FDA Moves to Transform Plant Inspection System

For the past year, Margaret O'K. Glavin has been preparing for major changes at the US Food and Drug Administration's Office of Regulatory Affairs (ORA). Glavin became ORA director in May 2005, replacing John Taylor at a time when FDA's regional and district offices faced more responsibilities and shrinking funds. Meeting these demands will require "fundamental changes in the way we perform our work over the next 10 years," she said in a March 2006 memo. Glavin recognizes that ORA can't inspect all the facilities and operations under its purview and must decide which ones are most important to monitor more closely and more frequently. This prioritization involves reorganizing ORA staff, revising policies, and adopting risk-based approaches for modernizing the field inspection process.

Jill Wechsler

At the annual meeting of the Food and Drug Law Institute (FDLI) in April, Glavin acknowledged that ORA has "always had to contend with rising responsibilities and declining resources." In the 1970s, the field force made up half of FDA's staff. Now it accounts for about 35%, a change that reflects a drop in real numbers since 2002.

And during this period, ORA's job has grown considerably. More drug manufacturers are building plants overseas, and almost all bulk ingredients now are imported, Glavin explained in an interview with Pharmaceutical Technology. FDA must monitor a vast expansion of food imports and has added responsibility for combating counterfeit drugs and the spread of bovine spongiform encephalopathy. National emergencies such as Hurricane Katrina and the specter of avian flu also have created new demands for strengthening the front lines of FDA's inspection system. Another new challenge is to develop a compliance program for cellular and tissue products, which involves oversight of some 1900 registered locations with no additional resources.

Many of these activities can benefit from Glavin's counterterrorism expertise. She came to FDA in 2003 to head its counterterrorism activities, a role that exposed her to the complexities of product-safety concerns and the challenges of developing biodefense countermeasures.

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 plan involves reducing ORA's inspection burden by using third-party inspection programs, promoting global harmonization, improving information sources, and offering incentives for manufacturers to adopt internal quality assurance programs. The aim is to shift from a periodic, reactive inspection system to more proactive approaches.

An ORA Transformation Leadership Team composed of staffers from across the organization is developing a strategic plan to address these challenges. In September, the panel is scheduled to unveil specific goals for the next year and list the resources needed to accomplish them. One immediate challenge 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," and the Pacific region may be overpopulated. She hopes to make necessary adjustments through voluntary reassignment, but more drastic personnel shifts may be required, a prospect that already is generating concerns among ORA's rank and file.

Changes at the top

One of Glavin's first moves was to reorganize her administrative staff. Last year, she appointed three deputy associate commissioners to help her handle the "enormous job" of ensuring 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. Under Deborah Ralston, the latter office coordinates field inspections in the United States and overseas with FDA centers and manages FDA interaction with state inspection programs, US Customs officials, foreign regulatory authorities, and emergency preparedness activities.

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.

Modernizing GMPs

Fresh approaches for conducting inspections and encouraging compliance are nothing new for drug manufacturers. FDA's Good Manufacturing Practices (GMP) Modernization initiative, which was designed to establish risk-based approaches to compliance and encourage innovative quality production technologies, also has made several changes in drug inspection programs over the past five years. These include:

• increased input from Centers in issuing warning letters for GMP violations;

• integration of preapproval and GMP inspections;

• establishing a pharmaceutical inspectorate of highly trained investigators knowledgeable about process analytical technology and risk-management approaches;

• resolving scientific and technical disputes between manufacturers and regulators more effectively.

FDA issued a final dispute-resolution guidance in January 2006 that describes what types of issues the program can address and what procedures it must follow. In addition, FDA has implemented a systems-based inspection model that focuses drug inspections on certain key plant operations. Instead of spending weeks at a manufacturing site to scrutinize all processes, an FDA draft guidance written in September 2004 describes how GMP inspections will examine a plant's overall quality system plus one or two additional operations (e.g., facilities and equipment, materials, production, packaging and labeling, laboratory control) that are most important for ensuring product quality.

Evaluating risk

A more recent innovation is to adjust the level of regulatory scrutiny to a facility's overall risk level. CDER compliance officials have refined a risk model to select sites for GMP inspections, reported John Gardner, director of the division of compliance risk management in CDER's Office of Compliance, in a presentation at FDA's Science Forum in April. Gardner noted that this approach also is being applied to FDA oversight of manufacturer adverse event reporting programs and to drug-product sample analysis (see sidebar, "Risk models shape drug sampling and adverse-event oversight").

Risk models shape drug sampling and adverse-event oversight

FDA cannot inspect all 2800 US drug manufacturing sites, Gardner said, and regards this new model as a way to identify which facilities need closer and more frequent scrutiny. This approach calculates a risk score for each plant based on:

• type of facility, as determined by size (based on drug sales), compliance history, and type of operation (e.g., manufacturer, laboratory, packager);

• product characteristics such as oral or injectible, prescription or over-the-counter, sterile or nonsterile, and therapeutic category (e.g., critical treatment or dental product);

• manufacturing process characteristics such as degree of control and contamination potential;

• time since last inspection (all plants not inspected in the past five years are rated high priority).

