Demystifying The Common Technical Document For Global Submissions

By Fahimeh Mirakhori, M.Sc., Ph.D.

In the high-stakes world of biopharmaceutical development, few regulatory documents carry as much weight or pose as many formatting headaches as the CTD. Among its five modules, Module 3, CMC, is arguably the most complex. The focus is on providing a structured, science-based demonstration of how the therapeutic product is consistently manufactured, controlled, and compliant with regulatory expectations.^1-5

With the ever-evolving global standards, including updates from the ICH, and the increasing reliance on electronic submission tools, drug developers must navigate both scientific and technical terrain to get their CMC dossier submission-ready.

The CTD is a globally harmonized format for regulatory submissions, jointly adopted by the U.S. FDA, EMA, PMDA, and other regulatory authorities. Module 3 provides comprehensive data on the drug substance and drug product, including manufacturing processes, quality controls, and stability studies. This data must align with Modules 2, 4, and 5. Before submission, sponsors should ensure that they streamline submissions and reduce the risk of refusal-to-file (RTF) or regulatory queries by evaluating their CMC readiness using appropriate review checklists.^1-10

Manual data handling in CMC submissions has long contributed to inefficiencies, including transcription errors, delayed timelines, and inconsistent documentation. These challenges are compounded by regulatory divergence across regions, which complicates global reliance and harmonized assessments. Inadequate control strategies, poorly defined design spaces, and underdeveloped real-time release approaches further hinder submission quality, often accounting for a significant proportion of regulatory review concerns.^1-5

Documentation inconsistencies, such as fragmented CTD linkages and incomplete data on manufacturing, stability, or impurities, add another layer of complexity that slows the regulatory evaluation process. These systemic issues are exacerbated under compressed development timelines, particularly in accelerated or emergency contexts, where limited resources strain post-approval change management.^3,4,8 Transitioning to digital management tools and implementing standardized review checklists can address these challenges by improving data integrity, enhancing clarity across technical modules, and facilitating more efficient and transparent regulatory interactions.

Table 1. ICH CMC Quality Submission Guidance

ICH Guidance	Scope	Key Features
ICH M4Q (R2)1	Defines structure and content of CTD Module 3	Redesigned Module 2.3 and 3 for modularity Core Quality Information (CQI) standardization  Development Summary and Justifications (DSJ) Final adoption expected by June 2027
ICH M8 (v4.0)2	Specifies eCTD format and submission life cycle tracking	Enhanced life cycle tracking Improved metadata utilization Streamlined communication with authorities Supports dynamic submission frameworks
ICH Q12 Module 811	Provides framework for post-approval life cycle management	Established Conditions (ECs) for quality assurance Post-Approval Change Management Protocols (PACMPs) Product Life Cycle Management (PLCM) document Structured approaches for frequent CMC changes

 

Key Challenges In CMC Dossier Development

Developing a robust CMC dossier requires a strategic balance of scientific rigor, regulatory foresight, and operational coordination. While the CTD and eCTD frameworks offer a standardized approach, significant challenges remain in practice. These issues often span data management, evolving process understanding, regional regulatory divergence, and the technical execution of submissions.

One of the most pervasive hurdles is data fragmentation. In many organizations, particularly those operating across global teams or working with CDMOs, CMC data is dispersed across silos, platforms, and time zones. This fragmentation undermines version control, compromises data integrity, and leads to inconsistencies across submissions. Structured content management (SCM) and structured content and data management (SCDM) systems have been proposed to address these challenges by enabling modular content reuse and ML-based data models, thereby reducing human error and supporting automation in authoring, review, and submission processes.^1-4

This approach can significantly reduce global licensing timelines and variability in registered product details. The FDA has initiated efforts to encourage SCDM adoption for CMC data. However, real-world adoption of these systems remains limited, particularly in environments with diverse regulatory requirements and legacy systems.^4,5 SCDM is particularly beneficial for expedited regulatory pathways, where condensed timelines necessitate innovative approaches to data management and analysis. The concept of collaborative data sharing systems, such as ORCHESTRA, addresses the challenges of consensus building and frequent updates in scientific data management for regulatory submissions. Evolving process knowledge adds further complexity. Because process development often continues during clinical trials, specifications and control strategies are frequently revised late in the development life cycle.¹¹ These late-stage changes can cascade into significant documentation rework, delaying submission readiness and increasing the risk of inconsistencies.

