Countdown to M4Q(R2): ICH Prepares For Quality’s Digital Future

Twenty years ago, the ICH took a key step toward future-proof regulatory pathways

Flash back to 2001. Destiny’s Child and Staind were topping the charts. Y2K had come and gone, and somehow all our clocks still worked. 

For the drug development industry, though, the early Naughties were all about adopting the Common Technical Document (CTD). Seasoned veterans well remember the complex but invaluable process of harmonizing their submission and registration processes – and the timely arrival of ICH M4Q.  

After the launch of the CTD, drug developers and regulators were both debating the “right” way to bridge the story of a new therapy from the summaries in Module 2 to the body of data in Module 3. M4Q delivered a much-needed dose of clarity, establishing a harmonized approach to structuring and formatting quality information in both modules.

But as Beyoncé, Solange, and Aaron Lewis can all tell you, a lot has changed since then. 

In the twenty years since M4Q, the global therapeutic pipeline has been revolutionized by new scientific breakthroughs unheard of at the turn of the millennium. The ICH adopted six new guidelines. And a wave of digital transformation finally gathered momentum across the pharma and biotech industries – bringing it to the threshold of a new era in high-performance drug development

Fortunately, when it comes to managing these vital quality guidelines, the ICH has already shown clear and timely foresight. In a 2021 concept paper, they laid out their vision for modernizing M4Q – and how the guideline updates will help both regulators and drug developers unlock the full potential of today’s scientific and digital innovations. 

Now, at the threshold of M4Q(R2), it’s a good time to take stock of what the revisions will mean for tomorrow’s CMC programs. Welcome advances await. But capturing them will take some purposeful effort.

M4Q(R2) zeroes in on key industry challenges.

In their concept paper, the ICH highlights multiple revision drivers that came as no surprise to forward-thinking drug developers. Complex new product classes have emerged, from antibody-drug conjugates to mRNA vaccines, cell-and-gene therapies, and beyond. Data management practices have evolved alongside a new generation of digital tools designed to tap exponentially expanding lakes of life science data.

At the threshold of M4Q(R2), it’s a good time to take stock of what the revisions will mean for tomorrow’s CMC programs. Welcome advances await. But capturing them will take some purposeful effort.

But perhaps just as importantly, the industry also still faces the shopworn challenge of “organizing product and manufacturing information” in a “suitable format for easy access, analysis, and knowledge management.” 

M4Q(R2) zeroes in on several much-needed areas of improvement:

  • Using prior knowledge more effectively: Drug developers need stronger, more consistent frameworks for mapping accumulated process data to related product quality risks.
  • Creating more robust control strategies: The “backbone of the revised M4Q structure,” these critical assets need clearer links between the Quality Target Product Profile (QTPP), the manufacturing process, “elements of the product and process development and understanding,” and an overall quality protection strategy.
  • Streamlining regulatory submissions: The “efficiency and effectiveness of regulatory submissions and assessments” remains an industry pain point, one that M4Q(R2) aims to address by enhancing Module 2 of the CTD. 
  • Unlocking new technological advances: For the industry to integrate “emerging concepts” like advanced manufacturing and artificial intelligence, it first needs to address its long-lagging digital maturity – a goal M4Q(R2) aims to accelerate.

To help the industry achieve these goals, M4Q(R2) promises a substantial revision of the CTD Modules 2 and 3 – one that will help drug developers modernize the way they capture quality-related registrational and lifecycle management information. As the ICH alludes, this could have a transformative impact on the rate at which new therapies can be developed and delivered to patients – primarily by improving submission and assessment efficiency. 

We LOVE it. So how do we get there? 

The 6Es: Mapping a path to the goals of M4Q(R2)

For Regulatory and Quality stakeholders, this particular guideline update holds especially great promise for future CMC programs. Tucked in the ICH’s proposal is a vision for standardized, harmonized, and streamlined regulatory processes that help speed new therapies to patients. 

The Council picks out 6 specific objectives they aim to achieve with these revisions:

  1. Encouraging convergence of science and integrated risk-based approaches to regulatory dossier prep.
  2. Explaining and defining how quality information should be organized and positioned in Modules 2 and 3.
  3. Enriching regulator-applicant communication, especially by enhancing lifecycle and knowledge management.
  4. Embracing product and process innovation.
  5. Enabling efficient use of digital tools for submission and assessment, in preparation for the ICH’s upcoming guideline on structured quality submissions.
  6. Elucidating regulatory expectations and supporting efficient assessments, decision-making, and actions.


At QbDVision, of course, we fully support every one of these objectives. But with the first iteration of MQR(R2) on the way – public consultation may start as early as Q4 2023 – we also think it’s time for Quality and Regulatory teams to take a step past vision and start thinking about alignment and implementation. 

  • What kind of process evolutions, workflow shifts, and review methods do these revisions and goals infer? 
  • And perhaps just as importantly, what kind of modernized technological toolkit will be needed in tomorrow’s ICH-compliant CMC programs?

