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Good Laboratory Practice

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Title: Good Laboratory Practice


1
Good Laboratory Practice
  • Ainoon Othman
  • Department of Pathology
  • Faculty of Medicine, UKM

2
Role of Laboratories in Medicine
  • Medical Testing Laboratory
  • patient care
  • clinical drug trial
  • Research Laboratory
  • discovery development of new
  • drugs/therapy
  • fundamental research/mechanisms of
    diseases
  • Manufacturing
  • post clinical trials, bulk
  • drugs, cell-based therapy, plasma
    products, medical
  • device

3
Drug Development Process
  • Stage I Stage 2 Stage 3 Stage 4
  • Discovery Non-clinical Clinical
    Post-approval

  • Manufacturing
  • Time line approximately 10 yrs

4
Role of laboratories in drug development
  • Stage I discovery of active substance
  • Stage II non-clinical study on SAFETY
  • testing of drugs ,
  • Stage III Studies in human/CLINICAL
  • TRIALS
  • Stage IV Post approval Clinical trials

5
Role of laboratories in Clinical Trials -Medical
Testing Laboratories
  • Pre Study
  • During Study
  • End of Study
  • Screening
  • Enrolment inclusion criteria exclusion
  • Verify effects of drugs
  • clinical efficacy
  • Monitoring of adverse effects safety
  • Clinical efficacy
  • Data analysis
  • verification

6
Role of laboratories in non-clinical safety study
  • safety testing of drugs ,
  • toxicology,
  • mutagenicity,
  • safety pharmacology
  • bioavailability

7
The Term Good Laboratory Practice
  • Numerous meanings depending on
  • Research Laboratory
  • Sponsor
  • Regulatory body
  • Clients of Laboratory

8
  • Regulatory Authorities responsible for
    registering and controlling pharmaceuticals
    request
  • laboratory to demonstrate data in
    registration package for a new chemical/drugs has
    been gathered using good laboratory practice
  • require organisation be certified (or
    accredited) by a third party for GLP
  • Organisations (researchers and medical
    laboratories) often claimed that they are working
    under glp
  • Clients of laboratories often request that their
    work be done using good laboratory practice

9
Good Laboratory Practice
  • Patient care clinical studies Medical
    Testing laboratories must ensure results
    produced are valid, reliable, accurate and
    reproducible
  • Research Laboratory practice must be concern
    with quality, reliability and integrity of
    studies, reporting of verifiable conclusions and
    the tracebility of data and for non-clinical
    safety studies, must ensure product safety and
    efficacy
  • Manufacturing laboratory must ensure products
    are produced under strict conditions and is safe
    for use

10
Good Laboratory Practice
  • Requires laboratory
  • 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 purpose

11
Good Clinical Practice (ICH-GCP)
  • 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

12
Good Laboratory Practice - Standards
  • ISO
  • OECD Principle of Good Laboratory Practice (OECD
    GLP)

13
ISO
  • ISO (International Organisation of
    Standardisation) is a worldwide federation of
    national standards from 130 countries
  • NGO established in 1947 with a mission to promote
    development of standardisation and related
    activities in the world with a view to
  • - facilitate international exchange of
    goods
  • - develop coorperation in spheres of
    intellectual,
  • scientific, technological and
    economic activity

14
ISO Standards for accreditation of laboratories
  • For Competence of Testing and Calibration
    Laboratories
  • ISO/IEC Guide 25 (1990)
  • ISO/IEC 17025 (1999) new standards which meets
    those of ISO 9001 and 9002 covering both
    technical and managerial requirements
  • ISO/IEC 15189 (2002)
  • - expanded, Requirements for quality and
    competence of
  • Medical Laboratories

15
Standards for Laboratory involved in Clinical
Studies
  • Accreditation to ISO 17025
  • - requirements for the competence of
    testing and
  • calibration laboratories
  • Accreditation to ISO/IEC 15189 (2002)
  • - expanded from ISO 17025 to include
    requirements for quality and competence of
    Medical Testing Laboratories

16
Good Lab Practice in Laboratories for
Non-clinical Safety Testing
  • a set of standard applied to non-clinical
    environmental health and safety studies is the
    Principle of GLP
  • The principle of GLP is a formal term
  • Regulatory document

17
GLP
  • It is important to clearly differentiate between
    the formal, regulatory use of term good
    laboratory practice as opposed to the general
    application of good practices in scientific
    investigations

18
Formal concept of GLP
  • The term Good Laboratory Practice has a
    SPECIFIC meaning when applied to non-clinical
    environmental health and safety studies.

