Good Laboratory Practice

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

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

Drug Development Process Stage I Stage 2 Stage 3 Stage 4 Discovery Non-clinicalClinical Post-approval Manufacturing Time line approximately 10 yrs

Role of laboratories in drug development Stage I : discoveryof 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

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 Role of laboratories in Clinical Trials-Medical Testing Laboratories

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

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

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’

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 withquality, 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

Good Laboratory Practice Requires laboratory • Accredited or Compliant to a set of defined STANDARDS • Standardsare 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

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

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

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

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

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

Good Lab Practice in Laboratories for Non-clinicalSafety 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

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

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

Origin Formal conceptof 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

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

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 ProposedRegulations 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.

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

International Harmonisation-OECD Principle of GLP • The Organisation for Economic Cooperation and Development (OECD ) formulated the first worldwide OECD Principles of GLP1981 ( 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

OECD Principle of GLP Adherence of member countries to these OECD standards permits internationalacceptability of safety testing from different countries (1981) International harmonisationof tests

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 Authoritiesmust be given absolute power over testing laboratories Penalties included steep fines and criminal prosecution

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)

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

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

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.

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

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

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

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

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

Resources • Organisation and personnel • Facilities and equipment

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 Resources

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

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

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

Handling and disposal ofwaste 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 facilititesshould be provided for storage and retrieval of raw data, samples and specimens. Access to archive should be limited to personnel authorized by management

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.

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

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.

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

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

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

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

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

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

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

Good Laboratory Practice