Unlike traditional document-centric models, SCDM decouples CMC data from static files, enabling modular, metadata-tagged content blocks that can be dynamically assembled for internal reporting or tailored regulatory submissions. This “data on demand” model represents an advanced alternative to existing mechanisms, such as drug master files (DMFs), allowing for routine updates and cloud-based access to data. With SCDM, content can be reused across amendments, variations, and annual reports, ensuring consistency, scalability, and rapid response to queries from global health authorities.

Regulatory divergence remains a persistent obstacle despite ICH-driven harmonization efforts. Agencies such as the FDA and EMA may interpret quality expectations differently, especially for innovative product types like advanced therapy medicinal products (ATMPs).^12-14 Sponsors must navigate these differences by tailoring regional content in Module 1 and interpreting ambiguous expectations in Modules 2 and 3. The lack of clarity and alignment can result in prolonged review cycles or additional requests for information.  

Even technically minor issues, such as eCTD formatting errors, can have major regulatory consequences. Problems with file structure, incorrect hyperlinks, missing bookmarks, or noncompliant naming conventions can trigger RTF actions or technical rejections, delaying product development and review timelines.

Another significant challenge lies in change management and life cycle planning. Without a well-defined strategy aligned with ICH Q12 principles, organizations may struggle to manage post-approval changes efficiently. This can lead to regulatory delays, compliance gaps, and limited flexibility in responding to evolving manufacturing or market needs.

Underlying many of these challenges are broader strategic and operational misalignments. Data silos between analytical, manufacturing, and regulatory teams often result in inconsistent or incomplete documentation. Manual version control and inadequate life cycle tracking can introduce additional submission errors, resulting in slow response times. A lack of clear justification for critical quality attributes (CQAs), critical process parameters (CPPs), and associated control strategies frequently draws scrutiny during review.¹⁵ A stepwise process risk-assessment approach can aid in identifying CQAs, CPPs, and their correlations, thereby supporting science- and risk-based regulatory practices.

To address these challenges, sponsors can implement several mitigation strategies:

• Standardize data templates and style guides across internal teams and sites.
• Utilize structured authoring tools and validated eCTD publishing software.
• Conduct internal mock audits and gap assessments ahead of submission.
• Establish centralized CMC project management with cross-functional quality reviews.

These process enhancements not only improve submission quality and efficiency but also lay the groundwork for a smoother path through regulatory review and post-approval life cycle management.^1-12

Product-Specific CMC Challenges And Common Pitfalls:

Cell and gene therapies, often categorized as ATMPs/CGTs, present unique challenges in CMC dossier development due to their complex, evolving manufacturing processes and biological variability. Unlike small molecule drugs, ATMPs often lack standardized production platforms, and their manufacturing processes may continue to evolve well into clinical development.^13-16 As a result, maintaining consistency across submission modules, ensuring control strategy alignment, and demonstrating product comparability can be particularly difficult.

Regulatory uncertainties and fragmented data sources frequently compound these challenges. The integration of multiple CDMOs, the use of non-standardized data formats, and limited internal expertise with ATMP-specific regulatory expectations can lead to inconsistencies, delays, or even technical rejections. For ATMPs in particular, harmonized control strategies, robust comparability protocols, and clear documentation across CTD modules are essential to avoiding regulatory delays and ensuring review readiness. The importance of early alignment, standardized data practices, and centralized oversight is particularly more challenging when collaborating with multiple partners or exploring novel modalities.  

