Fixing a broken MD5 checksum

Some eCTD publishing software comes with a tool which allows for the creation of xml files and valid MD5 checksums for eCTDs which have been published and then edited in the eCTD output folder. ISI’s eCTDXpress and eCTD Office are two publishing tools which incorporate this handy feature.

This feature is especially useful when making minor changes to the published eCTD, such as PDF file open settings, creating a new hyperlink or bookmark, etc., without the need to republish the entire eCTD in order to create the valid MD5 checksums.
Without such a tool, changes have to be made to source documents, usually within a document management system (DMS), and the entire eCTD will need to be republished.

Recently I’ve been using a publishing tool which does not include this handy function, and making these minor changes has been a needlessly annoying and time consuming task.
Fix MD5 is a useful (and importantly, free) tool for eCTD publishers who need to make small changes to an eCTD after it has been published.

Example: After QC checking a technically valid eCTD I find a document which contains an incorrect hyperlink. As I’m pushed for time I don’t want to amend the document within the DMS and republish the entire submission, so I make the change on the eCTD output drive.

The eCTD is now of course, invalid:

Running Fix MD5 will fix the broken checksums, meaning that your eCTD will become technically valid. And it takes only a matter of seconds:

1. Download and extract the Fix MD5 files onto your local computer. This only needs to be done once.

2. Open the Fix MD5 program:

3.  Click “Browse” and select the eCTD sequence folder which you wish to ‘fix’. Then click on “Fix It!” to fix the broken checksum(s):

4. That’s it! The MD5 checksums have been fixed. Run a validation report to ensure that the eCTD is completely valid:

PDF Hyperlinking within the eCTD

The use of hypertext links in eCTD submissions to aid navigation within and between PDF documents is commonplace. Along with the use of bookmarks, links can play a vital role in accelerating and facilitating the eCTD review process. Whilst an eCTD will not necessarily fail technical validation if hyperlinks aren’t created correctly, validation tools should still show errors where this is the case, reporting a failure to comply with eCTD best practice rules.

eCTD Validation Criteria v3.0 (which will come into force September of this year) states that:

            “The applicant should make every effort to address these areas [failure to comply with best practice criteria] before the eCTD is submitted to the agency.  The applicant should be prepared to include justification for any Best Practice criteria not met in the submission cover letter/reviewer's guide.”

The best practice criteria address some of the link formatting issues which any eCTD publisher will face. These will be addressed in the sections which follow.

When to link

The use of links within and between documents submitted in eCTD format is an important consideration for any submission publisher. There is no absolute rule set in stone which determines how many links should be created in any document, but the eCTD spec. v3.2.2 states that:

            “Hypertext links throughout the document to support annotations, related sections, references, appendices, tables, or figures that are not located on the same page are helpful and improve navigation efficiency.”

The purpose of hypertext links, then, is to help the reviewer navigate through and between documents, and so this should always be in the mind of the publisher. Links to sections on the same page, for example, might not help the reviewer at all, and so such linking is merely an unnecessary waste of time.

Link Properties

The properties associated with any link are governed by the eCTD validation criteria v3.0 and the eCTD specifications v3.2.2. They are as follows:

16.BP2

PDF Files

Hyperlinks within documents, or between documents within the same sequence, have a valid target

This means that each link in any PDF included as part of an eCTD submission (a single sequence) must open to a valid document, or section within a document, within that sequence. A link must not be broken. For example, if the name of a document within the eCTD changes, all links (if not corrected) directing to that particular document will break.

16.BP4

PDF Files

Hyperlinks to targets within documents in a different sequence in the same application have a valid target

As above, but this refers to links to documents which are located within a different eCTD submission belonging to the same application (i.e. with a different eCTD sequence number).

16.BP9

PDF Files

All PDF hyperlinks are relative

A link will be relative if its path recognises only the folders and files which are included in the overall eCTD structure. If the link path contains the drive name and folders which sit outside the eCTD structure, the link will break. This is because the drive and folder setup outside the eCTD folder structure will be specific to your computer, and so the agency’s computer will not be able to follow the same path.

For example:

If a link appears as follows: ..\..\..\m1\eu\10-cover\emea\emea-cover-lou then its path relates only to those folders included within the overall submission structure. It is therefore a relative link.

If however, the link path is: Mark\Submissions\calcium\0002\m1\eu\10-cover\emea\emea-cover-lou then it relates to folders (namely “Mark” and “Submissions”) which sit outside of the overall eCTD structure, and so the link will not work on the agency’s computer. This link is said to be “absolute”.

