Application of a Statistical Approach to the Process Development of Futibatinib by Employing Quality-by-Design Principles. Part 2: Development of Design Space for Impurities Using the Response Surface Methodology

Abstract

This study aims to construct a design space of impurities for risk assessment based on the quality-by-design concept through focusing on the design of experiment and statistical analysis. First, we identify multiple regression equations for critical process parameters of impurities using face-centered composite design, which is a type of response surface methodology. Next, a design space is constructed by these prediction models for analyzing the risk of the impurities. Finally, this risk is evaluated by process understanding and control ranges in the construction of a control strategy. This study proves that the commercial manufacturing method is a robust process and futibatinib can be stably produced.

Efficient Process Development of Abiraterone Acetate by Employing Design of Experiments

“…Due to these impurities, the maximum isolated yield obtained was about 65%. Optimization of reaction conditions tended to improve the conversion and selectivity using the design of experiments (DoE) − approach. In the DoE study, based on the risk assessment using fishbone analysis (Figure ), three critical parameters, mole equivalents of iodine, TMG, and reaction temperature, were identified.…”

Olaparib Process Development Employing Quality by Design (QbD) Principles

“…Risk assessment through the Ishikawa diagram, heat maps, and FMEA remain widely used tools to assess risk in the pharmaceutical industry. [7][8][9][10]20 Several precedented literature examples illustrate this approach to identify the key material attributes (KMAs) and key process parameters (KPPs) for the reaction stages. These identified KMAs and KPPs are later studied using the DoE trials to gain in-depth insights into the impact of changes in factors (KMAs and KPPS) on the desired responses.…”

“…This work focuses on QbD as a systematic risk-based approach to Olaparib 1 (API) development, manufacturing, and lifecycle management. Each of the three chemical transformations was separately studied by employing QbD principles and optimized using the design of experiments (DOE) − to achieve maximum reaction conversion, excellent chemical purity, and isolated yield.…”

“…The International Council for Harmonization (ICH) Q9 defines the risk assessment and the approaches that can be used for design irrespective of what stage the product is and should be integrated with ICH Q8 with ICH Q10. Risk assessment through the Ishikawa diagram, heat maps, and FMEA remain widely used tools to assess risk in the pharmaceutical industry. − , Several precedented literature examples illustrate this approach to identify the key material attributes (KMAs) and key process parameters (KPPs) for the reaction stages. These identified KMAs and KPPs are later studied using the DoE trials to gain in-depth insights into the impact of changes in factors (KMAs and KPPS) on the desired responses.…”

Utilization of Quality by Design, Kinetic Modeling, and Computational Fluid Dynamics for Process Optimization and Scale-Up

“…After the selection of critical quality attributes, the risk assessment was conducted using failure mode and effect analysis (FMEA) (Table ) to identify the potential critical process parameters (CPPs) and critical material attributes (CMAs), which could substantially impact the final critical quality attributes (CQAs) like the conversion of starting material 16-AHP ( 1) , epimer A, and impurity 2 formation, etc. The risk scoring and risk priority number (RPN), which are calculated as a product of severity, probability, and detectability, have been followed as discussed in the literature. − …”