"batch" means a specific quantity or lot of a test or reference substance produced during a defined cycle of manufacture in such a way that it could be expected to be of a uniform character and should be designated as such;

(a) ensure that qualified personnel, appropriate facilities, equipment, and materials are available;

(b) maintain a record of the qualifications, training, experience and job description for each professional and technical individual;

(c) ensure that personnel clearly understand the functions they are to perform and, where necessary, provide training for those functions;

(d) ensure that health and safety precautions are applied according to national and/or international regulations;

(e) ensure that appropriate standard operating procedures are established and followed;

(f) ensure that there is a quality assurance programme with designated personnel;

(g) where appropriate, agree the study plan in conjunction with the sponsor;

(h) ensure that amendments to the study plan are agreed upon and documented;

(i) maintain copies of all study plans;



(j) maintain a historical file of all standard operating procedures;

(k) for each safety study ensure that a sufficient number of personnel is available for its timely and proper conduct;

(l) for each safety study designate an individual with appropriate qualifications, training, and experience as the study director before the safety study is initiated. If it is necessary to replace a study director during a safety study, this should be documented;

(m) ensure that an individual is identified as responsible for the management of the archives.

The study director's responsibilities
     2.  - (1) The study director has the responsibility for the overall conduct of the safety study and for its report.

    (2) These responsibilities should include, but not be limited to, the following functions - 

(a) agreeing to the study plan;

(b) ensuring that the procedures specified in the study plan are followed, and that authorisation for any modification is obtained and documented together with the reasons for them;

(c) ensuring that all data generated are fully documented and recorded;

(d) signing and dating the final report to indicate acceptance of responsibility for the validity of the data and to confirm compliance with the principles of good laboratory practice;

(e) ensuring that after termination of the safety study, the study plan, the final report, raw data and supporting material are transferred to the archives.

Personnel responsibilities
     3.  - (1) Personnel should exercise safe working practices. Chemicals should be handled with suitable caution until their hazard has been established.

    (2) Personnel should exercise health precautions to minimise risk to themselves and to ensure the integrity of the safety study.

    (3) Personnel known to have a health or medical condition that is likely to have an adverse effect on the safety study should be excluded from operations that may affect the safety study.

(a) ascertaining that the study plan and standard operating procedures are available to personnel conducting the safety study;

(b) ensuring that the study plan and standard operating procedures are followed by periodic inspections of the laboratory and/or by auditing the safety study in progress. Records of such procedures should be retained;

(c) promptly reporting to management and the study director unauthorised deviations from the study plan and from standard operating procedures;

(d) reviewing the final reports to confirm that the methods, procedures, and observations are accurately described, and that the reported results accurately reflect the raw data of the safety study;

(e) preparing and signing a statement, to be included with the final report, which specifies the dates inspections were made and the dates any findings were reported to management and to the study director.

(a) Test and reference substances

     receipt, identification, labelling, handling, sampling and storage;

(b) Apparatus and reagents

     use, maintenance, cleaning, calibration of measuring apparatus and environmental control equipment; preparation of reagents;

(c) Record keeping, reporting, storage and retrieval

     coding of studies, data collection, preparation of reports, indexing systems, handling of data, including the use of computerised data systems;

(d) Test system (where appropriate)


(i) room preparation and environmental room conditions for the test system,

(ii) procedures for receipt, transfer, proper placement, characterisation, identification and care of test system,

(iii) test system preparation, observation examinations before, during and at termination of the safety study,

(iv) handling of test system individuals found moribund or dead during the safety study,



(v) collection, identification and handling of specimens including necropsy and histopathology;



(e) Quality assurance procedures

     operation of quality assurance personnel in performing and reporting study audits, inspections and final study report reviews;

(f) Health and safety precautions

     as required by national and/or international legislation or guidelines.

(a) Identification of the test and reference substance


(i) a descriptive title,

(ii) a statement which reveals the nature and purpose of the safety study,

(iii) identification of the test substance by code or name (IUPAC, CAS number, etc.),

(iv) the reference substance to be used;



(b) Information concerning the sponsor and the laboratory



(i) name and address of the sponsor,

(ii) name and address of the laboratory,

(iii) name and address of the study director;



(c) Dates



(i) the date of agreement to the study plan by signature of the study director, and when appropriate, of the sponsor and/or the laboratory management,

(ii) the proposed starting and completion dates;



(d) Test methods

     reference to OECD test guidelines or other test guidelines to be used;

(e) Issues (where applicable)



(i) the justification for selection of the test system,

(ii) characterisation of the test system, such as the species, strain, substrain, source of supply, number, body weight range, sex, age and other pertinent information,

(iii) the method of administration and the reason for its choice,

(iv) the dose levels and/or concentration, frequency, duration of administration,

(v) detailed information on the experimental design, including a description of the chronological procedure of the safety study, all methods, materials and conditions, type and frequency of analysis, measurements, observations and examinations to be performed;


(f) Records

     a list of records to be retained.

