Drug Quality at Center Stage for FDA and Manufacturers

Published on: 
BioPharm International, BioPharm International-01-01-2013, Volume 26, Issue 1
Pages: 40–45

Shortages spur efforts to overhaul manufacturing oversight.

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.

Jill Wechsler

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.

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"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, Woodcock notes.


The potential impact of quality manufacturing systems on innovation and drug access provides a strong platform for change in quality regulation, says Woodcock. CDER's pharmaceutical quality initiatives have yielded many successes, as seen in expanded online monitoring of production lines; development of software and other technology to monitor manufacturing processes and detect errors; harmonization of quality risk-management concepts through the International Conference on Harmonization; and implementation of QbD approaches at many companies.

FDA has been less productive with efforts to provide industry with relief on manufacturing supplements and to build a pharmaceutical inspectorate with greater expertise for evaluating innovative quality production systems. Woodcock is hopeful that added resources provided by the Generic Drug User Fee Act (GDUFA) will revive the inspectorate program and provide more parity between foreign and domestic site visits.

CDER also is responding to these developments by establishing an Office of Pharmaceutical Quality (OPQ), another "super office" that will coordinate the review of chemistry, manufacture, and controls (CMC) data in applications with compliance efforts to ensure adherence to good GMPs at plant sites. OPQ will replace the Office of Pharmaceutical Science (OPS), whose long-time director, Helen Winkle, is retiring from the agency.

This change will bring together all CMC reviewers for generic drugs, conventional drugs, and biologics. In addition, the Office of Manufacturing and Product Quality (OMPQ) in CDER's Office of Compliance will join the new entity. Meanwhile, the Office of Generic Drugs (OGD) is becoming a separate CDER super office and will operate more like CDER's Office of New Drugs, with responsibility for reviewing bioequivalence, microbiology, and clinical data and clearing product labels. More details about the reorganization and OPQ should emerge over the next six months.

The regulations for CMC submissions and GMPs cover much of the same territory, so it makes sense to bring together the staff members that evaluate them, commented Jon Clark, OPS associate director for regulatory policy, at the IQ symposium. One advantage of the new structure is that it will encourage discussion of GMPs much earlier in the development process and hopefully avoid the kinds of production delays that could stymie market approval. The appointment of Howard Sklamberg, deputy associate commissioner for regulatory affairs, to head CDER's compliance office also brings in someone highly familiar with FDA's field force operations to help shape new inspection models.

Woodcock is hopeful that this reorganization and other initiatives will promote better ways to ensure drug quality, while also encouraging innovation. The current system for monitoring manufacturing activities is highly resource intensive, yet it fails to direct oversight to higher risk situations. "We're not just moving boxes," she insists, but looking to focus more on data surveillance and metrics, instead of site inspections, to provide faster review of applications plus improved procedures for ensuring quality manufacturing around the world.

Jill Wechsler is BioPharm International's Washington editor, Chevy Chase, MD, 301.656.4634, jwechsler@advanstar.com. Read Jill's blogs at PharmTech.com/wechsler.