The promise of the US Food and Drug Administration's quality-by-design (QbD) initiative is that manufacturers that demonstrate
extensive process understanding and control will enjoy a flexible regulatory approach, as well as increased assurance that
their products are safe, effective, and of high quality. For the past decade, FDA has been striving to modernize good manufacturing
practices (GMPs), improve its pharmaceutical inspectorate's abilities, and promote quality manufacturing on a global basis.
Recent crises involving adulterated and contaminated drugs and pharmaceutical ingredients have raised the profile of FDA's
ongoing campaign. Janet Woodcock, director of FDA's Center for Drug Evaluation and Research (CDER), has championed these initiatives
for years, and they remain top priorities for her.
Woodcock and leaders of CDER's Office of Pharmaceutical Science (OPS) are counting on industry to implement sophisticated
quality testing and production methods to help monitor thousands of products that are quickly shipped around the world. A
series of standards developed by the International Conference on Harmonization (ICH) describes how, on a global basis, process
understanding and control should be based on sound science and quality risk management.
Manufacturers, for their part, have been hearing speeches about QbD and design space for nearly a decade. Now they are looking
for evidence that investment in quality systems and processes will improve the efficiency of the application-review and approval
process, ease the burden of plant inspections, and rationalize the postapproval drug-monitoring system.
FDA officials seek to meet such expectations through pilot programs and new policies that link QbD approaches to flexible
regulation and real-world management of product risks. QbD is not just a "buzzword," commented Moheb Nasr, director of OPS's
Office of New Drug Quality Assessment (ONDQA) and a member of Pharmaceutical Technology's Editorial Advisory Board, at the Drug Information Association annual meeting in June 2008.
In Washington This Month
Nasr believes that quality risk management has become sufficiently accepted around the world to define a systematic approach
to pharmaceutical development and manufacturing. QbD can provide cost savings and improved systems for manufacturers, as well
as efficient regulatory oversight by FDA and other authorities, Nasr said at the Pharmaceutical Technology "Quality and Process Excellence" conference in July 2008. QbD helps manufacturers overcome real-world challenges by supporting
a formalized approach to quality risk management that improves product design, increases process understanding, encourages
continual improvement, and better uses modern manufacturing and analytical technologies. By adopting modern manufacturing
methods to ensure quality, manufacturers also can enhance efficiency and reduce costs.
Flexible regulatory oversight is an added benefit for companies that adopt QbD approaches. Nasr explained that by establishing
a design space based on pro-duct characteristics and performance, a manufacturer may gain leeway to reduce end-product release
testing and to make process improvements without further regulatory review.
Another potential reward for manufacturers that use QbD is relaxed requirements governing postapproval manufacturing changes.
FDA has developed a guidance to spell out opportunities for reduced oversight of certain low-risk chemistry, manufacturing,
and controls (CMC) changes. The agency's plan outlines more than 40 categories of changes that could be downgraded to allow
manufacturers to report such actions in annual reports instead of filing changes-being-effected supplemental applications.
Many of the reductions essentially involve administrative changes that do not need extensive CMC review, Nasr explained. Simplified
reporting may apply to changes involving the following elements:
- Components and composition (e.g., formulation changes that do not alter drug release, the elimination of an overage, or a
switch to a new nonfunctional coating material previously approved by FDA for other products).
- Manufacturing processes (e.g., installing new equipment of similar design to equipment being replaced or adding a duplicative
process as part of scale-up without changing parameters).
- Site changes for test laboratories or the packaging of oral solids. A move to a new facility for producing active pharmaceutical
ingredients (APIs) could be simplified if the facility is already approved for another product that is administered by the
same route and made by the same company. Most site changes affecting biotechnology products would still require notification
and FDA review.
- Specifications related to an additional in-process test or to tightening existing acceptance criteria.
- Container-closure systems (e.g., changes for nonsterile drug substances or a switch to a new glass supplier for the same product
- Stability protocols (e.g., to reduce testing frequency or shorten the expiry date, provided that stability is maintained).