TL/DR:
- In its full draft form, M4Q(R2) is a comprehensive update that explicitly covers all modern therapeutic modalities and establishes a new framework for CMC data supporting submissions across the product lifecycle.
- While final adoption has been delayed to mid-2027, the implications are already clear: Granular, structured, interlinked quality data in a QbD framework will now be mandated in the CTD.
- The update also further embeds ICH Q12 principles into the CTD, especially Module 2 — which must now be modular and cross-linked for efficient life-cycle evolution.
- The legacy “Quality Overview” will now be reconfigured into 6 structured sections that must be fully interlinked with defined control and lifecycle management strategies.
- New expectations are also set for Module 3, which must follow a uniform Description–Manufacture–Control–Storage (DMCS) template with explicit cross-references to Module 2.
First impressions: M4Q(R2) puts Digital CMC at the core of the CTD.
At last, it’s official: With M4Q(R2), Quality by Design (QbD) principles, structured CMC knowledge, and lifecycle management have now been formally endorsed within ICH guidelines. It’s a pivotal shift in regulatory expectations for chemistry, manufacturing, and controls (CMC) submissions.
This new framework directly emphasizes the importance of several fundamental QbD assets, including a well-defined Quality Target Product Profile (QTPP), clear and traceable links to Critical Quality Attributes (CQAs), and an overarching control strategy. What’s more, supporting knowledge and data must now be systematically organized to facilitate ongoing lifecycle management, transforming regulatory submissions from static documents into dynamic, knowledge-driven assets.
Long, long ago, in 2023(!!), our team placed a few bets on what we expected to see in the fully drafted version of M4Q(R2). Now that the full draft is available, it’s clear that the ICH is thinking even bigger than we anticipated: the “real” M4Q(R2) is a sweeping overhaul of the CMC framework, embedding QbD, ICH Q12, and many more Digital CMC principles in a key regulatory pathway.
Let’s have a look at the big reveals in those complete draft guidelines, and what they’ll likely mean for the Digital CMC movement.
What is M4Q(R2)?
M4Q(R2) is the upcoming second revision of the ICH M4 Quality CTD guideline. It establishes a new and modernized structure for the quality information required in the registration applications of all medicinal products for human use, effectively updating how sponsors organize and submit CMC data across the product lifecycles.
What is the Common Technical Document (CTD)?
The CTD is the ICH’s standardized format for submitting pharmaceutical product information to regulatory authorities in major global markets. It organizes that data into five modules—including quality, safety, and efficacy—to streamline the drug approval process across regions.
So, how exactly would the current M4Q(R2) impact CMC workflows?
The current draft introduces several notable developments in the CMC domain. The circulating version is a draft, of course: the final rules could see substantial changes before they’re approved and implemented.
But even with this work-in-progress version, we can already see that some big, meaningful changes are coming to the CTD — and not just for novel therapies, “complex” molecules, and groundbreaking modalities either. M4Q(R2) applies to “all pharmaceutical drug substances and products (both chemical and biological) that require a marketing authorization.”
Net/net, the current draft would make M4Q(R2) the central organizing framework for all CMC quality data globally, for all submission types — from initial NDAs/BLAs to supplements, comparability studies, standalone master files, and more. Here are a few critical updates we predicted the ICH would include, and that feature prominently in the draft guidelines:
- A data structure requirement: While the draft doesn’t go so far as to dictate file formats, it definitely requires applicants to submit their CMC data in a robustly structured format. And it does so with the explicit purpose of facilitating digital submissions, AI/ML compatibility, easy data extraction, and knowledge management.
- A lifecycle management mandate: Revisions to Module 2 would embed ICH Q12 even deeper in the regulatory approval process. The current working version would require CTD submissions to arrive optimized for efficient, flexible evolution, enabled by purposefully organized knowledge in scalable submission and dossier structures.
- A demand for fully dimensionalized, traceable data lineage: The current draft also calls for rich, detailed interlinking between the updated Module 2 and Module 3. It’s a clear indication that regulators now expect detailed visibility into both the decisions and conclusions that shape each submission, as well as the data that support them.
The draft guidance also delivers another significant advance in Digital CMC implementation: it mandates a CTD that’s deliberately granular and digital-friendly.
In M4Q(R2), we finally see guidance promoting a “globally harmonized format with sufficient granularity to facilitate digitalisation” and directing applicants to organize data for “easy access, analysis, and knowledge management”. The guidelines even call out advanced manufacturing, structured data processes, and AI/ML as targets.
(Sound familiar? You might have heard a lot of this at the Digital CMC Summit!)
That’s a lot of game-changing updates in one document, though, so it’s small wonder the ICH pushed final signoff to mid-2027. These are major modifications that will require industry input and global buy-in.
Among the most impactful elements for Digital CMC: The proposed updates to Module 2.3 and Module 3. These sections warrant close examination as the industry prepares for the transition.
The draft guidance also delivers another significant advance in Digital CMC implementation: it mandates a CTD that’s deliberately granular and digital-friendly.
Module 2.3 revamped: Control strategy, core CMC data & lifecycle
If your organization is still on the fence about Digital CMC — or maybe inching its way toward transformation one pilot at a time — take a moment, sit down, and have a good look at the brand-new layout of Module 2.3, the “Quality Overall Summary.”
If you’ve been on the CMC frontlines for a while, you know this section all too well: It’s infamously taxing to consolidate and an ancient foe in the battle against static, unstructured data locked away in documents. Now, M4Q(R2) aims to divide that narrative into a structure of six distinct subsections, 2.3.1 through 2.3.6, each with its own discrete purpose. But three of them are especially important for Digital CMC.
