The International Conference on Harmonization (ICH) Q8 and Q9 guidance documents2,3 , for example, define a scientific approach to process characterization, advocating a quality by design framework. Risk management is an integral part of this approach.Similarly, the US FDA's "GMPs for the Twenty-First Century" initiative focused on quality by design, risk management, continuous process improvement, and quality systems. Rolled out in 2004, this initiative challenged industry's traditional approaches to ensuring product quality by encouraging employees to look beyond traditional inspection methodologies for ensuring product performance. The early process and product characterization emphasized in the quality-by-design and risk-management approaches do not inherently conflict with validation. On the contrary, by deepening the level of scientific understanding of a manufacturing process, the approaches ensure that a process is well understood before it is considered "validated." Methods that involve continuous improvement and real-time control, however, do pose a significant question: Are these quality methods inconsistent with the basic tenets of validation that have served as the backbone of the industry's quality structure for so many years? Once you have "validated" a manufacturing process, how much can you improve it—through real-time control or any sort of continuous improvement step incorporated into Lean, Six Sigma, etc.—without having to file manufacturing supplements with FDA? How much of an impediment are those filing requirements?
THE VALIDATION PARADIGM
The challenge of validation is that it has been viewed as a necessary evil—a regulatory activity that cannot be avoided when manufacturing regulated products. The effort and cost associated with validation continue to escalate as industry and regulatory groups increase their understanding of pharmaceutical processes and identify an increasing number of process variables that must be controlled. Biotech adds another layer of complexity by introducing the qualified pilot or intermediate-scale model as an integral component of the validation equation.4
The prohibitive cost of characterization studies at full scale requires us to establish clear, scientific arguments to show how process development studies relate to full-scale validation lots. The complexity of biotech processes demands an even higher level of scientific argument. As we increase our understanding of biopharmaceutical processing, the value associated with traditional validation diminishes, and industry responds accordingly.
The integration of equipment validation and process validation provided incentive to measure the capability of our processes and analytical methods. However, somewhere along the way, the incentive for validation shifted from a need to measure processes, to a need to satisfy a regulatory requirement as quickly and as cheaply as possible.