At the end of the 1990s, many pharmaceutical companies embarked on Six Sigma programs that brought chemometric tools such as design of experiments (DOE) and risk-analysis tools such as failure mode and effects analysis (FMEA) to developers. The Current Good Manufacturing Practices (GMPs) for the 21st Century initiative in 2002, the process analytical technology (PAT) guidance, and the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use's ICH Q8 Pharmaceutical Development and ICH Q9 Quality Risk Management have accelerated the acceptance of these engineering tools (1–4).
However, developers were initially confused about how to implement ICH Q8. Scientists wondered how to put the guideline into practice in the diverse product-development teams spread around the globe, whether one could only realize quality by design (QbD) by applying PAT, how a product team could track how a project moves toward realization of QbD, and how to ensure that knowledge increases after a product is launched.
As the concepts of QbD began to mature, the US Food and Drug Administration's Office of New Drug Chemistry (ONDC) announced a formal pilot program to provide additional information to help ONDC implement a new quality-assessment system to facilitate the submission and review of QbD in applications (5). The aforementioned tools found widespread use during the past decade. On the other hand, the integrated use of these tools in the research-and-development environment and their operational use in manufacturing settings have only been explored during the past several years. Similarly, the application of these tools in regulatory filings has evolved and continues to evolve in the regulatory, development, and manufacturing environments, mostly aided by exercising these practices as in the pilot program.The authors participated in the QbD pilot program for a postapproval change: an additional active pharmaceutical ingredient (API) manufacturing site and additional strengths of a product that had been granted accelerated approval one year before. The authors' contribution to the pilot program was not in the application of complex DOEs or PAT. Rather, it showed new ways of tracking the product knowledge, process, and material understanding, and how risk analysis is used to designate which process parameters or material attributes are critical and which are not.
If QbD is presented in too complex a way, one will struggle to implement it. It is therefore important to keep the message simple, find the right emphasis, and offer development teams the key tools to guide them along the path to QbD. Key tools include a target product profile, a multigeneration plan, a concept-selection matrix, prior knowledge of formulation and process platforms and materials, a project risk analysis, criticality management, a development plan, DOE, and PAT. Other systems such as technical-design review meetings, development-deliverables checklists, and stage-gate decision meetings ensure and control the progress of the project.
In addition, the development team must have scientific and quality-engineering or chemometrics competencies. When combined with scientific principles and relevant measurement responses, DOE is the most important tool for understanding causality in an efficient and multivariate way as well as the related factors and interactions. In contrast, the analysis of historical data (even from as many as 100 batches) that were not set up in a designed way, will never provide certainty about which factors are responsible for the observed variation. Most of the time, factors are confounded and show chance correlations. Initially, even PAT should once be combined with a DOE if one must understand causality.
Another important tool is criticality management, which the authors define as a systematic approach to define the critical quality attributes of the drug product; the critical variability in formulation, packaging, materials, and the manufacturing process; and how critical variability can be optimally controlled. Criticality management combines pharmaceutical product, process, and material knowledge (required by ICH Q8) and risk management (required by ICH Q9) in one approach, which is reflected in a single document. Just as in the risk-management process, criticality management assesses, controls, communicates, and reviews criticality. During process-technology transfer, the criticality-management document is transferred to manufacturing operations and updated with new knowledge that is acquired during technology transfer. This update will also happen after approval throughout the entire product life cycle.