Principles Of Good Laboratory Practice Research Articles

Ensuring quality of in vitro alternative test methods: Issues and answers

Many in vitro and ex vivo methods have been developed or are under development to reduce or replace animal usage in toxicity tests. Consistent with the goal of obtaining scientifically sound test data for hazard and risk assessment of chemicals, changes are being made in current policies and procedures to facilitate the acceptance of data developed using these methods. National and international organizations are developing policies and standards for scientific practice to assure quality in implementation of in vitro methods. Consensus is developing in the scientific community for the quality control measures needed for in vitro methods; including appropriate controls, data reporting elements, and benchmarks to be identified in test guidelines so that the potential risks of chemicals can be reviewed and reliably assessed. Additional guidance to the OECD’s Good Laboratory Practice principles [Organization for Economic Cooperation and Development ( OECD, 2004. Advisory Document of the Working Group on Good Laboratory Practice: The Application of the Principles of GLP to in vitro Studies. OECD Series on Principles of Good Laboratory Practice and Compliance Monitoring Number 14 (ENV/JM/MONO(2004)26). Paris, France] will help to ensure that in vitro tests used for regulatory purposes are reproducible, credible, and acceptable. Generic test guidelines incorporating performance standards are being written to allow acceptance of proprietary test methods by regulatory agencies and to provide assurance that any in vitro system performs over time in a manner that is consistent with the test system as it was originally validated.

GIQAR position paper on ‘Archiving and Good Laboratory Practice’

Archiving of documents and specimens generated during a non-clinical laboratory study is a basic Good Laboratory Practice (GLP) requirement. The records and materials that should be archived as well as the characteristics and the organisation of archive facilities are addressed in the OECD Series on Principles of Good Laboratory Practice No. 1 (OECD Principles of Good Laboratory Practice (as revised in 1997) [1]. However, in recent years, questions concerning archiving have been raised and the need for a more detailed guidance on this matter has become evident The aim of the Society for Applied Pharmacological Sciences/Italian Group of Quality Assurance in Research (SSFA/GIQAR) working group on ‘Archiving according to GLP’ was to issue a position paper, present it for discussion in an ad hoc round table with representatives of the Italian GLP monitoring authority to promote common standards and to provide additional recommendations on storage and retention of records. Copyright © 2005 John Wiley & Sons, Ltd.

Mutual acceptance of data: harmonised test methods and quality assurance of data—the process explained

An essential aspect of the OECD is that it should not be considered a supranational organisation, but rather a center for discussion where governments express their points of view, share their experiences and search for common ground. This implies that decisions are made by consensus instead of majority. Once the Council, which is the highest authority of the OECD, adopts a formal Decision, such a decision is binding on all Member countries. The OECD Guidelines for the Testing of Chemicals, which are considered the leading international standard for safety testing, form an integrated part of such a binding Council Decision. An even more important part of that same Council Decision is that on Mutual Acceptance of Data, where it states that: ‘Data generated in the testing of chemicals in an OECD Member country in accordance with OECD Test Guidelines and OECD Principles of Good Laboratory Practice (GLP) shall be accepted in other Member countries for purposes of assessment and other use relating to the protection of man and the environment.’ In the various steps of the process of Test Guideline development, the National Co-ordinators of the Test Guideline Programme play an important role. The initiative to start the development of a particular guideline can be taken by the OECD Secretariat, by one or more Member countries or, most importantly, by the scientific community itself. Proposals, received by the Secretariat are discussed at the yearly Meeting of the National Co-ordinators. During these meetings, priorities for future activities are set and the approach that should be followed in dealing with the selected activities is discussed. Quite often, so-called Detailed Review Papers (DRP's) form the basis of a new or updated Guideline. These DRP's, which are either prepared by a Member country or by a consultant appointed by the Secretariat, describe the current ‘state of the art’ in scientific progress and technical possibilities of a well-defined area of research. After completion, either an expert meeting or a commenting round will be organised. All Member countries will have sufficient possibilities to express their views. When the DRP is acceptable to the experts of all Member countries, the next step is to actually develop a Test Guideline. Similar to the procedure followed for the DRP, the Test Guideline proposal will be circulated for comment to all Member countries and should reach the desks of relevant experts, nominated by their National Co-ordinator. Frequently, in addition to the commenting rounds, Test Guideline proposals are discussed in special expert meetings. Once the experts reach consensus on a particular Test Guideline, the proposal is put forward to the Meeting of the National Co-ordinators for approval. Since each guideline will form an integrated part of the earlier mentioned Council Decision, each new guideline also needs formal adoption by the Council before it becomes effective.

