Quality Assurance - College of Agriculture and Life Sciences

Report
General Overview of Code of
Regulations
21 Part 58
Good Laboratory Practices
Why GLP regulations ?
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
Chapter 1, Title 21 CFR 58
Subpart A: General Provisions
Subpart B: Organization/Personnel
Subpart 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
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:
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
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.
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.
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
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 comparison…commonly referred
to as positive control or an analytical
standard
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
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
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.
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
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
FDA……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 section 58.15….
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
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.
Subpart B Organization/Personnel
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.

Training Records
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
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
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.
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.
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
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
Management Organizational Chart, University of Arizona
21 CFR 58 Compliance
Vice President for Research
Dr. Leslie Tolbert
Director of Compliance
Alice Langen
Quality Assurance Officer
Marilyn M. Marshall
GLP Laboratories
IACUC
GLP Protocols
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 ……
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.
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
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.
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
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
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
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.
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
Everyone bears responsibility
for compliance
• Management
• Study Director
• Study Facilitates
• Quality Assurance
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
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.
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.
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.
Subpart C: Facilities
58.47 Facilities for handling test and
control articles
(a) Separate areas for:
1. Receipt and storage of the test and
control articles
2. Mixing of the test and control articles
with a carrier
3. Storage of the test and control article
mixtures
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
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
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
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.
Subpart D:Equipment
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) 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
Subpart D:Equipment
58.63 Maintenance and calibration of
equipment
(c) Written records shall be maintained of all
inspection, maintenance, testing, calibration,
and/or standardizing operations.
Subpart E: Testing Facilities
Section 58.81
Standard Operating
Procedures [SOPs]
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.
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.
Subpart E: Testing Facilities
58.83 Reagents and Solutions
All reagents and shall be labeled to indicate:

identity

titer/concentration

storage requirements

expiration date
Subpart E: Testing Facilities
58.83 Reagents and Solutions
Deteriorated or outdated reagents and
solutions shall not be used
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
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.
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
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.
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:
> recorded directly
> promptly
> and legibly in ink
Subpart G: Protocol for and Conduct of a nonclinical Laboratory
Study
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.
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 dates…be sure to include
the year
• For clarity use military time or AM/PM
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!!
Raw Data/Documentation
Directly (original)
Onto appropriate forms
Into appropriate logs
First entry is the RAW data
Raw Data/Documentation
Legibly
Understandable – can a third party
figure it out?
If it can’t be read, it is not legible
If you are sloppy, slow down and print
Do not “scrunch” data
Don’t write on backs of pages
Don’t write in borders or margins, use
additional paper
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
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
Laboratory/Study Documentation :
Corrections/updates to
documentation (other than SOPs)
may be made at any time as long as
each…..
> is initialed
> is dated
> includes a short
explanation as to why the
information was not included
before
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
Subpart J: Records and Reports
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
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
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
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
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
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
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 reports…Conditions 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
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
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
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
IND’s (Investigational New Drug)
IDE’s (Investigational Device Exemptions
Subpart J: Records and Reports
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
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.
(d) Master schedule sheet, copies of protocols
and records of QA inspections shall be
maintained by the QAU
(e) Summaries of training and experience and
job descriptions shall be retained….
(f) Records of maintenance, and calibration
Subpart J: Records and Reports
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.
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
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.
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.
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.
Everyone bears responsibility
for compliance
• Management
• Study Director
• Study Facilitates
• Quality Assurance
• Plan What You Do
• Do
What You Plan
• Document That You Did It
If it is not written down…..
It did not Happen!!!
Good Practices = Good Science
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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