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MANUAL FOR INSPECTORS

MONITORING COMPLIANCE

WITH THE PRINCIPLES OF

GOOD LABORATORY PRACTICE

by the Inspection Procedures Group of

the National and Länder Working Party on GLP(since 1997: NLWP on GLP and other QA Systems)

8th edition, August 1999

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Contents

1. PREPARATION OF AN INSPECTION OR STUDY AUDIT....................................7

1.1. Questions to put to the Test Facility before an inspection.................................7

1.2. Formation of the inspection team ......................................................................7

1.3. Request for documents by the inspection team..................................................7

2. PRELIMINARY INSPECTION...................................................................................8

2.1. Introductory discussion ......................................................................................8

2.2. Brief introductory inspection of rooms..............................................................8

2.3. Concluding discussion .......................................................................................8

3. REQUEST FOR DOCUMENTS BETWEEN PRELIMINARYINSPECTION AND INSPECTION (SEE ALSO 1.3) ................................................9

4. INSPECTION OF A TEST FACILITY OR A TEST SITE .........................................9

4.1. Introductory discussion on the way the inspection is to be conducted ..............9

4.2. Discussion of documents .................................................................................11

4.2.1. Organisation.......................................................................................11

4.2.2. Personnel............................................................................................11

4.2.3. Rooms/installations............................................................................11

4.2.4. Standard Operating Procedures..........................................................11

4.2.5. Miscellaneous ....................................................................................11

4.3. Quality Assurance ............................................................................................11

4.3.1. Quality Assurance programme...........................................................12

4.3.2. Quality Assurance activity .................................................................12

4.3.3. Quality Assurance and animal keeping..............................................13

4.3.4. Quality Assurance and field studies...................................................14

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4.3.5. Quality Assurance and data processing (DP).....................................14

4.3.6. Quality Assurance and instrumental analysis or collection ofphysical-chemical data.......................................................................15

4.4. Inspection.........................................................................................................15

4.4.1. Preliminary remark ............................................................................15

4.4.2. Rooms/installations............................................................................15

4.4.3. Questioning of personnel: ..................................................................16

4.4.4. Standard Operating Procedures..........................................................16

4.4.5. Apparatus, materials and reagents .....................................................16

4.4.6. Studies carried out on animals ...........................................................17

4.4.7. Studies carried out on microbial, cellular and subcellular testsystems...............................................................................................18

4.4.8. Greenhouse and semi-field studies ....................................................18

4.4.9. Field studies (see. 4.3.4) ....................................................................19

4.4.10. Studies in the area of instrumental analysis or collection ofphysical-chemical data.......................................................................20

4.4.11. Test and reference items ....................................................................21

4.4.12. Data processing (see also 4.3.5).........................................................21

4.5. Archiving .........................................................................................................24

4.5.1. General aspects of archiving ..............................................................24

4.5.2. Data archive .......................................................................................24

4.5.3. Materials archive................................................................................25

4.6. Audit of completed studies ..............................................................................25

4.6.1. Selection of studies ............................................................................25

4.6.2. Preparation for study audits ...............................................................25

4.6.3. Carrying out the study audit ...............................................................26

4.6.4. Possibly take a look at particular procedures in a comparablecurrent study.......................................................................................27

4.6.5. Discussion of results of study audit ...................................................27

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4.7. Concluding discussion .....................................................................................27

4.7.1. Participants.........................................................................................27

4.7.2. Communication of defects found.......................................................27

4.7.3. Setting deadline for rectifying defects ...............................................27

4.7.4. Announcement of re-inspection in the case of serious defects ..........27

4.7.5. Binding designation of Test Facility..................................................27

4.7.6. Determination of study categories .....................................................27

4.7.7. Vote taken by inspection team...........................................................27

5. INSPECTION REPORT.............................................................................................27

5.1. Name and address of TF and all TSs if appropriate.........................................27

5.2. Reason for and period of inspection ................................................................27

5.3. Participants in inspection .................................................................................28

5.4. Study categories ...............................................................................................28

5.5. Names of structures audited/areas of TF..........................................................28

5.6. Names of current studies inspected and completed studies audited ................28

5.7. List of defects found ........................................................................................28

5.8. Overall impression of TF.................................................................................28

5.9. Inspection team's vote on granting of certificate..............................................28

5.10. Possible annexes to inspection report: .............................................................28

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Annexes

ANNEX 1: STANDARD OPERATING PROCEDURES

ANNEX 2: STUDY PLANS

ANNEX 3: FINAL REPORTS ANNEX 4: FIELD OF APPLICATION OF GOOD LABORATORY PRACTICE IN

GERMANY ANNEX 5: SHORT-TERM STUDIES ANNEX 6: STUDY CATEGORIES

ANNEX 7: LITERATURE

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Abbreviations:

GLP Good Laboratory Practice

TF Test Facility

TS Test Site

TFM Test Facility Management

SD Study Director

PI Principal Investigator

QA Quality Assurance

SOP Standard Operating Procedure

CV Curriculum vitae

Note:

This manual has been prepared on the basis of the ChemVwV-GLP (AdministrativeRegulation concerning chemicals - Good Laboratory Practice) and the experience ofinspectors in the Inspection Procedures Group of the National and Länder Working Partyon GLP (since 1997: NLWP on GLP and other QA Systems). It lays no claim tocompleteness. The points made here are examples only, to be adapted to the situation atindividual TFs.

Annexes

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1. PREPARATION OF AN INSPECTION OR STUDY AUDIT

1.1. Questions to put to the Test Facility before an inspection

1.1.1. Type, size of TF (e.g. number of personnel, scope of testing, anysponsors)

1.1.2. Nature of studies/study categories (any specification/limitation ofstudy categories), see also explanatory notes in Annex 6

1.1.3. Statement whether inspections are made in accordance with §19a or§19b of the Chemicals Act (GLP as an obligation or legitimateinterest)

1.1.4. Organisational structure (identification of changes since the lastinspection)

1.1.4.1. Find out who is responsible for what in the TF, e.g. TFM, SD, QA,PI if applicable, and who has responsibility for archives, computingand authorising use of the data processing system

1.1.4.2. Ask what are the established competences, terms of contract andmodes of behaviour between sponsors and the TF, between this andother TFs, between the TF and its branches/associated TSs andbetween the TF and outside/independent TSs (subcontractors)

1.1.4.3. For each site ask for the exact name, address (in another Land orabroad?). Does it have its own GLP certificate? Compare answerswith the Federal GLP Agency's list of officially inspected TFs or TSswith regard to valid GLP certificates

1.2. Formation of the inspection team

1.2.1. At least two inspectors (decide which one is in charge); as a rulewith a specialist knowledge of the TF's areas of study

1.2.2. In animal experiments: as a rule with a veterinary medical officerparticipating or a prior check that animal protection regulations arecomplied with

1.2.3. If necessary, participation of one or more experts (confidentialitymust be assured and guaranteed in writing; a problem in the case ofconsultants)

1.2.4. If necessary seek administrative assistance if associated TSs,independent TSs or TFs in other Länder are participating. If TFs orTSs abroad are to be involved, contact the Federal GLP Agency

1.3. Request for documents by the inspection team

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Note from the inspectors to the TF: confidential TF documents are to be marked"sealed, personal" for security reasons when sent to inspectors. (The sameapplies to postal communications between the inspectors).

1.3.1. List of all completed/current/discontinued studies at least since thelast inspection (if necessary: studies subject/not subject to GLPPrinciples), (see also 3.1)

1.3.2. Organisation charts (company/GLP structure), where appropriatetake into account associated TSs or independent TSs

1.3.3. List of GLP personnel (company hierarchy, responsibilities,training); where there are changes compared with the lastinspection any CVs of new employees

1.3.4. Quality Assurance programme

1.3.5. List of all Standard Operating Procedures, any copies of the mostimportant SOPs (see Annex 1, Standard Operating Procedures)

1.3.6. List of important apparatus

1.3.7. Building/site plans ( labelling of GLP areas); for TSs also.

2. PRELIMINARY INSPECTION

(Useful and necessary at least as a technical and organisational preparation forfirst inspections)

2.1. Introductory discussion

2.1.1. Participants: inspectors, TFM, SD, QA management, possiblyarchive manager, PI if applicable

2.1.2. Discussion of documents requested, representation rules,responsibilities, range of duties, any amendments called for

2.1.3. Confirmation of exact name of TF; any TSs, outsiders(subcontractors)

2.1.4. Deciding which areas of the TF are to be inspected

2.2. Brief introductory inspection of rooms

2.3. Concluding discussion

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2.3.1. Are the conditions right for an inspection?