Well, we have some ideas about that.

With the first iteration of MQR(R2) on the way – public consultation may start as early as Q4 2023 – it’s time for Quality and Regulatory teams to take a step past vision and start thinking about alignment and implementation.

M4Q(R2) – both its drivers and its goals – puts our industry on much-needed notice. In no uncertain terms, the ICH has announced that compliant CTDs and eCTDs will soon assume – not encourage – that applicants have a well-structured knowledge framework in place for their quality data. The message is clear: “improving submission and assessment efficiency” means casting off from narrative PDFs and setting sail for digital-first submissions. Not just at registration, but for PACM and life cycle evolution too. 

And looking at the timeline to acceptance of M4Q(R2), regulatory winds will blow drug developers to those shores much sooner than later. Now’s the time to start thinking about what kind of knowledge management methods and data frameworks that need to be in place when M4Q(R2) redefines expectations for Modules 2 and 3.

Modernizing knowledge management: The path to tomorrow’s submissions leads to Digital CMC

At the heart of ICH’s vision for M4Q(R2) is a clear assumption that digital tools and data-driven processes are the future of pharmaceutical regulatory submissions. That’s no surprise for industry observers watching waves of transformation that are already crashing into today’s drug development enterprise.

But for many Quality and Regulatory teams, these revisions will likely turn years of gentle nudging into a firm and unmistakable shove – away from a legacy of document-centric processes and into a future of digitally native regulatory pathways. As several experts pointed out at last year’s Digital CMC Summit, that transition is very much a work in progress for many CMC programs across the industry. But it’s one that’s very much due for acceleration.

In no uncertain terms, the ICH has announced that compliant CTDs and eCTDs will soon assume – not encourage – that applicants have a well-structured knowledge framework in place for their quality data.

Luckily, those programs already have numerous strong leads to follow as they consider their compliance strategies for M4Q(R2): So as the industry moves past “when,” and starts digging into “how,” many innovative, transformation-focused teams are already paving the way to success. But as the path becomes increasingly clear, an important new question comes next: which partners will help you reach the goals or M4Q(R2)?

How to start building transformation momentum today

As the ICH admits, finalizing and implementing M4Q(R2) will take “a significant effort” – but one that’s well worth it given the vast potential upsides for patients, consumers, industry, and regulators alike. 

What will that effort look like? That’s where there’s much more interesting work to be done. 

While the ICH notes that “the structured pharmaceutical quality submission is beyond the scope of M4Q(R2),” the ultimate goal is clear – this guideline is a stepping stone toward fully unified, consistently structured, globally implemented submission and registration frameworks. The rubber hits the road when we ask: what will that structure look like? And how will drug developers adopt and deliver it? 

Well, we think we have some pretty good answers to those questions – and if you’re interested in the power and potential of modernizing your CMC data resources, let’s talk. We’d love to share how our solution can help solve some of drug developers biggest knowledge management challenges, and how tools like our Technical Report Builder are already helping users automate development of key CTD modules and shave weeks off their reporting timelines.

Reach out to our team any time, and we’ll be happy to share our excitement about the promise of M4Q(R2), and how we can help you pave the way to efficient, digital-first regulatory submissions.


See what Digital CMC can deliver for your program.

Reach out to our team of experts to learn more about how to prepare for M4Q(R2), and how QbDVision can help automate and accelerate key compliance steps.

Shameek Ray

Head of Quality Manufacturing Informatics, Zifo

Shameek Ray is the Head of Quality Manufacturing Informatics and Zifo and has extensive experience in implementing laboratory informatics and automation for life sciences, forensics, consumer goods, chemicals, food and beverage, and crop science industries. With his background in services, consulting, and product management, he has helped numerous labs embark on their digital transformation journey.

Max Peterson​

Lab Data Automation Practice Manager, Zifo

Max Petersen is the Lab Data Automation Practice Manager at Zifo responsible for developing strategy for their Lab Data Automation Solution (LDAS) offerings. He has over 20 years of experience in informatics and simulation technologies in life sciences, chemicals, and materials applications.

Michael Stapleton

Board Advisor, QbDVision

Michael Stapleton is a life sciences leader with success spanning leadership roles in software, consumables, instruments, services, consulting, and pharmaceuticals. He is a constant innovator, optimist, influencer, and digital thought leader identifying the next strategic challenge in life sciences, executing and operationalizing on high impact strategic plans to drive growth.

Matthew Schulze

Head of Digital Pioneering Medicines & Regulatory Systems, Flagship Pioneering

Matt Schulze is currently leading Digital for Pioneering Medicines which is focused on conceiving and developing a unique portfolio of life-changing treatments for patients by leveraging the innovative scientific platforms and technologies within the ecosystem of Flagship Pioneering companies.

