Since the beginning of this century, the pharmaceutical industry has been experiencing a new era that is far more scientific, technologic, and sophisticated than anyone would have imagined. FDA’s Quality by Design/Process Analytical Technology (QbD/PAT) initiative states that “Quality cannot be tested, but should be built into the product’’. This initiative plays a critical role in ending the traditional ‘’trial and error’’ product development. Yet, “semi-traditional” SUPAC (Sacle-Up and Post Approval Changes) applications continue to be an alternative to the QbD approach.
The process of pharmaceutical product development by QbD is well described by means of the ICH Guidelines Q8 for pharmaceutical development, Q9 for quality risk management, Q10 for pharmaceutical quality systems as well as the FDA’s own guidelines and case studies. However, despite the well-established documentation on the QbD/PAT and the wide range of available PAT tools, the number of pharmaceutical companies adopting this approach remains limited. This is mainly due to the lack of “knowledge and skills” which are essential for building quality into product development.
Lack of knowledge on the mechanistic understanding of how formulation and process factors impact product performance may (and will highly likely) break the QbD chain of “Product profile - Critical Quality Attributes (CQAs) - Risk Assessment - Design Space - Control Strategy - Continual Improvement” at some stage. For example, a successful risk analysis requires in-depth knowledge of the physicochemical and mechanical properties of the formulation components, understanding the mechanistic of each unit processes, determination of critical process parameters, and the interactions between the active drug substance, excipients, and process parameters. Risk Analysis should be performed from the design phase to the end of product development, where the failure of such analysis is likely to offset the benefits of QbD efforts.
Bearing in mind the yearly cost of batch rejection to the pharmaceutical industry worldwide (billions of dollars), proper determination of Design Space is a highly critical aspect of QbD studies where, again, in-depth knowledge is essential since the outcome of such determination will be the “key” for eliminating/minimizing batch rejections during manufacturing. It is up to the QbD applicants to prove to the regulatory body that the outcome of Design Space study will provide robust manufacturing of their product.
The continued success in all areas of pharmaceutical product development will depend entirely on how fast the pharmaceutical scientists will adapt to the rapidly changing technology in terms of manufacturing efficiency and productivity. For example, continuous processing in pharmaceutical manufacturing is a relatively new approach that has generated significant attention (especially since the QbD/PAT initiative) while it has been used for decades in other industries. The shift from pharmaceutical batch processing towards a more continuous manufacture poses regulatory as well as technological challenges. While defining the batch/lot number and raw material traceability present regulatory challenges, technical hurdles arise from the pharmaceutical processes (which are typically characterized by a large variety of unit operations to manufacture a pharmaceutical product), as they can easily result in a complicated dynamic behavior once the processes are connected.
PAT tools are extremely useful in making sure that quality is built into product and process (batch or continuous) by design and based on scientific understanding, one should not forget that increase of in-process sample size or automated end product testing or real time monitoring (on-line, in-line or at-line measurement) alone will not qualify as PAT.
In this issue our readers will hopefully enjoy and benefit from articles addressing the application of PAT tools, and QbD to the study of tablet dissolution, coating, granulation and optimization of selected solid and liquid dosage forms.
Sincerely,