GOOD LABORATORY PRACTICES - A DETAILED STUDY

Ms. TENY SARA THOMAS
MOUNT ZION COLLEGE OF PHARMACEUTICAL
SCIENCES AND RESEARCH, ADOOR, KERALA
ASSISTANT PROFESSOR
B.PHARM SIXTH SEMESTER
PHARMACEUTICAL QUALITY ASSURANCE

GLP
DEFINITION
• Good Laboratory Practices (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 and reported.
• Regulations come under Title 21 of the Code
of Federal Regulations as Part 58 (21CFR58).

• GLP is an FDA regulation
• A formal regulation that was created by the
FDA in 1978.
• In early 70’s poor laboratory practices were
done
• Discovered fraudulent activities and poor lab
practices.
• Examples were like equipments not calibrated,
incorrect accounts, inadequate test systems,
replacement of animals and fabrication of test
results.
• Hence creation of GLP.

NON CLINICAL STUDY
• Conducted at a stage of medicine development
that uses animals or cells and tissues to determine
the safety of a medicine.
• Does not involve humans.
• Investigates the harmful effects of medicine on
body such as, - toxic effects, if medicine causes
genetic changes or any cancerous growth.
• Also called pre-clinical studies.

OBJECTIVES OF GLP
• GLP makes sure that the data submitted are a true
reflection of the results obtained from the studies.
• Certifies that the every step of analysis is valid or
not.
• Assures the quality and integrity of data
submitted to FDA in support of the safety of
regulated products.
• Makes sure that the data is traceable.
• Promotes international acceptance tests.

ADVANTAGES
• Generation of high quality and reliable test
data.
• Increases public confidence
• Shortens time to market new products.
DISADVANTAGES
• More man power is required.
• Expensive process.
• Time consuming process.

CONTENTS OF GLP
SECTIONS CONTENTS
SUBPART A GENERAL PROVISIONS
SUBPART B ORGANISATION & PERSONNEL
SUBPART C FACILITIES
SUBPART D EQUIPMENT
SUBPART E TESTING FACILITIES OPERATION
SUBPART F TEST AND CONTROL ARTICLES
SUBPART G PROTOCOL AND CONDUCT OF NON-
CLINICAL LABORATORY STUDY
SUBPART H RECORDS & REPORTS
SUBPART I DISQUALIFICATION OF TESTING
FACILITIES

SUBPART A – GENERAL
PROVISIONS
This part describes GLP for conducting non clinical
laboratory studies that support a research or
marketing permits for products regulated by FDA
like,
• Food and colour addictives
• Animal food addictives
• Human and animal drugs
• Medical devices
• Biological products
Compliance with GLP is intended to assure the
quality and integrity of safety data.

DEFINITIONS
• Test article - any product mentioned by FDA
meant for testing.
• Control article – any product mentioned by FDA
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 test article.
• Test system – means any product thereof to
which the test or control article is administered or
added for the study.

• Testing facilities – means a person or many
establishment who actually conducts a non
clinical study. The facility includes operational
units used for the study.
Person includes – individual, partnership,
government agency etc.
• Sponsor – a person who initiates and supports,
by provision of financial or other resources, a
non clinical study. They submit the report of
the non clinical study to the FDA, in support
of a research or marketing report.

• Study director – means the individual
responsible for the overall conduct of a non
clinical laboratory study.
• Quality assurance unit - any person or
organisation other except the study director,
designated by the testing facility management
to perform the duties relating to quality
assurance of non clinical study.

• Raw data – is result of original observations
and activities of the study and are necessary
for the reconstruction and evaluation of the
report.
Raw data includes –
• Lab worksheets, records, notes, memo
• Photographs, computer printouts, magnetic
media, recorded data from automated
instruments.
• When exact transcript of raw data have been
prepared, the exact copy may be substituted
for the original.

INSPECTION OF TESTING FACILITY –
MAJOR GENERAL PROVISION
• A testing facility shall permit an
authorized employee of the FDA, to
inspect the facility and inspect all records
and specimens required to be maintained
regarding studies.
• Any testing facility refusing to permit
inspection will be debarred or results will
not be applicable.