Conduct of the safety study
     22.  - (1) A unique identification should be given to each safety study. All items concerning this safety study should carry this identification.

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

    (3) All data generated during the conduct of the safety 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, and should indicate the reason, if necessary, for change and should be identified by date and signed 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. Corrections should be entered separately with the reason for the change, the date and the identity of the individual making the change.

(a) Identification of the test and reference substance


(i) a descriptive title,

(ii) identification of the test substance by code or name (IUPAC, CAS number, etc.),

(iii) identification of the reference substance by chemical name,

(iv) characterisation of the test substance including purity, stability and homogeneity;



(b) Information concerning the laboratory



(i) name and address,

(ii) name of the study director,

(iii) name of other principal personnel having contributed reports to the final report;



(c) Dates

     dates on which the safety study was initiated and completed;

(d) Statement

     a quality assurance statement certifying the dates inspections were made and the dates any findings were reported to management and to the study director;

(e) Description of materials and test methods



(i) description of methods and materials used,

(ii) reference to OECD test guidelines or other test guidelines;



(f) Results



(i) a summary of results,

(ii) all information and data required in the study plan,

(iii) a presentation of the results, including calculations and statistical methods,

(iv) an evaluation and discussion of the results and, where appropriate, conclusions;



(g) Storage

     The location where all samples, specimens, raw data and the final report are to be stored.

(a) the study plans;

(b) the raw data;

(c) the final reports;

(d) the reports of laboratory inspections and study audits performed according to the quality assurance programme;

(e) samples and specimens.

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

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

Retention
     26.  - (1) The following should be retained for the period specified by the appropriate authorities - 

(a) the study plan, raw data, samples, specimens and the final report of each safety study;

(b) records of all inspections and audits performed by the quality assurance programme;

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

(d) records and reports of the maintenance and calibration of equipment;

(e) the historical file of standard operating procedures.

    (2) Samples and specimens should be retained only as long as the quality of the preparation permits evaluation.

    (3) If a laboratory 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 safety study.

 -  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 laboratory inspections. Where no previous laboratory inspections have been conducted, a pre-inspection visit can be made to obtain relevant information.

    (4) Laboratories should be informed of the date and time of inspectors' arrival, the objective of their visit and the length of time they expect to be on the premises. This will allow the laboratory 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 laboratory in advance of the visit so that they will be immediately available during the laboratory inspection.

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

    (2) The administrative and practical details of a laboratory 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 laboratory 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, side-by-side, of studies subject to good laboratory practice principles with others for which they are not applied,

 -  make an initial determination as to the parts of the facility to be covered during the laboratory inspection,

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

    (3) Before proceeding further with a laboratory inspection, it is advisable for the inspector to establish contact with the laboratory 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.

Organisation and personnel
     3.  - (1) Purpose: To determine whether: the laboratory has sufficient qualified personnel, staff resources and support services for the variety and number of studies undertaken; the organisational structure is appropriate; and 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 key personnel involved in the type(s) of studies selected for the study audit,

 -  list(s) of on-going and completed studies with information on the type of study, initiation/completion dates, test system, route of administration and name of study director,

 -  staff training and health surveillance policies, where such policies have been established,

 -  staff training records where available,

 -  an index to the facility's standard operating procedures,

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

 -  list(s) of the study directors associated with the study(ies) being audited.

    (3) The inspector should check, in particular - 

 -  lists of on-going and completed studies to ascertain the level of work being undertaken by the laboratory,

 -  the identity and qualifications of the study directors, the head of the quality assurance unit and other key personnel,

 -  existence of standard operating procedures for the relevant areas of testing.

Quality assurance programme
     4.  - (1) Purpose: To determine whether the mechanisms used to assure manage ment that laboratory studies are conducted in accordance with good laboratory practice principles 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 and 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 quality assurance procedures 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, of studies or parts of studies done in contract laboratories,

 -  the part played, if any, by quality assurance in the review, revision and updating of standard operating procedures.

Facilities
     5.  - (1) Purpose: To determine whether the laboratory is of suitable size, construction, design and location to meet the demands of the studies being undertaken.

    (2) The inspector should check that - 

 -  the design enables an adequate degree of separation so that, e.g. test substances, animals, diets, pathological specimens etc., of one study cannot be confused with those of another,

 -  environmental control and monitoring procedures exist and function adequately in critical areas, e.g. animal and other biological test systems rooms, test substance storage areas and laboratory areas,

 -  the general housekeeping is adequate for the various facilities and that there are, if necessary, pest control procedures.

