Comparison Chart of FDA and EPA Good Laboratory Practice (GLP) Regulations and the OECD Principles of GLP

Transcription

1 Comparison Chart of FDA and EPA Good Laboratory Practice (GLP) Regulations and the OECD Principles of GLP Document issued on: June 2004 U.S. Department of Health and Human Services Food and Drug Administration Office of Regulatory Affairs (ORA) i

2 Preface Public Comment Comments and suggestions may be submitted at any time to the Division of Compliance Policy (HFC-230), Office of Enforcement, Office of Regulatory Affairs (ORA), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD Please refer to the exact title of this document when submitting comments or suggestions. For questions regarding the use or interpretation of this chart contact James F. McCormack at (301) or Additional Copies Additional copies are available from the Internet at: Submit written requests for single copies of the guidance entitled Comparison Chart of FDA and EPA Good Laboratory Practice (GLP) Regulations and the OECD Principles of GLP to the Division of Compliance Policy (HFC-230), Office of Enforcement, Office of Regulatory Affairs (ORA), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD Send one self-addressed adhesive label to assist the office in processing your requests. i

3 Table of Contents Preface... i Scope and Authority... 1 Definitions Organization and Personnel.. 8 Facilities.. 17 Equipment Facility Operation.. 21 Articles 27 Protocol and Conduct 31 Records and Reports.. 35 Disqualification ii

4 Scope & Authroity Scope Studies Conducted Under Contracts Sec (a) This part prescribes good laboratory practices for conducting nonclinical laboratory studies that support or are intended to support applications for research or marketing permits for products regulated by the Food and Drug Administration, including food and color additives, animal food additives, human and animal drugs, medical devices for human use, biological products, and electronic products. Compliance with this part is intended to assure the quality and integrity of the safety data filed pursuant to sections 406, 408, 409, 502, 503, 505, 506, 507, 510, , , 706, and 801 of the Federal Food, Drug, and Cosmetic Act and sections 351 and F of the Public Health Service Act (a) This part prescribes good laboratory practices for conducting studies relating to health effects, environmental effects, and chemical fate testing. This part is intended to ensure the quality and integrity of data submitted pursuant to testing consent agreements and test rules issued under section 4 of the Toxic Substances Control Act (TSCA). (b) This part applies to any study described by paragraph (a) of this section which any person conducts, initiates, or supports on or after September 18, (c) It is EPA s policy that all data developed under section 5 of TSCA be in accordance with provisions of this part. If data are not developed in accordance with provisions of this part, EPA will consider such data insufficient to evaluate the health and environmental effects of the chemical substances unless the submitter provides additional information demonstrating that the data are reliable and adequate When a sponsor conducting a nonclinical laboratory When a sponsor or other person utilizes the services of a study intended to be submitted to or reviewed by the consulting laboratory, contractor, or grantee to perform Food and Drug Administration utilizes the services of a all or a part of a study to which this part applies, it shall consulting laboratory, contractor, or grantee to perform notify the consulting laboratory, contractor, or grantee an analysis or other service, it shall notify the consulting that the service is, or is part of, a study that must be laboratory, contractor, or grantee that the service is part conducted in compliance with the provisions of this part. of a nonclinical laboratory study that must be conducted in compliance with the provisions of this part. 1. These Principles of Good Laboratory Practice should be applied to the non-clinical safety testing of test items contained in pharmaceutical products, pesticide products, cosmetic products, veterinary drugs as well as food additives, feed additives, and industrial chemicals. These test items are frequently synthetic chemicals, but may be of natural or biological origin and, in some circumstances, may be living organisms. The purpose of testing these test items is to obtain data on their properties and/or their safety with respect to human health and/or the environment. Non-clinical health and environmental safety studies covered by the Principles of Good Laboratory Practice include work conducted in the laboratory, in greenhouses, and in the field. Unless specifically exempted by national legislation, these Principles of Good Laboratory Practice apply to all non-clinical health and environmental safety studies required by regulations for the purpose of registering or licensing pharmaceuticals, pesticides, food and feed additives, cosmetic products, veterinary drug products and similar products, and for the regulation of industrial chemicals. 1

