To determine critical quality attributes (CQAs), for example, which risk assessment methodology is best—FMEA, PHA, HACCP—or none of the above? Is it better to have two rankings (critical and non-critical), or include a third level, such as "key"? At what point should one account for process capability? (For views on some of these questions).
Then, how can one use CQAs to develop a design space? Which parameters can be assessed accurately with scale-down models, and when do you need to test at a larger scale? How are the data generated during design space development translated into process ranges for routine manufacturing? And in a "flexible manufacturing process," who makes the decisions to shift parameters based on variable unit operation inputs—process experts on the floor, or quality or process development personnel?This complexity is fascinating. These challenges, however, lead naturally to questions of how much work this requires, how many companies have the resources to do it, and what the payoff is for anybody.
Few small biotechs will have the time or money to prepare a QbD filing. No matter, said Steve Kozlowski, director of the FDA's Office of Biotechnology Products; companies can still file using the conventional approach, or apply just some aspects of QbD. It doesn't have to be "total QbD or no QbD," he said.
But the volumes of data involved in full QbD filings can make even large companies nervous. Clearly, agency reviewers need sufficient information to understand how a company arrived at its conclusions to evaluate if they agree; that is their job. But the fear always arises: What will reviewers do with all that information? And will the data prompt so many questions that it will prolong the review?
And will all this work be worth it? Something called "regulatory relief" has always been the promise of QbD, but it is still unclear what that means, or how significant such relief might be.
Many in the room expressed optimism that some reduction in regulatory oversight will result—at least eventually— from QbD, allowing companies to make process adjustments and improvements without prior regulatory approval.
Ron Branning of Gilead Sciences (formerly of Genentech), however, said regulatory relief should not be the only driver for QbD projects."When is it not a good idea to understand your product and your process?" he asked rhetorically. "From a business perspective, it allows you to get the most from your operations, so you can be more profitable."
Most of the representatives from large companies seemed to agree. Furthermore, many said they have already seen one important gain from their work so far: improved internal communication, resulting from more interactions across functions like research, clinical, quality, regulatory, and process development. One participant took the argument for business benefits even further, saying there may be a business cost to not doing QbD.
At this stage, many questions remain about Quality by Design. The discussions at the CMC Strategy Forum, however, demonstrated that the industry and regulators are making good progress in clarifying areas of confusion and even disagreement, thus paving the way for future QbD submissions.
The FDA's upcoming QbD pilot program will be the next big test, and, I predict, the next big step forward. And one day, QbD will cease to be a theoretical concept and become a standard approach to process development.
Laura Bush is the editor in chief of BioPharm International, [email protected]