Application Of QbD Principles In Development And Validation Of HPLC Method

In recent years, along with the study and research of quality management of drugs, the mode of quality control is changing all the time. And the concept of QbD (Quality by Design) was been accepted and implemented.In the year of 2004, FDA confirmed the concept of QbD. And it was taken into ICH Q8 (Pharmaceutical Development) and Q9 (Quality Risk Management). Its main content was to make the predefined target product quality characteristics as the starting point of the research and development.Through understanding the key material properties and design of experiment, the key attribute quality products could be found, and the key process parameters could be confirmed. Taking all influence factors into account, set up a robust design space which can satisfy the product performance. And according to the design space, a quality risk management strategy and quality control strategy could be set up. At present, QbD is mainly used in the research and production of new drugs in the global pharmaceutical industry, but ICH Q8 guidance explicitly pointed out that it can also be used in the evaluation and validation of pharmaceutical analysis method. There are very few researches of QbD on the international, and many of them are in the primary stage. But with its progressive and the support of FDA and ICH, the wide application of QbD will be the trend.In this paper, we made QbD into the building and validation system of HPLC analysis methods. Taking the HPLC analysis method of high risk proton pump inhibitors of Pantopraole for example, a whole process of building and validation of HPLC analysis method by QbD was introduced. From the building of method to risk evaluation, through the validation, then a complete set of HPLC analysis method of quality control strategy was built.The dissertation is divided into six chapters as follows:In chapter 1,we briefly introduced the background and significance of the project.Mainly focused on the concept of QbD and its background and significance application in the global pharmaceutical industry.And we introduced the significance,tools and process of the building and validation of HPLC analysis method by QbD.And several softwares which could be used in QbD was been introduced too.In chapter 2, we used DryLab software to study the traditional HPLC analysis method of Rabeprazole Sodium. The main purpose is to validate the robustness of HPLC method, when there was only one or two parameters. The variable parameters of three intances were pH, organic phase content and both of them. According to the design of experiment, the parameters'scope in which the HPLC method was robust was established, and the optimum value was found.In chapter 3, a HPLC analysis method of the related Substance of Pantoprazole Sodium was built and validated by DOE. First, according to the 2010 edition pharmacopoeia, after the preliminary experiment, an available HPLC method of which the peak of API, impuritie A and B could be resoluted absolutely.The method was named Method I. Through the risk assessment, variable parameters and their scopes were determined. Then validate the parameters'scopes by Hunter design of JMP software.We got the critical parameters which lead to the failure of Method I, adjusting them to a scope in which Method I was valid, the scope was operating space. At last, according to the operating space and control space which was provided on pharmacopoeia, a quality control strategy was seted up.In chapter 4, a HPLC analysis method of the related Substance of Lansoprazole was built and validated by DOE. First, according to the pharmacopoeia, after the preliminary experiment, an available HPLC method of which the peak of API, impuritie A and B could be resoluted.The method was named Method II. Through the risk assessment, variable parameters and their scopes were determined.Then validate the parameters'scopes by Plackett—Burman design of JMP software.We got the critical parameters which lead to the failure of Method II, adjusting them to the operating space. Then according to the operating space and control space which was provided on pharmacopoeia, a quality control strategy of Method II was seted up.In chapter 5, a HPLC analysis method of the related Substance of Rabeprazole Sodium was built and validated by DOE. First, according to the pharmacopoeia, after the preliminary experiment, an available HPLC method of which the peak of API, impuritie A and B could be resoluted.The method was named Method III. Through the risk assessment, variable parameters and their scopes were determined.Then validate the parameters'scopes by response surface design of JMP software.An robust operating space was founded.At last, according to the operating space and control space which was provided on pharmacopoeia, a quality control strategy of Method III was seted up.Chapter 6 was a summary of the whole studies and researches. In consideration of different premises and requirements, different DOE designs were adopted to the building and validation of HPLC method. Although the designs of experiment were different, the thread and process were the same.They all aimed at exploring the operating space, and seting up a more perfect quality control strategy. This paper was a preliminary study of application of QbD. It combined the scientific and practical well. And it could be a reference and guidance of drugs analysis method development for Pharmaceutical industry.