Development & Application of Advanced QbD Concepts

Abstract
The new and modern concept of quality by design (QbD) ensures the quality and performance of a medicinal product by designing effective and efficient manufacturing processes, whose product and process specifications are based on a mechanistic understanding of how the formulation and process factors affect the product’s performance. Based upon preliminary theoretical and practical work of project A1.5, project A1.5b primary focuses on establishing practical approaches to QbD implementation in routine pharmaceutical manufacturing and quality management processes. The main objectives are to (i) develop and further elaborate process models for a systematic pharmaceutical development in the line of QbD and (ii) apply these models and associated expert tools to establish process knowledge with regard to the specific industrial partners’ use cases and (iii) leverage this understanding to generate quality-increasing and cost-saving benefits for the internal development and quality assurance approaches. The key focus is on using computer simulations to perform reliable data generation within a regulated pharmaceutical environment using efficient validation methods to prove the predictive capability and robustness of a simulation within a sufficiently small confidence interval.

Project Goals

• A detailed generic process model that guides the systematic and science-based performance of an efficient and effective pharmaceutical development and the establishment of optimized manufacturing processes
• Documented experience on leveraging QbD-generated process and product understanding for the implementation in routine pharmaceutical manufacturing and quality assurance processes and with regard to regulatory expectations
• Establishment of added-value benefits for the industrial project partners with respect to understanding and control of their specific products and processes
• Application strategies for computer simulations in a GMP-environment

Present Project Results
Based on the QbD guideline document established in the former project A1.5, the proposed concepts have been further developed and implemented with a special emphasis on the industrial partners’ use cases.  Innovative tools for process and equipment development and optimization have systematically been used to achieve a sound understanding and to define process conditions and equipment design for optimized pharmaceutical manufacturing. Furthermore, computer-simulations-based data generation has been challenged. On the one hand, simulations have been used in combination with risk assessment tools at an early stage of process characterization as a screening application to determine potentially critical input factors (e.g., raw material characteristics, process parameters, equipment design) and to prioritize them for further “real-life” process characterization. On the other hand, simulation approaches have been used directly during the main phase of process characterization. In the pharmaceutical process development, both applications have great potential with regard to the streamlining development and the manufacturing resources and costs.

Project Challenges
An efficient validation strategy to prove the predictive capability and robustness of a simulation within a sufficiently small confidence interval is an indispensable prerequisite for using computer simulation tools in a pharmaceutical environment. To that extent, additional project activities will be performed to define verification strategies for the simulation approaches. The ultimate goal is to include simulations along with real-life data generation into a pharmaceutical dossier. Although much remains to be done with that regard, this project has laid an important foundation for future work.

Project related Publications
Adam S., Suzzi D., Radeke C., Khinast J.G., 2011. An Integrated Quality-by-Design (QbD) Approach towards Design Space Definition of a Blending Unit Operation by Discrete Element Method (DEM) Simulation.  Europ. J. Pharm. Sci. 42, 106-115.

Adam S., Suzzi D., Toschkoff G., Khinast J.G., 2011. Application of Advanced Simulation Tools for Establishing Process Design Spaces within the Quality-by-Design Framework. Submitted as book chapter.

Hörmann T., Suzzi D., Adam S., Khinast J.G. DOE-based CFD optimization of pharmaceutical mixing processes. Journal to be defined.

Adam S., Suzzi D., Toschkoff G., Hörmann T., Radeke C., Khinast J.G., 2010. An Integrated Quality-by-Design (QbD) Approach towards Design Space Definition of three Key Unit Operations in the manufacturing of solid and liquid dosage forms by Discrete Element Method (DEM) and Computational Fluid Dynamics (CFD) Simulation. Presentation at the CESP 2010.

Gübitz B., Khinast J.G., 2011. A Risk Management Ontology for Quality-by-Design Based on a New Development Approach According GAMP 5.0. Expert Systems with Applications.