A while back, I wrote a blog post comparing TRS ToolBox with the dynamic duo of Aerialist Pharma and Acrobat for preparing regulatory submissions. Since then, a lot of you have quite reasonably asked how Aerialist Pharma and Acrobat align with the US FDA regulations themselves, rather than with other products seeking to solve the same problems. That is a fair enough question, I think, and this post is my answer to you.
There will always be a link to the most recent version of the guidelines here, but as of today, the current guidelines are here (in PDF, of course). Given the importance and stringency of the regulations, this document is surprisingly succinct, clear and simple. In the following sections, I have outlined each of the key areas mentioned, common areas of difficulty, along with the relevant functionality of Aerialist Pharma and Acrobat.
PDF Version
FDA Guidelines: The FDA accepts PDF versions 1.4 to 1.7. Specifically, submitted PDF files must be compatible with Acrobat 8.0, without requiring additional software like plug-ins.
Response: This is almost trivially easy to accomplish in Acrobat. If you haven’t originally created your PDFs using one of the acceptable versions, you can easily convert them using Acrobat’s PDF Optimizer (accessible via Save As > PDF, Optimized, click “Settings”). This conversion process can also be performed on thousands of PDF files at once using Acrobat’s Action Wizard (Tools > Action Wizard).
Security
FDA Guidelines: The guidelines stipulate that you can’t change the security on any PDFs used in your submission. Specifically, that means that you shouldn’t add security to your own documents (i.e., they should not be secured), and don’t modify the settings on the secured forms provided by the FDA (some forms are configured to prevent unauthorized changes).
Response: In general, this won’t require any action on the part of the user, since it essentially requires users to avoid changing security settings. All of this means that you might need to remove security from some of your own PDF files, which can be done in Acrobat (File > Properties, Security tab) if you have the appropriate privileges or password.
Fonts
FDA Guidelines: It’s important that your documents can be displayed consistently across machines. When a font is embedded, every glyph in that font is included in the PDF. That ensures that the PDF contains everything needed to consistently display its text content with appropriate formatting (i.e., the PDF is self-contained). Fonts that are not embedded can result in inconsistent appearance, structure, and can alter apparent meaning in some cases. This is because locally available fonts will be substituted for unembedded fonts unless the same fonts are installed on the viewing machine.
Response: Font embedding can be checked (File > Properties, navigate to Fonts tab) or completed (Tools > Print Production > Preflight) in Acrobat. Acrobat can also be used to process large batches of PDFs via its Action Wizard.
Page Orientation
FDA Guidelines: Page orientation must be such that reviewers don’t need to rotate pages. The most common manifestation of the problem is when landscape pages are not correctly oriented.
Response: This can be done easily for entire documents in Acrobat (Tools > Pages > Rotate). Acrobat allows you to select rotation angle, page range, and original orientation for rotation. This allows you to, for example, rotate all landscape pages counter-clockwise by 90 degrees. Again, the Action Wizard allows for this task to be completed in bulk.
Page Size and Margins
FDA Guidelines: Pages need to fit on a Letter (8.5″ x 11″) standard sheet and have a margin of at least 3/4″ on the left (portrait) or top (landscape) of the page, and at least 3/8″ on other sides. This allows for binding.
Response: If page sizes or margins are not sufficient to meet requirements when PDFs are originally created, these can be altered using the imposition features of Debenu PDF Aerialist Pharma (Tools > Debenu PDF Aerialist Pharma 11 > Imposition).
Source of Electronic Documents
FDA Guidelines: While not a firm requirement, this guideline recommends against the use of scanned documents. If they are used, they must be processed via Optical Character Recognition (OCR) and validated to ensure faithful, searchable text.
Response: Acrobat itself can be used to create PDF files with searchable text from any number of document formats. When working with scanned or other image-based documents, Acrobat’s built-in OCR feature (Tools > Text Recognition) can scan images to produce searchable text within documents. This can also be conducted across many files using Acrobat’s Action Wizard.
Methods for Creating PDF Document and Images
FDA Guidelines: These guidelines stipulate that grayscale and color should be used only when necessary, and that image resolution should be set to 300 dpi, except for photographs, gels and karyotypes, which require 600 dpi.
Response: As long as the original images are of sufficient quality, images can be selectively downsampled using Acrobat’s PDF Optimizer (accessible via Save As > PDF, Optimized > Settings). Individual images can also be downsampled using Acrobat’s Edit Object Tool (Tools > Print Production > Edit Object) and a suitable image editor like Photoshop.
Image Compression to Reduce File Size
FDA Guidelines: The FDA guidelines stipulate lossless compression of images. They mandate Zip (AKA Flate) for color and grayscale images, and CCITT Group 4 for black and white images (e.g., faxes).