5 Scope & Authroity Inspection Authority (a) A testing facility shall permit an authorized employee (a) A testing facility shall permit an authorized of the Food and Drug Administration, at reasonable employee or duly designated representative of EPA or times and in a reasonable manner, to inspect the facility FDA, at reasonable times and in a reasonable manner, and to inspect (and in the case of records also to copy) to inspect the facility and to inspect (and in the case of all records and specimens required to be maintained records also to copy) all records and specimens regarding studies within the scope of this part. The required to be maintained regarding studies to which records inspection and copying requirements shall not this part applies. The records inspection and copying apply to quality assurance unit records of findings and requirements shall not apply to quality assurance unit problems, or to actions recommended and taken. records of findings and problems, or to actions recommended and taken, except the EPA may seek production of these records in litigation or formal adjudicatory hearings. Consequences of Refusing to Permit Inspection (b) The Food and Drug Administration will not consider a nonclinical laboratory study in support of an application for a research or marketing permit if the testing facility refuses to permit inspection. The determination that a nonclinical laboratory study will not be considered in support of an application for a research or marketing permit does not, however, relieve the applicant for such a permit of any obligation under any applicable statute or regulation to submit the results of the study to the Food and Drug Administration. (b) EPA will not consider reliable for purposes of showing that a chemical substance or mixture does not present a risk of injury to health or the environment any data developed by a testing facility or sponsor that refuses to permit inspection in accordance with this part. The determination that a study will not be considered reliable does not, however, relieve the sponsor of a required test of any obligation under any applicable statute or regulation to submit the results of the study to EPA. Statement of Compliance or Non- Compliance Any person who submits to EPA a test required by a testing consent agreement or a test rule issued under section 4 of TSCA shall include in the submission a true and correct statement, signed by the sponsor and the study director, of one of the following types: (a) A statement that the study was conducted in accordance with this part; or (b) A statement describing in detail all differences between the practices used in the study and those required by this part; or (c) A statement that the person was not a sponsor of the study, did not conduct the study, and does not know whether the study was conducted in accordance with this part. 2

6 Definitions Good Laboratory Practice Good Laboratory Practice (GLP) is a quality system concerned with the organisational process and the conditions under which non-clinical health and environmental safety studies are planned, performed, monitored, recorded, archived and reported. Nonclinical Laboratory Study Short-term Study (d) Nonclinical laboratory study means in vivo or in vitro experiments in which test articles are studied prospectively in test systems under laboratory conditions to determine their safety. The term does not include studies utilizing human subjects or clinical studies or field trials in animals. The term does not include basic exploratory studies carried out to determine whether a test article has any potential utility or to determine physical or chemical characteristics of a test article. Study means any experiment at one or more test sites, in which a test substance is studied in a test system under laboratory conditions or in the environment to determine or help predict its effects, metabolism, product performance (efficacy studies only as required by 40 CFR ), environmental and chemical fate, persistence and residue, or other characteristics in humans, other living organisms, or media. The term study does not include basic exploratory studies carried out to determine whether a test substance or a test method has any potential utility Non-clinical health and environmental safety study, henceforth referred to simply as study, means an experiment or set of experiments in which a test item is examined under laboratory conditions or in the environment to obtain data on its properties and/or its safety, intended for submission to appropriate regulatory authorities Short-term study means a study of short duration with widely used, routine techniques. Sponsor (f) Sponsor means a person who initiates and supports, (1) A person who initiates and supports, by provision of by provision of financial or other resources, a nonclinical financial or other resources, a study; (2) A person who laboratory study; (2) A person who submits a nonclinical submits a study to the EPA in support of an application study to the Food and Drug Administration in support of for a research or marketing permit; or (3) A testing an application for a research or marketing permit; or (3) facility, if it both initiates and actually conducts the A testing facility, if it both initiates and actually conducts study. the study Sponsor means an entity which commissions, supports and/or submits a non-clinical health and environmental safety study. Testing Facility 58.3 (g) Testing facility means a person who actually conducts a nonclinical laboratory study, i.e., actually uses the test article in a test system. Testing facility includes any establishment required to register under section 510 of the act that conducts nonclinical laboratory studies and any consulting laboratory described in section 704 of the act that conducts such studies. Testing facility encompasses only those operational units that are being or have been used to conduct nonclinical laboratory studies Testing facility means a person who actually conducts a study, i.e., actually uses the test substance in a test system. ``Testing facility'' encompasses only those operational units that are being or have been used to conduct studies 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. 3

