Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Good Laboratory Practice Standards (GLPs) 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
Table of Contents
Introduction
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.
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Questions and Answers
Applicability
- 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.
- 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.
- 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.
- 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.
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Definitions
- 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.
- 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.
- 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.
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Study Director
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Quality Assurance Units (QAUs)
- 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.
- 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.
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Facilities
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Test Control And Reference Substance Characterization
- 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.
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Test Substance Storage Containers
- 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).
- 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.
- 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.
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Protocols
- 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.
- 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.
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Reporting
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Archives
- 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.
- 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.
- 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.
- 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.
- 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.
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GLP Violations
- 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.
- 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.
- 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.
- 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.
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