Response: These compression techniques are supported by Acrobat. Image compression settings can be configured using Acrobat’s PDF Optimizer (accessible via Save As > PDF, Optimized > Settings).
Optimize for Fast Web View
FDA Guidelines: This option needs to be set to allow for faster opening of PDF files. This allows users or readers to download one page at a time rather than having to wait for the entire file to download before they can view the document.
Response: This option can be enabled in the (hopefully) now-familiar PDF Optimizer (see above). In the PDF Optimizer, this can be enabled by selecting the Clean Up tab and and checking “Optimize the PDF for fast web view”.
Image Color Matching
FDA Guidelines: The guidelines state that CMYK (i.e., print-based) color spaces offer more control than RGB (screen-based) ones, and that the International Color Consortium (ICC) color profile specification should be used when printing.
Response: Color matching is an extremely exacting process. While it’s possible to convert any images into an appropriate color space using Acrobat’s Print Production tools (Tools > Print Production), this will not by itself guarantee fidelity between the final document and the image creator’s intent, as the image was not created in that color space. Nevertheless, converting images into an appropriate color space can at least improve consistency between the submission as sent (i.e., post-conversion) and received (i.e., as it arrives in the reviewer’s inbox).
Despite Acrobat’s powerful capabilities here, conversion should be combined with testing and, if necessary, color correction to ensure the highest level of consistency when this is important to the submission. The better solution, of course, is to create the images using the same color space as that used in the submission version, precluding the need for conversion.
Thumbnails
FDA Guidelines and Response: These are not required for PDF submissions, or indeed any PDFs, as thumbnails can be automatically generated by viewing software.
Hypertext Linking and Bookmarks in Text and Table of Contents
FDA Guidelines: The guidelines endorse the liberal use of hyperlinks throughout PDF files to facilitate navigation within and between documents. When they are used, hyperlinks should be designated by thin rectangles or blue text. To minimize confusion, a consistent design is recommended. It is also recommended that relative rather than absolute paths are used to ensure that inter-document links are not broken when files are copied to a new location.
For documents containing tables of contents (TOCs), the guidelines state that both bookmarks and links should be created for each entry. The use of invisible rectangles and blue text is recommended to signal hyperlinks without obscuring important text. Bookmarks must be hierarchical, organized in precisely the same way as TOC entries (up to four levels deep). Finally, all links and bookmarks should be set to “Inherit Zoom” to ensure a consistent reading experience.
Response: Using Acrobat, users can manually create, edit or delete bookmarks and links (Tools > Content Editing). Acrobat can also be used to remove all links from a PDF (Tools > Document Processing > Remove All Links). Debenu PDF Aerialist Pharma adds a range of powerful options here, many of which can be used to process large batches of documents via their compatibility with Acrobat’s Action Wizard. These are set out in more detail, below.
Links
First of all, Aerialist Pharma can be used to dynamically create links based on keywords (Tools > Debenu PDF Aerialist Pharma 11 > Links > Create Keyword Links) or page numbers (Tools > Debenu PDF Aerialist Pharma 11 > Links > Create Page Links), which is ideal for adding links to an existing TOC. Links can also be imported or exported between PDFs (Tools > Debenu PDF Aerialist Pharma 11 > Links > Export/Import Links).
Aerialist Pharma can also be used to modify link properties throughout a given document (Tools > Debenu PDF Aerialist Pharma 11 > Links > Set Link(s) Properties), which can be used to modify the appearance and behavior (e.g., setting zoom level) of links to conform with FDA guidelines.
Additionally, Aerialist Pharma can selectively delete all links or just dead ones (Tools > Debenu PDF Aerialist Pharma 11 > Links > Delete Links), and features a link auditor (Tools > Debenu PDF Aerialist Pharma 11 > Links > Audit Links) that can be used to find and fix broken links and bookmarks. Aerialist Pharma’s functionality also allows users to generate reports about problem links, bookmarks, external dependencies, or simply count links (Tools > Debenu PDF Aerialist Pharma 11 > Links > Reports).
Bookmarks
Meanwhile, Aerialist Pharma also allows the dynamic creation of bookmarks based on existing TOCs or folder structure or folder structure (Tools > Debenu PDF Aerialist Pharma 11 > Bookmarks > Add Bookmarks, click Import), text formatting such as headings (Tools > Debenu PDF Aerialist Pharma 11 > Bookmarks > Build Bookmarks). Like links, bookmarks can also be imported or exported between PDFs (Tools > Debenu PDF Aerialist Pharma 11 > Bookmarks > Add Bookmarks, click Import or Export) or settings files (Tools > Debenu PDF Aerialist Pharma 11 > Bookmarks > Build Bookmarks, click Import). Aerialist Pharma can also bind separate documents, adding a shared bookmark structure to all selected documents (Tools > Debenu PDF Aerialist Pharma 11 > Bookmarks > Bind Documents).
