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Jill Wechsler is Pharmaceutical Technology's Washington Editor, firstname.lastname@example.org.
Fewer field offices and inspectors will increase reliance on manufacturers to ensure product and process quality.
The US Food and Drug Administration plans to shut down its regional offices and some additional field facilities, a move that reflects an ever-tightening squeeze on agency funding and staff. FDA also seeks to make more efficient use of its limited resources by establishing risk-based approaches for selecting those drug-manufacturing sites most in need of frequent oversight, while reducing inspections for less risky facilities. More highly trained inspectors will be able to assess modern manufacturing systems with greater efficiency, and field staff will collaborate better with reviewers in FDA Centers to understand company quality-control systems better.
These changes in FDA inspection operations fit the agency's Pharmaceutical Quality in the 21st Century initiative, which encourages broader industry adoption of quality-control and risk-management methods that can better ensure quality drug production and distribution with less direct oversight by the agency. Instead of frequent, in-depth plant inspections, the goal is for FDA to initially verify a manufacturer's process control and quality system and follow up periodically with more efficient audits, commented FDA deputy commissioner Janet Woodcock at a March workshop on pharmaceutical quality initiatives cosponsored by FDA, the American Association of Pharmaceutical Scientists, and the International Society for Pharmaceutical Engineering. Under the "desired state" of pharmaceutical manufacturing, regulators will use risk-based approaches to make regulatory decisions and further streamline the inspection process, she explained.
The reorganization of FDA's Office of Regulatory Affairs (ORA) has been in the works for several months and now is nearing implementation. Margaret Glavin, FDA associate commissioner for regulatory affairs, described efforts to "dramatically change" ORA in a February message to staff. Gary Dykstra, director of FDA's Southeast regional office, unveiled some of the specifics at an industry conference in March. In addition to eliminating regional offices, ORA plans to streamline the reporting structure of its 20 district offices to create a more efficient operation. ORA also plans to close 7 of its 13 field laboratories, a move that has generated controversy since first announced in December 2006 (see sidebar, "Losing laboratories").
This downsizing of ORA reflects cuts in the agency's budget and staff. FDA's field force has dropped from a peak of about 4000 in 2003 to some 3400 today. Glavin emphasizes that the planned reorganization is not designed to accommodate further personnel cuts, but unions representing agency personnel are leery of likely staff relocations and changes in responsibilities and authority.
A recent ORA report on inspections and enforcement actions in fiscal year 2006 documents the downward trend in domestic and foreign inspections of biologic and drug-manufacturing facilities. ORA inspected 2411 drug facilities in the United States and abroad last year, compared with more than 2600 in the three previous years. Similarly, the agency inspected 1826 facilities producing biologics last year, down from about 2000 in previous years.
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FDA's budget proposal for 2008 allots much of ORA's budget increase to food oversight, relying on prescription-drug user fees to maintain the current level of drug-manufacturing oversight. Any additional funding for ORA is needed to handle new and expanding assignments. ORA is charged with responding quickly to public-health emergencies such as Hurricane Katrina and the rising number of food contamination crises. The agency also monitors a fast-rising volume of imported food and medical products and is responsible for FDA involvement in detecting and preventing bioterrorism events. ORA's Office of Criminal Investigations is expanding efforts to prosecute Web sites that illegally market counterfeit drugs. And, ORA is working with the Department of Defense to build the Shelf Life Extension Program, a cooperative effort to test drugs in strategic stockpiles to determine if product expiration dates can be extended to reduce unnecessary drug replacement. The program focuses on pharmaceuticals important to the military that are purchased in very large quantities such as antibiotics and antivirals.
To bolster its resources, FDA has proposed a reinspection user fee that would collect $23 million to cover the cost of revisiting manufacturing facilities cited for violations in initial good manufacturing practice (GMP) inspections. The agency would use $13 million of that new fee revenue to support 100 additional ORA field staffers.
