Subpart A General Provisions
Sec.
58.1 Scope.
58.3 Definitions.
58.10 Applicability to studies performed under grants and
contracts.
58.15 Inspection of a testing facility.
Subpart B Organization and Personnel
58.29 General.
58.31 Testing facility management.
58.33 Study director.
58.35 Quality assurance unit.
Subpart C Facilities
58.41 General.
58.43 Animal care facilities.
58.45 Animal supply facilities.
58.47 Facilities for handling test and control articles.
58.49 Laboratory operation areas.
58.51 Specimen and data storage facilities.
Subpart D Equipment
58.61 Equipment design.
58.63 Maintenance and calibration of equipment.
Subpart E Testing Facilities Operation
58.81 Standard operating procedures.
58.83 Reagents and solutions.
58.90 Animal care.
Subpart F Test and Control Articles
58.105 Test and control article characterization.
58.107 Test and control article handling.
58.113 Mixture of articles with carriers.
Subpart G Protocol for and Conduct of a Nonclinical
Laboratory Study
58.120 Protocol.
58.130 Conduct of a nonclinical laboratory study.
Subparts H I [Reserved]
Subpart J Records and Reports
58.185 Reporting of nonclinical laboratory study results.
58.190 Storage and retrieval of records and data.
58.195 Retention of records.
Subpart K Disqualification of Testing Facilities
58.200 Purpose.
58.202 Grounds for disqualification.
58.204 Notice of and opportunity for hearing or proposed
disqualification.
58.206 Final order on disqualification.
58.210 Actions upon disqualification.
58.213 Public disclosure of information regarding
disqualification.
58.215 Alternative or additional actions to disqualification.
58.217 Suspension or termination of a testing facility by a
sponsor.
58.219 Reinstatement of a disqualified testing facility.
AUTHORITY: Secs. 402, 406, 408, 409, 501, 502, 503, 505, 506,
507, 510, 512516, 518520, 701, 706, 801 of the Federal Food,
Drug, and Cosmetic Act (21 U.S.C. 342, 346, 346a, 348, 351, 352,
353, 355, 356, 357, 360, 360b360f, 360h360j, 371, 376, 381);
secs. 215, 351, 354360F of the Public Health Service Act (42
U.S.C. 216, 262, 263b263n).
(a) This part prescribes good laboratory practices for
conducting nonclinical laboratory studies that support or are
intended to support applications for research or marketing
permits for products regulated by the Food and Drug
Administration, including food and color additives, animal food
additives, human and animal drugs, medical devices for human use,
biological products, and electronic products. Compliance with
this part is intended to assure the quality and integrity of the
safety data filed pursuant to sections 406, 408, 409, 502, 503,
Food, Drug, and Cosmetic Act and sections 351 and 354360F of the
Public Health Service Act.
(b) References in this part to regulatory sections of
the Code of Federal Regulations are to Capter I of Title 21,
unless otherwise noted.
[43 FR 60013, Dec. 22, 1978, as amended at 52 FR 33779, Sept. 4,
1987]
SS 58.3 Definitions.
As used in this part, the following terms shall have the
meanings specified:
(a) Act means the Federal Food, Drug, and Cosmetic Act, as
amended (secs. 201902, 52 Stat. 1040 et seq., as amended (21
U.S.C. 321392)).
(b) Test article means any food additive, color additive,
drug, biological product, electronic product, medical device for
human use, or any other article subject to regulation under the
act or under sections 351 and 354360F of the Public Health
Service Act.
(c) Control article means any food additive, color
additive, drug, biological product, electronic product, medical
device for human use, or any other article subject to regulation
under the act or under sections 351 and 354360F of the Public
Health Service Act.
(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) Application for research or marketing permit includes:
(1) A color additive petition, described in part 71.
(2) A food additive petition, described in parts 171 and
571.
(3) Data and information regarding a substance submitted
as part of the procedures for establishing that a substance is
generally recognized as safe for use, which use results or may
reasonably be expected to result directly or indirectly, in its
becoming a component or otherwise affecting the characteristics
of any food, described in SS 170.35 and 570.35.
(4) Data and information regarding a food additive
submitted as part of the procedurres regarding food additives
permitted to be used on an interim basis pending additional
study, described in SS 180.1.
(5) An investigational new drug application, described in
part 312 of this chapter.
(6) A new drug application, described in part 314.
drug for human use, submitted as part of the procedures for
classifying such drugs as generally recognized as safe and
effective and not misbranded, described in part 330.
(8) Data and information about a substance submitted as
part of the procedures for establishing a tolerance for
unavoidable contaminants in food and foodpackaging materials,
described in parts 109 and 509.
