FDA Promotes QbD for Biotech Therapies

New pilot supports manufacturers that establish quality systems to manage product risk.
Oct 01, 2008
Volume 21, Issue 10

Jill Wechsler
The promise of the Food and Drug Administration's Quality by Design (QbD) initiative is that manufacturers able to demonstrate a high degree of process understanding and control will gain from more flexible regulatory oversight, while also boosting confidence that their products are safe, effective, and high in quality. To achieve these goals, the FDA has launched several initiatives to demonstrate how QbD can support real-world management of product risks and more flexible regulatory approaches. The FDA's efforts to modernize good manufacturing practices (GMPs) and to promote quality manufacturing on a global basis have gained new momentum, moreover, from recent crises involving adulterated and contaminated biopharmaceuticals and their components.

"Quality by Design is not just a buzz word," commented Moheb Nasr, director of Office of New Drug Quality Assessment (ONDQA) in the Center for Drug Evaluation and Research (CDER), when speaking at the Drug Information Association annual meeting in June. QbD, he said, can improve product design, increase process understanding, support a more formal approach to quality risk management, encourage the use of modern manufacturing and analytical technologies, and promote continual improvement. Such approaches offer flexibility to adopt modern manufacturing methods to ensure quality, while enhancing efficiency and reducing manufacturing costs.


To apply these concepts more specifically to biotech manufacturing, CDER has launched a pilot initiative offering more individualized examination of QbD initiatives submitted in market applications for biotech therapies. The FDA announced the program in July, calling for manufacturers to voluntarily provide chemistry, manufacturing, and controls (CMC) information in an expanded change protocol that describes the implementation of QbD and risk management approaches for large molecules. CDER's Office of Biotechnology Products (OBP) will manage the pilot, which will assess five original biologic license applications or new drug applications and 10 supplements. Ideally, the candidate products have been monitored by OBP through the product development and testing process and have benefited from early discussions between the manufacturer and FDA reviewers about R&D issues. Several manufacturers have indicated interest in participating and should be submitting applications and supplements for pilot review over the next two years.

The stated aim of the OBP pilot is to define clinically relevant attributes for complex products and to link these approaches to the manufacturing process. The FDA and manufacturers have used comparability protocols to describe specific tests and acceptance criteria to ensure that a manufacturing change will not produce negative effects. The expanded protocols will describe QbD approaches and critical quality attributes as applied more broadly to multiple unit operations.

Although many QbD principles apply equally to small molecules and biologics, assessing relevant attributes is "a much greater challenge for complex pharmaceuticals," the FDA stated in announcing the pilot (Federal Register, vol. 73, No. 128, July 2, 2008, p. 37973). Quality control often is more difficult with biotech products because they are hard to characterize, and manufacturing processes are more complex and variable.

The pilot should provide information that can help the FDA implement a QbD, risk-based approach for complex products and to develop further guidance for industry. By examining QbD approaches taken by individual manufacturers, the FDA hopes to gain more evidence that such innovations can reduce process variability and support the production of consistent therapies that meet quality attributes.

The OBP pilot builds on a similar initiative that has examined how manufacturers apply design space and control strategies to drug manufacturing. ONDQA launched a CMC pilot program in 2005 that offered a more individual review of drug applications and supplements featuring QbD approaches. So far, ONDQA has reviewed and approved eight applications; three were still under review as of July, and one more application remained to be submitted. The pilot applications have presented examples of how design space and process knowledge can be captured at an operational level and relate to normal operating ranges, to equipment, and to scale.

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