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Quality Assurance

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Title: Quality Assurance


1
General Overview of Code of Regulations 21 Part
58 Good Laboratory Practices
2
Why GLP regulations ?
3
  • SAFETY
  • Non-clinical safety studies are to protect the
    safety of the participants in clinical studies
  • By assuring that non-clinical data is in a
    accordance with the GLP regulations 21 CFR 58

4
Chapter 1, Title 21 CFR 58 Subpart A General
Provisions Subpart B Organization/Personnel Sub
part C Facilities Subpart D Equipment Subpart
E Testing Facilities Operation Subpart F Test
and Control Articles Subpart G Protocol for and
Conduct of a nonclinical Laboratory
Study Subpart J Records and Reports Subpart K
Disqualification of Testing Facilities
5
Summary of Regulations 21 CFR 58 Subpart
A General Provisions 58. 1 Scope a This part
prescribes good laboratory practices for
conducting nonclinical laboratory in vivo or in
vitro studies that support, or are intended to
support, applications for research or marketing
permits for products regulated by FDA
including
6
  • Subpart A General Provisions
  • 58. 1 Scope. Continuation . . .
  • food and color additives
  • animal food additives
  • human and animal drugs
  • medical devices for human use
  • biological products

7

Subpart A General Provisions 58.3 GLP
Definitions Sponsor The entity that pays the
bills and holds registration. Management UA
Office of the Vice President for Research
Appoints Study Director and assures that the
testing facility is in compliance. Study
Director Legally responsible for the conduct of
the study. Quality Assurance Designated by
management to perform the duties relating to
quality assurance of the study.
8
  • Subpart A General Provisions
  • 58.3 Study
  • Any experiment at one or more test sites, in
    which a test substance is studied in a test
    system under laboratory conditions or in the
    environment to determine or help predict its
    effects
  • metabolism
  • product performance
  • environmental and chemical fate
  • persistence and residue
  • or other characteristics in humans, other
    living organisms or media.

9
Subpart A General Provisions 58.3 Protocol
Approved, written document that clearly indicates
objectives, study design and all methods to be
used in conducting the study Standard operating
procedures Written, approved procedures that
describe in detail standard and repetitive
actions including policies Test system the
entity that the test substance is tested in or
added to
10
Subpart A General Provisions 58.3 Test
Article Any material or device administered to a
test system Control Article Any chemical
substance or mixture, analytical standard, or
material, other than a test substance, feed, or
water, administered to or used in analyzing the
test system to establish bases for
comparisoncommonly referred to as positive
control or an analytical standard
11
Subpart A General Provisions 58.3 Study
Dates Study Initiation Date date protocol is
signed by the Study Director Study Completion
Date date final report is signed by the Study
Director Experimental Start Date first date the
test substance is administered/ applied to the
test system Experimental Completion Date last
day data are collected for the study
12
Subpart A General Provisions 58.3 Specimen
any material derived from a test system for
examination or analysis Sample a portion of
the test, control or reference material
Batch a specific quantity or lot of a test,
control or reference material Vehicle an
agent which facilitates the mixture, dispersion
or solubilization of a test substance with a
carrier Carrier the material with which the
test substance is combined for administration to
the test system
13
Subpart A General Provisions 58.3 Archives
Area used for the orderly storage and expedient
removal of all raw data, documentation,
protocols, specimens, and interim and final
reports.
14
Subpart A General Provisions 58.3 Raw Data
Any laboratory worksheets, records, memoranda,
notes, or exact copies, that are the result of
original observations and activities of a study
and are necessary for the reconstruction and
evaluation of the report of study
15
Subpart A General Provisions 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 FDAit 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 section 58.15.
16
Subpart A General Provisions 58.15
Applicability to studies performed under grants
and contracts (a) A testing facility shall
permit an authorized employee of the FDA, at
reasonable times in a reasonable manner to
inspect to copy records ..regarding the
studies with in the scope of part 58
17
Subpart A General Provisions 58.15
Applicability to studies performed under grants
and contracts (b) The FDA will not consider a
non-clinical laboratory study in support of an
application for research or marketing permit if
the testing facility refuses to permit
inspection.
18
Subpart B Organization/Personnel 58.29
Personnel
  • 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.
  • Training Records

19
Subpart B Organization/Personnel 58.29
Personnel
  • (b) Each testing facility shall maintain a
    current summary of training and experience and
    job descriptions for each individual engaged in
    or supervising the conduct of a nonclincal
    laboratory study.
  • Maintain Training Records and Job Descriptions

20
Training Records CV/Education summary GLP
training certificates Professional meetings
attended Campus/industry certificates Chemical
safely Animal Care Radiation
Safety Proficiency on methods required by
protocol and SOPs
21
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22
Subpart B Organization/Personnel 58.29
Personnel
(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 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.

