Good Laboratory Practices

&
Good Clinical Practices


Presented by:-
Mr. Swapnil L. Patil
M.Pharm (Semester-2)
Department of Pharmaceutics


Pad. Dr. D. Y. Patil College of Pharmacy,
Akurdi, Pune, Maharashtra, India, 411018.

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Good Laboratory Practices

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Contents:
Introduction
History
Objective
Rules and regulation
Noncompliance


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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, recorded,
reported and archived.

GLP is sometimes confused
with the standards of
laboratory safety like
wearing safety goggles.
GOOD LABORATORY
PRACTICE

GLP applies to nonclinical studies
conducted for the assessment of the safety
or efficacy of chemicals (including
pharmaceuticals).

GLP helps assure regulatory authorities that
the data submitted are a true.

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HISTORY
The formal regulatory concept of Good
Laboratory Practice (GLP) originated in the
USA in the 1970s.

The FDAs publication of Proposed Regulations on
GLP in 1976, with establishment of the Final Rule in
June 1979 (21 CFR 58).

In 1981 an organization named OECD produced
GLP principles that are international standard.





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WHY WAS GLP CREATED?
In the early 70s FDA became aware
of cases of ( PLP ) poor laboratory
practice all over the United States.
FDA decided to do an in-depth
investigation in 40 toxicology labs.
They discovered a lot fraudulent
activities and a lot of poor lab
practices.
Examples of some of these ( PLP )
poor lab practices found were
Equipment not been calibrated to
standard form , therefore giving
wrong measurements.
Incorrect/inaccurate accounts of the
actual lab study
Inadequate plan
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 lotion and
deodorants had developed cancer
and died
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Industrial Bio Test lab threw the dead mice and covered
results deeming the products good for human use.

Those involved in production, distribution and sales for
the IBT lab eventually served jail time.
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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.
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MISSION OF GLP
Test systems
Archiving of records .
Apparatus, material and reagent facilities.
Quality assurance programs.
Performance of the study.
Reporting of study results.
Standard operating procedures (SOP)
21 CFR Part 58: Non-Clinical
Laboratory Studies
Subpart A: General Provisions
Subpart B: Organization and 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 Non-Clinical
Laboratory Study
Subpart J: Records and Reports
Subpart K: Disqualification of Testing Facilities
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GLP Regulations: Rules and Tools
Chemical and sample inventory,
expiration dates
TEST, CONTROL, AND
REFERENCE SUBSTANCES
Timely reporting, storage of raw
data and reports
RECORDS AND REPORTS
Standard operating procedures FACILITY OPERATION
Calibration, logbooks of use, repair,
and maintenance
EQUIPMENT
Maintain adequate space/separation
of chemicals from office areas
FACILITIES
Training records, CVs, GLP training ORGANIZATION AND
PERSONNEL
Documentation (Tools) GLP Regulations (Rules)
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Organization and 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.

(b)Each testing facility shall maintain a current summary of
training and experience and job description for each
individual engaged in or supervising the conduct of a
nonclinical laboratory study.

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Organization and Personnel

58.33 Study Director

For each nonclinical laboratory
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, as
well as for the interpretation,
analysis, documentation, and
reporting of results, and represents
the single point of study control.

58.35 Quality Assurance
Unit

A testing facility shall have a
quality assurance unit which shall
be responsible for monitoring
each study to assure management
that the facilities, equipment,
personnel, methods, practices,
records, and controls are in
conformance with the regulations
in this part. For any given study,
the quality assurance unit shall be
entirely separate from and
independent of the personnel
engaged in the direction and
conduct of that study.

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Facilities
58.41 General

Each testing facility shall be of suitable size and
construction to facilitate the proper conduct of
nonclinical laboratory studies. It shall be designed so
that there is a degree of separation that will prevent any
function or activity from having an adverse effect on the
study.

Animal care facilities
Animal supply facilities
Facilities for handling test and control articles
Laboratory operation areas
Specimen and data storage facilities

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Equipment
58.61 Equipment Design

Equipment used in ... shall be of appropriate design and adequate capacity
...

58.63 Maintenance and Calibration

(a) The written standard operating procedures ...

(b) Written records shall be maintained ...

