Vol 81 – Ensuring Data Integrity in CMC Submissions: Regulatory Expectations and Best Practices

August 22, 2023The Pathfinder 23 Min Read

Building a QBD Framework for CMC Submissions: A Paradigm Shift in Pharmaceutical Development  


The pharmaceutical industry is in the midst of a transformative era. With a constantly evolving regulatory landscape and an unceasing demand for innovation, there’s no time for complacency. One of the most groundbreaking approaches to emerge in recent years was Quality by Design (QbD), a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control. Integrating QbD into Chemistry, Manufacturing, and Controls (CMC) submissions can spell the difference between success and failure.  


An Old Philosophy in Drug Development  


QbD represented a shift from traditional methods and was more of a buzzword in the pharmaceutical world. It did highlight, however, that understanding of that quality must be built into the product from the start. It was a reminder that good science is the key, and this approach profoundly impacts how products are developed, manufactured, and regulated.  


Enhanced Understanding and Control 


With QbD, you understand the process and the product at an unprecedented level. You’re not just reacting to quality issues after they arise; you’re designing quality into the process. This predictive approach reduces variability, improves efficiency, and ensures that the product meets the required standards.  


  • Understanding the Process: QbD encourages a profound understanding of both the product and the process. This understanding comes from thoroughly examining material attributes, equipment, operational conditions, and more. This approach facilitates consistent control over the process by focusing on the science and the risk. 

  • Predictive Approach: Rather than reacting to quality problems, QbD fosters a predictive approach that minimizes variability and improves efficiency. This aligns with the FDA’s guidance on Process Validation, which focuses on understanding process variation, controlling the variables, and monitoring performance. 

  • FDA Guidance Alignment: The FDA’s Guidance for Industry, “Q8(R2) Pharmaceutical Development,” provides a comprehensive framework that emphasizes understanding and controlling formulation and manufacturing processes through a science- and risk-based approach, encapsulating the principles of QbD. 


Regulatory Alignment 


Agencies like the FDA are promoting QbD, recognizing its potential in improving pharmaceutical development. Implementing a QbD framework for CMC submissions aligns your strategy with the current regulatory expectations, potentially streamlining the review process.  


  • Promotion by the FDA: The FDA has been a keen promoter of QbD, recognizing its potential to enhance pharmaceutical development and regulation. This includes guidance and initiatives focusing on innovation and efficiency in pharmaceutical manufacturing. 

  • Alignment with Current Expectations: QbD principles are harmonized across various FDA guidelines, such as the Quality Systems Approach to Pharmaceutical CGMP Regulations and the guidance on PAT (Process Analytical Technology) — a system for designing, analyzing, and controlling manufacturing. 

  • Streamlining the Review Process: The FDA’s support for QbD can potentially expedite the review process, provided that the submissions are consistent with the principles defined in guidelines like Q8, Q9, and Q10. 


Risk-Based Approach 


Risk management is at the core of QbD. Mitigation strategies can be implemented by identifying and understanding potential risks early in the process, resulting in a robust manufacturing process and high-quality product.  


  • Identification of Risks: QbD encourages early identification and understanding of potential risks, allowing the development of a robust manufacturing process. This aligns with the FDA’s guidance on Quality Risk Management (Q9), which provides principles and examples of tools for risk assessment. 

  • Mitigation Strategies: Through systematic evaluation, control, communication, and review of risks, mitigation strategies can be crafted to ensure consistent quality, complying with the FDA’s expectations on risk management. 

  • Resulting in a Robust Process: The FDA recognizes that understanding and controlling risks lead to a robust manufacturing process, a hallmark of high-quality product development. 


Building a QBD Framework for CMC Submissions: Key Components  


Identify Quality Attributes 


Understanding a product’s Critical Quality Attributes (CQAs) is the foundation of the QbD framework. These CQAs must be carefully defined, analyzed, and controlled.  


Defining Critical Quality Attributes (CQAs): CQAs are essential properties or characteristics that should be within an approved limit to ensure the desired product quality. Identifying and understanding these attributes are fundamental to the QbD framework.  


