The Good Laboratory Practice Regulations 1999

• (1) The test facility should be of suitable size, construction and location to meet the requirements of the regulatory study and to minimise disturbance that would interfere with the validity of the regulatory study.

• (2) The design of the test facility should provide an adequate degree of separation of the different activities to assure the proper conduct of each regulatory study.

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• (1) The test facility should have a sufficient number of rooms or areas to assure the isolation of test systems and the isolation of individual projects, involving substances known or suspected of being biohazardous.

• (2) Suitable facilities should be available for the diagnosis, treatment and control of diseases, in order to ensure that there is no unacceptable degree of deterioration of test systems.

• (3) There should be storage rooms or areas as needed for supplies and equipment. Storage rooms or areas should be separated from rooms or areas housing the test systems and should provide adequate protection against infestation, contamination and deterioration.

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• (1) To prevent contamination or mix-ups, there should be separate rooms or areas for receipt and storage of the test and reference items, and mixing of the test items with a vehicle.

• (2) Storage rooms or areas for the test items should be separate from rooms or areas containing the test systems. They should be adequate to preserve identity, concentration, purity, and stability, and ensure safe storage for hazardous substances.

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Archive facilities should be provided for the secure storage and retrieval of study plans, raw data, final reports, samples of test items and specimens. Archive design and archive conditions should protect contents from untimely deterioration.

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Apparatus, including validated computerised systems, used for the generation, storage and retrieval of data, and for controlling environmental factors relevant to the regulatory study, should be suitably located and of appropriate design and adequate capacity.

2

Apparatus used in a regulatory study should be periodically inspected, cleaned, maintained, and calibrated according to standard operating procedures. Records of these activities should be maintained. Calibration should, where appropriate, be traceable to national or international standards of measurement.

3

Apparatus and materials used in studies should not interfere adversely with the test systems.

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Chemicals, reagents and solutions should be labelled to indicate identity (with concentration if appropriate), expiry date and specific storage instructions. Information concerning source, preparation date and stability should be available. The expiry date may be extended on the basis of documented evaluation or analysis.

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• (1) Apparatus used for the generation of physical/chemical data should be suitably located and of appropriate design and adequate capacity.

• (2) The integrity of the physical/chemical test systems should be ensured.

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• (1) Proper conditions should be established and maintained for the storage, housing, handling and care of biological test systems, in order to ensure the quality of the data.

• (2) Newly received animal and plant test systems should be isolated until their health status has been evaluated. If any unusual mortality or morbidity occurs, the relevant lot should not be used in regulatory studies and, where appropriate, should be humanely destroyed. At the experimental starting date of a regulatory study, test systems should be free of any disease or condition that might interfere with the purpose or conduct of the study. Test systems that become diseased or injured during the course of a regulatory study should be isolated and treated, if necessary to maintain the integrity of the study. Any diagnosis and treatment of any disease before or during a regulatory study should be recorded.

• (3) Records of source, date of arrival, and the arrival condition of test sytems should be maintained.

• (4) Biological test systems should be acclimatised to the test environment for an adequate period before the first administration or application of the test or reference item.

• (5) All information needed to identify properly the test systems should appear on their housing or containers. Individual test systems that are to be removed from their housing or containers during the conduct of the regulatory study should bear appropriate identification, wherever possible.

• (6) During use, housing or containers for test systems should be cleaned and sanitised at appropriate intervals. Any material that comes into contact with the test system should be free of contaminants at levels that would interfere with the regulatory study. Bedding for animals should be changed as required by sound husbandry practice. Use of pest control agents should be documented.

• (7) Test systems used in field studies should be located so as to avoid interference in the regulatory study from spray drift and from past usage of pesticides.

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• (1) Records including test item and reference item characterisation, date of receipt, expiry date, quantities received and used in regulatory studies should be maintained.

• (2) Handling, sampling, and storage procedures should be identified in order that the homogeneity and stability are assured to the degree possible and contamination or mix-up are precluded.

• (3) Storage containers should carry identification information, expiry date, and specific storage instructions.

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• (1) Each test and reference item should be appropriately identified (eg code, chemical abstracts service registry number (CAS number), name, biological parameters etc.).

• (2) For each regulatory study, the identity, including batch number, purity, composition, concentrations, or other characteristics to appropriately define each batch of the test or reference items should be known.

• (3) In cases where the test item is supplied by the sponsor, there should be a mechanism, developed in co-operation between the sponsor and the test facility, to verify the identity of the test item subject to the study.

• (4) The stability of test and reference items under storage and test conditions should be known for all regulatory studies.

• (5) If the test item is administered or applied in a vehicle, the homogeneity, concentration and stability of the test item in that vehicle should be determined. For test items used in field studies (eg tank mixes), these may be determined through separate laboratory experiments.