19
Origin
  • Formal concept of GLP
  • 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

20
  • 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
  • FDA found 4 IBT managers guilty of frauds

21
GLP regulations (US)
  • Deficiencies made public in the Kennedy Hearings
    of the US Congress. FDA decide to regulate
    laboratory testing.
  • 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.

22
GLP regulations-Origin
  • 1976 GLP guideline proposed
  • 1978 GLP guideline finalised
  • 1979 GLP guidelines effective
  • 1987 additional changes ( Code of Federal
    Regulation 21, part 58)
  • 2000 International GLP

23
International Harmonisation- OECD Principle of
GLP
  • 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

24
OECD Principle of GLP
  • Adherence of member countries to these OECD
    standards permits international acceptability of
    safety testing from different countries (1981)
  • International harmonisation of tests

25
Establishment of Regulation of Laboratory
Practice for Non clinical Safety Testing
  • Need drivers
  • Not all scientific work was good work
  • Guidelines required to ensure the quality and
    integrity of safety data
  • To allow correct construction of all experiments
    to
  • -support the approval and
    manufacturing safety
  • regulated products
  • To effect compliance to regulations
  • Authorities must be given absolute
    power over testing
  • laboratories
  • Penalties included steep fines and
    criminal
  • prosecution

26
OECD Principle of GLP
  • 1981, Member countries
  • (31 member countries)
  • 1997, Non-member countries, full adherence (4)
  • Non-member countries/ Provisional
  • Mutual Acceptance of data
  • Compliance programme
  • Compliance programme
  • Malaysia launched in 2009
  • if full adherence GLP safety data will be
    accepted by members (31) non-members (4)

27
The principle of Good Laboratory Practice in
general
  • is concerned with how we organise our
    laboratories and how we organise our studies.
  • addresses responsibilities for managing people,
    facilities and equipment for good science
  • concerned with how we plan, perform and report
    our experiments and studies
  • importantly it does not interfere with the
    ability of scientists to make scientific decision

28
Fundamental Points of ISO/IEC 17025 and 15189
  • Management requirement
  • Technical requirements

29
Standards for Laboratory involved in Clinical
Studies
  • Medical laboratory services must meet the needs
    of all patients and the clinical personnel
    responsible for the care of those patients.
  • Such services include arrangements for
    requisition, patient preparation, patient
    identification, collection of samples,
    transportation, storage , processing and
    examination of clinical samples together with
    subsequent validation interpretation reporting
    and advice, in addition to safety and ethics in
    medical laboratory work.

30
Management requirement
  • Organisation management\quality management
    system
  • Document control
  • Review of contracts
  • Examination by referral laboratories
  • External services and supply
  • Advisory services
  • Resolution of complaints
  • Identification and control of non-conformities
  • Corrective action
  • Preventive action
  • Continual improvement
  • Quality and technical records
  • Internal audits
  • Management review

31
Technical requirements
  • Personnel
  • Accomodation and environmental conditions
  • Laboratory equipment
  • Pre-examination procedures
  • Examination procedures
  • Assuring quality of examination procedures
  • Post-examination procedures
  • Reporting of results

32
OECD Principles of GLP
  • 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 or in
    vitro experiments in which test articles are
    studied prospectively in test systems under
    laboratory conditions to determine their safety

33
GLP in the OECD Principles
  • a quality system concerned with the
    organisational process and the conditions under
    which non-clinical health and environmental
    studies are planned, performed, monitored,
    recorded, archived and reported.
  • It does not concern with the technical validity
    of the studies

34
Fundamental points of GLP
  • Good Laboratory Practice applied in whatever
    industry targeted, stresses the importance of the
    following main points
  • Resources Organisation, personnel, facilities,
  • equipment
  • Rules Protocols, Standard Operating Procedures,
  • concept of Study Director
  • Characterisation Test items, test systems
  • Documentation Raw data, final report, archives
  • Quality Assurance Independence from study
    conduct

35
Resources
  • Organisation and personnel
  • Facilities and equipment

36
Resources
  • Organization Personnel
  • Structure of orgn and Orgn 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
  • Full responsibility of GLP compliance of all
    activities within study, signed compliance
    statement
  • Aware of all occurances, judge impact and
    institute corrective action

37
  • Facilities and Equipment
  • Adequate and sufficient to perform the studies
  • suitable size, construction and location
  • 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

38
  • Separation physically and by organization ensures
    that different functions or activities do not
    interfere with one another
  • Important in
  • Pharmacy and dose mixing areas
  • Histopatholoy or analytical laboratories
  • 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

