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FDA is buried in postapproval manufacturing submissions and seeks to reduce the scope of changes that require agency scrutiny.
To ensure drug quality throughout a product's life cycle, the US Food and Drug Administration requires manufacturers to report changes in processes or products that could have even a moderate effect on product performance or safety. Current regulations (21 CFR 314.70) set fairly strict guidelines for reporting postapproval changes. Companies file supplements even for routine revisions in raw materials, production processes, equipment, and facilities if there is any chance a change will affect product quality. Only a relatively short list of changes that have "minimal" potential for harm can be submitted to the agency after the fact in an annual report.
FDA consequently is swamped with postmarketing submissions. Industry filed some 6000 supplements for new drugs, biologics, and generics last year. About 2000 involve "major" changes that require FDA prior approval before a company can distribute drugs produced by the altered system (see sidebar, "Sorting out supplements"). The supplement volume has grown steadily and may accelerate more as industry mergers and reorganizations lead to plant closings and shifts to new manufacturing sites and processes.
Risk and quality
The task of preparing and filing supplements is a huge burden for industry and FDA. Consequently, manufacturers think twice about upgrading equipment or revising processes, even if it means forgoing opportunities to modernize outdated systems and improve formulations. That reluctance runs counter to FDA's initiative to modernize current good manufacturing practices (CGMPs) for the 21st century, which encourages manufacturers to adopt modern quality-control tools and systems able to ensure consistent product quality, safety, and efficacy. FDA advocates a quality-by-design (QbD) approach for achieving the "desired state" of quality drug manufacturing—one in which companies apply extensive knowledge about critical product and process parameters and quality attributes to achieve continuous improvement throughout the product life cycle.
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This CGMP-modernization initiative is five years old and provides a framework for taking a new look at manufacturing-supplement filing requirements. FDA acknowledges that its current policy reflects a desire for "extensive control over virtually every aspect of the manufacturing process," according to the announcement of a February public meeting to discuss agency proposals for revising policies governing supplements and manufacturing changes. Companies adopting QbD approaches ideally would be rewarded with reduced regulatory oversight in terms of modified manufacturing supplement filing requirements and less-frequent plant inspections.
FDA officials consequently are looking for ways to reduce the volume of supplements involving relatively low-risk changes to process and product. That involves considering how a manufacturer's internal change-control system may allow more manufacturing modifications to be made without FDA prior approval or oversight, explained Jon Clark, deputy director for policy at the Office of Pharmaceutical Science (OPS) in the Center for Drug Evaluation and Research (CDER).
Instead of a prescriptive and rules-based approach, FDA wants to leverage advances in manufacturing science to reduce the need to review low-risk manufacturing changes. Manufacturers would gain more flexibility to make timely, low-risk improvements in processes, and FDA would make more efficient use of its resources by not having to review many supplements. A risk-based approach to postmarketing regulation also would permit agency staffers to focus oversight on those changes most likely to have serious consequences for product safety and quality.
OPS director Helen Winkle acknowledged that FDA feels there is a "lack of flexibility" in the current rule and wants to allow more manufacturing changes to be made without notifying the agency. "We're inundated by supplements," she commented at the public meeting. FDA is reviewing and evaluating comments from industry and other interested parties. Following the February meeting, FDA sought industry input on these issues at a workshop on FDA's Pharmaceutical Quality Initiatives, which was cosponsored by the American Association of Pharmaceutical Scientists and the International Society of Pharmaceutical Engineers. Further discussion is scheduled for the May meeting of FDA's Pharmaceutical Sciences Advisory Committee. The agency plans to revise current regulations to permit a more flexible regulatory approach. New guidances would provide details for reporting different kinds of postapproval changes based on a company's quality-control capabilities.
This latest effort to modify and clarify postapproval changes policy is not without precedent; FDA and industry have been collaborating since the early 1990s on ways to update the supplement process. FDA issued its first scale-up and postapproval changes guidance in 1995, which modified reporting requirements for changes in immediate-release solid oral dosage forms of new drugs and generics. Additional guidances reduced reporting requirements for low-risk changes in modified release, semisolid dosages and bulk active ingredients. FDA also issued new policies permitting reduced oversight of any minor changes in biotechnological manufacturing processes.
The FDA Modernization Act of 1997 codified agency authority to make such revisions in postapproval reporting requirements and sought rules to clarify a streamlined postapproval changes policy. After a long rule-writing and comment process, FDA published final rules in 2004 for reporting major, moderate, and minor changes to approved drugs, including generic products. Major changes require FDA prior approval, but minor changes can be described in an annual report and need no supplemental filing.
Moderate changes tend to fall into a gray area. These have to be reported in a changes-being-effected (CBE) supplement that FDA reviews, but the changes can be implemented pending approval. Many moderate changes require a CBE-30 supplement, which establishes a 30-day waiting period during which FDA can review and block a change if warranted. FDA has issued additional guidance documents that describe whether a CBE-30, CBE, or prior-approval supplement should be filed for specific changes to drug components, manufacturing sites, production processes, product specifications, container closure systems, and labeling.
Sorting out supplements
The new regulation and guidances, though, were out of date even before they were published. Not only do they ignore the relationship between company quality-control systems and postapproval regulations, but sponsors find it difficult to determine which changes require which kind of supplements, particularly when it comes to CBEs. So, FDA officials are going back to the drawing board to write new rules that better reflect current FDA risk-based regulatory approaches and scientific advances in manufacturing and quality control.
