FDA Encourages Quality by Design Initiatives - - BioPharm International


FDA Encourages Quality by Design Initiatives

BioPharm International
Volume 21, Issue 3


FDA also wants to reduce manufacturing supplements across the board. Winkle was hopeful at the January WCBP conference that a much anticipated proposal for eliminating many supplements soon would be published in the Federal Register. FDA held a public meeting a year ago to discuss options for revising CMC supplement regulations [see BioPharm International, Regulatory Beat, April 2007]. FDA pointed to the emergence of new tools and approaches for assessing and managing product risks as supporting modified requirements for controlling the postapproval manufacturing process. Such an approach would curb rules that inhibit companies from improving manufacturing processes, while also encouraging the adoption of quality systems. These changes will appear in a new guidance and a proposed new regulation that would eliminate most changes-being-effected (CBE) supplements.

Manufacturers now may file CBE manufacturing supplements to inform FDA of changes involving process, equipment, packaging, and other activities that are unlikely to compromise important safety or efficacy characteristics. The company does not have to wait for agency approval to make these changes, although a CBE-30 requires a 30-day delay before adopting new practices. Even without preapproval requirements, FDA still is obliged legally to examine thousands of CBE supplements every year.

FDA now wants manufacturers to report these low-impact changes in their annual reports to the agency. A supplement would be required only for more significant changes that require agency review and approval before implementation, says Winkle. An example would be a site relocation, which often involves installing new equipment and other alternations in a production process and usually requires field inspection of the new facility.

Filing more change information in annual reports would expand the role of FDA's field force. Plant inspectors would shoulder responsibility for examining changes described in annual report listings, as well as the manufacturer's annual product review, which is kept at the manufacturing site. The process would be more efficient, manufacturing executives say, if FDA provided more synergy between the annual report filed with the agency and the company's internal review.

While eliminating most CBE supplements appears logical, the specifics raise many questions. One challenge for FDA, says Winkle, is to apply these new policies to legacy products that have no QbD data in original applications. While some manufacturers may want to compile QbD information for established therapies, others will not want to invest resources in such an undertaking. But it may be difficult for FDA to offer regulatory relief only to those manufacturers that adopt modern manufacturing practices.

In addition, any regulatory change that even remotely appears to compromise drug safety is sure to raise a red flag. In the current political climate, critics of the industry and FDA could regard modified reporting rules for manufacturers as allowing production system alterations without appropriate oversight of safety impacts. A recent FDA proposal to clarify when manufacturers can file CBE supplements for labeling changes involving new safety information ran into a buzz-saw on Capitol Hill. Congressional leaders objected that the new proposed rule would give pharmaceutical companies a rationale for hiding drug safety information and would protect marketers of unsafe products from legal action. While the objective of reducing supplements aims to help FDA deal with its expanding workload and to encourage manufacturer adoption of modern manufacturing practices, even benign actions face intense scrutiny these days.

Jill Wechsler is BioPharm International's Washington editor, Chevy Chase, MD, 301.656.4634,

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