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A central part of FDA's responsibilities to protect the public health includes: 1) ensuring that manufacturing establishments and the products being produced by these establishments--both domestic and imported--are meeting safety and quality standards that are acceptable to the U.S. and 2) monitoring these products to identify and correct any problems associated with their consumption and use. Through inspection and monitoring activities, potential hazards are identified and corrected in time to prevent or minimize public exposure.
The discussion that follows is divided into these two areas of postmarket responsibility.
FDA is responsible for ensuring the safety of products produced and distributed by more than 100,000 domestic establishments. The Agency uses its inspection authority, as directed by the statute, to provide this assurance. Approximately 45,000 of these establishments manufacture or process regulated product. FDA inspected 30 percent of these facilities in FY 1997. A sizable number of the remaining establishments (23,000) are distribution facilities, of which FDA inspected 10 percent in FY 1997. The remainder includes 10,000 mammography facilities, which FDA inspects at a nearly annual rate, and a varied assortment of other establishment types, e.g. control laboratories, importer/brokers, clinical investigators, and conveyances, of which FDA inspected about 14 percent in FY 1997. Overall, approximately 40 percent of FDA's current inspectional coverage is provided through contracts with states.
As these varying inspectional coverage statistics indicate, FDA exercises considerable discretion regarding the frequency and comprehensiveness of inspections. For approximately 25 percent of this inventory, however, the law requires FDA to conduct inspections at specified maximum time intervals. Certain manufacturing facilities must be inspected at least once every 2 years, and mammography facilities must be inspected at least once each year. In recent years, inspection coverage has fallen short of meeting these statutory requirements. The table below summarizes the Agency's recent coverage of the domestic inventory including the segment subject to statutory minimum inspection coverage as well as the segment over which the Agency has discretion regarding inspection frequency. To meet the statutory requirements, 100 percent of the mammography facilities and at least 50 percent of the other statutory establishments should have been inspected in FY 1997. As the data show, with the exception of mammography facilities, neither goal was reached.
| Program Area | Inventory | Statutory Coverage Establishments* |
Statutory Coverage Coverage in FY 1997 |
Non-Statutory Coverage Establishments* |
Non-Statutory Coverage Coverage in FY 1997 |
|---|---|---|---|---|---|
| Biologics | 5,685 | 2,787 | 46 percent | 2,898 | 13 percent |
| Human Drugs | 19,749 | 6,408 | 23 percent | 13,341 | 12 percent |
| Devices (excluding mammography) | 27,638 | 4,870 | 28 percent | 22,768 | 9 percent |
| Mammography | 10,000 | 10,000 | 96 percent | ||
| Foods | 49,000 | n.a. | n.a. | 49,000 | 23 percent |
| Animal Drugs and Feeds | 6,414 | 1,688 | 27 percent | 4,726 | 13 percent |
* Status as of May 1998.
Agency stakeholders expressed strong support for more regulatory enforcement in general, and the continued focus on risk-based inspections in particular.
Stakeholders tended to support the idea of third-party inspections, especially noncritical inspections.
The Agency's domestic inspection program is an integral part of the strategy for monitoring the compliance status of the regulated industry. The goals of an inspection may be many and varied, i.e., to verify data submitted to the FDA in a new drug or biologic application, and to ensure continued compliance with application commitments. Inspections monitor the regulatory control over manufacturing operations including compliance with current GMP regulations. The results of inspections form the basis for many of the Agency's administrative and regulatory decisions, including new drug, device, or biologic approvals, as well as detecting industry problems or objectionable conditions and practices.
Establish Risk-Based Priorities
Given the large inventory of establishments it must inspect with limited resources, FDA targets the highest risk products and those facilities whose violations of standards would most likely expose the public to unnecessary risk. The cornerstone of the Agency's drug (human and animal), medicated feed, biological, and medical device inspection strategy is the biennial inspection requirement, which mandates the inspection of critical establishments in the Agency's inventory, primarily manufacturers, at least once every 2 years. While FDA has no such legal mandate for food inspections, it is moving toward establishing a vertically integrated food safety system that is risk-based and which would allow it to inspect high-risk establishments every 1 to 2 years and moderate-to-low risk establishments every 4 years.
Adopt a Systems Rather than a Piecemeal Approach to Agency Regulation
Manufacturing processes are becoming more complex due to the rapid advancement of science and technology. This trend continues to accelerate. This increasing complexity is mirrored in FDA's approach to ensuring comprehensive, consistent, and fair inspections. Where, in the past, the Agency often perceived its role as providing quality control for the industries it regulated, today, it recognizes the essential role that establishments themselves must play to ensure product quality assurance. The Agency is focusing more on ensuring that the systems the industry has in place to monitor the quality of its products are adequate. This approach stresses the importance of HACCP-type inspections and frequently requires that the Agency take a multidisciplined, team approach to inspections.