16.BP6

PDF Files

All bookmarks and links are set to "inherit zoom"

The “inherit zoom” property means that when the link is used, the reviewer’s view settings (i.e. the page zoom level) for the PDF document will not change. Some settings will change how the PDF is viewed, which could slow the reviewing process.

Link Appearance

The eCTD specifications state that a link may appear either with a thin line appearing around the text, or with the link text turned to blue:

Blue text should be used where the document has been created in a Word Processing tool such as MS Word and rendered to PDF. A thin line should be used where this is not possible, for example where a scanned document is being included in a submission (although scanned documents should undergo OCR, it may still not be possible to change the link text to blue).

How do I change the properties of my document hyperlinks?

Adobe Acrobat will let you change properties of document links, however there are numerous Adobe Acrobat third party plug-ins which will enable your submission publishers to change the properties of hyperlinks within eCTD submission documents by batch. Such applications will save hours of document publishing time. Some eCTD publishing tools will also automatically change such properties (and other document properties, e.g. document open properties) when publishing the eCTD.

If you would like any advice choosing the right software for your needs, please feel free to visit our website at www.apexregulatory.co.uk and contact us by phone or using our contact form and we’ll be glad to help.

Document Granularity within the eCTD Structure

Deciding where a document should begin and end is one of the key considerations when drafting certain documents which are to be submitted as part of an eCTD submission. For the most part, the eCTD structure allows no legroom when deciding where and how to include a document as part of an eCTD.  For example, your Cover Letter (section 1.0) and Application Form (section 1.2) cannot be submitted as one merged PDF document in either section.

In some sections of Modules 2 and 3, there is some scope to choose how to submit your documents. For example, it is possible to submit one document in 2.3 which covers all CTD sections below this level; or you may submit one document per CTD section (e.g. 2.3.S.1, 2.3.S.2…). The second approach is said to be the more “granular” approach as documents are broken down into smaller sections. Document granularity, therefore, means the level into which documents are broken down for submission. The screenshot below displays the documents which can be submitted at more than one level.

Also, it is possible to submit documents such as QP and GMP certificates separately (per certificate) or merged together.

Similarly, in Modules 4 and 5, study reports can be submitted either with all appendices attached to the study itself, or as separate documents within the same document section. The latter may be preferable in the case of documents which, when combined with annexes, would exceed the applicable size limits for individual files.

Before deciding the appropriate granularity for your documents, it’s worth considering some of the practical eCTD implications of adopting either approach.

For example - You decide to submit a complete 2.3 QoS section as one document in your initial eCTD sequence. If at some point you need to update only section 2.3.S Drug Substance, it would not be possible to submit in the new sequence only the updated Drug Substance section. This is because it’s not possible to replace a complete 2.3 with only a 2.3.S – If you were to do this, all of the other non-Substance related data (e.g. 2.3.P, 2.3.A and 2.3.R) would be deleted from the eCTD current view. You would therefore have to update the entire 2.3 document with only the changes made in 2.3.S, and replace the ‘old’ 2.3 document in the eCTD.

The real advantage to this ‘less granular’ approach is that the overall number of documents to be submitted will be kept to a minimum, improving the manageability of the CTD sections.

There are however, quite a few disadvantages to this approach…

The first major disadvantage is the potential for more linking and bookmarking in sections which have not been updated but are still submitted as part of the greater ‘complete’ document. This may well increase the time it takes to publish a submission.

Secondly (and probably most importantly), where sections will be authored by more than one individual, updating only one document could lead to possible errors or omissions and an overall delay in the authoring process.

Thirdly, this approach provides more scope for publishing error. For example, if in your initial submission you submit three QP Declarations submitted as a merged document, one of which subsequently needs to be updated, your submissions specialist will need to: be aware of which certificate has been updated, delete the old certificate within the originally submitted PDF and insert the new certificate in its place, then replace the old document in the eCTD outline. If the certificates had been submitted separately there would be no need to manipulate the documents, but only to replace the old document in the eCTD outline.

Lastly, the time it takes to review the dossier will be longer if currently approved sections are included in the eCTD dossier. The reviewer will need to know which sections have been updated, and scroll through the pages of sections which haven’t.

You should consider various things carefully before deciding which method to adopt:

Is the dossier particularly large and complex?

