Good Laboratory Practice Facilities: Building and Equipment Hedwig Beernaert

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1 Good Laboratory Practice General Manager EuroQAM 1 Facilities Facilities consist of buildings and equipment which should be fit for the job 2 Building Non-clinical health and environmental safety studies covered by the GLP principles can be carried out in laboratories, greenhouses and in the field Laboratory Greenhouse Field 3 1

2 Building - definitions Facilities are part of the whole organization where GLP studies or phases of GLP studies are carried out Test facility means the persons, premises and operational unit(s) that are necessary for conducting the non-clinical health and environmental safety study; For multi-site studies, those which are conducted at more than one site, the test facility comprises the site at which the study director is located and all individual test sites, which individually or collectively can be considered to be test facilities (GLP doc No. 1, II, 2.2.1) Test site means the location(s) at which a phase(s) of a study is conducted (e.g. field studies); (GLP doc No. 1, II, 2.2.2) 4 Building general requirements The requirements will be different in function of the type of activities and the risk of cross-contamination The test facility should be of suitable size, construction and location to meet the requirements of the study and to minimize disturbance that would interfere with the validity of the study (GLP doc No. 1, II, 3.1.1) Analytical lab Animal housing 5 Chemical analysis Physical analysis Microbiological analyis Environmental requirements Type of studies Type of species Type of activities 6 Building general requirements (2) The design of the test facility should provide an adequate degree of separation of the different activities to assure the proper conduct of each study (GLP doc No. 1, II, 3.1.2) Rooms or areas Physical/Chemical studies Toxicological studies Field studies In-vitro studies Reception: test item, test system X X X X Handling - preparations X X X X Balance X X X X Quarantine test system - X - - Test system(s) X X X X Computerized system X X X X Feed storage - X - - Test system plots - - X - Laminar flow cabinets - X - X Storage (items, specimens) X X X X Waste disposal X X X X Archive X X X X 2

3 7 Test system facilities Capacity and design are crucial to work in optimal conditions Sufficient number of rooms or areas to: Assure the isolation of test systems The isolation of individual projects, involving substances or organisms known to be, or suspected of being, biohazardous (GLP doc No. 1, II, 3.2.1) Suitable rooms or areas should be available for the diagnosis, treatment and control of diseases, in order to ensure that there is no unacceptable degree of deterioration of test systems (GLP doc No. 1, II, 3.2.2) There should be storage rooms or areas as needed for supplies and equipment; Storage rooms or areas should be separated from rooms or areas housing the test systems and should provide adequate protection against infestation, contamination, and/or deterioration (GLP doc No. 1, II, 3.2.3) Test system facilities (2) Field studies are performed wholly or partially in outdoor study areas or in greenhouses (GLP, doc No. 6) 8 Control of environmental conditions is not easily achievable Management of security and oversight of operations and facilities is difficult Potential for contamination of the study plots from drift or overspray of pesticides being used on neighboring property Study plot locations should be chosen so as to ensure minimal possibility of off-site interferences Preferably, the plots should be located in areas free of interfering chemicals or where the historical pesticide use (both study and normal use applications) has been documented Physical access to facilities in multi-site studies should be ensured Test system facilities (3) It is important to take provisions to avoid any kind of cross-contamination (GLP doc No. 1, II, 3.2.3) Receipt and storage areas for specimens must be separate from storage areas for pesticide formulations and other test or reference items Storage areas for test and reference items should be environmentally monitored stability of test and reference items Adequate storage and disposal facilities should be available for pesticide and related wastes In-vitro studies only need limited workplaces; Therefore, measures should be taken to ensure the appropriate separation of in vitro studies co-existing in the same physical environment 9 3

4 Test and reference item facilities Handling of test and reference items should be separated from other activities To prevent contamination or mix-ups, there should be separate rooms or areas for receipt and storage of the test and reference items, and mixing of the test items with a vehicle (GLP doc No. 1, II, 3.3.1) 10 Storage rooms or areas for the test items should be separate from rooms or areas containing the test systems; They should be adequate to preserve identity, concentration, purity, and stability; and ensure safe storage for hazardous substances (GLP doc No. 1, II, 3.3.2) Test and reference item facilities (2) Handling of test and reference items should be separated from other activities Test and reference items should not be placed in the same storage containers with collected test system specimens and other materials of low concentrations which are being stored for shipment to the analytical laboratory or to off-site archives (GLP doc No. 6, field studies) 11 Test and reference item facilities (3) Handling of test and reference items should be separated from other activities In vitro studies: rooms or areas used for preparation and mixing of test and reference items with vehicles should be equipped so as: To allow working under aseptic conditions To protect the test system and the study by minimizing the probability of their contamination by test and reference item preparations (GLP doc No. 14) 12 4