Work More Closely With External Stakeholders
The Agency increasingly has emphasized communication and education as alternatives that are at times preferable to and more effective in achieving and maintaining compliance than the more traditional enforcement approaches used in isolation. It accomplishes this by providing training and workshops for industry groups, seeking the views of stakeholders, and sharing information with stakeholders and colleagues. Some examples of the Agency working closely with external stakeholders include:
Under provisions of the Food, Drug and Cosmetic Act and the Public Health Service Act, FDA is required to conduct biennial inspections of approximately 16,000 registered drug, biologic and device production facilities. Although there is no statutory requirement that mandates a particular frequency for the inspection of any food establishment, or those drug, biologic and device facilities excluded from the biennial requirement, the statute obliges the Agency to ensure the safety of regulated products within these establishments. Accordingly, goals have been set within these establishment categories to achieve an average inspection cycle of once every 4 years, with appropriate risk-based variations in this cycle where warranted.
FDA fell short of meeting its statutory biennial and annual inspection obligations by approximately 4,000 inspections in FY 1997. In an effort to improve its performance in these critical areas, FDA plans to rely increasingly on states and other third parties, both for direct help with some statutory inspections and for other important inspectional obligations, thus freeing some of FDA's own resources to cover additional statutory obligations. Because all public and private sector organizations in the future will be subject to the same resource-constrained environment, FDA may have to consider that even a highly collaborative inspectional network may not be adequate to completely meet existing statutory inspectional requirements. A strategic reassessment may be in order to determine the kinds of statutory flexibility that would be desirable to preserve the comprehensive consumer protection intent of the FD&C Act, and at the same time, allow FDA to address the most critical health and safety priorities. Some examples of Agency initiatives either planned or already underway include the following:
Special Emphasis on Food Safety: The Agency recognizes its obligation to ensure the safety of the food supply, and the public expects food to be safe. To meet this expectation, FDA needs to inspect high-risk establishments every 1 to 2 years and moderate-to-low risk establishments every 4 years. This level of inspection coverage will require an additional 4,000 to 6,000 annual inspections. FDA's own food safety assurance efforts is being integrated with a national risk-based food safety system. This will require close collaboration with USDA, CDC, the states, food manufacturers and food retailers. Key elements of the initiative are:
This section contains two tables. The first table summarizes the Agency's domestic inspection performance goals for FY 1999. The second table links these performance goals to the statutory requirements.
Inspect 46 percent of registered biologic firms
Inspect 23 percent of registered drug manufacturers, propagators, compounders, or processors
Inspect 28 percent of registered class II and III medical device manufacturers, propagators, compounders, or processors
Conduct 8,898 inspections of mammography facilities
Ensure that 50 percent of seafood industry operating under HACCP
Develop HACCP final rule for fruit and vegetable juices
Inspect 50 percent of registered animal drug and feed establishments
| Statutory Authority | Relevant Statute and/or Regulation | Relevant FY 1999 Performance Goals | FY 1997 Performance Baseline |
|---|---|---|---|
| Biennial GMP inspections of biologic firms (50 percent annually). | FD&C Act - Sec. 510(h) | Coverage: 46 percent | Coverage: 46 percent |
| Biennial inspections of registered drug manufacturers, propagators, compounders, or processors (50 percent annually). | FD&C Act - Sec. 510(h) | Coverage: 23 percent | Coverage: 23 percent |
| Biennial inspections of registered class II and III medical device manufacturers, propagators, compounders, or processors (50 percent annually). | FD&C Act- Sec. 510(h) | Coverage: 28 percent | Coverage: 28 percent |
| Annual inspections of mammography facilities | PHS Act (Sec. 354) | Conduct 8,898 inspections | Conduct 8,280 inspections |
| General authority to inspect food, drugs, devices, or cosmetic establishments | FD&C Act (Sec. 704) | Ensure that 50 percent of seafood industry operating under HACCP. Develop the HACCP final rule for fruit and vegetable juices. | |
| Biennial inspections of registered animal drug and feed establishments (50 percent annually). | FD&C Act -Sec. 510(h) | Coverage: 20 percent | Coverage: 27 percent |
FY 2000 Performance Goals are not identified in this Plan. Specification of these goals is dependent upon final determination of the President's FY 2000 Budget submission to Congress.
Imported products pose multiple challenges to FDA. These include the sheer volume and diversity of products, the difficulty of ascertaining exactly which establishments are shipping products to the United States, and the difficulty of verifying conformity with GMPs quality systems. Each of these challenges is described in the following paragraphs.