2.3.2. Set time and scope of inspection (agreement on current studiesduring inspection, where appropriate decision on inspections ofassociated TSs or independent TSs)

2.3.3. Determination of study categories (type of studies) for the GLPcertificate

2.3.4. Identification of discussion partners for inspection

2.3.5. Provision of an office and if necessary a secretariat (copiers,printers) for the inspectors during inspection

2.3.6. Indication of any defects already detected

3. REQUEST FOR DOCUMENTS BETWEEN PRELIMINARY INSPECTION AND INSPECTION(SEE ALSO 1.3)

3.1. Master schedule (complete list of all current, completed and discontinuedstudies specifying: study code, test item, test system, type of study, SD,start/end/status of study, sponsor), if necessary since the last inspection,confirmation by QA that list is complete

3.2. Specimen study plan, or study plan and final report for one or more studies(see 4.6.1.1. and 4.2.5.3)

3.3. Selected SOPs (see also 4.2.4)

4. INSPECTION OF A TEST FACILITY OR A TEST SITE

(When inspecting TSs inspect the relevant points in the same way)If no preliminary inspection has been carried out, deal with the points mentionedin section 2 during the inspection itself.

4.1. Introductory discussion on the way the inspection is to be conducted

4.1.1. Persons carrying out or who have carried out GLP tasks must ifpossible be present/reachable (TFM, SD, QA, PI if applicable,archive manager or representative)

4.1.2. Accompanying the inspectors through the TF:

− QA throughout the inspection− TFM at least during the introductory discussion and the concluding

discussion− SD, PI if applicable, archive manager in their respective areas− personnel in their respective areas of competence

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4.1.3. Fixing the schedule for the inspection (take account of studies inprogress)

4.1.4. Provision of an office for the inspectors, organisation of a secretariat(see also 2.3.5)

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4.2. Discussion of documents

4.2.1. Organisation

4.2.1.1. Organisation chart from GLP point of view (especially independenceof individual GLP functions, TFM with written authorisations),procedure and documentation on rules relating to representatives

4.2.1.2. Number of studies subject/not subject to GLP Principles4.2.1.3. Number of personnel (academic, technical, other), of whom part-

time4.2.1.4. Master schedule for estimating the workload on GLP personnel and

on the area in which the TF is being used. Updating and archiving ofthe master schedule.

4.2.2. Personnel

4.2.2.1. Qualifications and areas of activity of personnel

− curriculum vitae− education and training (specialist, GLP)− task descriptions

4.2.2.2. Health and safety precautions; exclusion of employees whose stateof health might adversely affect the study.

4.2.2.3. List of names/signatures/initials

4.2.3. Rooms/installations

4.2.3.1. Appropriate size, construction, functionality and position on thebasis of up-to-date building/site plans (incl. TSs)

4.2.4. Standard Operating Procedures

4.2.4.1. Are the study areas sufficiently covered by SOPs in the studycategories to be certified?

4.2.4.2. SOP on the form, drafting, amendment, updating, indexing,authorisation, distribution, archiving of SOPs

4.2.4.3. SOPs on the QA programme4.2.4.4. All SOPs covering more than one study (e.g. receipt of test item,

coding of studies, archiving, etc.), see Annex 1

4.2.5. Miscellaneous

4.2.5.1. Animal protection

− Animal protection officer− Veterinary medical officer's certificate of compliance with the animal

protection rules4.2.5.2. Selection of current studies practical sections of which are being

examined in the course of the inspection (see also 2.3.2)4.2.5.3. Selection of completed studies for study audits, except where already

specified in the preliminary inspection (see 3.2 and 4.6.1.1)

4.3. Quality Assurance

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(Since specific questions to QA frequently arise only in the course of theinspection it generally makes sense to leave inspection of QA until just before theconcluding discussion.)

4.3.1. Quality Assurance programme

4.3.1.1. Number and qualification of QA personnel, taking into accountassociated TSs and independent TSs

4.3.1.2. Independence of QA from execution of study4.3.1.3. Arrangements for representatives4.3.1.4. Scope of work:

− Find out share of GLP work in activity as a whole - if necessary askwhat additional tasks there are

− Is there an even balance of inspection and GLP office work? (In thecase of toxicological studies there should be an inspection about every 4weeks on average)

− Frequency of inspections independent of studies (including associatedTSs and independent TSs)

− Interval between delivery of final report to QA and issue of QAstatement

− Number of final reports inspected in the past year taking into accountthe nature of the studies

− Number of final report inspections still outstanding− Interval between QA inspection and drafting of QA report to TFM

4.3.1.5. Motivation/acceptance of QA (QA support by TFM and SD)

4.3.1.6. Presence of all current SOPs (including list of SOPs with versionnumbers) at QA

4.3.2. Nature of QA participation in drafting, revision and updating ofSOPsQuality Assurance activity

4.3.2.1. Audit of organisation and personnel

− Building plans, layout, construction and suitability of rooms− Separation of work operations, test systems, clean/unclean areas,

GLP/non-GLP areas− Safety precautions, health protection measures− Organisation charts, job descriptions, list of names and initials,

documentation on initial and continuous training− Human resources capacity

4.3.2.2. Audit of study plans

− Checking of form and content of study plans before they are put intoeffect; documentation

− Are the approved study plans available before the start of the practicalpart of the study?

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− Are amendments to the study plans and other GLP-relevantamendments by QA communicated in good time and is thisdocumented?

4.3.2.3. Planning and conduction of study-based, process-based and facility-based inspections

− use of checklists, e.g. for critical phases such as receipt and registrationof test items, selection of specimens to be retained, storage (for furtherdetails see also 4.3.3, 4.3.4 and 4.3.6)

− Random sampling in the case of short-term studies (see Annex 5)− Inspections of associated TSs or independent TSs− Inspections of suppliers− QA reports to SD and TFM; consequences of any defects found

(Under § 21 of the Chemicals Act inspectors have the right to examine QA inspection reports. They should, however, make use of this right only in justified exceptional cases.)

− Audit of measures carried out after complaints arising out of the lastQA inspection

4.3.2.4. Audit of final reports

− Form and content of final reports, correspondence with raw data,completeness of documentation; correct and full reproduction of results(QA statement)

4.3.2.5. Audit of SOPs− SOP administration (drafting, indexing, amendment, updating,

dissemination)− Form and content of newly drafted SOPs− Archiving of all SOPs

4.3.2.6. Documentation of all QA activities

4.3.3. Quality Assurance and animal keeping

4.3.3.1. How are animal keeping (quarantine, acclimatisation and veterinaryexamination on arrival), feed stores and compliance with safetyprogramme monitored?

4.3.3.2. Is there contact with the animal protection officer?

4.3.3.3. Critical phases:

− Randomisation− Weight measurement− Feed consumption− Preparation of forms of application− Application− Observation of experimental animals− Blood sampling− Preparation of specimens

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− Analysis− Killing and removal of organs

4.3.4. Quality Assurance and field studies

(Due to the multiplicity of sites/branch facilities particular problems mayarise here and additional QA personnel may be necessary on site)

4.3.4.1. QA inspections in the field in critical phases such as:

− Storage of test items for the duration of use− Preparation of forms of application− Application of the test item− Sampling− Preparation of specimens− Storage of specimens− Transport of specimens

4.3.4.2. Fixing deadlines

4.3.4.3. Defined communication routes between TFM, SD, QA and PI, ifapplicable; compliance and documentation

4.3.5. Quality Assurance and data processing (DP)

4.3.5.1. Audit of QA's organisation of DP systems

− Organisation chart and network topology of the DP system− Validation concept− Safety precautions− Authorised access to the DP system− DP system capacity− DP system changes

4.3.5.2. Does QA have direct read-only access to all raw data and can it get ahistory of all inputs and corrected inputs, e.g. using an audit trail?

4.3.5.3. Does QA check all manual or non-validated on-line data input,processing and output processes of the DP system with adequaterandom sampling?

4.3.5.4. Does QA check, where necessary, the validation and revalidation ofthe DP system?

4.3.5.5. Does QA check the evaluation of old DP equipment for GLPconformity?

4.3.5.6. Does QA have sufficient basic DP knowledge for assessing thevalidation of the DP system? Does the QA use the services of anoutside expert?

