Finding a Path to Unified CMC
Managing CMC dossiers across multiple regions presents ongoing operational complexities, requiring sponsors to balance country-specific expectations with long-term commercial goals.
During the past few decades, the International Council for Harmonisation (ICH) has made strides toward aligning technical and scientific standards across global pharmaceutical markets. Despite these efforts, global harmonization for chemistry, manufacturing, and controls (CMC) remains a work in progress as each sovereign health authority interprets guidance through regional lenses.
As a result of this regulatory divergence, bio/pharma companies seeking global access are often required to develop multiple versions of CMC dossiers to satisfy local regulatory demands. To find out more about where drug developers experience the greatest CMC friction, the practical limits of mutual recognition agreements (MRAs), and how digital CMC standards could shape the future, The Pharma Navigator spoke with Mark Macdonald, Technical Sales Director, Codis.
Navigating Friction Points
TPN: While ICH guidelines have established a foundation for regulatory alignment, true global CMC harmonization remains an ongoing challenge. From an operational perspective, where are drug developers experiencing the most friction when managing global CMC dossiers today?
Macdonald: That is certainly correct. While the ICH has done exceptional work over several decades to align and harmonize global regulatory standards, individual sovereign regulators such as the FDA, EMA, MHRA, and PMDA retain ultimate legal authority for interpreting and enforcing requirements within their respective jurisdictions. As a result, region-specific requirements and differing interpretations of globally harmonized guidance can still lead to regulatory divergence.
This is often most evident in areas such as post-approval change management, country-specific stability requirements, differing expectations around comparability and control strategies, and variations in review and approval timelines for CMC changes.
In practice, this [variance] can require drug developers to maintain multiple versions of what is fundamentally the same CMC dossier in order to satisfy regional requirements. This [requirement] creates additional complexity, increases resource demands, and can slow implementation of manufacturing improvements across global markets.
An additional challenge arises when sponsors seek to introduce a product into new markets after development is already well advanced. Frequently, the original development strategy and supporting CMC package were designed around the requirements of the intended launch regions. If a new territory has specific regulatory expectations that were not considered earlier in development, additional studies, justification packages, or data generation may be required, potentially resulting in delays and increased costs.
Consequently, companies are increasingly encouraged to consider their long-term geographical ambitions earlier in development and to adopt a globally minded CMC strategy wherever possible. While this may require generating broader datasets than are immediately required for the initial filing, it can significantly simplify future lifecycle management and market expansion activities.
At Codis, we strongly encourage early discussions around CMC and regulatory strategy to ensure development programs generate the right data at the right time, applying a pragmatic, risk-based approach that supports both immediate development objectives and longer-term global regulatory ambitions.
Drivers Behind Divergence
TPN: What are the underlying drivers that cause individual health authorities to maintain unique regional requirements, even when subscribing to global standards?
Macdonald: Fundamentally, health authorities remain accountable to their own citizens and governments for safeguarding public health within their respective jurisdictions. As a result, factors such as national legal frameworks, public health priorities, risk tolerance, available regulatory resources, and political accountability can all influence how regulatory requirements are implemented and enforced.
While ICH guidelines provide a highly effective framework for scientific and technical harmonization, they are not themselves legally binding. Individual jurisdictions must therefore incorporate these principles into their own legislative and regulatory frameworks, which can lead to differences in interpretation, implementation, and regulatory expectations.
In many cases, the divergence is not driven by disagreement over the underlying science, but rather by differences in local laws, regulatory processes, and the responsibilities that individual health authorities have to their own populations.
Mutual Recognition Versus Regulatory Reliance
TPN: MRAs are often cited as the gold standard for reducing regulatory burden. Is full mutual recognition of CMC reviews realistic on a global scale, or is regulatory reliance a more achievable steppingstone?
Macdonald: Full mutual recognition remains an attractive long-term objective, but it is unlikely to become universal in the foreseeable future.
For most regulatory agencies, the ability to independently assess medicinal products is closely linked to their statutory responsibilities, regulatory sovereignty, and accountability to the patients and citizens they serve. Consequently, many authorities are understandably reluctant to fully delegate approval decisions to another regulator.
Regulatory reliance therefore represents a more pragmatic and achievable approach. Under a reliance model, a health authority can leverage the scientific assessments, inspection findings, and regulatory conclusions of a trusted reference agency, while retaining responsibility for the final approval decision within its own jurisdiction.