One of the most persistent issues for these products is the complexity and variability of technical documentation. Multiple studies have reported difficulties in generating clear, consistent records across quality control data, manufacturing process descriptions, stability testing, and analytical method validation.^6-9,12-16 These challenges are further exacerbated as products progress from early-stage development to marketing authorization, where data expectations escalate significantly. The biological variability inherent to ATMPs/CGTs also complicates the creation of robust and reproducible documentation, requiring tailored regulatory strategies and quality assurance mechanisms.^12,16-19

Moreover, global regulatory harmonization poses significant challenges in developing unified CMC dossiers for ATMPs/CGTs.  Divergent guidelines between regions, particularly among ICH member countries and WHO-prequalified markets, impede the development of unified, consistent dossiers.¹² These disparities hinder collaborative assessments and reliance frameworks, ultimately delaying patient access to critical therapies. Several studies have proposed solutions, including the development of standard core documents, the use of adaptable templates, increased automation, and earlier engagement with regulatory authorities, to align expectations and improve submission quality.^3-8,12-16

Control strategy implementation remains a common focus of regulatory scrutiny. Deficiencies in defining appropriate control strategies, design spaces, and real-time release testing continue to trigger a substantial proportion of review questions. Quality by design (QbD), quality by review (QbR), and structured quality overall summaries (QOS) have been recommended to address these challenges, yet their adoption and impact vary significantly by region. In ICH regions such as the United States, European Union, and Japan, implementation of these tools shows promise, but consistency in execution remains limited.^8,10-11.

Outside ICH regions, the regulatory landscape presents additional difficulties.^6,8,10 Resource constraints, limited technical guidance, and varied regulatory expectations contribute to inconsistent dossier quality and extended review timelines. Studies emphasize the need for harmonized international frameworks, technical assistance, and scalable digital solutions to support submissions from low-resource settings, particularly those participating in the WHO Prequalification of Medicines Program.^4,6  

In addition to technical hurdles, resource and timeline management pose substantial risks, particularly for accelerated development programs and pandemic response initiatives. Compressed timelines, limited review capacity, and fragmented global guidance create bottlenecks in submission preparation and post-approval change management. Proposed mitigation strategies include regulatory reliance, rolling review mechanisms, and expanded use of digital platforms to streamline data submission and review workflows. Limited industry expertise also represents a barrier.⁵ The COVID-19 pandemic highlighted the need for accelerated CMC development strategies, emphasizing the importance of early decision-making, streamlined regulatory engagement, and leveraging prior knowledge. The rapid evolution of regulatory guidance and the novelty of advanced therapy platforms create a steep learning curve for both sponsors and regulators. This is particularly evident among academic institutions and smaller developers that may lack the regulatory infrastructure and specialized knowledge needed for compliant eCTD submissions.^18-19 Outsourcing, targeted training, and collaborative initiatives between industry and regulators have been suggested to mitigate these gaps.

To support accelerated programs, the EMA published a finalized CMC acceleration toolbox under the PRIME initiative in 2022. Similarly, the FDA issued a new MAPP titled Quality Assessment for Products in Expedited Programs and announced the launch of the CMC Development and Readiness Pilot (CDRP) in 2023, aimed at expediting CMC development for both CBER and CDER IND sponsors.^19-20

Conclusion 

Developing a robust and compliant CMC submission is a complex yet essential component of successful drug development, particularly for advanced therapies. As regulatory expectations increase and electronic submissions are the standard, companies must navigate scientific complexity, evolving global requirements, and operational constraints. Common challenges, such as data fragmentation, inconsistent documentation, divergent regional standards, and inadequate control strategies, can significantly delay approvals if not addressed early.

To overcome these hurdles, sponsors should adopt proactive strategies including SCDM, automation, and standardized templates. Leveraging tools like eCTD publishing platforms, applying QbD principles, and utilizing frameworks such as the QOS and QbR can further enhance the clarity and coherence of submissions. Moreover, there is a growing need to enhance digital maturity and global harmonization in regulatory submissions. The following best practices are recommended to help developers better manage regulatory complexity, improve dossier coherence, and accelerate review timelines for novel therapeutics:

• Engage early with regulators through scientific advice procedures, pre-IND meetings, or FDA’s INTERACT program to clarify expectations and mitigate future queries and IND-enabling packages.

