Transcript Good Laboratory Practice

Angela Ng Min Hwei, PhD
Tissue Engineering Centre
Faculty of Medicine, UKM
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Established in 2008 as Centre of Research Excellence
in UKMMC
Completed building of a GMP facility for cell and tissue
processing in 2011
Obtained certificate of compliance to GMP standards in
2012
Currently, running clinical trial for MyDerm™, a tissue
engineered skin
R&D facility has completed ISO9001 and in the midst of ISO
17025 audits
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Discovery
Safety of
personnel &
facilities
CT Phase II
Efficacy in
patients
Non-clinical/
Pre-clinical trial
Clinical
TrialPhase I
Safety & toxicology
in in vitro and
animal studies
Safety in human
(normal subjects)
CT Phase III
(Multi-centre)
Marketing
CT Phase IV
Post-marketing
Continuous monitoring of adverse effects
*Time line approximately 10-20 yrs
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Research Laboratories
• Discovery & development of new drugs /
device/therapy
• Fundamental research/mechanisms of
diseases
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Animal Laboratories
• In vivo studies
• Animal models / preclinical studies
• Safety and sensitivity testing
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Calibration Laboratories
• Equipment & device calibration
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Non clinical Testing & Analytical Laboratories
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Toxicology
Mutagenicity
Safety pharmacology
Bioequivalence / bioavailability
pharmacokinetics
Clinical Testing & Analytical Laboratories
◦ Screening & Diagnosis (Enrolment : inclusion criteria
exclusion)
◦ Quality control
◦ Trial monitoring : Verify effects of drugs clinical efficacy
◦ Monitoring of adverse effects safety
◦ Data analysis
◦ Verification
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Manufacturing Laboratories
◦ Production of drugs, cell-based therapy, plasma products,
medical device
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Laboratories are required to be Accredited or
Compliant to a set of defined STANDARDS
Standards are documented agreements containing
technical specifications or other precise criteria
used consistently as rules, guidelines and
definitions of characteristics to ensure that
material, products, process and services are fit for
its claimed purpose.
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Good practice
in Lab/ ISO /
HIRAC
Discovery
Safety of
personnel &
facilities
GLP
Non-clinical/
Pre-clinical trial
Safety & toxicology
in in vitro and
animal studies
GCP
GMP / GTP
GLCP
Clinical Trial Phase I (Safety in
human, tolerance of test drugs,
define human pharmacokinetics)
GCP is the basis for quality
standards, ethical conduct and
regulatory compliance
GDP
CT Phase II
(Efficacy,
dose-effect
relationship)
CT Phase III
(full-scale, often multi-centre clinical
efficacy trials in patients)
Clinical trial data submit for approval
CT Phase IV
Post-marketing
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International Organisation of Standardisation
(ISO)
Good Clinical Practice (GCP)
Good Manufacturing Practice (GMP)
Good Distribution Practice (GDP)
Good Tissue Practice (GTP)
Good Clinical Laboratory Practice (GLCP)
OECD Principle of Good Laboratory Practice
(OECD GLP)
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Standards must be adhered during Clinical Drugs
Trial for design, conduct, performance,
monitoring, auditing, recording, analysis and
reporting in order to provide assurance that data
and reported results are credible and accurate and
integrity and confidentiality of trial subjects are
protected
Section 2.13
 Systems with procedure that assure the quality of
every aspect of the trial should be implemented
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For Accreditation of Competence of Testing and
Calibration Laboratories
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ISO/IEC Guide 25 (1990) – replaced by ISO/IEC 17025
ISO/IEC 17025 (2005) new standards which meets
those of ISO 9001 and 9002 covering both technical
and management requirements. In general, more
mandatory in nature compared to the
recommendations if ISO 25
ISO/IEC 15189 (2002) - expanded, requirements for
quality and competence of Medical Laboratories e.g.
JPMD, UMBI
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A standard that should be followed by manufacturers
of registered pharmaceutical / traditional products
and cosmetics to ensure that the product
manufactured is safe, efficacious and of quality.
Satisfactory GMP compliance is one of the
requirements for product registration, as well as to
apply for a manufacturing license with the Drug
Control Authority (DCA).
Uncontrolled manufacturing operations may be
detrimental to consumer health.
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Guideline developed by FDA specifically to
establishments that manufacture Human Cell and
Tissue Products (HCT/Ps). Not implemented in M’sia
yet.
Similar to GMP but taking into considerations that the
nature of the product is very different (biologics vs
drugs)
Additional guidelines e.g.:
All donor eligibility requirements
Prevention of the introduction, transmission, or
spread of communicable diseases,
Ship in quarantine
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Defined as important steps that should be
considered in the storage, transportation and
distribution (cold chain, integrity of labels &
everyone involved in the distribution channel, etc)
of registered products / notified cosmetics,
including associated materials in order to preserve
its characteristics and quality until it reaches the
consumer.
Generally, GDP is included into the scope of a GMP
inspection.
