Quality Assurance
Japanese Ministry of Agriculture, Forestry and Fisheries
Chapter I. General Provision
Article 1. Purpose
Article 2. Definitions
Article 3. Notification to a contract laboratory by a sponsor
Chapter II. Personnel and organization
Article 4. Personnel
Article 5. Testing facility management
Article 6. Study director
Article 7. Quality assurance unit
Chapter III. Facilities
Article 8. General
Article 9. Animal care facilities
Article 10. Animal supply facilities
Article 11. Facilities for handling test and control substances
Article 12. Laboratory operation area
Article 13. Archives
Article 14. Administrative facilities
Chapter IV. Equipment
Article 15. Design and function of equipment
Article 16. Location of equipment
Article 17. Equipment control
Chapter V. Operation
Article 18. Standard operating procedures
Article 19. Reagents and solutions
Article 20. Animal and quarantine care
Chapter VI. Test and control substance
Article 21. Test and control substance characterization
Article 22. Test and control substance handling
Article 23. Mixture and carriers
Chapter VII. Protocol for and conduct of a study
Article 24. Protocol
Article 25. Conduct of a study
Chapter VIII. Report and records
Article 26. Final report
Article 27. Storage and retrieval of records and specimens
Article 28. Retention period of records and specimens
Chapter 1 – General Provision
Article 1. Purpose
This prescribes good laboratory practice standards for conducting toxicology studies on agricultural chemicals. Compliance with these standards is intended to assure the quality and integrity of toxicological data filed pursuant to the provision of Paragraph 2 of Article 2 of the Agricultural Chemicals Regulation Law (The Law No.82, 1948 thereinafter referred to as “Law”).
Article 2. Definitions
The following terms used in these standards shall have the meanings specified in the following items.
(2) “Testing facility” means any operational unit, which is operated and controlled under a single management, organized with facilities capable of conducting a toxicological study or a part thereof and the personnel working at the facilities.
(3) “Testing facility management” means an individual responsible for the overall operation of a testing facility.
(4) “Study director” means an individual who is designed by the management responsible for the overall conduct of the study and in charge of the technical advice on the study, the analysis and interpretation of the result, and the record and report of the study.
(5) “Quality assurance unit”, which is a part of a testing facility, means any person or organizational element in order to perform duties related to quality assurance of a study.
(6) “Archives” means a facility for the storage and retrieval of protocols, specimens, raw data, documentation records and final reports.
(7) “Study” means any experiment in which a test substance is studied prospectively in a test system under laboratory conditions to evaluate its safety.
(8) “Test system” means any animal, plant, microorganism, or subpart thereof, to which the test or control substance is administered for the purpose of detecting actions of test substance to living organisms. Test system also includes animal, plant, microorganism, or subpart thereof not treated with the test or control substance if it serves as a control in a study.
(9) “Lot” means a batch of test or control substance with uniformity manufactured with an identical method during a certain period of time.
(10) “Master schedule sheet” means a document indexed by a test substance containing the test system, nature of study, date study was initiated, current status of each study, name of the sponsor, name of the study director, and status of the final report on all studies conducted at the test facility.
(11) “Protocol” means a document established in each study which is to ensure that the study methods and operating procedures required to attain the intended purpose of the study will be authentically adopted.
(12) “Standard operating procedure” means any document in writing setting forth concretely the conducting methods of and procedures for the study that are adequate and appropriate to ensure the quality and integrity of the data.
(13) “Raw data” means any laboratory worksheets, notes, unretouched records, or exact transcripts thereof, etc. which record original observations and activities in a study and are necessary for the reconstruction and evaluation of the report of that study. Photographs, microfilm or microfiche copies, computer printouts, magnetic media, including dictated observations, and recorded data from automated instruments, etc. may be included.
(14) “Record document” means any written document which is required to prepare for record in accordance with the provision of these standards.
(15) “Final report” means a record which is prepared finally to compile the result of the study conducted in the testing facility.[/well]
Article 3. Notification to a contract laboratory by a sponsor
When a sponsor commissions a contract laboratory to conduct a study or a part thereof under the application of this standards, it shall notify the contract laboratory in advance that the study must be conducted in compliance with the provisions of these standards.