ORA's streamlining plan is scheduled to take effect on Oct. 1, 2007 unless it is sidetracked by opposition, which is surfacing within the agency as well as among manufacturers. Agency staffers are nervous, and industry fears more difficulty in contacting field officials and getting answers to specific questions. Members of Congress have opposed closing FDA laboratories at a time of increased public concern about food contamination and medical-product safety.
New approaches to quality assurance
FDA officials would like to shift the focus from counting the number of plant inspections it conducts to evaluating how well it can ensure medical-product quality and safety. This approach involves adopting more efficient strategies for targeting inspections to high-risk operations likely to have the greatest impact on public health and safety.
FDA's risk-based approach to regulating GMPs fits ORA's need to do more with less to ensure drug quality. David Horowitz, ORA deputy associate commissioner for compliance policy, noted at the pharmaceutical quality workshop that in addition to a "significant decline in resources for inspections," more complex manufacturing processes require more expertise to evaluate. And, the need to oversee a growing number of foreign drug-manufacturing facilities also stretches ORA resources.
Moreover, FDA regulatory operations suffer from industry efforts to sidestep the rules, Horowitz said. Industry compliance with GMPs "is bad and getting worse," he remarked, observing that manufacturers are "studying for the test"—correcting specific deficiencies but not investing in systems that can avoid problems and correct root causes. Modern manufacturing and technological developments such as process analytical technology (PAT) provide opportunities for both FDA and industry to establish quality-oriented approaches, Horowitz added, and risk management can better focus and target regulatory and manufacturing activities to "get the most bang for the buck."
FDA is helping manufacturers adopt innovative approaches for ensuring that drugs meet quality standards, as seen in its Quality Systems Approach to Pharmaceutical CGMP Regulations guidance published in September 2006. Additional guidances from FDA will clarify approaches for aseptic processing, process validation, investigating out-of-specification test results, and manufacturing standards for Phase I clinical supplies. The anticipated Q10 standard from the International Conference on Harmonization will further describe approaches for harmonizing quality systems on a global basis. FDA also plans to revise its rules governing Part 11 and GMPs. In approaching the long, cumbersome rulemaking process, FDA envisions an "incremental approach" to adjusting specific policies, starting perhaps with those governing potable water and aseptic processing.
In addition to providing advice to manufacturers, FDA is incorporating quality approaches into internal programs for training field inspectors and for issuing Warning Letters. ORA's transformation initiative, said Horowitz, aims to embed risk-based approaches in all its operations and to better coordinate the perspectives of field and Centers. This strategy, he hopes, will lead to greater harmonization in management approaches internationally and enhanced integration of inspection with review and compliance.
A key ORA initiative seeks to improve the knowledge and training of pharmaceutical field inspectors so that they better grasp complicated quality-management systems and risk-management approaches they encounter at production sites. The centerpiece is establishing the Pharmaceutical Inspectorate (PI), a group of highly trained individuals with the knowledge needed to evaluate facilities that have adopted the latest scientific and technological innovations for ensuring drug quality.
ORA and the Center for Drug Evaluation and Research (CDER) are working hard to build a cadre of 50 certified PI members by 2007. PI members would spend 80% of their time conducting drug-quality inspections, compared with about 25% for regular field inspectors. But unlike the agency's centrally located Team Biologics cadre, which inspects biotechnology manufacturing facilities, PI members work at district field offices and can inspect other facilities as needed.
The PI training and certification process is a joint ORA–CDER undertaking that exposes candidates to risk-management concepts, manufacturing innovations, and the importance of an integrated review and inspection process, explained Doug Ellsworth, director of ORA's New Jersey District Office. A fully trained PI member should be able to identify critical control variables and strategies and whether a manufacturer has established a sound state of control over its production process. PI training includes quality by design (QbD), sophisticated statistical analysis, and advanced concepts in change control, corrective and preventive action plans, and continuous improvement programs.
The development of the PI program supports FDA's PAT Team, another group of investigators trained in advanced PAT concepts. All PI members now have general training in PAT technology. As these inspectors gain more in-depth PAT knowledge, they most likely will absorb the PAT team, Ellsworth noted.