• Personnel
• Testing facility management
• Study director
• Quality assurance unit
SUBPART B – ORGANISATION &
PERSONNEL

ORGANISATION - FUNCTIONS
• Identification of quality activities.
• Dividing jobs among the personnel.
• Define the authority and responsibility of each
job and relationships of each job with other
jobs.
• Coordinate the work of internal departments
and outside agencies.

PERSONNEL
• Each individual engaged in a non clinical
laboratory study shall have education, training
and experience so that can perform the assigned
functions.
• Each testing facility should maintain a summary
of training and experience and job description of
each individual engaged in non clinical
laboratory study.
• Sufficient number of personnel for timely and
proper conduct of study.

• Personnel shall take necessary personal sanitation
and health precautions to avoid contamination of
test and control articles and test systems.
• Should wear clothing appropriate for the duties.
The clothing should be changed often to prevent
microbiological, radiological or chemical
contamination.
• Anyone with illness that may adversely affect the
non clinical study shall be excluded untill the
condition is corrected. All personnel should
report the illness immediately to the supervisors.

TESTING FACILITY MANAGEMENT
For each non clinical laboratory study, TFM shall,
• Designate study director before the study starts.
• Assure that a quality assurance unit is present.
• Assure that test and control articles are of
appropriate identity, strength, purity and stability.
• Assure the availability of personnel, resources,
facilities, equipments, materials & methodology.
• Assure each personnel clearly understands the
functions to perform.
• Assure that problems reported by QA unit are
reported to study director and corrected and
documented.

STUDY DIRECTOR
For each study, a scientist or professional of
appropriate education, training and experience
appointed as study director, who has the
responsibility of – technical conduct of study,
interpretation, analysis, documentation and reporting
of results
• Assures that the protocol is approved and followed.
• All data are accurately recorded and verified.
• Unforeseen circumstances that may affect the quality
of the study are noted, corrected and documented.
• Assures all GLP regulations are followed.
• All data, documents, protocols, specimens and final
reports are archived during or close of the study.

QUALITY ASSURANCE UNIT
• Responsible for monitoring each study to assure
that facilities, equipments, personnel, methods,
practices, records comply with the regulations.
• Maintain a copy of master schedule sheet of all
the studies conducted which includes test article,
nature of study, date of initiation of study, current
status of the study, identity of the sponsor and
name of study director.
• Maintain copies of all protocols of the non
clinical laboratory study.
• Inspect each study at intervals to assure integrity
of study

• Maintain written and signed records of each
inspection with the date of inspection, phase of
study, person performing inspection, findings and
problems, action recommended and date for
reinspection
• Problems reported to study director and
management.
• Periodically submit reports study director and
management.
• Assures that no deviations from protocols and
SOP’s are taken without approval.

• Review final study report to assure that report
describes methods and SOP’s and resulta are
accurate.
• Prepare a final statement showing the date of
inspections and findings reported.
• A designated representative of FDA shall access
the procedures of inspection and request the
management to certify that inspections are being
implemented, performed, documented and
followed up.

• Animal care facilities
• Animal supply facilities
• Facilities for handling test and control articles
• Laboratory operation areas
• Specimen and data storage facilities
SUBPART C – FACILITIES
• Each testing facility shall be of suitable size and
construction to facilitate proper conduct of non
clinical laboratory study
• There should be a degree of separation which
prevents any adverse effects on the study

ANIMAL CARE FACILITIES
• A testing facility should have sufficient number
of animal rooms to assure proper – separation of
species, isolation of individual projects,
quarantine of animals, specialized housing of
animals.
• Should have sufficient number of animal rooms
for studies being done with test or control articles
known to be bio hazardous which includes
volatile substances, radioactive materials, or
infectious agents.

• Separate areas for diagnosis, treatment and
control of laboratory animal diseases. Area
provides effective isolation for housing of
animals known or suspected of being diseased
or being carriers of disease from other animals.
• Facilities for collection and disposal of all
animal waste or safe storage of waste before
removal from testing facility. Disposal facilities
should minimize vermin infestation, odours,
disease hazards and environmental
contamination.