(9) Data and information regarding an antibiotic drug
submitted as part of the procedures for issuing, amending, or
repealing regulations for such drugs, described in SS 314.300 of
this chapter.
(10) A Notice of Claimed Investigational Exemption for a
New Animal Drug, described in part 511.
(11) A new animal drug application, described in part 514.
(12) [Reserved]
(13) An application for a biological product license,
described in part 812.
(14) An application for an investigational device
exemption, described in part 812.
(15) An Application for Premarket Approval of a Medical
Device, described in section 515 of the act.
(16) A Product Development Protocol for a Medical Device,
described in section 515 of the act.
(17) Data and information regarding a medical device
submitted as part of the procedures for classifying such devices,
described in part 860.
(18) Data and information regarding a medical device
submitted as part of the procedures for establishing, amending,
or repealing a performance standard for such devices, described
in part 861.
(19) Data and information regarding an electronic product
submitted as part of the procedures for obtaining an exemption
from notification of a radiation safety defect of failure of
compliance with a radiation safety performance standard,
described in subpart D of part 1003.
(20) Data and information regarding an electronic product
submitted as part of the procedures for establishing, amending,
or repealing a standard for such product, described in section
358 of the Public Health Service Act.
(21) Data and information regarding an electronic product
submitted as part of the procedures for obtaining a variance from
any electronic product performance standard as described in SS
1010.4.
(22) Data and information regarding an electronic document
product submitted as part of the procedures for obtaining a
variance from any electronic product performance standard, as
described in SS 1010.5.
(f) Sponsor means:
(1) A person who initiates and supports, by provision of
financial or other resources, a nonclinical laboratory study;
(2) A person who submits a nonclinical study to the Food
research or marketing permit; or
(3) A testing facility, if it both initiates and actually
conducts the study.
(g) Testing facility means a person who actually conducts
a nonclinical laboratory study, i.e., actually uses the test
article in a test system. Testing facility includes any
establishment required to register under section 510 of the act
that conducts nonclinical laboratory studies and any consulting
laboratory described in section 704 of the act that conducts such
studies. Testing facility encompasses only those operational
units that are being or have been used to conduct nonclinical
laboratory studies.
(h) Person includes an individual, partnership,
corporation, association, scientific or academic establishment,
government agency, or organizational unit thereof, and any other
legal entity.
(i) Test system means any animal, plant, microorganism, or
subparts thereof to which the test or control article is
administered or added for study. Test system also includes
appropriate groups or components of the system not treated with
the test or control articles.
(j) Specimen means any material derived from a test system
for examination or analysis.
(k) Raw data means any laboratory worksheets, records,
memoranda, notes, or exact copies thereof, that are the result of
original observations and activities of a nonclinical laboratory
study and are necessary for the reconstruction and evaluation of
the report of that study. In the event that exact transcripts of
raw data have been prepared (e.g., tapes which have been
transcribed verbatim, dated, and verified accurate by signature),
the exact copy or exact transcript may be substituted for the
original source as raw data. Raw data may include photographs,
microfilm or microfiche copies, computer printouts, magnetic
media, including dictated observations, and recorded data from
automated instruments.
(l) Quality assurance unit means any person or
organizational element, except the study director, designated by
testing facility management to perform the duties relating to
quality assurance of nonclinical laboratory studies.
(m) Study director means the individual responsible for
the overall conduct of a nonclinical laboratory study.
(n) Batch means a specific quantity or lot of a test or
control article that has been characterized according to SS
58.105(a).
(o) Study initiation date means the date the protocol is
signed by the study director.
(p) Study completion date means the date the final report
is signed by the study director.
[43 FR 60013, Dec. 22. 1978, as amended at 52 FR 33779, Sept. 4,
1987; 54 FR 9039, Mar. 3,1989]
SS 58.10 Applicability to studies performed under grants and
contracts.
When a sponsor conducting a nonclinical laboratory study
intended to be submitted to or reviewed by the Food and Drug
Administration utilizes the services of a consulting laboratory,
contractor, or grantee to perform an analysis or other service,
it shall notify the consulting laboratory, contractor, or grantee
that the service is Part of a nonclinical laboratory study that
must be conducted in compliance with the provisions of this part.
SS 58.15 Inspection of a testing facility.
(a) A testing facility shall permit an authorized employee
of the Food and Drug Administration, at reasonable times and in a
reasonable manner, to inspect the facility and to inspect (and in
the case of records also to copy) all records and specimens
required to be maintained regarding studies within the scope of
this part. The records inspection and copying requirements shall
not apply to quality assurance unit records of findings and
problems, or to actions recommended and taken.