Log book

Fit for use
Not for GLP use.
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Equipment
Verification (Testing):
external check of
equipment accuracy (e.g.
check balance accuracy
against weights at
laboratory- no adjustment)
Calibration: equipment is
adjusted based on
comparison to certified or
known reference materials
(e.g. balance adjusted after
comparison to certified
weights by trained
professional)
Standardization:
comparison with similar
equipment (e.g. use two
thermometers of similar
design to compare
readings)

Verification??
Calibration ? Standardization?
??
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Protocol , Reports and Records

58.120 Protocol
Each study shall have an approved written protocol that clearly indicates the
objectives and all methods for the conduct of the study.

58.130 Conduct of a Non-clinical Laboratory Study
The nonclinical laboratory study shall be conducted in accordance with the
protocol
58.185 Reporting of Non-clinical Laboratory Study Results

A final report shall be prepared for each nonclinical laboratory study ...

58.190 Storage and Retrieval of Records and Data

All raw data, documentation, protocols, final reports, and specimens ... shall
be retained.

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Raw Data

Definitions. Raw data means
any laboratory worksheets, records,
memoranda, notes, or exact copies
thereof, that are the result of original
observations and activities of a study and
are necessary for the reconstruction and
evaluation of the report of that study.
If anyone scribble some notes on a scrap of paper,
are those notes considered raw data?
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Raw Data
examples of raw
data:-

Logbooks (to record
temperatures or
equipment use, repair,
and maintenance)
Field or laboratory
notebooks
Forms (for field or
laboratory
observations, chain-of-
custody, sample or
chemical receipt)
Training reports
Computer printouts
Recorded data from
automated instruments
Question:
What happens if you
make a mistake?
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Standard Operating Procedures (SOP)










40 CFR Part 160 (EPA GLP regulations)
Section 160.81 Standard operating procedures. (a) A testing
facility shall have standard operating procedures in writing
setting forth study methods that management is satisfied are
adequate to insure the quality and integrity of the data
generated in the course of a study.
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 (SOP)
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Standard Operating Procedures
(SOP)






SOPs should
accurately reflect
how routine tasks
are performed
Routine inspection,
cleaning, maintenance,
testing and calibration.
Actions to be taken in
response to equipment
failure.
Reviewed on regular
basis.
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What happens if a workplace does
not comply with federal Good
Laboratory Practice standards?
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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.

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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


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Upon Disqualification
If the commissioner finds that the facility showed a
noncompliance, 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.
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Upon Disqualification
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



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Upon Disqualification
The FDA may turn it over to the federal, state or local
law enforcement
The facilitys 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


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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

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Good Clinical Practice
Contents

Glossary
Principles of GCP
IEC/IRB Responsibilities
Investigator Responsibilities
Sponsor Responsibilities
Protocols and Amendments
Investigators Brochure
Essential Documents


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Glossary
Adverse drug reaction (ADR)
Serious Adverse Event (SAE)
Audit
Blinding/masking
Investigator
Protocol
Sponsor
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History of Good Clinical Practice
Prior to an actual set of guidelines to follow for good clinical
practice, clinical studies were dangerous and could result in
serous disease, or possibly death.

The Nuremburg Code of 1947
Experiments performed in Germany during WWII opened the eyes of
the world for guidance for clinical testing on humans.
The code did set ethical guidelines, but it lacked legislation to back it
up.
Declaration of Helsinki
In 1964, the World Medical Association established
recommendations guiding medical doctors in biomedical research
involving human subjects. These guidelines influenced national
legislation, but there was no set standard between nations.
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GOOD CLINICAL
PRACTICE
FDA ICH
21 CFR International
Electronic Docs.
Inf. Consent
Financial Disclosure
IRBs
IND regs.
glossary
principles
IRBs
Investigator
Sponsor
Essential Docs


ICH Guidelines
ICH Guidelines are divided into 4 main topics:

Quality Topics relate to chemical and pharmaceutical quality
assurance
e.g. Q1 Stability Testing

Safety Topics relate to preclinical studies
e.g. S1 Carcinogenicity Testing

Multidisciplinary Topics cross-cutting topics
which dont fit into one of the other categories
e.g. M1 Medical Terminology

Efficacy Topics relate to clinical studies in human subjects
e.g. E6 Good Clinical Practice;
e.g. E2A Clinical Safety Data Management:
e.g. E9 Statistical Principles for Clinical Trials


