e-CTD best practices and PDF specifications for ANDA compilation:Comprehensive Tutorial

The e-CTD has a number of features that can speed up submission publishing and review times, including cross-application linking capabilities that allow sponsors to submit a document just once and refer to it as many times as necessary in subsequent submissions and applications.

This article will address the practical tools, applications and PDF specifications which are required by Regulatory Agencies to submit applications (NDA/ANDA) in eCTD format.

Following tools are required to learn to achieve e-CTD structure and functionality

  1. PDF version (How to check and Change the PDF version)
  2. Security:
  3. Fonts: Color, Type and Size.
  4. Paper size: page orientation, size and margin.
  5. PDF creation and document scanning
  6. Source of electronic documents:
  7. How to convert file from MS word to PDF form:
  8. Optical Character Recognition (OCR):
  9. File size: Individual file size.
  10. Fast web view optimization
  11. Document Navigation:
  12. Hypertext Links and Bookmarks:
  13. Magnification setting: set to inherit zoom
  14. Page Numbering.
  15. Adding header and footer in PDF document
  16. How to add multiple pdf documents in to single file
  17. Insert, delete, replace and extract pages from PDF file.
  18. Naming convention
  19. e-CTD validation process.

PDF Version:

FDA or other regulatory agencies typically require providing a specific version of PDF—most often PDF 1.4, the Acrobat 5 format.

Why change of version is required?

To ensure compatibility with a client or reviewer/viewer using an older version of Adobe Acrobat.

If you prepare a document by using newer version of Adobe Acrobat there may be chances that Certain PDF documents may not be viewable in older versions of Acrobat viewer /reviewer is using.

For example, if you send a PDF Package to a regulatory Agency using Acrobat 9, they will be prompted to download the latest version of the free Adobe Reader to view it.

What US FDA Guidance Says:

“PDF versions 1.4 through 1.7, PDF/A-1 and PDF/A-2 are acceptable for documents.

Submitted PDF files should be readable by Adobe Acrobat X, should not require additional software or plug-ins to be read and navigated, and should be text searchable.

If plug-ins are used during the creation of a PDF document, prior to submitting the document, ensure that a plug-in is not needed for review or archive.”

The following are some specific instances a typical user may encounter.

Acrobat Product Version PDF
Version
New Features Affecting
Backwards Compatibility
Viewability issues
Acrobat 5 PDF 1.4 §  OCR Text Layer PDFs can be opened with Acrobat 3.0 and
Acrobat Reader 3.0 and later. However, features specific to later versions are sometimes lost or not viewable.
Acrobat 6 PDF 1.5 §  Linked multimedia Most PDFs can be opened with Acrobat 4.0
and Acrobat Reader 4.0 and later. However, features specific to later versions are sometimes lost or not viewable.
Acrobat 7 PDF 1.6 §  Reader Enabled Review

§  Security Envelopes

§  XML Forms

§  Embedded multimedia including 3D content

§  Bookmark Compression

Most PDFs can be opened with Acrobat 4.0
and Acrobat Reader 4.0 and later. However, features specific to later versions are sometimes lost or not viewable.
Acrobat 8 and 9 PDF 1.7 §  Reader Enabled Forms

§  PDF Packages

§  PDF 1.7 XML Forms

Most PDFs can be opened with Acrobat 4.0
and Acrobat Reader 4.0 and later. However, features specific to later versions are sometimes lost or not viewable.


How to check the version of a PDF Document?

Click on File (on top left cornhow-to-check-the-version-of-a-pdf-document-2er of document)

Go to the Properties (Short keys: CTRL+D)
how-to-check-the-version-of-a-pdf-document-pharmalearners

 Check the Description tab

                                                                                   “click on image to enlarge”

How to change PDF versions using Acrobat?

Saving to a Previous PDF Version using “Reduce File Size”

This option is available in both Acrobat Standard and Professional.

Go to “File” > “Save as” > Reduced Size PDFhow-to-change-pdf-versions-using-acrobat-1

 

Choose the PDF compatibility requiredhow-to-change-pdf-versions-using-acrobat-2

Click OK

“Documents containing color images generally show the most reduction in file size. Typical documents such as scanned black and white documents or simple text-only documents generated from word processing will show little difference in file size.”

 

SECURITY:

FDA recommends that not to activate any security settings or password protection in PDF file. FDA maintains the integrity of the submitted files through Agency security and archival processes. A copy of the files, generated from the submitted files, will be provided to the reviewer.

FDA Forms downloaded from the FDA Forms website contain security settings that prevent changing the documents. These forms should be submitted as provided, with no additional security added and without removing the provided security settings.

How to check Security Settings?

