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