Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

ICH Q11 - Potential Regulatory Implications for the Development and Manufacture of Synthetic Drug Substances Using an Enhanced Approach ***

Dr. Markus Weidlich (Abschlußjahr: 2012)

Language: English

The application of the "traditional approach" to develop and manufacture novel drug substances mostly leads to a low regulatory and manufacturing flexibility. This is based on an empirically derived developmental process and consequently on the lack of understanding of interdependent critical process parameters, material attributes and quality attributes impacting the performance of the final drug substance.

The implementation of the Quality by Design (QbD) paradigm includes the application of science and risk-based approaches, which enables systematic pharmaceutical process development using sophisticated multivariate experiments, design spaces and control strategies.

In order to harmonise the regional differences in data requirements and data presentation on synthetic and biotechnological/biological drug substances in the context of regulatory submissions, the ICH published guideline Q11, which is currently under regulatory consultation (step 3).

The main aims of ICH Q11 are the clarification and guidance to apply the principles described in ICH guidelines Q8(R2), Q9 and Q10 on the development and manufacture of drug substances as well as the definition of required regulatory information to be provided in CTD sections 3.2.S.2.2 3.2.S.2.6.

The development of fictional case studies ("mock-up studies") based on QbD is highly appreciated by the community of the pharmaceutical industry and regulatory bodies, as a possible outline for the systematic presentation of information in accordance with valid regulations is given.

This thesis presents the simplified case study of the fictional synthetic drug substance linebacide to give an overview on the presentation of regulatory information in the framework of an enhanced development approach according to guideline ICH Q11.

The application of risk assessment tools (e.g. failure mode, effects and criticality analysis (FMECA)) facilitates the identification of critical quality attributes (CQAs) in linebacide. Furthermore, critical process parameters (CPPs) negatively impacting the occurrence of a toxic impurity during synthesis of the drug substance are identified. The conduct of DoE studies reveals multidimensional interactions between the determined CPPs and allows the establishment of a design space. Finally, the development of a partial control strategy based on the risk assessment of critical parameters of a selected HPLC method is described exemplarily.

The application of an enhanced, Quality by Design approach, presented in draft guideline ICH Q11, provides a drug substance manufacturer with high regulatory flexibility, manufacturing flexibility and operational flexibility. This potentially leads to a faster regulatory assessment, less post-approval changes, the continual improvement of the manufacturing process and therefore to an effective Return on Investments.

Pages: 63,
Annex: pages: 30