Go to “File” > “Properties”  (Or use short keys: CTRL+D) >  then click on Second tab how-to-check-security-settings“Security”

Choose the Security Method “NO SECURITY”

Ensure that in “Documents Restrictions Summary” all features in the pop up window should shows as “Allowed”

                                                                                                                   Click on Image to enlarge

Fonts (Color, Type and Size):

Font Type:

FDA has provided the list of standard fonts in its guidance, because when opening a document the font does not display correctly if the font is not available on the reviewer’s computer.

To avoid this problem the fonts are restricted to the standard fonts listed in below table.

 

“FDA Recommendations on Font Size:”

Font size Range: Use font sizes ranging from 9 to 12 point.

For narrative text:  Times New Roman 12-point font is recommended.

For Tables: point sizes 9-10 are recommended. Smaller point sizes should be avoided.

For footnotes: 10 point fonts are recommended.

 List of FDA Recommended Standard Fonts

Font type Font name
Serif Times New Roman
  Times New Roman Italic
  Times New Roman Bold
  Times New Roman Bold Italic
Sans Serif Arial
  Arial Italic
  Arial Bold
  Arial Bold Italic
Non Proportional Courier New
  Courier New Italic
  Courier New Bold
  Courier New Bold Italic
Other Symbol
  Zapf Dingbats


Font COLOR:

Black is the recommended font color  except that blue can be used for hypertext links. Light colors do not print well on gray scale printers.

When choosing a point size for tables, a balance should be made between providing sufficient information on a single page that may facilitate data comparisons while still achieving a point size that remains legible.

When creating documents which include scanned images, ensure that any resizing of the image does not reduce the effective font size below the recommended size.

 

PAPER SIZE: PAGE ORIENTATION, SIZE AND MARGIN:

Page Orientation:

Page should be saved in correct the page orientation for proper viewing and printing within the document. For e.g. Landscape and portrait pages should be saved in their respective orientation.

How to change the Page Orientation?How rotate page in pdf file

  1. Open the page Thumbnails
  2. select the page in Thumbnails to be rotated
  3. right click on the page
  4. Click on “Rotate page”

(Short Keys: Shift + Ctrl + R)

Direction: page-rotation-in pdf file 7-page-rotation-2

  • Counterclockwise 90 degrees
  • Clockwise 90 degrees
  • 180 degrees

Page range:

  • All
  • Selection
  • Pages: From     to       TO

Rotate:page-rotation n pdf file

  • Even and Odd pages
  • Even Pages Only
  • Odd pages Only
  • Landscape Page
  • Portrait Pages
  • Pages of any Orientation.

 

PAGE SIZE AND MARGINS:

Header and footer information should not invade the specified margins (i.e., header and footer information should not appear within 3/8 (0.375 Inch)  of an inch of the edge of the 8.5 by 11 inch page), so the text will not be lost upon printing or being bound. These margins allow printing on A4 as well.”

Set up the print area for pages to fit on a sheet of paper that is 8.5 inches by 11 inches.

Page Margins:

Left Side: 3/4 (0.75 Inch) of an inch to avoids obscuring information when pages are subsequently printed and bound.

Other Sides: at least 3/8 (0.375 Inch) of an inch

For landscape pages orientation: ¾ (0.75 Inch) of an inch at the top, to allow more information to be displayed legibly on the page.

For over sized documents: (e.g., CAD drawings or other specialized documents) and promotional materials submitted in PDF format should be created

PDF creation and Document Scanning:

Source of electronic documents:

Convert the Word documents which are typewritten directly from Word to PDF.

“If scanned files must be submitted for e.g. hand written documents and Signature pages, they should be made text searchable where possible by using optical character recognition software (OCR). Completeness and accuracy of imaged text in to text searchable form shall be verified and ensured.”

Document scanning:

During scanning please ensure that the pages of the document are legible both on the computer screen and when printed and, at the same time, minimizes the file size.

Following are the FDA recommended scanning Resolution Criteria for various types of documents:

Document type Resolution  (dotes per inceh-dpi)
Handwritten notes 300 dpi (black ink)
Plotter output graphics 300 dpi
Photographs – black and white 600 dpi (8 bit gray scale)
Photographs – color 600 dpi (24 bit RGB)
Gels and karyotypes 600 dpi (8 bit grayscale depth)
High pressure liquid chromatography 300 dpi

There are many reasons to be cautious in selecting the appropriate DPI, including the desired level of clarity, readability, file storage requirements, and the type of image you’re capturing.

How to convert file from MS word to PDF form:

Option 1 -: Click on “Office button”  > Save as > Adobe pdf

Option-2: Ctrl+P  > select the printer Adobe pdf  > click OK

 

Optical Character Recognition (OCR):

OCR (Optical Character Recognition) is typically a process of conversion of an image to full text which makes everything searchable.

When you scan a document, it is a pure image and the text within are not searchable, nor can you copy and paste the content in pdf file.

The OCR process can give you pdfs that can be searchable; user can copy and paste the required data from the document and can extract the data also.

