Department of Health and Human Services Food and Drug Administration
AGENCY: Food and Drug Administration.
21 CFR Part 58
Good Laboratory Practice Regulations
[Docket No. 83N-0142]
49 FR 43530
October 29, 1984
ACTION: Proposed rule.
SUMMARY: The Food and Drug Administration (FDA) is proposing to revise the
regulations that specify good laboratory practice for nonclinical laboratory studies. The
revisions are based on an agency determination that several provisions of the regulations
should be clarified, amended, or deleted to reduce regulatory burdens on testing
facilities. Major changes are proposed in the provisions on quality assurance, protocol
preparation, test and control article characterization, and retention of specimens and
samples. The changes proposed will not compromise the regulations' objective, which is to
ensure the quality and integrity of the safety data submitted in support of the approval
of regulated products. The action is intended to reduce the burden of compliance with the
regulations.
DATE: Comments by December 28, 1984.
ADDRESS: Written comments may be sent to the Dockets Management Branch (HFA-305),
Food and Drug Administration, Rm. 4-62, 5600 Fishers Lane, Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT: Paul D. Lepore, Bioresearch Monitoring Staff (HFC-30),
Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-443-2390.
TEXT: SUPPLEMENTARY INFORMATION: FDA discussed the need for regulations on good
laboratory practice for nonclinical laboratory studies (GLP's) in the preamble to the
proposed regulations (41 FR 51206; November 19, 1976). Agency inspections of toxicology
laboratories had revealed problems in the conduct of some nonclinical laboratory studies
so severe that in many instances the studies could not be relied on for regulatory
decisionmaking.
The importance of proper safety testing to the product approval
process prompted the agency to begin its Toxicology Laboratory Monitoring Program. To
ensure the quality and integrity of the safety data submitted to it in support of the
approval of any application for a research or marketing permit, FDA issued regulations
specifying standards for adequate safety testing, prepared an inventory of domestic and
foreign toxicology laboratories engaged in safety testing, conducted training sessions for
agency investigators to develop proficiency in evaluating testing facilities, and
instituted a compliance program that provided for periodic inspections of the testing
facilities.
These steps have been completed. In the Federal Register of December
22, 1978 (43 FR 60013), FDA issued final GLP regulations. The regulations, which were
codified as 21 CFR Part 58, became effective on June 20, 1979. In the Federal Register of
April 11, 1980 (45 FR 24865), FDA amended § 58.113(b) to delete the requirement that
reserve samples of test and control article-carrier mixtures be retained.
FDA maintains an inventory of testing facilities that have been
inspected for compliance with the GLP regulations. A recent listing contains entries for
475 laboratories, including 425 domestic and 49 foreign testing facilities. Affiliations
for the listed domestic facilities are as follows: 165 sponsor laboratories, 174
contractor laboratories, 72 university laboratories, and 14 government laboratories. The
inventory listing is updated quarterly to accommodate laboratories that have either ceased
or begun work on products regulated by the agency.
FDA has conducted 17 training courses at its National Center for
Toxicological Research in Jefferson, AR, to provide training in good laboratory practice
and the associated laboratory inspection techniques as well as "hands-on"
exercises in toxicology experimentation.
Finally, in 1976 the agency began an inspection program to assess
laboratory compliance with the GLP regulations. Program features include biennial
surveillance inspections to assess compliance with the procedural provisions of the GLP
regulations and data audit inspections to assess the accuracy of the information contained
in final study reports as required by § 58.185. By the end of the 1982 fiscal year, the
agency had evaluated the reports of 710 laboratory inspections made under the Toxicology
Laboratory Monitoring Program.
Background of This Proposal
Several circumstances have caused FDA to reevaluate the GLP
regulations and to propose changes that allow laboratories greater felixibility in
conducting nonclinical laboratory studies without compromising public protection. These
circumstances include the satisfactory levels of laboratory compliance observed during
agency inspections; the information received from regulated laboratories identifying
particularly burdensome provisions of the GLP's and the principles of regulatory reform.
FDA's laboratory inspection experience has revealed that affected
laboratories are in compliance with the GLP regulations and that the regulations can be
streamlined without undermining the program. At the time of the November 19, 1976
proposal, the agency did not have complete information on the severity and pervasiveness
of testing deficiencies. The available evidence showed, in a fraction of the testing
industry, serious problems that required prompt and definitive correction. The agency now
believes that the problems noted in the inspections made prior to 1976 were the exception
rather than the rule. Seventy-two percent of the inspection reports evaluated by the
agency since 1976 showed few or no substantial deviations from the GLP regulations. Four
percent of the inspection reports evaluated since that time showed major deviations from
the GLP regulations that required corrective action to be taken by a laboratory within a
specified time frame, and 23 percent of the reports contained evidence of
minor-to-significant deviations from the regulations that could be voluntarily corrected
by the laboratory. These facts show that the Toxicology Laboratory Monitoring Program has
met its objectives and that the regulated laboratories have made excellent progress in
achieving full compliance with the GLP regulations. Because of the good record of industry
compliance, FDA believes that the regulations can be simplified with no compromise to
study quality.
