GOOD-LABORATORY-PRACTICES-(GLP) GUIDELINES

GOOD LABORATORY PRACTICES(GLP)
1

GLP: GOOD LABORATORY PRACTICE
 GLP is an FDA regulation.
 Definition: GLP embodies a set of
principles that provides a
framework within which laboratory
studies are planned performed,
monitored, reported and archived.
 GLP is sometimes confused with the
standards of laboratory safety like
wearing safety goggles.

HISTORY
 GLP is a formal regulation that was created by the FDA
(United states food and drug administration) in 1978.
 Although GLP originated in the United States , it had a world
wide impact.
 Non-US companies that wanted to do business with the
United states or register their pharmacies in the United
States had to comply with the United States GLP regulations.
 They eventually started making GLP regulations in their
home countries.
 In 1981 an organization named OECD (organization for
economic co-operation and development ) produced GLP
principles that are international standard.

WHY WAS GLP CREATED?
 In the early 70’s FDA became
aware of cases of poor
laboratory practice all over the
United States.
 FDA decided to do an in-depth
investigation on 40 toxicology
labs.
 They discovered a lot
fraudulent activities and a lot of
poor lab practices.
 Examples of some of these poor
lab practices found were
1. Equipment not been calibrated
to standard form , therefore
giving wrong measurements.
2. Incorrect/inaccurate accounts of
the actual lab study
3. Inadequate test systems

FAMOUS EXAMPLE
 One of the labs that went
under such an investigation
made headline news.
 The name of the Lab was
Industrial Bio Test. This was a
big lab that ran tests for big
companies such as Procter and
Gamble.
 It was discovered that mice
that they had used to test
cosmetics such as lotion and
deodorants had developed
cancer and died.
 Industrial Bio Test lab threw
the dead mice and covered
results deeming the products
good for human consumption.
 Those involved in production,
distribution and sales for the
lab eventually served jail time.

OBJECTIVES OF GLP
GLP makes sure that the data submitted are a
true reflection of the results that are obtained
during the study.
GLP also makes sure that data is traceable.
Promotes international acceptance of tests.

MISSION OF GLP
 Test systems
 Archiving of records and materials.
 Apparatus, material and reagent facilities.
 Quality assurance programs.
 Performance of the study.
 Reporting of study results.
 Standard operating procedures (SOP)
 Personnel and test facility organization

Standard Operating Procedures (SOP)
Written procedures for a laboratories program.
They define how to carry out protocol-specified
activities.
Most often written in a chronological listing of
action steps.
They are written to explain how the procedures
are suppose to work

SOP
Routine inspection, cleaning, maintenance,
testing and calibration.
Actions to be taken in response to equipment
failure.
Analytical methods
Definition of raw data
Keeping records, reporting, storage, mixing, and
retrieval of data

Statistical Procedures for Data
Evaluation
Statistical procedures are not simply chosen
from a text book
Practitioners in a particular field may adopt
certain standards which are deemed acceptable
within that field.
Regulatory agencies often describe acceptable
statistical procedures.

Instrumentation Validation
 This is a process necessary for any analytical
laboratory.
 Data produced by “faulty” instruments may give
the appearance of valid data.
 The frequency for calibration, re-validation and
testing depends on the instrument and extent of
its use in the laboratory.
 Whenever an instrument’s performance is
outside the “control limits” reports must be
discontinued

Instrument Validation (cont)
Equipment records should include:
Name of the equipment and manufacturer
Model or type for identification
Serial number
Date equipment was received in the laboratory
Copy of manufacturers operating instruction (s)

Reagent/ Materials
Certification
This policy is to assure that reagents used are
specified in the standard operating procedure.
Purchasing and testing should be handled by a
quality assurance program.

Reagents and Solutions cont
Requirements:
Reagents and solutions shall be labeled
Deteriorated or outdated reagents and solutions
shall not be used
Include Date opened
Stored under ambient temperature
Expiration date

Analyst Certification
Some acceptable proof of satisfactory training
and/or competence with specific laboratory
procedures must be established for each analyst.
Qualification can come from education,
experience or additional trainings, but it should
be documented
Sufficient people
Requirements of certification vary

Laboratory Certification
Normally done by an external agency
Evaluation is concerned with issues such as
Adequate space
Ventilation
Storage
Hygiene

Specimen/Sample Tracking
Vary among laboratories
Must maintain the unmistakable connection
between a set of analytical data and the
specimen and/or samples from which they were
obtained.
Original source of specimen/sample (s) must be
recorded and unmistakably connected with the
set of analytical data.

