Sep 26, 2014 — embedded images; revise specifications related to document naviagation; and indicate maximum allowable PDF file size. 2016-9-14.
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PORTABLE DOCUMENT FORMAT (PDF) SPECIFICATIONS Technical Specifications Document This Document is incorporated by reference into the following Guidance Document(s): Guidance for Industry Providing Regulatory Submissions in Electronic Format Š Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications For questions regarding this technical specifications document, contact CDER at or CBER at U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER ) Center for Biologics Evaluation and Research (CBER) September 2016 v4.1

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iii Revision History Date Version Summary of Revisions 2005-04-08 1.0 Initial version 2008-06-04 2.0 Changed fi Bookmarks and Page fl to fi Bookmarks Panel and Page fl in Open Dialog Box section 2011-12-20 3.0 Updated to align with ICH recommendation on PDF version 1.7; add fiPurposefl section; clarify specifications related to security, usability, and promotional material s; revise list of standard fonts; add PDF optimization; and incorporate editorial changes 2012-1-13 3.1 Clarified language on acceptable PDF versions for documents; added page numbers 2014-9-26 4.0 Updated to align with ICH recommendation on PDF/A; clarify embedding of fonts and font size in embedded images ; revise specifications related to document naviagation ; and indicate maximum allowable PDF file size 2016-9-14 4.1 Updated fiSpecial Considerations for Promotional Labeling and Advertising Materialfl section

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Contains Nonbinding Recommendations 2 PORTABLE DOCUMENT FORMAT (PDF) SPECIFICATIONS PURPOSE These specifications are for creating documents in Portable Document Format (PDF) for submission to CDER or CBER, t hat align with ICH M2 recommendations 1 and that are in a format that the receiving Center currently supports. For purposes of this document, fisupportsfl means the receiving Center has established processes and technology i nfrastructure to support the receipt, processing, review and archive of files in the specified standard format . PDF is an open, published format created by Adobe Systems Incorporated ( ). Software from a variety of sources can be used to create files in the PDF format . VERSION PDF version s 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 navigate d, 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 . PDF files must not contain JavaScript; dynamic content wh ich can include audio, video or special effects and animations; attachments or 3D content. 2 Do not include PDF annotations in documents. 3 Ensure that all hypertext links in documents remain active after conversion to PDF/A. SECURITY Do not activate security settings or password protection. The integrity of the submitted files is maintained through Agency security and archival processes. A copy of the files, generated from the submitted files, will be provided to the reviewer. The r eviewer should be able to print, select text and graphics, and make changes to text, notes and form fields using the provided copy. FDA Forms downloaded from the FDA Forms website contain security settings that prevent changing the documents. These form s should be submitted as provided, with no additional security added and without removing the provided security settings. FONTS Fully e mbed all non-standard fonts. PDF viewing software automatically substitutes a font to display text if the font used to create the text is unavailable on the reviewer™s computer. In some cases, font substitution can occur even when the fonts are available. For example, Helvetica or Times are substituted even if available on the reviewer™s computer. Font substitution c an affect a 1 ICH has recommended several file formats for the exchange of regulatory documents. See 2,3 Exception noted in fiSpecial Considerations for Promotional Labeling and Advertising Materialfl

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Contains Nonbinding Recommendations 3 document™s appearance and structure, and in some cases it can affect the information conveyed by a document. Font availability to the reviewer is ensured if all non -standard fonts are fully embedded. When fonts are embedded, all characters for the font should be included not just a subset of the fonts being used in the document. Inspect documents to make sure all non-standard fonts are fully embedded prior to submission. Font embedding does not always solve the problems that occur when a r eviewer tries to copy and paste text from a PDF document into another software format. If the font is not available on the reviewer™s computer, font substitution results , even if the fonts are embedded. This problem is avoided if the fonts are restric ted to th e standard fonts listed in Table 1. Table 1: List of 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 Use font size s rang ing from 9 to 12 point. 4 Times New Roman 12 -point font is recommended for narrative text. 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. Generally, point sizes 9 -10 are recommended for tables; smaller point sizes should be avoided. Ten point fonts are recommended for footnotes. When creating documents which include scanned images, ensure that any resizing of t he image does not reduce the effective font size below the recommended size. Black is the recommended font color 5 except that blue can be used for hypertext links. Light colors do not print well on grayscale printers. Any colors used should be tested prior to submission by printing sample pages from the document using a grayscale printer. 4,5 Exception noted in fiSpecial Considerations for Promotional Labeling and Advertising Materialfl

