Glp

As might be expected from regulatory agencies such as FDA, OECD, and the U.S. Environmental Protection Agency (which has its own set of GLP regulations similar to the FDA's), the GLP requirements are extensive and detailed.10 Compliance with GLPs is accomplished and verified through both internal and external procedures and inspections. Internally, Quality Assurance (QA) units are required to perform a variety of specified duties. Externally, an authorized regulatory agency official can inspect a laboratory's facility, records, and specimens at any time and without prior notification.

The subparts of GLP regulations categorize requirements under General Provisions, Organizations and Personnel, Facilities, Equipment, Testing Facilities Operation, Test and Control Articles, Protocol for and Conduct of a Nonclinical Laboratory Study, Records, and Reports, and Disqualification of Testing Facilities. Subparts and special issues are described in more detail in the "Guidance Documents" (see, e.g., www.barqa.com). At organizations that conduct animal studies in support of applications for research or marketing permits from regulatory agencies, GLP-compliance activities will be required in most of these areas.

A frequently heard maxim that may have its roots in GLP compliance is, "If you didn't document it, you didn't do it." Documentation is, in fact, a hallmark of GLP compliance. There are anecdotal reports of pharmaceutical companies delivering entire truckloads of documents to the FDA when requesting marketing approval for a new drug. A key element of the documentation process is the Standard Operating Procedure (SOP), and the GLP regulations require SOPs in 12 specific areas (see Table 4.3). At least seven of these deal directly with animal-related aspects of the study. GLP SOPs must state exactly how the procedure is to be done each and every time. Regulations also require that historical records of SOPs, including all revisions be maintained.

Table 4.3 Areas Requiring SOPS under GLPS

Animal room preparation Animal care

Receipt, identification, storage, handling, mixing, and method of sampling of the test and control articles Test system observations Laboratory tests

Handling of animals found moribund or dead during study Necropsy of animals or postmortem examination of animals Collection and identification of specimens Histopathology

Data handling, storage, and retrieval

Maintenance and calibration of equipment

Transfer, proper placement, and identification of animals

Specific requirements in GLPs under the heading of animal care are all standard practices in well-run animal care and use programs. They include provisions for quarantine of newly arrived animals, health-status determinations, identification, separation of species, equipment cleaning and sanitization, feed and water analysis, and bedding changing. Although these are standard practices for many, strict adherence to SOPs and documentation of all key actions differentiate GLP studies from non-GLP studies.

Aside from the areas previously identified, other provisions of GLP regulations are also applicable in an animal care and use program. These include the appropriate training of personnel (although the scope and intensity are not specified); adequate numbers of personnel; use of personal protective equipment; adequate and appropriate storage areas; clean, well-maintained laboratory space; and inspected, well-maintained equipment. Maintenance of records, both of animal health and research data, are also critical components of GLP studies that should be part of any well-run animal care and use program. Given the basic GLP requirements in this area, one cannot assume a priori that full GLP compliance guarantees a high-quality animal care and use program.

The rigid nature and complexity of GLP requirements make them inherently difficult to comply with, especially for the duration of long-term studies that may last one or two years. The regulatory agencies at least tacitly acknowledge this through their provisions in GLPs for internal QA units. A QA unit may be "any person or organization element, except the study director, designated by testing-facility management," and is responsible for monitoring each study to assure that facilities, personnel, equipment, methods, practices, records, and controls conform with GLPs.10 The regulations further require that the QA unit be entirely separate from and independent of the personnel directing or conducting the study. QA units maintain schedules and protocols, and are required to conduct periodic inspections of studies, with reports provided to study directors and facility management. This ongoing internal oversight mechanism plays a significant role in assuring the facility, study sponsors, and regulatory agencies that the strict requirements of GLPs are met.

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