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4.3.6. Quality Assurance and instrumental analysis or collection ofphysical-chemical data

4.3.6.1. Reporting to QA exact time short critical phases are carried out orany changed times.

Examples of critical phases:

− Preparation of solutions− Removal of specimens− Charging and start-up of apparatus (e.g. steam pressure measurement)

4.3.6.2. See Annex 5 for procedure in the case of short-term studies

4.4. Inspection

4.4.1. Preliminary remark

As a rule inspection is carried out by all inspectors together (at least in pairs).

4.4.2. Rooms/installations

4.4.2.1. Checking that the function of the rooms corresponds to thedesignations in the building plans

4.4.2.2. Checking the suitability of the rooms as regards size, apparatus,functionality, order, cleanness, etc.

4.4.2.3. Separate rooms or sections for:

− network servers, mainframe computers, node computer− stores for apparatus and supplies− areas for working with radioactive or sterile materials− storage of test and reference items for as long as they are needed− preparation of forms of application− collection, storage and disposal of waste, test systems− cleaning of materials (washing units)− individual application areas (different processes)− individual biological test systems− clean/unclean areas− archive rooms (separate for wet material), external order archive if

necessary

4.4.2.4. Adequate separation of the GLP studies from other studies (if theycannot be put in separate rooms, it must be possible to work inconformity with GLP in the non-GLP area, i.e. all GLP rules arecomplied with up to the time of preparation of study plans and finalreports)

− Checking of room conditions/environmental conditions:temperature

− light conditions− air change

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− relative humidity

4.4.3. Monitoring of rooms/installations in accordance with SOPs, rulesfor unforeseeable events, alarms (rules for weekends and holidays)Questioning of personnel:

4.4.3.1. on "current" SOPs (comprehension)

4.4.3.2. on the progress of study in accordance with the study plan

4.4.3.3. on raw data collection:− direct recording of original and derived data, initialled and dated− rules for amendments, corrections (the original records must be

recognisable and the amendments furnished with date, reason andsignature)

− in the case of raw data collection by computer: acceptance criteria,authorisation to amend raw data, acquisition of amendment by audittrail

− authentication of raw data copies

4.4.3.4. on conduct in the case of unforeseeable events, e.g. power cut (isthere an emergency generator available, are functional tests carriedout and documented?)

4.4.3.5. The proper functioning of an audit trail is checked by amending araw data item as an example and checking whether it has beenproperly recorded and can be reproduced, e.g. using an example file.

4.4.4. Standard Operating Procedures

Checking SOPs on the spot:

− availability− latest version− readability− authorisation− completeness− establishing who is responsible for dissemination and exchanging

invalid SOPs for valid ones− no unauthorised summaries− no unauthorised changes

� see Annex 1

4.4.5. Apparatus, materials and reagents

4.4.5.1. Auditing maintenance, repair and release records, calibration andadjustment of apparatus (apparatus/logbooks), procedure if tolerancelimits are exceeded

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4.4.5.2. Checking that containers are properly labelled in the case of test andreference items (at least with the expiry date, special storageinstructions, opening date and shelf life if applicable) and reagents(provenance, identity, concentration, stability data, date ofmanufacture and expiry date, special storage instructions, any dangersymbols pursuant to the Dangerous Substances Order)

4.4.5.3. Disposal of materials and reagents

4.4.6. Studies carried out on animals

4.4.6.1. Qualification of animal minders

4.4.6.2. Animal provenance documentation

4.4.6.3. Quarantine for newly arrived animals; examinations on arrival andcontinuous documentation of health status (in case of sickness rejectif necessary, giving reasons)

4.4.6.4. Randomisation/allocation of animals

4.4.6.5. Dealing with superfluous animals

4.4.6.6. Unambiguous labelling of animals and cages/containers

4.4.6.7. Monitoring the health of the animals, administration of medicines ifrequired

4.4.6.8. Quality and purity of feed (delivery note, composition and impuritiescertificate)

4.4.6.9. Checking feed and water quality, what to do if defects are found

4.4.6.10. Feed storage conditions

4.4.6.11. Quality and purity of litter, substrate, etc.

4.4.6.12. Documentation of all stages of study (e.g. application, sampling,autopsy) for every animal

4.4.6.13. Does the pathologist have a suitable method for recording data?

(see also 4.4.12)

4.4.6.14. Disposal of cadavers

4.4.6.15. General cleanness

4.4.6.16. Cleaning of cages/containers, feed containers and other accessories

4.4.6.17. Separation of clean and unclean areas (cage washing facilities,animal rooms)

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4.4.6.18. Conduct in the case of unforeseeable events

4.4.6.19. Documentation when materials (sections, blocks, etc.) are sent toassociated or independent TSs or other TFs.

4.4.7. Studies carried out on microbial, cellular and subcellular testsystems

4.4.7.1. Does the TF have whatever official permits are necessary for dealingwith pathogenic microorganisms (Federal Act on the Prevention ofContagious Diseases)?

4.4.7.2. Are personnel given sufficient training as necessary on dealing withdangerous pathogenic test systems, and by whom?

4.4.7.3. Are there any rules regarding

− keeping conditions and culture (e.g. climatic chamber, making theculture medium, cultivation)

− hygiene precautions, other safety measures, examining state of health ofpersonnel

− prevention of contamination (sterility)for these test systems, and are they being complied with?

4.4.7.4 Characterisation of the test system (provenance, species, strain)

4.4.7.5 Disposal of biological test systems (collection, storage, decontamination and transport methods)

4.4.8. Greenhouse and semi-field studies

4.4.8.1. Test system:

− Species, variety, strain− Provenance− Quantity− State of health (quarantine if necessary)− Number and frequency of health checks

4.4.8.2. Substrate:

− Provenance− Composition− Nutrient content− Homogeneity− Absence of disturbing impurities

4.4.8.3. Care of the test system:

− Cultivation, reproduction and keeping conditions (in the case of plants:sowing, cuttings, refining, pruning if any, singling)

− Feeding (in the case of plants: supplying with water and nutrients)

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− Measures to protect the test system against attack from harmfulorganisms

4.4.8.4. In greenhouse only:

Cleanness, air conditioning, temperature and humidity recording, illumination(intensity, duration), shading (duration), ventilation (mechanical protectionagainst ingress of foreign and harmful organisms), sufficient size for separatekeeping of test systems (in the case of plants: type of standing surface andwatering, any measures against hardness of water; in the case of animals: typeand size of container/housing)

4.4.8.5. Test item: type and time of application

4.4.8.6. Disposal of test systems and substrate

4.4.8.7. What safety measures are provided for the personnel, are they awareand are they monitored (e.g. health protection)? What monitoringsystems are there?

4.4.9. Field studies (see. 4.3.4)

4.4.9.1. Description of the test system (location, history of plot, plot size,position in relation to wind direction, adjacent areas, labelling,locatability, mapping; in the case of plants: species, variety,provenance of seed or plants, state of health, care measures such aspruning, tilling, fertilising, watering, plant protection; in the case ofsoils: type of soil, organic substances, pH value, tilling)

4.4.9.2. Application of test item (calculation of dose, information on shelflife and behaviour for specific pH values of the water; type ofapplication, e.g. pouring, spraying, scattering, dusting; type ofapparatus, nozzle type, linkage; testing of application; frequency andtimes; if necessary fixing of dates on the basis of phenologicalinformation; recording of temperature and windspeed duringapplication; removal of liquid residues; measures to preventcontamination, e.g. by drift)

4.4.9.3. Labelling, maintenance and cleaning of apparatus (e.g. scales,pipettes, application equipment including nozzles, refrigerators,meteorological data recording instruments)

4.4.9.4. Specimens for residue analyses (type and date of sampling, labellingand storage of specimens, checking of storage conditions, suitabletransport to analytical laboratory, maintaining cold chain)

4.4.9.5. Preventing contamination (test item kept sufficiently separate fromspecimens during storage and handling; measures in the case ofapparatus, work tables, containers, rooms)

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4.4.9.6. Presence of SOPs, study plan and forms in the branch facility,recordings of communications (telephone calls, faxes), intermediatestorage of raw data at the branch facility

4.4.9.7. Cleanness (apparatus, containers, rooms)

4.4.9.8. Disposal of residues of the test item and the test system,documentation

4.4.9.9. Communication between LPE, SD, PI and QA; procedure forinforming QA on critical phases such as application of test item andtaking, preparation, storage and transport of specimens (dates to bespecified in study plan)

4.4.10. Studies in the area of instrumental analysis or collection of physical-chemical data

4.4.10.1. Methods in particular for ensuring GLP and non-GLP studies are atseparate times

4.4.10.2. Development of methods during the study requires timelyadditions/amendments to the study plan

4.4.10.3. Unambiguous and durable labelling of apparatus and equipmentmodules

4.4.10.4. Unambiguous matching of

− logbooks to equipment and modules− raw data to equipment (in the case of modular systems, to the respective

parts)− printouts (e.g. chromatograms) to the respective specimens or test and

reference solutions

4.4.10.5. Full and complete documentation of the calculations from the rawdata to the results in the final report

4.4.10.6. Matching of raw data relating to more than one study (e.g. astandard for several studies) to the individual studies (e.g. by meansof authenticated copies)

4.4.10.7. SOPs for equipment

− Person responsible− Instruction in routine operation, maintenance, calibration and

functionality checking of the equipment (e.g. type and frequency,tolerances and procedure if tolerance limits are exceeded, results to berecorded, labelling in the event of malfunctions, informing theSD/hierarchical superior if things are unclear)

− In the case of non-routine stages in the work, references to the operatinginstructions may be given. There is no need for them to be recorded inthe archives.