Documentation and Maintenance of
Records
Maintenance of all records provide
documentation which may be required in the
event of legal challenges due to repercussions
of decisions based on the original analytical
results.
General guidelines followed in regulated
laboratories is to maintain records for at least
five years
Length of time over which laboratory records
should be maintained will vary with the
situation

Important questions to be answered for any
analytical instrument
What is the equipment being used for?
Is the instrument within specification and is the
documentation to prove this available?
If the instrument is not within specifications, how
much does it deviate by?
If the instrument is not within specifications what
action has been taken to overcome the defect?
Can the standards used to test and calibrate the
instrument be traced back to national standards?

What happens if a workplace
does not comply with federal
Good Laboratory Practice
standards?

Disqualification of a Facility
Before a workplace can experience the
consequences of noncompliance, an explanation
of disqualification is needed
The FDA states the purpose of disqualification as
the exclusion of a testing facility from
completing laboratory studies or starting any
new studies due to not following the standards of
compliance set by the Good Laboratory Practice
manual

Possible Violations
Falsifying information for permit, registration or
any required records
Falsifying information related to testing~
protocols, ingredients, observations, data
equipment, ect.
Failure to prepare, retain, or submit written
records required by law

Grounds for Disqualification
 The testing facility failed to comply with one or
more regulations implemented by the GLP
manual
 The failure to comply led to adverse outcomes in
the data; in other words, it affected the validity
of the study
 Warnings or rejection of previous studies have
not been adequate to improve the facility’s
compliance

Consequences of Noncompliance
 The FDA states the following consequences of
noncompliance:
 The commissioner will send a written proposal of
disqualification to the testing facility
 A regulatory hearing on the disqualification will
be scheduled
 If the commissioner finds that after the hearing,
the facility has complied, then a written statement
with an explanation of termination of
disqualification will be sent to the facility
 Thus, if it can be shown that such disqualifications
did not affect the integrity and outcome of the
study itself, or did not occur at all, then the study
may be reinstated at the will of the commissioner

Upon Disqualification…
If the commissioner finds that the facility was
noncompliant on any of the grounds after the
hearing, then a final order of noncompliance will
be sent to the facility with explanations
 If a testing facility has been disqualified, any studies
done before of after the disqualification will need to
be determined as essential to a decision (acceptable
or not)
 If the study is determined unacceptable, then the
facility itself may need to show that the study was
not affected by the noncompliance that led to the
disqualification
 Once finally disqualified, the facility may not receive
or be considered for a research or marketing permit
and the study is rejected.

 The commissioner may notify the public and all
interested persons, including other federal agencies
the facility may have contacted
 The FDA may ask the other agencies to consider
whether to support the facility or not under the
disqualification
 Civil or criminal proceedings may occur at the
discretion of the commissioner
 Fines of up to $50,000 if one knowingly commits crime
and/or 1 year imprisonment~ for registration applicants
and producers
 Fines up to $5,000 all others~ civil penalty after failing to
improve after a minor violation warning was issued~
only those involved in testing will be given civil penalties
 Those involved in the distribution or sales will be
assessed more heavy penalties, such as criminal penalties

 The FDA may turn it over to the federal, state or
local law enforcement
 The facility’s sponsor may terminate or suspend
the facility from doing any non- clinical study for
a permit
 The sponsor is required to notify the FDA in
writing within 15 working days that the facility is
to be suspended or terminated and why

Reinstatement of a Disqualified Facility
The testing facility may be reinstated as
acceptable non-clinical study to be turned into
the FDA if the commissioner can be certain that
future studies will be conducted in compliance
with the Good Laboratory Practice standards
and that any current studies integrity have not
been severely harmed by the disqualification
The disqualified facility will be required to put
in writing to the commissioner reasons why it
should be reinstated and any actions the facility
will take or have taken to assure any
disqualification problems will not happen again

