That legislation divided manufacturing supplements into three categories: "major" changes require prior approval by FDA, while
"minor" changes can be described in an annual report and need no supplemental filing. About two-thirds of supplements fall
into the gray area of "moderate" changes, which require CBE and CBE-30 supplements. It took FDA years to issue new regulations
implementing this policy, along with additional guidance describing whether a CBE-30, CBE, or prior approval supplement should
be filed for specific changes to drug components, manufacturing sites, production processes, product specifications, container
closure systems, and labeling. Unfortunately, manufacturers continue to have problems determining which changes require which
kind of supplement. So FDA officials propose to start all over with new rules that better reflect current FDA risk-based regulatory
approaches and scientific advances in manufacturing and quality control.
Some manufacturers propose eliminating CBE supplements altogether and providing needed information on moderate changes in
annual reports. CBE supplements for packaging and testing site changes or for adopting equivalent or superior analytical methods
appear unnecessary. At a minimum, FDA and industry see a need to redefine "major" and "moderate" changes and other commonly
used terms. Phrases such as "moderate potential to adversely affect" a product are overly vague because almost any change
has some potential to affect a product.
While broad reductions in CBE supplements may be appropriate for conventional drugs, such a general revision may not fit regulatory
needs for biologics. CDER rejects only a handful of CBEs for drugs, but about 20% of postapproval changes for biologics raise
questions and lead to requests for additional data. One idea for biologics is to use policies governing comparability protocols
as a basis for managing postapproval changes. The challenge will be to design a flexible system, appropriate for the broad
range of biological products and varying quality control capabilities of different manufacturers.
KEEP THE OLD WITH THE NEW
An important issue for manufacturers is for FDA to retain its current postapproval changes policy for legacy products that
have extensive historical data on process parameters but little incentive to adopt QbD approaches. FDA acknowledges the need
to continue aspects of the existing regulatory scheme to "accommodate those manufacturers who choose to continue operating
within the current regulatory framework." But it will be a challenge for the agency to implement a modified approach for new
products adopting QbD and design space approaches, while retaining current policies for older products with established manufacturing
Policy revisions that rely more on annual reports to record postapproval-change information also point to the need to re-evaluate
the format and content of these documents. Manufacturers also urge better integration of annual reports, filed with FDA, and
annual product reviews, kept onsite for inspection. A reduction in prior approval and CBE supplements also shifts more responsibility
to FDA's field force.
Jill Wechsler is BioPharm International's Washington editor, 301.656.4634, firstname.lastname@example.org