7 Definitions Testing Facility Management Test Site Test Site Management Test facility management means the person(s) who has the authority and formal responsibility for the organisation and functioning of the test facility according to these Principles of Good Laboratory Practice Test site means the location(s) at which a phase(s) of a study is conducted Test site management (if appointed) means the person(s) responsible for ensuring that the phase(s) of the study, for which he is responsible, are conducted according to these Principles of Good Laboratory Practice. Person (h) Person means an individual, partnership, corporation, Person includes an individual, partnership, corporation, association, scientific or academic establishment, association, scientific or academic establishment, government agency, or organizational unit thereof, and government agency, or organizational unit thereof, and any other legal entity. any other legal entity. QAU 58.3 (l) Quality Assurance Unit means any person or organizational element, except the study director, designated by testing facility management to perform the duties relating to quality assurance of nonclinical laboratory studies Quality Assurance Unit means any person or organizational element, except the study director, designated by testing facility management to perform the duties relating to quality assurance of the studies Quality Assurance Programme means a defined system, including personnel, which is independent of study conduct and is designed to assure test facility management of compliance with these Principles of Good Laboratory Practice. Study Director 58.3 (m) Study director means the individual responsible for the overall conduct of a nonclinical laboratory study Study director means the individual responsible for the overall conduct of a study Study Director means the individual responsible for the overall conduct of the nonclinical health and environmental safety study. 4

8 Definitions Principal Investigator Principal Investigator means an individual who, for a multi-site study, acts on behalf of the Study Director and has defined responsibility for delegated phases of the study. The Study Director s responsibility for the overall conduct of the study cannot be delegated to the Principal Investigator(s); this includes approval of the study plan and its amendments, approval of the final report, and ensuring that all applicable Principles of Good Laboratory Practice are followed. Study plan Study plan means a document which defines the objectives and experimental design for the conduct of the study, and includes any amendments. Study Plan Amendment Study Plan Deviation Study plan amendment means an intended change to the study plan after the study initiation date Study plan deviation means an unintended departure from the study plan after the study initiation date. SOP Standard Operating Procedures (SOPs) means documented procedures which describe how to perform tests or activities normally not specified in detail in study plans or test guidelines. Test System 58.3 (i) Test system means any animal, plant, microorganism, or subparts thereof to which the test or control article is administered or added for study. Test system also includes appropriate groups or components of the system not treated with the test or control articles Test system means any animal, plant, microorganism, chemical or physical matrix, including but not limited to soil or water, or subparts thereof, to which the test, control, or reference substance is administered or added for study. Test system also includes appropriate groups or components of the system not treated with the test, control, or reference substance Test system means any biological, chemical or physical system or a combination thereof used in a study. Specimen 58 (j) Specimen means any material derived from a test system for examination or analysis Specimen means any material derived from a test system for examination or analysis Specimen means any material derived from a test system for examination, analysis, or retention. 5

9 Definitions Batch Test Article 58.3 (n) Batch means a specific quantity or lot of a test or control article that has been characterized according to Sec (a) (b) Test article means any food additive, color additive, drug, biological product, electronic product, medical device for human use, or any other article subject to regulation under the act or under sections 351 and F of the Public Health Service Act Batch means a specific quantity or lot of a test, control, or reference substance that has been characterized according to Sec (a) Test substance means a substance or mixture administered or added to a test system in a study, which substance or mixture: (1) Is the subject of an application for a research or marketing permit supported by the study, or is the contemplated subject of such an application; or (2) Is an ingredient, impurity, degradation product, metabolite, or radioactive isotope of a substance described by paragraph (1) of this definition, or some other substance related to a substance described by that paragraph, which is used in the study to assist in characterizing the toxicity, metabolism, or other characteristics of a substance described by that paragraph Batch means a specific quantity or lot of a test item or reference item produced during a defined cycle of manufacture in such a way that it could be expected to be of a uniform character and should be designated as such Test item means an article that is the subject of a study. Control Article 58.3 (c) Control article means any food additive, color additive, drug, biological product, electronic product, medical device for human use, or any article other than a test article, feed, or water that is administered to the test system in the course of a nonclinical laboratory study for the purpose of establishing a basis for comparison with the test article Control substance means any chemical substance or mixture, or any other material other than a test substance, feed, or water, that is administered to the test system in the course of a study for the purpose of establishing a basis for comparison with the test substance for known chemical or biological measurements Reference item ( control item ) means any article used to provide a basis for comparison with the test item. Reference Substance Reference substance means any chemical substance or Reference item ( control item ) means any article mixture, or analytical standard, or material other than a used to provide a basis for comparison with the test test substance, feed, or water, that is administered to or item. used in analyzing the test system in the course of a study for the purposes of establishing a basis for comparison with the test substance for known chemical or biological measurements. Carrier Carrier means any material, including but not limited to, feed, water, soil, and nutrient media, with which the test substance is combined for administration to a test system. 6

