Good Laboratory Practice:

Quality Assurance of Analytical

Measurements
Which Laboratory you will prefer to go?
ABC

• Having untrained staff

• Having old deviated instruments
• Having Expired chemicals
• Having poor housekeeping
XYZ

• Qualified and Trained Staff

• Calibrated instruments
• Valid Chemicals
• Proper storage mechanism
• Good Housekeeping
What more do you expect from Good
Laboratory?
What is ISO?
 ISO: International organization for
standardization, located in Geneva

• Purpose: To Establish Quality Standard framework

throughout the world
• First released its standard ISO 9001:1987
• NABL accreditation system in accordance with ISO/IEC
17025: 2017.
 NABL
National Accreditation Board for Testing and Calibration
Laboratories (NABL) is the sole Laboratory Accreditation body
authorised by Government of India (GOI). NABL is an
autonomous body under the aegis of Department of Science &
Technology (GOI).

The accreditation to testing and calibration laboratories are

granted in accordance with ISO/ IEC 17025: 2005 and medical
testing as per ISO 15189: 2003.
 COMPETENCE OF A LABORATORY

 In evaluating the competence of a

laboratory, the following methods are
used:
• On-the-spot assessment of the laboratory by the experts.
• By evaluating the results of a particular test /
measurement in a proficiency testing programme.
International Standards and Guides
applicable to laboratories
 ISO/IEC 17000 : Conformity assessment -
Vocabulary and general principles

 ISO/IEC 17025: General Requirements for the

Competence of Testing & Calibration
Laboratories

 ISO 15189 : Medical Laboratories -

Particular Requirements for Quality and
Competence
Functions of An Accreditation Body

 To promote the development and maintenance

of good practice in testing and measuring

 To establish and maintain international

recognition for its national accreditation
programmes
BENEFITS OF ACCREDITATION
 National and international recognition
 Public and industry acceptance
 Assurance to clients
 Provides global equivalence
 Provides comparability in measurements
 Decision makers can rely on test results
 Improves staff motivation
 Ensures better support in the event of legal
challenge
 Saves money by getting it right at first time.
Good Laboratory Practice - Definition:

•Quality system concerned with the

organisational process and the conditions
under which non-clinical health and
environmental safety studies are planned,
performed, monitored, recorded, archived
and reported.
What is Good Laboratory Practice (GLP)?

•The goal of GLP is to certify that every step of

the analysis is valid.
•Standard Operating Procedures (SOP)
•Quality Assurance Unit (QAU)
 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.
GLP – Objectives:

Promote the quality and validity of data

generated in the testing of chemicals
Protect human health and the environment
Facilitate data recognition
Avoidance of duplicative testing
Animal welfare
Time and resource efficiency
Avoidance of non-tariff barriers to trade
• GLP is about recognition of a quality system that has
organisational processes and conditions that in accordance
with OECD(Organization for Economic Cooperation and
Development) criteria. ISO/IEC 17025 accreditation is a
formal recognition for technical competence to undertake
specific tests or calibrations. In general GLP is used for non-
clinical health & safety studies that are often called for in
regulations while ISO/IEC 17025 accreditation is used
normally voluntary. Laboratory accreditation to ISO/IEC
17025 is for routine testing and measurement while GLP is a
non-routine work covers under the non-clinical safety
studies. Examples of non-routine work may include dosing
animals or spraying fields. Only OECD GLP compliance can
provide an effective quality system that gives regulators the
necessary confidence in relation to how non-clinical health
and safety studies are planned, performed, monitored,
recorded, reported and archived.
• Scope:
GLP is developed for conducting non-clinical laboratory
studies that support applications for research or marketing
permits for products regulated by the FDA.

ISO 17025 applied to all laboratories where testing and/or

calibration are performed and/or formed part of inspection
and product certification. In principle, ISO 9001 is adopted in
ISO 17025.