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FDA Regulations
21 C.F.R. Part 312, Subpart D (Duties of
Sponsors, Investigators)
21 C.F.R. Part 50 (Informed Consent)
21 C.F.R. Part 56 (Institutional Review
Boards)
21 C.F.R. Part 54 (Investigator Financial
Disclosure)

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What is
Good Clinical Practice (GCP) is defined as a
standard for the design, conduct,
performance, monitoring, auditing,
recording, analyses and reporting of clinical
trials that provides assurance that the data
and reported results are credible and
accurate, and that the rights, integrity and
confidentiality of trial subjects are
protected


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Good Clinical Practice (GCP) is an
international ethical and scientific quality
standard for designing, conducting,
recording, and reporting trials that involve
the participation of human patients.

Compliance with this standard provides
public assurance that the rights, safety and
well-being of trial patients are protected and
clinical trial data are credible.

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Are mainly focused on the protection of human rights
in clinical trial.
Provide assurance of the safety of the newly
developed compounds.
Provide standards on how clinical trials should be
conducted.
Define the roles and responsibilities of -
Clinical Sponsors,
Clinical Research Investigators,
Clinical Research Associates, And
Monitors.

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Principles of ICH GCP
1. Clinical trials should be conducted in accordance with the ethical
principles that have their origin in the Declaration of Helsinki, and
that are consistent with GCP and the applicable regulatory
requirements.

2. Before a trial is initiated, foreseeable
risks and inconveniences should be
weighed against the anticipated benefit
for the individual trial subject & society.

A trial should be initiated and continued only if the anticipated
benefits justify the risks.


Benefits
RISKS
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Principles of ICH GCP Continued
3. The rights, safety, and well-being of the trial subjects are
the most important considerations and should prevail
over interests of science & society.

4. The available non-clinical & clinical information on an
investigational product should be adequate to support the
proposed clinical trial.

5. Clinical trials should be scientifically sound, and
describe in a clear, detailed protocol.

6. A trial should be conducted in compliance with the
protocol that has received prior IRB (or IEC) approval.

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Principles of ICH GCP Continued
7. The medical care given to, and medical decisions made
on behalf of, subjects should always be the responsibility
of a qualified physician or, when appropriate, of a
qualified dentist.

8. Each individual involved in conducting a trial should be
qualified by education, training and experience to
perform his or her respective tasks.

9. Freely given informed consent should be obtained from
every subject prior to clinical trial participation.


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Principles of ICH GCP Continued

10. All clinical trial information should be recorded, handled,
and stored in a way that allows its accurate reporting,
interpretation, and verification.

11. The confidentiality of records that
could identify subjects should be
protected, respecting the privacy
and confidentiality rules in accordance
with the applicable regulatory
compliance.
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Principles of ICH GCP Continued

12. Investigational products should be manufactured, handled,
and stored in accordance with applicable good
manufacturing practice (GMP). They should be used in
accordance with the approved protocol



13.Systems with procedures that assure the quality of every
aspects of the trial should be implemented.
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Institutional Review Board (IRB),
Independent Ethics Committee (IEC)
A formally designated group that oversees research
involving human subjects.

Approves and disapproves human subject research.

According to the standards of the community or the
institution, the IRB/IEC may require modifications to a
protocol to ensure patient safety.

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IRB Function


The primary function of an IRB/IEC is to safe guard the
rights ,safety ,and well being of all trial subjects. This is
accomplished by initial, continuing and annual review.

An IRB should consist of members who collectively have
the qualifications and experience to review and evaluate
the science , medical aspects, and ethics of the proposed
trial.





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IRB Members

1.A minimum of five (5) members.
2.One member whose concern is not scientific.
3.One member who has no personal or familial
relationship to the institution or trial site.
4.Any member with a conflict of interest may not
participate in any part of the review or vote (except to
provide requested information).
5.Individuals with special expertise may be invited to assist
with areas of unique or complex nature. These will not be
voting members.
6.A list of IRB/IEC members and their qualifications
should be maintained.


