Incorporating Quality-by-Design Principles in LC-MS/MS Method Validation

Quality-by-design is a robust concept that can be applied to control and reduce variability at different phases of drug development. Any bioanalytical method that reduces reportable results can complement the quality-by-design concept. The quality-by-design approach is a risk and science-based system that leverages knowledge acquired from traditional method development and validation throughout the entire life cycle of a drug product. 

Method development assessments include modifications of experimental studies and risk evaluations. These assessments include experimental designs to develop and generate the preliminary knowledge base, clearly identifying the effects of LC-MS testing on the bioanalytical procedure and other operating conditions. Once LC-MS services develop a suitable method, the focus is on verifying the system and developing controlled strategies to establish the working protocol based on the available data. Only after a robust LC-MS method development and validation, researchers can use the system for routine purposes. The current article discusses incorporating quality by design principles in LC-MS/MS method validation. 

Quality by design principles in LC-MS/MS method validation

Quality should be an integral component of experimental design. An adequate understanding of drug development studies and manufacturing proves critical to understanding the scientific background in quality-by-design models. The ICH guidance describes quality-by-design as a systematic approach incorporating redefined objectives and emphasizing process and product understanding based on risk management and sound science. 

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The analytical understanding obtained from the method development initiative can be used to design LC-MS testing elements and manage any associated risk factors. The primary objective of the quality-by-design approach is to develop an appropriate system by understanding individual performance to achieve the desired result. Continuous improvement is a major element in achieving such desired performance, which in turn depends on the expertise gained during the preliminary development phase. In later stages of drug development and bioanalytical method development and validation, the concept of quality-by-design drifts towards achieving a desired system with adequate regulatory flexibility. In this stage of LC-MS/MS method development, researchers focus on developing adequate scientific knowledge, quality risk assessment, superior study design process, analytical technology tools, design of experiments, and continuous improvement in learning and drug life cycle management. 

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LC-MS testing is integral to drug discovery and development. While developing any pharmaceutical product, LC-MS method development and validation go hand in hand with the life cycle of the pharmaceutical product. Traditional LC-MS method development and validation are tedious. Hence incorporating quality-by-design principles in LC-MS/MS method development and validation can help eliminate several limitations encountered during the development and validation of LC-MS systems. Today researchers are focused on incorporating quality-by-design approaches to enhance the performance, flexibility, and robustness of LC-MS services. 

Employing quality by design to LC-MS/MS method validation has several advantages, such as:

  • Increased control and understanding of drug development studies
  • Fit-for-purpose ICH-based method validation protocols
  • Increased flexibility in analyzing drug compounds, impurities, and metabolites in complex biological matrices
  • Reduced variability and enhanced method robustness
  • No need for revalidation
  • Finally, smooth transition of LC-MS systems to production levels

In conclusion, incorporating quality-by-design approaches in LC-MS/MS method validation is critical for robust and cost-effective drug development initiatives. 

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