Similarities between both requirements:

i) Requirements on organization and personnel
ii) Requirements on equipment, sampling and validation
iii) Requirements on reporting / record and control of
records
GLP vs ISO 17025
Laboratory accreditation addresses and
underwrites the technical competence of a
laboratory to carry out specified determinations on
a continuing basis to defined standards.
A laboratory accredited according to ISO 17025
can be considered to have satisfied many of the
GLP requirements.
However, certain fundamental requirements of
the GLP Principles are not covered by or are less
stringent in laboratory accreditation
 GLP vs ISO 17025
• ISO/IEC 17025 accredited laboratory has approximately
70% of the managerial and technical issues of the GLP
directives covered, while 30% can be provided as an
extension of the existing laboratory quality
management system
• Not covered:
• use of study plans
• Study Director as a concept
• More stringent requirements under GLP:
• recording and reporting of data
• management of data retained in archives to allow complete
reconstruction of a study
• programme of independent quality assurance including
internal audits of every study.
GLP – the history

1975 FDA inspections were made at a contract research

laboratory (Industrial Biotest Corporation), 20.000 studies
for hundreds of drugs and pesticides
Experiments were poorly conceived, carelessly executed or
inaccurately analyzed or reported
Data fraud:
 Reporting of observations for animals previously designated as dead
or euthanized
 Pathology summary altered to present more favorable findings
Original records were unavailable for review
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.
GLP - History:
1976 : GLP regulation of FDA on non-clinical laboratory studies
1978 : OECD establishes expert group
1981 : OECD Council Decision on Mutual Acceptance of Data (MAD):
GLP-Principles contained in Annex II
1983 : Recommendation concerning compliance monitoring
1987/88 : EU adopts GLP Directives
1989 : OECD Council Decision-Recommendation on Compliance
Guides for Compliance Monitoring Procedures for GLP
Guidance for the Conduct of Laboratory Inspections and Study Audits
1995 : REVISED GUIDANCE FOR GLP MONITORING AUTHORITIES
FOR COMPLIANCE MONITORING PROCEDURES FOR GOOD LABORATORY
PRACTICE (GUIDES) + New expert group on GLP - Principles

1997 : Adoption of Revised GLP- Principles

1999 : Amendment of EU GLP Directives following OECD
2004: Codification of GLP Directives
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
The GLP Principles

1. Test facility organization and personnel

2. Quality Assurance (QA) program
3. Facilities
4. Apparatus materials and reagents
5. Test systems
6. Test and reference items
7. Standard Operating Procedures (SOP’s)
8. Performance of the study
9. Reporting of study results
10. Storage and retention of records and materials
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?
All GLP texts, irrespective of their origin, stress
the importance on the following points
five points:

1. Resources: organization, personnel, facilities

and equipment
2. Characterization: test items and test systems
3. Rules: study plans (or protocols) and written
procedures
4. Results: raw data, final report and archives
5. Quality Assurance.
1. Resources
Organization and personnel
GLP regulations require that the structure of R&D
organizations and the responsibilities
of R&D personnel be clearly defined.
GLP also stresses that there should be sufficient staff to
perform the tasks required. The
qualifications and the training of staff must also be defined
and documented.
Facilities and equipment
The regulations emphasize the need for sufficient facilities
and equipment to perform
the studies.
All equipment must be in working order. To ensure this, a
strict programme of qualification,
calibration and maintenance must be adopted.
2. Characterization

In order to perform a study correctly, it is essential

to know as much as possible about the
materials used during the study. For studies that
evaluate the properties of pharmaceutical
compounds during non-clinical studies, it is a
prerequisite to have details about the test item
and the test system (often an animal or plant) to
which the test item is to be administered.
3. Rules
Protocols and written procedures
The main steps of research studies are prescribed in the
study plan or protocol. Being
able to repeat studies and obtain similar results is a sine qua
non of mutual acceptance of
data and, indeed, a central tenet of the scientific method, so
the details of routine procedures
must also be available to scientists involved in the study.
However, the protocol,
which provides the experimental design and timeframe for the
study, does not contain all
the technical detail necessary to conduct the study. These
details are found in written
standard operating procedures (SOPs). With the protocol and
the SOPs it should be possible
to repeat the study exactly, if necessary.
4. Results
Raw data
All studies generate raw data. These are the outcome of research and
form the basis for
establishing scientific interpretations and arriving at conclusions. The raw
data must also
reflect the procedures and conditions of the study.
Final Report
The study report contains an account of the way in which the study was
performed,
incorporates the study results and includes the scientific interpretation of
the data. The
report is provided to regulatory authorities as part of the submission for
registration and
marketing approval.
Archives
Storage of records must ensure safekeeping for many years and allow
for prompt
retrieval.
5. Quality Assurance