The agency has received many questions and comments on the GLP
regulations, and these communications are filed under Docket No. 76-0400 in the Dockets
Management Branch (address above). Several comments stated that some provisions of the GLP
regulations do not appear to make a significant contribution to the quality and integrity
of the safety data derived from nonclinical laboratory studies. The agency has considered
these comments in preparing this proposal.
In the Federal Register of the July 14, 1981 (46 FR 36333), the
agency issued its plan for reviewing its rules to minimize regulatory burdens while
maintaining an acceptable level of consumer protection. FDA received six comments
suggesting that the GLP regulations be targeted for early review.
In view of the above, FDA established a GLP Review Task Team
composed of members drawn from all agency units involved in the Toxicology Laboratory
Monitoring Program. The task team was asked to conduct a thorough review of the GLP
regulations to identify provisions that could be amended or deleted to reduce regulatory
burdens on the testing facilities without compromising study quality. Following its
review, the task team prepared an issue paper that recommended that FDA amend 36
provisions of the regulations and that the agency prepare an appropriate Federal Register
proposal. The issue paper has been placed on file in the Dockets Management Branch
(address above) and is available for review between 9 a.m. and 4 p.m., Monday through
Friday.
Public Comment
FDA invites comments on all aspects of this proposal. In addition,
the agency invites interested persons to submit comments, data, and information on the
need to revise any other provisions of 21 CFR Part 58. Comments supported by data, cost
estimates, or other factual information about the impact of the regulations on various
industries, product groups, and laboratories of different sizes would be especially
useful. Any comments previously submitted need not be resubmitted because they are
included in the docket file for this proposal. All comments received will be considered in
preparing any final rule based on this proposal.
The Proposed Changes
Following is a discussion of the proposed changes in the GLP
regulations.
1. Section 58.1 Scope. FDA proposes to make editorial changes in §
58.1 to clarify references in the GLP regulations to other parts of Title 21 of the Code
of Federal Regulations. Elsewhere in Part 58, FDA also proposes to make appropriate
changes to reflect new § 58.1(b).
2. Section 58.3 Definitions:
a. In § 58.3(c), FDA proposes to amend the definition of
"control article" to exclude feed and water administered to the control groups
of a test system. Section 58.3(c) currently defines control article as "* * * any
other article other than a test article that is administered to the test system * * * for
the purpose of establishing a basis for comparison with the test article." Because
the control group of a test system provides the basis for comparison under the current
definition, any article administered to the control group is a control article. For
example, the following articles are control articles under the existing regulations:
(1) The feed and water given to the control groups of animals in
oral studies in which the test article is administered via the feed, via the drinking
water, or by gavage or injection.
(2) The water used to prepare the test article mixtures in a gavage
or injection study in animals when the water is administered to the control groups or used
as an inoculum for the control plates/tubes (as is typical in mutagenicity studies).
Because the current definition of control article includes the
substances in the situations described above, a variety of GLP provisions become
operative. The feed and water must be characterized (§ 58.105(a)), tested for stability
(§ 58.105(b)), stored appropriately (§ 58.105(c)), and sampled to provide reserve
samples (§ 58.105(d)). In addition, strict accountability records must be maintained (§
58.107). Some of these steps are not essential to study quality, while other are dealt
with elsewhere in the GLP regulations. Therefore, the term control article should be
reserved for those discrete substances/articles and vehicles administered to groups of the
test system for providing a basis of comparision (commonly referred to as positive
controls).
FDA believes that the proposed change will reduce recordkeeping for
a large number of nonclinical laboratory studies. Reserve samples of feed and water
administered to the control groups of the test system would not have to be retained;
characterization and stability assessment would not have to be done; and strict
accountability records of receipt, use, and disposition would not need to be generated and
maintained for such articles.
b. In § 58.3(d), FDA proposes to modify the definition of
"nonclinical laboratory study" to allow the conduct of several experiments using
the same test article under a single, comprehensive protocol. For example, a battery of
several studies of one test article conduct in several animal species to determine the
safety of the test article could be conducted under one protocol. Similarly, where several
test articles are to be studied concurrently using a single common procedure, e.g.,
mutagenicity testing, a single protocol could be developed and followed.
FDA believes that this approach will reduce the amount of required
paperwork with no loss in the quality or accuracy of test article data developed by a
testing facility.
c. In § 58.3(e), FDA proposes to delete from the definitions of
"Application for research or marketing permit" those categories of data and
information submitted as part of the procedures for classifying a prescription drug
(current § 58.3(e)(8)) and a drug for animal use (current § 58.3(e)(12)) as generally
recognized as safe and effective and not misbranded. The agency does not currently have or
intend to have such procedures.
d. In new § 58.3(e)(8), FDA proposes to add a new category
pertaining to data and information submitted as part of the procedures under 21 CFR Parts
109 and 509 for establishing a tolerance for unavoidable contaminants in human or animal
food and food-packaging materials. The final regulations establishing Parts 109 and 509
were issued after FDA issued its GLP proposal. Therefore, the final GLP regulations did
not include these procedures within the definitions of "Application for research or
marketing permit." The agency proposes to correct the definition at this time.
e. In § 58.3(e) (17) and (18), FDA proposes to amend the
definitions of "Application for research and marketing permit" for medical
devices to refer to the appropriate medical device regulations that have been issued since
the final GLP regulations were published.
