If you’ve been hearing about eCTD 4.0 and dismissing it as “another version bump” — it’s time to pay attention. This isn’t a minor update. It’s the biggest structural change to how regulatory submissions work since eCTD was introduced.
And for growing pharma and biotech companies, how you prepare now will determine whether the transition is a competitive advantage or a painful scramble.
What’s Actually Changing
eCTD 3.x uses a DTD-based XML structure that was designed in the early 2000s. It works. It’s well understood. And it’s reaching its architectural limits.
eCTD 4.0 moves to an HL7 RPS (Regulated Product Submission) standard — a fundamentally different approach to how submissions are structured, how documents are referenced, and how lifecycle management operates.
Here’s what that means in practical terms:
Document referencing changes completely. In 3.x, documents are organized in a folder-based hierarchy. In 4.0, documents are referenced through a structured data model. This affects how your publishing tool generates submissions, how document reuse works, and how health authorities process what you send them.
Lifecycle management gets native support. Version tracking, document replacement, and submission sequencing — things that required workarounds in 3.x — become first-class capabilities in the 4.0 schema. This is genuinely good news for regulatory teams managing complex submission histories.
Metadata becomes more structured. 4.0 requires richer, more standardized metadata about documents and their relationships. If your current metadata practices are loose, the transition will force discipline — which, again, is ultimately a positive thing.
The XML schema itself is completely different. We’re not talking about adding a few new elements to existing templates. The underlying schema changes so fundamentally that publishing tools need to generate entirely different XML output. This is where vendor readiness matters enormously.
Three Things to Evaluate Now
Even if eCTD 4.0 adoption is still ramping up, the decisions you make in the next 12 months will set the trajectory. Here’s where to focus:
1. Ask Your Publishing Vendor Hard Questions
Not “are you supporting 4.0?” — every vendor will say yes. Instead, ask:
“Is your 4.0 support a retrofit on your existing architecture, or was it designed for 4.0 from the beginning?“
This distinction matters. A tool that was architected in 2005 and is being extended to handle 4.0 will carry architectural baggage. A tool built (or rebuilt) with 4.0 in mind can handle the HL7 RPS model natively, without the compromises that come from backward compatibility.
Also ask about their transition support: will they handle dual publishing (3.x and 4.0 simultaneously) during the coexistence period? How will they migrate your existing submission history?
2. Audit Your Document Reuse Architecture
eCTD 4.0 handles document reuse differently than 3.x. In the current model, reuse is often managed through file-level references in the folder structure. In 4.0, reuse is managed through the data model — meaning the way you reference a previously submitted document, update its metadata, or replace it follows new rules.
If your current content strategy relies heavily on document reuse across submissions (as it should), map out how your existing references will translate to the 4.0 model. Your publishing tool should handle this translation, but understanding the implications helps you plan.
3. Start Building Metadata Discipline Now
eCTD 4.0 is more demanding about structured metadata. Rather than waiting for the mandate, start improving your metadata practices today — consistent document classification, standardized naming conventions, complete attribute tagging. This investment pays off regardless of 4.0 timing, and it makes the eventual transition dramatically smoother.
The Transition Timeline
Health authorities are at different stages of 4.0 readiness. The FDA and EMA have both signaled their direction, but full mandatory adoption will be phased. This creates a coexistence period where some agencies accept 4.0, some still require 3.x, and some accept both.
For multi-region submitters, this coexistence period is the real challenge. Your publishing tool needs to support both formats simultaneously, potentially generating different outputs from the same source content for different health authorities.
Companies that prepare early will navigate this dual-format period efficiently. Companies that wait until mandates are enforced will be scrambling to retrofit their processes under deadline pressure.
Why This Is an Opportunity for Smaller Companies
Here’s the part that doesn’t get discussed enough: eCTD 4.0 is a great equalizer.
Large pharma companies with massive installed bases of 3.x tools and processes face an enormous migration challenge. Years of accumulated submission history, deeply embedded workflows, and change management across hundreds of regulatory professionals — that’s a multi-year, multi-million-dollar program.
A 100-person biotech with a modern, cloud-native publishing tool? The transition is fundamentally simpler. Less legacy to migrate. Fewer workflows to retrain. More agility to adopt new approaches.
If you’re choosing a regulatory technology platform right now, make eCTD 4.0 readiness a top-tier evaluation criterion — not as a checkbox, but as an architecture question. The right platform will make this transition seamless. The wrong one will make it expensive.
How DnXT Is Approaching 4.0
We’ve been building DnXT with eCTD 4.0 support as a core architectural requirement — not a retrofit. Our HL7 RPS XML generation is designed alongside our existing 3.x support, so our customers will be able to publish in both formats from the same platform as health authority requirements evolve.
We believe the companies that treat 4.0 as an opportunity rather than a burden will have a meaningful advantage in submission speed and quality. And we’re building the tools to make that possible.
Questions about eCTD 4.0 and how it affects your submission strategy? We’re happy to talk through it — no pitch required.