Reinstatement of a Disqualified Facility
The commissioner will inspect the facility and
determine if it shall be reinstated
If it is reinstated, the commissioner is required to
notify all persons that were notified of the
disqualification including the facility itself

References
 http://www.sjsu.edu/faculty/chem55/55glpout.ht
m
 http://www.labcompliance.com/tutorial/glp/defau
lt.aspx?sm=d_a
 UGA Office of the Vice President for Research
 Wikipedia

Contents:
 Introduction to GLP
 History of GLP
 Scope of GLP
 Purpose of GLP
 Enforcement of GLP
 Primary areas covered by the GLPs
 Pitfalls and benefits
 Conclusion

Introduction to GLP
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•GLP is a series of guide lines that cover the conduct and data production
for non-clinical safety studies.
•They ensure quality and integrity of the data generated during the
laboratory studies.
•The objective of the GLPs is to ensure that a standard approach is
undertaken covering traceability and accountability and, while still
allowing freedom for the scientists, to impose certain restrictions on the
generation of data and the experimental work
•It must be remembered that GLP is merely common sense in a formal
environment.

OECD definition of GLP:
Good Laboratory Practice (GLP) is a quality system
concerned with the organizational process and the
conditions under which non-clinical health and
environmental safety studies are
 planned
 performed
 monitored
 recorded
 archived
 reported.

History of GLP:
• The Good Laboratory Practice Guidelines (GLP) have
been in existence for non-clinical safety studies since 1976.
• In the early 1970’s, the FDA investigated a number of cases of poor
practice in toxicology laboratories through out the USA.
• Introduced a new regulation to cover Non clinical safety studies.
• Draft GLP in 1976.
• An enforceable US regulation in 1979.
• In 1981 OECD also published GLP principles (signed by 30
countries so far) –currently accepted as the industry standard.
• This was revised and published in 1997.

Scope of GLP:
Any company or institution performing non-clinical safety studies for
the submission of data for
 a new chemical entity
 a new biological
 immunological,
 pesticide,
 veterinary or agrochemical product
or, for that matter, a similar product that will eventually appear in the
marketplace and be consumed by the general public must adhere to
GLP in the conduct of their non-clinical safety study
experimentation.

GLP is needed for
 Non Clinical safety studies of development of drugs
 Agricultural pesticide development
 Development of toxic chemicals
 Food control (food additives)
 Test of substances with regard to explosive hazards
GLP is not needed for
 Basic research
 Studies to develop new analytical methods
 Chemical tests used to derive the specifications of a marketed food
product

Purpose of GLP:
 To promote the development of quality test data.
 Comparable quality of test data to avoid duplicative testing.
 To avoid the creation of technical barriers to trade.
 Improve the protection of human health and the environment.
 Led to fewer repeated studies. This, inturn, is helping to achieve the
aim of all scientists in reducing the use of animals.
 The ability to reconstruct studies proves beyond reasonable doubt
that these were the values obtained and the results submitted.

Enforcement of GLP:
 In the OECD countries, for at least 14 years, an Inspectorate has been
set up.
 All countries, however, have a regulatory group that, in some
instances, also acts as the receiving authority for the review of data,
and reports to the GLP Monitoring Authority.
 This regulatory group visits on a 2-year basis or, in Germany, a 4
year basis, those companies that have claimed compliance and will
then be on a rolling program of review.
 Claim is verified in a visit from the regulatory inspector. The
inspection may be performed by one or two persons for 1 to 5 days.
 At the end of the inspection, an exit meeting is held, and the
company is usually given an indication of its performance.
 Noncompliance points are noted in writing and discussed, and a
report is then prepared.

Primary areas covered by the GLPs:
 Responsibilities
 Training
 Quality assurance (QA)
 Facilities
 Standard operating procedures (SOPs)
 Study plans and study reports
 Data production and recording
 Equipment maintenance and calibration
 Computers and validation
 Test systems and test substances
 Archiving

Responsibilities:
The prime players in a GLP scenario would be
Test facility Management
Sponsor
Study director
Principal investigator
QA