23
Subpart B Organization/Personnel 58.29
Personnel
(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 the
test systems, test and control articles and other
operations 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.

24
Subpart B Organization and Personnel 58. 31
Testing Facility Management For each
nonclinical laboratory study management OVPR
shall (a) Designate a study director before the
study is initiated (b) Replace the study
director promptly if it becomes necessary to do
so during the study (c) Assure that there is a
quality assurance unit (d) Assure that
personnel, resources, facilities, equipment,
materials and methods are available
25
Subpart B Organization and Personnel 58. 31
.Continuation (f) Assure that personnel
clearly understand the functions they are to
perform (g) Assure that any deviations from
these regulation reported by the quality
assurance unit are communicated to the study
director and corrective actions are taken and
documented
26
Management Organizational Chart, University of
Arizona 21 CFR 58 Compliance
27
Subpart B Organization/Personnel 58.33 Study
director
  • For each nonclincal laboratoty 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
  • interpretation
  • analysis
  • documentation
  • reporting of results

28
Subpart B Organization/Personnel 58.33 Study
director
.represents the single point of study
control The study director shall assure
that (a) The protocol, including any change, is
approved (b) All experimental data, including
observations of unanticipated responses of the
test system are accurately recorded and
verified.

29
Subpart B Organization/Personnel 58.33 Study
director
(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 raw data, documentation,
protocols, specimens, and final reports are
transferred to the archives during or at the
close of the study

30
Subpart B Organization/Personnel 58.35 Quality
Assurance Unit
  • Responsible for monitoring each GLP study to
    assure management that the following
  • facilities
  • equipment
  • personnel
  • methods
  • practices
  • records
  • controls
  • are in conformance with the regulation in 21
    CFR 58 and 40 CFR 160.

31
Subpart B Organization/Personnel 58.35 Quality
Assurance Unit
  • Quality Assurance Officer is responsible to
  • Maintain a copy of the Master Schedule of
    all studies conducted at the testing facility
  • Maintain copies of all protocols
  • Inspect each study at intervals to assure
    the integrity of the study
  • Immediately report any problems likely to
    affect study integrity to management and study
    director

32
Subpart B Organization/Personnel 58.35 Quality
Assurance Unit
  • Quality Assurance Officer is responsible to
  • Maintain written and properly signed records of
    each periodic Inspection
  • Date of Inspection
  • Study inspected
  • Phase or segment inspected
  • Findings and problems
  • Action recommended and taken to resolve existing
    problems
  • Scheduled date for re-inspection

33
Subpart B Organization/Personnel 58.35 Quality
Assurance Unit
  • Quality Assurance Officer is responsible to
  • Review the final study report to assure that
    such report accurately
  • describes the methods and SOPs
  • and that the reported results accurately
    reflect the raw data
  • Prepare and sign a statement to be included with
    the final study report which shall specify the
    dates inspections were made

34
Examples of Quality Assurance
  • Assuring protocols are followed
  • Assuring SOPs are followed
  • Assuring deviations are documented and reported
  • Assuring personnel are properly trained
  • Assuring equipment calibration meets SOP
    requirements and documented
  • Assuring that equipment is as specified in the
    protocol.

35
Examples of Quality Assurance
  • Assuring dosing/application rates as specified
  • Assuring problems are reported to management and
    study director immediately
  • Assuring study events are adequately documented
  • Assuring management that systems are functioning
    as intended

36
  • Everyone bears responsibility for compliance
  • Management
  • Study Director
  • Study Facilitates
  • Quality Assurance

37
  • Subpart C Facilities
  • 58.43 Animal Care Facilities
  • (a) A testing facility shall have a sufficient
    number of animal rooms or areas, as needed, to
    assure proper
  • isolation of individual projects
  • quarantine of animals and
  • routine or specialized housing of animals
  • separation of species or test systems

38
  • Subpart C Facilities
  • 58.43 Animal Care Facilities
  • (b) A testing facility shall have a number of
    animal rooms or areas or areas separate to ensure
    isolation of studies being done with test systems
    or test and control articles known to be
    bio-hazardous, including volatile substances,
    aerosols, radioactive materials, and infectious
    agents.