Care, housing and containment of biological test systems
     6.  - (1) Purpose: To determine whether the laboratory, if engaged in studies using animals or other biological test systems, has support facilities and conditions for their care, housing and containment, adequate to prevent stress and other problems which could affect the test system and hence the quality of data.

    (2) A laboratory may be carrying out studies which require a diversity of animal or plant species as well as microbial or other cellular or sub-cellular systems. The type of test systems being used will determine the aspects relating to care, housing or containment that the inspector will monitor. Using his judgment, the inspector will check, according to the test systems that - 

 -  there are facilities adequate for the test systems used and for testing needs,

 -  there are arrangements to quarantine animals and plants being introduced into the facility and that these arrangements are working satisfactorily,

 -  there are arrangements to isolate animals (or other elements of a test system, if necessary) known to be, or suspected of being, diseased or carriers of disease,

 -  there is adequate monitoring and record-keeping of health, behaviour or other aspects, as appropriate to the test system,

 -  the equipment for maintaining the environmental conditions required for each test system is adequate, well maintained and effective,

 -  animal cages, racks, tanks and other containers, as well as accessory equipment, are kept sufficiently clean,

 -  analyses to check environmental conditions and support systems are carried out as required,

 -  facilities exist for removal and disposal of animal waste and refuse from the test systems and that these are operated so as to minimise vermin infestation, odours, disease hazards and environmental contamination,

 -  storage areas are provided for animal feed or equivalent materials for all test systems; that these areas are not used for the storage of other materials such as test substances, pest control chemicals or disinfectants, and they are separate from areas in which animals are housed or other biological test systems are kept,

 -  stored feed and bedding are protected from deterioration by adverse environmental conditions, infestation or contamination.

Apparatus, materials, reagents and specimens
     7.  - (1) Purpose: To determine whether the laboratory has suitably located, operational apparatus in sufficient quantity and of adequate capacity to meet the requirements of the tests being conducted in the facility and that the materials, reagents and specimens are properly labelled, used and stored.

    (2) The inspector should check that - 

 -  apparatus are clean and in good working order,

 -  records have been kept of apparatus operation, maintenance, standardisation and calibration,

 -  materials and chemical reagents are properly labelled and stored at appropriate temperatures and that expiry dates are not being ignored. Labels for reagents should indicate their source, identity and concentration and/or other pertinent information.

 -  specimens are well identified by test system, study, nature and date of collection,

 -  apparatus and materials used do not interfere with the test systems.

Test systems
     8. Purpose: To determine whether adequate procedures exist for the handling and control of the variety of test systems required by the studies undertaken in the facility, e.g. chemical and physical systems, cellular and microbial systems, plants or animals.

Physical and chemical systems
     9. The inspector should check that - 

 -  where required by study plans, the stability of test and reference substances were determined and that the reference substances specified in test plans were used,

 -  standard operating procedures exist to cover laboratory activities and that their provisions are observed,

 -  in automated systems, data generated as graphs, recorder traces or computer print-outs are documented as raw data and archived.

Biological test systems
     10. Taking account of the relevant aspects referred to above relating to care, housing or containment of biological test systems, the inspector should check that - 

 -  test systems are as specified in study plans,

 -  test systems are adequately identified,

 -  animals are adequately and, if necessary and appropriate, uniquely identified throughout the study,

 -  housing or containers of test systems are properly identified with all the necessary information,

 -  there is an adequate separation of studies being conducted on the same animal species (or the same biological test system) but with different substances,

 -  the biological test system environment is as specified in the study plan or in standard operating procedures for aspects such as temperature or light/dark cycles,

 -  the recording of the receipt, handling, housing or containment, care and health evaluation is appropriate to the test systems,

 -  written records are kept of examination, quarantine, morbidity, behaviour, diagnosis and treatment of animal and plant test systems or other similar aspects as appropriate to each biological test system,

 -  there are provisions for the appropriate disposal of test systems at the end of tests.

Test and reference substances
     11.  - (1) Purpose: To determine whether the laboratory has procedures designed - 

(i) to ensure that the identity, potency, quantity and composition of test and reference substances are in accordance with their specifications, and

(ii) to properly receive and store test and reference substances.

