Applicability – Questions 1-7
Definitions – Questions 8-12
Study Director – Questions 13-14
Quality Assurance Units (QAUs) – Questions 15-16
Facilities – Question 17
Test, Control, and Reference Substance Characterization – Questions 18-20
Test Substance Storage Containers – Questions 21-25
Protocols – Questions 26-27
Reporting – Question 28
Archives – Questions 29-35
GLP Violations – Questions 36-40
Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Good Laboratory Practice Standards – Questions and Answers
Prepared by the Pesticides Enforcement Policy Branch
Policy and Grants Division
Office of Compliance Monitoring
Office of Prevention, Pesticides, and Toxic Substances
U.S. Environmental Protection Agency
May 12, 1992
On August 17, 1989, EPA published in the Federal Register revisions to the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Good Laboratory Practice standards (GLPS) (54 FR 34052). This revision included changes that the Food and Drug Administration made to its GLPS (September 4, 1987; 52 FR 33768) and expanded the scope of the regulations to include data submissions which had previously not been under GLPS. The expansion of GLPS to include field studies has brought many facilities under GLPS for the first time while also making the standards applicable to entirely different types of testing environments than had previously been the case.
Since the publication of the revised rule in 1989, EPA has received many questions from persons who wish clarification regarding the applicability of the rule to their activities. These questions have ranged from simply asking whether the work they are doing is required to comply to technical questions regarding how the standards should be applied in the context of field as opposed to laboratory studies. Many written replies have been made to persons who have submitted specific questions in writing to EPA. Copies of specific correspondence have been provided upon request.
Notwithstanding, the correspondence file is of limited usefulness to other persons since the issues addressed are often specific to a particular situation. There have been requests for a general guidance document regarding EPA’s FIFRA GLP policy. The following questions and answers have been prepared by the Policy and Grants Division of the Office of Compliance Monitoring to serve as official written policy for the regulated community.
Questions and Answers
[collapse title=”What is the applicability of GLPS to work in progress at the time that the rule became effective?”] The GLPS apply to all study-related work which is performed on or after the effective date of the rule. Studies in progress must be in compliance with GLPS from the effective date onward. A statement of compliance or non-compliance must accompany the final study report for such a study. This statement must either (1) state that the study was in compliance with GLPS, (2) describe in detail how it did not comply with GLPS, or (3) state that the submitter did not sponsor or conduct the study and does not know its compliance status. The statement must account for compliance or deviations with both the previous GLP rule (effective 1984), and the current rule (effective 1989), as applicable.
[/collapse] [collapse title=”If a study was in progress on October 16, 1989, must it have a protocol? What parts of the study should the protocol address?”] All portions of the study performed on or after the effective date must be performed according to a written protocol as provided at 40 CFR 160.120. That protocol need only address those parts of the study performed on or after the effective date. Please note that if a study was subject to the 1984 GLPS, a protocol was required for all parts of the study conducted after the effective date of that rule. The compliance statement submitted with that study’s report must specify in detail those study activities which were not performed in accordance with GLPS.
[/collapse] [collapse title=”Current reregistration procedures involve submission of data that resulted from studies performed prior to the effective date of GLPS. Do GLPS apply to such data, and if so, how?”] Any data presently submitted in support of a pesticide research or marketing permit must be accompanied by a true and correct compliance statement as described at 40 CFR 160.12 regardless of when the study was performed. Therefore, data submitted to meet reregistration requirements are required to be accompanied with a true and correct compliance statement informing EPA in detail of all differences between the practices used in the study and those require~ by GLPS. It is not unlawful to truthfully admit that studies supporting such submissions did not comply with GLPS, nor would such an admission necessarily lead to rejection of the data. The compliance statement will help the Agency to determine the reliability of the data based on current data requirements. Note that such an admission may nevertheless result in an enforcement action if they indicate that an unlawful act has occurred. For example, other regulations, i.e., books and records as stated at 40 CFR 169.2(k), require retention of raw data generated in support of registered pesticides prior to the effective date of GLPS. Admitting to destruction of records would not exclude the Agency from taking enforcement actions for the books and records violation.