39
Subpart C Facilities 58.43 Animal Care
Facilities (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
housing of animals either known or suspected of
being diseased, or of being carriers of disease,
from other animals.
40
Subpart C Facilities 58.43 Animal Care
Facilities (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.
41
  • Subpart C Facilities
  • 58.47 Facilities for handling test and control
    articles
  • (a) Separate areas for
  • Receipt and storage of the test and control
    articles
  • Mixing of the test and control articles with a
    carrier
  • Storage of the test and control article mixtures

42
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43
Subpart C Facilities 58.47 Facilities for
handling test and control articles (b) Storage
areas for the test and/or control articles and
test and control mixtures shall be separate from
housing the test systems and shall be adequate
to preserve the identity, strength, purity, and
stability of the articles and mixtures
44
Subpart C Facilities 58.49 Laboratory
Operation Areas Separate laboratory space shall
be provided for the performance of the routine
and specialized procedures required by nonclincal
laboratory studies
45
Subpart C Facilities 58.51 Specimen and Data
Storage Space shall be provided for archives,
limited access by authorized personnel, for the
storage and retrieval of all raw data and
specimens from completed studies
46
Subpart D Equipment 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.
47
  • Subpart DEquipment
  • 58.63 Maintenance and calibration of equipment
  • 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.
  • SOPs shall describe methods, materials and
    schedules to be used in the routine inspection,
    cleaning, maintenance, testing, calibration and
    designate the person responsible for the
    performance of each operation

48
Subpart DEquipment 58.63 Maintenance and
calibration of equipment (c) Written records
shall be maintained of all inspection,
maintenance, testing, calibration, and/or
standardizing operations.
49
Subpart E Testing Facilities Section 58.81
Standard Operating Procedures SOPs
50
  • Subpart E Testing Facilities
  • Section 58.81
  • Standard Operating Procedures SOPs
  • (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 study.
  • All deviations in a study from the SOPs shall
    be authorized by the study director and shall be
    documented in the raw data.
  • Significant changes in established SOPs shall
    be properly authorized in writing by the
    management.

51
Subpart E Testing Facilities 58.81 SOPs.
(c) Each laboratory area shall have immediately
available laboratory manuals and SOPs relative to
the laboratory procedures being performed.
Published literature may be used as a supplement
to SOPs. (d) A historical file of SOPs and all
revisions thereof, including the dates of such
revisions, shall be maintained.
52
Subpart E Testing Facilities 58.83
Reagents and Solutions
  • All reagents and shall be labeled to indicate
  • identity
  • titer/concentration
  • storage requirements
  • expiration date

53
Subpart E Testing Facilities 58.83
Reagents and Solutions
Deteriorated or outdated reagents and solutions
shall not be used
54
  • Subpart G Protocol for and Conduct of a
    nonclinical Laboratory Study
  • 58.120 Protocol.
  • (a) Each study shall have an approved written
    protocol
  • Descriptive title and statement of the purpose
    of the study
  • Identification of the test and control articles
    by name, chemical abstract number, or code number
  • Name of the sponsor and the name and address of
    the testing facility at which the study is being
    conducted

55
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56
  • Subpart G Protocol for and Conduct of a
    nonclinical Laboratory Study
  • 58.120 Protocol
  • Number, body weight range, sex, source of
    supply, species, strain, substrain, and age of
    the test system.cell line, original source,
    passage number
  • Procedure for identification of the test system
  • A description of the experimental design
  • 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.