(b) The Food and Drug Administration will not consider a
nonclinical laboratory study in support of an application for a
research or marketing permit if the testing facility refuses to
permit inspection. The determination that a nonclinical
laboratory study will not be considered in support of an
application for a research or marketing permit does not, however,
relieve the applicant for such a permit of any obligation under
any applicable statute or regulation to submit the results of the
study to the Food and Drug Administration.
SS 58.29 Personnel.
(a) Each individual engaged in the conduct of or
responsible for the supervision of a nonclinical laboratory study
shall have education, training, and experience, or combination
thereof, to enable that individual to perform the assigned
functions.
(b) Each testing facility shall maintain a current summary
of training and experience and job description for each
individual engaged in or supervising the conduct of a nonclinical
laboratory study.
(c) There shall be a sufficient number of personnel for
the timely and proper conduct of the study according to the
protocol.
(d) Personnel shall take necessary personal sanitation and
health precautions designed to avoid contamination of test and
control articles and test systems.
(e) Personnel engaged in a nonclinical laboratory study
Such clothing shall be changed as often as necessary to prevent
microbiological, radiological, or chemical contamination of test
systems and test and control articles.
(f) Any individual found at any time to have an illness
that may adversely affect the quality and integrity of the
nonclinical laboratory study shall be excluded from direct
contact with test systems, test and control articles and any
other operation or function that may adversely affect the study
until the condition is corrected. All personnel shall be
instructed to report to their immediate supervisors any health or
medical conditions that may reasonably be considered to have an
adverse effect on a nonclinical laboratory study.
SS 58.31 Testing facility management.
For each nonclinical laboratory study, testing facility
management shall:
(a) Designate a study director as described in SS 58.33,
before the study is initiated.
(b) Replace the study director promptly if it becomes
necessary to do so during the conduct of a study.
(c) Assure that there is a quality assurance unit as
described in SS 58.35.
(d) Assure that test and control articles or mixtures have
been appropriately tested for identity, strength, purity,
stability, and uniformity, as applicable.
(e) Assure that personnel, resources, facilities,
equipment, materials, and methodologies are available as
scheduled.
(f) Assure that personnel clearly understand the functions
they are to perform.
(g) Assure that any deviations from these regulations
reported by the quality assurance unit are communicated to the
study director and corrective actions are taken and documented.
[43 FR 60013, Dee. 22, 1978, as amended at 52 FIR 33780,
Sept. 4, 1987]
SS 58.33 Study director.
For each nonclinical laboratory study, a scientist or other
professional of appropriate education, training, and experience,
or combination thereof, shall be identified as the study director. The study director has overall responsibility for the
technical conduct of the study, as well as for the interpretation, analysis, documentation and reporting of results, and
represents the single point of study control. The study director
shall assure that:
(a) The protocol, including any change, is approved as
provided by SS 58.120 and is followed.
(b) All experimental data, including observations of
recorded and verified.
(c) Unforeseen circumstances that may affect the quality
and integrity of the nonclinical laboratory study are noted when
they occur, and corrective action is taken and documented.
(d) Test systems are as specified in the protocol.
(e) All applicable good laboratory practice regulations
are followed.
(f) All raw data, documentation, protocols, specimens, and
final reports are transferred to the archives during or at the
close of the study.
[43 FR 60013, Dec. 22, 1978; 44 FIR 17657, Mar. 23, 1979]
SS 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 study.
(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,
identity of the sponsor, and name of the study director.
(2) Maintain copies of all protocols pertaining to all
nonclinical laboratory studies for which the unit is responsible.
(3) Inspect each nonclinical laboratory study at intervals
adequate to assure the integrity of the study and maintain
written and properly signed records of each periodic inspection
showing the date of the inspection, the study inspected, the
phase or segment of the study inspected, 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.
(4) Periodically submit to management and the study
director written status reports on each study, noting any
problems and the corrective actions taken.
(5) Determine that no deviations from approved protocols
or standard operating procedures were made without proper
authorization and documentation.
(6) Review the final study report to assure that such
report accurately describes the methods and standard operating
procedures, and that the reported results accurately reflect the
raw data of the nonclinical laboratory study.
final study report which shall specify the dates inspections were
made and findings reported to management and to the study
director.
(c) The responsibilities and procedures applicable to the
quality assurance unit, the records maintained by the quality
assurance unit, and the method of indexing such records shall be
in writing and shall be maintained. These items Including
inspection dates, the study inspected, the phase or segment of
the study inspected, and the name of the individual performing
the inspection shall be made available for inspection to
authorized employees of the Food and Drug Administration.
(d) A designated representative of the Food and Drug
Administration shall have access to the written procedures
established for the inspection and may request testing facility
management to certify that inspections are being implemented,
performed, documented, and followed-up in accordance with this
paragraph.
