The Chemistry, Manufacturing, and Controls (CMC) section of a regulatory dossier is critical in ensuring product quality and regulatory compliance. Educo delivers the course “Completing the Quality/CMC Module of the CTD” which includes a free-to-attend module 1 training session. Over the years, attendees of the free session have raised insightful questions that led to detailed discussions. Below, we compile key questions and responses to provide clarity on crucial aspects of CMC compliance, dossier preparation, and regulatory expectations.

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General Questions on CMC and CTD

Q: What is the most common mistake seen in CMC dossiers?
A: The most frequent mistake is the lack of clear linkage between sections. Many dossiers provide detailed individual sections but fail to establish a coherent connection between development pharmaceuticals, manufacturing processes, and final specifications. Ensuring consistency and justification throughout the document is critical.

Q: How much flexibility is there in CMC submissions across different regulatory regions?
A: While the CTD format provides a harmonised structure, regional variations exist, especially concerning regulatory expectations. For example, the US FDA might demand more process validation data than the EMA. It is essential to use a ‘global dossier’ approach but be prepared for region-specific requirements and justifications.

Q: How can we best approach writing the Quality Overall Summary (QOS)?
A: The QOS should be an accurate summary of Module 3, not a place to introduce new data. A well-written QOS highlights the rationale behind critical decisions and provides a clear narrative for the reviewer. Ensure it aligns with the body of the dossier to avoid inconsistencies.

Q: What is CMC regulatory intelligence?
A: CMC regulatory intelligence involves gathering, interpreting, and applying the latest regulatory guidance, ensuring compliance and minimising risks. Companies should have a system in place to monitor regulatory updates and assess their impact on SOPs and processes.

Q: What is the scope of the complete CTD and module three in particular? How many pages is a normal range?
A: It depends on the complexity of your product. A simple solution or small molecule may require relatively few pages, while a gene therapy or biologic product will require extensive documentation. The more complex your materials and processes, the more data is required. It is directly proportional to the complexity of your product.

Analytical Methods and Specifications

Q: How do you justify the analytical methods used in the dossier?
A: Justification should be based on method suitability and validation results. Regulatory agencies expect robust analytical validation according to ICH Q2 (R1) and, in the future, ICH Q14. This includes demonstrating specificity, accuracy, precision, linearity, and robustness for the intended use.

Q: What is the importance of control strategy in the CTD?
A: A well-defined control strategy ensures product quality by identifying critical process parameters (CPPs) and critical quality attributes (CQAs). It links material attributes, manufacturing controls, and analytical methods to ensure batch-to-batch consistency.

Q: How do we handle nitrosamines and elemental impurities in CMC submissions?
A: Regulatory authorities expect risk assessments and control measures for nitrosamines and elemental impurities. ICH M7 outlines approaches for mutagenic impurities, while ICH Q3D provides guidelines on elemental impurities. Mitigation strategies should be included in the control strategy.

Q: If an assay is based on an early version of a pharmacopoeia, do we need to update it?
A: Not necessarily. If your assays and final product are based on pharmacopoeial methods, you do not need to update them unless required by regulatory guidance. However, the method should be fully validated for your product to ensure suitability.

Regulatory Considerations and Global Submissions

Q: How should we manage changes post-submission to avoid unnecessary variations?
A: Properly structured development pharmaceutical sections (P2 and S2.6) allow for flexibility in post-approval changes. Implementing principles from ICH Q12 (Lifecycle Management) can help reduce variation filings by defining established conditions and post-approval change management protocols (PACMPs).

Q: When is the new CTD format expected to be released by ICH and available to use?
A: It could take anywhere from two to five years, depending on the ratification process. However, companies should start preparing source documents that align with the new format to ensure a smooth transition.

Q: Where do you see the most challenges for an experienced small molecule CMC manager with regards to the future of the CTD changes coming in?
A: The increasing level of detail required for small molecules will present challenges. As expectations from biologics trickle down to small molecules, regulatory agencies will demand more comprehensive control strategies and justifications.

