Chapter 4: Regulatory Inspections

Inspection Authority

The Food, Drug, and Cosmetic Act (FDCA) grants the United States Food and Drug Administration (FDA) the authority to conduct establishment inspections and collect samples to enforce the Act. FDA, in the Center for Biologics Evaluation and Research (CBER) Compliance Program Guidance Manual, Inspection of Biological Products, 7345.848, outlines three reasons for conducting inspections:

• To safeguard the public health by reducing the risk of adulterated or misbranded drugs reaching the marketplace

• To increase communication between the industry and FDA

• To provide timely input to firms during inspections to improve the firm’s compliance with current good manufacturing practices (cGMP) requirements

Countries that import drugs manufactured in the United States can inspect drug manufacturing establishments in the United States. For example, Health Canada performs inspections for on-site monitoring and assessment of applicable requirements in the Canadian Food and Drugs Act and associated regulations. Health Canada inspections routinely are conducted on a predetermined cycle or as required to assess compliance.

Types of Inspections

Regulatory inspections for GMP compliance in the pharmaceutical industry typically are categorized as preapproval inspection, routine surveillance (post-approval), and compliance (one of which is “for cause”). A preapproval inspection of a drug manufacturing facility is conducted as part of the evaluation of a new drug before it is approved for commercial sale by FDA. If an active pharmaceutical ingredient (API) or excipient is made by a facility other than the manufacturer of the drug product, these facilities may also be inspected. If major issues are observed during a preapproval inspection, a follow-up inspection may be required before drug approval to review corrective actions implemented by the firm.

Routine surveillance inspections, conducted after a drug product is approved by the FDA, are intended to be conducted every two years. The FDA uses a risk management approach to assess which products pose a high risk and, as a result, require more-frequent oversight. A firm is considered to be a higher risk if the company has a history of cGMP compliance issues or is closer to the end of the processing of a drug product, or issues have occurred with similar categories of products (for example, heparin API contamination).

A compliance inspection is conducted to examine the effectiveness of corrective actions implemented by a firm due to a regulatory action. A compliance inspection may be referred to as a “for cause” inspection when an issue has occurred, such as contamination, adverse events (for example, patient deaths or severe side effects), or lack of drug effectiveness (perhaps due to a counterfeit drug).

Inspections of Foreign Drug Manufacturers

Part of FDA’s mission is to assure that drug, medical device, biologic, and food products manufactured in foreign countries and intended for US distribution are in compliance with the law and regulations, that noncompliance is identified and corrected, and that any unsafe or unlawful products are removed from the marketplace. FDA performs inspections of products at the US border on a risk-based approach. Materials that do not meet requirements are destroyed or exported back to the source. FDA typically conducts inspections of foreign drug manufacturing firms when:

• The firm is identified in an application or submission as the main supplier or alternate supplier of materials, products, or services.

• The firm has had a violative inspectional history and/or problems.

• The firm was prioritized using a tiered approach based on factors such as risk, volume of products, or complexity of processes.

• The firm had problems related to adverse reactions or was involved in recalls.

Inspection Techniques

During a regulatory inspection, FDA may evaluate the systems in place to assess the firm’s cGMP compliance. If the system is determined to be in a state of control for the product or products examined during the inspection, the system should be adequate for the same class of products made by that firm.

FDA can conduct a comprehensive inspection, often referred to as a full inspection, for a broad and deep evaluation of the firm’s cGMP compliance. The full inspection covers every system at the facility subject to FDA jurisdiction to determine compliance status. A full inspection is required for a compliance inspection and for the initial FDA inspection of a facility.

Alternatively, FDA can conduct a directed inspection, also known as an abbreviated inspection, to provide an efficient update of the firm’s cGMP compliance. The abbreviated inspection covers specific areas to the depth necessary to address the purpose of the inspection.

FDA evaluates an organization by inspecting its cGMP systems. The FDA review of a system includes the systems being used as well as specific examples that illustrate the effectiveness of system implementation. The systems and evidence of implementation are covered in sufficient detail so that FDA can determine whether the system is in a state of control. FDA divides systems into six categories: quality, facilities and equipment, materials, production, packaging and labeling, and laboratory control. Full inspections require assessment of a minimum of four systems, one of which must be the quality system. Abbreviated inspections require a minimum of two systems, one of which must be the quality system. During subsequent abbreviated inspections, the systems evaluated are rotated so that all six systems are periodically addressed. Depth of coverage of each system depends on the findings during an inspection.

Inspection Process

Upon arrival at the facility being inspected, and regardless of the type of inspection conducted, the FDA investigator displays credentials and gives documentation of the inspection on form FDA 482, Notice of Inspection, to the top management official at the facility. The FDA 482 usually is presented during an opening meeting with the inspection team and company management.

Inspections can be conducted by one investigator or a team of experts from within the firm’s FDA district, from other districts, and/or from FDA headquarters, with one member designated as team leader. The inspection may consist of any combination of observing processes and the facility, reviewing procedures and records, and asking employees of the firm questions about their responsibilities and the tasks they perform.

Frequently, the inspection begins with a walk through the facility while it is in operation. FDA investigators take notes during all parts of the inspection to document what they have seen, the personnel encountered, and any concerns they have. Daily debriefings may occur so that FDA can indicate their concerns as they are encountered.

At the close of the inspection, the investigator provides the top management official with any inspection findings on form FDA 483, Inspectional Observations, usually during a closing meeting with company management. Observations listed on the FDA 483 are cGMP deficiencies related to a requirement in the cGMP regulations. If no observations of significance were identified, no FDA 483 is issued. Form FDA 484, Receipt for Samples, is presented to top management if samples were taken during the inspection. Routine surveillance samples are often collected during regulatory inspections. Samples also may be collected as a result of enforcement action.

After the close of the on-site inspection, the FDA investigator(s) are obligated to complete an establishment inspection report (EIR). Once the inspection is considered closed, and the EIR is available, it is typically forwarded to the company for inclusion in their inspection files.