Vol 85 Developing a Robust Due Diligence Framework for Evaluating CMC

August 31, 2023The Pathfinder 32 Min Read

Due diligence in CMC drug development is an ongoing, multi-stage process essential for mitigating risks and ensuring quality. Initial assessments often occur at the pre-investment or pre-acquisition stage to gauge project viability. Further specialized reviews are crucial during in-licensing agreements, pre-IND submissions, and before initiating clinical trials. As the drug moves toward commercialization, another layer of CMC due diligence is essential to confirm scalability and compliance. Even post-market, periodic reviews are necessary, especially during mergers, acquisitions, or when considering an exit strategy. Therefore, integrating due diligence across these pivotal phases is vital for successful drug development and commercialization. 

In an industry as complex and regulated as pharmaceuticals, conducting thorough due diligence is non-negotiable. This exercise is especially crucial for Chemistry, Manufacturing, and Controls (CMC) in drug development. The CMC information associated with a drug substance or product is ensuring a compound meets the required technical and quality elements. Therefore, building a robust due diligence framework for evaluating CMC drug development projects is a cornerstone for any pharmaceutical company. 


The Importance of CMC Due Diligence 


Evaluating the CMC aspects is not merely a ‘check-the-box’ exercise. It’s a comprehensive review that can identify potential bottlenecks or roadblocks that could affect the drug’s journey from concept to market. Failing to conduct a rigorous due diligence process can result in financial setbacks, regulatory scrutiny, and a tarnished reputation. 


Critical Components of a Robust CMC Due Diligence Framework 


Regulatory Compliance 

Given the ever-changing landscape of drug regulations, the first step in your due diligence should be a thorough examination of the regulatory compliance of the drug product or substance. This includes assessments for Orphan Drug Designation, Fast Track, breakthrough therapy, Accelerated Approval, ANDA, and 505(b)(2) submissions. 


Technical and Quality Assessment 

This involves an in-depth look into the formulation, process, and analytical development. It also includes validation, quality assurance compliance, and stability data assessment. A technical and quality assessment can reveal gaps in the development process that could prove costly in the long run. 


Risk-Based Strategies 

Employing a risk-based approach can be beneficial for assessing the product’s viability. This involves identifying and prioritizing potential risks, followed by developing mitigation plans. 


Building the Team 

Select individuals with expertise in regulatory affairs, CMC, quality assurance, and other pertinent areas. This multidisciplinary approach ensures that all aspects of CMC are critically evaluated. 


Execution Plan 

Once you have the framework in place, develop a detailed execution plan that outlines the steps, responsibilities, and timelines. This ensures that the due diligence process is not just robust but also efficient. 


Creating a robust due diligence framework for evaluating CMC drug development projects is an investment in the future of your company. It minimizes risks and sets the stage for the seamless development and commercialization of drug products. Therefore, allocating the time and resources to build a comprehensive framework is not just recommended; it’s a business imperative. 


The Cornerstone when acquiring or in-licensing 


Due diligence is a crucial cornerstone in the pharmaceutical industry, especially when acquiring or in-licensing compounds for market commercialization. The importance of a detailed investigation into the CMC information associated with a drug substance and/or drug product cannot be overstated. This investigation ensures that a given compound meets the technical and quality elements essential for successful commercialization.  

To streamline this meticulous process, it’s recommended to follow a structured approach. Focus CMC due diligence in the context of drug substance and aligns with the format of the Common Technical Document (CTD) for the Registration of Pharmaceuticals for Human Use: Module 3, Quality, as per the ICH Harmonized Tripartite Guideline. Some sections of the CTD template are combined to simplify the presentation. 


Why Align with the ICH Harmonized Tripartite Guideline? 


The ICH Harmonized Tripartite Guideline serves as a global standard for the registration of pharmaceuticals for human use. By following the CTD format, you not only ensure a comprehensive review but also facilitate easier communication with regulatory agencies, including the FDA. Adopting this approach in your CMC due diligence ensures a comprehensive review and augments smooth regulatory interactions. 


Key CMC Components as per CTD Module 3, Quality (Simply focused on Drug Substance here) 


Drug Substance Information 


  • General Information 

Start with a thorough review of the nomenclature, structural formula, and other identifiers of the drug substance. This sets the foundation for understanding the substance you’re dealing with. 

This is your starting point, requiring a meticulous review of the drug substance’s nomenclature, structural formula, molecular weight, and other identifiers. This foundational knowledge provides the context for all subsequent evaluations. It’s not just about knowing the name and structure; it’s also about understanding the substance’s classification and any previous regulatory history. 


  • Manufacture 

Examine the manufacturing process, including the facilities and equipment used. This could entail an on-site audit for compliance with Good Manufacturing Practices (GMP). 

Scrutinize the entire manufacturing process, including starting materials, synthetic pathways, and intermediates. Pay close attention to the facilities and equipment, which should comply with Good Manufacturing Practices (GMP). An on-site audit may be invaluable here, as it provides direct insights into process integrity, personnel capabilities, and quality control measures. 


  • Characterization 

Review all available data on the characterization of the drug substance, including impurity profiles and potential degradation products.  

Characterization goes beyond mere identification. This involves a detailed study of the drug substance’s physicochemical properties, impurity profiles, and potential degradation products. The use of advanced analytical techniques like NMR, mass spectrometry, and X-ray crystallography might be necessary for a full understanding of the compound. 


Control of Drug Substance 


  • Specification(s) 

This entails a review of the quality control measures in place, including batch-to-batch consistency.  