57
  • Subpart G Protocol for and Conduct of a
    nonclinical Laboratory Study
  • 58.120 Protocol
  • Each dosage level expressed in milligrams per
    kilogram of body weight, or other appropriate
    units of the test control article to be
    administered and the method of administration
  • The type and frequency of tests, analyses, and
    measurements to be made
  • The date of approval of the protocol by the
    sponsor and dated signature of the study director
  • A statement of the proposed statistical methods
  • All changes to the approved protocol shall be
    documented, signed by study director and dated
    maintained with the protocol

58
Subpart G Protocol for and Conduct of a
nonclinical Laboratory Study 58.130 Conduct (
a) study shall be conducted in accordance with
the protocol. (b) test systems shall be
monitored in conformity with protocol (c)
specimens shall be identified by test system,
study, nature, and date of collection. This
information must be located on the specimen
container or accompany the specimen in a manner
that precludes error in the recording and storage
of data.
59
  • Subpart G Protocol for and Conduct of a
    nonclinical Laboratory Study
  • 58.130 Conduct
  • (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
    study except those that are generated by
    automated data collection systems, shall be
  • gt recorded directly
  • gt promptly
  • gt and legibly in ink

60
58.130 Conduct 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 and shall indicate
the reason for such a change and shall be dated
and signed or identified at the time of
change.
Subpart G Protocol for and Conduct of a
nonclinical Laboratory Study
61
  • Laboratory/Study Documentation
  • Write neatly
  • Use a pen with ink that does not smear
  • Make sure all boxes, and lines are completed on
    checklists.if there is no information, enter n/a
    for not applicable or draw a line through empty
    line/box.
  • Always sign and/or initial and date entries
  • For documenting datesbe sure to include the
    year
  • For clarity use military time or AM/PM

62
  • Raw Data/Documentation
  • Promptly
  • Recorded as generated
  • Take forms to the field/lab
  • No keeping several measurements in your
    head
  • No filling out data sheets at the end of the
    day or when time allows
  • .real time data!!

63
  • Raw Data/Documentation
  • Directly (original)
  • Onto appropriate forms
  • Into appropriate logs
  • First entry is the RAW data

64
  • Raw Data/Documentation
  • Legibly
  • Understandable can a third party figure it
    out?
  • If it cant be read, it is not legible
  • If you are sloppy, slow down and print
  • Do not scrunch data
  • Dont write on backs of pages
  • Dont write in borders or margins, use
    additional paper

65
  • Raw Data/Documentation
  • Other considerations
  • In permanent medium (INK)
  • Color not specific must be indelible
  • Entries signed/dated at the time of entry
  • Data corrections in compliance with GLP
  • Must not obscure original (one line
    through)
  • Reason given (error code)
  • Signed and dated by person making
    correction

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67
  • Raw Data/Documentation
  • Maintained in an organized manner
  • - Data collection forms
  • All data points required by the protocol
    collected
  • Values of lab analyses recorded on a
    record sheet or attached
  • Normal reference values included

68
Laboratory/Study Documentation
Corrections/updates to documentation (other
than SOPs) may be made at any time as long as
each.. gt is initialed gt is dated gt
includes a short explanation as to why the
information was not included before
69
  • Laboratory/Study Documentation
  • Legibility .must be able to read
  • Identifiably.who did the work
  • Retrievability .can find the raw data
  • Documentation should allow you to be able to
    reconstruct the study for legal and regulatory
    purposes if needed

70
  • 58.185 Reporting of nonclinical laboratory study
    results
  • (a) Final report
  • Name and address of the facility performing the
    study and the dates on which the study was
    initiated and completed
  • Objectives and procedures stated in the approved
    protocol, including any changes in the original
    protocol
  • Statistical methods employed

Subpart J Records and Reports
71
  • 58.185 Reporting of nonclinical laboratory study
    results
  • (a) Final report
  • The test and control articles identified by
    name, chemical code number, strength, purity, and
    composition or other appropriate characteristics
  • Stability of the test and control articles under
    the conditions of administration
  • A description of the method used

Subpart J Records and Reports
72
  • 58.185 Reporting of nonclinical laboratory study
    results
  • (a) Final report
  • A description of the test system used including
    the number of animals used, sex, body weight
    range, source of supply, species, strain, age and
    procedure used for identification
  • A description of the dosage, dosage regimen,
    route of administration, and duration.