(Information collection requirements approved by the Office of
Management and Budget under control number 0910-0203)
[43 FR 60013, Dec. 22, 1978, as amended at 52 FR 3378Q, Sept. 4,
1987]
SS 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 in adverse effect on the study.
[52 FR 33780, Sept. 4, 1987]
SS 58.43 Animal care facilities.
(a) A testing facility shall have a sufficient number of
animal rooms or areas, as needed, to assure proper: (1)
Separation of species or test systems, (2) isolation of
individual projects, (3) quarantine of animals, and (4) routine
or specialized housing of animals.
(b) A testing facility shall have a number of animal rooms
or areas separate from those described in paragraph (a) of this
section to ensure isolation of studies being done with test
systems or test and control articles known to be biohazardous,
including volatile substances, aerosols, radioactive materials,
and infectious agents.
(c) Separate areas shall be provided, as appropriate, for
the diagnosis, treatment, and control of laboratory animal
diseases. These areas shall provide effective isolation for the
or of being carriers of disease, from other animals.
(d) When animals are housed, facilities shall exist for
the collection and disposal of all animal waste and refuse or for
safe sanitary storage of waste before removal from the testing
facility. Disposal facilities shall be so provided and operated
as to minimize vermin infestation, odors, disease hazards, and
environmental contamination.
[43 FR 60013, Dec. 22, 1978, as amended at 52 FR 33780, Sept. 4,
1987]
SS 58.45 Animal supply facilities.
There shall be storage areas, as needed, for feed, bedding,
supplies, and equipment. Storage areas for feed and bedding
shall be separated from areas housing the test systems and shall
be protected against infestation or contamination. Perishable
supplies shall be preserved by appropriate means.
[43 FR 60013, Dec. 22, 1978, as amended at 52 FR 33780, Sept. 4,
l987]
SS 58.47 Facilities for handling test and control articles.
(a) As necessary to prevent contamination or mixups, there
shall be separate areas for:
(1) Receipt and storage of the test and control articles.
(2) Mixing of the test and control articles with a
carrier, e.g., feed.
(3) Storage of the test and control article mixtures.
(b) Storage areas for the test and/or control article and
test and control mixtures shall be separate from areas housing
the test systems and shall be adequate to preserve the identity,
strength, purity, and stability of the articles and mixtures.
SS 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.
[52 FR 33780, Sept. 4, 1987]
SS 58.51 Specimen and data storage facilities.
Space shall be provided for archives, limited to access by
authorized personnel only, for the storage and retrieval of all
raw data and specimens from completed studies.
SS 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.
[52 FR 33780, Sept. 4, 1987]
SS 58.63 Maintenance and calibration of equipment.
(a) Equipment shall be adequately inspected, cleaned, and
maintained. Equipment used for the generation, measurement, or
assessment of data shall be adequately tested, calibrated and/or
standardized.
(b) The written standard operating procedures required
under SS 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. The written standard operating
procedures shall designate the person responsible for the
performance of each operation.
(c) Written records shall be maintained of all inspection,
maintenance, testing, calibrating and/or standardizing
operations. These records, containing the date of the operation,
shall describe whether the maintenance operations were routine
and followed the written standard operating procedures. Written
records shall be kept of nonroutine repairs performed on
equipment as a result of failure and malfunction. Such records
shall document the nature of the defect, how and when the defect
was discovered, and any remedial action taken in response to the
defect.
(Information collection requirements approved by the Office of
Management and Budget under control number 0910-0203)
[43 FR 60013, Dec. 22, 1978, as amended at 52 FR 33780, Sept. 4,
1987]
î
SS 58.81 Standard operating procedures.
(a) A testing facility shall have standard operating
procedures in writing setting forth nonclinical laboratory study
methods that management is satisfied are adequate to insure the
quality and integrity of the data generated in the course of a
study. All deviations in a study from standard operating
documented in the raw data. Significant changes in established
standard operating procedures shall be properly authorized in
writing by management.
(b) Standard operating procedures shall be established
for, but not limited to, the following:
(1) Animal room preparation.
(2) Animal care.
(3) Receipt, identification, storage, handling, mixing,
and method of sampling of the test and control articles.
(4) Test system observations.
(5) Laboratory tests.
(6) Handling of animals found moribund or dead during
study.
(7) Necropsy of animals or postmortem examination of
animals.
(8) Collection and identification of specimens.
(9) Histopathology.
(10) Data handling, storage, and retrieval.
(11) Maintenance and calibration of equipment.
(12) Transfer, proper placement, and identification of
animals.
