The role of ICH M4Q and M16 in creating a more efficient, effective and globally aligned CMC regulatory process that can help release the potential of digitization and advanced data management technologies including artificial intelligence (AI) drew active dialogue from key thought leaders at the concluding session of the 2026 CASSS Well Characterized Biotechnology Product (WCBP) Symposium, which took place in Washington, DC in late January.

The four speakers at the session provided valuable insights into how appropriately structured and digitalized CMC data submissions enable cross-agency comparability and shared analytics, drive streamlined marketing authorization and post-approval change assessments, and expand the potential for regulatory collaboration and reliance.

The session opened with an informed talk by Gilead CMC Regulatory Affairs Executive Director Sarah Pope Miksinski, who serves as the PhRMA representative on the Expert Working Group (EWG) developing the second revision (R2) of the ICH’s quality common technical document (CTD) guideline M4Q. She described how the goal of the revision is to promote better management of the explosion in data under the rubric of quality by design (QbD) and submissions that clearly articulate the control strategy and provide “contextualized, decision-ready information supporting efficient, digital-ready CMC regulation.”

Roche Senior Director of Regulatory Policy Rodrigo Palacios, the PhRMA Topic Lead on the development of ICH M16 on “Structured Product Quality Submissions” [SPQS], then explained how M16 complements the M4Q(R2) submission structure with technical specifications and standardized data exchange formats that will streamline submission assembly and regulator evaluation and help transition the industry “toward a fully machine-readable data ecosystem.”

FDA CDER Office of Product Quality Assessment III Product Quality Team Leader Willie Wilson followed Palacios with a review of the agency’s experience with an International Coalition of Medicines Regulatory Authorities (ICMRA) collaborative post-approval change assessment pilot with which he was actively engaged. Wilson’s review of the rationale for and challenges of the collaborative assessment process shed light on the value of the M4Q/M16 efforts.

NNIT Director Kåre Hyttel then took a deeper dive into how data management architecture supported by digitalization and Fast Healthcare Interoperable Resources (FHIR) and Pharmaceutical Quality Industry (PQI) standards opens the pathway to a more efficient, empowered, globally aligned and collaborative CMC regulatory process.

The four speakers at the session on “modernizing CMC regulatory submissions” were joined for a panel discussion by South African Health Products Regulatory Authority (SAHPRA) Pharmaceutical Evaluation Manager Mphako Ratlabyana.  At a previous session at the symposium, Ratlabyana had presented on the various initiatives that SAHPRA is involved with to progress local vaccine manufacturing and quality testing and regulatory convergence and regional harmonization in support of biotech innovation in Africa.

Control Strategy Narrative Draws Spotlight in M4Q(R2)

In her presentation, Miksinski drew on her extensive experience as an FDA reviewer in describing the changing CMC landscape and the impact of QbD and ICH Q8-10 on the amount of data that reviewers have to assess – leading to the international dialogue on how to address the regulatory burdens both industry and regulators were facing as a result and make the submission and review process more efficient on both sides.

A primary focus of the M4Q(R2) initiative, she stressed, is to make a clear explication of the control strategy central to the CMC submission and, in turn, the regulatory evaluation process.

M4Q(R2) is targeting a redesigning of the CTD framework to have Module 2 tell the overall control strategy narrative, including the lifecycle management plan – with Module 3 then becoming the technical data repository, having a flexible modular structure in line with ISO’s Identification of Medicinal Products (IDMP) standards.

The potential benefits for industry, Miksinski explained, will be clearer regulatory expectations, streamlined submission preparation, and more support for lifecycle management and post-approval changes. For regulators, the rewards include improved assessment efficiency, facilitation of science and risk-based assessment, and support for global reliance and work sharing. In turn, patients will benefit from accelerated access to new medicines and the reduction in supply issues from improved product lifecycle management.

M4Q(R2) will not solve all of the problems of global convergence, she summarized, but will be a “step in the right direction” – in recognition of “the incredible importance of alignment and collaboration between regulators and industry” in addressing the global health challenges.

[CLICK HERE for Miksinski’s full remarks at the CASSS session.]

M16 Targets Unlocking the Power of Structured Data

Roche’s Palacios began by explaining the problem of the vast amount of rich CMC data now in drug applications – reflecting QbD and the new product modalities – which is “mostly in PDF, locked inside archives,” providing “no way to then use that information downstream in other processes by other people or the healthcare system.”

He then reviewed how ICH M16 in conjunction with M4Q(R2) would allow the information to be structured and formatted in submissions “to better serve the new product modalities and also better serve the future of digitalization.”

The deliverables of M16, Palacios pointed out, would include standardized templates, technical specifications, and a structured data standard through which “regulators can speak the same language and can see each other’s work,” significantly facilitating the reliance processes. 

