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Samples of biologic specimens and their derivatives (eg, wet tissues, paraffin-embedded tissue blocks, histology slides, frozen tissues, whole blood, serum/plasma, and urine) are routinely collected during the course of nonclinical toxicity studies. Good Laboratory Practice regulations and/or guidance specify minimum requirements for specimen retention duration, with the caveat that retention of biologic specimens need not extend beyond the duration of sample stability. However, limited availability of published data regarding stability for various purposes following storage of each specimen type has resulted in confusion, uncertainty, and inconsistency as to the appropriate duration for storage of these specimens. To address these issues, a working group of the Society of Toxicologic Pathology Scientific and Regulatory Policy Committee was formed to review published information, regulations, and guidance pertinent to this topic and to summarize the current practices and rationales for retention duration through a survey-based approach. Information regarding experiences reaccessing biologic specimens and performing sample stability investigations was also collected. Based on this combined information, the working group developed several points to consider that may be referenced when developing or revising sample retention practices. [Box: see text]

With advancements in whole slide imaging technology and improved understanding of the features of pathologist workstations required for digital slide evaluation, many institutions are investigating broad digital pathology adoption. The benefits of digital pathology evaluation include remote access to study or diagnostic case materials and integration of analysis and reporting tools. Diagnosis based on whole slide images is established in human medical pathology, and the use of digital pathology in toxicologic pathology is increasing. However, there has not been broad adoption in toxicologic pathology, particularly in the context of regulatory studies, due to lack of precedence. To address this topic, as well as practical aspects, the European Society of Toxicologic Pathology coordinated an expert international workshop to assess current applications and challenges and outline a set of minimal requirements needed to gain future regulatory acceptance for the use of digital toxicologic pathology workflows in research and development, so that toxicologic pathologists can benefit from digital slide technology.

In 2014, the Organisation for Economic Co-operation and Development (OECD) issued guidance no. 16, Guidance on the GLP Requirements for Peer Review of Histopathology. The stated purpose of the guidance document is “to provide guidance to pathologists, test facility management, study directors and quality assurance personnel on how the peer review of histopathology should be planned, managed, documented, and reported in order to meet Good Laboratory Practice (GLP) expectations and requirements.” On behalf of and in collaboration with the global societies of toxicologic pathology, the Society of Toxicologic Pathology initiated a review of OECD guidance no. 16. The objectives of this review are to provide a unified interpretation of the guidance, to recommend compliant processes for organizations to implement, and to avoid inconsistent process adaptations across the industry. This review of the guidance document is the product of a global collaboration with other societies of toxicologic pathology and provides a section-by-section international consensus view and interpretation of the OECD guidance on peer review.

Experimental treatment strategies and neuroprotective drugs that showed therapeutic promise in animal models of stroke have failed to produce beneficial effects in human stroke patients. The difficulty in translating preclinical findings to humans represents a major challenge in cerebrovascular research. The reasons behind this translational road block might be explained by a number of factors, including poor quality control in various stages of the research process, the validity of experimental stroke models, and differences in drug administration and pharmacokinetics. Another major difference between animal studies and clinical trials is the choice of end point or outcome measures. Here, we discuss the necessity of poststroke behavioral testing to bridge the gap between clinical and experimental end points. We review established sensory-motor tests for outcome determination after focal ischemia based on the published literature as well as our own personal experience. Selected tests are described in more detail and good laboratory practice standards for behavioral testing are discussed. This review is intended for stroke researchers planning to use behavioral testing in mice.

Benzocaine has a long history of use in human medicine. However, benzocaine also has been used in aquaculture with finfish for more than 40 years for sedating fish for marking, transport, surgery, and so on, although benzocaine does not have a current Food and Drug Administration (FDA) approval for this application in the United States. As part of a FDA approval for use as an animal drug, the genotoxicity of benzocaine was evaluated in the in vitro bacterial reverse mutation assay and the forward mutation assay and in vivo in the mouse micronucleus assay. These studies were conducted in compliance with Good Laboratory Practice regulations and according to Veterinary International Conference on Harmonisation guidelines. Based on the results of these studies, benzocaine was determined not to be genotoxic.