(c) Each laboratory area shall have immediately available
laboratory manuals and standard operating procedures relative to
the laboratory procedures being performed. Published literature
may be used as a supplement to standard operating procedures.
(d) A historical file of standard operating procedures,
and all revisions thereof, including the dates of such revisions,
shall be maintained.
[43 FR 60013, Dec. 22, 1978, as amended at 52 FR 33780, Sept. 4,
1987]
SS 58.83 Reagents and solutions.
All reagents and solutions in the laboratory areas shall be
labeled to indicate Identity, titer or concentration, storage
requirements, and expiration date. Deteriorated or outdated
reagents and solutions shall not be used.
SS 58.90 Animal care.
(a) There shall be standard operating procedures for the
housing, feeding, handling, and care of animals.
(b) All 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.
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.
(d) Warm-blooded animals, excluding suckling rodents, used
In laboratory procedures that require manipulations and
observations over an extended period of time or in studies that
require the animals to be removed from and returned to their home
cages for any reason (e.g., cage cleaning, treatment, etc.),
shall receive appropriate identification. All information needed
to specifically identify each animal within an animal-housing
unit shall appear on the outside of that unit.
(e) Animals of different species shall be housed in
separate rooms when necessary. Animals of the same species, but
used in different studies, should not ordinarily be housed in the
same room when inadvertent exposure to control or test articles
or animal mixup could affect the outcome of either study. If
such mixed housing is necessary, adequate differentiation by
space and identification shall be made.
(f) Animal cages, racks and accessory equipment shall be
cleaned and sanitized at appropriate intervals.
(g) Feed and water used for the animals shall be analyzed
periodically to ensure that contaminants known to be capable of
interfering with the study and reasonably expected to be present
in such feed or water are not present at levels above those
specified in the protocol. Documentation of such analyses shall
be maintained as raw data.
(h) Bedding used in animal cages or pens shall not
interfere with the purpose or conduct of the study and shall be
changed as often as necessary to keep the animals dry and clean.
(i) If any pest control materials are used, the use shall
be documented. Cleaning and pest control materials that
interfere with the study shall not be used.
(Information collection requirements approved by the Office of
Management and Budget under control number 0910-0203)
[43 FR 60013, Dec. 22, 1978, as amended at 52 FR 33780, Sept. 4,
1987; 54 FR 15924, Apr. 20, 1989; 56 FIR 32088, July 15, 1991]
@
SS 58.105 Test and control article characterization.
(a) The identity, 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. Methods of synthesis, fabrication, or derivation of
the test and control articles shall be documented by the sponsor
or the testing facility. In those cases where marketed products
are used as control articles, such products will be characterized
by their labeling.
determined by the testing facility or by the sponsor either: (1)
Before study Initiation, or (2) concomitantly according to
written standard operating procedures, which provide for periodic
analysis of each batch.
(c) Each storage container for a test or control article
shall be labeled by name, chemical abstract number or rode
number, batch number, expiration date, if any, and, where
appropriate, storage conditions necessary to maintain the
identity, strength, purity, and composition of the test or
control article. Storage containers shall be assigned to a
particular test article for the duration of the study.
(d) For studies of more than 4 weeks' duration, reserve
samples from each batch of test and control articles shall be
retained for the period of time provided by SS 58.195.
(Information collection requirements approved by the Office of
Management and Budget under control number 0910-0203)
[43 FIR 60013, Dec. 22, 1978, as amended at 52 FR 33781, Sept. 4,
1987]
SS 58.107 Test and control article handling.
Procedures shall be established for a system for the
handling of the test and control articles to ensure that:
(a) There is proper storage.
(b) Distribution is made In a manner designed to preclude
the possibility of contamination, deterioration, or damage.
(c) Proper identification is maintained throughout the
distribution process.
(d) The receipt and distribution of each batch is
documented. Such documentation shall include the date and
quantity of each batch distributed or returned.
SS 58.113 Mixtures of articles with carriers.
(a) For each test or control article that is mixed with a
carrier, tests by appropriate analytical methods shall be
conducted:
(1) To determine the uniformity of the mixture and to
determine, periodically, the concentration of the test or control
article in the mixture.
(2) To determine the stability of the test and control
articles in the mixture as required by the conditions of the
study either:
(i) Before study initiation, or
(ii) Concomitantly according to written standard operating
procedures which provide for periodic analysis of the test and
control articles in the mixture.
(b) [Reserved]
(c) Where any of the components of the test or control
article carrier mixture has an expiration date, that date shall
an expiration date, the earliest date shall be shown.
[43 FR 60013, Dec. 22, 1978, as amended at 45 FR 24865, Apr. 11,
1980; 52 FR 33781, Sept.4,1987]
Study
SS 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 reasonably 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.