ANIMAL SUPPLY FACILITIES
• Storage areas needed for feed, bedding, supplies and
equipment
• Storage areas for feed and bedding shall be separated
from the area of testing systems and protected from
infestation and contamination
LABORATORY OPERATION AREAS
• Laboratory space provided for the performance of
routine and specialized procedures required by non
clinical laboratory studies.
SPECIMEN AND DATA STORAGE FACILITIES
• Space shall be provided for archives, limited access to
authorised personnel, storage and retrieval of all raw
data and specimens from completed studies.

FACILITIES FOR HANDLING TEST AND
CONTROL ARTICLES
A) To prevent contamination or mix-ups, there shall
be separate areas for:
• Receipt & storage of test and control articles
• Mixing of test and control articles with a carrier
• Storage of test and control article mixtures.
B) Storage areas for test and control article and test
and control mixtures shall be separate from areas
housing the test systems
• Facilities should preserve the identity, strength,
purity, and stability of articles and moistures

Equipments used in generation, measurement or
assessment of data and equipment used for
facility environmental control
• Shall have adequate design and capacity to
function according to the protocol
• Shall be suitably located for operation,
inspection, cleaning and maintenance.
SUBPART D – EQUIPMENTS

MAINTENANCE AND CALIBRATION OF
EQUIPMENTS
• Equipment shall be adequately inspected, cleaned,
and maintained
• Adequately tested, calibrated and standardized.
• Written SOP’s of methods , materials and schedules
to be used in the routine inspection, cleaning and
maintenance testing, calibration and standardization
of equipments should be followed.
• In case of failure or malfunction, remedial action
should be taken.
• Written sop shall also contain the person responsible
for the performance of each operation

• Written records of inspection , maintenance,
testing, calibrating and standardizing operations
• Records should contain date of operation,
describes whether the maintenance operations
were routine and follow the SOP’s.
• Written records of non routine repairs performed
on equipment as a result of failure or malfunction
should be maintained.
• Such records should also document the nature of
the defect, how and when the defect was
discovered and any remedial action in response
to the defect.

• Standard Operating Procedures
• Reagents and Solutions
• Animal Care
SUBPART E – TESTING
FACILITIES OPERATION

STANDARD OPERATING PROCEDURES
A) SOP’s shall be established for ,
• Animal room preparation
• Animal care
• Receipt, identification, storage, handling, mixing and method
of sampling of test and control articles.
• Test system operations
• Laboratory test
• Handling of animals found moribund or dead during the
study.
• Necropsy of animals or postmortem examination of animals.
• Collection and identification of specimens
• Histopathology
• Data handling, storage, and retrieval
• Maintenance and calibration of equipment
• Transfer, proper placement and identification of animals

B) Each laboratory
• Shall have laboratory manuals and SOP’s of the
laboratory procedures being performed
• Published literature can also be used as supplement of
the SOP’s.
C) A historical file of SOP’s and all its revisions
including the dates of the revisions shall be
maintained.
D) A testing facility shall have SOP’s that the
management is satisfied are adequate to ensure
quality and integrity of data generated in the study.
• All deviations from SOP’s shall be authorized by the
study director and documented.
• Significant changes in SOP’s should properly authorized
in writing.

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.

ANIMAL CARE
• SOP’s for housing, feeding, handling, and care of
animals
• All newly received animals from outside sources shall
be isolated and their health status shall be evaluated with
acceptable veterinary medical practice.
• At the initiation of the study, animals shall be free of any
disease or condition that may affect the study.
• If during the course of study, animals contract any
disease or condition, they should be isolated, treated.
• Diagnosis, authorizations of treatment, description of
treatment and each date of treatment shall be
documented and retained.