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Contains Nonbinding Recommendations 5 Gels and karyotypes 600 dpi (8 bit grayscale depth) High pressure liquid chromatography 300 dpi IMAGE COMPRESSION TO REDUCE FILE SIZE Compress f iles using either Zip/Flate or CCITT Group 4. File compression is a method for reducing file size. Some methods of compression can result in loss of data and can introduce compression artifacts that affect the reviewability of the information. The following two methods provide lossless compression. Zip/Flate (one technique with two names) for lossles s compression of color and grayscale images is specified in Internet RFC 1950 and RFC 1951. CCITT Group 4 Fax compression technique recommendations for lossless compression of black and white images is specified in T.6 (1988) – Facsimile coding schemes an d coding control functions for Group 4 facsimile apparatus. OPTIMIZE FOR FAST WEB VIEW Create files from source documents using the fiOptimize the PDF for fast web viewfl option to reduce file sizes and file opening times. IMAGE COLOR MATCHING Because color varies from monitor to monitor, it is difficult to ensure that the reviewer will see exactly the same color as in the actual image. However, for printing, there is more control over the color by using CMYK (Cyan, Magenta, Yellow, Black) colo r model as opposed to the RGB model. Pantone Matching using the color profile provided by CMYK ensure color consistency for printing. The International Color Consortium (ICC) 6 color profile specification is used when PDF documents are printed. USE OF T HUMBNAILS PDF documents do not need embedded thumbnails. DOCUMENT NAVIGATION A table of contents (TOC), h ypertext 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 document s to link to supporting annotations, related sections, references, appendices, tables or figures that are not located on th e 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 . Using relative paths when creating hypertext links minimizes the loss of hyperlink functionality when 6

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Contains Nonbinding Recommendations 6 submissions are loaded onto network servers ; both absolute links that reference specific drives and links to root directories do not work once the submission is loaded . The document TOC helps the reviewer navigate to the information of interest within the document that is not provided in the submission table of contents. For documents with a table of co ntents, 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 fiInherit Zoom fl so the destination page displays at the same magnification level us ed in the primary document . INITIAL VIEW SETTINGS Set the Navigation Tab to open to fiBookmarks Panel and Page.fl This sets the initial doc ument view when the file is opened. If there are no bookmarks, set the Navigation Tab to fiPage Only.fl Page Layout and Magnification should be set to fiDefault.fl PAGE NUMBERING In general, it is easier to navigate through an electronic document if the p age numbers for the document and the PDF file are the same , with the initial page of the document numbered as page one. There is an exception when a document is spl it because of its size and the second or subsequent file is numbered consecutively to that of the first or preceding file. NAMING PDF FILES Use lower case characters and avoid using special characters except hyphens and underscores in file names. Special characters to avoid include punctuation , spaces, or other non -alphanumeric symbols. The current FDA validation criteria and the ICH eCTD specification both provide additional guidance on allowable special characters in file names. SPECIAL CONSIDERATIONS FOR PROMOTIONAL LABELING AND ADVERTISING MATERIAL Promotional materials submitted in PDF format may need special consideration to ensure accurate representation of the actual image. PDF restrictions for font size, color, and annotations stated in this document are not applicable to these materials. Since color varies from monitor to moni tor, it is difficult to ensure that the reviewer will see exactly the same color as in the actual image. Provide images at the highest resolution and depth practical. For photographs, the image should be obtained with a resolution of at least 600 dpi. D ocuments that are available only in paper should be scanned at resolutions that will ensure the pages are legible both on the computer monitor and when printed ; at least 600 dpi is recommended. Promotional material should be submitted according to

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Contains Nonbinding Recommendations 7 its act ual size when practical. When an image size is altered , the original dimensions must be stated . Images of three -dimensional promotional pieces must show all sides and components. Promotional materials submitted in PDF format may need special considerati on to ensure accurate representation of functionality. For example, screenshots of websites submitted in PDF format should contain links that allow the reviewer to click on them to simulate navigation in the actual website. Dynamic content such as audio, video , special effects , animations , attachments or 3D content are permitted if embedded in the PDF and playable via Adobe Acrobat X without the need for plug -ins or other special software.

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