Test facility management’s responsibilities:
 In a hierarchical structure, management would be totally responsible
for:
 Providing optimal environment for conducting GLP compliance of
the test facility.
 Provide sufficient number of qualified personnel, appropriate
facilities, equipment and materials for timely and proper conduct of
studies.
 Ensure that personnel clearly understand the function they need to
perform (provide training where necessary).
 Appoint study director
 It is the responsibility of management that the deviations in the test
study are reported by QA and are communicated to study director.
 Ensure that SOPs are established and are being followed as required
 Ensure that computer systems are suitable for intended purpose and
are validated, operated, maintained in accordance with the principles
of GLP

Study director’s responsibilities:
 Study director has the principal responsibility for conduct
of the study as per approved study plan, coordinate the
activities during the study and for final report preparation
and approval.
 Design the study plan and approve
 Identify and appoint principal investigator
 Ensure that all raw data generated are fully documented
and recorded
 Ensure that computerized systems in use are validated
 Should supervise all activities during the study

Principal investigator’s responsibilities:
 The principal investigator is the next in line of
responsibility after the study director in a multi site study.
 The principal investigator should ensure that delegated
phases of the study are conducted in accordance with the
applicable GLP.

Study personnel responsibilities:
 The personnel involved in the study team should be
knowledgeable especially in GLP and SOPs.
 Document any deviations in study plan and communicate
these deviations to study director
 Responsible for quality of raw data recorded
 Should take utmost precautions to maintain sound health
and in the event of any abnormality in health condition,
should report to study director.

Sponsor’s responsibilities:
Sponsor should be:
 Aware of the concerned regulatory authority requirements
 Knowledgeable with the requirements of the GLP
principles
 Should evaluate the test facility,facility management,study
director and the scope of the study
 The final report should be thoroughly reviewed for
compliance with the current GLP principles before
submission of the dossier to the regulatory authority.

Quality Assurance Unit(QAU)
 Independent group-Does not become involved in the conduct of the
study
 Responsibilities
review of the study plan
review of the study in the in-life phase
data audits
final study report audit.
 The aim of QA is to assure the management that compliance with
GLP is maintained throughout the entire study, that the data integrity
is maintained, and that compliance with the SOPs and the study plan
is adhered to by all experimental study staff
 to ensure that all critical aspects of this process are reviewed through
different studies over a period of time.

 Various audits performed by QAU
study audit
systems audit
process audit
 After every audit, a report is produced that is then
discussed with the study director and circulated to the
management with the overall agreement from the study
director relating to the audit findings and their explanation
of the resolution.

Facilities:
General:
1. The test facility should be of suitable size, construction
and location to meet the requirements of the study and to
minimize disturbance that would interfere with the
validity of the study.
2. The design of the test facility should provide an adequate
degree of separation of the different activities to assure
the proper conduct of each study.

Test System Facilities:
1. The test facility should have a sufficient number of rooms
or areas to assure the isolation of test systems and the
isolation of individual projects, involving substances or
organisms known to be or suspected of being
biohazardous.
2. Suitable rooms or areas should be available for the
diagnosis, treatment and control of diseases, in order to
ensure that there is no unacceptable degree of
deterioration of test systems.
3. There should be storage rooms or areas as needed for
supplies and equipment. Storage rooms or areas should be
separated from rooms or areas housing the test systems
and should provide adequate protection against
infestation, contamination, and/or deterioration.

Facilities for Handling Test and Reference Items:
1. To prevent contamination or mix-ups, there should be
separate rooms or areas for receipt and storage of the test
and reference items, and mixing of the test items with a
vehicle.
2. Storage rooms or areas for the test items should be
separate from rooms or areas containing the test systems.
They should be adequate to preserve identity,
concentration, purity, and stability, and ensure safe
storage for hazardous substances.

Archive Facilities:
 Archive facilities should be provided for the secure
storage and retrieval of study plans, raw data, final
reports, samples of test items and specimens. Archive
design and archive conditions should protect contents
from untimely deterioration.
 Material retained in the archives should be indexed so as
to facilitate orderly storage and retrieval.
 Only personnel authorized by management should have
access to the archives. Movement of material in and out of
the archives should be properly recorded.
 If a test facility or an archive contracting facility goes out
of business and has no legal successor, the archive should
be transferred to the archives of the sponsor(s) of the
study(s).

Waste Disposal:
 Handling and disposal of wastes should be carried out in
such a way as not to jeopardize the integrity of studies.
 This includes provision for appropriate collection, storage
and disposal facilities, and decontamination and
transportation procedures.