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− If the operating instructions or parts of them are formally declared to beSOPs, they become a part of all authenticated versions and as SOPshave to be archived.

4.4.10.8. Audit of− receipt, labelling and storage of test items, reagents and specimens,− preparation, labelling and storage of solutions

4.4.11. Test and reference items

4.4.11.1. SOP on handover of the test item from the sponsor to the TF (e.g.handling, environmental conditions such as temperature and relativehumidity, storage conditions, if necessary classification inaccordance with Dangerous Substances Order)

4.4.11.2. Authenticity of test item on arrival at TF:

4.4.11.3. Procedure for verification of identity, e.g. by testing at last twospecific characteristics from the analysis certificate, in exceptionalcases return of a specimen to the manufacturer for confirmation orother duplicable method for establishing identity; otherwise a clearindication must be given in the study plan and the final reportLabelling as test or reference item, clear coding

4.4.11.4. Distribution of the test item in the Test Facility; documentation

4.4.11.5. Accounting of quantity received, use and disposal of the test item(possibly return to manufacturer)

4.4.11.6. Archiving reference samples of test and reference items

4.4.11.7. Preparation of application form of test and reference items

− cleanness of apparatus− avoidance of contamination

4.4.11.8. Labelling, homogeneity, stability and storage of application form

4.4.12. Data processing (see also 4.3.5)

4.4.12.1. Is there an exact description of the computer system used? Does itshow the network topology and data flow?

4.4.12.2. Is there an inventory of the GLP computer equipment used?

4.4.12.3. Are apparatus and modules unambiguously and durably labelled?

4.4.12.4. Is there an inventory of the software the TF has purchased ordeveloped itself?

4.4.12.5. What methods are used to protect the computer systems fromdamage?

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4.4.12.6. Is there an SOP which specifies which data are to be regarded asraw data (electronically stored data or paper printouts)?

4.4.12.7. Are there suitable methods available to protect against raw datalosses (e.g. defective or incomplete data transmission)?

4.4.12.8. Does the program used permit only authorised persons to correctinput errors? Can this be verified (audit trail)?

4.4.12.9. Are any changes made in accordance with GLP? Does the programallow data corrected after storage to be recognised as such? Can theoriginal input be called up (audit trail)?

4.4.12.10. Does the program used allow display of an error function?

4.4.12.11. Has the DP system been developed, manufactured andvalidated by the manufacturer in accordance with recognised qualityand technical standards?

4.4.12.12. Does the DP system specification meet the requirements ofthe application ?

4.4.12.13. Is the computer equipment in the Test Facility subject to avalidation concept? (What is validated when and by whom?)

4.4.12.14. Is an acceptance test for the application carried out beforefirst use?

4.4.12.15. Is old apparatus validated retrospectively by means of aGLP conformity evaluation plan? What documented considerationsis this based on and what documents are consulted for retrospectivevalidation?

4.4.12.16. Are there documented and approved rules for controlledsystem changes, i.e. exchange of hardware components (e.g. harddisk, processor) or changes to software components (e.g. update,upgrade, replacement) in computer equipment?

4.4.12.17. Are there rules for revalidation after a control systemchange?

4.4.12.18. Have computer systems been regularly revalidated inaccordance with the validation concept?

4.4.12.19. Are there specifications regarding the air conditioning inthe computer room? How are they monitored?

4.4.12.20. Is it ensured as far as necessary that the computerequipment has a continuous power supply?

4.4.12.21. Are plausibility tests carried out on data input (e.g. dosingonly after input of body weight)?

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4.4.12.22. How does the SD ensure that the data input is regularly andadequately checked for correctness?

4.4.12.23. Are the storage times and conditions for electronicallystored raw data GLP-compliant?

4.4.12.24. Is an audit trail automatically generated with information inparticular on: person, date of data input, date of data change, reasonfor change?

4.4.12.25. Which data are input online or offline by clinical-pathological/haematological or environmental monitoring systemsfor a specific study or more than one study? Is there data matchingbetween storage medium and printout and what is saved?

4.4.12.26. Are the above points, where relevant and necessary, set outin SOPs in a reproducible way?

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4.5. Archiving

See also the consensus paper of the Working Party on the Archiving and Storage ofRecords and Materials(possibly independent order archive: TS)

4.5.1. General aspects of archiving

4.5.1.1. Structural factors, e.g. protection against fire (fire-retardant design),water, theft and other negative influences

4.5.1.2. Control of access, archive manager or representative

4.5.1.3. Inventory list and organisation and indexing system for archiveddocuments and materials (including discontinued studies), fastlocation

4.5.1.4. QA inspection of data and materials archives

4.5.1.5. Procedure in the case of preparation of several originals of finalreports

4.5.2. Data archive

4.5.2.1. Audit of documents for completeness, e.g. study plan, raw data, finalreport, miscellaneous documents; source references for data coveringmore than one study, e.g. scales data, air conditioning control data,instrument calibration, any authorised copies

4.5.2.2. Pagination or adequate method for fast location and for protectionagainst loss and mix-up of the raw data belonging to a study,possibly also using study plan, final report and miscellaneous data

4.5.2.3. List of contents of archived documents for each study

4.5.2.4. Rules for borrowing and returning archived documents (as a rule,copies to be made)

4.5.2.5. Ensuring legibility when data saved on magnetic media

4.5.2.6. Method for microfilming data, audit

4.5.2.7. Safe intermediate storage of data in associated TSs or independentTSs and communication to SD or archive (including order archive)

4.5.2.8. Archiving of QA documents

4.5.2.9. Chronological collection of all SOPs

4.5.2.10. Archiving of data covering more than one study (logbooks, recordsof air conditioning checks, etc.)

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4.5.2.11. Archiving of building and floor plans

4.5.2.12. Archiving of organisation charts, personal files, Master Schedule

4.5.3. Materials archive

4.5.3.1. Archive for reference samples of test and reference items, labelling,duration of storage

4.5.3.2. Archive for specimens, temperature control in the case ofrefrigerated storage

4.5.3.3. Archive for wet items, special requirements e.g. for formaldehydepreparations

4.5.3.4. Archive for paraffin wax blocks, sections, smears

4.5.3.5. Intermediate storage of specimens in associated TSs or independentTSs; refrigeration, maintaining cold chain in transport

4.5.3.6. Notification of QA before removal from archive at end of storageperiod

4.6. Audit of completed studies

4.6.1. Selection of studies

4.6.1.1. Selection as shortly as possible before or at beginning of inspection(see 3.2 and 4.2.5.3)

4.6.1.2. Studies should be relevant to study categories applied for and ifpossible suitable for submission to an evaluating authority

4.6.1.3. Studies should be carried out, completed and archived in accordancewith GLP and as a rule not older than the previous inspection

4.6.2. Preparation for study audits

4.6.2.1. Preparation of copies of study plans and final reports for memos,comparisons, etc., also translations if appropriate

4.6.2.2. If appropriate, consultation with SD of the study in question and/orQA

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4.6.3. Carrying out the study audit

4.6.3.1. Audit for completeness of documents (contents list, pagination asnecessary), classification criteria and consistent coding

4.6.3.2. Audit of dated signatures in original

4.6.3.3. Audit of study plan (see Annex 2)

4.6.3.4. Audit of raw data (random if necessary) for:

− reproducibility− completeness (laboratory journals, delivery notes, air conditioning

control data, apparatus logbooks, substance data sheets, etc.)− correct amendments− dated initials

4.6.3.5. Audit of final report (see Annex 3)

If parts of the study were not carried out in accordance with GLP, this mustbe noted in the SD's statement.