Chapter II – Personnel and Organization
Article 4. Personnel
1. Each individual engaged in the conduct of a study (hereinafter referred to as `personnel’) shall have education and training, or job experience, necessary for performing the job and shall be capable of performing the assigned functions.
2. Personnel shall satisfy the following items in conducting a study.
(2) Personnel found at any time to have an illness that may adversely affect the quality and integrity of the study shall be excluded from direct contact with the study unti the health condition is corrected.[/well]
- ARTICLE 5. TESTING FACILITY MANAGEMENT
1. Testing facility management shall be capable of management and operation of overall testing facility.
2. Testing facility management shall:
(2) Designate a study director before the study is initiated.
(3) Designate a quality assurance unit from among persons who are not engaged in the conduct of that study.
(4) Designate an individual responsible for the archives.
(5) Prepare a master schedule sheet of all studies conducted at the testing facility.
(6) Prepare a protocol.
(7) Prepare standard operating procedures.
(8) Assure that any deviations from these standards reported by the quality assurance unit and corrective actions are
taken and documented.
(9) Assure that test and control substances or mixtures thereof have been appropriately measured for identity, strength, purity, stability, and uniformity, as applicable.
(10) Give directions, considerations and supervision as necessary to assure that personnel, resources facilities, equipment, materials, etc. are available as scheduled for the proper and smooth conduct of the study.[/well]
- ARTICLE 6. STUDY DIRECTOR
The study director shall:
[well](1) Conduct the study in compliance with the protocol approved by the management.(2) Assure that all raw data (including observations of unanticipated responses of the test system) are accurately recorded and verified.
(3) Prepare documents in writing setting forth unforeseen circumstances that may affect the quality and integrity of the study and corrective actions taken.
(4) Take corrective actions against the deviations reported by the quality assurance unit and prepare documents in writing setting forth the deviations and actions taken thereof.
(5) Assure that deviations from standard operating procedures shall be approved and shall be documented in raw data.
(6) Prepare a final report.
(7) Transfer the protocols, specimens, all raw data, record document and final reports to the archives during or at the close of the study.[/well]
Article 7. Quality assurance unit
1. The quality assurance unit shall be responsible to the testing facility management for the duties in performing the job.
2. The quality assurance unit shall:
(2) Maintain copies of all protocols pertaining to studies for which the unit is responsible.
(3) Inspect each phase of a study periodically and maintain written and properly signed or sealed records of each periodic inspection showing the nature of inspection, findings, problems recorded, action taken to resolve the problems, and any scheduled date for reinspection, etc.
(4) Immediately report any significant problems which are likely to affect the quality and integrity of the study found during the course of an inspection to the management and the study director.
(5) Periodically submit to management and the study director written status reports on each study, noting any problems and the corrective actions taken.
(6) Assure that revisions of the standard operating procedures or of the protocol were approved by the management and documented and that deviations from the standard operating procedures were approved by the study director and documented.
(7) Review the final 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.
(8) Prepare documents in writing 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 and maintain the documents.[/well] 3. All records maintained by the quality assurance unit shall be kept in the testing facility or in the place designated by the testing facility. Such records shall be maintained as long as the registration of the length of time for which the registration relating to the studies agricultural chemical relevant to the studies conducted at the testing facility are valid.
Chapter III – Facilities
Article 8. General
Each testing facility shall be of suitable size, constructions and location to facilitate the proper conduct of studies. It shall be designed so that there is a degree of separation that will prevent any function from having an adverse effect on the study.
Article 9. Animal care facilities, etc.
1. A testing facility shall have animal care facilities of suitable size and construction, equipped for necessary environmental control such as temperature, humidity, ventilation and lighting, etc.
2. A testing facility shall have a sufficient number of animal rooms or area, as needed, to assure proper.
(2) Isolation of individual projects.
(3) Quarantine of animals.
(4) Routine or specialized housing of animals.[/well] 3. A testing facility shall have specialized animal rooms or area where studies are done, in isolation from other studies, with test or control substances that are volatile substances, aerosols, radioactive materials, and microorganism, etc.
4. As needed, a testing facility shall have facilities for isolation and treatment of diseased animals.
5. When animals are housed, facilities shall exist for the collection and sanitary disposal of all animals’ waste and refuse or for safe sanitary storage of waste before removal from the testing facility.