10 Definitions Vehicle Vehicle means any agent which facilitates the mixture, dispersion, or solubilization of a test substance with a carrier Vehicle means any agent which serves as a carrier used to mix, disperse, or solubilise the test item or reference item to facilitate the administration/application to the test system. Raw Data Master Schedule 58.3 (k) Raw data means any laboratory worksheets, records, memoranda, notes, or exact copies thereof, that are the result of original observations and activities of a nonclinical laboratory study and are necessary for the reconstruction and evaluation of the report of that study. In the event that exact transcripts of raw data have been prepared (e.g., tapes which have been transcribed verbatim, dated, and verified accurate by signature), the exact copy or exact transcript may be substituted for the original source as raw data. Raw data may include photographs, microfilm or microfiche copies, computer printouts, magnetic media, including dictated observations, and recorded data from automated instruments Raw data means any laboratory worksheets, records, Raw data means all original test facility records memoranda, notes, or exact copies thereof, that are the and documentation, or verified copies thereof, which result of original observations and activities of a study are the result of the original observations and activities in and are necessary for the reconstruction and evaluation a study. Raw data also may include, for example, of the report of that study. In the event that exact photographs, microfilm or microfiche copies, computer transcripts of raw data have been prepared (e.g., tapes readable media, dictated observations, recorded data which have been transcribed verbatim, dated, and from automated instruments, or any other data storage verified accurate by signature), the exact copy or exact medium that has been recognised as capable of transcript may be substituted for the original source as providing secure storage of information for a time period raw data. Raw data may include photographs, as stated in section 10, below. microfilm or microfiche copies, computer printouts, magnetic media, including dictated observations, and recorded data from automated instruments Master schedule means a compilation of information to assist in the assessment of workload and for the tracking of studies at a test facility. Experimental Starting Date Experimental End Date Study Initiation Date 58.3 (o) Study initiation date means the date the protocol is signed by the study director Experimental start date means the first date the test substance is applied to the test system Experimental end date means the last date on which data are collected directly from the study Study initiation date means the date the protocol is signed by the study director Experimental starting date means the date on which the first study specific data are collected Experimental completion date means the last date on which data are collected from the study Study initiation date means the date the Study Director signs the study plan. Study Completion Date 58.3 (p) Study completion date means the date the final report is signed by the study director Study completion date means the date the final report is Study completion date means the date the signed by the study director. Study Director signs the final report. 7

11 Organization & Personnel Training & Experience of Personnel Summary of Training & Job Descriptions (a) Each individual engaged in the conduct of or responsible (a) Each individual engaged in the conduct of or for the supervision of a nonclinical laboratory study shall have education, training, and experience, or combination thereof, to enable that individual to perform the assigned functions (b) Each testing facility shall maintain a current summary of training and experience and job description for each individual engaged in or supervising the conduct of a nonclinical laboratory study. responsible for the supervision of a study shall have education, training, and experience, or combination thereof, to enable that individual to perform the assigned functions. (b) Each testing facility shall maintain a current summary of training and experience and job description for each individual engaged in or supervising the conduct of a study All personnel involved in the conduct of the study must be knowledgeable in those parts of the Principles of Good Laboratory Practice which are applicable to their involvement in the study (c) ensure the maintenance of a record of the qualifications, training, experience and job description for each professional and technical individual; Personnel Access to & Responsibility to Follow SOPs Study personnel will have access to the study plan and appropriate Standard Operating Procedures applicable to their involvement in the study. It is their responsibility to comply with the instructions given in these documents. Any deviation from these instructions should be documented and communicated directly to the Study Director, and/or if appropriate, the Principal Investigator(s). Personnel Responsibility to Record Data Sufficient Personnel Personnel Health Precautions (c) There shall be a sufficient number of personnel for the timely and proper conduct of the study according to the protocol (d) Personnel shall take necessary personal sanitation and health precautions designed to avoid contamination of test and control articles and test systems All study personnel are responsible for recording raw data promptly and accurately and in compliance with these Principles of Good Laboratory Practice, and are responsible for the quality of their data (c) There shall be a sufficient number of personnel for the timely and proper conduct of the study according to (b) ensure that a sufficient number of qualified the protocol. personnel, appropriate facilities, equipment, and materials are available for the timely and proper conduct of the study; (d) Personnel shall take necessary personal sanitation and health precautions designed to avoid contamination of test, control, and reference substances and test systems Study personnel should exercise health precautions to minimise risk to themselves and to ensure the integrity of the study. 8

