FDA Promotes QbD for Biotech Therapies

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.

Jill Wechsler

"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.

PILOT FOR BIOLOGICS

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.

FEWER SUPPLEMENTS

An important payoff for manufacturers that adopt QbD may be more lenient requirements governing postapproval manufacturing changes. The FDA is developing guidance that will spell out opportunities for reduced oversight of certain low-risk CMC changes. The plan is to propose some 40 categories of changes that could be downgraded to allow manufacturers to report such actions in annual reports, instead of having to file CBE (changes being effected) or CBE-30 (changes being effected in 30 days) supplemental applications. Some actions that may not need agency review involve changes to:

• Components and composition involving a switch to a new non-functional coating material previously approved by the FDA for other products.

• Manufacturing processes, such as installing new equipment of similar design to what's being replaced, or adding a duplicative process as part of scale-up, with no changes in parameters.

• Site changes for testing laboratories and packaging of oral solids, but not for most biotech products.

• Specifications related to an additional in-process test or tightening of existing acceptance criteria.

• Container–closure systems for nonsterile drug substances or a switch to a new glass supplier for the same type of product.

• Stability protocols that reduce test frequency or shorten an expiry date, provided there is no stability failure.

Such anticipated postapproval manufacturing changes may be spelled out in a CMC postapproval management plan currently under development by the FDA. The plan would reflect the company's understanding of process and product, and provide a scientific basis for managing change.

LEEWAY FOR CLINICAL SUPPLIES

Another FDA effort to establish more appropriate oversight of drug manufacturing and quality control programs involves modifying some rules for producing supplies for Phase 1 clinical trails. The FDA issued a revised policy two years ago, but withdrew that proposal because of objections that the change could jeopardize the health and safety of study participants. Since then, the FDA has revised its policy to explain more clearly its rationale for modifying certain CMC requirements for producing very small quantities of a test therapy (Federal Register, Vol. 73, no. 136, July 15, 2008, p. 40453–62). The new rule drops the need for a fully validated manufacturing process for products made for use in Phase 1 trials; for rotation of stock for drug product containers; and for separate packaging and production areas.

The main beneficiaries of the policy should be research laboratories and clinics involved in investigator initiated studies. Small biotech companies that are developing vaccines, recombinant therapies, in vivo diagnostics, blood products, or gene therapies also might find the new rule helpful for simplifying the production of small quantities of costly biologics for early trials.

However, most established pharmaceutical and biotech manufacturers are expected to continue to meet GMP standards even for early clinical supplies to ensure that all procedures are in place for future scale-up to larger trials and for eventual commercial production. Those biotech companies that decide to drop irrelevant manufacturing procedures, moreover, still have to ensure the quality and safety of their investigational drugs. The FDA emphasizes that it retains the right to halt a clinical trial if it finds that a test drug fails to meet quality standards.

To avoid such problems, the FDA also issued a companion guidance with recommendations for establishing quality control procedures for meeting GMP requirements for clinical supplies. The guidance emphasizes that manufacturers of test products should have well-defined written procedures, an adequately controlled manufacturing system, and accurate records from product testing and manufacture. The guidance points out that anyone producing a drug, even if just for early human testing, should conduct a comprehensive evaluation of the manufacturing setting to identify and eliminate potential hazards. Small-scale operations may do this more efficiently by using disposable equipment and prepackaged materials that can reduce the risk of contamination.

Jill Wechsler is BioPharm International's Washington editor, Chevy Chase, MD, 301.656.4634, jwechsler@advanstar.com