• Animal cages, racks and accessory equipments shall
be cleaned and sanitized at appropriate intervals.
• Bedding used in animal cages or pens shall not
interfere with the study and shall be changed often
as necessary to keep the animals dry and clean.
• If any pest control materials are used, the use shall
be documented. Cleaning and pest control materials
that interfere with study shall not be used.
• Animals of different species shall be housed in
separate rooms. Animals of same species but used in
different studies should not be in same rooms as they
may interfere the with the outcome of the study. If
mixed housing is necessary, adequate differentiation
by space and identification shall be made.

• Feed and water used for the animals shall be
analysed periodically to ensure that the
contaminants known to be capable of interfering
the study and reasonably expected to be present
in feed and water are not present at levels above
those specified in protocol.
• Warm blooded animals used in the study or in
studies that require animals to be removed from
and returned to their home cages for any reason
(eg, cleaning, treatment) shall receive appropriate
identification. All the information needed for
identification shall appear outside the animal
housing unit.

• Test and Control Article Characterization
• Test and Control Article Handling
• Mixture of Articles with Carriers
SUBPART F – TEST AND CONTROL
ARTICLES

TEST AND CONTROL ARTICLE
CHARACTERIZATION
• Identity, strength, purity and composition that
defines the test and control article shall be
determined and documented.
• Methods of synthesis, fabrication, or
derivation of test and control article shall be
documented by sponsor and testing facility.
• Stability of the article shall be determined :
before the study or concomitantly according to
the written SOP’s.

• Each storage container for the article shall be
labelled by name, chemical abstract number,
code number, batch number, expiration date,
appropriate storage conditions – necessary to
maintain the identity, strength, purity and
composition of test and control article.
• For studies more than 4 weeks, samples from
each batch of test and control articles shall be
retained for the period of time.

TEST AND CONTROL ARTICLE
HANDLING
Procedures for handling of test and control article
are established to ensure that:
• Proper storage.
• Distribution of articles is made in a manner to
avoid any contamination, deterioration or
damage.
• Receipt and distribution of each batch of article is
documented. Such documentation shall include
the date and quantity of batch distributed and
returned.

MIXTURE OF ARTICLES WITH CARRIERS
A) For each article that is mixed with a carrier, tests by
appropriate analytical methods shall be conducted:
• To determine the uniformity of mixture
• To determine the concentration of each article in
mixture.
• To determine the stability of article in mixture
before the study or concomitantly according to
written SOP’s
B) Date of the components of the test and control
article carrier mixture should be clearly shown on
the container. If more than one component is present
the earlier expiry date should be shown.

• Protocol of the study
• Conduct of the study
SUBPART G – PROTOOLAND
CONDUCT OF NON CLINICAL
STUDY

PROTOCOL OF THE STUDY
Each study shall have an approved written protocol
that indicates the objective and methods to conduct
the study.
Protocol contains:
• A descriptive title and purpose of study
• Identification of article by name, chemical abstract
number, code number
• Name of sponsor, name of address of testing facility
• Number, body weight, sex, source of supply, species,
strain, sub strain and age of test system.
• Procedure of identification of test system
• Description of experimental design

• Description or identification of the diet used in the study
• Description or identification of the solvents, emulsifiers
or materials used to solubilise and suspend the test and
control article before mixing with the carrier.
• Description shall include specifications of acceptable
level of contaminants that may interfere the study.
• Type and frequency of test, analyses and measurements
to be made.
• Each dosage level, expressed in mg/kg of body weight
of the article to be administered and its frequency.
• Records to be maintained. Date of approval of protocol
by the sponsor and signed with date of study director
• All changes or revisions of approved protocol shall be
documented, signed by study director.

CONDUCT OF THE STUDY
• Conduct of study should be in accordance with
the protocol.
• Test systems shall be monitored about conformity
with the protocol.
• Specimens shall be identified by test system,
study, nature, and date of collection. Also this
information should be present on the specimen
container.
• Records of gross findings for a specimen from
post-mortem observations should be available to
pathologist.