In certain cases, quantitative tissue structural data derived from tissue sections may be required to make critical decisions in the drug development or risk assessment process. Most frequently, these questions center on test article–related effects on cell number. In this opinion article, the limitations of estimating cell number by standard cell or nuclear profile counts from sections/blocks collected for routine histopathology are discussed from both a scientific and regulatory perspective and contrasted with the robust, sensitive, statistically based methods of design-based stereology. Specific existing industry practices are reviewed. Recent advances in stereological theory, software, hardware, and automated immunohistochemical staining now make it feasible to implement unbiased stereological methods to assess test article–related effects on cell number in a regulatory toxicology setting. These design-based stereological methods for counting cells are recommended when the quantification of small changes in cell number is critical to the risk assessment or decision-making process. These methods provide levels of sensitivity and statistical guarantees of accuracy that no other currently available tissue section–based methodology can provide.

With the changing development paradigms in the pharmaceutical industry, laboratories are challenged to release materials for clinical studies with rapid turnaround times. To minimize cost demands, many businesses are looking to develop ways of using early Good Manufacturing Practice (GMP) materials of active pharmaceutical ingredients (API) for Good Laboratory Practice (GLP) toxicology studies. To make this happen, the analytical laboratory releases the material by one of three scenarios: (1) holding the GLP release until full GMP testing is ready, (2) issuing a separate lot number for a portion of the GMP material and releasing the material for GLP use, or (3) releasing the lot of material for GLP using alternate (equivalent) method(s) not specified for GMP release testing. Many companies are finding the third scenario to be advantageous in terms of cost and efficiency through the use of quantitative nuclear magnetic resonance (q-NMR). The use of q-NMR has proved to be a single-point replacement for routine early development testing that previously combined elements of identity testing, chromatographic assay, moisture analysis, residual solvent analysis, and elemental analysis. This study highlights that q-NMR can be validated to meet current regulatory analytical method guidelines for routine pharmaceutical analysis.

The consensus of current international guidelines for the treatment of HIV infection is that data on therapeutic drug monitoring (TDM) of non-nucleoside reverse transcriptase inhibitors and protease inhibitors provide a framework for the implementation of TDM in certain defined scenarios in clinical practice. However, the utility of TDM is considered to be on an individual basis until more data are obtained from large clinical trials showing the benefit of TDM.In April 2004, a panel of experts met in Rome, Italy. This followed an inaugural meeting in Perugia, Italy, in October 2000, which resulted in the article published in AIDS 2002, 16(Suppl 1):S5–S37. The objectives of this second meeting were to review the questions surrounding TDM of antiretroviral drugs and discuss the clinical utility, current concerns and future prospects of drug concentration monitoring in the care of HIV-1-infected individuals.This report, which has been updated to include material published or presented at international conferences up to the end of September 2004, reviews pharmacokinetic and pharmacodynamic data and reports the issues discussed by the panel, offering advice to clinical care providers who may be currently, or are considering incorporating TDM into the routine care of their patients. In addition, the panel formulated a series of position statements that are relevant to the interpretation of current data and can aid the design of future clinical trials.Part 2 of this Special article, Therapeutic drug monitoring and drug–drug interactions involving antiretroviral drugs, will be published in Antiviral Therapy 10(4).

In vitro toxicology methods are being adopted by regulatory agencies worldwide. Many of these methods have been validated by using proprietary materials, often in the form of test kits. Guidelines for the use of Good Laboratory Practice methods for in vitro methods have been proposed. However, users of the data from these methods also need to be reassured that the proprietary materials and the test kits will provide consistent, good quality data over time, not just during the validation process. This paper presents an overview of the methods currently used by representatives of kit manufacturers and contract testing laboratories to ensure that the results from methods that utilise test kits are reproducible over time and across different types of test materials. This information will be valuable as a basis for future discussion on the need for formalised oversight of the quality of these materials.

The polymerase chain reaction (PCR) is a highly efficient gene amplification procedure which is increasingly being applied to the safety assessment of nucleic acid (NA) medicines such as gene therapies and DNA vaccines. Although clinical experience is limited, a number of potential safety issues exist with these new compounds including toxicity associated with the expression of encoded gene products, autoimmunity due to the induction of anti-DNA antibodies and insertional mutagenesis. PCR enables these questions to be addressed and provides data on mRNA expression, biodistribution and integration. In this review the use of PCR methodologies in the preclinical safety evaluation of NA medicines is discussed. Particular consideration is given to the issues surrounding the use of PCR in regulatory toxicology, including sensitiv-ity requirements, cross-contamination problems, tissue sampling procedures and good laboratory practice (GLP) compliance. In addition, the use of a PCR-based assay to demonstrate the integration of DNA vector into host DNA is described. As the use of PCR in the development of NA medicines will undoubtedly increase over the next few years, it is important that pathologists and toxicologists familiarise themselves with the principles and applications of this technique.