The specifications set the quality benchmarks for the drug substance. These include criteria like purity, potency, and physical characteristics (e.g., particle size, solubility). Check for batch-to-batch consistency and ensure that the specifications are in line with regulatory guidelines. 


  • Analytical Procedures and Validation 

Ensure that the analytical methods used are validated and appropriate for their intended use. This may require independent verification.  

Any analytical methods used should be robust, reproducible, and validated to ensure they are fit for their intended purpose. This may involve statistical methods for measuring the accuracy and reliability of these tests. Independent verification by a third-party lab can add an extra layer of assurance. 


  • Stability 

Stability data provides insights into how the substance will behave over time under various environmental conditions. This is crucial for determining shelf life and storage conditions. 

Stability studies are indispensable. This involves assessing how the drug substance behaves under various environmental conditions such as temperature, humidity, and light exposure. The data informs on shelf life, storage conditions, and any special handling requirements. 


Regulatory Filings 

Review any existing regulatory filings, including any submissions for Orphan Drug Designation, Fast Track, Break-through Therapy, Accelerated Approval, ANDA, and 505(b)(2). 

Review every existing and relevant regulatory filing. Look for any flags or issues that could complicate the regulatory approval process. This includes an analysis of submissions for Orphan Drug Designation, Fast Track, Break-through Therapy, Accelerated Approval, ANDA, and 505(b)(2). 


Risk Assessment 

This should be a part of your risk-based strategy and involves identifying gaps in data or processes that could affect the commercial viability of the drug substance.  

This should encompass a comprehensive gap analysis, identifying missing data, inconsistencies in the submitted documents, or any other concerns that could jeopardize the drug’s commercial viability. Develop a risk mitigation strategy to address these gaps.  

The CMC due diligence process, when aligned with the ICH Harmonized Tripartite Guidelines, ensures a structured, comprehensive, and globally accepted approach. This not only minimizes the risks associated with drug substance development but also optimizes the path towards successful commercialization.  

For specialized assistance in CMC due diligence activities, consult with experts who can guide you through the maze of regulations and best practices to ensure a successful outcome. 


Why CMC Due Diligence is Mission-Critical 


Traditional due diligence efforts often focus on clinical trials, patents, and market assessment. However, an in-depth scrutiny of CMC activities provides invaluable insights into a project’s: 


  • Technical Feasibility: Is the production process scalable? Are the required materials and technologies readily available? 
  • Regulatory Compliance: Are the manufacturing procedures compliant with FDA guidelines? How robust is the quality control mechanism? 
  • Financial Pragmatism: What are the anticipated costs? Are there unforeseen expenditures that could impede project scalability?  

Ignoring any of these factors can be catastrophic. 


Core Components of a Robust CMC Due Diligence Framework 


Data Integrity and Accessibility 

Incorporate advanced data analytics tools to collate, assess, and interpret a large volume of data swiftly and efficiently. Ensure that data integrity is maintained throughout the data lifecycle. 


Regulatory Review and Risk Assessment 

Integrate a detailed evaluation of the regulatory landscape, both domestically and globally. This involves a thorough understanding of FDA guidelines, especially in specialized areas like Orphan Drugs Designation, Fast Track, Break-through Therapy, and Accelerated Approval. Adopt a risk-based strategy to identify bottlenecks in formulation, process, and analytical development. Conduct gap assessments to highlight weaknesses in your current approach and develop contingency plans. 


Financial Modeling and Stakeholder Engagement 

Perform advanced financial models that factor in potential changes in regulations, availability of raw materials, and labor costs to gauge the financial feasibility of the project. Due diligence isn’t just an internal endeavor; it should involve all key stakeholders, including suppliers, legal advisors, and regulatory authorities. 


Advanced Strategies: Next-Level Due Diligence 


Leverage Augmented Intelligence 

Harness the power of augmented intelligence to scan regulatory updates, patents, and scholarly articles. This provides a comprehensive, real-time perspective of the project landscape. 


FDA-Style Review of Submissions 

Performing an internal ‘FDA-style’ review of all documents can streamline the FDA engagement process by identifying potential red flags beforehand. 


Scenario Planning 

Conduct “what-if” analyses to prepare for various market conditions, such as rapid shifts in consumer demand or sudden regulatory changes.  

In today’s volatile pharmaceutical landscape, traditional due diligence methods are insufficient. A robust CMC due diligence framework is vital for the accurate evaluation of drug development projects. By integrating data analytics, regulatory expertise, financial modeling, and stakeholder engagement into your due diligence strategy, you can significantly mitigate risks and elevate your drug development projects to the next level of success. 

 Elevate your strategy, and your results will follow suit. 


Final Thoughts 


Due diligence in drug development is not just a box-ticking exercise; it’s a crucial step that can make or break a project. A thorough due diligence process can help identify potential risks and uncertainties before they become costly problems. It ensures that all regulatory requirements are met, and that the drug is safe, effective, and of high quality.  

Developing a robust due diligence framework for evaluating CMC drug development projects requires a multifaceted approach. It involves a comprehensive assessment of the CMC data package, regulatory compliance review, risk assessment, and financial analysis.  

By ensuring that these components are thoroughly addressed, companies can mitigate risks, ensure regulatory compliance, and increase their chances of success in the highly competitive and challenging field of drug development. Remember, due diligence is not just about ticking off boxes; it’s about ensuring the safety, efficacy, and quality of drugs — because ultimately, it’s about the health and well-being of patients worldwide. 



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