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.
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 Instead of spending weeks at a manufacturing site to scrutinize all processes, an FDA draft
guidance written in September 2004 describes how GMP inspections will examine a plant's overall quality system plus one or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.
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.