The Volume and Diversity of Products
FDA is responsible for ensuring the safety of nearly 4 million line entries that cross our borders annually, or over 12,000 entries per day. Imports of all products that FDA regulates have been increasing; pharmaceuticals, both finished and bulk, are increasing very rapidly. Approximately $57 billion of FDA-regulated product was imported in 1997. The sources are diversifying and including more products from countries that are typically categorized as emerging economies, with emerging regulatory infrastructures. The products include, among others, food products that have been implicated in serious disease outbreaks in the United States, food products that could pose health threats if not processed and handled properly, over-the-counter drugs that do not require a new drug application with the Agency, as well as approved drugs, biologics, and medical devices.
Difficulty in Ascertaining Establishments Shipping to the United States
Section 417 of FDAMA [510(i) of the Act] now requires all foreign manufacturing establishments whose drug and device products are imported into the United States to register. There is, however, no universal registration requirement for producers of imported food products. Manufacturers/packers of low-acid canned food, acidified foods, and infant formula (all of which products are considered at high risk) register or list with the FDA; other food producers and processors are not required to register or list with FDA, making identification of sources of product difficult.
Difficulty of Verifying Conformity with GMPs/Quality Systems
There are two ways that typically are used to confirm that product has been produced properly--end point product testing (which for imports could be analysis of border samples) and on-site inspections. There are difficulties with both of these approaches. To date, no effective, scientifically based method has been established for general screening of foreign drug product for adherence to GMPs. Analysis of product samples is reasonably effective in assuring conformity, but the volume of trade and resource limitations preclude high rates of analysis. On-site inspections, the way of affirming conformity with good manufacturing practices/quality systems, are expensive and pose a host of logistical and practical difficulties. All foreign firms are aware that an FDA inspection is planned well in advance of the inspection, unlike the inspection of domestic establishments. Regardless of these challenges, there is consistent expectation from the Congress that FDA assure foreign product safety, and there is recurring congressional focus on FDA inspections of foreign manufacturing facilities.
Stakeholders want assurances that foreign products meet the high standards expected of domestic products, and encourage FDA to conduct foreign inspections and periodic testing of product to confirm quality. Stakeholders strongly support FDA's activities in Codex and international harmonization, reflecting a desire to minimize regulatory burden while assuring that foreign produced food products are safe and therapeutic products are safe and effective. Stakeholders especially stress the importance of effective participation in Codex, because of the special place Codex holds in resolving international trade issues: the international standards that are adopted must reflect the standards and the high level of safety required in the United States. Support for pharmaceutical GMP mutual recognition agreements (MRAs) was predicated on the likelihood of there being equivalent standards as well as truly effective regulatory programs in MRA countries. The need for expanded funding support for Codex activities and for monitoring of imports was noted. A few typical comments are as follows:
Assurance that Foreign Product Meets High Standards Expected of Domestic Product
Support for Codex Activities
Support for Mutual Recognition Agreements (MRAs)
. . . but a Cautionary Note
FDA must ensure that the structure in place at the point of origin results in product being shipped to the United States meeting FDA requirements for safety, quality and/or therapeutic efficacy. This is a prevention-based strategy. A secondary strategy is detection based: conduct inspections of establishments shipping product to the United States, and screen product at the border for more intensive review. Electronic screening allows conforming product to move quickly into commerce, while identifying product that may need more review at the border.
To deal with an explosively expanding workload and flat resources, FDA has directed its non-Prescription Drug User Fee Act of 1992 (non-PDUFA) foreign inspection activities toward higher risk products and is expanding PDUFA inspections to include more comprehensive inspections of facilities. More screening of product at the border is being accomplished through electronic means. And finally, analysis of product at the border is increasingly targeted toward product that is expected to pose high risk, as identified in the electronic screening. This risk-based prioritization means that many medium-risk product manufacturing facilities are not inspected, and most lower risk product facilities are not inspected.
With additional resources, FDA expects to strengthen the safety net that extends from the point of production in source countries through their entry into the U.S. These strategies encompass: 1) Reducing the probability that violative products will be exported to the United States.; 2) Making rapid and reliable decisions on product entry at the border; and 3) Targeting violative products at the border and preventing their entry.
To reduce the probability that violative products will be exported to the United States, FDA will continue to participate in international negotiations and establishment of mutual recognition agreements with other nations. These activities will assure that products from those nations are meeting FDA standards, and will also increase the number of foreign inspections. As international regulatory agreements are negotiated among trading nations, the Agency will explore new and innovative institutional arrangements, such as third-party certification of both imports and exports. These arrangements will have to be cost-effective, within statutory mandates, and enforce health and safety standards. To allow rapid entry of safe products, FDA continues to enhance its electronic screening process. To target violative products at the border, the Agency will maintain its ability to conduct laboratory analysis on a small percentage of products with potential problems, by increasing its sample analysis. The Agency will also enhance the electronic import entry system to provide for a broad-scope collection and analysis of information on product-country intersects that will allow development of national profiles. These profiles will provide the basis for establishing systematic risk-based priorities in examining import entries. Many of these efforts are obviously resource intensive and linked closely with the steadily rising volume of imports.