4.6.3.6. Audit for congruence of study plan, raw data and final report(systematic approach from study plan via raw data to final report orvice versa), e.g.:

− comparison of dates of beginning and end of practical part of a studyand other relevant data between study plan, raw data and final report

− checking whether all requirements of study plan including those of theSOPs mentioned (disclosure) have been fulfilled in the final report(note any changes including date). Check time of notification of QA

− in the case of animal experiments, random checking or examination ofindividual animals on the basis of the reproducibility of the raw datathroughout the study (possibly with the inclusion of an animal whichdied during the study)

− random check of individual raw data against the final report, also withregard to the correct presentation of the results

4.6.3.7. If appropriate, supplementary audit of:

− personnel documents− QA documentation (matching of QA inspections with the QA statement

(dates, study phases and reports to TFM))− rooms, archives− animal keeping− reference samples of test and reference items, specimens− SOPs valid at time of inspection− raw data covering more than one study− interfaces between TF and associated TSs or independent TSs− procedure in the case of discontinued studies

4.6.3.8. If the study audit is carried out not in the framework of a normalGLP inspection but in response to enquiries from the evaluatingauthorities, the following points are to be observed:

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− determination of human resources requirement for the study selectedand right to inspect personal documents

− audit of individual pieces of apparatus− right to inspect records on the test item (possibly physical inspection of

archive, comparison of quantities), systematic checking of raw data inlight of enquiry

− possibly a brief look around the laboratory and questioning of relevantpersonnel

4.6.4. Possibly take a look at particular procedures in a comparablecurrent study

4.6.5. Discussion of results of study audit

4.6.5.1. Agreement within team of inspectors

4.6.5.2. Discussion with SD, QA, TFM and if necessary others, e.g. PI

4.6.5.3. Request of a supplement to the final report if there are relevantdefects

4.6.5.4. In the case of serious defects, classification of study as not GLP-compliant and immediate notification of Federal GLP Agency

4.7. Concluding discussion

4.7.1. Participants: inspectors, TFM, SD, QA management, possiblyarchive manager, PI if applicable

4.7.2. Communication of defects found, as a rule in writing (brief report)

4.7.3. Setting deadline for rectifying defects

4.7.4. Announcement of re-inspection in the case of serious defects

4.7.5. Binding designation of Test Facility

4.7.6. Determination and specific arrangement of study categories(see also 2.3.3 and Annex 6)

4.7.7. Any provisional vote taken by inspection team

5. INSPECTION REPORT

5.1. Name and address of TF and any associated TSs or independent TSs

5.2. Reason for and period of inspection

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5.3. Participants in inspection

5.4. Study categories (see Annex 6)

5.5. Names of structures audited/areas of TF pursuant to ChemVwV-GLP1,Annex to 4.1

5.6. Names of current studies inspected and completed studies audited

5.7. List of defects found (possible distinction between slight, medium andserious defects), any TF measures notified on the basis of it

5.8. Overall impression of TF

5.9. Inspection team's vote on granting of certificate

5.10. Possible annexes to inspection report:− Brief report in accordance with 4.7.2− Layout of Test Facility (GLP area marked)− Organisation chart(s)− List of current, completed and discontinued studies (Master Schedule)− List of SOPs in all areas− Quality Assurance programme− List of studies carried out/study categories for certificate− if applicable, written opinion of TF on elimination of defects

1 Administrative Regulation relating to Chemicals (Good Laboratory Practice)

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Annex 1: Standard Operating Procedures

1. Requirements

The Test Facility must have at its disposal written Standard Operating Proceduresin the German language, approved by the Test Facility management.

Standard Operating Procedures must be available on site. Only the latest versionmust be kept. Superseded versions must be either removed (collected in) orlabelled as invalid. Technical manuals, operation instructions, etc. can be used as an additional help.If they are a part of the Standard Operating Procedure, they must be archivedalong with it. This is not necessary if they are only referred to in the StandardOperating Procedure and the main information in the manual is already containedin it.

Formal requirements:

− Labelling with descriptive title and name− Name of Test Facility− Code and version number on each page− Total number of pages including annexes− Area of validity− Distribution list− Author and date of drafting− Approval and date of entry into force (signature of Test Facility

management)− Documented visa of Quality Assurance

Additional requirements:

Source references or apparatus manufacturers' operating instructions

Additions and amendments must be approved and dated (amendments guaranteedon all authorised copies)

There must be audit and updating procedures available.

A historical archive must be kept of all Standard Operating Procedures.

Standard Operating Procedures for audit of apparatus, installations, etc., mustcontain instructions for cases where the prescribed tolerances or conditions are notcomplied with.

In the "Organisation and Personnel" sector the points listed below requireadequate written rules, but not necessarily in the form of Standard OperatingProcedures:

− Organisation chart− Task descriptions− CVs− Training and continuing training− List of names, initials− Distribution list for Standard Operating Procedures

2. At least the following areas must be covered by Standard Operating Procedures,while several of these points may be combined in a single SOP:

a) Test and reference items

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Reception Identification/authentication Purity (composition, concentration of active ingredient) Labelling Handling Removal Preparation Use Stability Homogeneity and stability of mixtures (carriers) Reference samples Storage Disposal

b) Apparatus, materials and reagents Labelling of reagents Labelling of apparatus Operation Maintenance (logbooks) Cleaning (logbooks) Calibration, possibly indicating permissible tolerances Validation, operation, maintenance, safety, system change control and backupin the case of computer-assisted systems Expiry dates Preparation of reagents Preparation of application form Monitoring of environmental conditions

c) Record-keeping, reporting, storage and retrieval Coding of studies Data collection Drafting of reports Indexation systems Data handling Validation of DP systems Keeping of records and reports Access rules Registration of borrowings and returns Preparation of Standard Operating Procedures (drafting, amendment,updating, authorisation, distribution, archiving) Drafting of study plans Historical development of Standard Operating Procedures

d) Test systems Preparation of rooms Preparation and audit of room environment conditions Reception Quarantine Transfer (forwarding) Accommodation/storage Handling Characterisation Identification Permanent and unambiguous labelling Feeding, care, medical attention Storage of feed, litter, etc. Checking quality of feed and water, procedure if defects are found Cleaning of cages, feed containers and other accessories Separation of clean and unclean areas (cage washing facilities, animal rooms) Preparation of test systems

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Randomisation Application Observation of test systems Examination of test systems Dealing with superfluous animals, plants, etc. Dealing with moribund or dead individual test systems Disposal of test systems Collection/taking of specimens Naming/labelling of specimens Handling of specimens (autopsy, histopathology) Placing and choosing location for test systems on study surfaces

e) Quality Assurance procedures Audits Inspections Checking of study plans and final reports Reporting Quality Assurance statement Participation in the preparation of Standard Operating Procedures

f) Methods - Standard Operating Procedures (analyses, studies)

g) Computer-assisted systems

� Operation of DP system� Responsibilities of personnel� Safety measures� Definition of raw data� Method for determining specifications of apparatus� Method for changing the programme� Validation method� Documentation method� Regular audit of correct function� Maintenance method� Software development� Acceptance tests and documentation� Back-up method� Archiving of data� Making legible electronically recorded data

h) Dispatch of materials and documents to associated/independent TSs or other TFs

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Annex 2: Study plans

Name of study, code Descriptive title Declaration of type and purpose Designation of test item by

− trade name− code− name (IUPAC, CAS No, etc.)− molecular formula− structural formula− batch

Reference item (chemical name) Name and address of sponsor Name(s) and address(es) of TF(s), associated TS or independent TS Name and address of Study Director or representative Dated signatures to the study plan

− Study Director− Test Facility management (only necessary in the case of standardised study

plans for short-term studies)− Quality Assurance (documented verification)

Dates (planned deadlines for beginning and end of experimental phase) Study methods

− individual descriptions− OECD study guidelines or similar− special Standard Operating Procedures− general Standard Operating Procedures

Individual data (where applicable)

− justification of the choice of test system− characterisation of the test system− application method (justification)− dosages− details of the study set up− field study: obtaining climatic data

Full list of records to be kept Amendments, deviations and corrections

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− justification and dated signature of Study Director− Quality Assurance visa, signed and dated in good time− notification, where appropriate, of the Test Facility management and/or the

sponsor− archiving of amendments with the study plan− archiving of deviations with the raw data

Specifications for field test systems: Study area

− site− type of soil, pH value, organic substances− arrangement, size and number of repetitions of study and control plots− size and nature of separating strips, areas− marking and mapping for the purpose of relocation− history (e.g. previous crop, fertilisation measures, plant protection) for at least

the two previous vegetation periods− recording of environmental conditions such as temperature, precipitation,

duration of sunshine, special events, in the case of greenhouses: periods oflight/darkness, etc.