This enables regulators to reduce duplication of effort, improve efficiency, and accelerate access to medicines, without compromising national oversight or patient safety.
As a result, I believe expanding regulatory reliance frameworks is a far more realistic and meaningful stepping stone towards greater global CMC harmonization than pursuing universal mutual recognition in the near term.
TPN: What practical mechanisms or governance frameworks need to be in place for a health authority to confidently rely on another agency’s CMC assessment without compromising national oversight or patient safety?
Macdonald: In both MRA and regulatory reliance frameworks, a significant degree of trust is required between regulatory authorities. The relying authority must have confidence in the scientific expertise, regulatory processes, and inspection capabilities of the reference agency.
In practice, reliance arrangements are most commonly built around assessments conducted by well-established reference authorities such as the FDA, EMA, and MHRA. Other health authorities may choose to leverage these assessments to supplement their own review activities, enabling more efficient use of resources while maintaining local oversight and decision-making authority.
Several practical mechanisms are essential to support these arrangements:
Trust and transparency — authorities need confidence in the scientific competence, GMP inspection capability, quality management systems, and decision-making processes of the reference agency.
Common standards — reliance works most effectively when agencies operate using common technical frameworks, such as ICH quality guidelines and the Common Technical Document (CTD), ensuring assessments are based on broadly aligned scientific principles.
Secure information sharing — authorities require legal and technical mechanisms to exchange assessment reports, inspection outcomes, regulatory findings, and post-approval information in a timely and secure manner.
Risk-based approaches — not every product or manufacturing change requires the same level of scrutiny. Reliance frameworks are particularly effective when agencies can focus resources on higher-risk products and leverage trusted assessments for lower-risk or well-understood submissions.
Ongoing collaboration — reliance should extend beyond initial approval to encompass GMP inspections, lifecycle management, post-approval CMC changes, pharmacovigilance activities, and supply-chain oversight.
Fundamentally, regulatory reliance does not mean relinquishing oversight; it means applying oversight more efficiently by leveraging trusted scientific assessments while retaining responsibility for the final regulatory decision.
With manufacturing facilities in both the U.S. and UK, operating under the oversight of two of the world's leading regulatory authorities, the FDA and MHRA, Codis is well positioned to generate robust CMC data packages that support our partners' broader global development and regulatory objectives.
A Digital Catalyst for Future Harmonization
TPN: Looking ahead over the next 5 to 10 years, which single policy shift or collaborative initiative would yield the greatest progress toward a unified global CMC ecosystem?
Macdonald: Like many aspects of pharmaceutical development, the CMC field continues to evolve, with the ultimate objectives of improving patient access to medicines while enabling drug developers to progress programs safely, efficiently, and with greater predictability.
Over the next 5 to 10 years, one of the most impactful initiatives would be the widespread adoption of digital CMC and structured regulatory data standards across both industry and health authorities.
Today, much of the CMC review process remains document-centric, requiring large volumes of data to be translated into static reports and regulatory submissions. Moving towards structured, interoperable digital data would enable more efficient review, facilitate information sharing between agencies, and support greater consistency in regulatory decision-making.
Digital CMC also creates opportunities to leverage advanced modelling approaches, including in silicodevelopment tools, process modelling, and digital twins, helping to reduce development timelines and focus experimental work on the highest-value areas.
Most importantly, a common digital framework could provide the foundation for increasing regulatory reliance, allowing agencies to more effectively access, review, and leverage assessments conducted by trusted reference authorities. In that sense, Digital CMC is not simply a technological advancement; it is a key enabler of greater transparency, regulatory convergence, and ultimately a more unified global CMC ecosystem.
About the Contributor
Mark Macdonald is Technical Sales Director for Codis. Mark is a chartered Chemical Engineer with over 20 years of experience in the pharmaceutical industry across CDMO and Big Pharma enterprises. He has extensive experience in technical roles across the UK, Europe, and the U.S. spanning Engineering, Safety and Project Management and has led Operational teams in a GMP environment. In the commercial space, Mark leverages his years of experience to match client needs with operational capabilities. Mark earned a Master’s degree in Chemical and Process Engineering from the University of Newcastle.
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