Subpart J Records and Reports
73
  • 58.185 Reporting of nonclinical laboratory study
    results
  • (a) Final report
  • A description of all circumstances that may have
    effected the quality or integrity of the data
  • The name of the study director, the names of
    other scientists or professionals, and the names
    of all supervisory personnel, involved in the
    study

Subpart J Records and Reports
74
  • 58.185 Reporting of nonclinical laboratory study
    results
  • (a) Final report
  • 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
  • Locations where all specimens, raw data, and the
    final report are to be stored
  • The statement prepared and signed by the quality
    assurance unit

Subpart J Records and Reports
75
  • 58.185 Reporting of nonclinical laboratory study
    results
  • (b) 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

Subpart J Records and Reports
76
  • 58.190 Storage and retrieval of records and data
  • (b) There shall be archives for orderly storage
    and expedient retrieval of all raw data,
    documentation, protocols, specimens, and interim
    and final reportsConditions of storage shall
    minimize deterioration of the documents or
    specimens
  • (c) An individual shall be identified as
    responsible for archives

Subpart J Records and Reports
77
  • 58.190 Storage and retrieval of records and data
  • (a) All raw data, documentation, protocols,
    final reports and specimens.
  • (except wet specimens of blood, urine, feces
    and biological fluids.)
  • generated as a result of a nonclinical
    laboratory study shall be retained..

Subpart J Records and Reports
78
  • 58.190 Storage and retrieval of records and data
  • (d) Only authorized personnel shall enter the
    archives
  • (e) Material retained or referred to in the
    archives shall be indexed to permit expedient
    retrieval

Subpart J Records and Reports
79
  • 58.195 Retention of records
  • Different interpretations as to time period.
  • (1) A period of a 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 FDA
  • (2) A period of at least 5 years for
  • INDs (Investigational New Drug)
  • IDEs (Investigational Device Exemptions

Subpart J Records and Reports
80
  • 58.195 Retention of records
  • (3) In other situations where the study does not
    result in submission of the study. at least 2
    years following the date on which the study was
    completed, terminated or discontinued

Subpart J Records and Reports
81
  • 58.195 Retention of records
  • (c) Wet specimens . samples of test or control
    articles shall be retained only as long as the
    quality of the preparation affords evaluation.
  • Master schedule sheet, copies of protocols and
    records of QA inspections shall be maintained by
    the QAU
  • Summaries of training and experience and job
    descriptions shall be retained.
  • Records of maintenance, and calibration

Subpart J Records and Reports
82
58.195 Retention of records (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 testing goes
out of business, all raw data, documentation, and
other material shall be transferred to the
archives of the sponsor of the study. FDA should
be notified of transfer.
Subpart J Records and Reports
83
  • Benefits of GLP
  • SOPs as training tools
  • SOPs for reproducible methodologies
  • Record of equipment maintenance and use
  • Record of reagent lot s or instrument operating
    parameters that provide traceability, and
    verification of study results
  • Easier preparation of final reports

84
Life after GLPs
  • WCAC
  • All procedures are now written down and in
    notebooks.
  • The procedures are done consistently and records
    are uniformly kept by everyone.
  • All procedures done with known standardized and
    current chemicals.
  • It is much easier to train new students and
    personnel with written procedures.
  • Equipment is maintained on a yearly basis.
  • Facility has maintained GLPs, throughout, even
    though only one room is used for the FDA project.

85
Life after GLPs
  • Main Campus
  • We survived.
  • All procedures are now written in a consistent
    form and easily found in notebooks.
  • Inconsistencies of procedures have been corrected
    and everyone is doing procedures uniformly.
  • Maintenance records of equipment and chemical/
    stain inventories are readily available.
  • Everyone is more aware of procedures, keeping
    records, etc., even in the areas not brought up
    to GLP standards.

86
Overall Advantages
  • As the decline in research funding continues, it
    is assumed being a GLP laboratory will give us an
    edge over other non-GLP research facilities.
  • Personnel CVs are always current.
  • Equipment is better maintained.
  • Procedures are known to be done the same by
    everyone and procedural questions are fewer.

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88
  • Everyone bears responsibility for compliance
  • Management
  • Study Director
  • Study Facilitates
  • Quality Assurance

89
  • Plan What You Do
  • Do What You Plan
  • Document That You Did It

90
If it is not written down.. It did not
Happen!!! Good Practices Good Science
91
Quality.
Quality is never an accident it is always the
result of high intention, sincere effort,
intelligent direction, and skillful execution
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