Bookmarks can be searched (Tools > Debenu PDF Aerialist Pharma 11 > Bookmarks > Find Bookmarks), sorted (Tools > Debenu PDF Aerialist Pharma 11 > Bookmarks > Sort Bookmarks), or deleted (Tools > Debenu PDF Aerialist Pharma 11 > Bookmarks > Delete Bookmarks), and their properties can be edited in bulk using Aerialist Pharma (Tools > Debenu PDF Aerialist Pharma 11 > Bookmarks > Edit All Properties). They also benefit from the reporting, auditing and fixing options noted above for links.
Tables of Contents
Aerialist Pharma allows for the dynamic creation of document or master (i.e., inter-document) tables of contents from bookmarks, headings/text formatting, file and folder structure (Tools > Debenu PDF Aerialist Pharma 11 > Table of Contents).
Initial View Settings
FDA Guidelines: PDFs should be set to show “Bookmarks Panel and Page” unless there are no bookmarks, in which case, they should be set to “Page Only”. Default settings should be used for Page Layout and Magnification.
Response: These settings are easily accessible in Acrobat (File > Properties in the Initial View tab), and can be set for large batches of PDF files using Acrobat’s handy Action Wizard.
Page Numbering
FDA Guidelines: Page numbers should match between document and file (i.e., the initial page should be page 1) unless the submission has been split into multiple files. In this case, page numbering should match intended logical reading order without duplication. For example, if sections of the submission are separated into different files and Section 1 ends at page 10, Section 2 should commence on page 11.
Response: This can be accomplished, with different sets of options, using either Acrobat (Tools > Pages > Header & Footer) or Aerialist Pharma (Tools > Debenu PDF Aerialist Pharma 11 > Stamps).
Naming PDF Files
FDA Guidelines: These guidelines stipulate that PDF file names use lower case letters and avoid special characters aside from hyphens or underscores.
Response: While no separate application is needed to name or rename PDF files, Acrobat’s Action Wizard does allow users to add prefixes and suffixes to output file names in bulk as they are processed.
Special Considerations for Promotional Material
FDA Guidelines: These guidelines relate to the submission of promotional material. As such, they require high resolution (minimum 600 dpi), consistent color display (see Image Color Matching, above), and should be submitted according to their actual size.
Response: Again, Acrobat allows for image downsampling and color space conversion, but as noted earlier, this may not be advisable without subsequent testing. Acrobat and PDF support very large page sizes, so the requirement for size fidelity is unlikely to run up against hard size limits.
Other Concerns
Long-Term Archiving of Documents
While it is not explicitly listed in the FDA guidelines for PDF, it can also be important to archive submissions. In the case of PDF, there is are several formal standards for this, known variously as PDF/A-1 (ISO 19005-1:2005), PDF/A-2 (ISO 19005-2:2011) and PDF/A-3 (ISO 19005-3:2012).
Acrobat supports these standards admirably. Acrobat’s Preflight tools support compliance-checking and conversion to these standards via pre-configured profiles (Tools > Print Production > Preflight, expand “PDF/A compliance”).
Presentation Fidelity
It is crucial that PDF submissions are identical in appearance to their paper equivalents. This consistency ensures that no information is lost in translation. This particular point speaks most to the choice of format for submissions. PDF’s page fidelity, cross-platform compatibility and (if appropriately prepared) self-contained nature make it an ideal transfer format.
Standardization of Document Processes
Human error is a random variable that can confound even quite sophisticated processes. As a rule, standardizing procedures and reducing manual handling minimize the risk of error. The ability of Aerialist Pharma and Acrobat to automate time- and labor-intensive processes within and across documents significantly reduce manual handling and hence, the risk of human error.
Final Thoughts
In concluding, I would like to reiterate that you can meet all of your PDF compliance requirements for US FDA submissions by using a combination of Acrobat and Aerialist Pharma. Some of the FDA’s guidelines, frankly, are best met at the content creation stage (color matching and correction come to mind). Even then, Acrobat and Aerialist Pharma can help with meeting one’s compliance burden with sub-optimal source content. Used together, Acrobat and Aerialist Pharma can drastically reduce manual handling time, improve consistency and minimize the risk of human error. As a result, your submissions will be more likely to be note-perfect when initially sent. This in turn reduces the significant costs, administration and lost opportunities associated with re-submission. Given that it can form such an integral part of the workflow, it is work noting that there is a fully-functional trial version of Debenu PDF Aerialist Pharma available. For that matter, there is also a free trial of Acrobat available from Adobe’s website. Why not try them out? We’re happy to help you get set up and answer any questions you might have.
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