Daniel Matlis

Founder and President, Axendia

Daniel R. Matlis is the Founder and President of Axendia, an analyst firm providing trusted advice to life science executives on business, technology, and regulatory issues. He has three decades of industry experience spanning all life science and is an active contributor to FDA’s Case for Quality Initiative. Dan is also a member of the FDA’s advisory council on modeling, simulation, and in-silico clinical trials and co-chaired the Product Quality Outcomes Analytics initiative with agency officials.

Kir Henrici

CEO, The Henrici Group

Kir is a life science consultant working domestically and internationally for over 12 years in support of quality and compliance for pharma and biotech. Her deep belief in adopting digital technology and data analytics as the foundation for business excellence and life science innovation has made her a key member of PDA and ISPE – she currently serves on the PDA Regulatory Affairs/Quality Advisory Board

Oliver Hesse

VP & Head of Biotech Data Science & Digitalization, Bayer Pharmaceuticals

Oliver Hesse is the current VP & Head of Biotech Data Science & Digitalization for Bayer, based in Berkeley, California. He has a degree in Biotechnology from TU Berlin and started his career in a Biotech start-up in Germany before joining Bayer in 2008 to work on automation, digitalization, and the application of data science in the biopharmaceutical industry.

John Maguire

Director of Manufacturing Sciences, Sanofi mRNA Center of Excellence

With over 18 years of process engineering experience, John is an expert in the application of process engineering and operational technology in support of the production of life science therapeutics. His work includes plant capability analysis, functional specification development, and the start-up of drug substance manufacturing facilities in Ireland and the United States.

Chris Kopinski

Business Development Executive, Life Sciences and Healthcare at AWS

As a Business Development Executive at Amazon Web Services, Chris leads teams focused on tackling customer problems through digital transformation. This experience includes leading business process intelligence and data science programs within the global technology organizations and improving outcomes through data-driven development practices.

Tim Adkins

Digital Life Science Operations, ZÆTHER

Tim Adkins is a Director of Digital Life Sciences Operations at ZÆTHER, serving the life science industry by assisting companies reach their desired business outcomes through digital IT/OT solutions. He has 30 years of industry experience as an IT/OT leader in global operational improvements and support, manufacturing system design, and implementation programs.

Blake Hotz

Manufacturing Sciences Data Manager, Sanofi

At Sanofi’s mRNA Center of Excellence, Blake Hotz focuses on developing data ingestion and cleaning workflows using digital tools. He has over 5 years of experience in biotech and holds degrees in Chemical Engineering (B.S.) and Biomedical Engineering (M.S.) from Tufts University.

Anthony DeBiase

Offering Manager, Rockwell Automation

Anthony has over 14 years of experience in the life science industry focusing on process development, operational technology (OT) implementation, technology transfer, CMC and cGMP manufacturing in biologics, cell therapies, and regenerative medicine.

Andy Zheng

Data Solution Architect, ZÆTHER

Andy Zheng is a Data Solution Architect at ZÆTHER who strives to grow and develop cutting-edge solutions in industrial automation and life science. His years of experience within the software automation field focused on bringing innovative solutions to customers which improve process efficiency.

Sue Plant

Phorum Director, Regulatory CMC, Biophorum

Sue Plant is the Phorum Director of Regulatory CMC at BioPhorum, a leading network of biopharmaceutical organizations that aims to connect, collaborate, and accelerate innovation. With over 20 years of experience in life sciences, regulatory, and technology, she focuses on improving access to medicines through innovation in the regulatory ecosystem.

Yash Sabharwal​

President & CEO, QbDVision

Yash Sabharwal is an accomplished inventor, entrepreneur, and executive specializing in the funding and growth of early-stage technology companies focused on life science applications. He has started 3 companies and successfully exited his last two, bringing a wealth of strategic and tactical experience to the team.

Joschka Buyel

Process & Knowledge Management Scientist, Bayer Pharmaceuticals | Ph.D., Drug Science

Joschka is responsible for the rollout and integration of QbDVision at Bayer Pharmaceuticals. He previously worked on various late-stage projects as a Quality-by-Design Expert for Product & Process Characterization, Process Validation, and Transfers. Joschka has a Ph.D. in Drug Sciences from Bonn University and a M.S. and B.S. in Molecular and Applied Biotechnology from the RWTH University.

Luke Guerrero

COO, QbDVision

A veteran technologist and company leader with a global CV, Luke currently oversees the core business operations across QbDVision and its teams. Before joining QbDVision, he developed, grew, and led key practices for international agency Brand Networks, and spent six years deploying technology and business strategies for PricewaterhouseCoopers’ CIO Advisory consulting unit.

Gloria Gadea Lopez

Head of Global Consultancy, Business Platforms | Ph.D., Biosystems Engineering

Gloria Gadea-Lopez is the Head of Global Consultancy at Business Platforms. Using her prior extensive experience in the biopharmaceutical industry, she supports companies in developing strategies and delivering digital systems for successful operations. She holds degrees in Chemical Engineering, Food Science (M.S.), and Biosystems Engineering (Ph.D.)

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