• (6) A sample for analytical purposes from each batch of test item should be retained for all regulatory studies except short-term studies.

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A test facility should have written standard operating procedures approved by test facility management that are intended to ensure the quality and integrity of the data generated by the test facility. Revisions to standard operating procedures should be approved by test facility management.

2

Each separate test facility unit or area should have immediately available current standard operating procedures relevant to the activities being performed therein. Published textbooks, analytical methods, articles and manuals may be used as supplements to these standard operating procedures.

3

Deviations from standard operating procedures related to the regulatory study should be documented and should be acknowledged by the study director and any principal investigators, as applicable.

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Standard operating procedures should be available for, but not be limited to, the following categories of test facility activities. The details given under each heading are to be considered as illustrative examples—

Test and reference itemsareceipt, identification, labelling, handling, sampling and storage;

Apparatus, materials and reagentsbiapparatus: use, maintenance, cleaning and calibration,iicomputerised systems: validation, operation, maintenance, security, change control and back-up,iiimaterials, reagents and solutions: preparation and labelling;

Record keeping, reporting, storage, and retrievalccoding of studies, data collection, preparation of reports, indexing systems, handling of data, including the use of computerised data systems;

Test system (where appropriate)diroom preparation and environmental room conditions for the test system,iiprocedures for receipt, transfer, proper placement, characterisation, identification and care of test system,iiitest system preparation, observation and examinations, before, during and at the conclusion of the regulatory study,ivhandling of test system individuals found moribund or dead during the regulatory study,vcollection, identification and handling of specimens including necropsy and histopathology,visiting and placement of test systems in test plots;

Quality assurance procedureseoperation of quality assurance personnel in planning, scheduling, performing, documenting and reporting inspections.

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• (1) For each regulatory study, a written plan should exist prior to initiation of the study. The study plan should be approved by dated signature of the study director and verified for good laboratory practice compliance by quality assurance personnel as specified in paragraph 2(b) of Part II of this Schedule.

• (2) As respects the study plan—

• (a) amendments to it should be justified and approved by dated signature of the study director and maintained with the study plan;

• (b) deviations from it should be described, explained, acknowledged and dated in a timely fashion by the study director and/or any principal investigators and maintained with the study raw data.

• (3) For short-term studies, a general study plan accompanied by a study specific supplement may be used.

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• (1) The study plan should contain, but not be limited to, the following information—

Identification of the study, the test item and the reference itemaia descriptive title,iia statement which reveals the nature and purpose of the regulatory study,iiiidentification of the test item by code or name (IUPAC, CAS number, biological parameters etc.),ivthe reference item to be used;

Information concerning the sponsor and the test facilitybiname and address of the sponsor,iiname and address of any test facilities and test sites involved,iiiname and address of the study director,ivname and address of any principal investigator, and the phase of the study delegated by the study director to, and under the responsibility of, the principal investigator;

Datescithe date of approval of the study plan by signature of the study director,iithe proposed experimental starting and completion dates;

Test methodsdreference to OECD test guideline or other test guideline or method to be used;

Issues (where applicable)eithe justification for selection of the test system,iicharacterisation of the test system, such as the species, strain, sub-strain, source of supply, number, body weight range, sex, age, and other pertinent information,iiithe method of administration and the reason for its choice,ivthe dose levels and/or concentration, frequency, duration of administration or application,vdetailed information on the experimental design, including a description of the chronological procedure of the regulatory study, all methods, materials and conditions, type and frequency of analysis, measurments, observations and examinations to be performed, and statistical methods to be used (if any);

Recordsfa list of records to be retained.

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• (1) a unique identification should be given to each regulatory study. All items concerning this regulatory study should carry this identification. Specimens from the study should be identified to confirm their origin. Such identification should enable traceability, as appropriate for the specimen and study.

• (2) The regulatory study should be conducted in accordance with the study plan.

• (3) All data generated during the conduct of the regulatory study should be recorded directly, promptly, accurately, and legibly by the individual entering the data. These entries should be signed or initialled and dated.

• (4) Any change in the raw data should be made so as not to obscure the previous entry, should indicate the reason for change and should be dated and signed or initialled by the individual making the change.

• (5) Data generated as a direct computer input should be identified at the time of data input by the individual responsible for direct data entries. Computerised system design should always provide for the retention of full audit trails to show all changes to the data without obscuring the original data. It should be possible to associate all changes to data with the person having made those changes, for example by the use of timed and dated (electronic) signatures. Reasons for changes should be given.

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• (1) A final report should be prepared for each regulatory study. In the case of short-term studies, a standardised final report accompanied by a study specific extension may be prepared.

• (2) Reports of principal investigators or scientists involved in the regulatory study should be signed and dated by them.