Q: How do you see the implementation of Quality by Design (QbD) principles? Will regulatory agencies require QbD for method development?
A: While not a formal requirement, QbD principles align with how regulators are trained to think. QbD enhances product and process understanding and supports risk-based decision-making, making it beneficial for regulatory submissions.

Q: Are contract manufacturing organisations (CMOs) allowed to implement changes before regulatory approval?
A: This depends on the quality agreement between the sponsor and the CMO. Some changes can be implemented and held under quarantine until approval, while others may require approval before execution.

Q: What are the major differences in expectations between small molecules and biologics?
A: Biologics require more extensive characterisation, in-depth analytical controls, and additional stability and comparability studies. Regulatory agencies expect comprehensive process validation, considering the complexity of biologics and their sensitivity to manufacturing changes.

Q: How do emerging technologies like continuous manufacturing impact CMC submissions?
A: Continuous manufacturing requires a different approach to control strategy, real-time release testing, and validation. ICH Q13 addresses these aspects, and regulators are increasingly open to such innovations, provided robust scientific justification is included.

Practical Considerations for CTD Compilation

Q: Who should be involved in writing and reviewing Module 3?
A: A cross-functional team, including regulatory affairs, analytical scientists, formulation scientists, and manufacturing experts, should contribute. Ensuring alignment between departments avoids conflicting data and inconsistencies.

Q: How can we simplify our CMC dossier while maintaining compliance?
A: The key is to focus on justifications rather than excessive raw data. A well-structured P2 section allows for a streamlined P3 manufacturing description, reducing unnecessary complexity and change control burdens.

Q: How can we improve communication with regulatory agencies during CMC review?
A: Proactively engage with agencies through scientific advice meetings, pre-IND/IMPD discussions, and the use of question-based review (QBR) approaches. Clearly articulated justifications can reduce the number of queries and facilitate faster approvals.

Q: How do I approach an IND/IMPD filing as per the CTD Module 3 format?
A: The European IMPD and US IND formats differ slightly. European IMPDs follow a structured format under the Clinical Trials Regulation, while the US IND requires a separate submission format with CMC expectations based on the development phase.

Special Considerations for Gene Therapy and Advanced Products

Q: Can you comment on the level of detail expected in Module 3 for gene therapy products?
A: The level of detail is enormous. Depending on whether you’re introducing a direct gene-editing system or a gene-edited cell therapy like CAR-T, the required data spans plasmids, viral seeds, and more. Sections like S2.3 (Control of Materials) are critical, and missing key information can compromise the entire dossier.

Conclusion

These questions and answers provide a valuable resource for professionals working on CMC regulatory submissions. The insights shared here emphasise the importance of consistency, scientific justification, and strategic dossier compilation to facilitate regulatory approval and minimise post-approval changes.

For further details, consider attending the full Educo Life Sciences CMC training programme to deepen your understanding and apply these best practices effectively.

Answers from our Educo Life Sciences Expert, Andrew Willis

Andrew Willis is a regulatory and development consultant with 35 years of experience. His management roles have seen him act as global Vice President of Regulatory Affairs and Medical Affairs, creating business and marketing strategies for complex pharmaceutical development projects. Andrew has gained therapeutic experience in areas covering CNS, oncology, urology and pain management.

Experienced with both EU and US applications (NDA, 505 B 2, ANDA, BLA, MAA) for NCEs, generics and line extensions, with particular knowledge of sterile and biotech products. Experience covers multiple applications, scientific advice meetings, Clinical Trial applications (IND and IMPD compilation and submission), orphan drug applications. Significant Experience with novel drug delivery systems has been utilized in all of the above type of applications.

Andrew continues to provide training for all major companies and also a number of EU Member states agencies in CMC, variations and advanced regulatory affairs. More recently for IO Biotech, Andrew was SVP of Quality, Regulatory and CMC sitting on core C-suite providing CTO support activities – overseeing all pharmaceutical development of drug substance and drug products for peptide molecules and ensuring appropriate quality systems are in place.

He currently delivers extensive training courses in Quality By Design, Global Module 3 Requirements, global generic development and Optimizing the Life of Your Products. Specializing in Lifecycle management, creation of new line extensions and development strategies to maximize return on investment.