Apparatus, Material, and Reagents:
1. Apparatus, including validated computerized systems, used for the
generation, storage and retrieval of data, and for controlling
environmental factors relevant to the study should be suitably located
and of appropriate design and adequate capacity.
2. Apparatus used in a study should be periodically inspected, cleaned,
maintained, and calibrated according to Standard Operating
Procedures. Records of these activities should be maintained.
Calibration should, where appropriate, be traceable to national or
international standards of measurement.
3. Apparatus and materials used in a study should not interfere
adversely with the test systems.
4. Chemicals, reagents, and solutions should be labeled to indicate
identity (with concentration if appropriate), expiry date and specific
storage instructions. Information concerning source, preparation date
and stability should be available. The expiry date may be extended
on the basis of documented evaluation or analysis.

Standard operating procedures:
 Standard operating procedures (SOPs) are written procedures for a
laboratories program. They define how to carry out protocol-
specified activities.
 SOPs must be reviewed on a regular basis, (approximately every 2
years).
 Revisions to SOPs should be approved by test facility management.
 Each separate test facility unit or area should have immediately
available current Standard Operating Procedures relevant to the
activities being performed therein.
 Deviations from Standard Operating Procedures related to the study
should be documented and should be acknowledged by the Study
Director and the Principal Investigator(s), as applicable.

Standard Operating Procedures should be
available for the following categories of test
facility activities:
1. Test and Reference Items
Receipt, identification, labeling, handling,
sampling and storage.
2. Apparatus, Materials and Reagents
a) Apparatus
Use, maintenance, cleaning and calibration.
b) Computerized Systems
Validation, operation, maintenance, security,
change control and back-up
c) Materials, Reagents and Solutions
Preparation and labeling.

3. Record Keeping, Reporting, Storage, and Retrieval
Coding of studies, data collection, preparation of reports,
indexing systems, handling of data, including the use of
computerized systems.
4. Test System (where appropriate)
a) Room preparation and environmental room conditions for
the test system.
b) Procedures for receipt, transfer, proper placement,
characterization, identification and care of the test system.
c) Test system preparation, observations and examinations,
before, during and at the conclusion of the study.
d) Handling of test system individuals found moribund or
dead during the study.
e) Collection, identification and handling of specimens
including necropsy and histopathology.
f) Siting and placement of test systems in test plots.
5. Quality Assurance Procedures
Operation of Quality Assurance personnel in planning, scheduling,
performing, documenting and reporting inspections.

Study plan & Reports:
 The study plan is merely an indication of all of the
activities that will take place, resources required, time
frames, and objectives.
 It can be likened to a road map that allow participants to
start at the beginning and to proceed through the various
mazes to the final completion point indicated by the study
report.
 The one golden rule in GLP is one study plan, one study
director, and one report.
 The study report itself is a mirror image of all the
headings in the study plan
 Both the study plan and the report are audited by QA, and
each study plan and report are generally determined by the
company’s format.

Content of the Study Plan:
1. Identification of the Study, the Test Item and Reference Item
a) A descriptive title;
b) A statement which reveals the nature and purpose of the
study;
c) Identification of the test item by code or name (IUPAC;
CAS number, biological parameters, etc.);
d) The reference item to be used.
2. Information Concerning the Sponsor and the Test Facility
a) Name and address of the sponsor;
b) Name and address of any test facilities and test sites
involved;
c) Name and address of the Study Director;
d) Name and address of the Principal Investigator(s), and the
phase(s) of the study delegated by the Study Director and
under the responsibility of the Principal Investigator(s).
3. Dates
a) The date of approval of the study plan by signature of the Study
Director. The date of approval of the study plan by signature of the test
facility management and sponsor if required by national regulation or
legislation in the country where the study is being performed.
b) The proposed experimental starting and completion dates.

4. Test Methods
Reference to the OECD Test Guideline or other test guideline or
method to be used.
5. Issues (where applicable)
a) The justification for selection of the test system;
b) Characterization of the test system, such as the species, strain,
substrain, source of supply, number, body weight range, sex, age
and other pertinent information;
c) The method of administration and the reason for its choice;
d) The dose levels and/or concentration(s), frequency, and duration
of administration/ application;
e) Detailed information on the experimental design, including a
description of the chronological procedure of the study, all methods,
materials and conditions, type and frequency of analysis,
measurements, observations and examinations to be performed, and
statistical methods to be used (if any).
6. Records
A list of records to be retained.