[/collapse] [collapse title=” Do GLPS apply to data used to support tolerance petitions?”] Yes. The scope of the regulations as stated at 40 CFR 160.1 require that studies conducted to develop data pursuant to sections 408 and 409 of the Federal Food, Drug, and Cosmetic Act be performed in accordance with GLPS.
[/collapse] [collapse title=”Are studies conducted under the Interregional Research Project Number 4 (IR-4) program to support the registration of minor uses subject to the GLPS?”] Yes.
[/collapse] [collapse title=” Do GLPS apply to weather data and soil analysis data?”] Any data which are collected as part of a study listed in 40 CFR 160.1 must be collected according to GLPS. This includes weather data and soil analyses which are collected as part of a larger study which must comply with GLPS. If non-study data such as local weather data are cited in a study report, and the study report clearly indicates that such data were not gathered as part of the study, GLPS would not apply to such data.
[/collapse] [collapse title=” What applicability do GLPS have when State, Federal, or independent laboratories are used to provide soil or weather data for GLP studies?”] GLPS are applicable in such circumstances if such data are gathered as part of a FIFRA study. Only where such data are gathered independently of the study, and the study report clearly indicates that such data were not gathered as part of the study, would GLPS not apply.
[collapse title=”Will EPA issue separate GLP standards for field testing as opposed to laboratory testing?”] The expansion of GLPS to cover field studies was based on the need to assure identical standards for all data submitted to EPA under FIFRA, and on the determination that the GLPS are technically general enough to cover virtually any type of research environment. EPA does not intend to issue separate standards.
[/collapse] [collapse title=”Can an experiment be divided into more than one study, based on where or when the work is performed, or the phase of the experimental work?”] Under GLPS, the term study refers to an experiment to determine or predict the effects or characteristics of a test substance. EPA considers a study to be composed of all of the necessary elements of research which are performed in order to obtain the reported results. If the elements of research consist of several phases of work which must be taken in the context of each other to get meaningful results, they are all considered to be elements of the same study. An example of this would be where one laboratory treats a test system with a test substance and sends the treated test system to another laboratory for analysis.
If the experiment involves treatment of test systems in several different locations, the experiment may be considered to be composed of either one study encompassing all locations or several studies each involving one or more locations. In the latter case, however, it would be necessary that each separate study stand entirely by itself, i.e., meet all of the criteria of a study. There would have to be separate compliance statements for each, separate tracking on master schedules, separate quality assurance inspections, etc. Each study would have to have a study director (and only one study director), although it may be possible for the same study director to oversee several of such studies at the same time. Finally, where several studies are compiled for submission, the submission must include true and correct compliance statements for each study involved in the submission.
[/collapse] [collapse title=”What is EPA’s formal policy on certifying copies of raw data? Must each page be signed and dated?”] EPA stated in the preamble to the August 17, 1989 rule (54 FR 34066) that acceptable alternatives to signing and dating each page may be devised and incorporated into standard operating procedures. EPA did not further elaborate in order to allow each testing facility flexibility in implementing SOPs that would provide adequate assurances within its facilities. Note that EPA may inspect the original records, which must be maintained by the registrant as provided at 40 CFR 169.2(k), to assure that they have been kept and that the copies are correct.
[/collapse] [collapse title=”Is it permissible to discard original raw data worksheets after exact copies have been made?”] Destruction of original raw data is prohibited. The registrant is responsible for maintaining all original raw data as specified at 40 CFR 169.2(k). Copies of data may be used to assure compliance with GLPS at the level of the testing facility, but EPA requires that the registrant maintain all original data that support a study.