Quality management of pharmacology and safety pharmacology studies.

Pharmacology has traditionally been excluded from the mandatory application of good laboratory practice (GLP) principles. Consensus has been reached through the process of the International Conference on Harmonisation (ICH, Topic S7A) with regard to the definitions of the different types of pharmacology studies (ICH S7A): primary pharmacodynamic, secondary pharmacodynamic and safety pharmacology studies, and guidance on the quality standards (expectations for GLP conformity) for these study types have been provided. Primary pharmacodynamic studies are the only study types that are fully exempt from GLP requirements. Secondary pharmacodynamic and safety pharmacology studies are expected to be conducted to GLP quality standards -- preferably to full, formal GLP compliance, when results are used for human safety assessment. At the present time, regulatory authorities will most likely be prepared to exercise flexibility in their requirement for GLP compliance, however, if non-clinical studies used in human safety assessment are not formally in compliance with the principles of GLP, regulatory acceptance may not be guaranteed. Historically, the application of formal GLP standards in safety pharmacology studies appears to vary between test facilities, and a number of study components in safety pharmacology studies, e.g. ECG monitoring, may not always conform to formal GLP standards. Apparently, however, formal GLP standards for these study components can be implemented for a relatively low additional cost. Based on the guidance given in the ICH S7A guideline, it thus appears logical to recommend that test facilities and sponsors consider their organisation of safety pharmacology studies in view of sound study management and formal implementation of GLP, where needed. Organisation of study management should facilitate collaboration across scientific disciplines because a plethora of data, originating from basic pharmacodynamics, toxicology, kinetics, and metabolism, as well as from clinical investigations, are involved in a safety pharmacology assessment. Applying formal GLP standards to safety pharmacology studies, and, when indicated, to secondary pharmacodynamic studies, does not influence the scientific standards of studies. However, applying formal GLP standards will ensure the quality, reliability and integrity of studies, which reflect sound study management. It is important to encourage a positive attitude among researchers and academics towards these lines, whenever possible. GLP principles applied to the management of non-clinical safety studies are appropriate quality standards when studies are used in the context of protecting public health, and these quality standards are therefore obviously pivotal for regulatory acceptance of non-clinical safety studies in general, and of safety pharmacology studies in particular.

Clinical gene transfer: education is the key.