12 Organization & Personnel Clothing for Personnel Personnel Illness Precautions (e) Personnel engaged in a nonclinical laboratory study shall (e) Personnel engaged in a study shall wear clothing wear clothing appropriate for the duties they perform. Such appropriate for the duties they perform. Such clothing clothing shall be changed as often as necessary to prevent shall be changed as often as necessary to prevent microbiological, radiological, or chemical contamination of test microbiological, radiological, or chemical systems and test and control articles. contamination of test systems and test, control, and reference substances (f) Any individual found at any time to have an illness that may (f) Any individual found at any time to have an illness adversely affect the quality and integrity of the nonclinical laboratory study shall be excluded from direct contact with test study shall be excluded from direct contact with test systems, test and control articles and any other operation or systems, test, control, and reference substances and function that may adversely affect the study until the condition is corrected. All personnel shall be instructed to report to their immediate supervisors any health or medical conditions that may reasonably be considered to have an adverse effect on a nonclinical laboratory study that may adversely affect the quality and integrity of the They should communicate to the appropriate person any relevant known health or medical condition in order that they can be excluded from operations that may affect the study. any other operation or function that may adversely affect the study until the condition is corrected. All personnel shall be instructed to report to their immediate supervisors any health or medical conditions that may reasonably be considered to have an adverse effect on a study. Statement Identifying Testing Facility Management (TFM) TFM - Assure Compliance with GLPs TFM - Designate a Study Director TFM - Replace a Study Director (a) Designate a study director as described in Sec , before the study is initiated (b) Replace the study director promptly if it becomes necessary to do so during the conduct of a study (a) Designate a study director as described in Sec before the study is initiated (b) Replace the study director promptly if it becomes necessary to do so during the conduct of a study (a) ensure that a statement exists which identifies the individual(s) within a test facility who fulfil the responsibilities of management as defined by these Principles of Good Laboratory Practice; Each test facility management should ensure that these Principles of Good Laboratory Practice are complied with, in its test facility (g) ensure that for each study an individual with the appropriate qualifications, training, and experience is designated by the management as the Study Director before the study is initiated (g) Replacement of a Study Director should be done according to established procedures, and should be documented. 9

13 Organization & Personnel TFM - Assure Study Director Approves Protocol TFM - Assure Study Director Provides Protocol to QAU (i) ensure documented approval of the study plan by the Study Director; (j) ensure that the Study Director has made the approved study plan available to the Quality Assurance personnel; TFM - Establish a QAU TFM - Assure Appropriate Testing (c) Assure that there is a quality assurance unit as described in Sec (d) Assure that test and control articles or mixtures have been appropriately tested for identity, strength, purity, stability, and uniformity, as applicable (c) Assure that there is a quality assurance unit as described in Sec (d) Assure that test, control, and reference substances or mixtures have been appropriately tested for identity, strength, purity, stability, and uniformity, as applicable (f) ensure that there is a Quality Assurance Programme with designated personnel and assure that the quality assurance responsibility is being performed in accordance with these Principles of Good Laboratory Practice; (p) ensure that test and reference items are appropriately characterised; TFM- Assure Availability of Resources (e) Assure that personnel, resources, facilities, equipment, materials, and methodologies are available as scheduled (e) Assure that personnel, resources, facilities, equipment, materials and methodologies are available as scheduled (n) ensure that test facility supplies meet requirements appropriate to their use in a study; TFM - Assure Personnel Understand Their Functions (f) Assure that personnel clearly understand the functions they are to perform (f) Assure that personnel clearly understand the functions they are to perform (d) ensure that personnel clearly understand the functions they are to perform and, where necessary, provide training for these functions; TFM - Assure Corrective Actions (g) Assure that any deviations from these regulations reported (g) Assure that any deviations from these regulations by the quality assurance unit are communicated to the study reported by the quality assurance unit are director and corrective actions are taken and documented. communicated to the study director and corrective actions are taken and documented. 10