Is there a need for multiple Drug Product or Drug Substance sections?
How often will the dossier need to be updated?

Without considering the particulars of any individual scenario, my preferred approach is to submit documents in a more granular fashion. In this way the potential for authoring and publishing errors is kept to a minimum, and one of the overall ideals of eCTD – that the dossier should be easy to review – is achieved.

If you would like advice regarding document granularity, or any other eCTD issues, please visit us at www.apexregulatory.co.uk, contact us using our contact form, or give us a call on the number at the top of the site.

Preparing Documents for Submission

The preparation of documents for submission in CTD format can be a time consuming and arduous task. Your document authors should be well aware of the restrictions and requirements for such documents, and take care to ensure that their output remains compliant.

Some of the considerations to bear in mind are:

1. Is the document formatted correctly?

Best practice guidelines exist which regulate such things as the size and type of font used, the size of page margins, the use of headers and footers, page sizes, etc… When your documents are reviewed, are these guidelines taken into consideration as well as the document content itself?

2. Does the document follow the correct granularity guidelines?

Whilst there is flexibility regarding the granularity of documents in some CTD sections, in others there is not. Documents submitted in eCTD format cannot simply be submitted wherever and however you like – it may fail technical validation if you’re not careful. Even where there is flexibility, you should consider which is the best level of granularity to submit documents, bearing in mind eCTD lifecycle considerations. With existing eCTD applications this will largely depend upon how documents have been submitted in previous sequences. Replacing a high-level CTD document with a low level document will mean that some sections are lost from the current view.

3. Where should the document be linked?

Much of the time, the document author will have a better idea of where a document should contain a link to another document or section in order to facilitate its review. Where the document referenced was submitted in a previous lifecycle, would it be obvious to your eCTD compiler that this is the case? Consider changing the colour of text to blue in the source document to make the lives of your eCTD publishers a little easier.

There are many more considerations than those outlined above; however some of these provide common examples of how the use of document templates can greatly reduce the time it takes to create and publish documents for use in submissions. How can templates help you?

• All formatting (font size, style, margins, heading styles etc…) can be preloaded into the template. This would remove the need to format individual documents before, during or possibly even after authoring; greatly reducing the time it takes to create them, ensuring that they’re completely compliant whilst maintaining a professional and standardised style across all CTD sections and eCTD lifecyles.

• Automatic bookmarking using heading styles. It is possible to set up your templates in such a way that when converted to PDF, multilevel bookmarks are automatically generated. This can save hours when publishing submissions.

• Consistent and compliant granularity. If CTD templates are used, there will be no worrying about inconsistency of granularity when documents are authored.

If you’d like to know more about the preparation of CTD templates, and how they can benefit your authors, Apex would be happy to help. After consultation, Apex will even be able to create them for you. Please get in touch with us via our website: www.apexregulatory.co.uk. We’re also on Twitter, and LinkedIn!

How to file eCTD in MRP/DCP - One decision already made?

When filing a new eCTD using the Mutual Recognition or Decentralised Procedure, you need to be aware of the following question:

“When an application refers to multiple strengths or dosage forms, should I create one eCTD covering ALL strengths and dosage forms, or should I create one eCTD for EACH?”

This is no concern under the centralised procedure, where one eCTD will be submitted to cover all dosage forms and strengths: i.e. there’s no room for discretion.The advantages and disadvantages of both approaches are discussed in the TIGes guidance, but can be summarised as follows:

One eCTD for all forms/strengths:

Advantages
-                Common documentation, including Clinical, Nonclinical and some Quality data is provided only once.
-                Only one eCTD needs to be published (less publishing required, easier to control…etc.).

Disadvantages
-          The overall application will contain a greater number of sequences than if the eCTD is split (i.e. one sequence added per change to each and any of the forms/strengths).
-          Where some countries apply only for certain strengths, it can become confusing when tracking which countries are involved in any individual lifecycle.

One eCTD per form/strength

Advantages
-          Fewer sequences per eCTD application.
-          No confusion about which countries are involved in any individual application update.

Disadvantages
-          Common data is duplicated across different applications
-          More overall eCTD lifecycles to create and maintain (more publishing time required)

 However, following a recent publication by the Slovakian NCA (kindly Tweeted by Exalon), it’s clear that the discretionary nature of the above methods of application isn’t quite as clear cut as it may seem:

              “for each registration number in Slovakia (for each strength, each pharmaceutical form), or procedural number (MRP, DCP) to which the application relates [it] is necessary to create a separate directory…”    [emphasis my own]

Clearly there is a need either:

-          For the approved TIGes guidance to be updated, or
-          For all NCAs to understand that either filing approach is allowable.

