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 21 CFR 58 - Good Laboratory Practice Regulations
Reg. No. Regulatory Text
Subpart A - General Provisions
58.1 Scope
(a) This part prescribes good laboratory practices for conducting
non-clinical laboratory studies that support or are intended to
support applications for research or marketing permits for products
regulated by the FDA, including food and colour 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, 505, 506, 507, 510, 512-516, 518-520, 721, and 801 of
the Federal Food, Drug, and Cosmetic Act and sections 351 and
354 - 360F of the Public Health Service Act.
(b) References in this part to regulatory sections of the Code of
Federal Regulations are to chapter 1 of title 21, unless otherwise
noted.
[43 FR 60013, Dec. 22, 1978, as amended at 52 FR 33779, Sept. 4,
1987]
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 (sections 201-902, 52 Stat. 1040 et seq.,as amended (21
U.S.C. 321-392)).
(b) Test article means any food additive, colour additive, drug,
biological product, electronic product, medical device for human
use, or any other article to regulation under the act or under
sections 351 and 354-360F of the Public Health Service Act.
(c) Control article means any food additive, colour additive, drug,
biological product, electronic product, medical device for human
use or any other article, feed, or water that is administered to the
test system in the course of a non-clinical laboratory study for the
purpose of establishing a basis for comparison with the test article.
(d) Non-clinical 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 utilising 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) Applications for research or marketing research permit
includes:
(1) A colour 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
recognised 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 paragraphs 170.35 and 570.35.
(4) Data and information regarding a food additive submitted as
part of the procedures regarding food additives permitted to be used
on an interim basis pending additional study, described in
paragraph 180.1
(5) an investigational new drug application, described in part
312 of this chapter.
(6) A new drug application, described in part 314.
(7) Data and information regarding as over the counter drug for
human use, submitted as part of the process for classifying such
drugs as generally recognised 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 food-packaging 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 paragraph 314.300 of this
chapter.
(10) A Notice of Claimed Investigational Exemption for 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 601.
(14) An application for an investigational device exemption,
described in part 812.
(15) An Application for Pre-market 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 procedure for establishing, amending, or repealing a
performance standard for such devices, described in part 861.
(19) Data and electronic information regarding an electronic
product submitted as part of the procedures for obtaining an
exemption from notification of a radiation safety defect or 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
paragraph 1010.4.
(22) Data and information regarding an electronic product
submitted as part of the procedures for granting, amending, or
extending an exemption from any electronic product performance
standard, as described in paragraph 1010.5.
(f) Sponsor means:
(1) A person who initiates and supports, by provision of financial
or other resources, a non-clinical laboratory study;
(2) A person who submits a non-clinical study to the Food and
Drug Administration in support of an application for a 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 non-clinical
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 non-clinical laboratory studies.
(h) Person includes an individual, corporation, association,
scientific or academic establishment, government agency, or
organisational unit thereof, and any other legal entity.
(i) Test system means any animal, plant, micro-organism, 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 non-clinical 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 organisational
element except the study director, designated by testing facility
management to perform the duties relating to quality assurance of
non-clinical laboratory studies.
(m) Study director means the individual responsible for the overall
conduct of a non-clinical laboratory study.
(n) Batch means a specific quantity or lot of a test or control article
that has been characterised according to paragraph 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 3379, Sept. 4,
1987; 54 FR 9039, Mar.3, 1989]
58.10 Applicability to studies performed under grants and contracts.
When a sponsor conducting a non-clinical laboratory study
intended to be submitted to or reviewed by the FDA utilises 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.
58.15 Inspection of a testing facility
(a) A testing facility shall permit an authorised employee of the
FDA, at reasonable times and in a reasonable manner, to inspect the
facility (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 FDA will not consider a non-clinical 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 non-clinical 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 FDA.
Reg. No. Regulatory Text
Subpart B - Organisation and Personnel
58.29 Personnel
(a) Each individual engaged in the conduct of or responsible for the
supervision of a non-clinical laboratory study shall have education,
training, and experience, or a 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 non-clinical 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 non-clinical laboratory study shall wear
clothing appropriate for the duties they perform. 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 non-clinical
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.
58.31 Testing facility management
For each non-clinical laboratory study, testing facility management
shall:
(a) Designate a study director as described in paragraph 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
paragraph 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, Dec. 22, 1978, as amended at 52 FR 33780, Sept.
4,1987]
58.33 Study director.
For each non-clinical 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 the 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
paragraph 58.120 and is followed.
(b) All experimental data, including observations of unanticipated
response of the test system are accurately recorded and verified.
(c) Unforeseen circumstances that may affect the quality and
integrity if the non-clinical laboratory study are noted when they
occur, and corrective action is taken and documented.
(d) The 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 FR 17657, Mar. 23, 1979]
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, practice, 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 non-clinical
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 , the identity of the
sponsor, and name of the study director.