• All data generated during the study shall be
recorded directly in legible ink. Data entry shall
be dated on the date of entry and signed by
person entering data
• Any changes in the entry should also be entered
along with the reason of the change and the sign
of the person entering the data
• In automated data collection and any changes in
the automated data collection along with the
reason of change, the individual responsible for
direct data input shall be identified at the time of
data input.

• Reporting of non clinical laboratory study
results.
• Storage and retrieval of records and data
• Retention of records
SUBPART H – RECORDS AND
REPORTS

REPORTING OF THE STUDY
CONDUCTED
A final report shall be prepared for each study
and shall include the following :
• Name and address of the facility.
• Date of initiation and completion of study
• Objectives and procedures including any
changes in the original protocol.
• Statistical methods used to analyze data
• Test and control articles used along with their
name, code number, strength, purity, and
composition.

• Description of methods used
• Description of test system
• Number of animals used, sex, body weight range,
source of supply, species, strain and sub strain,
age and procedure of identification
• Description of dosage, dosage regimen, route of
administration, and duration
• Description of circumstances that can affect the
quality and integrity of the data
• Name of study director, scientists and other
professionals involved.

• Description of transformations, calculations, or
operations performed on the data, a summary and
analysis of the data
• Signed and dated reports of each individual
scientists
• Locations where all specimens, raw data, and
final report.
• Final report to be signed and dated by the study
director.
• Corrections/additions to a final report shall be in
the form of an amendment by the study director.

STORAGE & RETRIEVAL OF RECORDS
AND DATA
• All raw data, documentation, protocols, final
reports and specimens generated as a result of a
non clinical laboratory study shall be retained.
(except those specimens of mutagenicity tests or
wet specimens like urine or blood)
• Archives for orderly storage and expedient
retrieval of records and data should be present.
• Conditions of storage shall minimize damage of
documents or specimens in accordance for the
time period of their retention and nature of
documents and specimens

• A testing facility may contract with
commercial archives to provide a repository
for all material to be retained.
• An individual shall be identified as
responsible for the archives and only the
authorized personnel shall enter the
archives.
• Material retained or referred to within the
archives shall be indexed to permit
expedient retrieval.

RETENTION OF RECORDS AND DATA
A) Documents, records, data and specimens of a non
clinical laboratory study shall be retained in the
archives for a period of :-
• At least 2 years following the date on which an
application for a research and marketing permit were
submitted for approval by FDA.
• At least 5 years following the date on which an
application for a research and marketing permit of
Investigational New Drug (IND) or Investigational
Device Exemptions (IDE ) were submitted for approval
by FDA.
• At least 2 years following the date on which the study is
completed, terminated, or discontinued for which no
application is submitted for research or marketing permit.

B) Wet specimens, samples of test and control articles
which are fragile and differ markedly in stability and
storage shall be retained as the quality of preparation
affords evaluation.
C) Master schedule sheet, copies of protocols and records
of quality assurance inspections shall be maintained as
an easily accessible system of records.
D) Summaries of training and experience and job
descriptions maintained to be retained with the testing
facility employment records
E) Records and reports of maintenance, calibration and
inspection of equipment shall be retained.
F) If a testing facility goes out of business, all raw data,
documentation shall be transferred to the archives of the
sponsor of study and should be reported to FDA.
G) Records retained should be original or true copies such
as photocopies, microfilm etc

• Purpose
• Grounds for Disqualification
• Notice of and opportunity for hearing on proposed
disqualification.
• Final order on disqualification
• Actions upon disqualification
• Public disclosure of information regarding
disqualification
• Alternative or additional actions on disqualification
• Suspension or termination of testing facility by sponsor.
• Reinstatement of a disqualified testing facility.
SUBPART I – DISQUALIFIACTION OF
TESTING FACILITY

PURPOSE
• Permit exclusion from completion of studies which
has failed to comply with requirements of GLP
regulations until it can be adequately demonstrated
that such non compliance does not occur and affect
the validity of data.
• Exclude studies completed after date of
disqualification until the facility satisfies the GLP
guidelines.
• Determine that a non clinical study may or may not
be considered in support of an application for
research or marketing permit.