(b) All changes In or revisions of an approved protocol
and the reasons therefor shall be documented, signed by the study
director, dated, and maintained with the protocol.
(Information collection requirements approved by the Office of
Management and Budget under control number 0910-0203)
43 FR 60013, Dec. 22, 1978, as amended at 52 FR 33781, Sept.
SS 58.130 Conduct of a nonclinical laboratory study.
(a) The nonclinical laboratory study shall be conducted in
accordance with the protocol.
(b) The test systems shall be monitored in conformity with
the protocol.
(c) Specimens shall be identified by test system, study,
nature, and date of collection. This Information shall be
located on the specimen container or shall accompany the specimen
in a manner that precludes error in the recording and storage of
data.
(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 initialed by the person entering the data.
Any change in entries shall be made so as not to obscure the
original entry, shall indicate 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 input shall be identified at the time
of data input. Any change in automated data entries shall be
made so as not to obscure the original entry, shall indicate the
reason for change, shall be dated, and the responsible individual
shall be identified.
(Information collection requirements approved by the Office of
Management and Budget under control number 0910-0203)
[43 FR 60013, Dec. 22, 1978, as amended at 52 FR 33781, Sept.
4,1987]
ÿ
SS 58.185 Reporting of nonclinical laboratory study results.
(a) A final report shall be prepared for each nonclinical
laboratory study and shall include, but not necessarily be
limited to, the following:
(1) Name and address of the facility performing the study
and the dates on which the study was initiated and completed.
(2) Objectives and procedures stated in the approved
protocol, including any changes in the original protocol.
(3) Statistical methods employed for analyzing the data.
(4) The test and control articles identified by name,
chemical abstracts number or code number, strength, purity, and
(5) Stability of the test and control articles under the
conditions of administration.
(6) A description of the methods used.
(7) A description of the test system used. Where
applicable, the final report shall include the number of animals
used, sex, body weight range, source of supply, species, strain
and substrain, age, and procedure used for identification.
(8) A description of the dosage, dosage regimen, route of
administration, and duration.
(9) A description of all circumstances that may have
affected the quality or integrity of the data.
(10) The name of the study director, the names of other
scientists or professionals, and the names of all supervisory
personnel, involved in the study.
(11) A description of the transformations, calculations,
or operations performed on the data, a summary and analysis of
the data, and a statement of the conclusions drawn from the
analysis.
(12) The signed and dated reports of each of the
individual scientists or other professionals involved in the
study.
(13) The locations where all specimens, raw data, and the
final report are to be stored.
(14) The statement prepared and signed by the quality
assurance unit as described in SS 58.35(b)(7).
(b) The final report shall be signed and dated by the
study director.
(c) Corrections or additions to a final report shall be in
the form of an amendment by the study director. The amendment
shall clearly identify that part of the final report that is
being added to or corrected and the reasons for the correction or
addition, and shall be signed and dated by the person
responsible.
[43 FR 60013, Dec. 22, 1978, as amended at 52 FR 33781, Sept. 4,
1987]
SS 58.190 Storage and retrieval of records and data.
(a) All raw data, documentation, protocols, final reports,
and specimens (except those specimens obtained from mutagenicity
tests and wet specimens of blood, urine, feces, and biological
fluids) generated as a result of a nonclinical laboratory study
shall be retained.
(b) There shall be archives for orderly storage and
expedient retrieval of all raw data, documentation, protocols,
specimens, and interim and final reports. Conditions of storage
shall minimize deterioration of the documents or specimens in
accordance with the requirements for the time period of their
retention and the nature of the documents or specimens. A
testing facility may contract with commercial archives to provide
specimens may be retained elsewhere provided that the archives
have specific reference to those other locations.
(c) An individual shall be identified as responsible for
the archives.
(d) Only authorized personnel shall enter the archives.
(e) Material retained or referred to in the archives shall
be indexed to permit expedient retrieval.
(Information collection requirements approved by the Office of
Management and Budget under control number 0910-0203)
[43 FR 60013, Dec. 22, 1978, as amended at 52 FR 33781, Sept.
4,1987]
SS 58.195 Retention of records.
(a) Record retention requirements set forth in this
section do not supersede the record retention requirements of any
other regulations in this chapter.
(b) Except as provided in paragraph (c) of this section,
documentation records, raw data and specimens pertaining to a
nonclinical laboratory study and required to be made by this part
shall be retained in the archive(s) for whichever of the
following periods is shortest:
(1) A period of at least 2 years following the date on
which an application for a research or marketing permit, in
support of which the results of the nonclinical laboratory study
were submitted, is approved by the Food and Drug Administration.
