Tug of War

At last month's CMC Strategy Forum on Quality by Design (QbD), the discussions, as always, were refreshingly candid. Those conversations highlighted some core differences of opinion between members of industry and regulators. This time, the particular manifestation of this disagreement was non-critical process parameters. Do companies need to provide ranges for them, even though they are not critical? Do they belong in the design space? And should they become part of the company's regulatory commitment?

Laura Bush

The underlying issue, of course, is the same one that has been at the heart of the QbD initiative since its inception. Can companies that demonstrate a high degree of process and product understanding gain "regulatory relief"—greater freedom to make manufacturing changes (improvements) without regulatory involvement? Company representatives, of course, argued for more flexibility. The regulators showed a willingness to hear the case for reduced oversight, but expressed concern about letting go too much. In particular, regulators pointed to the potential for unexpected consequences of manufacturing changes, particularly at the edges of a design space or if the interaction of critical quality attributes is not fully understood.

In a hallway conversation, one member of industry shared his frustration over the FDA's reluctance to grant companies more freedom. "The agency should see that companies like ours have excellent scientific knowledge, and can manage our quality with greater flexibility," he said. "Yes," I said, "But not all companies are like yours. Some don't have as much experience, and others flout the rules."

As it turns out, just as we were wondering if the FDA could grant companies more freedom, only a few miles away in Washington, moves were being made to strengthen the FDA's oversight: US Representative Ed Towns (D-NY) introduced a bill giving the FDA mandatory recall authority.

The bill was prompted by recent recalls of several over-the-counter drugs made by McNeil, Johnson & Johnson's consumer division. None of the defects posed a serious health risk, but the incident raised concern because of apparent gaps in the company's quality systems, such as a failure to properly investigate consumer complaints about foreign particles. What's worse, the company is accused of having delayed reporting problems to regulators, and of having quietly removed products from shelves without formally recalling them, to reduce scrutiny. The issue was particularly unsettling precisely because it happened at a Big Pharma company that you assume will resolve such matters openly, swiftly, and fully.

As I watch this QbD debate, I find myself rooting for regulatory relief. We all want to see the continuous improvement that can come from it. Yet the McNeil case reminds us that product quality derives not just from the process and product understanding that can come out of process development, but from proper execution of the full gamut of actions required by cGMPs. Thus, regulatory relief requires that regulators trust companies to know what they are doing, and to do it—consistently.

Will the industry ever earn that trust from regulators? It's hard to say. At best, it will happen only slowly. As the FDA's Steven Kozlowski put it, "It's a bit like when your child goes off to college. At first, you want to have a lot of phone calls. Eventually, over time, you may become comfortable that he or she is acting responsibly and needs less attention."

So far, it looks like we are in for a long freshman year.

Laura Bush is the editor in chief of BioPharm International, lbush@advanstar.com