Quality assurance (QA), as defined by GLP, is a team of

persons (often called the
Quality assurance unit – QAU) charged with assuring
management that GLP compliance
has been attained within the laboratory. QA must be
independent from scientists involved
in the operational aspects of the study being performed.
QA functions as a witness to the
whole non-clinical research process.
Management must
appoint trained persons to perform the work

• Study director- Single point of Study control

• Quality assurance – Ensures management of GLP

compliance

• Archivist – manages archives

• Study Personnel – Perform study according to instructions

 Resources

Resources is divided into three parts:

1. Management
2. Personnel
3. Facilities: buildings and equipment

In addition to this section comprising general comments on

the GLP requirements for management, the manual includes
a separate section with more detailed information on
the responsibilities of management and the study director
Management has the overall responsibility for the implementation of
both good science and good organization within their institution

Good Science
• Careful definition of experimental design and study parameters.
• Science based on known scientific principles.
• Control and documentation of experimental and environmental variables.
• Careful and complete evaluation and reporting of results.
• Results becoming part of accepted scientific knowledge.

Good Organization
• Proper planning of studies and allocation of resources.
• Provision of adequate facilities, infrastructure and qualified staff.
• Definition of staff responsibilities and provision of staff training.
• Establishment of procedures to ensure proper conduct of studies.
• Good record keeping and organized archives.
• Implementation of verification procedures for study conduct and results.
Planning (Master Schedule)
The record of planning/resource allocation required by GLP
is called the master schedule.
• The system is described in an approved SOP.
• Responsibilities for its maintenance and updating are
defined by management.
• Various versions of the master schedule are approved
and maintained in the archive as data.
• Distribution is adequate and key responsibilities are
identified.
Test Facility Organization and Personnel
Test Facility Management’s Responsibilities

The management should ensure that

The principals of GLP are complied with
A sufficient number of qualified
personnel,appropriate facilities,equipment and
materials are available
Records of qualifications, job descriptions,
training and experience of personnel are
maintained
Personnel understand the functions they are
to perform
Test Facility Organization and Personnel
Test facility Management’s Responsibilities

Appropriate and Valid SOP’s are established

and followed
A Quality Assurance Program is in place
A Study Director and a Principal Investigator, if
needed, is designated
Documented approval of the study plan
The study plan is available to quality assurance
personnel
Test Facility Organization and Personnel
Test Facility Management’s Responsibilities

• A document control system is in place

• Purchased materials meet specified
requirements
• Test and reference items are appropriately
characterized
• Clear lines of communication exist
• Computerized systems are suitable for their
intended purpose
Test Facility Organization and Personnel
Study Director’s Responsibilities

Has the responsibility for the overall performance

of the study and the final report
Approves the study plan and amendments and
communicate them to the QA personnel
Ensures that SOP’s, study plans and their
amendments are available to study personnel
Ensures that the SOP’s are followed, assess the
impact of any deviations and takes appropriate
corrective and preventive action
Test Facility Organization and Personnel
Study Director’s Responsibilities

• Ensures that
• Raw data are documented and recorded
• Computerized systems are validated
• SOPs are followed
• Deviations are acknowledged
• Records and data are archived
• Sign and date the final report to indicate acceptance of responsibility
 PERSONNEL
• Organization chart
• Curriculum vitae
• Training records
• Job description

FACILITIES: BUILDINGS AND EQUIPMENT

• The laboratory must be big enough to accommodate the

number of staff working in it
• Each operator should have a workstation sufficiently large to
be able to carry out the operation efficiently.
• Separation ensures that different functions or activities do not
interfere with each other or affect the study.
Arrangement

Ideally there should be separate areas for:

• storage of test items under different conditions

• storage of control items
• storage of vehicles
• handling of volatile materials
• weighing operations
• mixing of different material forms
• storage of prepared material
• cleaning equipment
• offices and refreshment rooms
• changing rooms.
Equipment Suitability and Calibration

• To perform a study properly, adequate equipment must

be available.
• All equipment should be suitable for its intended use.
• All equipment properly calibrated and maintained.
• The scientist must decide the appropriate frequency of
calibration for each instrument.
• This frequency should be documented in an SOP and
respected. Logbooks should be kept to record the use of
equipment.
• Records must be kept for all acts of maintenance involving
buildings/equipment.