How to perform ORC in scanned pdf document? Optical Character Recognition

Go to the Tools  . Recognize text   > in this file  >  OR Multiple files

 

Pop up window (Recognize Text)will openOptical Character Recognition

All pages

Current page

Page range (from to to)

Settings: Select the following settingsOptical Character Recognition

Primary OCR Language : English (US)

Pdf output style: Searchable Image

Down sample to : 300dpi

File size:

Individual file size should not be more than 100 mb (Keep the cut off up to 95 mb for safer side)

Fast web view Optimization:

What is Fast Web View in a PDF?
Fast Web View restructures a PDF document for page-at-a-time downloading (byte-serving) from web servers instead of waiting until the entire PDF’s data is downloaded. With Fast Web View, the web server sends only the requested page, rather than the entire PDF file. This is especially important with large documents that can take a long time to download from a server. So as soon as the first page is processed, the first page can be viewed on the viewers screen.

If you had made fast web view to optimize your pdf file, it is very fast to view your pdf file online for the readers.

How to check if Document is Fast web viewed or not?how-to-check-the-fast web view status of-a-pdf-document
  • Go to file
  • properties
  • Click on Description tab
  • Check Fast web view status (Yes or NO)

(Short Key: Ctrl +D)

Follow this procedure to make sure that you have Acrobat set up to enable Fast Web View during the PDF creation process.

1) Choose Edit -> Preferences (Short Key:Ctrl +K)
2) Under Categories, select Documents.
3) On the right side of the dialog box, under Save Settings, make sure that Save as Optimizes for Fast Web View is selected, or select it now, and click OK.

fast-web-view

 

fast-web-view

 

Enable Fast Web View for an existing PDF

Use this procedure after you have verified your Fast Web View Preferences setting and checked the PDF properties to be sure that the file is not already enabled for Fast Web View.

1) Open the PDF that you want to have Fast Web View.
2) Choose File > Save As. Select the same file name and location.
3) When a message appears asking if you want to overwrite the existing file, click OK.

Document Navigation:

Initial Page View:

Initial view for a PDF document determines how the document displays when it is opened.

If document has bookmarks Initial page view should be set as Bookmark panel and page.

If document have fewer pages and does not have bookmark Initial page view should be set as page only.

Layout and Magnification should be set to “Default.”

Setting Initial page View for a PDF Documentinitail-page-view-setting-in-pdf

Go to the File > Properties  OR press (Ctrl +D)

Click on the Initial View tab and do the following:

Layout and Magnification

Navigation Tab:

Define how to display pages: to display pages only, or with a Panel

(Bookmarks Panel, Pages Panel, or Attachments Panel, Layers panel and page).

  • To show default page layout, or a specific layout. (Single page, Continuous, Facing, or Continuous-Facing).
  • Select to show default magnification, or a set zoom option. (Fit Page, Fit Width, Fit Height, or a predefined value).
  • Select a page to show in the first view.

 Window Option:

  • Let the window be resized to the first page, centered on screen, or with Full Screen mode.
  • Select what displays on the window title bar (File name or Document title).
  • Hide
  • Decide whether to show or hide the Menu bar, Tool bars, or Window Controls.
  • If you choose to hide the Menu bar, all the tabs and ribbons disappear. If you receive such a file, press F9 to display them.

To show the Bookmarks panel:
Choose File> Properties and choose the Initial View tab.

  1. Set Navigation tab to Bookmarks Panel and Page
    – This sets the Bookmarks Panel to open automatically when the file is opened.
  2. Set Page Layout to Single Page
    -Better viewing experience for documents which have pages of different sizes.
  3. Click OK and Save the document.

Bookmarks and Hypertext Links:

Bookmarks are text based links that you can find in the Bookmarks Panel along the left side of your screen. It is TOC-like interface to working with a document and is very useful in accurately navigating through a long PDF file.

Nicely bookmarked and hyperlinked document is reviewer friendly and it saves the reviewers time to see the various sections in the documents and finely it is the best way to present your long document.

Both bookmarks and links to achieve the objective of creating a well organized document.

What FDA Guidance says:

“A table of contents (TOC), hypertext links and bookmarks provide essential navigation through PDF documents. Include a hypertext linked TOC and bookmarks in documents 5 pages or longer. Use hypertext links throughout the body of all documents to link to supporting annotations, related sections, references, appendices, tables or figures that are not located on the same page as the narrative text. Hypertext links in text can be designated by rectangles using thin lines or by blue text. A consistent method of designating links in a document avoids confusion. Hypertext links that open a file or document should be set to open the file or document in a new window.”

Key points to Remember:
  • Table of Contents and Bookmarks should match up to 4 levels in the hierarchy
  • Bookmark should be there for documents 5 pages or longer.
  • Magnification setting should be “Inherit Zoom”.