• (3) The final report should be signed and dated by the study director to indicate acceptance of responsibility for the validity of the data. The extent of compliance with these principles of good laboratory practice should be indicated.

• (4) Corrections and additions to a final report should be in the form of amendments. Amendments should clearly specify the reason for the corrections or additions and should be signed and dated by the study director.

• (5) Reformatting of the final report to comply with the submission requirements of a national registration or regulatory authority does not constitute a correction, addition or amendment to the final report.

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The final report should include, but not be limited to, the following information—

Identification of the regulatory study, the test item and the reference itemaia descriptive title,iiidentification of the test item by code or name (IUPAC, CAS number, biological parameters etc.),iiiidentification of the reference item by name,ivcharacterisation of the test item including purity, stability and homogeneity;

(b)Information concerning the sponsor and the test facilityiname and address of the sponsor,iiname and address of any test facilities and test sites involved,iiiname and address of the study director,ivname and address of any principal investigators and the phase of the study delegated, if applicable,vname and address of scientists having contributed reports to the final report;

Datescexperimental starting and completion dates;

Statementda quality assurance programme statement listing the types of inspections made and their dates, including the phases inspected, and the dates any inspection results were reported to management and to the study director and any principal investigators, if applicable. This statement would also serve to confirm that the final report reflects the raw data;

Description of materials and test methodseidescription of methods and materials used,iireference to OECD test guidelines or other test guidelines or methods;

Resultsfia summary of results,iiall information and data required in the study plan,iiia presentation of the results, including calculations and determinations of statistical significance,ivan evaluation and discussion of the results and, where appropriate, conclusions;

Storagegthe location where the study plan, samples of test and reference items, specimens, raw data, and the final report are to be stored.

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• (1) The following should be retained in the archives for the period specified by the appropriate regulatory authorities—

• (a) the study plan, raw data, samples of test and reference items, specimens and the final report of each regulatory study;

• (b) records of all inspections performed by the quality assurance programme, as well as master schedules;

• (c) records of qualifications, training, experience and job descriptions of personnel;

• (d) records and reports of the maintenance and calibration of apparatus;

• (e) validation documentation for computerised systems;

• (f) the historical file of all standard operating procedures;

• (g) environmental monitoring records.

• (2) In the absence of a required retention period, the final disposition of any study materials should be documented. When samples of test and reference items and speciments are disposed of before the expiry of the required retention period for any reason, this should be justified and documented. Samples of test and reference items and specimens should be retained only as long as the quality of the preparation permits evaluation.

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Material retained in the archives should be indexed so as to facilitate orderly storage and retrieval.

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Only personnel authorised by management should have access to the archives. Movement of material in and out of the archives should be properly recorded.

4

If a test facility or an archive contracting facility goes out of business and has no legal successor, the archive should be transferred to the archives of the sponsor of the regulatory study.

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• (1) Purpose: to familiarise the inspector with the facility which is about to be inspected in respect of management structure, physical layout of buildings and range of studies.

• (2) Prior to conducting a test facility inspection or study audit, inspectors should familiarise themselves with the facility which is to be visited. Any existing information on the facility should be reviewed. This may include previous inspection reports, the layout of the facility, organisation charts, study reports, protocols andcurricula vitae (CVs) of personnel. Such documents would provide information on—

• —the type, size and layout of the facility,

• —the range of studies likely to be encountered during the inspection,

• —the management structure of the facility.

• (3) Inspectors should note, in particular, any deficiencies from previous test facility inspections. Where no previous test facility inspections have been conducted, a pre-inspection visit can be made to obtain relevant information.

• (4) Test facilities may be informed of the date and time of an inspector’s arrival, the objective of their visit and the length of time they expect to be on the premises. This could allow the test facility to ensure that the appropriate personnel and documentation are available. In cases where particular documents or records are to be examined, it may be useful to identify these to the test facility in advance of the visit so that they will be immediately available during the test facility inspection.

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• (1) Purpose: to inform the management and staff of the facility of the reason for the test facility inspection or study audit that is about to take place, and to identify the facility areas, study(ies) selected for audit, documents and personnel likely to be involved.

• (2) The administrative and practical details of a test facility inspection or study audit should be discussed with the management of the facility at the start of the visit. At the starting conference, inspectors should—

• —outline the purpose and scope of the visit,

• —describe the documentation which will be required for the test facility inspection, such as lists of on-going and completed studies, study plans, standard operating procedures, study reports, etc. Access to and, if necessary, arrangements for the copying of relevant documents should be agreed upon at this time,

• —clarify or request information as to the management structure (organisation) and personnel of the facility,

• —request information as to the conduct of studies not subject to principles of good laboratory practice in areas of the test facility where good laboratory practice studies are being conducted,

• —make an initial determination as to the parts of the facility to be covered during the test facility inspection,

• —describe the documents and specimens that will be needed for on-going or completed study(ies) selected for study audit,

• —indicate that a closing conference will be held at the completion of the inspection.

