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Glavin is preparing a plan to modernize ORA through organizational changes . . .
Margaret O'K. Glavin became the director of FDA's Office of Regulatory Affairs (ORA) in May 2005 and now faces a serious challenge: finding ways to manage expanding oversight responsibilities in the US and abroad for ORA's regional and district inspection teams despite shrinking resources. Glavin recognizes that ORA cannot inspect all the facilities and operations under its purview and has to determine which ones are most vital to monitor more closely with increased frequency. This determination involves reorganizing the ORA staff, revising policies, and adopting risk-based approaches for "transforming" the field inspection process.
Since the 1970s, FDA's field force has shrunk from half of the agency's staff to about 35 percent today. And also during this period, ORA's job has grown considerably. Pharmaceutical and biotech manufacturers are adopting more complex production processes and building more plants overseas, Glavin explained in an interview with BioPharm International. ORA has to monitor a vast expansion of food imports and has the added responsibility of combating counterfeit drugs and the spread of bovine spongiform encephalopathy (BSE). One new assignment is to develop a compliance program for cellular and tissue products, which involves oversight of some 1,900 registered locations with no additional resources. And national emergencies such as Hurricane Katrina and the specter of avian flu have created new demands for strengthening FDA front line defenses.
Glavin is preparing a 10-year plan to modernize ORA through organizational changes and new approaches that target resources to its most critical activities. This involves utilizing third-party inspection programs, promoting global harmonization, improving information sources, and offering incentives for manufacturers to adopt internal quality assurance programs. The plan's goal is to shift from a periodic, reactive inspection system to more proactive approaches.
An ORA Transformation Leadership Team composed of staffers within the organization plans to unveil a strategic plan in September 2006 to address these challenges. An immediate task is to correct staff imbalances among regions and districts that have developed in recent years. Changes in ORA's structure "certainly are a possibility," Glavin says, noting that ORA's central region probably is the "least well-staffed," while the Pacific region may be over-populated. The prospect of personnel shifts is already generating concerns among ORA's rank and file.
One of Glavin's initial moves has been to reorganize her top administrators. Last year, she appointed three deputy associate commissioners to help ensure consistent policies and procedures throughout this far-flung operation. Management of ORA's five regional offices, 20 district offices, and 13 field laboratories now is handled by deputy for field operations, Diana Kolaitis, a long-time and highly respected field leader.
Steven Niedelman, deputy for regulatory operations and chief operating officer, oversees regulatory policy implementation at the national level. ORA's Office of Enforcement, Office of Criminal Investigations, and Office of Regional Operations report to him. Regional Operations, under Deborah Ralston, coordinates field inspections in the US and overseas with FDA centers and manages Team Biologics, the specially trained cadre of national investigators established in 1997 to conduct routine inspections of biological manufacturers. Ralston also handles FDA interaction with state inspection programs, with US Customs officials, with foreign regulatory authorities, and with emergency preparedness organizations.
New to ORA is David Horowitz, deputy for compliance policy, who is spearheading efforts to implement risk-based approaches for ORA activities. Horowitz led similar efforts as the former head of the Office of Compliance in the Center for Drug Evaluation and Research (CDER), and now is extending these initiatives to medical devices, veterinary drugs, and other regulated products. CDER compliance officials have set the pace by devising a risk model for selecting sites for GMP inspections based on a range of risk factors: plant size and compliance history; product characteristics (sterile parenterals vs. dentifrices); complexity and contamination potential of manufacturing process; and time lapsed since last inspection. This approach is also being applied to FDA oversight of manufacturer adverse-event-reporting programs and to drug product sample analysis.
Most biotech manufacturing operations fall into the high-risk category because they involve sterile injectables and production methods susceptible to contamination. CDER is adopting this model to identify 500 domestic production facilities that fall into the high-risk tier and should be inspected by ORA this year. This group will account for about half of ORA's drug inspections for 2006, with the rest based on the need for a pre-approval inspection, a recall or complaint, or follow-up to a previously unsatisfactory inspection. District inspectors more familiar with specific plant operations have discretion to add or remove certain facilities on the priority list.
In addition to targeting inspections to high-risk operations, ORA is implementing other strategies to streamline the inspection process. FDA's Good Manufacturing Practices (GMPs) for the 21st Century Initiative, launched to encourage risk-based approaches to compliance and adoption of quality production technologies, has established several new approaches for GMP inspections. One initiative has given Centers more input in issuing warning letters for GMP violations identified during inspections; another seeks to better integrate pre-approval and GMP inspections.
An important development has been to extend the team inspection approach pioneered by Team Biologics to drugs and other medical products. ORA is establishing a Pharmaceutical Inspectorate of specially trained experts able to audit complex drug products and facilities. However, Team Biologics retains responsibility for inspecting manufacturers producing biotech therapeutics now regulated by CDER, as well as for biologics and blood establishments in the Center for Biologics Evaluation and Research (CBER).
For pre-approval inspections, CBER compliance staffers continue to take the lead in this area. And now a similar approach has been adopted by CDER for biotech products, explained Brenda Uratani of CDER's Office of Compliance (OC) at a recent conference on biotech regulation sponsored by Pharma Conference. Product specialists from OC's branch overseeing biotech therapeutic facilities and from CDER's Office of Biotechnology Products who review biotech process manufacturing controls now have lead responsibility for conducting pre-approval inspections for biotech therapeutics in CDER. FDA is incorporating this model of more ORA–Center shared responsibility in revising inspection approaches for drugs. Team Biologics and the Pharmaceutical Inspectorate are "the future" of federal GMP inspections, Glavin comments.
While FDA seeks to streamline the frequency and scope of its field inspection program at home, it is struggling to cope with a rising number of foreign-based inspections. FDA conducts about 1,000 foreign inspections for drugs and biologics each year, but this program, unfortunately, now is only the tip of the iceberg. More than 30 foreign regulatory agencies now want to inspect pharmaceutical manufacturing plants, and the number continues to increase, according to Malcolm Holmes, director of global quality assurance at GlaxoSmithKline. Industry is building large, sophisticated production facilities that may export products to more than 80 different markets, and inspectors from all over the world are showing up to conduct their own audits. This kind of "industrial tourism" does little to enhance public health and safety, Holmes stated, noting that industry now spends some 35,000 person-hours coping with multiple foreign inspectors from Mexico, Argentina, Africa, and Asia.
International adoption of risk-based inspection models and more sharing of information offer prospects for relief. Although no one is looking for mutual recognition of inspection decisions by foreign agencies, there is growing interest in bilateral agreements for sharing inspection information among regulatory authorities. US membership in the Pharmaceutical Inspection Cooperation Scheme (PIC/S), which is moving forward, could expand acceptance of PIC/S certificates to include that a plant also meets GMP standards. Foreign regulators could save resources by first examining what inspection report information is available from PIC/S, from FDA's inspections database, and from an EU database currently under development. Clarification by the World Health Organization of its recommendations for when plant inspections are needed would be helpful. Manufacturers with sound GMP compliance histories and corporate integrity programs also may gain some regulatory relief if foreign regulatory authorities accept such quality assurance policies as indications of compliance.
Jill Wechsler is BioPharm International's Washington editor, 7715 Rocton Avenue, Chevy Chase, MD 20815, 301.656.4634, firstname.lastname@example.org