Profound damage to public confidence in the discipline of gene therapy has been done in the past two years. The gene transfer incident at the University of Pennsylvania in 1999 and alleged financial conflicts associated with that trial, as well as subsequent revelations of massive underreporting of patient adverse events to the Recombinant DNA Advisory Committee (RAC) as required by the NIH Guidelines on Recombinant DNA Research, combined to cause much of this damage. In response to public concerns and congressional inquiries, relevant federal agencies, including the Food and Drug Administration (FDA), the Office of Biotechnology Activities (OBA) at the NIH, and the Department of Human and Health Services (DHHS), have tightened existing regulations and issued new rules and guidelines governing clinical gene transfer studies. One common feature among all of these federal activities is a call for education of investigators and team members to make them thoroughly familiar with all aspects of clinical gene transfer studies and to better protect patient safety. In response to this challenge, the ASGT sponsored a comprehensive Clinical Gene Transfer Training Course over a two-day period immediately preceding the Society’s 4th Annual Meeting in Seattle this past June. The training course was co-organized and cosponsored by the FDA, OBA, OHRP, and the Mount Sinai School of Medicine, and supported financially by only the OBA and the ASGT. Topics encompassed the following areas: 1. Planning for a Clinical Trial; 2. Preclinical Development of Gene Transfer Vectors; 3. Clinical Trial Design, Approval Process, and Trial Conduct; 4. Clinical Trial Compliance, Monitoring, and Oversight; and 5. Bioethics, Research Integrity, and Conflicts of Interest. Training course objectives were to provide education to basic scientists and trainees on the principles of Good Laboratory Practice (GLP) in generating and analyzing preclinical efficacy and pharmacology/toxicity data to support clinical translational research; production facility directors and staff members on the principles of Good Manufacturing Practice (GMP) in manufacturing and testing of gene transfer products for human applications; and clinical investigators and team members on the principles of Good Clinical Practices (GCP) in accordance with the International Conference on Harmonization (ICH) in conducting clinical trials. In addition, all registrants were educated on the relevant federal regulations and guidelines governing clinical gene transfer studies.

The handbook of analytical methods for trace elements as adopted by the national reference laboratories for residues

The instrumental approaches, quality assurance schemes and management of chemical laboratories should in general be harmonized at the highest possible level. This is all the more so for the national reference laboratories (NRLs) for residues in live animals and their products which have to implement quality assurance systems inspired to the principles of good laboratory practice as well as to the general norms for the operation of testing laboratories (EN 45000 criteria). Directive 23/96/EC of 29 April 1996 prescribes that NRLs are assisted in this process by the four community reference laboratories (CRLs) for residues. To this end, the Rome CRL systematically collects in a handbook all the analytical methods in use at NRLs for the determination of As, Cd, Cu, Hg and Pb, as well as other chemical elements, in animal matrices. One major goal of this action is to foster the harmonization of analytical approaches by the NRLs and their ability to provide comparable results of similar quality. The Rome CRL is committed to revise this handbook twice a year. The role of the handbook is also to encourage the exchange of information among the NRLs as regards the possibility of improving existing methods.

The ECVAM Prevalidation Study on the Use of EpiDerm for Skin Corrosivity Testing.

