The US Food and Drug Administration has been encouraging manufacturers to expand applications to include discussions of how
process knowledge and a full understanding of critical product parameters ensure drug quality. Adopting quality-by-design
(QbD) approaches offers manufacturers important benefits and savings, as well as the potential for regulatory relief. FDA
may waive the requirement to file supplements that describe postapproval manufacturing changes. The agency is also considering
further reductions to the scope and frequency of plant inspections for companies that demonstrate risk management and modern
Although such initiatives are gaining more currency in industry, formally establishing regulatory relief has been more difficult.
FDA officials are anxious to reduce the number of supplements manufacturers file with the agency but cannot decide exactly
how. A proposal that manufacturers could negotiate a "regulatory agreement" with the Center for Drug Evaluation and Research
(CDER) fell by the wayside because it seemed too much like a legal agreement that would oblige the agency to take certain
Extending CMC pilot
Initiatives to provide regulatory flexibility are moving forward now because of wider industry adoption of QbD approaches.
The Office of New Drug Quality Assessment (ONDQA) in CDER's Office of Pharmaceutical Science (OPS) initiated a chemistry,
manufacturing, and controls (CMC) pilot program to assess the value of applications that contain more scientific information
about product development and formulation than typical new drug applications do. ONDQA has reviewed and approved six pilot
applications that demonstrate an understanding of critical quality attributes, process development, and design space. Several
more applications await assessment.
The success of this program for drugs is encouraging regulators to extend it to biotechnology therapies. OPS's Office of Biotechnology
Products (OBP) is inviting biotechnology manufacturers to submit QbD information, demonstrate process control, and define
products' critical attributes. At the January WCBP conference on biotechnology regulation and analysis, in Washington, OPS
Director Helen Winkle explained that this information looks like an expanded comparability protocol for biologics. And because
relatively few new biologics license applications are filed each year, Winkle thinks the biotech QbD pilot will primarily
examine manufacturing supplements.
OBP director Steven Kozlowski recognizes that defining product attributes and design space is more complex for biotechnology
products. Compared with small-molecule drugs, finished biological products often have lower heterogeneity, and later manufacturing
steps are more likely to change the product, he noted at a workshop last year. The manufacturer's challenge is to determine
what data are relevant in defining critical product attributes. For innovative oncology products moving quickly through development
and review, it may be very difficult to include QbD data in an initial market application.
In Washington This Month
FDA is encouraging manufacturers to share information about the development of product-control strategies and process analytical
technology to better define what constitutes a QbD-based submission and science-based risk assessment. Many manufacturers
have adopted modern manufacturing methods, but have been afraid that providing information about such innovations would raise
more questions, delay application approvals, and generate objections from field inspectors.
To dispel such concerns, FDA would like to hold a workshop with industry to evaluate science-based risk assessment and lessons
learned from the pilot exercise. Winkle and her colleagues regard the CMC pilot as a means to help FDA understand the difficulties
in defining critical attributes. Some filings have inadequate quality information; others have too much data. Fully evaluating
the drug pilot, Winkle notes, would improve the program for biotechnology therapies.