• Clearly define CQAs, particularly those related to potency, identity, and biological variability.
• Adopt modular, version-controlled data platforms that support real-time updates and cross-functional collaboration.
• Leverage platform-based manufacturing data where applicable to streamline comparability assessments and reduce data redundancy.
  • Harmonizing global efforts and reliance mechanisms are also key to streamlining reviews and accelerating market access.

Ultimately, companies that invest in cross-functional planning, digital tools, and regulatory alignment will be better equipped to deliver high-quality submissions, reducing risk, improving efficiency, and expediting the availability of innovative therapies to patients.

References:

1. ICH M4Q- International Conference on Harmonisation; guidance on the M4 Common Technical Document-Quality. https://www.ich.org/page/ctd
2. ICH M8 v4.0- ICH electronic Common Technical Document - eCTD v4.0. https://ich.org/page/ich-electronic-common-technical-document-ectd-v40
3. Algorri, M., Cauchon, N. S., & Abernathy, M. J. (2020). Transitioning Chemistry, Manufacturing, and Controls Content with a Structured Data Management Solution: Streamlining Regulatory Submissions. Journal of Pharmaceutical Sciences, 109(4), 1427–1438. https://doi.org/10.1016/j.xphs.2020.01.020
4. Ahluwalia, K., Abernathy, M. J., Beierle, J., Cauchon, N. S., Cronin, D., Gaiki, S., Lennard, A., Mady, P., McGorry, M., Sugrue-Richards, K., & Xue, G. (2022). The Future of CMC Regulatory Submissions: Streamlining Activities Using Structured Content and Data Management. Journal of Pharmaceutical Sciences, 111(5), 1232–1244. https://doi.org/10.1016/j.xphs.2021.09.046
5. Popkin, M. E., Goese, M., Wilkinson, D., Finnie, S., Flanagan, T., Campa, C., Clinch, A., Teasdale, A., Lennard, A., Cook, G., Mohan, G., & Osborne, M. D. (2022). Chemistry Manufacturing and Controls Development, Industry Reflections on Manufacture, and Supply of Pandemic Therapies and Vaccines. The AAPS Journal, 24(6). https://doi.org/10.1208/s12248-022-00751-9
6. Ortega Diego, I., Fake, A., Stahl, M., & Rägo, L. (2014). Review of Quality Deficiencies Found in Active Pharmaceutical Ingredient Master Files Submitted to the WHO Prequalification of Medicines Programme. Journal of Pharmacy & Pharmaceutical Sciences, 17(2), 169. https://doi.org/10.18433/j3q60j
7. Cauchon, N. S., Oghamian, S., Hassanpour, S., & Abernathy, M. (2019). Innovation in Chemistry, Manufacturing, and Controls—A Regulatory Perspective From Industry. Journal of Pharmaceutical Sciences, 108(7), 2207–2237. https://doi.org/10.1016/j.xphs.2019.02.007
8. Borg, J. J., Robert, J.-L., Wade, G., Aislaitner, G., Pirozynski, M., Abadie, E., Salmonson, T., & Bonanno, P. V. (2009). Where is Industry Getting it Wrong? A Review of Quality Concerns Raised at Day 120 by the Committee for Medicinal Products for Human Use during European Centralised Marketing Authorisation Submissions for Chemical Entity Medicinal Products. Journal of Pharmacy & Pharmaceutical Sciences, 12(2), 181. https://doi.org/10.18433/j3fw2q
9. McMahon, M. E., Abbott, A., Babayan, Y., Carhart, J., Chen, C., Debie, E., Fu, M., Hoaglund-Hyzer, C., Lennard, A., Li, H., Mazzeo, T., McCaig, L., Pischel, S., Qiu, F., Stephens, D., Timpano, R., Webb, D., Wolfe, C., Woodlief, K., & Wu, Y. (2021). Considerations for Updates to ICH Q1 and Q5C Stability Guidelines: Embracing Current Technology and Risk Assessment Strategies. The AAPS Journal, 23(6). https://doi.org/10.1208/s12248-021-00641-6