Article 10. Animal supply facilities
A testing facility shall have storage area, as needed, for feed, bedding, supplies, and equipment. Storage area for feed and bedding shall be separated from area housing the test systems and shall be protected against infestation and contamination.
Refrigeration shall be provided for storage of perishable supplies or feed.
Article 11. Facilities for handling test and control substances
1. As necessary to prevent contamination or mixups of a test or control substance, a testing facility shall have areas for
(2) Mixing of the test or control substance with a carrier.
(3) Storage of the test or control substance mixture with a carrier.[/well] 2. The area specified in the preceding paragraph shall be separated from areas housing the test systems and shall be designed to preserve the quality of the substance and mixture.
Article 12. Laboratory operation area
A testing facility shall have separate laboratory space for the performance of measurements and other operations such as biochemical tests, histopathology, surgery, and necropsy, etc. and shall have separate space for cleaning, sterilizing and maintaining equipment and supplies used during the course of the study.
Article 13. Archives
A testing facility shall have archives.
Article 14. Administrative facilities, etc.
1. A testing facility shall have space necessary for the administration, supervision, and direction of the study and the testing facility.
2. A testing facility shall have showers, lockers, washing facilities, toilets, etc., as needed.
Chapter IV – Equipment
Article 15. Design and function of equipment
A testing facility shall have equipment of appropriate design and adequate capacity to function for the accurate and precise conduct of a study.
Article 16. Location of equipment
Equipment used in a testing facility shall be suitably located for proper operation, inspection, cleaning and maintenance.
Article 17. Equipment control
To assure the accuracy and precision of measurement, equipment shall be controlled as described in the following items.
(2) There shall be standard operating procedures setting forth in sufficient detail the methods of appropriate operation, inspection, adjustment and maintenance, and specifying remedial actions to be taken in the event of failure or malfunction of equipment. The written standard operating procedures shall designate the person responsible for each equipment, and copies of the standard operating procedures shall be made available to laboratory personnel.
(3) Written records shall be prepared for inspection and maintenance, and repairs performed on equipment as a result of failure or malfunction with the date and nature of the operation and name of personnel engaged.[/well]
Chapter 5 – Operation
Article 18. Standard operating procedures
l. Testing facility management shall prepare standard operating procedures by the following items in principle, which shall be available at each laboratory area where operations mentioned in the items are made.
(2) Animal room preparation and animal care.
(3) Maintenance and repair of facilities and equipment.
(4) Identification, housing, proper placement, and transfer of test animals.
(5) Test system observation such as general signs.
(6) Methods of measurement, laboratory tests, and analysis on test animals.
(7) Handling of animals found moribund or dead during the study.
(8) Necropsy or postmortem examination of test animals.
(9) Collection and identification of specimens.
(10) Histopathology.
(11) Data handling, storage and retrieval.[/well] 2. Testing facility management may change the standard operating procedures as needed.
3. Testing facility management shall specify each date of preparation or change of the standard operating procedures and shall retain a historical file of standard operating procedures.
Article 19. Reagents and solutions
1. In order to prevent misuses, all reagents and solutions in the laboratory area shall be labeled to indicate identity as well as concentration, storage requirement and expiration date as needed.
2. Deterioration or outdated reagents and solutions shall not be used.
Article 20. Animal and quarantine care
1. All newly received animals from outside sources shall be housed in a facility which enables protection of other animals from infestation and contamination, and their health status shall be evaluated by observation and shall be recorded.
2. Animals found during the observation mentioned under the preceding paragraph to have diseases or conditions that might interfere with the purpose or conduct of a study shall be isolated from healthy animals and shall not be used in the study.
3. If, during the course of a study, animals are under found to contract diseases or conditions that might interfere with the purpose or conduct of the study, such animals shall be isolated from other animals.
4. If necessary, the isolated animals mentioned under the preceding paragraph may be authorized by the study director to be treated for diseases provided that such treatment does not interfere with the study. Rational for treatment, description of treatment. prescription of remedies, each date of treatment and the result, etc. shall be documented.
5. Animals shall be acclimatized to the laboratory environment during an appropriate period before the initiation of the study.
6. Animals shall receive appropriate identification, as needed, such as tattoo, ear punch, ear tag, color code, etc.
7. For animals used in a study, information for identification of each animal shall appear on the outside of cages, pens, or racks, as needed.