For documents with a table of contents, provide bookmarks and hypertext links for each item listed in the table of contents including all tables, figures, publications, other references, and appendices that are essential for navigation through documents. The use of invisible rectangles and blue text in the table of contents for hypertext links avoids obscuring text. Other help for navigation includes a bookmark hierarchy identical to the table of contents; up to four levels deep in the hierarchy.

When creating bookmarks and hyperlinks, set the magnification setting to “Inherit Zoom” so the destination page displays at the same magnification level used in the primary document.

Creating Links (Hypertext Links)

Follow these steps to create a link on text:

  1. Select the text where you want the link to appear with the cursor tool
  1. Right-Click and choose Create Link
  2. Set the appearance of the link.
    Note: These settings are “sticky” so you’ll only need to do this for the first link.
  1. Link Type: Visible Rectangle
    B) Highlight Style: Invert
    C) Line Thickness: Thin
    D) Line Style: Solid
    E) Color: Set to Blue
    F) Link Action: Go to a page view

 

  1. The Create Go to View window appears.
  2. Click the Bookmark which is the destination for the link (If document has Bookmark)
    (Acrobat will take you to the destination page)
    B. Click theSet Linkbutton
    ( Acrobat returns you to the initial Page)

 

Repeat as needed for additional links.

What if I don’t have a bookmark?
Just use the page navigation tools to go to the page you want to link to, then click the Set Link button.
What if I delete, add or replace the pages after creating the link within the document?

In the example above, all of the links created were to a place within the same document. If you add or delete pages, Acrobat will resolve and update the links for you and there will be no error.

For example, if you create a link to show on page 23, then later delete page 1, the link will be updated to point to page 22.

If you delete the destination page for a link, the link will still be present, but will no longer resolve. When you click on it, nothing will appear.

You can even replace a page or range of pages (Document> Replace Pages) and the links will stay intact.

Linking between Separate Documents:

It is possible to create links that refer to other PDF documents. In the Go to View step above, simply switch windows and then go to the page or bookmark in the destination document.

Be careful if you change the document set after creating links between the documents. PDF Document 1 doesn’t know if PDF Document 2 has changed.

Creating Bookmarks in the PDF Document:

Follow these steps to Add Bookmark of text in the document:

Select the text or Heading for which you want to Add Bookmark with the cursor tool

Right-Click and choose Add Bookmark

(Short Key: Press Ctrl+ B)

Magnification setting:

Magnification setting: set to inherit zoom.

“Inherit Zoom” in Acrobat means that when you click a link, the zoom level the link appears at will be the same as the zoom level you were at when you clicked the link.

However, the links change the zoom level of the PDF to “Fit Page”, as shown in the following dialog box

Now we have to change it to  “Inherit Zoom”.

Follow these steps to change the zoom level:

First select the Link tool (Image)

Now right click in the Link and again click on the “Properties” in the pop up window.

(Short Key: Ctrl + I)

Now click on the Action Tab, here click on Edit button and set the zoom level to “Inherit Zoom”

How to combine two or multiple pdf files together (How to add multiple pdf documents in to single PDF file)?

Acrobat can combine various file types (Word, Excel, PowerPoint, PDF, TIFF) into a PDF Binder. A PDF Binder is a single, multiple page PDF document.

  1. Choose File> Create PDF> Combine files into a single PDF…
  2. Click theAdd Files button at the top of the window and choose Add Files to add a file(s) to the binder
  3. Next, arrange your files in the correct order:
    A)Click the Move Up or Move Down buttons to re-order files
    B)Click the Remove button to take a file out of the binder
    C) Click the Choose Pages button to select a range of pages from a file, instead of the entire file

 

Change the Bookmark Name
Acrobat creates bookmarks from the file names in the window. Right-click a file in the list and choose Edit Bookmark for File to enter a different bookmark name.

  1. Click theCombine Files button and Acrobat will combine all of the files into a single PDF.
    – Acrobat will ask you to name the resulting file.
    -Save it to a location of your choice.
  2. The combined PDF will open in Acrobat.
How to Insert, Extract, Replace, Delete, and rotate the pages in pdf documents?

Individual File size Requirement in e-CTD compilation:

NMT 100 mb (Tips: Keep cut off of 95 mb.)

Page numbering.

Page numbering can be done in the PDF document by adding Header or Footer, discussed below in detail.

Adding header, footer Page numbers and date in PDF document:

Headers and footers can include a date, automatic page numbering or the title and author, Module Number or any text you want. You can add headers and footers to one or more PDFs.

You can define and save your headers and footers to reuse them later, or you can simply apply a header and footer and forget it. After applying a header and footer, you can edit, replace, or delete it in the PDF. You can also preview headers and footers before applying them and adjust the header and footer margins so that they don’t overlap other page content.

 

 

November 28, 2016

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