Meeting time frames
The current postapproval review system also imposes a heavy burden on FDA staff. The Prescription Drug User Fee Act sets specific performance goals for reviewing manufacturing supplements for new drugs and biologics. CDER and the Center for Biologics Evaluation and Research review prior-approval supplements within four months and CBE supplements in six months, but timely review is a continuing challenge.
CDER's Office of New Drug Quality Assessment reorganized last year to improve its ability to apply a pharmaceutical quality-assessment system to the application-review process. One important change was to establish a separate Division of Post-Marketing Evaluation (DPME) to review the 1800 supplements CDER receives each year for new drugs, about one third of which require prior approval. In the first year or two following market approval, manufacturers tend to submit two or three prior-approval supplements, primarily to implement important changes in manufacturing systems or facilities and in production-control systems.
Reviewing these submissions in a timely way is a "great task," says DPME Director Eric Duffy. Although there are fewer supplements for new drugs compared with generics, FDA must pay more attention to them because it has relatively little experience with the new products, Duffy points out. The goal of his office is to develop a streamlined review process that encourages manufacturers to be innovative and adopt continuous-improvement approaches. DPME uses a risk-based triage approach to identify supplements that require more extensive scrutiny because of the impact a proposed change would likely have on pro-duct performance. The approach also considers manufacturers' degree of understanding of product design, desired product performance, and the manufacturing process.
The importance of user-fee support for the drug-review program can be seen in the much slower pace for processing supplements for generic drugs. A generic manufacturer often files 20–30 postapproval supplements during a product's life cycle, pointed out Hospira vice-president Richard Stec, representing the Generic Pharmaceutical Association at the public meeting. This adds up to thousands of supplements submitted each year to FDA's Office of Generic Drugs (OGD). It takes 9–18 months for OGD to review a typical chemistry, manufacturing, and controls prior-approval supplement, says Stec. The whole process of developing a new production system, filing the supplement, and obtaining FDA approval can take four years, Stec explained. OGD Division Director Vilayat Sayeed says that the agency strives to review important supplements within a year but acknowledges that this is a very long time for a company to wait.
To deal with its voluminous workload, OGD is implementing a triage approach to identify the risk associated with the type of change being reporting and the importance of more immediate review. OGD also has launched a question-based review process to accelerate the review of applications that provide information about how the sponsor's quality-control system can ensure consistent product quality. This approach streamlines the application-review process for new generics and also facilitates the evaluation of supplements.
Although there is broad agreement that the current supplement-review system is outmoded and overprescriptive, revising the rules will not be easy. Some manufacturers propose eliminating CBE supplements altogether and providing needed information in annual reports. One idea is to create a new reporting category of "changes that do not require notification to FDA," suggests Clark of OPS.
A key need is to redefine "major" and "moderate" changes and other terms. Phrases such as "moderate potential to adversely affect" a product are too vague. Almost any change has potential to affect a product, and the language encourages companies to file supplements even for changes with limited adverse effects.
Manufacturers agree that many reporting categories described in current rules and guidances are not necessary. Leo Lucisano of GlaxoSmithKline, representing the Pharmaceutical Quality Steering Committee of the Pharmaceutical Research and Manufacturers of America, advocated reducing or eliminating CBE supplements for packaging and testing-site changes and adopting equivalent or superior analytical methods, among other low-risk revisions.
Generics manufacturers similarly would like to use risk-based approaches to reduce supplements. FDA should establish more-specific criteria for major changes that require prior approval, advised Stec, and should eliminate CBE-30 supplements for various less-critical changes such as changes in and at raw material suppliers, as well as modifications to their own manufacturing processes. Manufacturers are developing several lists of changes that can best be managed by a firm's internal quality systems, instead of requiring FDA review and approval (see sidebar, "Opportunities to reduce supplements for generics manufacturers").
Opportunities to reduce supplements for generics manufacturers
While revising its own rules, industry wants FDA to pay attention to similar efforts in Europe to streamline oversight of drug product "variations." These activities provide an opportunity for regulatory authorities to harmonize postapproval policies globally. European manufacturers back a system with two variation categories: minor changes to be filed with the regulatory authority and major changes requiring prior assessment. This structure could establish a model for revising US rules.
Keep the old with the new
An important issue for manufacturers is for FDA to retain its current post-approval change policy for legacy products that have extensive historical data about process parameters and little incentive to adopt QbD approaches. FDA acknowledges the need to continue aspects of the existing regulatory scheme to accommodate those manufacturers who choose to continue operating within the current regulatory framework. But it will be a challenge for the agency to implement a modified approach for new products adopting process analytical technology and design-space approaches while retaining current policies for older products with established manufacturing systems.
Policy revisions that rely more on annual reports to present postapproval change information also may warrant re-evaluation of the format and content of these documents. Lengthy descriptions of multiple minor changes could be replaced by an index or listing of these activities, with supporting data available at the plant site for FDA inspection.
Manufacturers also urge better integration of new drug annual reports, which companies file with FDA, and annual product reviews, which are kept on site for inspection.
Such developments rely heavily on FDA's field force to ensure that a company's internal systems and controls operate as intended. Plant inspectors would assume more responsibility for checking quality systems and production records during periodic inspections.
Proposals to depend more on a manufacturer's quality system as the basis for reduced supplement filing also raise questions about how FDA would evaluate such status. Would regulatory relief apply to an entire company, to a specific product, or to a production platform? But even if FDA looks to industry to monitor quality internally, or on field inspectors to assume more oversight responsibility for ongoing quality assurance, the agency reminds manufacturers that they remain responsible for ensuring product quality, even if they do not have to report a change.
Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, email@example.com