    (2) The inspector should check that - 

 -  there are standard operating procedures for recording the receipt, and for the handling, sampling, usage and storage of test and reference substances,

 -  test and reference substances containers are properly labelled,

 -  storage conditions are appropriate to preserve the concentration, purity and stability of the test and reference substances,

 -  there are standard operating procedures for the determination of identity, purity, composition, stability, and for the prevention of contamination of, test and reference substances, where applicable,

 -  records are kept of the composition, characterisation, concentration and stability of test and reference substances, where applicable,

 -  there are procedures for the determination of the homogeneity and stability of mixtures containing test and reference substances, where applicable,

 -  containers holding mixtures (or dilutions) of the test and reference substances are labelled and that records are kept of the homogeneity and stability of their contents, where applicable,

 -  when the test is of longer than four weeks' duration, samples from each batch of test and reference substances have been taken for analytical purposes and that they have been retained for an appropriate time,

 -  procedures for mixing substances are designed to prevent errors in identification or cross-contamination.

Standard operating procedures
     12.  - (1) Purpose: To determine whether the laboratory has written standard operating procedures relating to all the important aspects of the laboratory's operation, considering that one of the most important management techniques for controlling laboratory operations is the use of written standard operating procedures. These relate directly to the routine elements of tests conducted by the laboratory.

    (2) The inspector should check that - 

 -  each laboratory area has immediately available relevant, authorised copies of standard operating procedures,

 -  any amendments or changes to standard operating procedures have been authorised and dated,

 -  historical files of standard operating procedures are maintained,

 -  standard operating procedures are available for, but not necessarily limited to, the following activities - 


(i) receipt, identification, labelling, handling, sampling, usage and storage of test and reference substances,

(ii) maintenance, cleaning and calibration of measuring apparatus and environmental control equipment,

(iii) preparation of reagents and dosing formulations,

(iv) record-keeping, reporting, storage and retrieval of records and reports,

(v) preparation and environmental control of areas containing the test systems,

(vi) receipt, transfer, location, characterisation, identification and care of test systems,

(vii) handling of the test systems before, during and at the termination of the study,

(viii) disposal of test systems,

(ix) use of pest control and cleaning agents,

(x) quality assurance programme operations.

Performance of the study
     13.  - (1) Purpose: To verify that written study plans exist and that the plans and the conduct of the study are in accordance with good laboratory practice principles.

    (2) The inspectors should check that - 

 -  the study plan was signed by the study director,

 -  any amendments to the study plan were signed and dated,

 -  the date of the agreement to the study plan by the sponsor was recorded (where applicable),

 -  measurements, observations and examinations were in accordance with the study plan and relevant standard operating procedures,

 -  the results of these measurements, observations and examinations were recorded directly, promptly, accurately and legibly and were signed (or initialled) and dated,

 -  any changes in the raw data, including data stored in computers, did not obscure previous entries, included the reason for the change and were signed and dated,

 -  computer-generated or stored data have been identified and that the procedures to protect them against unauthorised amendments or loss are adequate,

 -  the computer software used within the study is reliable, accurate, and can be validated,

 -  any unforeseen events recorded in the raw data have been investigated and evaluated,

 -  the results presented in the reports of the study (interim or final) are consistent and complete and that they correctly reflect the raw data.

Reporting of study results
     14.  - (1) Purpose: To determine whether final reports are prepared in accordance with good laboratory practice principles.

    (2) When a final report is available, the inspector should check that - 

 -  it is signed and dated by the study director and, where appropriate, by other principal scientists,

 -  the study director has signed a statement indicating acceptance of responsibility for the validity of the study and confirming that the study was conducted in accordance with good laboratory practice principles,

 -  a quality assurance statement is included in the report and that it is signed and dated,

 -  any amendments were made by the responsible personnel,

 -  it lists the archive location of all samples, specimens and raw data.

Storage and retention of records
     15.  - (1) Purpose: To determine whether the facility has generated adequate records and reports and whether adequate provision has been made for the safe storage and retention of records and materials.

    (2) The inspector should check - 

 -  the archive facilities for the storage of study plans, raw data, final reports, samples and specimens,

 -  the procedures for retrieval of archived materials,

 -  the procedures whereby access to the archives is limited to authorised personnel and records are kept of personnel given access to raw data, slides, etc.,

 -  that an inventory is maintained of materials removed from, and returned to, the archives,

 -  that records and materials are retained for the required or appropriate period of time and are protected from loss or damage by fire, adverse environmental conditions, etc.

 -  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 are 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 substances, analyses of test substance 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 - 


(i) the study plan,

(ii) standard operating procedures in use at the time the study was done,

(iii) log books, laboratory notebooks, files, worksheets, print-outs of computer stored data, etc.,

(iv) the final report.

     19. In studies in which animals (i.e. rodents and other mammals) are used, the inspectors should follow a certain percentage of individual animals from their arrival at the laboratory 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.