In 1996 and 1997, ECVAM supported a formal validation study on in vitro methods for predicting skin corrosivity. Two of the in vitro tests included in the study employed human skin models, the Skin2™ ZK1350 and EPISKIN™ models. In the ECVAM validation study, BASF, Huntingdon Life Sciences (HLS) and ZEBET tested the Skin2 human skin model, production of which ceased in October 1996, while the validation study was still in progress. Since both of the skin models had shown basic usefulness for corrosivity testing and, in particular, the EPISKIN corrosivity test had proved to be a scientifically valid test, the three laboratories decided to conduct a study to determine whether another commercially available human skin model, EpiDerm™, could also be successfully used to predict skin corrosivity. The study was performed according to the ECVAM prevalidation scheme, to allow for refinement of the test protocol and the prediction model, as well as for independent assessment of the performance of the refined methodology in a final blind trial in the three laboratories. In phase I of the study, ZEBET (Laboratory 1) drafted a Standard Operating Procedure (SOP), including a prediction model (PM1), and the project plan for the study. It was a major task to simplify an existing EpiDerm test protocol, which used the time-course of cytotoxicity as its endpoint. To evaluate the predictivity of the simplified method, which used only a 3-minute exposure to test chemicals, 50 chemicals representing a wide spectrum of chemical entities were tested, revealing that the test sensitivity was too low (65%), whereas the specificity was very high (88%). In addition, acceptance criteria for the negative and positive controls were established. Before proceeding to the next phase of the study, ZEBET distributed a refined SOP, data-recording software and documentation sheets, which allowed Good Laboratory Practice (GLP)-compliant quality assurance for each assay. The main goal of phase II was to produce sufficient data to assess the reproducibility of the EpiDerm skin corrosivity test after transfer to Laboratory 2 (HLS). Repeated testing of several chemicals in both laboratories revealed excellent intralaboratory and interlaboratory reproducibility. In addition, chemicals classified as "non-corrosive" (NC) with a 3-minute exposure in phase I, were re-tested by ZEBET with extended exposure periods of 1 hour and 4 hours. The test sensitivity could be significantly increased, if chemicals classified NC with a 3-minute exposure were tested with a 1-hour exposure. Before proceeding to the final blind trial, a refined SOP was drafted, according to which all chemicals had to be tested with exposure times of 3 minutes and 1 hour, and data for these two exposure times were used in the refined hierarchical prediction model, PM2. In phase III, the blind trial, BASF (Laboratory 3) joined the study. ECVAM selected 24 chemicals from the test chemical set used in the ECVAM skin corrosivity validation study, and BIBRA International (UK) purchased, coded and distributed the chemicals. Each chemical was tested twice, independently, according to the principles of GLP, and coded data were submitted to the Humboldt University (Berlin, Germany) for biostatistical analysis. The analysis revealed that the final test protocol and the refined prediction model (PM2) provided a highly balanced prediction of 88% sensitivity and 86% specificity, which is regarded as the best predictivity an in vitro skin corrosivity test can be expected to achieve. In conclusion, the EpiDerm skin corrosivity test gives an excellent prediction for a wide spectrum of chemicals, and could be used within the context of the new Annex V (EU Dangerous Substances Directive) test method (human skin model assay) for skin corrosion. The results obtained were reproducible, both within and between laboratories, and showed that EpiDerm could be used for testing a wide range of chemicals (both liquids and solids), including organic acids and bases, neutral organics, inorganic acids and bases, electrophiles and phenols. The concordances between the skin corrosivity classifications derived from the in vitro data were very good, and the test was able to distinguish.

Quality management in analytical R&D in the pharmaceutical industry: Building quality from GLP

The pharmaceutical industry is one of the most regulated activity sectors. The regulation includes specific quality systems such as good laboratory practice (GLP), good clinical practice (GCP) and good manufacture practice (GMP). The principles of GLP mainly cover the formal quality aspects of a procedure and do not evaluate the technical aspects in depth. On the other hand, EN 45001 accreditation covers technical performance and is not suitable for pharmaceutical research and development (R&D) as it is almost impossible to comply with the requirements of the European standard in the pharmaceutical environment. The challenge to the pharmaceutical industry is, therefore, to develop quality systems, compatible with GLP principles, that not only cover formal quality items but also ensure good scientific and technical performance. An implementation process focused on real quality improvement is the best way to achieve this objective, culminating in formal recognition of the quality system by third-party assessment.

The Revised Principles of Good Laboratory Practice of the Organisation for Economic Cooperation and Development—Changes, Chances, and Controversies

This paper is the condensed result of the presentations and discussions held at the DIA Workshop “The Revised OECD Principles of Good Laboratory Practice,” held September 3 and 4, 1998, in Brussels. The workshop brought together inspectors from compliance monitoring authorities and quality assurance units in industry, as well as study directors working according to the rules of Good Laboratory Practice (GLP). They discussed a number of issues important to the successful implementation of the revised Principles of Good Laboratory Practice of the Organisation for Economic Cooperation and Development (OECD), were informed about the changes which had taken place in this set of rules, debated areas of controversy, and looked at opportunities in the revised principles to improve the quality of safety studies. Specific areas covered included the new definitions given in the revised principles and their pragmatic application, the question of whether the new position of the principal investigator would offer any benefits to the procedures in the pharmaceutical industry, the issue of what constitutes a short-term test and how a test facility and its quality assurance unit could sensibly deal with it, and the impact of information technology, including the possibility of electronic signatures on Good Laboratory Practice and its implementation in the future. There are no easy solutions or handy recipies for any of the issues tackled in these discussions, nor were they expected. The result of the workshop was a better understanding of the various viewpoints that could be taken when it comes to interpreting and implementing the Principles of Good Laboratory Practice. The rules governing this quality system are general terms which must be adapted in a pragmatical manner to widely differing situations, and a workshop such as this can help to bridge the gaps between this wide array of disciplines working under GLP. In this, the DIA Workshop on the “The Revised OECD Principles of Good Laboratory Practice” succeeded in full measure.