5 13 Good Laboratory Practice Waste disposal facilities Lack of policy of waste disposal can be a potential problem of cross-contamination Handling and disposal of wastes may not jeopardize the integrity of studies provision for appropriate collection, storage and disposal facilities, and decontamination and transportation procedures (GLP doc No. 1, II, 3.5) Adequate storage and disposal facilities should be available for pesticide and related wastes to avoid any potential cause for cross-contamination of test systems, of test or reference items or of collected specimens (GLP doc No. 6) It is recommended to prepare a minimum volume of pesticide solutions It should also be assured that unused test and reference items are returned to the sponsors or suppliers, or are disposed of in a legal and responsible manner (GLP doc No. 6) Archive facilities Test facility management should ensure that rooms are available for the secure storage of records and materials (GLP doc No. 1, II, 3.4) Archive facilities should be provided for the secure storage and retrieval of study plans, raw data, final reports, samples of test items and specimens Archive design and archive conditions should protect contents from untimely deterioration 14 Facilities - deviations Physical/Chemical test systems and preparation activities in the same room suitable working of the test system? Insufficient fume hoods for the treatment of biohazardous substances safety problems? Storage of test items and specimens in the same refrigerator cross contamination? Storage of test and reference items, specimens and reagents in the same room as the test system contamination? Absence of a weighing room optimal working of balances? 15 5

6 Facilities deviations (2) Reception desk too small loss of products and specimens? Waste disposal collection room not available Two studies with 2 different test items in the same room administration of test item? Two studies with the same test item on different species in the same room administration of the test item? Capacity of quarantine rooms and testing rooms too small respect of study conditions 16 Facilities deviations (3) Clean and dirty corridors not separated contamination? Cleaning and pest control materials stored in the testing rooms impact on health status of animals Specific pathogen free building not available for specific studies (e.g. cancerogenicity studies) health status of animals cannot be assured There is no specific room available for the isolation of diseased animals Storage of test and reference items, specimens and reagents in the same room as the test system contamination? 17 Facilities deviations (4) The room for the storage of feed is not suitable microbiological contamination The washing room of the cages is not separated from the testing room cross contamination Testing rooms not designed to work in the required environmental conditions (e.g. temperature, humidity, light cycle, etc.) Central room for the collection of animal carcasses and bedding waste not available There is no specific room available for the isolation of diseased animals Cross-contamination in the incubator used for in-vitro studies (e.g. volatility of test item, separation of different studies) 18 6

7 Equipment Equipment: general term for the implements (apparatus, materials) used in an operation or activity Apparatus: Branch to deal with measurement and control Ability to monitor or measure the level of a product s performance, to diagnose errors and writing trace information GLP requirements All the equipment used in GLP studies should be fit for the intended purposes Apparatus should be suitably located, of adequate capacity and of appropriate design (GLP doc No. 1, II, 4.1) Environmental conditions should be monitored and documented (GLP doc No. 1, II, 4.1) Apparatus should be periodically inspected, cleaned, maintained and calibrated; These activities should be documented and calibration should be traceable to international standards (GLP doc No. 1, II, 4.2 GLP doc No. 13 GLP doc No. 6 GLP doc No. 14) Apparatus and materials should not adversely interfere with test systems (GLP doc No. 1, II, 4.3) Chemicals, reagents and solutions should be correctly labeled (GLP doc No. 1, II, 4.2 GLP doc No. 13 GLP doc No. 6 GLP doc No. 14) Location A floor plan of the test facility should be available indicating the activities and the corresponding equipment 21 Critical control points Floor plan: activity/equipment The operation of the ventilation system Environmental conditions? Manuals? Logbook? Calibration program? Maintenance program? SOPs? 7

8 22 Capacity and design Test facility management should ensure that the capacity and design are suitable for the performance of the GLP studies The capacity of the equipment depends on the number and the experimental period of the studies, the number of samples to be analyzed and the calibration and maintenance program of the apparatus The design of the equipment should be as such that it can meet the requirements defined in the study; For each measuring equipment it is necessary to have a master validation plan including: Design qualification (responsibility of vendor) Installation qualification (responsibility of the vendor) Performance qualification (responsibility of the vendor) Operation qualification (responsibility of the test facility) Capacity and design (2) The quality and delivery of the supplies are important elements in the performance of a GLP study TFM should ensure that supplies meet requirements appropriate to their use in a study (GLP doc No. 1, II, 1.1.2,n 7.4.2) Which type of apparatus and materials are used in GLP studies? Is there a policy of purchase? Is there a policy for the validation of apparatus? Are SOPs available? Calibration of apparatus For each apparatus a calibration program should be available Calibration should, where appropriate, be traceable to national or international standards of measurement (GLP doc No. 1, II, 4.2) Internally or externally? Competence of performer? SOP available? Acceptance criteria? Deviations? corrective actions? Use of national or international standards? Certificate? Raw data? 8