[/collapse] [collapse title=”What type of sponsor-testing facility communication is considered to be raw data which must be archived at the end of the study?”] All records of sponsor-testing facility communication which occur as part of the activities of a study are considered to be raw data, as defined at 40 CFR 160.3. This includes memoranda, letters, and records of telephone conversations which occur during the course of the study. Communication conducted prior to the study (i.e., before the protocol is signed) or following the completion of the study (i.e., after the report is signed) would not normally be considered to be raw data. Note that certain records not specific to a particular study which are generated when the study is not in progress still need to be retained to prove that study’s compliance with GLPS. Examples include records of a sponsor’s notifying a facility of the need to comply with GLPS as required at 40 CFR 160.10, and records of facility documents such as standard operating procedures.
[collapse title=”Many field studies involve more than one technical phase, each involving different personnel and different methodologies, often by different contractors. Concern has been raised aver the difficulty for a single individual to physically oversee all phases and to be expert in all techniques involved. Within the same study, is it acceptable to assign a different study director to different phases?”] No. Each study must have a single study director who represents the single source of study control. This is explicitly stated in the GLPS at 40 CFR 160.33. A single point of control is necessary to the integrity of the study and to avoid the potential for conflicting instructions and confusion in study implementation.
[/collapse] [collapse title=” If there can only be one study director assigned to a study, is it acceptable to assign field directors and analytical directors to manage the work which involves different phases and/or locations?”] The assignment of responsibility for the study to the study director need not interfere with ordinary delegation of authority necessary for the performance of study duties. Any authority accepted by persons other than the study director does not reduce the study director’s overall responsibility for the study.
Quality Assurance Units (QAUs)[collapsibles]
[collapse title=”Is it acceptable to inspect study-related procedures at a time other than when the study is ongoing?”] The GLPS state at 40 CFR 160.35(a) that a testing facility shall have a Quality Assurance Unit (QAU) that shall monitor each study to assure management that the facilities, equipment, personnel, methods, practices, records, and controls are in conformance with the GLPS. The GLPS further state at 40 CFR 160.35(b)(3) that the QAU shall inspect each study at intervals adequate to ensure the integrity of the study.
Clearly, the QAU must conduct inspections adequate to provide the assurances required at 40 CFR 160.35(a) and, in the course of so doing, must inspect each study at least once. All parameters must be verified adequate for each site, but it is acceptable to use inspections conducted during other studies to provide necessary assurances. It is also acceptable to use inspections conducted when no study is in progress to assure that methods, personnel, etc. at a particular site are in conformance with GLPS. However, acceptability of such inspections is contingent on assuring that the facilities, personnel, methods, etc., which are inspected are representative of those used in the study. Note that it is necessary to reinspect facilities periodically to account for changes in personnel, equipment etc. Finally, no matter how complete QAU inspectional coverage is regarding the sites involved in a study, it is still necessary to conduct at least one inspection of study activities while the study is in progress.
[/collapse] [collapse title=”What would constitute adequate inspection of the ongoing study? Would an audit of the protocol or of data records be adequate?”] At least one inspection must be conducted while the study is in progress. Under GLPS, the QAU monitoring of protocols, data records, or other documentation phases of a study are important just as is directly observing the experimental phase of the study. However, the GLPS state at 40 CFR 160.35(b)(3) that inspections must be done at intervals adequate to ensure the integrity of the study, and further, at 40 CFR 160.35(b)(4), that periodic status reports noting problems and corrective actions be submitted to management.
An audit of a study protocol would be of very limited utility since the subsequent reporting would be to management which, in all likelihood, has already reviewed the protocol. Data record audits would also be of very limited utility since they may occur after all experimental work is completed — in short, too late for any corrective actions to be taken. This problem also applies to protocol audits conducted after the experimental phase is completed. Thus, reliance solely on such types of audits would not meet the GLP requirements as stated at 40 CFR 160.35.
[collapse title=”Is it permissible to store mixed feeds containing the test substance in the same room with the test system during feeding studies?”] As discussed at 40 CFR 160.47(b) test substance mixture storage areas must be stored in separate areas from the areas where test systems are kept. However, working quantities of test substance mixtures need not be stored in separate rooms from test systems. Separate areas within the same room may be designated for test substance mixture storage and test systems as long as the separation is adequate to preserve the integrity of the study and the identity, strength, purity and stability of the mixture.