10. Kuno, K., & Toyoshima, S. (2016). Review Experiences and Regulatory Challenges for Pharmaceutical Development in Japan Using a Quality-by-Design Approach. Therapeutic Innovation & Regulatory Science, 50(3), 368–374. https://doi.org/10.1177/2168479015620832
11. ICH Q12 IWG Regulatory and Technical Considerations for Pharmaceutical Product Lifecycle Management.
12. Sia, C. H., Koh, C., & Chan, L. W. (2022). Manufacture and regulation of cell, tissue and gene therapy products: global perspectives, challenges and next steps. Generics and Biosimilars Initiative Journal, 11(2), 65–80. https://doi.org/10.5639/gabij.2022.1102.012
13.  Salazar-Fontana, L. I. (2022). A Regulatory Risk-Based Approach to ATMP/CGT Development: Integrating Scientific Challenges with Current Regulatory Expectations. Frontiers in Medicine, 9. https://doi.org/10.3389/fmed.2022.855100
14.  Bak, A., & Ho, R. J. Y. (2021). Advancing Cell and Gene Therapeutic Products for Health Impact – Progress on Pharmaceutical Research, Development, Manufacturing and Controls. Journal of Pharmaceutical Sciences, 110(5), 1869–1870. https://doi.org/10.1016/j.xphs.2020.10.053
15. Beierle J, Algorri M, Cortés M, Cauchon NS, Lennard A, Kirwan JP, Oghamian S, Abernathy MJ. Structured content and data management-enhancing acceleration in drug development through efficiency in data exchange. AAPS Open. 2023;9(1):11. doi: 10.1186/s41120-023-00077-6. Epub 2023 May 8. PMID: 37193559; PMCID: PMC10164450.
16. Cauchon, N. S., Oghamian, S., Hassanpour, S., & Abernathy, M. (2019). Innovation in Chemistry, Manufacturing, and Controls—A Regulatory Perspective From Industry. Journal of Pharmaceutical Sciences, 108(7), 2207–2237. https://doi.org/10.1016/j.xphs.2019.02.007
17.  Gianelli, F. (2020). The challenges of potency assay development for cell and gene therapy products. Cytotherapy, 22(5), S144–S145. https://doi.org/10.1016/j.jcyt.2020.03.291
18.  Olesti, E., Nuevo, Y., Bachiller, M., Guillen, E., Bascuas, J., Varea, S., Saez-Peñataro, J., & Calvo, G. (2024). Academic challenges in the development of advanced therapy medicinal products: a regulatory perspective. Cytotherapy, 26(3), 221–230. https://doi.org/10.1016/j.jcyt.2023.12.005
19. EMA Toolbox on CMC Flexibilities has been Evolving to Incorporate Industry Input and Learnings from the Pandemic. https://ipq.org/ema-toolbox-on-cmc-flexibilities-has-been-evolving-to-incorporate-industry-input-and-learnings-from-the-pandemic/
20. U.S. FDA Chemistry, Manufacturing, and Controls Development and Readiness Pilot (CDRP) Program.  https://www.fda.gov/drugs/pharmaceutical-quality-resources/chemistry-manufacturing-and-controls-development-and-readiness-pilot-cdrp-program

About The Author:

Fahimeh Mirakhori, M.Sc., Ph.D., is a consultant who addresses scientific, technical, and regulatory challenges in cell and gene therapy, genome editing, regenerative medicine, and biologics product development. Her areas of expertise include autologous and allogeneic engineered cell therapeutics (CAR-T, CAR-NK, iPSCs), viral vectors (AAV, LVV), regulatory CMC, as well as process and analytical development. She earned her Ph.D. from the University of Tehran and completed her postdoctoral fellowship at Johns Hopkins University School of Medicine. She has held diverse roles in the industry, including at AstraZeneca, acquiring broad experience across various biotechnology modalities. She is also an adjunct professor at the University of Maryland.