The Food and Drug Administration (FDA) has been encouraging manufacturers to demonstrate how process knowledge and full understanding
of critical product parameters can ensure drug quality. Such quality by design (QbD) approaches offer potential benefits and
savings for manufacturers, as well as the prospect of regulatory relief. Officials at FDA's Center for Drug Evaluation and
Research (CDER) are relating field inspections to site risks and seek to modify requirements for filing supplements on postapproval
manufacturing changes. However, an earlier proposal that manufacturers could negotiate a regulatory agreement with FDA has
fallen by the wayside for appearing too much like a legal agreement that would bind the agency to certain actions.
EVALUATING QUALITY BY DESIGN
Some innovations are now moving forward based on wider industry adoption of modern manufacturing systems and risk management
approaches. A chemistry, manufacturing, and controls (CMC) pilot program for drugs is being extended to biotech therapies.
The drug initiative, under the Office of New Drug Quality Assessment (ONDQA) in CDER's Office of Pharmaceutical Science (OPS),
is assessing the value of QbD information in applications. Under the pilot, drug manufacturers have submitted nearly a dozen
new drug applications (NDAs) containing more information on product development and formulation than in typical filings. By
demonstrating the company's understanding of critical quality attributes, process development, and design space, these submissions
aim to identify those manufacturing changes or product variations that fall in defined parameters for maintaining drug safety,
efficacy, and quality.
The ONDQA has reviewed and approved six pilot applications, and several more are lined up for assessment. The program's success
is prompting OPS's Office of Biotechnology Products (OBP) to invite biotech manufacturers to similarly include QbD information
in submissions. Filing data that demonstrate process control and product critical attributes essentially resemble an expanded
biotech comparability protocol, explained OPS director Helen Winkle at the Well Characterized Biotechnology Pharmaceutical
(WCBP) conference held in Washington in January. Because there are relatively few new biologics license applications (BLAs)
each year, Winkle expects the biotech QbD pilot will involve more manufacturing supplements.
OBP Director Steven Kozlowski acknowledges that defining relevant product attributes and design space may be more complex
for biotech products. At a workshop last year, he noted that there is greater risk that later manufacturing steps may change
the product. The challenge for a manufacturer is to determine what data are most relevant in defining critical product attributes.
The QbD pilots aim to help FDA better define what constitutes a QbD-based submission. The agency wants to hold a workshop
with the industry to evaluate the benefits and lessons learned from this exercise and to discuss the level of detail needed
in submissions to define product quality. In some filings, QbD information appears inadequate, says Winkle; in others, there
is too much data. A better evaluation of the ONDQA experience with drugs, she notes, would inform the pilot for biotech therapies.
CMC POSTMARKETING PLANS
Describing QbD and design space in submissions is important for ensuring product quality throughout a product's full lifecycle.
During development, a manufacturer defines critical quality performance inputs and outputs along with the design space and
controls needed to validate a process. When filing an application, the manufacturer describes its critical quality attributes
and how they affect product performance to establish product specifications. All this information would then be used to prepare
a CMC postmarketing plan (PMP), a concept under development at FDA. As part of an NDA or BLA, a PMP would provide a roadmap
for the agency and the manufacturer to manage postapproval changes. It would outline anticipated changes and how they will
be measured to ensure that quality will be maintained. Those planned changes in equipment, process, site, and other procedures
not likely to have an impact on product quality would be distinguished from more significant changes, such as site relocation.
Winkle hopes to implement the program in the coming months, initially for drugs and later expanding to biologics. The concept
can be regarded as an "individual SUPAC," referring to FDA's earlier scale-up and post-approval changes initiative that
aimed to streamline reporting requirements for manufacturing changes according to dosage form.