After two years of pilot testing, CDER has implemented this model to select 500 domestic drug-production facilities for its high-risk tier that should be inspected by ORA this year. This group will account for about half of ORA's drug inspections for 2006; the rest are directed inspections based on the need for a preapproval inspection (PAI), a recall or complaint, or follow-up to a previously unsatisfactory inspection. District inspectors who are more familiar with specific plant operations and inspection histories also have the discretion to add or remove certain facilities on the priority list.

Manufacturers have objected to CDER's use of plant size as a risk factor. Gardner acknowledged that although a high-production automated facility might be more safe and reliable than a small, obsolete operation, a quality problem with the potential to affect a lot of people carries higher risk. Companies also would like to know the risk scores of their facilities, but FDA has no plans to provide that information, Gardner emphasized, just as the Internal Revenue Service does not tell taxpayers its audit criteria. "Every manufacturer needs to know that it will be inspected, and that the frequency will be determined by risk, by FDA resources, and by the particular policy emphasis at FDA, which may change every year," Gardner pointed out.

Integration and coordination

In addition to setting inspection priorities, FDA aims to avoid redundant site visits by better coordinating GMP and PAIs. The agency recently dropped its mandatory PAI policy and is waiving more PAIs for generic drugs and for manufacturers who receive high marks on GMP inspections and can demonstrate that a facility is in full compliance and shows a state of control.

Improved coordination also involves closer communication among ORA field offices and FDA centers. The agency supports a stronger team approach in which Center reviewers identify key issues for inspectors to address during site visits, and field offices include reviewers in inspections that involve complex production issues. FDA is encouraging manufacturers to retain more raw stability data and other records on-site, which requires field inspectors to have broader familiarity with new drug applications and issues raised during review to conduct an efficient inspection.

FDA has had team-based inspections for biologics for several years, and Glavin considers Team Biologics and the Pharmaceutical Inspectorate "the future" of federal inspections. The Team Biologics cadre conducts routine GMP inspections for products regulated by the Center for Biologics Evaluation and Research (CBER), while CBER reviewers head preapproval inspections. ORA is incorporating these elements into new compliance models for drugs and medical products, a trend accelerated by the shift of biotech therapeutics to CDER and reflected in the establishment of the Pharmaceutical Inspectorate.

Seeking information

One problem for FDA in assessing site risk is a lack of information about manufacturer production volume by product and by facility. Companies do not have to provide specific manufacturing data to the agency, and many hesitate to do so for fear of unveiling trade secret information about product formulation, manufacturing process, engineering plans, or other issues. FDA inspectors get a sense of plant volume from site visits, but such information is not precise and may become outdated quickly.

FDA also lacks information about bulk ingredient imports, which now come largely from countries without a long history of information exchange with US regulators. ORA would like to know if manufacturers have quality problems with certain active ingredients or refuse certain shipments; such information, Glavin points out, would inform inspection and sampling decisions. She is contemplating new incentives for manufacturers to share such information with FDA. One idea proposed by generic drug manufacturers is a "Green Lane" for faster processing of drug and bulk ingredient imports for companies that provide information about a foreign producer's quality-control and testing capabilities.

Manufacturers generally support FDA efforts to streamline the frequency and scope of its foreign inspections, which total about 1000 per year. Unfortunately, FDA's program now is only the tip of the iceberg. More than 30 foreign regulatory agencies want to inspect pharmaceutical manufacturing plants, and the number continues to increase, according to Malcolm Holmes, director of global quality assurance at GlaxoSmithKline (Hertfordshire, United Kingdom, www.gsk.com). 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 complained at the FDLI April meeting. He noted that industry spends some 35,000 employee-hours coping with multiple foreign inspectors, now coming more frequently from Mexico, Argentina, Africa, and Asia. One GlaxoSmithKline site experienced five inspections last year, and all manufacturers are suffering from "inspection overload," Holmes commented.

International adoption of risk-based inspection models and more information sharing 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 that a plant 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 now under development. And, clarification by the World Health Organization of its recommendations for when plant inspections are needed would be helpful.

Increased reliance on risk management to reduce low-priority oversight by FDA assumes stronger self-regulation and compliance by industry. Manufacturers with sound GMP compliance histories and corporate-integrity programs may gain some regulatory relief, especially for low-risk products.

FDA aims to encourage manufacturers to ensure product quality by establishing internal quality-control units, written process-control procedures, and processes to fully validate operations. Such policies can demonstrate a corporate environment that encourages compliance with rules and regulations.

Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, jwechsler@advanstar.com