39
  • 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 and
    specific storage instruction
  • Separate facilities for handling and storage of
    test and reference material to prevent
    contamination and ensure safe storage for
    hazardous substances

40
  • 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 facilitites should be provided for
    storage and retrieval of raw data, samples and
    specimens. Access to archive should be limited to
    personnel authorized by management

41
Rules
  • Protocols
  • 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.

42
Rules
  • Written Procedures
  • 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

43
Rules
  • Study Director
  • 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. The Study Director is the person
    fully responsible the adequacy of the protocol
    and the GLP compliant conduct of the study. The
    Study Director has to formally accept
    responsibility for GLP compliance by signing the
    compliance statement.

44
Characterisation
  • 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

45
Documentation
  • Raw Data
  • Results of investigations, documentation of
    procedures and circumstances under which study
    was conducted
  • Results and their intepretation 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
    intepretation of the results

46
Documentation
  • Archives
  • For reasons of reconstruction many years later
  • Safekeeping of all records, kept in integer 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

47
Quality Assurance
  • QA defined by GLP
  • A team of persons charged with assuring the
    management that GLP compliance has been attained
    in a test facility as a whole as well as within
    each study.
  • QA has to be independent of the operational
    conduct of the studies and it functions as
    witness to the whole preclinical research process

48
ISO Accreditation vs GLP
  • 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

49
Compliance to Standards
  • ISO compliance technical assessment by
    Accrediting Body
  • Australia NATA
  • Malaysia Standards
    Malaysia (MOSTI)
  • OECD GLP compliance Compliance Monitoring
    Authority
  • Australia NATA,
  • Malaysia- NPCB

50
Accreditation Authorities/Bodies for ISO
  • Most trading nations establish systems for
    laboratory accreditation.
  • The accreditation authorities are usually
    government-owned or government-endorsed and
    operate free from any commercial influence
  • Countries established international network of
    Mutual Recognition Arrangements

51
ISO Accreditation Authorities/Bodies
  • European Coorperation for Accreditation in Europe
    which include UK Accreditation Services (UKAS)
  • International Laboratory Accreditation
    Co-operation (ILAC)
  • International Accreditation Forum
  • Asia Pacific Laboratory Accreditation
    Coorperation

52
Malaysia
  • Standards Malaysia, MoSTI responsible for
  • - ISO Accreditation of Testing and
    Calibration
  • Laboratories
  • - Accreditation of Medical Laboratories
    (SAMM)
  • Skim Akreditasi Makmal Malaysia (MS ISO
  • 15189) launched in 2004
  • Malaysia is a member of APLAC

53
GLP compliance
  • basic GLP document
  • facility claim to be compliant with
    OECD Principle of GLP must be by NATA/NPCB
  • e.g. Pharmaceuticals
  • Australia Therapeutics Good Administration
    (TGA), Malaysia DCA
  • OECD Principles of GLP
  • Each country has a national GLP compliance
    monitoring authority
  • Registration Authorities looks for compliance

54
OECD GLP Compliance Monitoring Authorities for
Malaysia
  • National Pharmaceutical Control Bureau (NPCB) MoH
  • STANDARDS MALAYSIA, MoSTI
  • Pharmaceutical products
  • Cosmetics
  • Food additive products
  • Veterinary
  • Pesticides
  • Industrial products
  • Feed Additive products
  • Biotechnology (non-pharmaceutical) products

55
Classical drug development process 4
well-defined stages
  • Stage I
  • Discovery of potential new drug products
  • Not covered by a regulatory standard

56
  • Stage II
  • non-clinical, not in human
  • Safety Testing
  • GLP Principles specific for this stage
  • toxicology
  • safety pharmacology
  • pharmacokinetics
  • bioavialbility

57
  • Stage III
  • Clinical Studies, in human
  • GCP is the basis for quality standards, ethical
    conduct and regulatory compliance
  • (Standard ISO)
  • Phase I ( tolerance of test drugs, define human
    pharmacokinetics) to Phase II ( dose-effect
    relationship) and Phase III (full-scale, often
    multi-centre clinical efficacy trials in patients)

58
  • Stage IV
  • Post-approval.
  • Drug registered , available on market
  • Any subsequent clinical trials (Phase IV) must
    comply with GCP (Standard ISO)

59
  • From stage 3 of development and continuing
    throughout the rest of the drugs lifetime. GMP
    applies to all manufacturing of bulk and
    formulated product.
  • Good Manufacturing Practice (GMP)
  • - WHO standards/document (Geneva, WHO 1999)
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