by Joe Cobb, R. Justin Brett, Michael D. Ruff, Anthony Berry, Robert Epps

OBJECTIVE
To improve robustness of a core tablet for a novel modified release oral solid dosage form using Quality by Design (QbD) principles.

General Background
As stated in the International Conference on Harmonisation Harmonised Tripartite Guidance on Pharmaceutical Development, ICH Q8 (R2), “The aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product.”1 Several tools are available as guidance issued by FDA such as “Quality Systems Approach to cGMP Manufacturing”2 that includes ideas such as Quality by Design (QbD) in the development process. This guidance, amongst others, lay the framework for expectations of regulatory reviewers in their examination of client submittal documentation.

This project involved first the technical transfer of a formulation and process of a novel modified release oral solid dosage form (i.e. an active core tablet with an a series of coatings that modified the release and delivered additional quantities of the same active ingredient) that was originally manufactured at a relatively small scale. The next step was a scale-up of the process to commercial scale but due to time constraints not all of the unit operations had been completely optimized. Upon discovering processing issues such as relatively high friability and low breaking strength of the core tablets the client agreed to proceed with optimization utilizing principles of QbD.

The first step of the QbD process was to establish a Quality Target Product Profile (QTPP) for the core tablets. The second step was to determine the Critical Quality Attributes (CQA) of the core tablets. The third step incorporated a risk assessment exercise to identify the Critical Processing Parameters (CPP). The final step involved drafting an informal Design of Experiments (DOE) to determine optimal settings of the CPP’s for the critical high shear wet granulation process.