14 Organization & Personnel TFM - Assure Appropriate SOPs TFM - Assure Historical SOPs TFM- Assure there is a PI (e) ensure that appropriate and technically valid Standard Operating Procedures are established and followed, and approve all original and revised Standard Operating Procedures; (k) ensure the maintenance of an historical file of all Standard Operating Procedures; (h) ensure, in the event of a multi-site study, that, if needed, a Principal Investigator is designated, who is appropriately trained, qualified and experienced to supervise the delegated phase(s) of the study. Replacement of a Principal Investigator should be done according to established procedures, and should be documented. TFM - Assure there is Archivist TFM - Assure Master Schedule TFM - Clear Lines of Communication TFM - Validation of Computerized Systems (l) ensure that an individual is identified as responsible for the management of the archive(s); (m) ensure the maintenance of a master schedule; (o) ensure for a multi-site study that clear lines of communication exist between the Study Director, Principal Investigator(s), the Quality Assurance Programme(s) and study personnel; (q) establish procedures to ensure that computerised systems are suitable for their intended purpose, and are validated, operated and maintained in accordance with these Principles of Good Laboratory Practice. 11

15 Organization & Personnel Test Site Management Responsibilities General Responsibilites of a Study Director For each nonclinical laboratory study, a scientist or other For each study, a scientist or other professional of professional of appropriate education, training, and appropriate education, training, and experience, or experience, or combination thereof, shall be identified combination thereof, shall be identified as the study as the study director. The study director has overall director. The study director has overall responsibility for responsibility for the technical conduct of the study, as the technical conduct of the study, as well as for the well as for the interpretation, analysis, documentation interpretation, analysis, documentation, and reporting of and reporting of results, and represents the single point results, and represents the single point of study control. of study control When a phase(s) of a study is conducted at a test site, test site management (if appointed) will have the responsibilities as defined above with the following exceptions: g), i), j) and o) The Study Director is the single point of study control and has the responsibility for the overall conduct of the study and for its final report. Study Director - Protocol Approval & Compliance Study Director - Assure QAU has Protocol (a) The protocol, including any change, is approved as provided by Sec and is followed (a) The protocol, including any change, is approved as provided by Sec and is followed (a) approve the study plan and any amendments to the study plan by dated signature; (e) ensure that the procedures specified in the study plan are followed, and assess and document the impact of any deviations from the study plan on the quality and integrity of the study, and take appropriate corrective action if necessary; acknowledge deviations from Standard Operating Procedures during the conduct of the study; (b) ensure that the Quality Assurance personnel have a copy of the study plan and any amendments in a timely manner and communicate effectively with the Quality Assurance personnel as required during the conduct of the study; Study Director - Assure Personnel have Protocol (c) ensure that study plans and amendments and Standard Operating Procedures are available to study personnel; 12

16 Organization & Personnel Study Director - Assure PI Role (d) ensure that the study plan and the final report for a multi-site study identify and define the role of any Principal Investigator(s) and any test facilities and test sites involved in the conduct of the study; Study Director - Recording & Verification of Data (b) All experimental data, including observations of unanticipated responses of the test system are accurately recorded and verified (b) All experimental data, including observations of unanticipated responses of the test system are accurately recorded and verified (f) ensure that all raw data generated are fully documented and recorded; Study Director - Unforseen Circumstances (c) Unforeseen circumstances that may affect the quality and integrity of the nonclinical laboratory study are noted when they occur, and corrective action is taken and documented (c) Unforeseen circumstances that may affect the quality and integrity of the study are noted when they occur, and corrective action is taken and documented. Study Director - Test Systems (d) Test systems are as specified in the protocol (d) Test systems are as specified in the protocol (e) All applicable good laboratory practice regulations are followed. Study Director - GLP Compliance (e) All applicable good laboratory practice regulations are followed (h) sign and date the final report to indicate acceptance of responsibility for the validity of the data and to indicate the extent to which the study complies with these Principles of Good Laboratory Practice; Study Director - Archiving (f) All raw data, documentation, protocols, specimens, and final reports are transferred to the archives during or at the close of the study. (f) All raw data, documentation, protocols, specimens, and final reports are transferred to the archives during or at the close of the study (i) ensure that after completion (including termination) of the study, the study plan, the final report, raw data and supporting material are archived. Study Director - Validation of Computerized Systems (g) ensure that computerised systems used in the study have been validated; 13