(2) Maintain copies of all protocols pertaining to all non-clinical
laboratory studies for which the unit is responsible.
(3) Inspect each non-clinical 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 re-inspection. Any problems
found during 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
standing operating procedures were made without proper
authorisation 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 non-clinical laboratory study.
(7) Prepare and sign a statement to be included with the final study
report which shall specify the dates inspections were made and
finding 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, and the name of the individual performing the
inspection shall be made available for inspection to authorised
employees of the FDA.
(d) A designated representative of the FDA 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 33780, Sept. 4,
1987]
Reg. No. Regulatory Text
Subpart C - Facilities
58.41 General
Each testing facility shall be of suitable size and construction to
facilitate the proper conduct of non-clinical laboratory studies. It
shall be designed so that there is a degree of separation that will
prevent any further function or activity from having an adverse
effect on the study.
[52 FR 33780, Sept. 4, 1987]
58.43 Animal care facilities
(a) A testing facility shall have 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 specialised 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
control articles known to be bio-hazardous, including volatile
substances, aerosols, radioactive materials, and infectious agents.
(c) Separate areas shall be provided, as proposed, for the diagnosis,
treatment, and control of laboratory animal disease. These areas
shall provide effective isolation for the housing of animals either
known or suspected of being diseased, 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 minimise vermin
infestation, odours, disease hazards, and environmental
contamination.
[43 FR 60013, Dec. 22, 1978, as amended at 52 FR 33780, Sept.4,
1987]
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,
1987]
58.47 Facilities for handling test and control articles
(a) As necessary to prevent contamination or mix-ups, 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.
Reg. No. Regulatory Text
58.49 Laboratory operation areas
Separate laboratory space shall be provided, as needed, for the
performance of the routine and specialised procedures required by
non-clinical laboratory studies.
[52 FR 33780, Sept. 4, 1987]
58.51
58.61
58.63
Specimen and data storage facilities
Space shall be provided for archives, limited access by authorised
personnel only, for the storage and retrieval of all raw sata and
specimens from completed studies.
Subpart D - Equipment
Equipment design
Equipment used in the generation, measurement, or assessment of
data and eqiupment used for facility enviromental control shall be
of appropriate design and adequate capacity to function according
to the protocol and shall be suitabiility located for operation,
inspection, cleaning and maintenance.
[52 FR 33780, Sept. 4, 1987]
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
standardised.
(b) The written standard operating procedures required under
paragraph 58.81(b)(11) shall be set forth in sufficient detail the
methods, materials, and schedules to be used in the routine
inspection, cleaning, maintenance, testing, calibration, and/or
standardisation 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, calibration and/or standardising 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 non-routine 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]
Subpart E - Testing Facilities Operation
58.81 Standard operating procedures.
(a) A testing facility shall have standard operating procedures in
writing setting forth non-clinical laboratory study methods that
management is satisfied are adequate to ensure the quality and
integrity of the data generated in the course of a study. All
deviations in a study from standard operating procedures shall be
authorised by the study director and shall be documented in the raw
data. Significant changes in established operating procedures shall
be properly authorised 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 post mortem 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,
1978]
58.83 Reagents and solutions
All reagents and solutions in the laboratory areas shall be labelled
to indicate identity, titre or concentration, storage requirements, and
expiration date. Deteriorated or outdated reagents and solutions
shall not be used.
Reg. No. Regulatory Text
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 non-clinical 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, authorisation 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 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 animalhousing
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 mix-up
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 sanitised at appropriate intervals.
(g) Feed and water used for the animals shall be analysed
periodically to ensure that contaminants known to be capable of
interfering with study and reasonably expected to be present in
such feed or water are not present in levels above those specified in
the protocol. Documentation of such analyses shall be maintained
as raw data.
(h) Bedding used in animal cages shall not interfere with 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 FR 32088, July 15, 1991]
Subpart F - Test and Control Articles
58.105 Test and control article characterisation
(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 characterised by their labelling.
(b) The stability of each test or control article shall be 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
labelled by name, chemical abstract number, or code number, batch
number, expiration date, if any, and, 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 paragraph 58.195.
(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]
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.
58.113 Mixtures of articles with carriers.
(a) For each test or control article that is mixed with a carrier, test
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 control article carrier
mixture has an expiration date , that date shall be clearly shown on
the container. If more than one component has 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]
Reg. No. Regulatory Text
Subpart G - Protocol for and Conduct of a Non-clinical
Laboratory Study
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 the identification of the system.
(6) A description of the experimental design, including the
methods for the control 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
solubilise or suspend the test or control particles before mixing
with the carrier. The description shall include specification 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, and 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 of an approved protocol and the reasons therefore 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. 4,
1987]
58.130 Conduct of a non-clinical laboratory study.
(a) The non-clinical laboratory study shall be conducted in
accordance with the protocol.
