FDA Moves to Transform Plant Inspection System - Pharmaceutical Technology

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FDA Moves to Transform Plant Inspection System
ORA leadership looks to staff redeployment and risk management to ensure product quality despite diminishing resources.


Pharmaceutical Technology


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 Instead of spending weeks at a manufacturing site to scrutinize all processes, an FDA draft guidance written in September 2004 describes how GMP inspections will examine a plant's overall quality system plus one or two additional operations (e.g., facilities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


Risk models shape drug sampling and adverse-event oversight
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").

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.


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