17 Organization & Personnel Principal Investigator 1.3 The Principal Investigator will ensure that the delegated phases of the study are conducted in accordance with the applicable Principles of Good Laboratory Practice. QAU General Responsibilities Sec Sec Quality assurance unit. (a) A testing facility shall have a quality assurance unit which shall be responsible for monitoring each study to assure management that the facilities, equipment, personnel, methods, practices, records, and controls are in conformance with the regulations in this part. (a) A testing facility shall have a quality assurance unit which shall be responsible for monitoring each study to assure management that the facilities, equipment, personnel, methods, practices, records, and controls are in conformance with the regulations in this part. The quality assurance unit shall conduct inspections and maintain records appropriate to the study The test facility should have a documented Quality Assurance Programme to assure that studies performed are in compliance with these Principles of Good Laboratory Practice The Quality Assurance Programme should be carried out by an individual or by individuals designated by and directly responsible to management and who are familiar with the test procedures. QAU Independence QAU - Maintain Copy of Master Schedule Sec (a) For any given study, the quality assurance unit shall be entirely separate from and independent of the Sec Quality assurance unit. (a) For any given study, the quality assurance unit shall be entirely separate from and independent of the This individual(s) should not be involved in the conduct personnel engaged in the direction and conduct of that personnel engaged in the direction and conduct of that of the study being assured. study. study (b) (b) (1) Maintain a copy of a master schedule sheet of all (1) Maintain a copy of a master schedule sheet of all nonclinical laboratory studies conducted at the testing studies conducted at the testing facility indexed by test facility indexed by test article and containing the test substance and containing the test system, nature of system, nature of study, date study was initiated, current study, date study was initiated, current status of each status of each study, identity of the sponsor, and name study, identity of the sponsor, and name of the study of the study director. director (a) have access to an up-to-date copy of the master schedule; QAU - Maintain Copies of Protocols (b) (2) Maintain copies of all protocols pertaining to all nonclinical laboratory studies for which the unit is responsible (b) (2) Maintain copies of all protocols pertaining to all studies for which the unit is responsible (a) maintain copies of all approved study plans and Standard Operating Procedures in use in the test facility QAU - Verify Content of Protocol (b) verify that the study plan contains the information required for compliance with these Principles of Good Laboratory Practice. This verification should be documented; 14

18 Organization & Personnel QAU - Maintain copies of SOPs QAU - Inspections QAU - Reporting (b) (b) (3) Inspect each nonclinical laboratory study at intervals adequate to assure the integrity of the study and maintain written and properly signed records of each periodic inspection showing the date of the inspection, the study inspected, the phase or segment of the study inspected, inspection showing the date of the inspection, the study inspected, the phase or segment of the study inspected, the person performing the inspection, findings and problems, action recommended and taken to resolve existing problems, and any scheduled date for reinspection (b) (3) Any problems found during the course of an inspection which are likely to affect study integrity shall be brought to the attention of the study director and management immediately. Periodically submit to management and the study director written status reports on each study, noting any problems and the corrective actions taken. (3) Inspect each study at intervals adequate to ensure the integrity of the study and maintain written and properly signed records of each periodic inspection showing the date of the inspection, the study inspected, the phase or segment of the study inspected, the person performing the inspection, findings and problems, action recommended and taken to resolve existing problems, and any scheduled date for re-inspection (a) maintain copies Standard Operating Procedures in use in the test facility (c) conduct inspections to determine if all studies are conducted in accordance with these Principles of Good Laboratory Practice. Inspections should also determine that study plans and Standard Operating Procedures have been made available to study personnel and are being followed. Inspections can be of three types as specified by Quality Assurance Programme Standard Operating Procedures: - Study-based inspections, - Facility-based inspections, - Process-based inspections. Records of such inspections should be retained (b) (3) Any problems which are likely to affect study integrity (e) promptly report any inspection results in writing to found during the course of an inspection shall be management and to the Study Director, and to the brought to the attention of the study director and Principal Investigator(s) and the respective management immediately. management, when applicable; (4) Periodically submit to management and the study director written status reports on each study, noting any problems and the corrective actions taken. QAU - Assure Deviations are Authorized (b) (b) (3) Determine that no deviations from approved (5) Determine that no deviations from approved protocols or standard operating procedures were made protocols or standard operating procedures were made without proper authorization and documentation. without proper authorization and documentation. QAU - Review of Final Report (b) (3) Review the final study report to assure that such report accurately describes the methods and standard operating procedures, and that the reported results accurately reflect the raw data of the nonclinical laboratory study (b) (6) Review the final study report to assure that such report accurately describes the methods and standard operating procedures, and that the reported results accurately reflect the raw data of the study (d) inspect the final reports to confirm that the methods, procedures, and observations are accurately and completely described, and that the reported results accurately and completely reflect the raw data of the studies; 15