Conduct of the study:
 A unique identification should be given to each study. All items
concerning this study should carry this identification.
 The study should be conducted in accordance with the study plan.
 All data generated during the conduct of the study should be
recorded directly, promptly, accurately, and legibly by the individual
entering the data. These entries should be signed or initialed and
dated.
 Any change in the raw data should be made so as not to obscure the
previous entry, should indicate the reason for change and should be
dated and signed or initialed by the individual making the change.

Content of the Final Report:
1. Identification of the Study, the Test Item and Reference Item
a) A descriptive title
b) Identification of the test item by code or name (IUPAC,CAS number,
biological parameters, etc.);
c) Identification of the reference item by name;
d) Characterization of the test item including purity, stability and
homogeneity.
2. Information Concerning the Sponsor and the Test Facility
a) Name and address of the sponsor;
b) Name and address of any test facilities and test sites involved;
c) Name and address of the Study Director;
d) Name and address of the Principal Investigator(s) and the phase(s) of the
study delegated, if applicable;
e) Name and address of scientists having contributed reports to the final
report.
3. Dates
Experimental starting and completion dates.

4. Statement
A Quality Assurance Programme statement listing the types of inspections
made and their dates, including the phase(s) inspected, and the dates any
inspection results were reported to management and to the Study Director
and Principal Investigator(s), if applicable. This statement would also serve
to confirm that the final report reflects the raw data.
5. Description of Materials and Test Methods
a) Description of methods and materials used;
b) Reference to OECD Test Guideline or other test guideline or method.
6. Results
a) A summary of results;
b) All information and data required by the study plan;
c) A presentation of the results, including calculations and determinations
of statistical significance;
d) An evaluation and discussion of the results and, where appropriate,
conclusions.
7. Storage
The location(s) where the study plan, samples of test and reference items,
specimens, raw data and the final report are to be stored.

Pitfalls:
 A pitfall could be seen as a restriction on the scientist
against performing free research.
 It could also be seen as an intrusion by an independent
body looking at why problems occur and at the sorts of
problems that occur and carrying out regular reviews with
senior management about these problems.
 Costs will increase because of time pressures and the
necessity of involving third-party reviews.
 The recording of data will now be subject to more QC,
more required approvals, extra costs, and, generally, more
data presented.
 Time must be taken to write and review SOPs. This in
itself can be a very costly exercise.

Benefits:
 GLP system allows for a better standard of research, less
repeated work, the ability to have full accountability and
traceability of everything within the experimental phase,
and the knowledge that all documentation produced at the
end of the study is now safe and secure in the archive and
can be readily accessed for regulatory review or
inspection.
 Fewer studies are being repeated, and, therefore, the
immediate benefit is the lowering of subject usage.
 Data, when generated with a certificate or a compliance
statement, will now be accepted by all OECD member
countries means that once the study is completed and the
regulatory submission made, the time for acceptance
several countries (if submissions are made in a multistate
procedure) will be reduced dramatically.

Conclusion:
 All non-clinical safety studies, when conducted according
to the principles of GLP and adequately addressing
science as well as compliance, can achieve a very high
success rate both in the outcome of the science and in the
acceptance of data for a regulatory submission.

References:
 OECD Series on Principles of Good Laboratory Practice and
Compliance Monitoring, ENV/MC/CHEM (98)17, As revised in
1997. http:www.oecd.org/ehs/ehsmono/index.htm#GLP
 U.S. Food and Drug Administration (FDA), Nonclinical Laboratory
Studies. Proposed Regulations for Good Laboratory Practice
Regulations. Proposed Rule, Federal Register, 1976; 41, 51206–
51228.
 U.S. Food and Drug Administration, Good Laboratory Practice for
Nonclinical Laboratory Studies: Title 21, Part 58, Code of Federal
Regulations, FDA, 1993.
 Jurg P. Seiler, Good Laboratory Practice-The Why and the How.

GOOD-LABORATORY-PRACTICES-(GLP) GUIDELINES

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