The Principles of Good Laboratory Practice: Application to In Vitro Toxicology Studies

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

Essentials of quality in "the gold standard veterinary clinical trial".

Quality Assurance (QA) has played a pivotal role within Good Laboratory Practice (GLP) since its inception in 1976. GLP is now recognized as a quality standard, as can be seen from the introductory statement of the recently issued OECD Principles of GLP (revised in 1997) that clearly state "GLP is a quality system concerned with the organisational process and the conditions under which non-clinical health and environmental safety studies are planned, performed, monitored, recorded, archived and reported". We can, therefore, see a close comparison between GLP compliance and the ISO/EN accreditation systems that have been adopted by other institutes on a worldwide basis.

Transforming Traditional Sophomore Quant into a Course on Modern Analytical Science

We are involved in a curriculum development project at San Jose State University directed at transforming traditional sophomore quantitative analysis into a course on modern analytical science. This project is supported by an NSF Curriculum Development Grant. The new sophomore course emulates the working environment of a modern commercial laboratory where students must deal directly with contemporary analytical problems and technology. We have developed several laboratory investigations that reflect a commitment to addressing organic, biological, and environmental studies, in place of much of the traditional emphasis on simple inorganic systems. The types of investigations include separations science (mixture analysis), multielement and trace analysis, and combined physical and chemical characterization. Laboratory studies are conducted, as far as possible, with state-of-the-art equipment and methodology. Pervading all of this is a laboratory structure based on Good Laboratory Practice principles, where s...

The Europeon Union and the Analysis of Residues: An Account of Proficiency Testing

Several groups of potentially toxic substances and their residues in animals and in animal products require constant monitoring for effective protection of human health. To properly deal with this challenge, in 1993 four institutes were designated by the European Union as community reference laboratories (CRLs) for the analysis of residues in food of animal origin, namely, RIVM in Bilthoven (The Netherlands), CNEVA-LMV in Fougères (France), BGVV in Berlin (Germany), and ISS in Rome (Italy). The functions of the four CRLs and the substances they are responsible for have been updated and listed in the annexes to Council Directive 96/23/EC (April 29, 1996). Particular emphasis is placed on that part of the activities of the CRLs aimed at promoting and supporting harmonization of approaches among national reference laboratories (NRLs). This action is achieved, among others, through coordination of research to develop new analytical methods, implementation of appropriate quality assurance schemes based on the principles of good laboratory practice, as well as on EN 45001 criteria, and, last but not least, organization of interlaboratory exercises to the benefit of the NRLs. The goal of these proficiency tests is the evaluation of the performance of each participating laboratory to improve the quality of the analytical data obtained in terms of trueness, credibility, and comparability. In the light of the mandate prescribed by Council Directive 96/23/EC the CRL at the ISS is at present responsible for the following categories of residues: (i) all chemical elements; (ii) organochlorine compounds including polychlorinated biphenyls; (iii) carbamates and pyrethroids; (iv) organophosphorous compounds. Trials of increasing difficulty are permanently conducted for the determination of organochlorine compounds, on the one hand, and As, Cd, Hg, and Pb, on the other hand. A detailed description of the two intercomparison exercises already completed for these trace elements and cursory information on the third one still in progress are given.