19 Organization & Personnel QAU - Final Report Statement (b) (3) Prepare and sign a statement to be included with the final study report which shall specify the dates inspections were made and findings reported to management and to the study director (b) (7) Prepare and sign a statement to be included with the final study report which shall specify the dates inspections were made and findings reported to management and to the study director (f) prepare and sign a statement, to be included with the final report, which specifies types of inspections and their dates, including the phase(s) of the study inspected, and the dates inspection results were reported to management and the Study Director and Principal Investigator(s), if applicable. This statement would also serve to confirm that the final report reflects the raw data. QAU - Responsibilities & Procedures QAU - Management Certification of QAU Inspections (c) The responsibilities and procedures applicable to the quality assurance unit, the records maintained by the quality assurance unit, and the method of indexing such records shall be in writing and shall be maintained. These items including inspection dates, the study inspected, the phase or segment of the study inspected, and the name of the individual performing the inspection shall be made available for inspection to authorized employees of the Food and Drug Administration (d) A designated representative of the Food and Drug Administration shall have access to the written procedures established for the inspection and may request testing facility management to certify that inspections are being implemented, performed, documented, and followed-up in accordance with this paragraph (c) The responsibilities and procedures applicable to the quality assurance unit, the records maintained by the quality assurance unit, and the method of indexing such records shall be in writing and shall be maintained. These items including inspection dates, the study inspected, the phase or segment of the study inspected, and the name of the individual performing the inspection shall be made available for inspection to authorized employees or duly designated representatives of EPA or FDA (d) An authorized employee or a duly designated representative of EPA or FDA shall have access to the written procedures established for the inspection and may request testing facility management to certify that inspections are being implemented, performed, documented, and followed up in accordance with this paragraph. 16

20 Facilities General Facility Requirements Animal Care Facilities - Animal Rooms Each testing facility shall be of suitable size and construction to facilitate the proper conduct of nonclinical laboratory studies. It shall be designed so that there is a degree of separation that will prevent any function or activity from having an adverse effect on the study (a) A testing facility shall have a sufficient number of animal rooms or areas, as needed, to assure proper: (1) Separation of species or test systems, (2) isolation of individual projects, (3) quarantine of animals, and (4) routine or specialized housing of animals Each testing facility shall be of suitable size and construction to facilitate the proper conduct of studies. Testing facilities which are not located within an indoor controlled environment shall be of suitable location to facilitate the proper conduct of studies. Testing facilities shall be designed so that there is a degree of separation that will prevent any function or activity from having an adverse effect on the study (a) A testing facility shall have a sufficient number of animal rooms or other test system areas, as needed, to ensure: proper separation of species or test systems, isolation of individual projects, quarantine or isolation of animals or other test systems, and routine or specialized housing of animals or other test systems. (1) In tests with plants or aquatic animals, proper separation of species can be accomplished within a room or area by housing them separately in different chambers or aquaria. Separation of species is unnecessary where the protocol specifies the simultaneous exposure of two or more species in the same chamber, aquarium, or housing unit. (2) Aquatic toxicity tests for individual projects shall be isolated to the extent necessary to prevent cross-contamination of different chemicals used in different tests The test facility should be of suitable size, construction and location to meet the requirements of the study and to minimise disturbance that would interfere with the validity of the study The design of the test facility should provide The test facility should have a sufficient number of rooms or areas to assure the isolation of test systems and the isolation of individual projects, involving substances or organisms known to be or suspected of being biohazardous. Animal Care Facilities - Isolation of Biohazardous Agents (b) A testing facility shall have a number of animal rooms (b) A testing facility shall have a number of animal rooms The test facility should have a sufficient number of or areas separate from those described in paragraph (a) of this section to ensure isolation of studies being or other test system areas separate from those described in paragraph (a) of this section to ensure rooms or areas to assure the isolation of test systems and the isolation of individual projects, involving substances done with test systems or test and control articles known isolation of studies being done with test systems or test, or organisms known to be or suspected of being to be biohazardous, including volatile substances, aerosols, radioactive materials, and infectious agents. control, and reference substances known to be biohazardous, including volatile substances, aerosols, radioactive materials, and infectious agents. biohazardous. Animal Care Facilities - Disease Control Areas (c) Separate areas shall be provided, as appropriate, for the diagnosis, treatment, and control of laboratory animal diseases. These areas shall provide effective isolation for the housing of animals either known or suspected of being diseased, or of being carriers of disease, from other animals. (c) Separate areas shall be provided, as appropriate, for the diagnosis, treatment, and control of laboratory test system diseases. These areas shall provide effective isolation for the housing of test systems either known or suspected of being diseased, or of being carriers of disease, from other test systems 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. 17