This requirement does not apply to studies supporting
investigational new drug applications (IND's) or applications for
investigational device exemptions (IDE's), records of which shall
be governed by the provisions of paragraph (b)(2) of this
section.
(2) A period of at least 5 years following the date on
which the results of the nonclinical laboratory study are
submitted to the Food and Drug Administration in support of an
application for a research or marketing permit.
(3) In other situations (e.g., where the nonclinical
laboratory study does not result in the submission of the study
in support of an application for a research or marketing permit),
a period of at least 2 years following the date on which the
study is completed, terminated, or discontinued.
(c) Wet specimens (except those specimens obtained from
mutagenicity tests and wet specimens of blood, urine, feces, and
biological fluids), samples of test or control articles, 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.
records of quality assurance inspections, as required by SS
58.35(c) shall be maintained by the quality assurance unit as an
easily accessible system of records for the period of time
specified in paragraphs (a) and (b) of this section.
(e) Summaries of training and experience and job
descriptions required to be maintained by SS 58.29(b) may be
retained along with all other testing facility employment records
for the length of time specified in paragraphs (a) and (b) of
this section.
(f) Records and reports of the maintenance and calibration
and inspection of equipment, as required by SS 58.63(b) and (c),
shall be retained for the length of time specified in paragraph
(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.
(h) If a facility conducting nonclinical testing goes out
of business, all raw data, documentation, and other material
specified in this section shall be transferred to the archives of
the sponsor of the study. The Food and Drug Administration shall
be notified in writing of such a transfer.
[43 FR 60013, Dec. 22, 1978, as amended at 52 FR 33781, Sept. 4,
1987; 54 FR 9039, Mar. 3,1989]
4
SS 58.200 Purpose.
(a) The purposes of disqualification are: (1) To permit
the exclusion from consideration of completed studies that were
conducted by a testing facility which has failed to comply with
the requirements of the good laboratory practice regulations
until it can be adequately demonstrated that such noncompliance
did not occur during, or did not affect the validity or acceptability of data generated by, a particular study; and (2) to
exclude from consideration all studies completed after the date
of disqualification until the facility can satisfy the
Commissioner that It will conduct studies in compliance with such
regulations.
(b) The determination that a nonclinical laboratory study
may not be considered in support of an application for a research
or marketing permit does not, however, relieve the applicant for
such a permit of any obligation under any other applicable
regulation to submit the results of the study to the Food and
Drug Administration.
SS 58.202 Grounds for disqualification.
The Commissioner may disqualify a testing facility upon
(a) The testing facility failed to comply with one or more
of the regulations set forth in this part (or any other
regulations regarding such facilities in this chapter);
(b) The noncompliance adversely affected the validity of
the nonclinical laboratory studies; and
(c) Other lesser regulatory actions (e.g., warnings or
rejection of individual studies) have not been or will probably
not be adequate to achieve compliance with the good laboratory
practice regulations.
S58.204 Notice of and opportunity or hearing on proposed
disqualification.
(a) Whenever the Commissioner has information indicating
that grounds exist under SS 58.202 which in his opinion justify
disqualification of a testing facility, he may issue to the
testing facility a written notice proposing that the facility be
disqualified.
(b) A hearing on the disqualification shall be conducted
in accordance with the requirements for a regulatory hearing set
forth in part 16 of this chapter.
SS 58.206 Final order on disqualification.
(a) If the Commissioner, after the regulatory hearing, or
after the time for requesting a hearing expires without a request
being made, upon an evaluation of the administrative record of
the disqualification proceeding, makes the findings required In
SS 58.202, he shall issue a final order disqualifying the
facility. Such order shall include a statement of the basis for
that determination. Upon issuing a final order, the Commissioner
shall notify (with a copy of the order) the testing facility of
the action.
(b) If the Commissioner, after a regulatory hearing or
after the time for requesting a hearing expires without a request
being made, upon an evaluation of the administrative record of
the disqualification proceeding, does not make the findings
required in SS 58.202, he shall Issue a final order terminating
the disqualification proceeding. Such order shall include a
statement of the basis for that determination. Upon issuing a
final order the Commissioner shall notify the testing facility
and provide a copy of the order.
SS 58.210 Actions upon disqualification.
(a) Once a testing facility has been disqualified, each
application for a research or marketing permit, whether approved
or not, containing or relying upon any nonclinical laboratory
study conducted by the disqualified testing facility may be
examined to determine whether such study was or would be
would be essential, the Food and Drug Administration shall also
determine whether the study is acceptable, notwithstanding the
disqualification of the facility. Any study done by a testing
facility before or after disqualification may be presumed to be
unacceptable, and the person relying on the study may be required
to establish that the study was not affected by the circumstances
that led to the disqualification, e.g., by submitting validating
information. If the study is then determined to be unacceptable,
such data such be eliminated from consideration in support of the
application; and such elimination may serve as new Information
justifying the termination or withdrawal of approval of the
application.