GROUNDS FOR DISQUALIFICATION
The commissioner may disqualify a testing facility if:-
• Testing facility fails to comply the GLP regulations
• Non compliance adversely affects the validity of the
non clinical studies.
NOTICE OF AND OPPURTUNITY FOR
HEARING OF DISQUALIFICATION
• A written notice proposing that the facility be
disqualified will be issued by the commissioner
indicating the grounds of disqualification.
• A hearing on the disqualification shall be conducted
in accordance with the requirements of the
regulations

FINAL ORDER ON DISQUALIFICATION
• If the commissioner, after the hearing, and an
evaluation of the records of disqualification, makes
the findings and shall issue a final order
disqualifying the facility. Such final order shall
include a statement of basis of determination and
notify the testing facility.
• If the commissioner, after the regulatory hearing and
an evaluation of the records of disqualification, does
not make any findings and shall issue a final
order terminating the disqualification. Such final
order shall include a statement of basis of
determination and notify the testing facility ad
provide a copy.

ACTIONS UPON DISQUALIFICATION
• Once a testing facility has been disqualified , any
non clinical study conducted by the disqualified
facility may be examined to determine whether such
study would be essential.
• If it is determined to be essential, the FDA shall also
determine whether the study is acceptable,
notwithstanding the disqualification of facility.
• Any study 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, by
submitting validating information.

• If study is determined to be unacceptable, such
data will be eliminated and such elimination may
serve as new information justifying the termination
or withdrawal of approval of application.
• No nonclinical study begun by a facility after the
date of disqualification shall be considered in
support of application for research or marketing
permit unless the facility has been reinstated.
• The determination that a study may not be
considered in support of an application does not
relieve the applicant for a permit of any obligation
under any regulation to submit the results of the
study to the FDA.

PUBLIC DISCLOSURE OF
DISQUALIFICATION
• Upon issuance of final order disqualifying, the
commissioner notifies interested persons.
• Such notice may be given, when it is believed that
the such disclosure would further promote
compliance with GLP regulations.
• Such notice shall state that the studies performed
by the disqualified facility will not be considered
by the FDA.
• If the notice is sent to another Federal Government
Agency, the FDA will recommend that the agency
also consider that the non clinical study should be
accepted or not.

• If notice is sent to any other person, it shall state
that it is given because of the relationship
between the facility and the person being notified
and that the FDA is not advising or
recommending any action be taken by the person
notified.
• A determination that a testing facility has been
disqualified and the administrative record are
disclosable to the public.

ALTERNATIVE OR ADDITIONALACTIONS
TO DISQUALIFICATION
• The FDA can refuse to consider a study for the
application of research or marketing permit, if it
finds that the study was not conducted in accordance
with the regulations of GLP, without disqualifying
the testing facility that conducted the study.
• The FDA may initiate judicial proceedings(civil or
criminal) against the testing facility or sponsor of a
non clinical laboratory study simultaneously or
subsequently with disqualification.

SUSPENSION OR TERMINATION OF A
TESTING FACILITY BY A SPONSOR
• Termination by a sponsor from participation in a
non clinical study that is being conducted as a
part of application for research or marketing
permit submitted to FDA, shall be notified to the
FDA within 15 working days and the notice hall
include the reasons for termination or suspension
• Suspension or termination of a facility does not
relieve it of any obligation under any regulation
to submit the results of study to the FDA.

REINSTATEMENT OF DISQUALIFIED FACILITY
• If a testing facility wishes to be reinstated, they shall
present a writing to the commissioner reasons why it
believes to be reinstated and a detailed description of
the corrective actions taken to assure there is no
reason for disqualification anymore.
• The commissioner evaluates the submission, and
ensures that the testing facility will conduct future
studies in compliance with the regulations of GLP,
and if any studies are being conducted, that the
quality and integrity is not compromised.
• If a testing facility is reinstated, the commissioner
shall notify the facility and all other organisations
which were reported about the disqualification.

GOOD LABORATORY PRACTICES - A DETAILED STUDY

GOOD LABORATORY PRACTICES - A DETAILED STUDY

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