Consistent with the strategic directions noted above, FDA has established performance goals that support moving toward higher assurance of imported product safety in a time of increasing imports, as noted in the table below. The FD&C Act provides for sampling of product at import, and FDAMA modifications require the Agency to engage in activity designed to harmonize regulatory requirements with the objective of reducing the burden of regulations. Goals to support these activities address the short-term screening of imports at the border as well as longer term infrastructure development internationally, and these are noted in the table below. A more comprehensive table, illustrating legislative provisions, follows.
Associated with the immediate need at the border, the performance goals relate broadly to assuring the integrity of the screening system, such as by confirmation of the accuracy of entries and continual updating of the screening criteria and by improving the overall sampling and the targeted sampling rates at the border. Goals relating to international infrastructure development reflect ongoing commitment and heavy investment in international standard setting forums and negotiating equivalence agreements and mutual recognition agreements. Success in these realms would allow FDA to rely more on the regulatory structures in place at the point of origin of products being shipped to the United States. And finally, there are times when direct FDA inspections of foreign manufacturing sites are necessary to ensure the quality of product being shipped to the United States, and several performance goals reflect this need.
Enhance the safety of imported products through increased surveillance of imported food products at the border, increased foreign inspections (from 40 to 75-100), education and outreach activities to foreign countries, and the evaluation of food production systems in foreign countries.
Enhance import screening capabilities for public health while ensuring that 55 percent of entries are released within 15 minutes.
Assess potentially violative imports through direct examination of 3 percent of entries.
Accept at least 20 percent of imports into the U.S. market through evidence that source country quality systems/standards/audits meet the requirements of the FD&C Act.
| Statutory Authority | Relevant Statute and/or Regulation | Relevant FY 1999 Performance Goals | FY 1997 Performance Baseline |
|---|---|---|---|
The Secretary of the Treasury shall deliver to the Secretary of Health and Human Services, upon his request, samples of foods, drugs, devices and cosmetics which are being imported or offered for import into the United States, giving notice thereof to the owner or consignee, who may appear before the Secretary of Health and Human Services and have the right to introduce testimony...If it appears from the examination of such samples or otherwise that (1) such article has been manufactured, processed, or packed under unsanitary conditions, or in the case of a device, the methods used in, or the facilities or controls used for, the manufacture, packing, storage or installation of the device do not conform to the requirements of section 520(f) [GMPs] or (2) such article is forbidden or restricted in sale in the country in which it was produced or from which it was exported, or (3) such article is adulterated, misbranded, or in violation of section 505 [NDA provision], then such article shall be refused admission, except as provided in subsection (b) of this section [relabeling, reconditioning]... |
FD&C Act 801 (a) |
Enhance import screening capabilities for public health while ensuring that 55 percent of entries are released within 15 minutes. Assess potentially violative imports through direct examination of 3 percent of entries. Enhance the safety of imported products through increased surveillance of imported food products at the border, increased foreign inspections (from 40 to 75-100), education and outreach activities to foreign countries, and the evaluation of food production systems in foreign countries.
| FY 1997: 50 percent FY 1996: approximately 3.3 percent FY 1998: Data from foreign inspections/evaluations (40 is the target) and data from border surveillance sampling. |
The Secretary shall support the Office of the United States Trade Representative, in consultation with the Secretary of Commerce, in meetings with representatives of other countries to discuss methods and approaches to reduce the burden of regulation and harmonize regulatory requirements if the Secretary determines that such harmonization continues consumer protections consistent with the purposes of this Act. The Secretary shall support the Office of the United States Trade Representative, in consultation with the Secretary of Commerce, in efforts to move toward the acceptance of MRAs relating to the regulation of drugs, biological products, devices, foods, food additives, and color additives, and the regulation of GMPs, between the European Union and the United States. The Secretary shall regularly participate in meetings with representatives of other foreign governments to discuss and reach agreement on methods and approaches to harmonize regulatory requirements. The Secretary shall, not later than 180 days after the date of enactment of the Food and Drug Administration Modernization Act of 1997, make public a plan that establishes a framework for achieving mutual recognition of good manufacturing practices inspections |
FD&C Act 803 |
Accept at least 20 percent of imports into the U.S. market through evidence that source country quality systems/standards/audits conform to the requirements of the FD&C Act. |
The international trade data used to evaluate the status of this goal are affected by the nature and timing of evolving international agreements and standards. These data will be used to determine the volume of imports that conform with FDA requirements under these agreements and standards. |
FY 2000 Performance Goals are not identified in this Plan. Specification of these goals is dependent upon final determination of the President's FY 2000 Budget submission to Congress.