• (3) Before proceeding further with a test facility inspection, it is advisable for the inspector to establish contact with the facility’s quality assurance unit.

• (4) As a general rule, when inspecting a facility, inspectors will find it helpful to be accompanied by a member of the quality assurance unit.

• (5) Inspectors may wish to request that a room be set aside for examination of documents and other activities.

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• (1) Purpose: to determine whether the test facility has sufficient qualified personnel, staff resources and support services for the variety and number of studies undertaken, whether the organisational structure is appropriate, and whether management has established a policy regarding training and staff health surveillance appropriate to the studies undertaken in the facility.

• (2) The management should be asked to produce certain documents, for example—

• —floor plans,

• —facility management and scientific organisation charts,

• —CVs of personnel involved in any types of studies selected for the study audit,

• —lists of on-going and completed studies with information on the type of study, initiation/completion dates, test system, method of application of test item and name of study director,

• —staff health surveillance policies,

• —staff job descriptions and staff training programmes and records,

• —an index to the facility’s standard operating procedures,

• —specific standard operating procedures related to the studies or procedures being inspected or audited,

• —lists of the study directors associated with the study(ies) being audited.

• (3) The inspector should check, in particular—

• (0) lists of on-going and completed studies to ascertain the level of work being undertaken by the test facility,

• —the identity and qualifications of the study directors, the head of the quality assurance unit and other personnel,

• —the existence of standard operating procedures for all relevant areas of testing.

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• (1) Purpose: to determine whether the mechanisms used to assure management that regulatory studies are conducted in accordance with the principles of good laboratory practice are adequate.

• (2) The head of the quality assurance unit should be asked to demonstrate the systems and methods of quality assurance inspection and monitoring of studies, and the system for recording observations made during quality assurance monitoring. Inspectors should check—

• —the qualifications of the head of quality assurance, and of all quality assurance staff,

• —that the quality assurance unit functions independently from the staff involved in the studies,

• —how the quality assurance unit schedules and conducts inspections, how it monitors identified critical phases in a study, and what resources are available for quality assurance inspections and monitoring activities,

• —that where studies are of such short duration that monitoring of each study is impracticable, arrangements exist for monitoring on a sample basis,

• —the extent and depth of quality assurance monitoring during the practical phases of the study,

• —the extent and depth of quality assurance monitoring of routine test facility operation,

• —the quality assurance procedure for checking the final report to ensure its agreement with the raw data,

• —that management receives reports from quality assurance concerning problems likely to affect the quality or integrity of a study,

• —the actions taken by quality assurance when deviations are found,

• —the quality assurance role, if any, if studies or parts of studies are done in contract laboratories,

• —the part played, if any, by quality assurance in the review, revision and up-dating of standard operating procedures.

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Test facility inspections will generally include, inter alia, study audits, which review on-going or completed regulatory studies. Specific study audits are also often requested by regulatory authorities, and can be conducted independently of test facility inspections. Because of the wide variation in the types of regulatory studies which might be audited, only general guidance is appropriate, and inspectors and others taking part in study audits will always need to exercise judgement as to the nature and extent of their examinations. The objective should be to reconstruct the study by comparing the final report with the study plan, relevant standard operating procedures, raw data and other archived material.

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In some cases, inspectors may need assistance from other experts in order to conduct an effective study audit, for example where there is a need to examine tissue sections under the microscope.

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When conducting a study audit, the inspector should—

• —obtain names, job descriptions and summaries of training and experience for selected personnel engaged in the study(ies) such as the study director and principal scientists,

• —check that there is sufficient staff trained in relevant areas for the study(ies) undertaken,

• —identify individual items of apparatus or special equipment used in the study and examine the calibration, maintenance and service records for the equipment,

• —review the records relating to the stability of the test items, analyses of test items and formulations, analyses of feed, etc.,

• —attempt to determine, through the interview process if possible, the work assignments of selected individuals participating in the study to ascertain if these individuals had the time to accomplish the tasks specified in the study plan or report,

• —obtain copies of all documentation concerning control procedures or forming integral parts of the study, including—the study plan,standard operating procedures in use at the time the study was done,log books, laboratory notebooks, files, worksheets, print-outs of computer-stored data, etc., checking calculations where appropriate,the final report.

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In studies in which animals (i.e. rodents and other mammals) are used, the inspector should follow a certain percentage of individual animals from their arrival at the test facility to autopsy. They should pay particular attention to the records relating to:

• —animal body weight, food/water intake, dose formulation and administration etc.,

• —clinical observations and autopsy findings,

• —clinical chemistry,

• —pathology.

Editorial notes