Setting forth a plan
FDA is working on new strategies for linking QbD investments to regulatory relief. Instead of negotiating a firm regulatory
agreement as part of bringing a new drug to market, CDER officials are talking about devising a CMC postmarketing plan (PMP)
that provides a roadmap for FDA and manufacturers to manage postapproval changes. Companies would collect data on critical
quality performance and design controls during product development. They would include this information in the market application,
along with a list of anticipated changes in equipment, process, site, and other procedures. The PMP would distinguish between
upcoming changes that are not expected to affect product quality, and thus not likely to require a supplement application,
from significant changes such as site relocation, which would likely require a supplement.
Winkle hopes to implement the PMP program in the coming months, initially for drugs and later for biologics. The PMP concept
has been described as an "individual SUPAC," which reflects some similarities to FDA's earlier Scale-Up and Post-Approval
Changes initiative. SUPAC aimed to streamline reporting requirements for postapproval manufacturing changes based on dosage
forms. Difficulties in establishing broad reporting policies for a wide spectrum of products, though, ultimately led to SUPAC's
FDA also wants to reduce manufacturing supplements across the board. At the January WCBP meeting, Winkle expressed hope that
a much-anticipated new policy for eliminating many supplements would soon be published in the Federal Register. FDA held a
public meeting in February 2007 to discuss options for revising CMC supplement regulations (see "Down with Supplements!" Pharmaceutical Technology, April 2007).
Agency officials discussed how new tools and approaches that let manufacturers assess and manage product risks and establish
quality systems should permit modifications to policies that manage the postapproval manufacturing process. These developments
could support changes in policies that inhibit manufacturing process improvements and, instead, encourage companies to adopt
quality-systems approaches. FDA has prepared a guidance and a proposed new regulation to eliminate most changes-being-effected
Manufacturers now must file supplements to inform the agency of most changes made to processes, equipment, packaging, and
other elements that will alter the product. Significant changes require prior FDA approval. Innovations that are unlikely
to compromise product safety or efficacy can be described in a CBE supplement and implemented without the agency's sanction.
A company must wait 30 days after filing certain CBEs before it can make the change. But the CBE process still requires FDA
to examine thousands of supplements every year. Filing a supplement also involves a good deal of work for the manufacturer.
If a change is important enough to warrant filing a supplement, says Winkle, it likely requires a prior-approval submission.
Site relocations generally fit this category because they often involve installing new equipment and altering production processes,
and a field inspection of the new facility is usually required.
Most routine changes, though, would be submitted in annual reports that manufacturers file with FDA. This approach would expand
the role of FDA's field force in assessing on site the impact of a greater number of postapproval manufacturing changes described
in companies' annual reports.
Manufacturing executives would like more similarity between the submitted annual report and their companies' internal annual
product reviews, which are kept at the manufacturing site.
Facing new challenges
A reduction in supplements will help CDER deal with its expanding workload. But the broader goal is to encourage manufacturers
to incorporate QbD and risk management approaches into production processes. Adopting these approaches will ensure drug quality
throughout a product's life cycle. A flexible approach to managing change will encourage process improvement, which, in turn,
will raise production yields and simplify manufacturing processes.
Although many pharmaceutical companies say they have been adopting QbD practices for several years, they still have many questions
about QbD policies, about how much information to share with regulators, and about differences between FDA and European QbD
One challenge for FDA, says Winkle, is to apply these QbD policies to legacy products that have no QbD data in their original
applications. Some manufacturers may gather QbD information for legacy products to establish a CMC postmarketing plan and
gain flexibility in managing change. Others will not want to invest resources in such an undertaking for older products.