(b) No nonclinical laboratory study begun by a testing
facility after the date of the facility's disqualification shall
be considered in support of any application for a research or
marketing permit, unless the facility has been reinstated under
SS 58.219. The determination that a study may not be considered
in support of an application for a research or marketing permit
does not, however, relieve the applicant for such a permit of any
obligation under any other applicable regulation to submit the
results of the study to the Food and Drug Administration.
SS 58.213 Public disclosure of information regarding
disqualification.
(a) Upon issuance of a final order disqualifying a testing
facility under SS 58.206(a), the Commissioner may notify all or
any interested persons. Such notice may be given at the
discretion of the Commissioner whenever he believes that such
disclosure would further the public interest or would promote
compliance with the good laboratory practice regulations set
forth in this part. Such notice, if given, shall include a copy
of the final order issued under SS 58.206(a) and shall state that
the disqualification constitutes a determination by the Food and
Drug Administration that nonclinical laboratory studies performed
by the facility will not be considered by the Food and Drug
Administration in support of any application for a research or
marketing permit. If such notice is sent to another Federal
Government agency, the Food and Drug Administration will
recommend that the agency also consider whether or not it should
accept nonclinical laboratory studies performed by the testing
facility. If such notice is sent to any other person, it shall
state that it is given because of the relationship between the
testing facility and the person being notified and that the Food
and Drug Administration is not advising or recommending that any
action be taken by the person notified.
(b) A determination that a testing facility has been
disqualified and the administrative record regarding such
determination are disclosable to the public under part 20 of this
chapter.
SS 58.215 Alternative or additional actions to disqualification.
(a) Disqualification of a testing facility under this
subpart is independent of, and neither in lieu of nor a
precondition to, other proceedings or actions authorized by the
act. The Food and Drug Administration may, at any time,
institute against a testing facility and/ or against the sponsor
of a nonclinical laboratory study that has been submitted to the
Food and Drug Administration any appropriate judicial proceedings
(civil or criminal) and any other appropriate regulatory action,
in addition to or in lieu of, and prior to, simultaneously with,
or subsequent to, disqualification. The Food and Drug
Administration may also refer the matter to another Federal,
State, or local government law enforcement or regulatory agency
for such action as that agency deems appropriate.
(b) The Food and Drug Administration may refuse to
consider any particular nonclinical laboratory study in support
of an application for a research or marketing permit, if it finds
that the study was not conducted in accordance with the good
laboratory practice regulations set forth in this part, without
disqualifying the testing facility that conducted the study or
undertaking other regulatory action.
SS 58.217 Suspension or termination of a testing facility by a
sponsor.
Termination of a testing facility by a sponsor is
independent of, and neither in lieu of nor a precondition to,
proceedings or actions authorized by this subpart. If a sponsor
terminates or suspends a testing facility from further
participation in a nonclinical laboratory study that is being
conducted as part of any application for a research or marketing
permit that has been submitted to any Center of the Food and Drug
Administration (whether approved or not), it shall notify that
Center in writing within 15 working days of the action; the
notice shall include a statement of the reasons for such action.
Suspension or termination of a testing facility by a sponsor does
not relieve it of any obligation under any other applicable
regulation to submit the results of the study to the Food and
Drug Administration.
[43 FR FR 60013, Dec. 22, 1978, as amended at 50 FR 8995, Mar. 6,
1985] 58.219 Reinstatement of a disqualified testing facility.
A testing facility that has been disqualified may be
reinstated as an acceptable source of nonclinical laboratory
studies to be submitted to the Food and Drug Administration if
the Commissioner determines, upon an evaluation of the submission
of the testing facility, that the facility can adequately assure
that it will conduct future nonclinical laboratory studies in
compliance with the good laboratory practice regulations set
conducted, that the quality and integrity of such studies have
not been seriously compromised. A disqualified testing facility
that wishes to be so reinstated shall present in writing to the
Commissioner reasons why it believes it should be reinstated and
a detailed description of the corrective actions it has taken or
intends to take to assure that the acts or omissions which led to
its disqualification will not recur. The Commissioner may
condition reinstatement upon the testing facility being found in
compliance with the good laboratory practice regulations upon an
inspection. If a testing facuity is reinstated, the Commissioner
shall so notify the testing facility and all organizations and
persons who were notified, under SS 58.213 of the
disqualification of the testing facility. A determination that a
testing facility has been reinstated is disclosable to the public
under part 20 of this chapter.