3. Section 58.31 Testing facility management. FDA proposes to delete
from § 58.31(b) the requirement that the replacement of a study director be documented as
"raw data."
Section 58.31(b) requires that the replacement of a study director
be documented and that the documentation be retained as a raw data record. The
documentation required here is not necessary because a change of study director is
recorded elswhere in the laboratory's records (personnel files, Master Schedule Sheet).
4. Section 58.33 Study director. In § 58.33(b), FDA proposes to
delete the phrase "and verified." Testing facilities have misconstrued the
provision in § 58.33(b) that "All experimental data * * * are accurately recorded
and verified" to mean that the study director is required personally to witness each
data observation -- an activity that is neither feasible nor required to ensure data
accuracy.
The study director needs to assure that data collection procedures
include the accurate recording of unforeseen circumstances. This responsibility is
reflected in the revised provision.
5. Section 58.35 Quality assurance unit:
a. In § 58.35(a), FDA proposes to substitute "which" for
the current phrase "composed of one or more individuals who" to make clear the
personnel who can perform quality assurance duties.
As written, the phrase has been misunderstood to mean that the
Quality Assurance Unit (QAU) is to be composed of individuals whose only duties are
quality assurance functions (in other words, the QAU is seen as a fixed, permanently
staffed unit). In fact, the agency intended that § 58.35(a) only require that quality
assurance activities be separated from study direction and conduct activities, i.e., a
person who works on one study can perform quality assurance monitoring on any study in
which he or she is not otherwise involved.
b. FDA proposes to delete the existing requirement in § 58.35(b)(1)
that the status of the final report be a distinct entry on the Master Schedule Sheet. The
agency believes this requirement is redundant because the other information required by §
58.35(b)(1), e.g., date study began and current status, provides the necessary information
on final report status.
c. In § 58.35(b)(3), FDA proposes to modify the requirement that
the QAU inspect each phase of a study at periodic intervals according to rigid schedules.
A review of the data collected during agency inspections of
nonclinical testing facilities shows that this provision, as now worded, has been
difficult to interpret and implement and that the requirements have been more rigid than
is necessary. Indeed, on April 2, 1981, the Pharmaceutical Manufacturers Association (PMA)
petitioned the agency to clarify the QAU inspection requirement described in §
58.35(b)(3). The petition sought relief from the requirement of frequent QAU inspection of
routine repetitive study phases. The agency reviewed the facts of the PMA petition and
concluded that testing facilities may have been overly strict in interpreting §
58.35(b)(3). Accordingly, the agency issued an advisory opinion letter (dated November 30,
1981, Docket No. 81P-0127) that declined to amend the GLP's because the relief sought was
already available under the existing GLP provisions. In reviewing the PMA petition, the
agency concluded that an inspection of each study phase was neither required nor necessary
to ensure study quality. The agency therefore advised PMA that the inspection schedule
should take into account the need for inspection of each study on a schedule adequate to
assure the validity of the study being monitored. The changes proposed now are intended to
clarify the pertinent provisions of § 58.35(b)(3) consistent with the advice given in the
November 30, 1981 letter. The proposed changes will give the QAU reasonable leeway to
identify critical study phases and to set reasonable inspection schedules so that studies
can be monitored appropriately. In addition, the proposed changes will allow the QAU a
measure of judgment in conducting its duties and will allow adjustment of monitoring
activities to meet anticipated problems.
d. Current § 58.35(b) (4) and (7) contains information collection
requirements that are subject to the Paperwork Reduction Act of 1980. FDA proposes to
delete § 58.35(b)(4) which currently requires that the QAU submit periodic status reports
to management and to the study director (remaining § 58.35(b) (5), (6), and (7) would be
renumbered as (b) (4), (5), and (6) respectively). FDA also proposes to amend renumbered
§ 58.35(b)(6) to require that the QAU include, with the final report, a statement that
identifies the phases of the study that were inspected and the frequency of inspection.
The agency believes that the periodic submission of routine QAU
inspection reports to management and to the study director is not essential to assuring
study quality, and that it will be sufficient to document such inspections. Proposed §
58.35(b)(6) provides that any final study report identify the phases inspected and cite
the number of inspections conducted. Of primary importance is the requirement of §
58.35(b)(3) that any problems that are likely to affect study integrity be indentified and
reported immediately so that prompt corrective action can be taken by the testing
facility.
e. FDA proposes to delete § 58.35(e) which currently requires that
all QAU records be kept in one location at testing facilities.
Section 58.190(b) requires that records be kept in such a way that
they can be retrieved expediently. The agency believes that a single location for QAU
records is not necessary so long as the records can be retrieved in accord with §
58.190(b) and so long as those records required to be made available to FDA investigators
are easily accessible.
6. Section 58.41 General. FDA proposes to delete
"location" as a consideration for a testing facility as specified in § 58.41.
The agency believes that "location" is not relevant to
proper study conduct. Poorly located facilities may function adequately if the size,
design, and construction are suitable to overcome the poor location.
7. Section 58.43 Animal care facilities:
a. In § 58.43(c), FDA proposes to modify the requirement that
separate areas for the diagnosis, treatment, and control of laboratory animal diseases be
provided.