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Applies those principles established under GLP for
data generation used in regulatory submissions
relevant to the analysis of samples from a clinical
trial.
Ensures the reliability and integrity of data
generated by analytical laboratories.
Ensures that the objectives of the GCP principles
are carried out.
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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 reflection of the results
obtained during the study and can therefore be
relied upon when making risk/safety assessments.
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Define and describe a quality system concerned with
the organisational processes and conditions under
which a non-clinical health and environmental safety
study is conducted
Non-clinical laboratory study means in vivo (in
experimental animals) or in vitro experiments in
which test articles are studied prospectively in test
systems under laboratory conditions to determine
their safety
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1st evolved in USA, 1970s as a result of concerns
about validity of preclinical safety data submitted to
FDA for new drug applications
1950s -1 970s : 40% toxicology testing were carried
out by Industrial Biotest Laboratories (IBT)
1961-1976, FDA imposed requirements for
manufacturers to prove drug effectiveness and
responsible in determining if benefits outweigh
risks
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History of GLP
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GLP was first introduced in New
Zealand and Denmark in 1972.
Most notably, the lab that ran tests
for big companies such as Procter
and Gamble called Industrial
Bio Test.
It was discovered that mice that
they had used to test lotion and
deodorants had developed
cancer and died.
867 audits of IBT performed by
FDA (1962 Law of Drug
Amendments) : 518 were found to
be invalid due to numerous
discrepancies between study
and data
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 Industrial Bio Test lab threw the dead mice and covered results
deeming the products good for human use.
 FDA found 4 IBT managers guilty of frauds
Those involved in production, distribution and sales for the IBT
lab eventually served jail time.
 GLP was instituted in US following these cases of fraud generated
by toxicology labs in data submitted to the FDA by pharmaceutical
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companies.
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The Organisation for Economic Cooperation and
Development (OECD ) formulated the first worldwide
OECD Principles of GLP 1981 ( revised in 1997)
- to avoid non-tariff barriers to trade
- to promote mutual acceptance to non-clinical safety
test
- to eliminate unneccessary duplication of experiments
- International harmonisation of tests
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Adherence of member countries to these OECD
standards permits international acceptability of safety
testing from different countries (1981). Malaysia
became a provisional member in 1998.
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Good Laboratory Practice (GLP) embodies a set of
principles that provides a framework within which
laboratory studies are planned, performed,
monitored, recorded, reported and archived. These
studies are undertaken to generate data by which
the hazards and risks to users, consumers and third
parties, including the environment, can be assessed
for pharmaceuticals (only preclinical studies),
agrochemicals, cosmetics, food additives, feed
additives and contaminants, novel foods, biocides,
detergents etc....
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Deficiencies made public in the Kennedy Hearings
of the US Congress. FDA decide to regulate
laboratory testing. GLP is an FDA regulation.
Political outcome led to the publication by FDA of
Proposed Regulations on Good Laboratory Practice
in 1976, Final Rule , June 1979
This forms the regulatory basis for assurance that
reports on studies submitted to FDA would reflect
faithfully and completely the experimental work
carried out.
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Effective from 29th March 2013, Malaysia is officially a
non-member with full adherent to the Organisation for
Economic Cooperation and Development (OECD)
Council Acts related to Mutual Acceptance of Data
(MAD) in the Assessment of Chemicals on Good
Laboratory Practice (GLP)
GLP compliance is not mandatory but voluntary in
Malaysia - certification by NPCB
In countries in OECD group such as US, it is required by
law that any non-clinical studies must to be conducted
in compliance with the OECD Principles of GLP for
products to be registered in their countries.
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GLP makes sure that the data submitted are a true
reflection of the results that are obtained during
the study.
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GLP also makes sure that data is traceable.
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Promotes international acceptance of tests.
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It does not concern with the technical validity of
the studies
GLP is sometimes confused with the standards of
laboratory safety like wearing safety goggles (Good
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Laboratory Practices).
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GLP Regulations (Rules)
Documentation (Tools)
ORGANIZATION AND
PERSONNEL
Training records, CVs, GLP training
FACILITIES
Maintain adequate space/separation
of chemicals from office areas
EQUIPMENT
Calibration, logbooks of use, repair,
and maintenance
FACILITY OPERATION
Standard operating procedures
TEST, CONTROL, AND
REFERENCE SUBSTANCES
Chemical and sample inventory,
expiration dates
RECORDS AND REPORTS
Timely reporting, storage of raw
data and reports
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Good Laboratory Practice applied in whatever industry targeted,
stresses the importance of the following main points
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Resources : Organisation, personnel, facilities,
equipment
Rules : Protocols, Standard Operating Procedures,
concept of Study Director
Characterization : Test items, test systems
Documentation : Raw data, final report, archives
Quality Assurance : Independence from study conduct
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Organization & Personnel
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Structure of org and Org chart must reflect realities
and up-to date
Responsbilities of all personnel clearly defined; job
description, qualifications & competence defined in
training and education records.