(b) The 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 post-mortem
observations should be available to a pathologist when examining
that specimen histopathologically.
(e) All data generated during the conduct of a non-clinical
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 initialled by the person entering the data. Any change in
these 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 the data input. Any change in
automated data entries shall be made so as not to obscure the
original entry, shall indicate the reason for the 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]
Reg. No. Regulatory Text
Subparts H - I (Reserved)
Subparts J - Records and Reports
58.185 Reporting of non-clinical laboratory study results.
(a) A final report shall be prepared for each non-clinical laboratory
study and shall include, but 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 analysing data.
(4) The test and control articles identified by name, chemical
abstracts number or code number, strength, purity, and composition
or other appropriate characteristics.
(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 sub-strain, age,
and procedure used for the 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 paragraph 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 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]
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, faeces, and biological
fluids) generated as a result of a non-clinical 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 minimise
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 a repository for all
material to be retained. Raw data and specimens may be retained
elsewhere provided that the archives have specific reference to
those other locations.
(c) An individual shall be identified as being responsible for the
archives.
(d) Only authorised 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]
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.
Reg. No. Regulatory Text
(b) Except as provided in paragraph (c) of this section,
documentation records, raw data and specimens pertaining to a
non-clinical laboratory study and required to be made by this part
shall be retained in the archive(s) for whichever of the following
periods is the 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 non-clinical laboratory study were submitted, is
approved by the FDA. This requirement does not apply to studies
supporting investigational new drug applications for investigational
device exemptions (IDE’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 of which the
results of the non-clinical laboratory study are submitted to the
FDA in support of an application for a research or marketing
permit.
(3) In other situations (e.g., where the non-clinical 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 faeces, and
biological fluids), samples of tests, 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.
(d) The master schedule sheet, copies of protocols, and record of
quality assurance inspections, as required by paragraph 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 paragraph 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 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 non-clinical 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 FDA 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]
Subpart
Subpart K - Disqualifications of Testing Facilities
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
demonstrated that such non-compliance 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 will conduct studies in compliance
with such regulations.
(b) The determination that a non-clinical 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 FDA.
58.202 Grounds for disqualification
The Commissioner may disqualify a testing facility upon finding all
of the following:
(a) The testing facility failed to comply with one or more of the
regulations set forth in this part of (or any other regulations
regarding such facilities in this chapter);
(b) The non-compliance 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.
58.204 Notice of and opportunity for hearing on proposed
disqualification.
(a) Whenever the Commissioner has information indicating that
grounds exist under paragraph 58.202 which in his opinion justify
disqualification of a testing facility, h 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.
Reg. No. Regulatory Text
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 disqualification proceeding, makes the
findings required in paragraph 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
paragraph 58.202 he shall issue 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.
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 non-clinical laboratory study
conducted by the disqualified testing facility may be examined to
determine whether such study was or would be essential to a
decision. If it is determined that a study was or would be essential
the FDA 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 will 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 non-clinical 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 paragraph 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
FDA.
[43 FR 60013, Dec. 22, 1978, as amended at 59 FR 13200 Mar. 21,
1994]
58.213 Public disclosure of information regarding disqualification.
(a) Upon issuance of a final order disqualifying a testing facility
under paragraph 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
58.206(a) and shall state that the disqualification constitutes a
determination by the FDA that non- clinical laboratory studies
performed by the facility will not be considered by the FDA in
support of any application for a research or marketing permit. If
such notice is sent to another FDA agency, the FDA will
recommend that the agency also consider Whether or not it should
accept non-clinical 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 FDA 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.
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 pre-condition to, other
proceedings or actions authorised by the act. The FDA may, at any
time, institute against a testing facility and/or against the sponsor of
a non-clinical laboratory study that has been submitted to the FDA
any appropriate judicial proceedings (civil or criminal) and other
appropriate regulatory action, in addition to or in lieu of, and prior
to, simultaneously with, or subsequent to, disqualification. The
FDA 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 FDA may refuse to consider any particular non-clinical
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.
58.217 Suspension or termination of a testing 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
authorised by this subpart. If a sponsor terminates or suspends a
testing facility from the further participation in a non-clinical
laboratory study that is being conducted as part of any application
for a research or marketing permit that has been submitted to any
Centre of the FDA ( whether approved or not), it shall notify that
Centre 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 FDA.
[43 FR. 60013, Dec. 22, 1978, as amended at 50 FR. 8995, Mar. 6,
1985]
Reg. No. Regulatory Text
58.219 Reinstatement of a disqualified testing facility.
A testing facility that has been disqualified may be reinstated as an
acceptable source of non-clinical laboratory studies to be submitted
to the FDA 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 non-clinical laboratory
studies in compliance with the good laboratory practice regulations
set forth in this part and, if any studies are currently being
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 do 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 facility is reinstated, the Commissioner shall so notify the
testing facility and all organisations and persons who were notified,
under paragraph 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

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