The existing provision has been interpreted to require devoted
laboratory areas for diagnosis, treatment, and control in every case, but a laboratory may
elect to destroy diseased animals thereby obviating the need for the specified devoted
areas. The agency believes that it is not cost-effective to require devoted space that
will not be used and proposes to revise § 58.43(c) to require that such separate areas be
provided "as appropriate."
b. In § 58.43, FDA proposes to delete paragraph (e) which currently
requires that animal facilities be designed, constructed, and located so as to minimize
disturbances that interfere with a study.
The agency believes that § 58.41, which requires that facilities be
adequate for proper study conduct, is sufficient to cover this point.
8. Section 58.45 Animal supply facilities. FDA proposes to revise
the specific refrigeration requirement for perishable supplies or feed to read,
"Perishable supplies shall be preserved by appropriate means."
The existing provision requires refrigeration as the uniform method
of choice for preserving perishable supplies and feed. In fact, a variety of storage
procedures, e.g., dessication, room temperature-low humidity, constant
temperature-constant humidity, can and need to be used depending on the stability
characteristics of the perishable materials. The change is intended to permit the
selection of the most appropriate storage method.
9. Section 58.47 Facilities for handling test and control articles.
FDA proposes to make editorial changes in this section. The changes clarify the
requirement that separate areas be provided for receipt, mixing, and storage of test and
control articles and their mixtures as necessary to prevent contamination or mixups.
10. Section 58.49 Laboratory operation areas. FDA proposes to revise
this section to delete paragraph (b). Paragraphs (a) and (b) each currently describe
particular activities to illustrate the need for separate space. The activities are not
all inclusive and the examples are not necessary for clarity. The revised section simply
requires that separate space should exist, as needed, for the performance of both routine
and specialized procedures.
11. Section 58.53 Administrative and personnel facilities. FDA
proposes to delete § 58.53. The agency believes that the requirements for administrative
and personnel facilities are not a necessary part of these regulations.
12. Section 58.61 Equipment design. FDA proposes to delete the
qualifying terms "automatic, mechanical, or electronic" from § 58.61. The
proposed changes are editorial.
13. Section 58.63 Maintenance and calibration of equipment. FDA
proposes to amend § 58.63(b) to allow that written standard operating procedures (SOP)
for equipment need specify remedial action in the event of equipment failure or
malfunction only when remedial action is appropriate to the specific piece of equipment.
The change would allow SOP's for equipment to provide that laboratories may elect to
discard rather than repair faulty equipment.
14. Section 58.81 Standard operating procedures. FDA proposes to
delete the examples of SOP's listed in § 58.81(c). This is also an editorial change.
15. Section 58.90 Animal care:
a. In § 58.90(b), FDA proposes to modify the requirement that newly
received animals be quarantined to require, instead, that newly received animals be
isolated and that the health status of all newly received animals be evaluated in
accordance with acceptable veterinary medical practice.
The term "quarantine" refers to a rigid set of procedures
applied to animals prior to their use in any study. Such procedures include a mandatory
holding period, a specified list of diagnostic procedures, and the use of specialized
facilities and animal care practices. The agency believes that isolation and a health
status evaluation conducted to prevent the entry of unhealthy animals into a study rather
than rigid quarantine procedures will be sufficient to satisfy the intent of the
regulations. The evaluation would be required to be in accord with acceptable veterinary
practice and should be attuned to the specific study.
The proposed change would permit laboratories to develop specific
isolation and health status evaluation procedures in concert with the age, species, and
class of animals and with the type of study to be done.
b. In § 58.90(c), FDA proposes to require isolation of diseased
animals only when necessary rather than in every case as now required in § 58.90(c).
Because the existing provision requires that animals contracting any
disease that might interfere with the purpose of the study during a study be isolated, it
also requires that the laboratory shall have a devoted area equipped to provide adequate
isolation of diseased animals. The proposed change will permit several options for
handling the diseased animals -- they can be left in the experiment (if such action would
not adversely affect the integrity of the study); they can be destroyed (in which case no
isolation facilities would be required); or they may be isolated, treated, and returned to
the study. These options will permit increased flexibility of laboratory operation.
16. Section 57.105 Test and control article characterization:
a. In § 58.105(a), FDA proposes to delete the phrase "before
the initiation of the study." The change would permit test and control article
characterization after completion of the study.
The course of new product development is a sequential process based
on a logical series of experimental findings. For example, a potential new product is
synthesized (or derived from fermentation or isolated from natural sources) and subjected
to a battery of tests for pharmacologic/functional activity. If the product shows
promising activity, it is then subjected to the sequence of tests necessary to establish
the toxicologic profile, e.g., 30-day, subacute, chronic toxicology studies. If unusual
toxicity is observed in any of the tests in the toxicologic profile, further product
testing ends. Indeed, many products fail to reach the marketplace because unusual toxicity
is observed in the early toxicology studies. Section 58.105(a) currently requires that,
prior to initiating the first safety test in the toxicology profile, product sponsors
shall fully characterize the test article. Such characterization is expensive, and it is
currently being conducted on many products that are destined to fall by the wayside. The
agency has been informed that the cost of test article characterization greatly exceeds
the cost of conducting the initial safety studies that are done. Similar facts apply to
control articles used in nonclinical laboratory studies. Characterization of such articles
is expensive and need not be done unless the test article to which the control article is
compared shows reasonable promise of reaching the marketplace.