Study Director
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Full responsibility of GLP compliance of all activities
within study, signed compliance statement
Aware of all occurrences, judge impact and institute
corrective action
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Adequate and sufficient to perform the studies
Suitable size, construction and location causing
minimize disturbances that would interfere with
validity of study.
Avoid problem of overcrowding, cross
contamination, confusion between projects and
cramped working condition.
Utilities ( water, electricity etc) must be adequate
and stable
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Separation physically and by organization ensures
that different functions or activities do not
interfere with one another
Important in:
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Pharmacy and dose mixing areas
Histopathology or analytical laboratories – sample
mixed up
Animal facility- minimize the effects of
environmental variables on the animals, facility
designed and operated to prevent animals
coming in contact with the disease or with a test
item other than the one under investigation
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Equipment : strict programme of validation,
qualification, calibration and maintenance. Records
of procedures maintained
Reagents: labeled appropriately to indicate source,
identity, concentration and stability information,
earliest expiratory date (in a kit) and specific
storage instructions
Separate facilities for handling and storage of test
and reference material to prevent contamination
and ensure safe storage for hazardous substances
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Handling and disposal of waste should be carried out
in such a manner so as not to influence the integrity
of the study in progress and consistent with
regulatory requirements
Appropriate collection, storage, disposal facilities,
decontamination, transportation and destruction
procedures
Archive facilities should be provided for storage and
retrieval of raw data, samples and specimens. Access
to archive should be limited to personnel authorized
by management
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Protocols
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The principle steps of studies have to be described
in a Study Protocol or Study Plan
The Protocol has to be adopted by the Study
Director through dated signature before study
starts and alterations to the study design cannot be
made unless by formal amendment procedures.
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Written Procedures
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Routine procedures described in Standard
Operating Procedures (SOP)
Standardization of certain techniques to facilitate
comparisons of results
Procedures must be reviewed regularly and
modified if necessary to reflect the actual state of
the art
SOPs must be available at the work place and in
current version
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Study Director
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Concept of SD as the pivotal point of study control
The single most important individual in a GLP study
as he/she represents the pivotal point of study
control.
is the person fully responsible the adequacy of the
protocol and the GLP compliant conduct of the
study.
has to formally accept responsibility for GLP
compliance by signing the compliance statement
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Preclinical safety testing of pharmaceutical
compunds requires detail knowledge about the
properties of the test items and of the test system
(often animal ) to which it is administered.
Identity, purity, composition, stability, impurity
profile should be known for the test item, for the
vehicle and for the reference material.
If the test system is an animal, it is essential to
know such details as its strain, health status and
normal biological values
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Raw Data
 Results of investigations, documentation of
procedures and circumstances (temperature,
pressure, etc) under which study was conducted
 Results and their interpretation must be a true
reflection of the raw data
Study Report
 Responsibility of Study Director
 Ensures contents of report describe the study
accurately
 Study Director responsible for scientific
interpretation of the results
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If anyone scribble some notes on a
scrap of paper, are those notes
considered raw data?
Examples of raw data
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Logbooks (to record
temperatures or
equipment use, repair,
and maintenance)
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Question:
What happens if you
make a mistake?
Field or laboratory
notebooks
Forms (for field or
laboratory observations,
chain-of-custody, sample
or chemical receipt)
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Training reports
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Computer printouts
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Recorded data from
automated instruments
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Archives / Retention of records & materials
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For reasons of reconstruction & traceability many
years later (usually 7 years; medical records:
20years)
Safekeeping of all records, kept in integral state
and can neither be lost nor altered
Restrict access to archives to a limited number of
people and maintain records of log-in and log-out
for both documents and people
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The test facility should have a documented Quality
Assurance Programme to assure that studies
performed are in compliance with these Principles
of GLP.
The Quality Assurance Programme should be
carried out by an individual or by individuals
designated by and directly responsible to
management and who are familiar with the test
procedures.
QA personnel has to be independent of the
operational conduct of the studies and it functions
as witness to the whole preclinical research process
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Fundamental requirement of the GLP Principles not
covered in ISO/IEC : the use of study plans and
Study Director as a concept
More stringent under GLP
- Recording and reporting of data
- Management of data retained in archive to
allow complete reconstruction of study
- A program of independent QA including
internal audits of every study
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ISO compliance:
technical assessment
by Accrediting Body
Registration
Authorities looks for
GMP & GLP compliances
Standards Malaysia – ISO
15189, 17025
SIRIM QAS Internation –
ISO 9001
Drug Control Authority or
National Pharmaceutical
Control Bureau
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National Pharmaceutical
Control Bureau (NPCB)
MoH
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STANDARDS MALAYSIA,
MOSTI
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Pharmaceutical
products
Cosmetics
Food additive products
Veterinary
Pesticides
Industrial products
Feed Additive products
Biotechnology (nonpharmaceutical)
products
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Say what you do,
do what you say,
prove it and
improve it
Janet Woodcook, M.D.
Director, Center for Drug Evaluation and Research, FDA
Record what you do, not recorded not done
"If it's not written down, it didn't happen”
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