This transformation into structured data will allow industry to assemble applications much easier and help with internal sponsor assessments of the data being submitted and ultimately global cloud-based dossiers. For regulators, the payoff is better risk analysis and more rapid decision making, and the potential for more regulatory collaboration.

Palacios concluded his remarks by affirming that the obstacles to implementation “are many,” but well worth the work needed to overcome them.

[CLICK HERE for Palacios’ full remarks at the CASSS session.]

FDA’s Wilson Reviews Learnings from Collaborative PAC Assessment

Wilson framed his review of FDA’s experience with the collaborative assessment of a PAC management protocol (PACMP) under the ICMRA pilot by pointing out the regulatory challenges of submitting and maintaining quality dossiers with numerous health authorities, complying with region-specific regulatory expectations and managing varying region-specific review processes and timelines, and explaining how the collaborative assessment of PACs will support their timely approval and implementation for the global market.

He reviewed the ICMRA collaborative assessment pilot program and companion hybrid inspection pilot and their overall goal of identifying potential areas for alignment across regulatory regions. He then focused on the first ICMRA pilot involving collaborative assessment of PACMPs, which was led by EMA with FDA serving as the “participating authority.”  

The pilot involved a PACMP to support the transfer of drug substance and drug product manufacturing and testing sites, with the goal of reaching alignment in regulatory decisions and information requests. Wilson noted that while the collaborative assessment and aligned regulatory decision making proved to be a resource intensive process, it did result in information request (IR) alignment and simultaneous approval.

In line with the previous speakers, in his concluding review of the lessons learned and future directions, Wilson emphasized the value of establishing: ● a secure document-sharing platform allowing authorities to easily gain and maintain access ● a global collaborative assessment process with harmonized milestone dates and the flexibility to accommodate region-specific requirements, and ● standardized template documents that can capture draft IRs from each health authority and their rationales and confirm alignment.

[CLICK HERE for Wilson’s full remarks at the CASSS session.]

From Document-Centered Workflow to AI-Empowered Data Analytics

NNIT’s Hyttel began by drawing an analogy between the conversion from wooden to “ironclad” ships during the American Civil War and the “seismic shift” that is now taking place to try better navigate the deep river of CMC data that is flowing between industry and regulators.

He reviewed the stakes involved with moving from a document-centric manual workflow to a FHIR and PQI-based standard in which “unstructured narrative documents become machine-readable resources” – allowing for the tracking of “every single touchpoint this data has as it moves through the organization or through the partner ecosystem.”

A FHIR-facilitated shared semantic structure, in turn, allows for the defining of “enterprise-wide validated lifecycle-governed CMC data” in domains like manufacturing, stability and specifications, upon which AI and predictive modeling can then be confidently deployed to empower the analytics.

[CLICK HERE for Hyttel’s full remarks at the CASSS session.]

Data Structuring Journey Further Explored in Panel Discussion

During the panel discussion, Hyttel responsed to a query from Amgen’s Paul Kirwan on the respective advantage of investing resources in the M4Q(R2) formatting vs. the data structuring part of the puzzle.

“What I was trying to say is that we don’t, as industry, have control over what regulators accept” in terms of formats. “What we do have control over is how we generate the stuff that they do accept.”

The winds of change, he added, “are blowing over the industry. The regulators are moving towards structured data. You can see it in FDA’s latest guidance. It will happen. It is not now a question of if. It is when.”

Both Palacios and Hyttel responded to a comment from Genentech’s Elaine Schultz on the challenges and pitfalls posed for companies at different stages of maturity along this digitalized data structuring journey.

A mindset shift is needed to realize the potential, Palacios cautioned. The roadblock may be that “this document process has been ingrained in our brains, and the first thing we go to when we think about technology is: How can we replicate the paper process but using a computer system? And I think that is a big obstacle. We need to really change the way we think.”

The potential power of the structured data approach is that “you no longer need to have everything locked in this document. It is automatically syncing up between different systems, and that is the type of thinking I think we need to apply. But it is hard.”

The transition, Hyttel commented, is an organization change management (OCM) “exercise just as much as it is a technical endeavor.”

What is needed is “executive sponsorship – ideally at the VP level and above – because the pharmaceutical organizations that I have worked with at least are political, like all the big companies are. And once you get into the cross-functional nature of these projects, there are certain dynamics that are challenging to work with.

NNIT’s job in those cases is to come in and explain that this is for the common good” – freeing up smart people from being bogged down in administrative burdens and providing “a strategic rationale for why this makes sense.”