The proposed change will permit the conduct of the characterization
studies after the results of the initial toxicology studies are available. If these
studies show unusual toxicity, and the product is dropped from further consideration, no
characterization need be done. If the studies show promise, the product would need to be
characterized in accord with the regulation. The proposed change is intended to reduce the
regulatory burden by eliminating the need to characterize products not destined for
marketing. The proposed change does not relieve the sponsor of submitting to the agency,
in an application for a research or marketing permit, the complete characterizations as
described in § 58.105(a).
b. In § 58.105(b), FDA corrects the typographical error in the
first sentence by changing the word "or" to read "of."
17. Section 58.113 Mixtures of articles with carriers. FDA proposes
to change § 58.113(a)(2) to clarify that stability data need be collected only as
necessary to accommodate the conditions of use of a test article mixture. For example,
test article mixtures that are prepared and dispensed on the same day require stability
data to support only 1 day of use. Similarly, test article-feed mixtures that are to be
used within 2 weeks require only 2 weeks of stability data. The agency has been informed
that § 58.113(a)(2) has been interpreted to require the conduct of a formal stability
trial sufficient to show long-term stability of the mixtures; such trials frequently take
longer than the nonclinical laboratory study in which the mixture will be used. The
revision makes it clear that although full long-term stability studies are not required,
the term of the stability study may not be shorter than the actual term of use.
18. Section 58.120 Protocol:
a. Current § 58.120(a) contains information collection requirements
that are subject to the Paperwork Reduction Act of 1980. In § 58.120(a), FDA proposes to
replace the qualifying phrase "but shall not necessarily be limited to" with the
words "as applicable." Section 58.120(a) now requires that each protocol contain
entries for each of 16 listed items. FDA proposes to revise § 581.20(a) because some of
the items are not necessary for all studies. For example, § 58.120(a)(9) requires a
description of the diet used in a study as well as solvents, emulsifiers, and/or other
materials used to dissolve or suspend the test articles before mixing with the carrier.
Clearly, this section does not apply to radiation-emitting products. Likewise, dosage
level (§ 58.120(a)(11)) is not necessary for all test articles, e.g., implantable medical
devices.
The revision will permit the laboratory to identify in the protocol
information that is applicable to the articles being tested, thereby eliminating unneeded
protocol entries.
b. FDA proposes to delete § 58.120(a)(4), which currently requires
that the protocol contain the proposed starting and completion dates for the study.
Section 58.120(b) requires the study director to issue a formal
protocol amendment whenever there is a change in the proposed time frame for the study.
Because the actual scheduling of a study is a management prerogative, there is no need to
have this information in the protocol. The elimination of the provision will simplify the
protocol and eliminate the need for formal protocol amendments whenever study time frames
change.
c. FDA also proposes to delete § 58.120(a)(5) which requires that
the selection of the test system be justified in the protocol.
The existing provision confuses the purpose of the protocol. FDA
believes that the protocol constitutes a plan of work rather than justification for use of
a specific test system. Although use of a proper test system is essential to achieving the
study's objectives, it is a scientific consideration that need not be stated in the
protocol.
d. FDA also proposes to delete § 58.120(a)(10) which requires that
route of administration and reason for its choice be listed in the protocol.
Section 58.120(a)(11), renumbered as proposed § 58.120(A)(8),
requires that the method and frequency of administering the test or control article be
identified in the protocol. Because this provision encompasses route of administration,
the agency believes that § 58.120(a)(10) is redundant. Further, the agency believes that
the reason for choosing a particular route of administration of the test or control
article is a scientific study consideration that need not be stated in the protocol. It
is, of course, a matter that needs to be discussed in the final report. For these reasons,
FDA believes that § 58.120(a)(10) is unnecessary and should be removed from the GLP
regulations.
e. Finally, FDA proposes to delete § 58.120(a)(12) which requires
that the method by which test and control article absorption is determined be included
because the information is not necessary in the protocol.
9. Section 58.130 Conduct of a nonclinical laboratory study:
a. FDA proposes to revise § 58.130(d) to provide that the records
of gross findings observed at necropsy should be made available to the pathologist.
The agency believes that the need to provide necropsy findings to
the pathologist is a scientific study consideration that should be assessed by management
and the study director. Certain studies may require such findings to be kept from the
pathologist; other studies may require informing the pathologist to achieve the study
objectives. In either event, a determination should be based on the facts of a study. The
proposed change provides that the pathologist may be informed of the necropsy findings
whenever such procedure comports with the study objectives.
b. FDA proposes to revise § 58.130(e), renumbered as proposed §
58.130(d), to recognize that data may be generated by automated systems other than
"computer driven." The terms "computer" or "computer driven"
do not adequately provide for new technologies in data collection and storage methods. The
agency believes that the proposed term "automated data collection" more
accurately reflects current terminology in use by testing facilities.
20. Section 58.190 Storage and retrieval of records and data:
a. Current § 58.190(a) contains information collection requirements
that are subject to the Paperwork Reduction Act of 1980. In § 58.190(a), FDA proposes to
amend the provisions to allow specimens obtained from mutagenicity tests as well as wet
specimens of blood, urine, feces, and biological fluids from any nonclinical laboratory
study to be discarded after evaluation.