Test Control And Reference Substance Characterization[collapsibles]
[collapse title=”Do characterization requirements at 40 CFR 160.105 apply to analytical standards?”] Analytical standards are considered to be reference substances and are subject to all GLP standards that apply to reference substances, including characterization.
[/collapse] [collapse title=”Can data developed by the supplier of the standard be accepted? If not, can it be used on an interim basis until the standard is adequately characterized?”] Information developed by a supplier can be used to support characterization requirements, but the compliance statement for the overall study must state whether such data were developed under GLPS. Any data not developed under GLPS may be rejected by the Agency. Analyses must be performed to characterize the reference substance before it is used. In the case that a standard is used before it is analyzed, this is a violation of 40 CFR 160.105(a), which requires such determinations to be made before the standard is used in the study.
[/collapse] [collapse title=”What documentation would apply to standards?”] Full characterization information as stated at 40 CFR 160.105 is required of standards. This section requires that any information that is appropriate for defining the standard, including identity, strength, purity, or composition, shall be determined for each batch before it is used. In the case of an analytical standard, for example, it is necessary to obtain analysis data documenting the identity, strength, and purity, for each batch. A labeled assay value, in and of itself, is insufficient.
Test Substance Storage Containers[collapsibles]
[collapse title=”Is it necessary to retain test substance storage containers for the duration of a field study?”] Yes, as provided at 40 CFR 160.105(c), storage containers for test substances shall be assigned for the duration of a study. This requirement is necessary to assure that test substances are stored in proper containers, and that the containers that are used can be accounted for during the study. At any time during the study, it must be possible to examine the containers to assure that this standard is met. However, requests for waivers involving large numbers of containers or safety concerns may be made to the Director, Policy and Grants Division (see question #23).
[/collapse] [collapse title=”If a large number of containers are involved in a study and/or unusual safety problems are caused by the storage of such containers, is there any alternative to storage?”] Yes, but only if written permission is obtained from the Director, Policy and Grants Division (see question # 23). The written letter authorizing disposal of containers will impose certain requirements that will ensure that the intent of the GLP standards are met.
[/collapse] [collapse title=”How does one obtain such permission?”] A request for permission must be submitted in writing to the Director, Policy and Grants Division, Office of Compliance Monitoring (EN-342), U.S. Environmental Protection Agency, 401 M Street, SW, Washington, DC 20460. The request must identify the study for which permission is requested, the testing facility, the nature and quantity of containers involved, and the time and location(s) of the study. The request should also identify any special storage burdens or safety hazards which retention of the containers may pose.
[/collapse] [collapse title=”What types of conditions would be imposed by EPA in granting such permission?”] EPA will request that sufficient documentation be available to assure that any containers which have been used for test substance storage during the course of a study are thoroughly accounted for from the time of receipt to disposal. This documentation would generally include such items as bills of lading, inventory records, receipts, use logs, and any other supportive records. In addition, the letter will stipulate that the Director of the Laboratory Data Integrity Assurance Division of OCM be notified of the location of such records in order that they be available for inspection.
[/collapse] [collapse title=”Can generic permission be obtained to cover multiple studies and/or test substances?”] No. Each case will be evaluated individually. However, more than one study and/or test substance may be included in given request, as long as each study and test substance is specifically identified.
[collapse title=”Can a generic protocol be used for obtaining sponsor approval?”] The GLPS require that the protocol be approved by the sponsor, and the date of approval must be included with the protocol; however the GLPS also provide flexibility in how this approval is obtained. A generic protocol approach may be acceptable for obtaining sponsor approval of certain protocol elements. In such a case, the testing facility which is drafting the protocol for a study would only need to obtain approval of those elements which were not included in the generic protocol. Please note that since the GLPS require protocols to include certain information that would not be included in a generic protocol, such as the test substance or the proposed start and termination dates, it would still be necessary to obtain sponsor approval for such information in addition to the approval of the generic protocol.
