A decade-long effort to modernize biopharmaceutical production and regulatory policies has fallen short of its goals and is
prompting a re-evaluation of FDA regulatory efforts and industry's response. The shift in drug sourcing and production to
foreign sites heightens demand for more efficient oversight, as do provisions in the FDA Safety and Innovation Act (FDASIA)
that support accelerated development and approval of breakthrough therapies to enhance patient care.
Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), consequently is taking a fresh look at FDA
programs designed to ensure that manufacturing quality requirements promote biomedical innovation that leads to safe and effective
products. The CDER "Pharmaceutical Quality for the 21st Century" initiative was launched in 2002 to encourage manufacturer
adoption of modern quality management systems, process analytical technology, and automated production methods. This program
has yielded many accomplishments, "but we're not there yet," Woodcock stated at the December symposium sponsored by the International
Consortium for Innovation & Quality in Pharmaceutical Development (IQ).
Woodcock made similar observations about lagging manufacturer investment in quality-by-design (QbD) approaches in June 2012
at the FDA/ISPE conference in Baltimore. Despite years of discussion about QbD and modern manufacturing systems, FDA still
sees high reject rates and widespread product defects, Woodcock notes. Ongoing drug shortages, the recent drug compounding
crisis, and frequent product recalls have intensified FDA's focus on strategies for improving quality drug production. These
failures add to the cost of drug production, which depletes a company's R&D resources and often leads to higher drug prices.
Instead, biopharmaceutical executives should regard quality drug production as a means to achieve a clear competitive advantage
over competitors and as a "core competency" for management—an attitude that Woodcock finds rare. This approach could involve
developing quantifiable metrics of quality, something that is done in other industries such as with automobile or television
repair rates or airline on time percentage.
For pharmaceutical companies, metrics could be public, such as product recalls or inspection citations. More internal measures
may include production cycle delays, rates in meeting specifications, or theoretical versus actual cycle times. Such assessments
can document how more efficient production reduces waste and saves money, while also avoiding the recalls and safety problems
that can damage corporate reputations. And savings in the manufacturing arena that support lower prices for new therapies
will be particularly important as more personalized treatments emerge. Pharmaceutical management may be more willing to invest
in modern production technology if it can decrease the cost of production, support faster approvals, avoid burning up patent
coverage time, and facilitate reimbursement by payers.
Ensuring quality drug production has become more urgent as FDA faces added pressure to facilitate patient access to new "breakthrough"
drugs, a goal that could be undermined by delays in manufacturing scale-up. The new Breakthrough Therapy Designation, which
FDA can apply early in clinical development as authorized by FDASIA, "looks like a game changer" for cancer, genetic diseases,
and other serious conditions, Woodcock observes. If FDA is prepared, however, to approve a priority drug while the sponsor
is still at clinical production scale, final approval could be delayed if reviewers find that the product does not meet "ready
for manufacture" criteria.
"This has happened," Woodcock asserts, "and it's going to get worse" as FDA encounters more highly targeted cancer therapies
that demonstrate complete response in phase I or II, but manufacturers that lack the capability to supply the product quickly.
At a November 2012 conference on cancer research sponsored by Friends of Cancer Research and the Brookings Institution, Woodcock
highlighted the potential benefits of the new policy for breakthrough therapies, while warning that drug manufacturing could
be a "rate-limiting step" in development. To avoid such roadblocks, she recommended early, separate FDA meetings with sponsors
on manufacturing issues to discuss the scale-up plan for a potentially critical drug.
Such discussions could highlight the benefits of adopting continuous manufacturing processes and QbD approaches to facilitate
efficient transfer from development to commercial production. Manufacturers that adopt QbD early in the development process
also may experience "fewer nasty surprises" in production, less waste, and more positive plant inspections down the road,