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More informed submissions may lead to regulatory flexibility for postapproval changes.
The Food and Drug Administration (FDA) has been encouraging manufacturers to demonstrate how process knowledge and full understanding of critical product parameters can ensure drug quality. Such quality by design (QbD) approaches offer potential benefits and savings for manufacturers, as well as the prospect of regulatory relief. Officials at FDA's Center for Drug Evaluation and Research (CDER) are relating field inspections to site risks and seek to modify requirements for filing supplements on postapproval manufacturing changes. However, an earlier proposal that manufacturers could negotiate a regulatory agreement with FDA has fallen by the wayside for appearing too much like a legal agreement that would bind the agency to certain actions.
Some innovations are now moving forward based on wider industry adoption of modern manufacturing systems and risk management approaches. A chemistry, manufacturing, and controls (CMC) pilot program for drugs is being extended to biotech therapies. The drug initiative, under the Office of New Drug Quality Assessment (ONDQA) in CDER's Office of Pharmaceutical Science (OPS), is assessing the value of QbD information in applications. Under the pilot, drug manufacturers have submitted nearly a dozen new drug applications (NDAs) containing more information on product development and formulation than in typical filings. By demonstrating the company's understanding of critical quality attributes, process development, and design space, these submissions aim to identify those manufacturing changes or product variations that fall in defined parameters for maintaining drug safety, efficacy, and quality.
The ONDQA has reviewed and approved six pilot applications, and several more are lined up for assessment. The program's success is prompting OPS's Office of Biotechnology Products (OBP) to invite biotech manufacturers to similarly include QbD information in submissions. Filing data that demonstrate process control and product critical attributes essentially resemble an expanded biotech comparability protocol, explained OPS director Helen Winkle at the Well Characterized Biotechnology Pharmaceutical (WCBP) conference held in Washington in January. Because there are relatively few new biologics license applications (BLAs) each year, Winkle expects the biotech QbD pilot will involve more manufacturing supplements.
OBP Director Steven Kozlowski acknowledges that defining relevant product attributes and design space may be more complex for biotech products. At a workshop last year, he noted that there is greater risk that later manufacturing steps may change the product. The challenge for a manufacturer is to determine what data are most relevant in defining critical product attributes.
The QbD pilots aim to help FDA better define what constitutes a QbD-based submission. The agency wants to hold a workshop with the industry to evaluate the benefits and lessons learned from this exercise and to discuss the level of detail needed in submissions to define product quality. In some filings, QbD information appears inadequate, says Winkle; in others, there is too much data. A better evaluation of the ONDQA experience with drugs, she notes, would inform the pilot for biotech therapies.
Describing QbD and design space in submissions is important for ensuring product quality throughout a product's full lifecycle. During development, a manufacturer defines critical quality performance inputs and outputs along with the design space and controls needed to validate a process. When filing an application, the manufacturer describes its critical quality attributes and how they affect product performance to establish product specifications. All this information would then be used to prepare a CMC postmarketing plan (PMP), a concept under development at FDA. As part of an NDA or BLA, a PMP would provide a roadmap for the agency and the manufacturer to manage postapproval changes. It would outline anticipated changes and how they will be measured to ensure that quality will be maintained. Those planned changes in equipment, process, site, and other procedures not likely to have an impact on product quality would be distinguished from more significant changes, such as site relocation.
Winkle hopes to implement the program in the coming months, initially for drugs and later expanding to biologics. The concept can be regarded as an "individual SUPAC," referring to FDA's earlier scale-up and post-approval changes initiative that aimed to streamline reporting requirements for manufacturing changes according to dosage form.
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, email@example.com