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CDER is reorganizing staffs and developing new policies to encourage industry adoption of quality production systems.
For three years, US Food and Drug Administration officials have talked about revising the system for regulating pharmaceutical development and manufacturing, and now, major changes are in the works (see sidebar "Reshaping CDER"). FDA can no longer afford to spend months reviewing overloaded applications or spend weeks inspecting manufacturing facilities in view of limited resources and a growing workload, explained Helen Winkle, director of the Office of Pharmaceutical Science (OPS) in FDA's Center for Drug Evaluation and Research (CDER) at the October Regulatory Affairs Professionals Society's annual meeting in Baltimore. Although FDA may receive few new drug applications (NDAs) for truly innovative therapies, the agency has been overwhelmed this past year with some 800 submissions for generic drugs and thousands of postapproval supplements. And, many of the applications filed are for complex products that require a high level of expertise for appropriate evaluation.
The current process is costly and wasteful, and it encourages industry to conduct more tests and file more data than needed. Inappropriate product specifications for new drugs require FDA to review many more manufacturing supplements than should be necessary, and FDA reviewers make inconsistent decisions and fail to adjust oversight to product risk. Scale-up also is unpredictable. Establishing new production sites takes years, manufacturing operations are fragmented around the world, and a poor understanding of manufacturing failures leads to endless investigations, complained FDA deputy commissioner Janet Woodcock at the October workshop sponsored by FDA and the American Association of Pharmaceutical Scientists (AAPS). This high-cost, low-efficiency system leads to drug shortages, slower drug development, and intensive regulatory oversight, she pointed out.
To remedy the situation, FDA is establishing a pharmaceutical quality assessment system (PQAS) that rewards manufacturers for adopting modern processing and testing approaches and for submitting data that document product quality to FDA. The desired state of drug regulation, says Woodcock, is "a maximally efficient, agile, flexible pharmaceutical-manufacturing sector that reliably produces high-quality drugs without extensive regulatory oversight." Manufacturers can achieve this state by adopting quality-by-design (QbD) methods that use a thorough knowledge of critical quality attributes (e.g., chemistry, pharmaceutical formulation, manufacturing process, and product performance) and of process parameters to ensure product quality. This quality-based development and review approach also provides a scientific framework for more efficient development and regulation of generic drugs, biotech therapies, and possibly follow-on versions of protein products in the future.
At the same time, FDA is adopting a systems-based review process that focuses more resources on problematic products and efficiently assesses information describing how a manufacturer will ensure that a drug reliably meets quality standards. More detailed product-development information from manufacturers will permit FDA to adopt appropriate levels of oversight, with low-risk drugs produced through QbD methods that merit less frequent and less extensive review and inspection.
A key PQAS theme is to reduce the volume of chemistry, manufacturing, and controls data (batch records and raw stability data) usually included in market applications. Instead, much of the information needed by FDA and other regulators will be outlined in the Quality Overall Summary (QOS) of the Common Technical Document (CTD), a uniform market application for drugs and biologics that is being adopted by regulatory authorities around the world. The QOS includes basic information about the drug substance or drug product such as a description of manufacturing process, critical control steps, specifications, analytical procedures, and packaging specifications. An important component is the pharmaceutical development (PD) report that describes how the applicant developed its formulation, specifications, and QbD manufacturing approaches. The QOS already serves as a template for CMC review by some regulators, and FDA is contemplating a similar approach. Electronic CTDs can guide reviewers to pertinent scientific information about the drug product and link to supporting documentation such as batch records and stability data.
This approach has emerged from FDA's initiative to revise good manufacturing practices (GMPs). This past fall, the GMP modernization effort concluded its first phase with the publication of documents describing how industry should assess product risk, establish systems to correct problems, engineer manufacturing changes, and create internal quality units to manage these activities. CDER is implementing the concepts described in these papers by reorganizing agency review activities and establishing programs to encourage industry adoption of systems able to ensure drug quality on a continuing basis.
Foremost, OPS is overhauling its CMC review process. Historically, FDA has assigned a chemistry reviewer to evaluate all CMC data for a particular drug from clinical testing through postapproval supplements, working closely with new-drug medical reviewers. The rise in manufacturing supplements, however, has made it difficult for some reviewers to balance pre- and postapproval assignments. An evaluation of product development reports and QbD approaches may require review by a team that includes microbiologists, engineers, and other specialists.
Adopting a review team approach means locating these staffers in a central office (now at FDA's new White Oak campus), instead of spreading them among medical-review offices. This effort involves a major restructuring of OPS's Office of New Drugs Chemistry (ONDC), which became the Office of New Drug Quality Assessment (ONDQA) on Nov. 1. Under a reorganization plan engineered by ONDQA Director Moheb Nasr, the office has separated the review of premarket applications from postmarket manufacturing supplements. Three divisions review the CMC sections of INDs and NDAs for a group of products and indications. Rik Lostritto is director of the Division of Pre-Marketing Assessment I, which handles drugs indicated for cardio–renal, neurology, psychiatry, pulmonary, and endocrinology. Division II under Elaine Moorefield covers reproductive, gastroenterology, dermatology–dental, ophthalmology, antiviral, and anti-infective products. And, Division III, headed by John Simmons, assesses drugs for oncology, medical imaging, hematology, analgesics, anesthetics, and rheumatology. Pharmaceutical Assessment Leads (PALs) in each division initially examine each application to assess critical quality attributes, assign reviewers, and set a timetable for completing the review. John Simmons also directs a manufacturing science branch of experts that will address critical manufacturers issues.