9 25 Calibration of a balance Balances are important apparatus in the preparation of solutions and the weight of animals and specimens SOP available? Which parameters? Acceptance criteria? Adjusting? Raw data? Report? Fitness for purpose? Frequency? 26 Calibration of a chromatographic: Spectroscopic system Different injection techniques can be used in the analysis of samples Performance of injector? Injector leak test (pressure drop?) Pressure/Flow accuracy and stability Repeatability Split mode (RSD 3%) Splitless mode (RSD 3%) Temperature accuracy and stability Carry over ( 2%) Frequency Calibration of a chromatographic: Spectroscopic system (2) The efficiency of the separation of analytes is related with the quality of the column Performance of column? Temperature control? RRT RSD r (acceptance criteria) Accuracy (acceptance criteria) Resolution power? (> 1.5) 27 9

10 Calibration of a chromatographic: Spectroscopic system (3) Different types of detectors can be used to produce spectra or signals of certain magnitude Performance of detector? Linearity? Constant detector response? Noise? mean value of 10 measurements of 1 minute acceptance criteria Drift? slope of baseline acceptance criteria Histopathology equipment Histopathology refers to the microscopic examination of tissues in order to study the manifestations of diseases The most important equipment used in histopathological examinations are: Automatic tissue processor Slide warming table Microtome Slide warming table Grossing table Rotator Tissue floatation bath Rotator Disposable blades for microtome Microscope Tissue embedding station Microslide and paraffin tissue block cabinet Histopathology equipment: Automatic tissue processor This instrument is used for the complete automatic dehydration and filtration of human, animal and plant's tissues, up to final fixing in wax Continuous agitation of the tissues to obtain a thorough penetration of the reagents Micro processed based control Time program available Temperature control Data are retained in case of power failure Specimen identification(s) maintained Reagents properly identified, prepared, rotated and replaced Temperatures maintained within acceptable range (recorded) Equipment maintenance log 30 10

11 Histopathology equipment: Tissue embedding instrument This technique is used for the placement of cells or tissues in a supporting medium so that thin slices can be cut with a microtome The medium can be paraffin wax (paraffin embedding) or plastics (plastic embedding) such as epoxy resins All tissues must be embedded according to scheme as described in SOP Consistent tissue orientation assures consistent sampling Cassettes numbered or otherwise uniquely identified Double-check for presence of all tissues 31 Histopathology equipment: Microtome instrument Important device in microscopy preparation Instrument used for the cutting of extremely thin slices (5µm) of material The slices (sections) are used for the preparation of samples (slides) ID written/printed on slide (water/reagent-resistant) Full face section of uniform thickness required SOP preparation samples SOP maintenance instrument The quality of the prepared samples is extremely important for the observation of deviations under transmitted light or electron radiation 32 Histopathology equipment: Microscope This instrument is especially used for the detection and identification of diseased tissues Qualification and experience of technicians and pathologist Consistency in terminology Blind reading avoiding bias Complete identification of lesions Use of standards Registration system Peer review 33 11

12 Histopathology equipment: Incubator 34 This instrument is very often used in stability or in in-vitro GLP studies Temperature accuracy and monitoring Maintenance Calibration SOP Acceptance criteria Frequency Cross-contamination (volatile test items) Labeling 35 Deviations Apparatus without inventory number which apparatus has been used in the study cannot be traced back in the raw data Some raw data have been obtained with an apparatus having a different serial number as mentioned in the logbook the original apparatus was replaced by a leased one without registration and validation Logbooks without specifications of the apparatus Manuals of the apparatus are present but the operators didn t know the existence of it Lack of apparatus responsibilities problems in the case of a failure Specifications of the apparatus were not fit for purpose (e.g sensitivity, resolution power) In the case of a failure no contingency plan Lack of calibration and maintenance programs Acceptance criteria for calibration results were not defined Use of standards that were not traceable to national or international standards of measurements (e.g. use of some reference materials) Standard operating procedures as required by the OECD GLP principles, point 7.4, are not available Raw data of calibration and maintenance not traceable or incomplete The master validation plan containing criteria of installation qualification (IQ), performance qualification (PQ) and operation qualification (OQ) for computerized apparatus systems are not completely elaborated and followed up The alarm system for storage equipment is not functioning 36 Deviations (2) 12

13 Conclusions It is the responsibility of test facility management to ensure that resources of facilities and equipment are available for the performance of GLP studies in accordance with the OECD GLP principles Separation of activities is critical to avoid cross-contamination The apparatus used in GLP studies should be fit for purpose, meaning that they have to be maintained, calibrated and validated periodically according to a pre-established program 37 More in formation can be obtained from: Consultant GLP expert Belac assessor BVBA EuroQAM Kasteelstraat Brakel Belgium GSM beernaert.qam@skynet.be 38 13