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    Quality Assurance Monitoring

    Suppliers of in vitro test systems should be audited prior to accepting their product for use in a GLP study.

    Depending on the test system, suppliers should maintain a set of in-house release criteria for test systems and associated components. Some of this information may not be available at the time of test system receipt, but it should be evaluated and archived appropriately when it does become available. Even if suppliers perform release testing, controls need to be run with the assay at the Test Facility to account for any changes in the test system due to manufacturing changes or shipping damage.

    In-life audits of studies could be performed a number of ways, including a process-based inspection that might not require auditing a phase from each GLP assay. At IIVS, at least one critical phase in each GLP assay is audited.

    Documentation audits include inspections of the protocol and initial study placement paperwork, the workbook or notebook (raw data), and the study report. Elements of documentation critical to in vitro studies such as justification for use of the test system and protocol-defined acceptance criteria should be examined carefully.

    The monitoring of in vitro GLP studies requires the auditors to interpret regulations and guidance documents within a new framework. Emphasis in auditing should be placed on those areas of the in vitro laboratory and assay systems that are critical to control when working with in vitro systems.

    The supplier's source of materials and cells should be verified. To avoid potential legal problems with proprietary components (e.g. donor cells), it is necessary to assure that the supplier is licensed to use, or is the owner of the materials they are using to provide their product. The supplier should be audited to assure that they are maintaining their facility and equipment to a level of control appropriate for the type of test system they are supplying. Laboratories need to hold suppliers of cells and three-dimensional tissue constructs to a different standard than they would hold a supplier of ex-vivo tissue (e.g. an abattoir).

    (See Figure 9 for an example of Manufacturing vs. Testing Facility ET response to 0.3% Triton X-100 over time).50

    Critical phases are identified prior to performing the study based on the protocol design. Some examples of phases that would be considered "critical" are: test system receipt and handling, test system preparation, application of the test material to the test system, and collection of data. During the in-life audits of the study, auditors should review the documentation (i.e. laboratory notebook or workbook), equipment used, personnel training, and the actual performance of the chosen step. The results of the audit would be circulated to the Study Director and Facility Management.

    All elements of documentation combined should provide a full explanation of the conduct of the assay without the need for additional clarification. The final report should accurately reflect the conduct of the assays without any of the data gaps, fabrications, or creative penmanship that led to the establishment of the GLPs in the late 1970s.

    TMEpiOcular tissue

    Applying Good Laboratory Practices (GLPs) to In Vitro Studies: One Laboratory's Perspective

    Amanda K Ulrey, Rodger D Curren, John W Harbell, Greg Mun, and Hans A RaabeInstitute for In Vitro Sciences, Inc., Gaithersburg MD 20878

    ABSTRACTThe steady increase in industry use and regulatory acceptance of in vitro test methods has resulted in an increased need to apply Good Laboratory Practice (GLP) regulations to these systems. The original GLP regulations, developed to address the conduct of animal studies, are concerned with many special conditions that apply to animal housing and care, and the relatively long duration of animal studies, that are not present in the shorter in vitro studies. In animal studies, for example, emphasis is placed on the isolation of species and periodic analysis of feed and water; whereas in non-animal studies, there is increased importance on the justification of the test system. Recently, the Organization for Economic Cooperation and Development (OECD) has published advisories (No. 7, The Application of the GLP Principles to Short-term Studies, 1999; No. 14 The Application of the Principles of GLP to in vitro Studies, 2004) to clarify the application of the GLP principles to both short-term and in vitro studies. This poster outlines the approach applied at the Institute for In Vitro Sciences, Inc. (IIVS) to the conduct of in vitro GLP-compliant studies. We describe the translation of the OECD guidance documents into a framework for conducting assays which use ex vivo tissues, monolayer cell cultures, reconstructed skin constructs, and manufactured test kits. We are grateful to auditors from numerous study sponsors and regulatory agencies who have helped us develop what we feel is a best practices approach.

    INTRODUCTIONIn the mid 1970s and early 1980s, the US Food and Drug Administration (FDA), and Environmental Protection Agency (EPA) were discovering that the toxicology data submitted to them was not as reliable as they believed. As a result of these revelations, the United States Senate gave power to the agencies to set forth guidelines for laboratories to follow while conducting studies intended for submission. These guidelines, which grew out of industry "best practices", became the Good Laboratory Practices (GLPs) (FDA 21CFR58, EPA TSCA 21CFR792, FIFRA 21CFR160). Many new versions and revisions to the GLPs have been published since the 1970s, so that now, studies conducted in compliance with GLP regulations are recognized throughout the member countries of the OECD and elsewhere as promoting good science and yielding trustworthy data.

    The early versions of the GLPs were written with long-term, animal-based toxicology studies in mind. Today, many of these animal-based studies are being replaced by in vitro studies, which are being used by many companies to make safety decisions without accompanying animal data. In order to assure that the data from these validated in vitro methods are universally accepted as being of high quality, the studies must be carried out in compliance with Good Laboratory Practices. Confusion in the interpretation of the regulations arise when the traditional GLPs are applied to short-term, non-animal studies. Differences in test system handling and basic assay design require that the GLPs be supplemented with guidelines that fit the unique structure of these in vitro assays. Workshops were sponsored by such organizations as the European Center for the Validation of Alternative Methods (ECVAM) and IIVS where interested individuals (such as cell culture technologists, toxicologists and quality assurance personnel from industry, academia, and government) were able to discuss the possible design of GLPs for these methods. Following these consensus building workshops, the OECD published "The Application of the GLP Principles to Short Term Studies" (1993, rev. 1999), number 7 in their series on the Principles of GLP and Compliance Monitoring. This document was followed recently (November 2004) by the OECD advisory document titled "The Application of the Principles of GLP to In Vitro Studies" (number 14). These documents supplement the GLPs to effectively assure that there are GLP guidelines to cover all critical aspects of in vitro assay design. Figure 1 shows a time-line of milestones leading to the issuance of the OECD guidance documents for short-term and in vitro studies.

    Applying the OECD guidelines in a practical way to day-to-day laboratory work can be challenging. Three areas requiring unique interpretation for in vitro assays are; 1) The use of positive and negative controls and benchmarks; 2) The care and maintenance of test systems; and 3) quality assurance monitoring. At IIVS, we have developed an approach to addressing these areas that has withstood numerous sponsor and several regulatory audits. Although each laboratory will need to apply the Principles of GLP in a way that will complement their facility structure and infrastructure, there are some common concepts that could be applied to in vitro work performed in any laboratory.

    Figure 1

    Positive and Negative Controls and BenchmarksThe use of benchmarks and positive and negative controls provide valuable information that is highly useful in interpreting results obtained from any study; however, this additional information could not be obtained from in vivo assays without adding additional animals to the study. It is required by Institutional Review Boards (IRB)s and Institutional Animal Care and Use Committees (IACUC)s that measures be taken to reduce the number of animals used for testing as much as possible. In vitro tests allow for the addition of

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