If you’d like to know more about eCTD, please feel free to contact us via our website: www.apexregulatory.co.uk; our number’s at the top of the page, or use our Contact Form.
Also, find us on Twitter or LinkedIn!

Document Management

For my first ‘real’ post I thought I should approach the subject of document management, and more specifically, document management systems (DMS). The importance of effective document management can’t be overstated in founding and maintaining an efficient, well ordered and audit ready Regulatory department. DMSs such as SCORE or Documentum’ FirstDoc are powerful tools which primarily act as a repository for your company’s documents. But they can do so much more than this. They are designed to: interact with publishing software, enable document workflows, archive documents, provide audit trails…there are too many features to list here!  

So, what do I mean by ‘effective document management’? Well, from my experience working in a number of systems and seeing first hand the nightmares that substandard document management can cause, I would simmer it down to the following question:

                “Although I can find and use this document, could my
                                    successor or theirs…!?”

 At the lowest, most practical level, this really is the most important question to ask – everything else for now can wait. The ability to find and use documents efficiently underpins everything good document management practice is all about. Hours can be wasted searching for important documents in a DMS which, inevitably, were authored by someone no longer at the company and need to be located for an important Variation or possibly even worse, for audit purposes. I know, because I’ve been there.

I’ll address some of the usual pitfalls below…

• Are your colleagues even using the system?

If one thing’s for sure it’s this – if your documents aren’t even in your DMS, nobody will be able to find them within it. That’s a fairly obvious statement of fact. I’ve had people send me documents by email, or even on a portable hard drive in order to avoid having to upload important submission documents into a DMS [I’ll come to this again later]. This means that should anyone else need to cover for me, or replace me and my colleague on a permanent basis, it would be as if the document had never existed. Vanished for all eternity. A DMS can be an expensive tool, it’s probably a good idea to use it.

• How are you naming your documents?

The most important piece of metadata associated with a document is, of course, its name. It’s the most obvious way of differentiating between documents in any folder, but more than that, it should be used to tell you what the document actually is. Document names such as “Document 1” or “Appendix 2” give you very little idea about what you’re going to see when you open it up. A good naming convention could contain some or all of the following:

CTD Number or name: 1.2 Application Form

Product and/or INN name: Wonderdrug (amazingsubstance)
The date it was drafted: 03 June 2011

Simple things like naming conventions can dramatically reduce the time spent searching for documents.

• How are you organising your documents?

One of the most important features of any DMS is its folder structure. A typical DMS will file all of your products into so called ‘Cabinets’ but then the way in which folders are arranged below this level is mostly up to you. It’s a good idea to keep documents from different lines completely separate. Clinical, Nonclinical, CMC…etc. should all have their own areas of the DMS in which to operate. Within these areas it would be a good idea to use a folder hierarchy to keep documents separate. Break the structure down into a low level; for example a folder for each CTD section. Finding a file in a folder containing 5 documents is much easier than finding a file in a folder containing 500. It’s much easier to navigate a well designed folder structure than search through pages and pages of files.

• Are your staff well trained with access to well drafted user guides?

Keeping your staff trained, with access to well drafted training guides is absolutely critical to maintaining high standards of document management. A brand new DMS can be a daunting prospect for document authors, so make sure that they have the confidence to use it, and the ability to find help when they need it. If they don’t have this, they’ll either make mistakes or avoid using the system altogether (and who could blame them?). Remember, the DMS is only as useful as you make it.

 

These are but a few of the issues to consider when thinking about and implementing a DMS; I’ve only addressed a small number. If you need any advice on finding the right DMS for your company, or need help establishing processes please do get in touch with us via our website www.apexregulatory.co.uk and we’d be glad to help you take those all important next steps.

First Post!

Welcome to our blog! Apex Regulatory specialise in all things to do with Regulatory Operations. We'll use this blog from time to time to share updates and helpful snippets which will hopefully shed some light on our world. eCTD creation, document formatting and best practice for document storage - a few of the topics you can expect us to explain and (hopefully) help you with.

We do offer a professional publishing and consultancy service, so if this is something you require please have a look at our website (http://www.apexregulatory.co.uk/) and feel free to get in touch!

Apex