[/collapse] [collapse title=”What records of seeds or transplants of crops or plants used in field studies must be maintained?”] Where crops or plants are the test system or a component of the test system, all GLP standards relating to test system records are applicable. These include protocol provisions given at 40 CFR 160.120(a)(6) and (7), as applicable. Included, for example, would be the source of the test system supply, species, method of identification, etc. Lot numbers of seeds, brand names, and other information uniquely identifying the test system would be relevant.
[collapse title=”The GLPS at 40 CFR 160.185(a)(12) require that signed and dated reports of each scientist or other professional in the study be included in the final report. Can these reports be combined into one report, with all of the scientists and professionals dating and signing that report?”] This requirement is intended to ensure that all information related to the study is included in the final report. Specifically, when individual scientists findings are part of the study effort, they are required to be included separately. Combined reports may in effect be consensus documents, and that would defeat the purpose of this requirement. Note that this requirement is not intended to require separate reports of all scientists participating in a study if such scientists are not, in fact, providing individual findings or opinions. For example, pathologist’s reports are considered to be separate findings which must be reported separately.
[collapse title=”The GLPS state that the study director must assure that raw data are transferred to archives during or at the close of the study. Is there a grace period allowed after the end of the study to allow this to be done?”] Under GLPS, the study director is required to assure that all raw data, documentation, the protocol, specimens, and final reports are transferred to the archives during or at the close of the study (40 CFR 160.33(f)). Thus, there is no grace period. The study director must comply with this requirement prior to signing the compliance statement. This ensures that data are fully accounted for at the completion of the study.
[/collapse] [collapse title=”How does EPA define close of study in regard to archiving?”] The term at the close of the study is strictly interpreted to mean that point of time at which the study director signs the final study report. The act of signing the final report is one of assurance by the study director that the report is a true representation of the data that support the report. At or prior to the time that the study report is signed, the study director must pass control of the raw data to the archives where their integrity will be maintained. Any delay in the transfer of data beyond the close of the study creates a lapse between the time that the study director assures that the raw data support the study report and the time that the data are secured from damage, misuse, or loss.
[/collapse] [collapse title=”Given that data must be transferred to archives at the close of the study, is it possible to use temporary archives prior to transfer to a central archive?”] There is flexibility in the location of the archives of raw data and specimens. At 40 CFR 160.190(b), the GLPS state that retention of records at alternate locations is acceptable, provided that there is specific reference to those locations in the archives. Such off-location archives must still meet the full requirements of 40 CFR 160.190. Whether records are archived at the registrant’s facility, at a contractor’s central location, or at separate contractors’ locations, the study director must assure that all raw data and specimens have been archived before the study report is signed. If the study director cannot assure that records at a particular location are archived correctly, he should not sign a compliance statement that indicates that this standard has been met. Note that, for the purpose of complying with GLPS, true copies may be archived at the close of the study. The original records will have to be maintained as well but need not be archived at the end of the study if this is impractical, for example where the original data constitutes a facility record shared by other studies still in progress at the close of the study.
[/collapse] [collapse title=”Is it necessary to retain frozen tissue samples in archives, or may these be discarded after quality assurance verification?”] Under FIFRA GLPS, 40 CFR 160.195, frozen tissue samples are required to be retained in archives, and there are no specific allowances for their being discarded as there are for specimens obtained from mutagenicity tests, specimens of soil, water, and plants, and wet specimens of blood, urine, feces, and biological fluids. The GLPS do not require specially prepared material to be retained beyond the period that it affords evaluation if such material is relatively fragile and differs markedly in stability or quality during storage. EPA does not believe that this is the case for many types of frozen tissues. The reason that tissues are frozen is to retain their utility for evaluation. Please note that, as provided at 40 CFR 160.195(h), non-documentary material such as samples and specimens may be discarded after EPA has notified the sponsor or testing facility in writing that retention is no longer required.
[/collapse] [collapse title=”Must field notebooks be archived during or at the close of a study?”] If a notebook contains raw data, the notebook or the raw data must be archived at the close of the study. Note that the registrant is responsible for the original records under 40 CFR 169.2(k) and section 8 of FIFRA, so it is inadvisable to enter raw data for studies related to different registrations in the same bound notebook.