Section 58.190(a) currently requires a laboratory to retain in
storage all specimens for the term specified in the regulations or for a term during which
the quality of the specimens affords evaluation. This means that a laboratory is required
to retain a specimen as long as the retention term of the most stable constituent. FDA
proposes to exclude from the requirement specimens that are relatively fragile or
contribute only in a minor way to safety evaluation. FDA believes that the current
provision is burdensome and that allowing the listed specimens to be discarded will have
no effect on study quality.
b. FDA proposes to revise § 58.190(e) to delete the provision that
specifies index terms be used to catalogue archival contents.
The existing provision is too restrictive. The agency is not
concerned about which index terms are used so long as the archival information can be
retrieved expediently and proposed § 58.190(e) would so provide.
21. Section 58.195 Retention of records:
a. In § 58.195(c), FDA proposes to delete the examples. The
examples do not clarify what materials from a study are to be retained.
b. FDA proposes to add new § 58.195(g) to clarify the fact that
testing facilities may retain records either as original records or as true copies such as
microfilm, microfiche, photocopies, or other accurate reproductions of the original
records as contemplated in the definition of "raw data" set out in § 58.3(k).
This provision merely parallels similar provisions for record retention contained in other
regulations, e.g., 21 CFR Parts 211 and 820. The existing § 58.195(g) is redesignated as
§ 58.195(h).
Economic Assessment
FDA has examined the economic consequences of the proposed changes
in accordance with Executive Order 12291 and the Regulatory Flexibility Act (Pub. L.
96-354). The agency tentatively concludes that the revisions would have favorable economic
impacts on product sponsors and testing facilities without compromising the quality and
integrity of the safety data submitted to support product approval. Although agency
estimates are imprecise, cost savings are expected to accrue from changes affecting test
and control articles ($5.6 million per year), from revisions in protocol requirements
($6.2 million per year), and from changes in quality assurance procedures ($12.9 million
per year).
Accordingly, the agency concludes that the proposed revisions do not
constitute a major rule as defined in Executive Order 12291 and that no regulatory
flexibility analysis is required. The agency also certifies that the revisions will not
have a significant impact on a substantial number of small entities. The vast majority of
laboratories are not considered small businesses under the Regulatory Flexibility Act and
the agency estimates that the impact on those laboratories that are small is not
significant because toxicology testing is but a small portion of the work performed by
many laboratories. The savings described above will accrue to all sponsors and testing
facilities regardless of size. The agency's threshold assessment supporting these
conclusions is on file with the Docket Management Branch (address above) and is available
for public review between 9 a.m. and 4 p.m., Monday through Friday.
Environmental Impact
The agency has determined pursuant to 21 CFR 25.24(d)(14) (proposed
December 11, 1979; 44 FR 71742) that this proposed action is of a type that does not
individually or cumulatively have a significant impact on the human environment.
Therefore, neither an environmental assessment nor an environmental impact statement is
required.
Paperwork Reduction Act of 1980
Sections 58.35 (a), (b)(1), (3), and (6), 58.63(b), 58.90(c),
58.105(a), 58.120(a), 58.130(d), and 58.190 (a) and (e) of this proposed rule contain
collection of information requirements. FDA has submitted a copy of this proposed rule to
the Office of Management and Budget (OMB) for its review of these collection of
information requirements under section 3504(h) of the Paperwork Reduction Act of 1980 as
interpreted by OMB in 5 CFR Part 1320 (see 48 FR 13666; March 31, 1983). Other
organizations and individuals desiring to submit comments on the collection of information
requirements should direct them to the Dockets Management Branch (address above) and to
the Office of Information and Regulatory Affairs, OMB, Rm. 3208, New Executive Office
Bldg., Washington, DC 20503, Attn: Bruce Artim.
List of Subjects in 21 CFR Part 58
Laboratories.
Therefore, under the Federal Food, Drug, and Cosmetic Act (secs.
406, 408, 409, 502, 503, 505, 506, 507, 510, 512-516, 518-520, 701(a), 706, and 801, 52
Stat. 1049-1053 as amended, 1055, 1058 as amended, 55 Stat. 851 as amended, 59 Stat. 463
as amended, 68 Stat. 511-517 as amended, 72 Stat. 1785-1988 as amended, 76 Stat. 794 as
amended, 82 Stat. 343-351, 90 Stat. 539-574 (21 U.S.C. 346, 346a, 348, 352, 353, 355, 356,
357, 360, 360b-360f, 360h-360j, 371(a), 376, and 381)) and the Public Health Service Act
(secs. 215, 351, 354-360F, 58 Stat. 690, 702 as amended, 82 Stat. 1173-1186 as amended (42
U.S.C. 216, 262, 263b-263n)) and under 21 CFR 5.11, it is proposed that Part 58 be amended
as follows:
PART 58 -- GOOD LABORATORY PRACTICE FOR NONCLINICAL LABORATORY STUDIES
1. In § 58.1 by designating the existing text as paragraph (a) and
adding new paragraph (b), to read as follows:
§ 58.1 Scope.
* * * * *
(b) References in this part to regulatory sections of the Code of
Federal Regulations are to Chapter I of Title 21, unless otherwise noted.
