that the review starts on time and enables the review to be conducted with the support of the electronic navigation aids that are so critical to the review experience.

Antoinette Azevedo, founded e-SubmissionsSolutions.com (a California corporation) to advise all sizes of biotechnology and pharmaceutical companies on the use of technology to manage regulatory documents and publish electronic submissions. Ms. Azevedo's clients range from large, international pharmaceutical companies to small, virtual biotechnology companies -- all attempting to be better prepared to manage controlled documents and produce electronic INDs and drug/biologic registrations.

Ms. Azevedo was director of West Coast Operations for Liquent from 1997 to 2000. Ms. Azevedo was principal consultant in the CSC Consulting life sciences practice as technical lead for regulatory submission publishing from 1994 to 1997, working with pharmaceutical clients in North American and Western Europe. Her entire career has been devoted to document management and electronic publishing through a several generations of technologies and architectures, in various industries. She dedicated her focus to life sciences beginning in 1994. She is experienced with a number of document management systems, publishing systems and toolsets, and a wide array of options for successfully producing electronic submissions. Her experience ranges from developing strategies for document management and electronic publishing, to implementation of fully-validated systems, and production of paper and electronic submissions accepted for review by regulatory authorities worldwide.

Ms. Azevedo is the author of Competitors & Markets, Products & Applications, 1994-1998, Antoinette Azevedo and David Henry Goodstein with M. Elizabeth Hunter, European Supplement by Hans Andriese, 1994, InterConsult, Inc. Arlington, MA. Ms. Azevedo has lectured internationally for RAPS, DIA, at vendor user conferences, and for local regulatory affairs professional groups. Visit her website at www.e-submissionssolutions.com. You may contact her at 619-220-7081 or aazevedo@e-submissionssolutions.com.

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Click here to view all available resources.

GxP Lifeline Article

Accelerating Submissions Processes with Templates for Microsoft Word®


FDA Link

Guidance for Industry: Providing Regulatory Submissions in Electronic Format - Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications


EMEA Link

EMEA Implementation of Electronic Submissions and eCTD Submissions: Statement Of Intent