[/collapse] [collapse title=”Must analytical preparations (e.g., scintillation vials and solutions) be archived?”] Such preparations need not be retained beyond the period that they afford evaluation, as stated at 40 CFR 160.195(c). Generally, samples prepared for analysis have limited utility beyond the time of analysis and can be discarded.
[/collapse] [collapse title=”How long must soil, water and plant specimens be retained?”] These need only be retained until the QAU has verified that their disposal will not jeopardize the integrity of the study, as provided at 40 CFR 160.190(a) and 160.195(c). Please note that there may be study-specific sample retention requirements in addition to and independent of GLP requirements. Failure to retain such samples may result in rejection of data by EPA or enforcement actions independently of whether a GLP violation has occurred.
[collapse title=”Can EPA assess penalties for GLP violations?”] Yes. FIFRA section 14 states the EPA’s authority to assess penalties for violations of the Act.
[/collapse] [collapse title=”What are the possible violations under the statute?”] Violations of GLPS may constitute unlawful acts under FIFRA. Under section 12(a)(2)(M) it is unlawful to knowingly falsify all or part of any application for registration, application for experimental use permit, any information submitted to the Administrator pursuant to section 7, any records required to be maintained pursuant to this Act, any report filed under this Act, or any information marked as confidential and submitted to the Administrator under any provision of this Act to be submitted to EPA or of records required to be maintained. Under section 12(a)(2)(Q) of FIFRA it is unlawful to falsify all or part of any information relating to the testing of any pesticide (or any ingredient, metabolite, or degradation product thereof), including the nature of any protocol, procedure, substance, organism, or equipment used, observation made, or conclusion or opinion formed, submitted to the Administrator, or that the person knows will be furnished to the Administrator, or will become a part of any records required to be maintained by this Act. Under section 12(a)(2)(R) of FIFRA it is unlawful to submit to the Administrator data known to be false in support of a registration. Finally, it is unlawful under FIFRA section 12(a)(2)(B)(i) of FIFRA to refuse to prepare, maintain or submit any records required by or under sections 5, 7, 8, 11, or 19.
[/collapse] [collapse title=”What are the maximum penalties that can be imposed?”] Section 14(a) of FIFRA provides for maximum civil penalties of not more than $5000 per offense for violations of the Act by registrants, commercial applicators, wholesalers, dealers, retailers, or other distributors, and of not more than $1000 per offense for other persons. For knowing violations of the Act, FIFRA section 14(b) provides for maximum criminal penalties of not more than $50,000 and/or 1 year imprisonment for producers, registrants, or applicants for registration and of not more than $25,000 and/or 1 year imprisonment for other knowing violators.
[/collapse] [collapse title=”Will civil or criminal penalties be imposed for all GLP violations?”] No. Section 9(c)(3) of FIFRA allows a written notice of warning to be issued for a minor violation, if such warning is determined to be adequate to serve the public interest. Section 14(a)(4) of the Act further provides that in determining the size of a penalty EPA may issue a warning in the case that a violation occurred despite exercise of due caution or did not cause significant harm to health or the environment. Finally, section 14(a)(2) of FIFRA provides that persons other than registrants, commercial applicators, wholesalers, dealers, retailers or other distributors who violate any provision of the Act may be assessed a civil penalty only subsequent to receiving a written warning for a prior violation. Thus, persons who only perform testing and are not engaged in the distribution and sale of pesticides will not be assessed civil penalties for their first offense. This does not extend to criminal penalties as described at section 14(b)(2) of FIFRA.
[/collapse] [collapse title=”Can EPA reject studies not conducted in accordance with GLPS?”] Yes. The regulations specifically provide for this at 40 CFR 160.17(a), which states that EPA may refuse to consider reliable … any data from a study which [is] not conducted in accordance with [GLPS]. GLP violations associated with a study submitted to EPA may also result in enforcement actions whether or not a study is rejected.