3Qualitas, Danworth Lane, Hurstpierpoint, West Sussex BN6 9LN, UK; 4Institute for In Vitro Science, 21 Firstfield Road, Suite 220, Gaithersburg, MD 20878, USA; 5ECVAM, Institute for Health and Consumer Protection, European Commission Joint Research Centre, 21020 Ispra (VA), Italy; 6Charles University Faculty of Medicine, Simkova 870, Hradec Kralove, Czech Republic; 7FRAME Alternatives Laboratory, University of Nottingham Medical School, Queen’s Medical Centre, Nottingham NG7 2UH, UK; 8RCC Cytotest Cell Research, In den Leppsteinwiessen 19, 64380 Rossdorf, Germany; 9Human and Environmental Safety Division, The Procter and Gamble Company, Cincinnati, OH, USA; 10ZEBET, BgVV, Diedersdorfer Weg 1, 12277 Berlin, Germany; 11Genetic and In Vitro Toxicology, Janssen Pharmaceutica, Turnhoutse Weg 30, 2340 Beerse, Belgium ATLA 27, 539–577, 1999 539

The principles of Good Laboratory Practice (GLP) are designed to help ensure the proper management and conduct of studies. GLP compliance demonstrates to regulatory authorities that studies were undertaken in a manner which promotes confidence in the data and reporting. Formal validation of in vitro toxicity studies is being recommended as an inter-laboratory activity. Study management of interlaboratory studies in compliance with GLP is discussed. This includes: a) a clearly defined management, with responsibility for the GLP compliance of participating laboratories; b) one Study Director, who represents the single point of study control and who overviews study procedures and data, to ensure that procedures laid down in the protocol are being followed; and c) Principal Investigators, who may be appointed at some, or all, of the participating laboratories to facilitate supervision and communications with the Study Director.

The U.S. Food and Drug Administration (FDA) Good Laboratory Practice (GLP) Regulations have been in effect since December 22, 1978, and subsequently have become a way of life for all who need to conduct preclinical safety and health effects studies for regulatory submission. The Organization of Economic Co-operation and Development (OECD) with its world-wide membership of 26 (including Japan), and the European Community (EC) with its 12 members, utilized the GLPs to finalize their own standards. Japan, with its six GLP standards for assessing data integrity and quality, became an integral force in the Pacific Rim and a dominant figure in promulgating OECD GLP standards and directives. Third world countries are identifying with Japanese principles and administrative applications of these standards. This presentation focuses on an overview of Japan's GLP standards.

To review a quality control and quality assurance (QC/QA) model established to ensure the validity and reliability of collection, storage and analysis of biological outcome data, and to promote good laboratory practices (GLPs) and sustained operational improvements in international clinical laboratories, we conducted a two-arm randomized community-level HIV behavioural intervention trial in five countries: China, India, Peru, Russia and Zimbabwe. The trial was based on diffusion theory utilizing a Community Popular Opinion Leaders (CPOLs) intervention model with behavioural and biological outcomes. The QC/QA model was established by the Biological Outcome Workgroup, which collaborated with the Data Coordinating Center and John Hopkins University Reference Laboratory. Five international laboratories conducted chlamydia/gonorrhoea polymerase chain reaction (PRC)-based assays, herpes simplex virus type 2 enzyme immunoassay (EIA), syphilis serology (rapid plasma regain and Treponema pallidum particle agglutination assay, HIV serology (EIA/Western blot) and Trichomonas vaginalis culture. Data were collected at baseline, 12 and 24 months. Laboratory performance and infrastructure improved throughout the trial. Recommendations for improvement were consistently followed. Quality laboratories in resource-poor settings can be established, operating standards can be improved and certification can be obtained with consistent training, monitoring and technical support. Building collaborative partnership relations can establish a sustainable network for clinical trials, and can lead to accreditation and international laboratory development.

The Organization for Economic Cooperation and Development (OECD) has promoted Good Laboratory Practice (GLP) since the mid 1970s. This paper describes the development of the concept through international harmonisation, Quality Assurance (QA), and compliance monitoring. Ultimately this process permits Mutual Acceptance of Data (MAD). An important aspect of the OECD's programme is the promotion of related training and information exchange.