2. In § 58.3 by revising paragraphs (c), (d), and (e)(8); removing
paragraph (e)(12); by removing the phrase "of this chapter" in paragraph (e) (1)
through (7), (9) through (11), (13), (14), (19), (21), and (22); by replacing "in
section 513 of the act" with "in Part 860" in paragraph (e)(17); and by
replacing "section 514 of the act" with "in Part 861" in paragraph
(e)(18), as follows:
§ 58.3 Definitions.
* * * * *
(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.
(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.
(e) * * *
* * * * *
(8) Data and information about a substance submitted as part of the
procedures for establishing a tolerance for unavoidable contaminants in food and
food-packaging materials, described in Parts 109 and 509.
* * * * *
(12) [Reserved]
* * * * *
3. In § 58.31 by revising paragraph (b), to read as follows:
§ 58.31 Testing facility management.
* * * * *
(b) Replace the study director promptly if it becomes necessary to
do so during the conduct of a study.
* * * * *
4. In § 58.33 by revising paragraph (b), to read as follows:
§ 58.33 Study director.
* * * * *
(b) All experimental data, including observations of unanticipated
responses of the test system, are accurately recorded.
* * * * *
5. In § 58.35 by revising paragraphs (a) and (b) (1) and (3);
removing paragraphs (b) (4) and (e); redesignating (b) (5), (6), and (7) as (b) (4), (5),
and (6), respectively; and revising paragraph (b)(6), as redesignated, to read as follows:
§ 58.35 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. For any given study the quality assurance unit shall be
entirely separate from and independent of the personnel engaged in the direction and
conduct of that sutdy.
(b) The quality assurance unit shall: (1) Maintain a copy of a
master schedule sheet of all nonclinical laboratory studies conducted at the testing
facility indexed by test article and containing the test system, nature of study, date
study was initiated, current status of each study, name of the sponsor, and name of the
study director.
* * * * *
(3) Inspect each nonclinical laboratory 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 reinspection. 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.
* * * * *
(6) Prepare and sign a statement to be included with the final study
report which shall identify the phases inspected and shall cite the number of inspections
conducted.
* * * * *
6. By revising § 58.41, to read as follows:
§ 58.41 General.
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.
7. In § 58.43 by revising the first sentence of paragraph (c) and
by removing paragraph (e), as follows:
§ 58.43 Animal care facilities.
* * * * *
(c) Separate areas shall be provided, as appropriate, for the
diagnosis, treatment, and control of laboratory animal diseases. * * *
* * * * *
8. In § 58.45 by revising the last sentence to read as follows:
§ 58.45 Animal supply facilities.
* * * Perishable supplies shall be preserved by appropriate means.
9. By revising § 58.47, to read as follows:
§ 58.47 Facilities for handling test and control articles.
As necessary to prevent contamination or mixups, there shall be
separate areas for receipt and storage of test and control articles and their mixtures,
and for mixing of test and control articles with carriers.
10. By revising § 58.49, to read as follows:
§ 58.49 Laboratory operation areas.
Separate laboratory space shall be provided, as needed, for the
performance of the routine and specialized procedures required by nonclinical laboratory
studies.
§ 58.53 [Removed]
11. By removing § 58.53 Administrative and personnel facilities.
12. By revising § 58.61, to read as follows:
§ 58.61 Equipment design.
Equipment used in the generation, measurement, or assessment of data
and equipment used for facility environmental control shall be of appropriate design and
adequate capacity to function according to the protocol and shall be suitably located for
operation, inspection, cleaning, and maintenance.
13. In § 58.63(b) by revising the first sentence, to read as
follows:
§ 58.63 Maintenance and calibration of equipment.
* * * * *
(b) The written standard operating procedures required under §
58.81(b)(11) shall set forth in sufficient detail the methods, materials, and schedules to
be used in the routine inspection, cleaning, maintenance, testing, calibration and/or
standardization of equipment, and shall specify, when appropriate, remedial action to be
taken in the event of failure or malfunction of equipment. * * *
* * * * *
14. In § 58.81(c) by revising the first sentence, to read as
follows:
§ 58.81 Standard operating procedures.
* * * * *
(c) Each laboratory area shall have immediately available laboratory
manuals and standard operating procedures relative to the laboratory procedures being
performed. * * *
* * * * *
15. In § 58.90 by revising paragraphs (b) and (c), to read as
follows:
§ 58.90 Animal care.
* * * * *
(b) Newly received animals from outside sources shall be isolated and
their health status shall be evaluated in accordance with acceptable veterinary medical
practice.
(c) At the initiation of a nonclinical laboratory study, animals shall be
free of any disease or condition that might interfere with the purpose or conduct of the
study. If, during the course of the study, the animals contract such a disease or
condition, the diseased animals shall be isolated, if necessary. These animals may be
treated for disease or signs of disease provided that such treatment does not interfere
with the study. The diagnosis, authorizations of treatment, description of treatment, and
each date of treatment shall be documented and shall be retained.
* * * * *
16. In § 58.105 by revising the first sentence of paragraph (a) and by
changing in the first sentence of paragraph (b) "initiation or a nonclinical
laboratory study" to "initiation of a nonclinical laboratory study", as
follows:
§ 58.105 Test and control article characterization.