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IRB/Ethics Committee
All studies must be approved prior to recruiting
participants

IRB must review all documents given to participants

Reporting AEs and Deviations from protocol to the IRB

Maintenance of Records

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Investigator Responsibilities
Adequate Resources
Recruitment
Time
Qualified Staff
Facilities
Training
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Investigator Responsibilities
Medical Care
A qualified MD (or dentist) responsible for
trial-related medical decisions
Provide adequate medical care for AEs or other
significant medical condition
Inform PCP about participation in trial
Make a reasonable effort to ascertain why
participant withdrawals from study
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Investigator Responsibilities
Compliance with Protocol
Investigator should sign off on protocol
Investigator should not implement deviations
from protocol
If deviations occur, they should be documented
and reported at once to the sponsor, the IRB
and other regulatory authorities

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Investigator Responsibilities
Progress Reports
Written summary of trial
status to the IRB
Written reports to the
sponsor or regulatory
authority of any changes
affecting the trial
Safety Monitoring
SAEs should be reported
immediately
AEs should be reported
according to sponsor
guidelines
Supply sponsor & IRB
with requested materials
on participant deaths
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Investigator Responsibilities
Premature Termination
or Suspension
Promptly inform trial
subjects
Assure appropriate
therapy & follow-up
Inform sponsor,
regulatory authorities &
IRB
Final Reporting
Inform IRB of study
completion & a summary
of the trials outcome
Provide sponsor &
regulatory authorities
with all required reports
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Investigators Brochure
Defined as a compilation of the
clinical and nonclinical data on
the investigational product(s)
that are relevant to the study of
the product(s) in human
subjects.
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Clinical Trial Protocol
General Information
Background Information
Trial Objectives & Purpose
Trial Design
Selection & Withdrawal of Participants
Treatment of Subjects
Assessment of Efficacy
Assessment of Safety
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Sponsor Responsibilities
Quality Assurance & Quality Control
Provide written SOPs
Secures agreement between all parties
Data handling
Contract Research Organization (CRO)
Hired by the sponsor to implement trial-related duties
Medical Expertise
Designated medical personnel to advise on trial-related
medical questions and problems
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Sponsor Responsibilities
Trial Design
Designs CRFs
Planning analyses
Trial Management, Data Handling,
Recordkeeping, & Independent Data Monitoring
Committee (DMC)
Qualified personnel to supervise overall conduct of the
study
DMC assesses the progress of the clinical trial
Maintain SOPs for electronic data processing
Inform Investigator of guidelines for record retention

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Essential Documents for the Conduct of a
Clinical Trial
Preclinical trial
commencement

During clinical conduct
of trial

After completion or
termination of trial


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Storage of Essential Documents

Sponsor Rule: refer to study
protocol

FDA Rule: 2 options
2 years following marketing of
the drug or,
2 years after IND application
is withdrawn if drug was not
marketed






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References
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References
http://www.fda.gov/oc/gcp/guidance.htm
http://www.clinicaltrials.gov/
http://www.fda.gov/oc/ohrt/irbs/websites.html
http://ohrp.osophs.dhhs.gov/
http://privacyruleandresearch.nih.gov/
http://en.wikipedia.org/wiki/ICH-GCP
Handbook: good laboratory practice (GLP): quality
practices for regulated non-clinical research and
development -2nd ed., WHO Library Cataloguing-in-
Publication Data, 2nd ed., 7,15-20.





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References
OECD Principles of Good Laboratory Practice (as
revised in 1997)". OECD Environmental Health
and Safety Publications (OECD) 1. 1998.
http://www.oecd.org/document/63/0,2340,en_264
9_34381_2346175_1_1_1_37465,00.html.
Schneider, K (1983(Spring)). "Faking it: The case
against Industrial Bio-Test Laboratories". Amicus
Journal (Natural Resources Defence Council): 14-
26. http://planetwaves.net/contents/faking_it.html.
.
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References
Tweedale, AC (2011). "Uses of Good Laboratory
Practices by regulated industry and agencies, and
the safety of bisphenol A". J Epidemiol
Community Health (BMJ Group) Online First: 15
February 2011. doi:10.1136/jech.2010.127761.
Webster, Gregory K. et al. (2005). "JALA
Tutorial: Considerations When Implementing
Automated Methods into GcP". Journal of the
Association for Laboratory Automation (Elsevier)
10 (3): 182191. doi:10.1016/j.jala.2005.03.003
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Question????
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Thank you.
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