ONDQA's Division of Post-Marketing Assessment, headed by Eric Duffy, has two branches, each with PALs who will sort incoming supplements to identify those that need a comprehensive review and those low-risk situations that may not need any further evaluation. The aim is to reduce unnecessary reviews and prevent the postapproval review volume from interfering with evaluation of investigational new drug and new drug applications (IND–NDA). The downside, however, is that postmarket application reviewers may lack the knowledge gained by staffers who assess a product from pre- through postmarket status. Duffy aims to develop a database about what information is needed to determine the effect of a change in product quality and which types of supplements need more, less, or no review. If FDA succeeds in reducing the number of supplements it reviews, company annual reports are likely to play a more important role in monitoring and reporting quality-related events as they pertain to marketed drugs such as batch failures, out-of-specification results, and dissolution trends.
OPS's Office of Biotechnology Products, which examines the manufacturing sections of applications for biological therapeutics, is working to extend QbD approaches to its more complex and variable-protein products. A task for OBP leaders is to convince manufacturers that its reviewers can evaluate efforts appropriately to engineer proteins to increase product specificity, reduce immunogenicity, and adopt more reliable process controls and validation methods.
Implementing this new CMC paradigm may help establish a pathway for eventually approving generic versions of biotech therapies, or follow-on protein products (FOPPs), as FDA prefers. At the annual meeting of the Generic Pharmaceutical Association (GPhA) in October, Winkle linked efforts to apply QbD principles for generic drugs to establishing a scientific rationale for FOPPs. OPS aims to develop a common scientific decision framework for addressing uncertainty in new drugs, generics, and biotechnology products, Winkle said. All products, she noted, should apply QbD principles so that drug design is based on prior knowledge and a sound understanding of critical parameters. FDA still has much work to do to address legal and scientific issues related to FOPs, Winkle said, but manufacturers may support such efforts by incorporating QbD approaches into current systems.
Meanwhile, OPS's Office of Generic Drugs (OGD) is proposing a new review process to handle its soaring volume of abbreviated NDAs (ANDAs) without any additional staff. As with new drugs, OGD wants to focus more resources on high-risk products and to encourage manufacturers to demonstrate their ability to understand and implement QbD methods. OGD plans to accomplish this task by adopting a new question-based review (QbR) system in the coming year to replace the ANDA organization described in a 1999 guidance. OGD reviewers will follow a set of questions about drug-substance characterization and control and drug-product composition, manufacture, reference standards, container–closure systems, and stability, as outlined in an FDA white paper issued in August [www.fda.gov/cder/ogd/ObR_white_paper.htm]. The questions provide a common framework for CMC reviewers to evaluate applications and aim to produce more uniform decisions.
The question format also alerts manufacturers to issues that FDA considers critical in evaluating all ANDAs and what additional information is needed for more complex and narrow-therapeutic-index products. Manufacturers can follow this format to ensure that applications have product-development reports that define the critical steps in development and explain how drug substance and formulation variables affect drug performance.
OGD wants companies to submit ANDAs electronically based on the CTD structure, with answers to its questions in the quality summary. Although OGD is not requiring manufacturers to adopt the new system, staffers acknowledge that complete applications using quality-design approaches will be easier to evaluate and may receive a lower risk score when approved. NTIs and complex dosage forms will be rated higher risk automatically, as will poor-quality applications and those with inadequate development reports. But manufacturers of conventional drugs that document quality product and process may be designated low risk and gain more latitude in making postmarket manufacturing changes without prior approval from FDA. OGD Deputy Director for Science Lawrence Yu anticipates that the system will eliminate or reduce preapproval requirements for as much as 80% of current CMC supplements.
Despite promises of regulatory relief, manufacturers have not been jumping on the quality assessment bandwagon. Pharmaceutical companies are only beginning to use the CTD, and electronic CTDs are rare. Some manufacturers believe they must do more testing and analysis to fully define design space. And, companies fear that submitting development reports that provide more information on formulation failures and discarded methods will generate more questions from agency reviewers and inspectors.
CDER is taking several steps to overcome these concerns. One initiative is an NDA pilot program that offers speedier review and extra handholding to early adopters of the new quality-assessment paradigm. ONDQA is offering this special treatment for 12 NDAs filed in the next year as a way to encourage manufacturers to submit applications that present QbD information indicating high-level process understanding and defining design space. Sponsors also may gain more flexibility in setting specifications, and the process will help OPS develop guidance for its quality-assessment program. Several manufacturers have signed up, and Nasr would like to complete the list by next March.
FDA officials also are examining possibilities for negotiating regulatory agreements with manufacturers for newly approved drugs. Woodcock suggested at the AAPS workshop that a sponsor and FDA could agree on critical product attributes and design space at time of approval; then a manufacturer would not need FDA prior approval to make postmarket changes within the established parameters.
Another initiative is to collect information from manufacturers about what factors influence drug development and manufacturing decisions. OPS has signed a cooperative research and development agreement with Conformia Software (Redwood City, CA, www.conformia.com) to survey 25 companies about what factors encourage or block drug candidates from becoming commercial products such as information bottlenecks, pilot-plant limitations, or issues related to manufacturing science and quality systems. Conformia plans to discuss drug-development practices with research and development and regulatory employees on a confidential basis and to prepare an anonymous summary of its findings for FDA. Participating firms will be rewarded for their efforts with a confidential assessment of where their own company stands.
In the end, each manufacturer must make a business decision as to whether the benefits justify the costs of implementing QbD in drug development. Such decisions may differ for legacy products compared with new development programs. Future reductions in regulatory burdens may not justify heavy investment upfront, although benefits may increase if quality-based manufacturing systems gain acceptance among regulators around the world. And, everyone will benefit if the QbD approach yields safer and more reliable medicines that can be produced more efficiently and updated as new technologies emerge.
Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, firstname.lastname@example.org