(a) The indentity, strength, purity, and composition or other
characteristics which will appropriately define the test or control article shall be
determined for each batch and shall be documented.
* * * * *
17. In § 58.113(a)(2) by revising the first sentence, to read as follows:
§ 58.113 Mixtures of articles and carriers.
(a) * * *
* * * * *
(2) To determine the stability of the test and control articles in the
mixture as required by the conditions of the study.* * *
* * * * *
18. In § 58.120 by revising paragraph (a), to read as follows:
§ 58.120 Protocol.
(a) Each study shall have an approved written protocol that clearly
indicates the objectives and all methods for the conduct of the study. The protocol shall
contain, as applicable, the following information:
(1) A descriptive title and statement of the purpose of the study.
(2) Identification of the test and control articles by name, chemical
abstract number, or code number.
(3) The name of the sponsor and the name and address of the testing
facility at which the study is being conducted.
(4) The number, body weight range, sex, source of supply, species, strain,
substrain, and age of the test system.
(5) The procedure for identification of the test system.
(6) A description of the experimental design, including the methods for
the control of bias.
(7) A description and/or identification of the diet used in the study as
well as solvents, emulsifiers, and/or other materials used to solubilize or suspend the
test or control articles before mixing with the carrier. The description shall include
specifications for acceptable levels of contaminants that are reasonbly expected to be
present in the dietary materials and are known to be capable of interfering with the
purpose or conduct of the study if present at levels greater than established by the
specifications.
(8) Each dosage level, expressed in milligrams per kilogram of body weight
or other appropriate units, of the test or control article to be administered and the
method and frequency of administration.
(9) The type and frequency of tests, analyses, and measurements to be
made.
(10) The records to be maintained.
(11) The date of approval of the protocol by the sponsor and the dated
signature of the study director.
(12) A statement of the proposed statistical methods to be used.
19. In § 58.130 by revising paragraphs (d) and (e) to read as follows:
§ 58.130 Conduct of a nonclinical laboratory study.
* * * * *
(d) Records of gross findings for a specimen from postmortem observations
should be available to a pathologist when examining that specimen histopathologically.
(e) All data generated during the conduct of a nonclinical laboratory
study, except those that are generated by automated data collection systems, shall be
recorded directly, promptly, and legibly in ink. All data entries shall be dated on the
date of entry and signed or initiated by the person entering the data. Any change in
entries shall be made so as not to obscure the original entry, shall indicated the reason
for such change, and shall be dated and signed or identified at the time of the change. In
automated data collection systems, the individual responsible for direct data imput shall
be identified at the time of data input. Any change in automated data entires shall be
made so as to not obscure the original entry, shall indicate the reason for change, shall
be dated, and the responsible individual shall be identified.
§ 58.185 [Amended]
20. In § 58.185 Reporting of nonclinical laboratory study results in
paragraph (a)(14) and changing "§ 58.35(b)(7)" to read "§
58.35(b)(6)."
21. In § 58.190 by revising paragraphs (a) and (e), to read as follows:
§ 58.190 Storage and retrieval of records and data.
(a) All raw data, documentation, protocols, specimens, except those
obtained form mutagenicity tests and wet specimens of blood, urine, feces, and biological
fluids, and final reports generated as a result of a nonclinical laboratory study shall be
retained.
* * * * *
(e) Material retained or referred to in the archives shall be indexed to
permit expedient retrieval.
22. In § 58.195 by revising paragraph (c), redesignating paragraph (g) as
paragraph (h), and adding new paragraph (g), to read as follows:
§ 58.195 Retention of records.
* * * * *
(c) Wet specimens, samples of test or control articles, samples of test or
control article carrier mixtures and specially prepared material, which are relatively
fragile and differ markedly in stability and quality during storage, shall be retained
only as long as the quality of the preparation affords evaluation. In no case shall
retention be required for longer periods than those set forth in paragraphs (a) and (b) of
this section.
* * * * *
(g) Records required by this part may be retained either as original
records or as true copies such as photocopies, microfilm, microfiche, or other accurate
reproductions of the original records.
* * * * *
§ 58.204 [Amended]
23. In § 58.204 Notice of and opportunity for hearing on proposed
disqualification in paragraph (b) by changing "Part 16 of this chapter" to read
"Part 16."
§ 58.213 [Amended]
24. In § 58.213 Public disclosure of information regarding
disqualification in paragraph (b) by changing "Part 20 of this chapter" to read
"Part 20."
§ 58.219 [Amended]
25. In § 58.219 Reinstatement of a disqualified testing facility by
changing "Part 20 of this chapter" to read "Part 20."
Interested persons may, on or before (Decemeber 28, 1984), submit to the
Dockets Management Branch (address above) written comments regarding this proposed rule.
Two copies of any comments are to be submitted, except that individuals may submit one
copy. Comments are to be identified with the docket number found in brackets in the
heading of this document. Received comments may be seen in the office above between 9 a.m.
and 4 p.m., Monday through Friday.
Dated: August 27, 1984.
Frank E. Young,
Comissioner of Food and Drugs.
Margaret M. Heckler,
Secretary of Health and Human Services.
[FR Doc. 84-28403 Filed 10-26-84; 8:45 am]
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