FDA Guidance Alignment: The FDA’s Guidance for Industry, “Q8(R2) Pharmaceutical Development,” emphasizes the importance of identifying CQAs, linking product quality to safety and efficacy. By understanding CQAs, companies can develop a targeted control strategy to ensure that the product meets the necessary quality standards.  


Implement Design of Experiments (DoE) 


A scientific and statistical approach allows the understanding of variables and their impact on the process. Design of Experiments in a QbD framework guides the development of robust and optimized processes.  


Scientific and Statistical Approach: The design of Experiments is an organized, efficient method for determining the relationship between factors affecting a process and the output of that process. It’s a critical part of QbD in ensuring robust and optimized processes.  


FDA Guidance Alignment: FDA’s guidance on Process Analytical Technology (PAT) encourages the use of DoE to understand and control the process variables. The implementation of DoE is in line with the FDA’s mission to encourage innovative approaches to pharmaceutical development, manufacturing, and quality assurance.  


Analytical Method Development 

Robust analytical methods are needed to understand and control the CQAs, ensuring consistent quality throughout the product lifecycle.  


Robust Analytical Methods: The development of strong analytical methods is integral to understanding and controlling the CQAs, maintaining consistent quality throughout the product lifecycle.  


FDA Guidance Alignment: The FDA’s guidance document, “Analytical Procedures and Methods Validation for Drugs and Biologics,” underscores the importance of developing and validating analytical methods. This ensures the reliability, consistency, and accuracy of analytical data, aligning with the principles of QbD for product quality control.  


Continuous Improvement 

A QbD framework is not a one-and-done approach. Continuous monitoring and improvement ensure the product maintains its quality standards, adapting to new knowledge and technology.  


Ongoing Monitoring and Enhancement: QbD is a continuous process that adapts to new knowledge, technology, and process understanding. It involves regular monitoring, assessment, and improvement to uphold quality standards.  


FDA Guidance Alignment: Continuous improvement is aligned with the FDA’s Guidance for Industry, “Q10 Pharmaceutical Quality System.” This guidance emphasizes a commitment to continuous improvement across the product lifecycle, regularly evaluating quality performance and implementing necessary improvements.  




QbD is not merely a concept; it’s a comprehensive approach that aligns well with FDA guidance, aimed at redefining how pharmaceutical products are developed and manufactured. Through enhanced understanding, regulatory alignment, and a risk-based approach, the industry can achieve unprecedented quality and efficiency. By leveraging Enkrisi’s experience and expertise, your organization can embrace this paradigm, ensuring compliance with regulatory guidelines and leading the way in pharmaceutical innovation.  


The QbD approach resonates with a series of FDA guidances that together form an integrated perspective on product quality. From identifying quality attributes to implementing design experiments, developing robust analytical methods, and ensuring continuous improvement, QbD offers a comprehensive, risk-based approach to quality that is in harmony with regulatory expectations.  


The Enkrisi Approach  


Building a QbD framework for CMC submissions is not an easy task. It requires in-depth knowledge, skilled resources, and a clear vision. At Enkrisi, we understand the complex interplay of factors that make up a successful QbD implementation. Our comprehensive services, ranging from formulation to regulatory compliance, ensure a seamless transition into this new paradigm of pharmaceutical development.   

With an unwavering commitment to excellence and innovation, Enkrisi is uniquely positioned to guide your organization in adopting this revolutionary approach. Together, we can redefine what’s possible in pharmaceutical development, shaping the future of an industry that impacts lives around the world.   

For further insights and a tailored solution to your QbD needs, contact Enkrisi today. Let’s take this exciting journey together.   

Enkrisi’s in-depth understanding of these principles and alignment with regulatory guidances ensures that our clients are at the forefront of this revolutionary approach. Together, we can navigate the complexities of QbD, creating products that meet and exceed quality expectations. By building quality into the process rather than testing it, we can redefine what’s possible in the pharmaceutical landscape.   

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