2.3.2 “Overall Development and Control Strategy”
This key section now requires a high-level product overview tied to the QbD framework, with defined links between patient-focused attributes (QTPP) and a control plan. Sponsors must list the QTPP and CQAs together, outline the development strategy, and explicitly show how each control strategy element contributes to the Overall Control Strategy.
By itself, this one change makes it dramatically more important for drug developers to have a robust, structured framework for managing these interconnected properties.
2.3.3 “Core Quality Information (CQI)”
The CQI subsection is entirely new and establishes the authoritative source for a product’s “quality dataset,” from day 1 through post-approval. By these draft rules, all that data — process parameters, specification rationales, stability data, and more — must now be presented in a dedicated, machine-readable format.
The guidance even says the CQI must be kept current throughout the product’s life, and when ICH Q12 Established Conditions are defined, the relevant lifecycle activities should align with a formal PLCM document in 2.3.5.
Speaking of which…
2.3.5 “Product Life Cycle Management”
PLCM is an entirely new subsection and establishes the authoritative source for a product’s “quality dataset,” from day 1 through post-approval. By these draft rules, all that data — process parameters, specification rationales, stability data, and more — must now be presented in a dedicated, machine-readable format.
Together, these updates mean one thing: Drug developers can no longer rely on unstructured, moment-in-time quality narratives with no plan for future evolution. Instead, under M4Q(R2), every development narrative, control strategy, and change rationale in 2.3 must directly link to supporting data in Module 3 — where the instructions emphasize that each subsection must be “in support of information provided in 2.3”.
In other words, your Module 2 story must match your Module 3 data — no gaps, no mysteries. Here’s what’s changing in that subsequent supporting section.
Module 3 Reboot: Goodbye Data Dumping, Hello “DMCS”
Long a notorious pool of just-organized-enough datasets, Module 3 is getting an equally thorough makeover. Gone is the “kitchen sink” data appendix. Instead, M4Q(R2) imposes a uniform template for every component based on the familiar “Description – Manufacture – Control – Storage” (DMCS) structure:
- 3.2.DS.D (drug substance description) requires applicants to define a data structure and multiple key properties
- 3.2.DS.M (manufacture) demands a detailed, step-by-step process description
- 3.2.DS.C (control) calls for much-needed granularity in specifications and batch analysis
- 3.2.DS.S (storage) updates data representation requirements for stability and shelf life.
This same DMCS format repeats for excipients, drug product, etc., ensuring every piece of data falls into one of those categories.
Beyond consistency, the Module 3 updates also enforce clarity and machine-readable crawlability, breaking data into a consistent structure that regulators — as well as algorithms and agents — can more easily find and interpret. The guidelines also make it clear that Module 3 cannot be static and isolated: The data it houses must explicitly link to and support justifications in Module 2.3, and must also be organized in a structure that streamlines major updates while keeping the CQI consistent.
The message is clear: the CTD is evolving into a fully integrated framework, with the regulatory expectation that Modules 2 and 3 will be tightly aligned under a Quality by Design (QbD) paradigm. Under M4Q(R2), Module 3 will be a data dumping ground no more — it will become a modern data warehouse with a structured, cross-referencable framework that’s optimized for flexible lifecycle management and digital innovation.
Beyond consistency, the Module 3 updates also enforce clarity and machine-readable crawlability, breaking data into a consistent structure that regulators — as well as algorithms and agents — can more easily find and interpret.
Comprehensive as it is, M4Q(R2) leaves a few threads loose
As promising as the Module 2 and Module 3 updates may be, I came away from my review with a few unresolved questions. It will be important to watch the public comment period closely, as further clarification and stakeholder perspectives emerge. But I have two big questions already:
Will there be a “universal” eCTD format?
Regulatory experts have been on the lookout for structural harmonization for a while now, but M4Q(R2) doesn’t take us all the way there. It certainly lays groundwork for digital submissions — there’s heavy emphasis on granular, machine-readable data, which sounds like preparing for a structured eCTD — but it stops short of mandating a new file standard.
Will ICH follow up with a formal global eCTD standard? The hints are there. But for now, the guidance “just about” mandates much-needed structure that each applicant can define.
How feasible is that finalization window?
Big changes, big timeline. The draft has kicked final approval out to 2027. Two years of public consultation lie ahead, with comments due by October 2025. Even then, will that be enough to finalize such a transformative guideline? Stakeholders should be realistic: harmonizing globally on new structural requirements is a lengthy process.
Watch closely to see if ICH needs to extend or split efforts.
No matter what the answers turn out to be, these new guidelines will undoubtedly mark a major milestone in the development of a truly modern regulatory pathway for biopharma products. As many experts have said from the stage at the Digital CMC Summit, that’s a goal our industry can’t reach fast enough. With these timely updates to M4Q(R2), we can hopefully achieve it even sooner.
So what’s next for the draft of M4Q(R2)?
The clock is now officially ticking on the public comment period. If you’re a CMC leader, this is your chance to review the details carefully, feed back any practical concerns, and help steer the final guidance. After all, what else could you be doing on your summer vacation??
But while industry stakeholders still have the opportunity to shape the final rules, it’s already clear that the bar will be raised for the next generation of regulatory submissions. These draft guidelines make the mandate clear: modernize now, or risk being unprepared for critical future milestones.
That will be a substantial task for many drug developers. Hopefully, though, this new reality will inspire CMC stakeholders to spend the comment period doing more than logging their feedback. Now’s the time to prepare for the new future the ICH has just laid out, and to start investing in the robust digital CMC infrastructure programs need to prepare for compliance.
We’re ready when you are.
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