Good Laboratory Practice and Study Management for the Validation of In Vitro Toxicity Studies

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.

Principles of good laboratory practice

Principles of good laboratory practice

The revised OECD principles of good laboratory practice. A reflection upon the impact the proposed changes will have upon pre-clinical safety testing. Part 2

The significant changes in the Scope, Definition of Terms and Responsibilities sections of the new draft OECD GLP Principles were reviewed in part 1 of this article which was published in the previous edition of this journal. In this part, the remainder of the revised Principles is reviewed and the impact on current practices assessed. © 1997 John Wiley & Sons, Ltd.

The Revised OECD Principles of Good Laboratory Practice. A Reflection Upon the Impact of the Proposed Changes on Pre-Clinical Safety Testing:Part 1: Scope, Definition of Terms, Responsibilities

Through their regular consultation process, the OECD recently made available the draft of the revised Principles of Good Laboratory Practice. This article is a personal view of the impact these revised Principles, if adopted, are likely to have on the practices in Pre-clinical Safety Testing. This part (Part 1) of the article deals with the changes which are proposed to the sections of GLP concerning the Scope, Definition of Terms and Responsibilities

The Revised OECD Principles of Good Laboratory Practice. A Reflection Upon the Impact of the Proposed Changes on Pre‐Clinical Safety Testing: Part 1: Scope, Definition of Terms, Responsibilities

The Revised OECD Principles of Good Laboratory Practice. A Reflection Upon the Impact of the Proposed Changes on Pre‐Clinical Safety Testing: Part 1: Scope, Definition of Terms, Responsibilities

Comparison Between the 1992 Principles of Good Laboratory Practice as Defined in the Environment Monograph No. 45 and the Draft Revision of the Principles of GLP as Published by OECD on 6 January 1997

Whilst it is accepted that the draft revised OECD Principles, which were developed in 1995 and 1996 by the Expert Group, has been put out to industry for review, it is likely that the changes, following the review period, will not be of any great significance or difference from that document which has been provided to industry. In fact, in the covering letter that accompanies the OECD draft Revision from the Environmental Health and Safety Division, there was a paragraph which indicated ‘those issues for which consensus could not be reached were not included in the draft Revision’. This indicates that there are some areas where it will be impossible for harmonization to be achieved and, in general, it is thought that with the expansion of the GLPs there is very little in terms of contentious issues which will be seen by industry as an imposition on the current use of the GLPs and the implementation of these in non-clinical safety studies. The following personal viewpoint therefore is a summary of the changes and a comparison between the two guidelines which it is hoped will give the reader immediate information as to where changes have occurred and the implication of those changes for the personnel involved in non-clinical safety studies.

The international register of potentially toxic chemicals

The benefits and drawbacks consequent to the widespread use of chemicals are inextricably interwoven. According to recent estimates, more than 8 million substances are presently known, 70,000 of which are in common use as industrial compounds, pesticides, Pharmaceuticals, food additives, cosmetics and the like. It is estimated that substances used as such will increase annually by 1000 in number. The deleterious consequences deriving from their exploitation pose tremendous challenges to the scientific community for the protection of human health and the environment. Therefore it is of utmost priority to appropriately select valid information generated in this investigation area and to convey it correctly to users. Here, the adoption of the principles of good laboratory practice in experimental activities is essential, as well as the creation of global networks for data exchange on the safe use of chemicals. The structure and goals of the International Register of Potentially Toxic Chemicals (IRPTC, the database of the United Nations Environment Programme) are detailed to give an example of such an undertaking. Seventeen fields are covered,i.e. identifiers, properties and classification, production/trade, production processes, use, pathways into the environment, concentrations, environmental fate tests, environmental fate, chemobiokinetics, mammalian toxicity, special toxicity studies, effects on organisms in the environment, sampling/preparation/analysis, spills, treatment of poisoning, waste management and recommendations/legal mechanisms.