Test system

− plant species, variety, age, interval− soil parameters− permitted care measures (avoiding interference with the test item)− in the case of seeds: clone, providence, pre-treatment

Study method

− description of type of application and of apparatus (spatial or area treatment,size of outriggers, type of nozzles, pressure, advance, tolerances, removal ofspray fluid residues)

− application and sampling deadlines− sampling methods, apparatus if appropriate, soil and plant specimens− labelling, preparation, transport and storage of specimens− method of despatch to sponsor, analytical laboratory or processing firm− if appropriate, archiving of specimens

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Annex 3: Final reports Name of study, code Descriptive title Designation of test item by

− trade name− code− name (IUPAC, CAS No, etc.)− molecular formula− structural formula− characterisation− batch− purity− stability− homogeneity and a note to say whether an authentication was carried out and if not, why not.

Reference item (chemical name) Name(s) and address(es) of TF(s), associated TS or independent TS Name of Study Director, or representative Name of PI, if appropriate, or managing scientists from cooperating disciplines Dated GLP statement of Study Director (naming any phases not compliant with GLP) Dated signatures of Study Director, PI or managing scientists Dated Quality Assurance statement

− inspectors' deadlines− type of inspections− inspected phases of studies− deadlines for reports to the Study Director and the TF management

Dates (deadlines for beginning and end of experimental phase) Description of materials used Study methods

− individual description− OECD study guidelines or similar− specific Standard Operating Procedures

Representation of results

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− summary− all information and data asked for in the study plan− calculations and statistical methods− evaluation and discussion− conclusions

Indication of where all the following are kept

− reference samples of test and reference items− specimens− raw data (in what form)− study plan, including amendments/additions− final report

Documentation

− classification criteria− uniform coding− completeness of raw data (contents list)− perfect archiving of raw data (dated, initialled, justified, dated and initialled

corrections)− perfect representation of results (avoiding errors by the use of word

processing or text modules and of transmission and calculation errors)− pagination or comparable possibilities for checking

Subsequent corrections and additions

− justification and dated signature of Study Director and, if appropriate, themanagement employee involved

− dated signature of Quality Assurance

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Annex 4: Field of application of Good Laboratory Practice in Germany The Chemicals Act makes it compulsory to comply with the GLP Principles for non-clinical experimental studies of substances or preparations, the results of which areintended to make possible the official evaluation of possible dangers to human beings andthe environment. The Chemicals Administrative Regulation (GLP) lays down the field of application forchemicals, plant pesticides, medicaments, explosives, substances involved in dangerousgoods transport and food and animal feedingstuffs additives. The following list (status as at December 1997) shows those studies which to theknowledge of the Federal GLP Agency are regarded by the competent evaluationauthorities as studies which have to be GLP-compliant in the areas of chemicals, plantpesticides and medicaments. In the list, an asterisk denotes those physical-chemical studies which can be carried out inaccordance with to the OECD consensus paper on short-term studies (see also Annex 5).

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Studies requiring GLP-compliance in the framework of the Chemical Substances,Plant Protection and Medicaments Act

I) Physical, chemical and physical-chemical studies

ChemicalsAct

PlantProtection

Act

MedicamentsAct

Type and proportion by weight of impurities,auxiliary substances and decay products

+

+

o

Melting point * * o

Boiling point * * o

Specific gravity * * o

Vapour pressure * * o

Surface tension * * o

Water solubility * * o

Fat solubility * - o

Partition coefficient * * o

Flash point * * o

Ignition point * * o

Explosion risk * * o

Autoflammability * * o

Oxidising properties * * o

Thermolytic behaviour o * o

Dissociation constant o * o

Abiotic decomposition:

Hydrolysis * + o

Photodecomposition, photolysis + + o

Adsorption/desorption(laboratory studies)

* * o

Adsorption/Desorption(field studies)

+ - o

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II) Ecological/ecotoxicological studies (including metabolism, environmental andresidue behaviour))

ChemicalsAct

PlantProtection Act

MedicamentsAct

Toxicity to:

Fish (acute, prolonged) + + o

Daphnia (acute, prolonged) + + o

Birds + + o

Effects on:

Bacteria (aquatic) + + o

Soil organisms + + o

Soil microflora o + o

Higher plants + o o

Green algae + + o

Honey bee o + o

Useful organisms (miscellaneous) o + o

Bait acceptance experiments o + o

Degradability:

Soil o + o

Biodegradability + + o

Bioaccumulation + + o

Mobility/retention in water, soil and air(field studies)

+ + o

Residue behaviour o + o

Metabolism: Soil o + o Plant o + o

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III) Toxicological studies Chemicals

Act Plant

ProtectionAct

MedicamentsAct

Acute toxicity (oral, dermal, inhalative) + + +

Subacute toxicity (28 days) + + +

Subchronic toxicity (90 days) + + +

Chronic toxicity + + +

Skin and eye irritation + + +

Sensitisation + + +

Behaviour-disturbing properties + + +

Carcinogenicity + + +

Mutagenicity (in vitro, in vivo) + + +

Reproduction toxicity + + +

Teratogenicity, embryotoxicity + + +

Toxicokinetics + + +

Special regulations in the area of plant protective agents: see also Annex 7: Bundesanzeiger [Federal Gazette] No. 132, 1993, p. 6560 Bundesanzeiger [Federal Gazette] No. 169, 1995, p. 10205

and

Guideline developed within the Standing Committee On Plant Health with regard to theapplicability of Good Laboratory Practice to data requirements according to Annexes II,Part A, and III, Part A, of Council Directive 91/414/EEC; Guidance Document7109/IV/94, Rev. 6.

Abbreviations

+ : subject to GLP Principles * : not subject to GLP Principles (short-term studies, see Annex 5) o : not yet subject to GLP Principles - : data not required

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Annex 5: Short-term studies

The OECD makes possible a simplified procedure for short-term studies which have tobe carried out in accordance with the GLP Principles: GLP Consensus Document No 7, The Application of the GLP Principles to Short-TermStudies.

Short-term studies are: a) short-term biological studies, which include acute toxicity studies, mutagenicitystudies and ecotoxicological studies for evaluating short-term environmental impacts; b) physical-chemical studies which are studies, tests or measurements of short duration(typically not more than one working week). They employ widely-used techniques (e.g.OECD Study Guidelines) and yield easily repeatable results, often expressed by simplenumerical values or verbal expressions (e.g. melting point, vapour pressure, partitioncoefficient). The regulatory agencies/receiving authorities in the Member countries specify which testsshould be submitted to them and which should be conducted under the Principles of GLP.

There follows a description of some of the special features of applying GLP Principles toshort-term studies.

Study plan 1. Standardised study plan 1.1 Version of standardised study plan 1.2 Name and address of Test Facility 1.3 Name of Test Facility 1.4 Statement of type and purpose of study 1.5 Name(s) and address(es) of Study Director(s) 1.6 Study method 1.7 Reasons for the choice of test system, where applicable:

− Characterisation of the test system− Application method and reasons for selecting it− Dosages and/or frequency and duration of application

1.8 List of documents to be archived1.9 Dated signatures of: Test Facility management, all Study Directors concerned,

Quality Assurance

Any amendments to the standardised study plan which may need to be carried out inindividual cases must be made in accordance with Annex 1 to §19a(1) Chemicals Act,Part II, 8.1, 8.2.

2. Annex to the standardised study plan

2.1 Reference to version of the standardised study plan2.2 Name and address of sponsor2.3 Code or name of test item2.3 Reference substance to be used

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2.4 Limit dates2.5 Dated signature of current Study Director (and of sponsor, where appropriate)2.6 Visa of Quality Assurance

Quality Assurance

1. Single audit of standardised study plan2. Visa in good time on all annexes to the standardised study plan3. Random audit of individual current studies4. Programme for carrying out process-based inspections5. Audit of final report for every study6. Quality Assurance statement with date and object of random inspections of

individual studiesorreference to data and object of process-based inspections

Final report

1. Standardised final report

1.1 Version of standardised final report1.2 Name and address of Test Facility1.3 Descriptive title1.3 Name(s) of Study Director(s)1.4 Name(s) of any PI(s), if applicable, or other senior scientists contributing reports

to the final report1.5 Description of methods and materials used1.6 Reference to OECD or other study principles1.7 Place of storage of all specimens, samples, raw data, study plan and final report1.8 Dated signatures of Test Facility management and Study Director (confirming

compliance with GLP Principles)

Any amendments to the standardised final report which may need to be carried out inindividual cases must be made in accordance with Annex 1 to §19a(1) Chemicals Act,Part II, 9.1, 9.2.

