Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

The application of the quality by design approach for the analytical method development in the pharmaceutical industry

Muhammad Zahid Iqbal (Abschlußjahr: 2015)

Summary
Language: English
The QbD concept is based upon the theory that the quality should not only be tested but be designed into the product or processes. The US federal drug agency encourages the enhanced approach (risk based) and the adoption of the QbD framework for the pharmaceutical product development and manufacturing.  The regulatory background of the QbD paradigm is based upon the issuance of the ICH Q8 (R2) (pharmaceutical development), ICH Q 9 (Quality risks management) and ICH Q 10 (Pharmaceutical quality system). These documents have been helpful for the establishment of the groundwork for the QbD framework, but still the lot of information has been missing in these documents. For example the ICH Q 8 (R2) outlines the QbD framework for the formulation development but it does not explicitly describe its application for the analytical method development.
A very reliable and robust analytical method is always required for the assessment of the quality of the pharmaceutical product and to insure the patient safety. The development of the HPLC analytical technique for the impurities profiling of the drug substance is one of the most important, challenging and complex technique to develop. The HPLC analytical method development starts rightly from the beginning of the pharmaceutical development for example during, the screening phase of the new chemical entity, the non-clinical and clinical phases, the formulation development and the stability studies.
In most of the cases the HPLC analytical method development technique is being developed by using the one factor optimization approach. The one factor optimization approach is done by changing the one variable and keeping the all other parameters constants. This approach is, also called as the trial and error approach, very time consuming. Another disadvantage of the one factor optimization approach is that it does not explore the factors interaction effect on the quality of the results.
The QbD framework can also be implemented to HPLC analytical method development just like the formulation development of the medicine. The QbD framework for the HPLC method development has these elements analytical target profile. Critical quality attributes risks assessment, method operable region, control strategy and continuous improvement. These elements are interlinked with each other in a systematic way. In the QbD framework, the design of experiments is the key methodology for exploring its elements and for the creation of the design space. The one of the main advantage of the design of experiments approach over the one factor optimization approach is that it gives more understanding of the process by screening the critical factors and their interaction effects on the quality of the results. The statistical results from the design of experiments help to establish the design space and control strategy for the analytical method. The movement within the design space does not require any regulatory approval and grants regulatory flexibility.
In this work, the QbD approach has been implemented for the impurities profiling of metformin drug substance. In this work, the introduction chapter elaborated the importance of the QbD framework and also the importance and regulatory requirements upon the results of the HPLC analytical technique. In the second chapter of this work, all the elements of QbD approach have been discussed in detail and its adoption for the HPLC analytical method development. The third chapter of this work is about the design of experiments covering its various types such as critical parameters screening design, optimization design and robustness testing design. This chapter also discuss about the essential graphs and ANOVA calculation necessary for the model building of the critical quality attribute. The fourth chapter of this work outlines how the QbD approach has been implemented for impurities profiling of metformin by defining, the analytical target profile, the risks assessment, the identification of the critical quality attribute. The critical process parameters and their ranges were screened by using the fractional factorial design. This investigation had leaded to the conclusion that the percentage of the salt in water and its pH in mobile phase are the most critical factors. These factors and their ranges have enormous impacts on the critical quality attribute of HPLC analytical method. The CQAs were further investigated by using the central composite design for the response surface modeling. The results of the central composite design helped to create the design space and control strategy by meeting the all requirements of the method for its intended use.
Pages: 38
Appendixes 6, Pages: 12