The biomanufacturing wing of the European Federation of Pharmaceutical Industries and Associations (EFPIA) Manufacturing & Quality Expert Group (MQEG) is heavily focused on how to gain more leverage from platform technologies, prior knowledge and risk-based tools in streamlining and harmonizing the regulatory expectations for assessing comparability, specification conformance, and lifecycle management for the expanding universe of biotech products.

The issues involved in adapting regulatory processes to make them more innovation supportive across the development and manufacturing spectrum for advanced biotech therapies and vaccines were in focus at the EFPIA satellite session that preceded the October 2025 CASSS Europe CMC Strategy Forum, held in Basel, Switzerland.

At the session, representatives from the biomanufacturing team provided status updates, shared data, and outlined emerging concepts and proposals from the team’s ongoing activities.

Roche EU CMC Regulatory Policy Head Markus Goese opened the session with an overview of EFPIA’s role, structure, and current biomanufacturing and quality priorities. Five presentations followed, addressing specific pressure points in contemporary practice and providing a snapshot of selected areas of current focus within the EFPIA biomanufacturing program:

● Novartis Global Biologics & CGT Science & Technology Director Karoline Bechtold-Peters presented findings from a recent EFPIA member survey on current trends in antibody-drug conjugate (ADC) development.

● GSK Vaccines Discovery and Development Global Regulatory Lead Mihai Bilanin provided an overview of prior and platform knowledge use in the EU and how to increase regulatory support through a master file approach.

● UCB Pharma Group Lead Cyrille Chéry provided an update on the EFPIA polysorbate working group – presenting recent industry-wide findings on polysorbate degradation and the implications for product quality and safety.

● Amgen Global Regulatory Affairs CMC team member Andrew Lennard outlined the “sister sites” concept – a risk-based approach for streamlining technology transfers to new manufacturing sites.

● Bechtold-Peters then returned to the podium to provide an update on EFPIA’s work on advancing subcutaneous formulations.

The second part of the morning EFPIA session explored the CMC challenges of multispecific antibodies – including managing product- and process-related impurities, quality control and analytical methods, and the formulation – and the diverse design architectures and engineering strategies involved.

Speakers included Paul-Ehrlich-Institute’s Steffen Gross on the “challenges of multispecific antibodies from the reviewers perspective.” [For a review of the discussions on the CMC challenges and regulatory experience with bioconjugates and multispecifics that took place at the Summer 2025 CASSS CMC Strategy Forum in Gaithersburg, MD see IPQ’s August 29, 2025 Weekly Supplement and October 29, 2025 News in Depth.]

[Click HERE for the complete story.  Non-subscribers can get information on subscribing to IPQ by contacting Karen Bertani (Karen@ipq.org).]

At the September 2025 PDA Regulatory Conference held in Washington, DC, two prominent experts on FDA inspections examined why data integrity (DI) failures continue to surface across the product life cycle and what it will take to build more resilient governance systems that prevent them.

The second-day plenary session on ‘Data Integrity at the Next Level’ provided the opportunity for Live Oak Quality Assurance President and former FDA investigator Peter Baker and CDER Office of Compliance (OC) Division of Drug Quality I Director Carmelo Rosa to share their complementary perspectives. The presentations were followed by an extended Q&A, moderated by industry consultant Susan Schniepp.

Baker’s insights were informed by more than a decade of service as an FDA drug investigator and the roles he played as Assistant Country Director for Drugs in the agency’s Beijing and Delhi foreign offices.

He explored how progress on DI has been limited due to companies remaining dependent on outdated tools and checklist thinking rather than designing workflows around risk-based data governance.

Rosa then followed with a discussion of the broader regulatory context. He reviewed the DI findings in FDA warning letters from 2014 through 2025, which underscore how falsified or missing records, weak audit trails, trial testing until acceptable results emerge and superficial investigations remain stubbornly persistent despite years of guidance and remediation efforts.

These recurring failures, Rosa stressed, are linked to deeper weaknesses in firms’ data governance and quality-unit authority and a lack of meaningful oversight of both internal operations and contract manufacturers.

In line with Baker, he made clear that the root causes extend beyond procedural lapses to deeper organizational and cultural deficiencies. “Data integrity is not just a technical compliance issue but a measure of an organization’s culture,” he said, and depends on leadership commitment, accountability, and engagement from executive management through to the manufacturing floor.

During the Q&A that concluded the session, Baker and Rosa provided additional insights on: ● changing the mindset for data integrity ● DI challenges with AI ● why DI problems persist ● the problem with checklist-driven quality ● common excuses for DI failures ● rethinking ALCOA for DI governance, and ● getting leadership on board for quality culture.

[Click HERE for the complete story.  Non-subscribers can get information on subscribing to IPQ by contacting Karen Bertani (Karen@ipq.org).]