All these points have to be well documented,

Facilities
Suitable size, construction and location
Adequate degree of separation of the different
activities
Isolation of test systems and individual projects to
protect from biological hazards
Suitable rooms for the diagnosis, treatment and
control of diseases
Storage rooms for supplies and equipment
Facilities
• Separate areas for receipts and storage of the test
and reference items
• Separation of test items from test systems
• Archive facilities for easy retrieval of study plans,
raw data, final reports, samples of test items and
specimen
• Handling and disposal of waste in such a way not
to jeopardize the integrity of the study
Apparatus, Materials and Reagents

Apparatus of appropriate design and adequate

capacity
documented Inspection, cleaning, maintenance
and calibration of apparatus. Calibration to be
traceable to national or international standards
Apparatus and materials not to interfere with the
test systems
Chemicals, reagent and solutions should be
labeled to indicate identity, expiry and specific
storage instructions.
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
 CHARACTERIZATION

Characterization is about accumulating knowledge about

the materials used in the experiments.

The GLP Principles require that proper conditions for the

receipt and storage of the test item are in place.

The test item is most frequently characterized by its analytical

profile e.g. chemical identity, impurity, solubility, stability, etc.
 Test and Reference Items
Characterization
• Identification of each test and reference item
• Code, number, name etc
• Identification of each batch of the test or reference items
• Batch number, purity, composition, concentration etc
• Cooperation between the sponsor and the test facility
• Verification of identity of the test item
Storage
•Test items should be stored under closely controlled conditions,
particularly with respect to access and environment.

•The stores manager should ensure that only designated staff have
access to the material
Test Systems
Records of source, date of arrival,
and arrival conditions of test systems
Acclimatization of biological systems to the test
environment
Proper identification of test systems in their housing
or container or when removed
Cleaning and sanitization of housings or containers
Pest control agents to be documented
Avoid interference from past usage of pesticides
 RULES
The institute’s rules for organizing and conducting GLP
studies must be defined in documents approved by
management. Rules defining who does what, how, when and
where, are called PRESCRIPTIVE documents.

There are two main types of prescriptive documents:

• The protocol (or study plan) which describes how the study
is designed and how it is to be conducted, including the
expected timeframe of the study;

• The standard operating procedures (SOP) which provide

detailed instructions about how to actually perform each
technical procedure.
THE PROTOCOL OR STUDY PLAN

The laboratory should have prescriptive documents that

support and regulate the conduct of the scientific studies.
The purpose of these documents is to:

• Describe general policies, decisions and principles

governing the way in which the research centre operates;

• Define the experimental design for particular studies;

• Instruct staff about how to carry out routine operations;

• Provide support retrospectively when investigating what

was actually done.
 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
Standard Operating Procedures

• Approved SOP’s to ensure the quality and integrity of the laboratory

data
• Immediately available current SOP’s relevant to the activities being
performed
• Deviations from SOP’s to be acknowledged by the study director
Standard Operating Procedures
• SOP’s for
• Test and reference items
• Receipt, identification, labeling,handling, sampling, storage
• Apparatus
• Use, maintenance, cleaning, calibration
• Computerized systems
• Validation, operation, maintenance security, change control, back-up
• Materials, reagents and solutions
• Preparation and labeling
Standard Operating Procedures