2. Annex to the standardised final report

2.1 Reference to version of standardised final report2.2 Code or name of test item2.3 Chemical name of reference item2.4 Characterisation of test item, including purity, stability and homogeneity2.5 Limit dates2.6 Summary of results2.7 All information and data asked for in the study plan2.8 Expression of results including calculation and statistical methods applied2.9 Evaluation and discussion of results and conclusions if any

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2.10 Dated signature of current Study Director2.11 Quality Assurance statement

Archiving

Originals of standardised study plans and standardised final reports to be archived inchronological order.

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Annex 6: Study categories

Category Field of application

1 Studies to determine physical-chemical properties and content

2 Studies to determine toxicological properties

3 Studies to determine mutagenic properties (in vitro and in vivo)

4 Ecotoxicological studies to determine impact on aquatic and terrestrialorganisms

5 Studies on behaviour in soil, water and air; studies of bioaccumulationand metabolisation

6 Studies to determine residues

7 Studies to determine impact on mesocosms and natural ecosystems

8 Analytical studies on biological materials

9 Other studies (with description)

Explanation of OECD study categories with examplesby the Federal GLP Agency

At the third meeting of the OECD GLP Panel in Paris on 21 and 22 January 1992 it wasdecided to harmonise the exchange of information between OECD member countries ontest facilities inspected nationally for GLP compliance. This information exchange takesplace on the basis of lists sent by the competent national authorities once a year to theother member countries, containing the following information:

• unambiguous name of Test Facility• month and year of inspection(s)• type of inspection (routine inspection, re-inspection, study audit)• GLP status• study categories

Information on the area of activity of test facilities has hitherto been contained only in thelists of a few member countries. It is intended to give authorities and sponsors of studiessubject to GLP Principles an overview of the area of test facilities which is covered bystate monitoring of GLP compliance. The reason for introducing study categories wasthat major differences exist in the execution of short physical-chemical studies relating tolong-term toxicity tests and that it is not practicable to list all the individual studies at aTest Facility. Nine study categories have been introduced for describing the area ofactivity in the lists of the OECD member countries.

With the entry into force of the General Administrative Regulation concerning Chemicals- Good Laboratory Practice (ChemVwV-GLP) of May 1997 the division of the GLPstudies into nine categories has been introduced in Germany as well.

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The definition of the term "study" is left wide open in the GLP Principles so as to givethe national authorities and industry plenty of room for manoeuvre in practicalimplementation. For example, a field study taking place at a number of locations can becarried out as an overall study or split up into several self-contained individual studies. Ingeneral it can be said that every complete study has to have a Study Plan, a StudyDirector and an independent Final Report. The competent evaluating authorities makesome suggestions as to what they mean by a study, but it is ultimately the Test Facilityitself which defines what it regards as a study in the sense of the GLP Principles.

The purpose of the study categories is to improve the information exchange between theOECD member countries and to inform evaluating authorities and potential sponsorsabout the areas taken into account in the national GLP inspections. Studies which do notobviously fit into any of the given categories are not rejected by the evaluating authoritiesfor formal reasons. If the evaluating authorities have serious reservations as to whetherthe studies submitted are covered by the study categories in the GLP certificate/list, thiscan be sorted out from case to case on the basis of the inspection reports or an enquiry tothe competent supervisory authorities.

All subsectors of a study, e.g. stockkeeping, breeding, analysis etc. in the case oftoxicological studies, are contained in the relevant study category. If a Test Facility,besides carrying out complete studies, also works on subsectors of studies in the samecategory, e.g. on behalf of other test facilities, these are also covered even if in this casenot the whole study is carried out. Analysis, for example, is contained in study categories2-7 and so it is not necessary to cover category 8 as well.

There is a special case with specialised analytical laboratories, which often carry outparts/phases of GLP studies for different sponsors. If this is done under a subcontract, theanalytical laboratories have to be included in any GLP inspection carried out by thesponsor. It may be more practical and meaningful in this case for the analyticallaboratories to have their own GLP certificate. This is why the OECD introduced studycategory 8, although with analysis it is rarely a case of complete studies and more oftenone of subsectors of studies subject to GLP Principles. For the laboratories to be giventheir own GLP certificate they must implement the GLP Principles in full.

Even if the full range of a study category is not covered, as a rule the whole categoryshould still be designated. Particular attention should then be given in the next inspectionto the possibility of an intermediate extension of the scope of the study. Only if there arejustified reservations, e.g. about certifying a complete study category on the basis of avery small amount of testing done at a particular Test Facility, narrowly defined studyareas in categories 1 to 7 can also be placed in category 9.

Some explanations and examples for the individual OECD study categories:

Study category 1: Studies to determine physical-chemical properties andcontent

This category contains studies whose results are used exclusively for determiningphysical, chemical and physical-chemical parameters.

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Examples are deteminations of:nature and proportion by weight of impurities, auxiliary substances and decompositionproducts; melting point; boiling point; specific gravity; vapour pressure, surface tension;water solubility; fat solubility; partition coefficient; flash point; flammability; explosionrisk; autoflammability; oxidising properties; thermolytic behaviour; dissociation constant.

Study category 2: Studies to determine toxicological properties

The requirement for a study to be placed in this category is that a test item is applied tothe animal and the results of the study is to be used for evaluating toxic effects in thehuman being. All areas necessary for carrying out the study, such as rearing, keeping andcaring for the experimental animals, and the accompanying analyses, also fall into thiscategory.

Examples are studies on:acute toxicity (oral, dermal, inhalative); subacute toxicity (28 days); subchronic toxicity(90 days); chronic toxicity; skin and eye irritation; sensitisation; behaviour-disturbingproperties; carcinogenicity; mutagenicity; embryotoxicity; toxicokinetics.

Study category 3: Studies to determine mutagenic properties (in vitro and invivo)

This category comprises genetic toxicity studies, including in vitro mutagenicity tests. Inthe case of in vivo studies there are overlaps with study category 2.

Examples are studies on:reverse mutation (E. coli, S. typhimurium); gene mutation, mitotic recombination(Saccharomyces cerevisiae); lethal mutation (Drosophila melanogaster); mammalian cellsin vitro (DNA damage and repair, sister chromatid exchange, cell transformation); invivo mammalian (micronucleation test, dominant lethal test, germ-cell cytogenetic test,spot test, translocation test).

Study category 4: Ecotoxicological studies to determine impact on aquatic andterrestrial organisms

This category groups all ecotoxicological tests on individual species which are used forevaluating risks to the environment. The studies focus primarily on the effects of thesubstance on organisms. A distinction is made between aquatic and terrestrialhabitats/ecosystems on account of their sharply contrasting structures. In aquatic habitatsit is the medium - water - which determines the biotope. The terrestrial habitat is at leastdetermined by soil and air, which are also taken to be subdivisions of the terrestrialhabitat. The term "terrestrial organisms" is therefore more comprehensive than "soilorganisms", and category 4 therefore also includes useful animals, bees, insects and birds.

Examples are studies of toxicity to/effects on:

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fish (acute, prolonged), daphnia (acute, prolonged); birds, bacteria, soil organisms (soilfauna); soil microflora; higher plants; green algae; honey bees; useful organisms. Feedingstudies investigating the metabolism of residues in the feed in order to assess damage tothe health of farm animals or wild animals are also covered by this category.

Study category 5: Studies on behaviour in soil, water and air; studies ofbioaccumulation and metabolisation

The studies mainly cover assessment of the behaviour of the substance, such as itsvolatilisation, conversion, bonding, distribution and fate. Thus the availability of asubstance in the environment is examined, which can have an influence on the nature andduration of possible effects and forms the basis for an exposure analysis. Direct harmfuleffects on organisms are not covered by studies in this category.

Examples are studies on:ultimate fate in soil, water and air, photolysis, volatility from plants and from the soil,photochemical-oxidative decomposition, adsorption/desorption, bioaccumulation in fishand lysimeter studies.