8. Animals of different species shall be housed in separate rooms in principle.
9. If animals of the same species, but used in different studies, are housed in the same room, adequate differentiation by space and identification shall be made.
10. Animals cages, pens, racks and accessory equipment shall be cleared and sanitized at appropriate intervals.
11. Bedding used in animal cages or pens shall not interfere with the purpose or conduct of the study and shall be changed as often as necessary to keep the animals dry and clean.
12. Feed and water used for the animals shall be analyzed and recorded periodically to ensure that contaminations known
to be capable of interfering with the study are not present at levels above those specified in the protocol.
13. Cleaning or pest control materials that interfere with the study shall not be used. if any cleaning or pest control material are unavoidably used, the use shall be documented.
Chapter VI – Test and Control Substance
Article 21. Test and control substance characterization
1. Before initiation of a study, a testing facility or a sponsor shall determine the identity, strength, purity and composition or other characteristics which will define the test and control substance for each lot and shall document the result thereof.
2. A testing facility or sponsor shall method of synthesis, fabrication or derivation of the test and control substances.
3. A testing facility or a sponsor shall determine, in principle, the stability of each test or control substance before initiation of a study. If the stability of the test or control substance cannot be determined before initiation of a study, standard operating procedures shall be established and followed to provide for periodic reanalysis of each lot to assure the quality of the test or control substance.
4. A testing facility shall label each storage container for a test or control substance by name, abbreviated name or code number and lot number, as well as expiration date, if any, and storage conditions when special conditions are required. When necessary, storage containers for exclusive use shall be assigned to a particular test substance.
5. For studies of more than 4 weeks duration, a testing facility shall in principle, retain reserved samples from each lot of test and control substance for at least five years after the first registration application of, or the submission of the supplemental data on the agricultural chemical relevant to the studies. However, samples of a test or control substance, whose quality changes markedly shall be retained as long as the quality of the substance permits evaluation.
Article 22. Test and control substance handling
A testing facility shall satisfy the following items.
(2) Proper identification is maintained throughout the distribution process.
(3) The receipt and distribution of each lot is documented. Such documentation shall include the date and quantity of each lot distributed or returned.[/well]
Article 23. Mixture and carriers
1. For each test or control substance that is mixed with a carrier, a testing facility shall satisfy the following items.
(2) The uniformity of the mixture is assured.
(3) The concentration of the test or control substance in the mixture is determined.[/well] 2. Where any of the components of the test or control substance carrier mixture has an expiration date, that data shall be clearly shown on the container. If more than one component has an expiration date, the earliest date shall be shown.
Chapter VII – Protocol for and Conduct of a Study
Article 24. Protocol
1. Testing facility management shall prepare a protocol by each study, indicating the items specified in the following paragraph. Where the study is a contract study, testing facility management shall duly consult with the sponsor.
(1) A descriptive title and statement of the purpose of the study.
(2) The name and address of the sponsor and the name and address of the testing facility at which the study is being conducted.
(3) The name, address, and appointment of the study director.
(4) The proposed starting date and duration of the study.
(5) Identification of the test and control substance by name, abbreviated name or code number.
(6) Justification for selection of the test system.
(7) The species, strain, source of supply, number, age, sex and body weight range of the test system.
(8) The procedure for identification of the test system.
(9) A description of the method of the experimental design for the control of bias.
(10) The environmental conditions for the test systems.
(11) A description and/or identification of the diet used in the study. (The description shall include specifications for acceptable levels of contaminants that are reasonably expected to be present and are known to be capable of interfering with the purpose or conduct of the study if present at greater than established by the specifications.)
(12) A description and (or) identification of solvents, emulsifiers and!or other materials used to solubilize or suspend the test or control substance before mixing the carrier.
(13) The route of administration and the reason for its choice.
(14) Each dosage level of the test and control substances to be administered and the method, frequency and duration of administration, as well as the reason for their choice.
(15) Method by which the degree of absorption of the test and control substances by the test system will be determined if necessary to achieve the objectives of the study.
(16) The type, frequency and method of observations, measurements tests, and analyses to be performed.
(17) Statistical methods to be employed for the analyses of the data.
(18) Storage of the records and data.
(19) Any other items necessary to conduct a study.