Good laboratory practice standards (GLPs) were issued with the intended purpose of documenting the quality of laboratory research. These rules have improved laboratory operations and documentation. However, their approach emphasizes inspecting quality as a process rather than for preventing errors in the first place. Total Quality goes beyond GLPs and requires that systems be continually improved to build in quality. This latter approach builds toward elimination of rework that result when GLP inspections uncover unacceptable errors.

The scientific method was developed over a long period of time by many scientists from different disciplines. The procedure starts with an observation and the defining of a problem. This lead to postulating a hypothesis, conducting an experiment, and formulating a theory. The theory is then retested. Good Laboratory Practice (GLP) compliance was the first imposition of quality on top of the normal science process. To date, this improved compliance has contributed to documentation of science, but it has not done much to improve science itself. By learning and practicing the principles of total quality, both science and compliance can improve. The result of using the total quality principles is conducting toxicology studies right the first time. This goes beyond the GLPs and is not in opposition to them. Total quality requires planning, proper project execution, unbiased analysis of data, and reviewing and improving the process by capturing the good points and improving the weak ones. This process is very similar to the scientific method and consistent with good science. To use these principles in the management of a toxicology study, we must be good communicators and develop a common understanding with all professionals involved.

The aim of a Good Laboratory Practice (GLP) toxicology study is to provide useful information on the toxicity of a compound to a multiplicity of internal and external groups. Using the principles of total quality management (TQM), a multidisciplinary team is formed to plan the strategy for either an improvement or a change in a GLP toxicology study. The team members use their respective expertise to clarify their expectations and jointly define a common goal. Through carrying out the planned improvement or change, assessing the results, and replanning a GLP toxicology study, the stage is set for a continual improvement process. At the heart of the process is the willingness of team members to openly communicate and work together toward a common goal. The end result of using a dynamic TQM approach is that a GLP toxicology setting can result in continual improvements, better study planning, and a decrease in defects. Science and GLP compliance become members of the same team and a winning combination for successful management of GLP toxicology studies.

It was therefore considered pertinent to collate relevant base-line data from clinical laboratories in Africa in key areas like, quality assurance, appropriate technology, essential manpower, and instrument repair and maintenance, inorder to highlight areas that might require structured international intervention and assistance. This was especially germaine, as most clinical laboratories in developing countries were new comers to Quality Assurance or good laboratory practice. Additionally, it was noted that some previous attempts by international donor agencies to assist clinical laboratories in developing countries were largely unenduring because the assessment of needs were based mostly on Western values and expectations. Ten years ago, a survey was conducted by questionnaire distributed to several clinical laboratories in Africa (South of Sahara) inorder to obtain the desired base-line data. The present survey represents a 10-year follow-up designed to

Most quality assurance professionals can rightly claim that their units and the laboratories they inspect work in compliance with good laboratory practice (GLP) regulations. However, compliance itself is only the beginning. Quality assurance (QA) should now turn its attention to the process of optimizing operations in the industry by identifying weak links in the quality chain and working to remove the likelihood of failures and wasted time. Part of this process involves measuring QA impact. Impact can be evaluated in terms of effectiveness or efficiency. The difference between effectiveness and efficiency is discussed here. Measuring effectiveness involves quantifying effects; measuring efficiency involves quantifying the relationship between effect and effort. Some practical approaches to the collection of suitable data are outlined. There are no clear-cut rules for measuring QA impact. So far, the techniques available for assessing impact are rudimentary. However, it is important that all quality assurance professionals tackle the problems of evaluating their impact in order to strive toward higher standards of performance and toward greater understanding of the role of QA within the industry.

Recently, the Environmental Protection Agency (EPA) issued Good Laboratory Practice (GLP) Regulations under the Toxic Substances Control Act and the Federal Insecticide, Fungicide, and Rodenticide Act (and under some sections of the Federal Food, Drug, and Cosmetic Act). Quality assurance professionals, toxicologists, and laboratory managers are now confronted with complying with two new sets of regulations in addition to those promulgated by the Food and Drug Administration (FDA) in 1979. Immediately questions arose concerning the similarities and differences in the FDA and EPA requirements. Therefore, an analysis was performed to determine whether there were significant differences. The findings indicated that 19 sections were similar to the FDA requirements, 5 sections had minor differences, and 4 had major differences. In addition, new sections were added to the EPA regulations addressing compliance statements and the consequences of noncompliance for sponsors and laboratory personnel. The Toxic Substances GLP also incorporated a new subpart covering environmental testing.