How Does 21 CFR Part 11 Compliance Apply to eCTD Publishing Tools

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In my document management career, my company provided specialized EDMS solutions for Pharma (for submissions, SOPs, trial master files, etc.). It was a given that these systems needed to be Part 11 compliant, and I authored our position paper on how Part 11 compliance was achieved and demonstrated in our product. If our product had ever been viewed as being noncompliant, no one would buy it – end of story.

For whatever reason, few sponsors seemed to apply that same requirement to their publishing vendors. Back in the days of paper submissions, this didn’t seem too unreasonable. After all, the FDA says in Guidance for Industry: Part 11, Electronic Records; Electronic Signatures — Scope and Application”:

“Under the narrow interpretation of the scope of part 11, with respect to records required to be maintained under predicate rules or submitted to FDA, when persons choose to use records in electronic format in place of paper format, part 11 would apply. On the other hand, when persons use computers to generate paper printouts of electronic records, and those paper records meet all the requirements of the applicable predicate rules and persons rely on the paper records to perform their regulated activities, FDA would generally not consider persons to be “using electronic records in lieu of paper records…”

But eCTDs don’t meet these criteria. By definition, when you submit an eCTD you are asking the government to accept “in electronic format in place of paper”- and as part of the conditions of acceptance, they state that “Electronic documents that bypass the controls for electronic files described in 21 CFR 11 are not considered official documents for review.” (see Guidance for Industry: Providing Regulatory Submissions in Electronic Format — General Considerations.”)

Despite this, I don’t hear a lot of talk about Part 11 and publishing tools. Vendors don’t post much on their websites about Part 11 compliance (and what they have often applies more to document management). Googling Part 11 and electronic publishing doesn’t return anything useful.

So where does that leave sponsors in terms of the need for compliance? Granted that in these days of McNeil plant closures, tainted heparin, accusations of suppressed safety data, and etc., it seems unlikely that the FDA’s risk-based approach to inspections and audits will result in scrutiny of sponsors’ publishing systems. But sponsors certainly don’t intend to entirely flout requirements or fail to follow good practices. It would be interesting to define what the essential elements of compliance and good practices are.

Some areas are straightforward. Most people would agree that their publishing tools should have limited access and operational controls to prevent errors. But other areas aren’t so clear. To add to the ambiguity, in the Scope and Application document, the FDA announced its decision to exercise “enforcement discretion”, specifically lack of intention to take enforcement action to enforce compliance with the validation, audit trail, record retention, and record copying requirements of Part 11.

Audit trail almost always remains one of the most complicated issues for electronic systems – so given the “enforcement discretion” what needs to be audit trailed in a publishing system?

As a reminder, Part 11 applies to “Records that are required to be maintained under predicate rule requirements and that are maintained in electronic format in place of paper format.” In the document management world, almost everyone interprets this as meaning that draft documents do not require an audit trail, as you aren’t required to create or retain them at all in most cases. When you are publishing, everything is a draft, right up until you lock things down and send them through the gateway. When you are working on a sequence, if you add a specification, then remove it, is an audit trail needed? If so, is it because Part 11 requires it, or because the sponsor wants an “electronic watchdog” reporting on who made changes to the submission prior to finalization?

Many other Part 11 requirements should be important to the sponsor regardless of whether they are subject to inspection. I would want my electronic publishing system to be installed in accordance with an IQ protocol and validated with an OQ and PQ protocol regardless of whether they FDA requires this or not, because incorrect installation or operation could have a profound impact on my submission quality or timeliness.

I would be interested in hearing from my readers on this subject. Do you disagree with the assessment that Part 11 applies to publishing software? What do you consider the necessary elements for Part 11 compliance for your publishing tool? Is Part 11 the “elephant in the room” that no one will acknowledge related to publishing software, or addressed by following basic good practices?

Author: GS

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