Study category 6: Studies to determine residues

Study category 6 mainly comprises residue experiments in accordance with the guidelinesof the Federal Biological Institute for the Testing of Plant Protection Products inAuthorisation Procedures. If studies of residues in water and soil have to be carried out asa fixed part of these experiments they are to be included here. All subsectors of thesestudies, e.g. application, sampling, specimen preparation and analysis, are covered.

Study category 7: Studies to determine impact on mesocosms and naturalecosystems

In these studies the input, fate and ecological effects of test items in artificially createdcomplex ecosystems or direct in the field are studied. These studies can be important inthe framework of the authorisation procedure for plant protection products if comparisonof exposure analysis and ecotoxicological results on individual species do not permit anyconclusive risk analysis. The design of the study varies according to the task. For theaquatic sector the so-called "pond studies", in which different concentrations of the testsubstance are applied to several parallel artificial ponds, is the commonest type of studieson mesocosms. In the USA, GLP studies have been carried out on aquatic and terrestrialecosystems in accordance with the Federal Insecticide, Fungicide and Rodenticide Act(FIFRA) since 1989.

Study category 8: Analytical studies on biological materials

Category 8 concerns those test facilities which are exclusively carrying out analyticalstudies in categories 2 to 7.

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Study category 9: Other studies (with description)

This category covers all studies not included in categories 1 to 8. These may for examplebe studies which in Germany are not required to comply with GLP Principles (§ 19Chemicals Act) but which have been inspected for compliance with the GLP Principlespursuant to a "legitimate interest" in accordance with § 19b(1) Chemicals Act. Narrowlydefined study areas in categories 1 to 8 may also be placed in this category if theirparticular categories are too broad.

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Annex 7: Literature

Primary sources:

Germany:

OECD Principles of Good Laboratory Practice (GLP) of 4 February 1983;Bundesanzeiger Vol. 35, No 42a

Notice of 5 July 1993 on the performance of studies in accordance with the principles ofGood Laboratory Practice as a prerequisite for the authorisation of plant protectionproducts; Bundesanzeiger No 132, 20.7.1993, p. 6560ff

Notice on the performance of studies in accordance with the principles of GoodLaboratory Practice as a prerequisite for inclusion in Annex I to EC Directive91/414/EEC and the authorisation of plant protection products; Bundesanzeiger No. 169,1995, p. 10205

Amended version of Chemicals Act of 25 July 1994; Bundesgesetzblatt Part I, 1994, p.1703/1732

GLP Consensus Document: The Application of the Principles of GLP to ComputerisedSystems; Bundesanzeiger No. 231, 1996, pp. 12749-12753

Order amending Annex I to the Chemicals Act of 14.5.1997; Bundesgesetzblatt Part I,1997, p. 1060

Amended version of the General Administrative Regulation concerning the OfficialProcedure for Monitoring Compliance with the Principles of Good Laboratory Practice(ChemVwV-GLP), as last amended 15 May 1997; Gemeinsames Ministerialblatt[Common Ministerial Gazette] of 9 June 1997, Vol. 48, No 17, pp. 257-264

Notice of a Consensus Document of the National and Länder Working Party on GLP onthe archiving and storage of records and materials of 5.5.1998; Bundesanzeiger No. 98,pp. 7439-7440

Guide to the Harmonisation of the GLP Monitoring Procedure in the Federal Republic ofGermany of the BLAC-AK "GLP und andere Qualitätssicherungssysteme" (NLWP onGLP and other QA Systems) of December 1998; Federal GLP Agency

EU:

Council Directive 87/18/EEC of 18 December 1986 on the harmonisation of laws,regulations and administrative provisions relating to the application of the principles ofgood laboratory practice and the verification of their applications for tests on chemicalsubstances

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Council Directive 88/320/EEC of 9 June 1988 on the inspection and verification of GoodLaboratory Practice (GLP)

89/569/EEC: Council Decision of 28 July 1989 on the acceptance by the EuropeanEconomic Community of an OECD decision/recommendation on compliance withprinciples of good laboratory practice

Commission Directive 90/18/EEC of 18 December 1989 adapting to technical progressthe Annex to Council Directive 88/320/EEC on the inspection and verification of goodlaboratory practice (GLP)

Commission Directive 1999/11/EC of 8 March 1999 adapting to technical progress theprinciples of good laboratory practice as specified in Council Directive 87/18/EEC on theharmonisation of laws, regulations and administrative provisions relating to theapplication of the principles of good laboratory practice and the verification of theirapplications for tests on chemical substances

Commission Directive 1999/12/EC of 8 March 1999 adapting to technical progress forthe second time the Annex to Council Directive 88/320/EEC on the inspection andverification of good laboratory practice (GLP)

OECD:

OECD Series on Principles of Good Laboratory Practice and Compliance Monitoring,Number 1: The OECD Principles of Good Laboratory Practice (as revised in 1997), Paris1998

OECD Series on Principles of Good Laboratory Practice and Compliance Monitoring,Number 2 (revised): Guidance for GLP-Monitoring Authorities, Revised Guides forCompliance Monitoring Procedures for Good Laboratory Practice; EnvironmentMonograph No 110, Paris 1995

OECD Series on Principles of Good Laboratory Practice and Compliance Monitoring,Number 3 (revised): Guidance for GLP-Monitoring Authorities, Revised Guidance forthe Conduct of Laboratory Inspections and Study Audits; Environment Monograph No111, Paris 1995

OECD Series on Principles of Good Laboratory Practice and Compliance Monitoring,Number 4: GLP Consensus Document, Quality Assurance and GLP; EnvironmentMonograph No 48, Paris 1992

OECD Series on Principles of Good Laboratory Practice and Compliance Monitoring,Number 5: GLP Consensus Document, Compliance of Laboratory Suppliers with GLPPrinciples; Environment Monograph No 49, Paris 1992

OECD Series on Principles of Good Laboratory Practice and Compliance Monitoring,Number 6: GLP Consensus Document, The Application of the GLP Principles to FieldStudies; Environment Monograph No 50, Paris 1992

Official German translation of OECD: The Application of the GLP Principles to FieldStudies [Die Anwendung der GLP-Grundsätze auf Freilandprüfungen], Paris 1995

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OECD Series on Principles of Good Laboratory Practice and Compliance Monitoring,Number 7: GLP Consensus Document, The Application of the GLP Principles to short-term Studies; Environment Monograph No 73, Paris 1993

Official German translation of OECD: The Application of the GLP Principles to Short-Term Studies [Die Anwendung der GLP-Grundsätze auf Kurzzeit-Prüfungen], Paris 1995

OECD series on Principles of Good Laboratory Practice and Compliance Monitoring,Number 8: GLP Consensus Document, The Role and Responsibility of the StudyDirector in GLP Studies; Environment Monograph No 74, Paris 1993

Official German translation of OECD: The Role and Responsibilities of the StudyDirector in GLP Studies [Die Rolle und Verantwortlichkeiten des Prüfleiters bei GLP-Prüfungen], Paris 1995

OECD series on Principles of Good Laboratory Practice and Compliance Monitoring,Number 9: Guidance for GLP-Monitoring Authorities, Guidance for the Preparation ofGLP Inspection Reports; Environment Monograph No 115, Paris 1995

OECD series on Principles of Good Laboratory Practice and Compliance Monitoring,Number 10: GLP Consensus Document, The Application of the principles of GLP toComputerised Systems; Environment Monograph No 116, Paris 1995

OECD series on Principles of Good Laboratory Practice and Compliance Monitoring,Number 11: Advisory Document of the Panel on GLP, The Role and Responsibilities ofthe Sponsor in the Application of the Principles of GLP; Paris 1998

Other sources:

W.Y. Garner, M.S. Barge, J.P. Ussary (eds), Good Laboratory Practice, ACS ProfessionalReference Book, Washington 1992

IVA-Leitlinien, Rückstandsversuche [IVA Guidelines, Residue experiments] Teil I-VI,Industrieverband Agrar e.V., Fachbereich Pflanzenschutz, Frankfurt am Main, 1992

Schlottmann/Kayser (Hrsg.), GLP Gute Laborpraxis, Textsammlung und Einführung[Collection of texts and Introduction], Behr's Verlag Hamburg, 3. Auflage 1997

G.A. Christ, S.J. Harston, H.W. Hembeck, K.A. Opfer, GLP - Handbuch für Praktiker[GLP Handbook], 2. Auflage 1998, GIT-Verlag Darmstadt