2. Where the protocol is revised during the course of the study, the revisions and the reasons therefore shall be documented and maintained with the protocol by the testing facility. The testing facility management shall approve such revisions in the document.
Article 25. Conduct of a study
I. The study shall be conducted in accordance with the protocol and the standard operating procedures under the instruction and supervision of the study director.
2. Each study shall have unique identification. The records and specimens, etc. pertaining to the study shall be accompanied by such identification.
3. The specimens shall be identified with an appropriate methods, by the nature of the study, identification number of the test system, and date of collection.
4. Records of gross necropsy findings for a specimen from postmortem observation shall be available to a pathologist when examining that specimen histopathologically.
5. All data generated during the conduct of a study shall be recorded and revised according to the requirements specified under the following items.
(2) The person who enters the raw data shall enter the data on the day of entry and sign or seal the raw data. However, in case of direct computer input, the day of entry and the name of individual responsible for the input shall be recorded.
(3) Any change in raw data entries shall be made so as not to obscure the original entry, shall indicates the reason for such change and shall be dated and signed or identified at the time of change. Any change in computer entries shall be made so as not to obscure the original entry, shall indicate the reason for change, and shall be dated and the responsible individual
shall be identified.[/well]
6. Any abnormal or unanticipated phenomenon which occurred during the course of a study shall be promptly reported to the study director and shall be documented in details.
Chapter VIII – Report and Records
Article 26. Final report
I. A study director shall prepare a final report on the itemed specified in the following paragraph to submit to the management.
(2) The name and address of the testing facility.
(3) The dates of initiation and completion of the study.
(4) The name, abbreviated name or code number and lot number of test and control substances, and strength, purity and composition or other characteristics which identify test and control substances.
(5) Stability of the test and control substances under the conditions of administration.
(6) The species, strain, number, age, sex, body weight range, source of supply, date of receipt, and housing conditions of the test system.
(7) The administration route, dosage levels, and method, frequency and duration of administration of the test or control substance.
(8) Reason for the dosage design of the test or control substance.
(9) All circumstances that may have affected the quality of the data.
(10) The type, frequency and methods of observations, measurements, tests and analyses performed.
(11) The name of the study director and the names and job assignments of other scientists engaged in the study.
(12) Statistical methods employed for analyzing the data.
(13) Results of the study, discussion of results and their summary. (Included are signature or sealing with date of all scientists engaged in the study.)
(14) The locations where raw data and specimens are to be stored.
(15) The date when the final report was prepared.[/well] 2. A quality assurance unit shall review the final report and shall assure that the report accurately describes the methods of the study and that the reported results accurately reflect the raw data of the study, and shall document and submit that effect to the management.
3. when there are corrections or additions to the final report, the study director shall have the person responsible who is involved in such corrections or additions clearly identity that part of the final report that is being added to or corrected, the date and reasons therefore and seal or sign.
Article 27. Storage and retrieval of records and specimens
1. A testing facility shall retain protocols, specimens, raw data, documentation records, final reports and correspondence in archives. When specimens or raw data are retained separately from the archives for final reports, that effect shall be documented.
2. Only the individual responsible for the archives or personnel with permission by this individual shall enter the archives.
3. A testing facility shall design conditions of storage so as to minimize damage and deterioration of documents or specimens during the retention.
4. Protocols, specimens, raw data, documentation records and final reports shall be retained orderly for expedient retrieval with, for instances, index by the test substance, test system, and nature of study.
Article 28. Retention period of records and specimens
1. Retention of specimens required to be retained under Paragraph 1 of the preceding article shall be for at least five years after the first registration application of, or the submission of the supplemental data on the agricultural chemical relevant to the studies.
2. Regardless of the requirements mentioned under the preceding paragraph 1, wet specimens which differ markedly in quality during the storage, such as histochemical, electron microscopic, hematological, or teratological preparation, shall be retained only as long as the quality of the preparation permits evaluation.
3. Protocols, raw data, documentation records, final reports and correspondent specified under Paragraph 1 of the preceding article shall be retained as long as the registration of the agricultural chemical relevant to the studies is valid.
4. If a testing facility terminates its operation and closes down the facility, all materials specified in this article shall be transferred to the successor of the operation or the sponsor.
August 10, 1984