Record keeping, reporting, storage and retrieval

Coding system, data collection, preparation of reports,
indexing system, handling of data
Test system
Room preparation, environmental room conditions,
receipt, transfer, identification etc, test system
preparation, observations etc,
Quality Assurance Procedures
Operation of QA personnel
 RESULTS
Data collection requires:
– adequate numbers of well-trained staff
– appropriate equipment
– good preparation with planning records available
– complete instructions.
The raw data should include :
– “WHAT was done”
Relevant SOPs were followed and that the results of the observation or
measurement were included.
– “HOW it was done”
Indicating that data were collected and recorded in accordance with the
methods set out in the SOPs and protocol. There should be indications
of any deviations from the instructions.
– “WHEN the work was performed”
Demonstrating that the timeline in the protocol was followed. This
should be done by recording the date
– “WHO performed the work”
Reporting of Study Results
• General
• Final report for each study
• Scientists to sign and date their reports
• Approval by the Study Director
• Corrections, additions, amendments to be signed and dated by the study director
• Content of the final report
• Identification of the study
• Descriptive title, identification of the test and reference item, purity, stability.
Reporting of Study Results
Information on sponsor and test facility
Name and addresses of the sponsor, test facility, study
director, the scientists involved to the study etc)
Experimental starting and completion dates
A Quality Assurance Program Statement
Description of materials and test methods
Results
Including uncertainties, level of significance
Evaluation discussion and conclusions
Storage (of samples, reference items, raw data,
final reports etc
All data generated during the conduct of a
study should be identified and recorded
directly, promptly, accurately, legibly and
indelibly by the person entering the data, and
be signed or initialled, and dated. Any
changes should me made so that the previous
entry is not obscured and if necessary should
indicate the reasons for corrections. Such
changes should be accompanied by date and
signature of the person making the change.
What is Archived?

• Study data.
• Personnel data.
• Systems data.
• Quality assurance files.
Storage and Retention of Records and
Materials
What to retain in archives
The study plan, raw data, samples
Inspection data and master schedules
Qualification, training experience, job description
Maintenance and calibration data
Validation data
SOPs
Environmental, health & safety
monitoring records
Storage and Retention of Records and
Materials
Retention period to be defined
If any study material is disposed of before expiry
the reason to be justified and documented
Index of materials retained in the archives
Controlled access to the archives
In case that the laboratory goes out of business the
archives are transferred to the relevant sponsors(s)
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
QUALITY ASSURANCE (QA)
Lead Quality Assurance
• Lead quality assurance must regularly communicate with
test site QA so that there is proper inspection coverage of
the whole study. • The respective responsibilities for the lead
QA and site QA must be established before experimental work
starts.
• The lead quality assurance must make sure that the study plan is
checked and that the final report is inspected.
• “Quality assurance inspections of the final report should
include verification that the principal investigator contributions
(including evidence of quality assurance at the test site) have
been properly incorporated.”
• The lead quality assurance must make sure that the quality
assurance statement in the final report covers both the work
undertaken at the test facility and the work performed at the
various test sites.
Quality Assurance Program
General
• Documented Quality Assurance Program (QA)
• Designated individuals as members of the QA team directly
responsible to the management
• QA members not to be involved
in the conduct of the study being assured
Quality Assurance Program
Responsibilities of the QA Personnel

Access to the updated study plans and SOP’s

Documented verification of the compliance of
study plan to the GLP principals
Inspections to determine compliance of the study
with GLP principles. Three types of inspection
Study-based inspections
Facility-based inspections
Process-based inspections
Quality Assurance Program
Responsibilities of the QA Personnel

• Inspection of the final reports for accurate and full

description
• Report the inspection results to the management
• Statement
Test Facility Organization and Personnel
Study Personnel Responsibilities

Knowledge of the GLP principals

Access to the to the study plan and appropriate
SOP’s
Comply with the instructions of the SOP’s
Record raw data
Study personnel are responsible for the quality of
their data
Exercise health precautions to minimize risk
Ensure the integrity of the study
 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
What happens if a workplace does not
comply with Good Laboratory Practice
standards?
Disqualification of a Facility
Before a workplace can experience the consequences of
noncompliance, an explanation of disqualification is needed
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 following consequences of noncompliance:

 The authority will send a written proposal of

disqualification to the testing facility
 A regulatory hearing on the disqualification will be
scheduled
 If the authority 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 authority 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.
Thanks