FDA also has improved the operations of Team Biologics as part of its GMP modernization effort, with an eye to implementing quality-management systems approaches. This includes establishing standards to better assess team performance and to determine the need for improved training and qualification of team members. FDA is working with the Pharmaceutical Quality Research Institute to evaluate Team Biologics operations and their impact on manufacturers.
A main approach for using FDA resources more efficiently is to target inspections and oversight to industry operations most in need of FDA scrutiny. CDER has established a risk-based site-selection program for identifying those drug-manufacturing facilities to schedule for GMP inspection each year. This system uses a model for setting inspection priorities according to various risk factors associated with products, processes, and facility characteristics. Of some 1500 drug GMP inspections FDA conducts each year, about 500 are selected based on risk calculations, and 50 are identified as warranting review by the PI cadre.
Unfortunately, the program's current risk-analysis model does not consider how well a company establishes control strategies based on QbD and risk-management principles. The agency's evaluation system can tap only information in FDA data systems such as type of product (e.g., sterile, biotechnology), mode of operation, and production volume. FDA analysts can factor in past GMP-compliance history, which may reflect a manufacturer's state of control, but not whether an advanced PAT system can manage product variability.
Despite these limitations, ORA is extending this risk-based model to better target Team Biologics inspections to high-priority situations. The agency also plans to use risk factors to select veterinary-medicine plants for inspection. The long-term goals, says Horowitz, are to develop more outcomes-oriented standards for evaluating risk and to use science and data-driven targeting to determine inspection frequency and intensity, as well as FDA response to the inspectional findings.
In addition to using risk analysis to schedule inspections, FDA also wants to apply risk-based approaches to the plant-inspection process. A firm's ability to establish design space and control strategies may limit an inspection's scope. For firms with strong quality systems, preapproval inspections would be linked closely to the review process and targeted to answer specific questions related to the accuracy of underlying data. Postapproval inspections would focus on whether a firm's quality system can manage production so it stays within an approved design space. Ultimately, FDA and a manufacturer may negotiate a regulatory agreement at the time of approval that describes several acceptable postapproval changes that do not require supplements or inspection.
Integrating field and centers
Another important component of FDA's more science-based inspection process requires field staff to collaborate more closely with Center product specialists and technical experts in evaluating a firm's risk-management programs, product and process knowledge, process capability, and quality-system robustness, Ellsworth explained. Under an integrated review and inspection approach, says Joe Famulare, deputy director of CDER's Office of Compliance, inspectors would address key areas suggested by Center staff, verify process implementation and state of control, assess product life-cycle improvements, and ensure adequate change control. A PI Quality System Workgroup under FDA's Council on Pharmaceutical Quality is working to define a process for greater interaction of investigators and reviewers. The group is reviewing current operations to make recommendations about policies, procedures, and information-technology systems that will facilitate collaboration between these entities.
This move toward the increased integration of inspection and review for drugs builds on long-standing procedures in the Center for Biologics Evaluation and Research (CBER). Postapproval GMP inspections of biotechnology manufacturers has been performed by Team Biologics together with CBER product specialists for the past decade, commented Mary Malarkey, director of CBER's Office of Compliance and Biologics Quality. Such integration begins as early as the investigational new drug application stage and is particularly important for dealing with complex and innovative technologies.
Ironically, while ORA seeks to streamline its oversight responsibilities, other FDA regulatory initiatives require field inspections to play a larger role in ensuring industry compliance with standards. FDA is considering policy changes to permit manufacturers to describe more manufacturing changes in annual reports as one way to reduce the number of postapproval manufacturing changes that require prior approval by reviewers. These change reports would be available to inspectors at the plant to be evaluated as part of an inspection. At the pharmaceutical-quality workshop, attendees agreed that changes in current postapproval policies should not shift burdens from the Centers to the field, a concern likely to surface as FDA continues to seek new approaches for overseeing manufacturing compliance.
Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, email@example.com